Clinical Hepatology
Henryk Dancygier
Clinical Hepatology Principles and Practice of Hepatobiliary Diseases Volume 2 With Contributions by H.-D. Allescher · U. Beuers · H. Blum · R. S. Brown, Jr · E. Cay · H. Dancygier S. Dasarathy · C. F. Dietrich · M. Doss · A. Dragan · S. M. Erturk · S. A. Fink L. S. Friedman · G. Gerken · D. Häussinger · P. Hilgard · M. A. Kern · A. Koch J. H. Lefkowitch · U. Leuschner · T. Longerich · A. J. McCullough · U. Merle J. Mössner · S. Mueller · A. Niedenthal · C. Niederau · B. Riemann · J. N. Rogart P. Ros · C. Sarrazin · P. Schirmacher · O. Schober · H. K. Seitz · S. H. Sigal F. Stenschke · U. Stölzel · C. P. Strassburg · W. Stremmel · S. Susser · C. Trautwein M. Tröltzsch · I. S. Weisberg · M. Wiedman · C. Wittekind · H. Witzigmann P. S. Yachimski · S. Zeuzem Foreword by Scott L. Friedman
Henryk Dancygier, MD Professor of Medicine Chair, Department of Medicine II Klinikum Offenbach, Goethe University Frankfurt/Main Starkenburgring 66 63069 Offenbach, Germany email:
[email protected] Adjunct Professor of Medicine Department of Medicine, Division of Liver Diseases Mount Sinai School of Medicine New York, NY, USA email:
[email protected] ISBN: 978-3-642-04509-7
e-ISBN: 978-3-642-04519-6
DOI: 10.1007/978-3-642-04519-6 Springer Heidelberg Dordrecht London New York Library of Congress Control Number: 2009929701 © Springer-Verlag Berlin Heidelberg 2010 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Cover design: eStudioCalamar, Figueres/Berlin Printed on acid-free paper Springer is part & Springer Science + Business Media (www.springer.com)
Dedication
Dedicated to Dr. Herbert Falk (1924–2008). A humanist of great generosity, supporter of scientific advancement and the always visible, but never dominant magnanimous patron of global medical education.
v
Foreword
Modern hepatology would be unrecognizable to those clinicians and pathologists, who founded the field only a generation ago. From a discipline that was largely observational – with few diagnostic tests and even fewer therapies – has emerged an exciting area that is among the most rapidly changing in all of medicine, and which now offers remarkable new tools and treatments. This textbook edited by Professor Dancygier beautifully captures this dynamism of hepatology, and in doing so provides a remarkably complete opus. The work is beautifully laid out exactly as a clinician would think, weaving in the science underlying clinical hepatology with precision and clarity. Standardized and gorgeous drawings, comprehensive tables, and a very consistent style are among its most valuable assets – quite simply, this book is fun to read! While thoroughly modern, this work still proudly draws upon the roots of our specialty. A strong emphasis on pathology, patterns of injury, clinical presentations of disease, and approaches to clinical problems harken back to hepatology’s earliest treatises. The book is particularly reminiscent of early editions of Dame Sheila Sherlock’s classic single-author textbook, the fifth edition of which I read cover-tocover while spending 3 months at the Royal Free Hospital as a medical student in 1977; a signed copy sits proudly on my shelf to this day, and I suspect that many will come to value Professor Dancygier’s book for many of its similar virtues. The highly personal stamp of Professor Dancygier infuses this book with cohesion, and conveys the wonders of clinical hepatology. Underscoring another enduring feature of our specialty is the book’s transatlantic flavor, with authors from throughout Germany and the USA. This connection between our two countries is also personal – Professor Dancygier’s invitation for me to speak at a conference in Munich in 1989 was my first international meeting, and I am proud that our professional association and friendship continue to this day as a result of that first meeting 20 years ago. I am delighted to be associated with Clinical Hepatology. Thus, it is a great personal privilege to introduce this unique and valuable textbook, which is sure to appeal to practitioners of today and ignite a spark of enthusiasm among the hepatologists of tomorrow. Scott L. Friedman, M.D. President, American Association for the Study of Liver Diseases Fishberg Professor and Chief, Division of Liver Diseases The Mount Sinai School of Medicine
vii
Preface
Clinical hepatology is thriving. Hepatology has evolved from a pure diagnostic art to a science in which new treatment options are emerging at a quick pace. At this exciting time, based on the gratifying success of the German Edition of 2003, Springer Publishers have asked me to prepare a US-American/International edition. Gravely miscalculating the amount of labor, I gladly accepted this challenge. The present book is not merely an updated version of the German edition but a completely new work with new US-American authors, a transatlantic endeavor. In common with its German predecessor, however, it not only aims to provide knowledge in hepatology but also to promote an understanding of liver diseases, and to create joy in dealing with clinical hepatological problems. It is intended for everybody caring for adult patients with hepatobiliary problems, particularly gastroenterologists/hepatologists, internists and clinical pathologists. My aim was not to provide an encyclopedic behemoth. Instead, I intended to create a comprehensive, up-to-date (references until early 2009 are included), practical and readable book that outlines the current standards of diagnosis and treatment in hepatology and its associated biliary disorders. By elaborating on concepts in hepatology, disease mechanisms, common clinical problems and rare diseases alike it tries to serve the needs not only of the novice in hepatology, but also of the experienced practicing clinician. Ultimately, the success of the book will be determined by its ability to provide answers to clinically relevant questions and to guide clinical decisions. The competent clinical hepatologist, like hardly any other clinician, has to integrate histopathological, biochemical, immunological, instrumental and clinical skills. The organization of the text follows this principle. It is divided into 3 main parts with 30 sections covering Basic Principles, Clinical Methods, and Hepatobiliary Diseases. Starting from basic concepts the field of clinical hepatology gradually unfolds. Unlike other Hepatology Textbooks I preferred not to include a “stand alone” chapter on liver pathology. Instead hepatopathology has been integrated throughout the entire text as it represents an integral part of clinical hepatology. The first five sections integrate structure and function of the liver and basically provide a general pathology of the liver. The clinical chapters are stringently organized and uniformly structured to enable rapid retrieval of the desired information. In order to enhance readability I have accepted some redundancy, especially in chapters dealing with hepatocellular transporters. I am indebted to my coauthors, all renowned experts in hepatology. Without their help the creation of a textbook of this volume would not have been possible. My
ix
x
Preface
special thanks go to a young gastroenterologist from Yale, Jason Rogart. He not only served as a proof reader for the contributions by authors whose native language is not English, but also as an author of several chapters and as an editorial assistant. My thanks go also to Ms. Annette Hinze, Meike Stoeck, and Mr. Claus-Dieter Bachem from Springer Publishers who skillfully supported the development of the Textbook. Last but not least I thank my wife Hellena for her endurance and unwavering support. After immerging into the project and resurfacing after finishing the last chapter she was still there. Offenbach, May 2009
Henryk Dancygier
Volume 1 A. Basic Principles Part I Structure and Function of the Liver Part II Pathophysiology and Morphology of Liver Injury
B. Clinical Methods Part III Evaluation of the Patient with Hepatobiliary Disease
Volume 2 C. Hepatobiliary Diseases Part IV Diseases of the Liver Part V Diseases of the Gallbladder and Extrahepatic Bile Ducts
Contents of Volume 1
A. Basic Principles Part I Structure and Function of the Liver . . . . . . . . . . . . . . . . . .
3
Section I Embryology, Anatomy, and Histology. . . . . . . . . . . . . . . . . . . . . .
5
1
Embryonic Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
7
2
Gross Anatomy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
11
3
Microscopic Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
15
Section II Fundamentals of Hepatic Physiology and Biochemistry . . . . . .
53
4
Hepatic Circulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
55
5
Hepatocellular Transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
61
6
Hepatic Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier, Uta Merle, Wolfgang Stremmel, and Claus Niederau
75
7
Formation and Secretion of Bile and Bilirubin Metabolism . . . . . . . . Ulrich Leuschner
103
8
Hepatic Biotransformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
127
9
Functional Heterogeneity and Metabolic Zonation . . . . . . . . . . . . . . . . Henryk Dancygier
131
10
Liver Cell Hydration and Cell Function . . . . . . . . . . . . . . . . . . . . . . . . Dieter Häussinger
137
11
The Liver as an Immune Organ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
141
xiii
xiv
12
Aging and the Liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
153
13
Hepatic Regeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
157
Part II Pathophysiology and Morphology of Liver Injury . . .
169
Section III Causes and Mechanisms of Liver Injury . . . . . . . . . . . . . . . . . .
171
14
Volume 1
Contents
Free Radicals, Reactive Oxygen Species, Oxidative and Endoplasmic Reticulum Stress . . . . . . . . . . . . . . . . . . . Henryk Dancygier and Peter Schirmacher
173
15
Hypoxic Liver Injury. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier and Peter Schirmacher
181
16
Reperfusion Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier and Peter Schirmacher
185
17
Drug-Induced and Toxic Liver Injury . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier and Peter Schirmacher
189
18
Immune Mediated Liver Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier and Peter Schirmacher
191
19
Endotoxin Mediated Liver Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier and Peter Schirmacher
197
20
Cholestasis-Induced Liver Injury. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier and Peter Schirmacher
199
21
Metal-Induced Liver Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier and Peter Schirmacher
201
22
Radiation-Induced Liver Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier and Peter Schirmacher
203
Section IV Morphologic Patterns of Liver Injury . . . . . . . . . . . . . . . . . . . .
205
23
Liver Cell Degeneration and Cell Death . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier and Peter Schirmacher
207
24
Cellular Adaptation, Intracellular Inclusions and Deposits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier and Peter Schirmacher
219
25
Necroinflammatory Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier and Peter Schirmacher
235
26
Cholestatic Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier and Peter Schirmacher
241
27
Granulomatous Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier and Peter Schirmacher
247
28
Fibrogenic Reaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier and Peter Schirmacher
251
Contents
xv
Section V Scoring Systems in Hepatology . . . . . . . . . . . . . . . . . . . . . . . . . .
269
29
Histopathological Scoring Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thomas Longerich and Peter Schirmacher
271
30
Clinical Scoring Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
289
Part III Evaluation of the Patient with Hepatobiliary Disease . . . . . . . . . . . . . . . . . . . . . . . . .
297
Section VI History and Physical Examination . . . . . . . . . . . . . . . . . . . . . . .
299
31
History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier and Jason N. Rogart
301
32
Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier and Jason N. Rogart
305
33
Physical Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier and Jason N. Rogart
309
Section VII Laboratory Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
317
34
Basic Laboratory Parameters. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
319
35
Tests of Liver Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
333
36
Autoantibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
345
Section VIII Hepatobiliary Imaging and Manometric Studies. . . . . . . . . .
357
37
Ultrasonography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Christoph F. Dietrich
359
38
Computed Tomography and Magnetic Resonance Imaging . . . . . . . . Sukru M. Erturk, Esra Cay, and Pablo R. Ros
405
39
Nuclear Imaging. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Burkhard Riemann and Otmar Schober
425
40
Endoscopic Retrograde and Percutaneous Transhepatic Cholangiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Frank Stenschke, Henryk Dancygier, and Jason N. Rogart
41
Cholangioscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jason N. Rogart and Frank Stenschke
437 449
Volume 1
B. Clinical Methods
Volume 1
xvi
Contents
42
Endoscopic Ultrasonography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Andreas Niedenthal, Henryk Dancygier, and Jason N. Rogart
455
43
Percutaneous Liver Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Christian P. Strassburg
463
44
Transvenous Liver Biopsy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ilan S. Weisberg, Samuel H. Sigal, and Robert S. Brown, Jr.
473
45
Laparoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Philip Hilgard and Guido Gerken
485
46
Measurement of Portal Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
511
47
Sphincter of Oddi Manometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Hans-Dieter Allescher
519
Section IX Approaches to Common Hepatobiliary Problems . . . . . . . . . .
525
48
Approach to the Patient with Upper Abdominal Pain . . . . . . . . . . . . . Henryk Dancygier and Jason N. Rogart
527
49
Approach to the Patient with Abnormal Liver Enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier and Jason N. Rogart
533
50
Approach to the Patient with Hepatomegaly . . . . . . . . . . . . . . . . . . . . Henryk Dancygier and Jason N. Rogart
549
51
Approach to the Patient with Focal Liver Lesions . . . . . . . . . . . . . . . . Henryk Dancygier and Jason N. Rogart
553
52
Approach to the Patient with Cholestasis and Jaundice . . . . . . . . . . . Henryk Dancygier and Jason N. Rogart
559
53
Approach to the Patient with Portal Hypertension . . . . . . . . . . . . . . . Henryk Dancygier and Jason N. Rogart
593
54
Approach to the Patient with Ascites . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier and Jason N. Rogart
603
Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
S1
C. Hepatobiliary Diseases
Part IV Diseases of the Liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
617
Section X Developmental Anomalies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
619
55
Malformations and Malpositions of the Liver. . . . . . . . . . . . . . . . . . . . Henryk Dancygier
621
56
Bile Duct Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
625
57
Liver Cysts and Polycystic Liver Disease . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
631
58
Vascular Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
637
Section XI Circulatory and Vascular Disorders. . . . . . . . . . . . . . . . . . . . . .
639
59
Hepatic Veins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
641
60
Sinusoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
649
61
Portal Vein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
657
62
Hepatic Arteries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
663
xvii
Volume 2
Contents of Volume 2
Volume 2
xviii
Contents
Section XII Infectious Liver Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
669
63
Viral Infections by Hepatotropic Viruses . . . . . . . . . . . . . . . . . . . . . . . Simone Susser, Anette Dragan, Stefan Zeuzem, Christoph Sarrazin, Jay H. Lefkowitch, Henryk Dancygier
671
64
Viral Infections by Nonhepatotropic Viruses . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
823
65
Bacterial Liver Abscess and Other Bacterial Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
831
66
Amebic Liver Abscess and Other Protozoal Diseases . . . . . . . . . . . . . Henryk Dancygier
843
67
Helminthic Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
849
68
Fungal Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
859
Section XIII Hepatobiliary Diseases in HIV-Infected Patients. . . . . . . . . .
863
69
Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
865
70
Neoplastic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
873
71
Drug-Induced Liver Injury. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
875
Section XIV Autoimmune Liver Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . .
879
72
Autoimmune Hepatitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
881
73
Primary Biliary Cirrhosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
895
74
Autoimmune Cholangitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
909
75
Primary Sclerosing Cholangitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
911
76
Biliary Ductopenia (Vanishing Bile Duct Syndrome) . . . . . . . . . . . . . . Henryk Dancygier
921
77
Autoimmune Overlap Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
925
Section XV Acute Liver Failure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
929
78
931
Acute Liver Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alexander Koch and Christian Trautwein
Contents
xix
Section XVI Liver Cirrhosis and Sequelae . . . . . . . . . . . . . . . . . . . . . . . . . .
947
79
Liver Cirrhosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
949
80
Complications of Liver Cirrhosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Henryk Dancygier
967
81
Wilson’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1035 Uta Merle and Wolfgang Stremmel
82
Hereditary Hemochromatosis and Iron Overload . . . . . . . . . . . . . . . . 1045 Claus Niederau
83
a1-Antitrypsin Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1071 Henryk Dancygier
84
Porphyrias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1077 Ulrich Stölzel and Manfred O. Doss
85
Inherited Syndromes of Intrahepatic Cholestasis. . . . . . . . . . . . . . . . . 1093 Henryk Dancygier
86
Cystic Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1101 Henryk Dancygier
87
Amyloidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1105 Henryk Dancygier
88
Alcoholic Liver Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1111 Helmut Karl Seitz and Sebastian Mueller
89
Nonalcoholic Fatty Liver Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1153 Henryk Dancygier
90
Other Metabolic Diseases: Tabellary Overview . . . . . . . . . . . . . . . . . . 1181 Henryk Dancygier
91
Malnutrition and Nutrition in Liver Disease . . . . . . . . . . . . . . . . . . . . 1187 Srinivasan Dasarathy and Arthur J. McCullough
Section XVIII Drug-Induced and Toxic Liver Disease . . . . . . . . . . . . . . . . 1209 92
Hepatic Drug Metabolism and Drug Toxicity. . . . . . . . . . . . . . . . . . . . 1211 Henryk Dancygier and Christian P. Strassburg
93
Drug- and Toxin-Induced Liver Injury . . . . . . . . . . . . . . . . . . . . . . . . . 1223 Henryk Dancygier
Volume 2
Section XVII Genetic and Metabolic Liver Disorders. . . . . . . . . . . . . . . . . 1033
xx
Section XIX Granulomatous Liver Disease . . . . . . . . . . . . . . . . . . . . . . . . . 1233 94 Hepatic Granulomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1235 Henryk Dancygier 95 Sarcoidosis of the Liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1239 Henryk Dancygier Section XX Interaction Between the Liver and Other Organ Systems . . . 1243
Volume 2
96 Effects of Chronic Liver Disease on Other Organs: Tabellary Overview. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1245 Henryk Dancygier 97 Hepatic Involvement in Extrahepatic Disease: Tabellary Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1247 Henryk Dancygier Section XXI Pregnancy-Specific Liver Diseases. . . . . . . . . . . . . . . . . . . . . . 1255 98 Intrahepatic Cholestasis of Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . 1257 Henryk Dancygier 99 Acute Fatty Liver of Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1263 Henryk Dancygier 100 The Liver in Toxemia of Pregnancy. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1267 Henryk Dancygier Section XXII Primary Tumors of the Liver and Intrahepatic Bile Ducts . . . . . . . . . . . . . . . . . . . . . . . . . . 1271 101 Benign Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1273 Henryk Dancygier 102 Malignant Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1305 Henryk Dancygier Section XXIII Liver Transplantation and Surgery in Liver Disease . . . . . 1351 103 Liver Transplantation: Indications, Preoperative Evaluation and Posttransplantation Management . . . . . . . . . . . . . . . . 1353 Scott A. Fink and Robert S. Brown, Jr. 104 Risk of Surgery in Patients with Liver Disease . . . . . . . . . . . . . . . . . . . 1383 Patrick S. Yachimski and Lawrence S. Friedman
Section XXIV Gene Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1401 105 A Look to the Future: Gene Therapy in Liver Diseases . . . . . . . . . . . 1403 Hubert E. Blum
Contents
xxi
Part V Diseases of the Gallbladder and Extrahepatic Bile Ducts . . . . . . . . . . . . . . . . . . . . . . . . . 1413 Section XXV Anatomy, Histology and Physiology. . . . . . . . . . . . . . . . . . . . 1415 106 Gross and Microscopic Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1417 Ulrich Beuers and Henryk Dancygier 107 Physiology of the Gallbladder and the Extrahepatic Bile Ducts . . . . . 1423 Ulrich Beuers Section XXVI Developmental Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . 1427 108 Anomalies of the Gallbladder and the Cystic Duct . . . . . . . . . . . . . . . 1429 Michael A. Kern and Peter Schirmacher 109 Anomalies of the Extrahepatic Bile Ducts . . . . . . . . . . . . . . . . . . . . . . . 1433 Michael A. Kern and Peter Schirmacher 110 Benign Strictures of the Extrahepatic Bile Ducts . . . . . . . . . . . . . . . . . 1437 Michael A. Kern and Peter Schirmacher Section XXVII Motility Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1439 111 Motility Disorders of the Bile Ducts and Postcholecystectomy Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1441 Hans-Dieter Allescher Section XXVIII Gallstones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1457 112 Gallbladder Stones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1459 Ulrich Leuschner 113 Bile Duct Stones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1481 Ulrich Leuschner and Jason N. Rogart Section XXIX Infectious Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1491 114 Biliary Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1493 Ulrich Beuers Section XXX Tumors of the Gallbladder and Extrahepatic Bile Ducts. . . 1503 115 Benign Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1505 Marcus Wiedmann, Christian Wittekind, Michael Tröltzsch, and Joachim Mössner 116 Malignant Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1519 Marcus Wiedmann, Helmut Witzigmann, and Joachim Mössner Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1567
Volume 2
Contents
Contributors Numbers in brackets refer to the chapters written or co-written by the contributor.
Hans-Dieter Allescher, MD Professor of Medicine, Zentrum Innere Medizin, Klinikum Garmisch-Partenkirchen, Ludwig-Maximilians Universität München, Auenstr. 6, 82467 Garmisch-Partenkirchen, Germany [47, 111]
Ulrich Beuers, MD Professor of Gastroenterology and Hepatology, Department of Gastroenterology and Hepatology, G4–213, Academic Medical Center, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands [106, 107, 114]
Hubert E. Blum, MD University Professor of Medicine, Department of Medicine II, University Hospital, Hugstetter Strasse 55, 79106 Freiburg, Germany [105]
Robert S. Brown, Jr, MD Associate Professor of Medicine, Presbyterian Hospital 14, Room 202, Division of Digestive and Liver Diseases, Columbia University, 622 West 168th St, New York, NY 10032, USA [44, 103]
Esra Cay, MD Department of Radiology, Sisli Etfal Training and Research Hospital, Etfal Sokak, Istanbul, Turkey [38]
Henryk Dancygier, MD Professor of Medicine, Department of Medicine II, Klinikum Offenbach, Goethe University Frankfurt, Starkenburgring 66, 63069 Offenbach, Germany [1–6, 8, 9, 11–28, 30–36, 40, 42, 46, 48–62, 63.3, 64–77, 79, 80, 83, 85–87, 89, 90, 92–102, 106]
xxiii
xxiv
Srinivasan Dasarathy, MD Cleveland Clinic, Department of Gastroenterology, Mail Code NC22, 9500 Euclid Avenue, Cleveland, OH 44195, USA [91]
Christoph F. Dietrich, MD Professor of Medicine, Caritas-Krankenhaus, Department of Medicine 2, Uhlandstr. 7, 97980 Bad Mergentheim, Germany [37]
Manfred O. Doss, MD Professor of Medicine, Consultation Porphyria, Gabelsberger Str. 2535037 Marburg, Germany [84]
Anette Dragan Certified Biologist, Department of Medicine 1, University Hospital, Goethe University Frankfurt, Theodor Stern Kai 7, 60596 Frankfurt am Main, Germany [63.1]
Sukru M. Erturk, MD Department of Radiology, Sisli Etfal Training and Research Hospital Etfal Sokak, Istanbul, Turkey [38]
Scott A. Fink, MD Assistant Professor of Clinical Medicine Presbyterian Hospital 14, Division of Digestive and Liver Diseases, Columbia University 622, West 168th Street, New York, NY 11032, USA [103]
Lawrence S. Friedman, MD Professor of Medicine, Harvard Medical School and Tufts University School of Medicine, Department of Medicine, Newton-Wellesley Hospital, Department of Medicine, Massachusetts General Hospital, Boston, MA, 2014 Washington Street, Newton, MA 02462, USA [104]
Guido Gerken, MD University Professor of Medicine, Universitätsklinik Essen, Klinik für Gastroenterologie und Hepatologie, Zentrum für Innere Medizin, Hufelandstr. 55, 45122 Essen, Germany [45]
Dieter Häussinger, MD University Professor of Medicine, Department of Gastroenterology and Infectious Diseases, Heinrich Heine University, Moorenstrasse 5, 40225 Düsseldorf, Germany [10]
Contributors
Contributors
xxv
Philip Hilgard, MD Professor of Medicine, Universitätsklinik Essen, Klinik für Gastroenterologie und Hepatologie, Zentrum für Innere Medizin, Hufelandstr. 55, 45122 Essen, Germany [45]
Michael A. Kern, MD Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220, 69120 Heidelberg, Germany [108–110]
Alexander Koch, MD University Hospital Aachen, Aachen University (RWTH), Department of Internal Medicine III, Pauwelsstrasse 30, 52074 Aachen, Germany [78]
Jay H. Lefkowitch, MD Professor of Clinical Pathology, Presbyterian Hospital 15W-1574, Department of Pathology, Columbia University, 630 West 168th Street, New York, NY 10032, USA [63.2]
Ulrich Leuschner, MD Professor of Medicine, Center of Internal Medicine University Hospital, Goethe University Frankfurt, Theodor Stern Kai 7, 60596 Frankfurt am Main, Germany [7, 112, 113]
Thomas Longerich, MD Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220, 69120 Heidelberg, Germany [29]
Arthur J. McCullough, MD Professor of Medicine, Department of Medicine, Cleveland Clinic, MetroHealth Medical Center, 9500 Euclid Avenue Cleveland, OH 44195, USA [91]
Uta Merle, MD University Hospital Heidelberg, Department of Gastroenterology and Hepatology, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany [6, 81]
Joachim Mössner, MD University Professor of Medicine, Department of Medicine. Gastroenterology and Hepatology, University of Leipzig, Philipp-Rosenthal-Str. 27, 04103 Leipzig, Germany [115, 116]
xxvi
Sebastian Mueller, MD Center of Alcohol Research, Liver Disease and Nutrition, University of Heidelberg, and Department of Medicine, Salem Medical Center, Zeppelinstr. 11–33, 69121 Heidelberg, Germany [88]
Andreas Niedenthal, MD Department of Medicine II, Klinikum Offenbach, Goethe University Frankfurt, Starkenburgring 66, 63069 Offenbach, Germany [42]
Claus Niederau, MD Professor of Medicine, Katholische Kliniken Oberhausen gGmbH, St. Josef-Hospital, Department of Internal Medicine, University Duisburg-Essen, Mülheimer Str. 83, 46045 Oberhausen, Germany [6, 82]
Burkhard Riemann, MD Professor of Radiology, Department of Nuclear Medicine, Westfälische Wilhelms-Universität, Albert-Schweitzer-Strasse 33, 48149 Münster, Germany [39]
Jason N. Rogart, MD Assistant Professor of Medicine, Division of Gastroenterology and Hepatology, Department of Internal Medicine, UMDNJ-Robert Wood Johnson Medical School, One Robert Wood Johnson Place-MEB 478, New Brunswick, NY 08903, USA [31–33, 40–42, 48–54, 113]
Pablo R. Ros, MD Professor of Radiology, Brigham and Women’s Hospital Department of Radiology, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA [38]
Christoph Sarrazin, MD Professor of Medicine, Department of Medicine 1, University Hospital, Goethe University Frankfurt, Theodor Stern Kai 7, 60596 Frankfurt am Main, Germany [63.1]
Peter Schirmacher, MD University Professor of Pathology, Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220, 69120 Heidelberg, Germany [14–29, 108–110]
Otmar Schober, MD University Professor of Radiology, Department of Nuclear Medicine, Westfälische Wilhelms-Universität, Albert-Schweitzer-Strasse 33, 48149 Münster, Germany [39]
Contributors
Contributors
xxvii
Helmut K. Seitz, MD Professor of Medicine, Gastroenterology and Alcohol Research, Center of Alcohol Research, Liver Disease and Nutrition, University of Heidelberg, and Department of Medicine, Salem Medical Center, Zeppelinstr. 11–33, 69121 Heidelberg, Germany [88]
Samuel H. Sigal, MD Division of Gastroenterology and Hepatology, New York Weill Cornell Medical Center, New York, NY, USA [44]
Frank Stenschke, MD Department of Medicine II, Klinikum Offenbach, Goethe University Frankfurt, Starkenburgring 66, 63069 Offenbach, Germany [40, 41]
Ulrich Stölzel, MD Professor of Medicine, Department of Internal Medicine II, Porphyria Center Saxony, Klinikum Chemnitz gGmbH, Krankenhaus Flemmingstrasse, Flemmingstrasse 2, 09116 Chemnitz, Germany [84]
Christian P. Strassburg, MD Professor of Medicine, Department of Gastroenterology, Hepatology and Endocrinology, University Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany [43, 92]
Wolfgang Stremmel, MD University Professor of Medicine, University Hospital Heidelberg, Department of Gastroenterology and Hepatology, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany [6, 81]
Simone Susser, PhD Certified Biologist, Department of Medicine 1 University Hospital, Goethe University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany [63.1]
Christian Trautwein, MD University Professor of Medicine, University Hospital Aachen, Aachen University (RWTH), Department of Internal Medicine III, Pauwelsstrasse 3052074 Aachen, Germany [78]
Michael Tröltzsch, MD Department of Internal Medicine II, University of Leipzig, Philipp-Rosenthal-Str. 27, 04103 Leipzig, Germany [115]
xxviii
Ilan S. Weisberg, MD Division of Gastroenterology and Hepatology, New York Weill Cornell Medical Center, New York, NY, USA [44]
Marcus Wiedmann, MD Assistant Professor of Medicine, Department of Medicine I, St. Marien-Krankenhaus, Gallwitzallee 123–143, 12249 Berlin, Germany [115, 116]
Christian Wittekind, MD University Professor of Pathology, Institute of Pathology, University of Leipzig, Liebig-Str. 26, 04103 Leipzig, Germany [115]
Helmut Witzigmann, MD Professor of Surgery, Department of Surgery, Hospital Dresden-Friedrichsstadt, Friedrichstr. 41, 01067 Dresden, Germany [116]
Patrick S. Yachimski, MD, MPH Harvard Medical School, Gastrointestinal Unit, Massachusetts General Hospital and Division of Gastroenterology, Brigham and Women’s Hospital, Boston, MA USA [104]
Stefan Zeuzem, MD University Professor of Medicine, Department of Medicine 1, University Hospital, Goethe University Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany [63.1]
Contributors
Malformations and Malpositions of the Liver
55
Henryk Dancygier
Chapter Outline Riedel’s Lobe .................................................................. 621 Accessory Liver Lobe(s) ................................................ 621 Ectopy.............................................................................. 621 Extraabdominal Location of the Liver ......................... 622 Intraabdominal Displacement of the Liver ................. 622 Agenesis........................................................................... 622
Riedel’s Lobe Riedel’s lobe is not a true accessory liver lobe, but rather a caudally oriented tongue-like process of the right liver lobe lateral from the gallbladder [3]. The cause of this malformation, more common in women, is unknown. Histologically liver tissue is normal, and clinically this malformation is asymptomatic. Its clinical significance lies in the potential of being misinterpreted as a tumor.
Atrophy ........................................................................... 622 Zahn’s Grooves............................................................... 622 “Corset Liver” ................................................................ 622 References ....................................................................... 623
Accessory Liver Lobe(s) An accessory liver lobe (hepar succenturiatum) is encountered more often on the right side. It is connected to the right liver lobe by a stalk containing blood vessels and bile ducts. The accessory lobe may be located beneath or above the diaphragm. Usually this malformation is asymptomatic. However, torsion of the stalk may lead to acute right upper quadrant pain, nausea and vomiting. Accessory liver lobes are very rare and are encountered more often in women. Congenital hepar lobatum with the formation of abnormal, coarse lobes may be regarded as an abortive form of an accessory liver lobe.
Ectopy Ectopies of the liver (liver heterotopia or hepatic choristoma) are caused by germ dissemination. In contrast to accessory liver lobes, ectopic liver tissue is disconnected from the main organ. Approximately 50% of ectopic livers are located in the gallbladder, the remainder are
H. Dancygier, Clinical Hepatology, DOI: 10.1007/978-3-642-04519-6_55, © Springer-Verlag Berlin Heidelberg 2010
621
622
disseminated in the intra- or retroperitoneal space and in the thoracic cavity. Histologically ectopic livers exhibit a normal lobular architecture and may develop all pathologic changes seen in normal liver [1].
Extraabdominal Location of the Liver In congenital defects of the diaphragm the deformed liver can be located partially or totally within the chest. Liver dystopias in the pericardiac space have also been described. Usually these patients manifest additional malformations of the gastrointestinal tract, the lungs, the heart and the thoracic vessels. Large congenital abdominal wall defects and umbilical hernias are observed in 1:4,000 births, and may be associated with herniation of abdominal organs.
Intraabdominal Displacement of the Liver In circumscribed congenital diaphragmatic aplasia the liver may be partially displaced into the chest. Since the organ is still covered by a thin peritoneal and pleural layer, however, the liver technically still lies within the abdominal cavity. A cranial position of the liver is seen more often in acquired diaphragmatic elevation, which can occur in the setting of right sided diaphragmatic paresis. An insufficiency of hepatic ligaments may lead to hepatoptosis. Intestinal loops moving into the newly created free space between liver and diaphragm/abdominal wall characterize Chilaiditi’s syndrome. Hepatoptosis generally affects women older than 40 years. The most frequent cause for a caudal displacement of the liver is phrenoptosis, which can be seen in pulmonary emphysema or in marked right sided pleural effusion. An isolated transposition of the liver is rare. Most often it occurs in total situs inversus, in which the liver is located in the left upper quadrant. In partial situs inversus the liver is located in the median line. This anomaly often is associated with asplenia.
55
Malformations and Malpositions of the Liver
Agenesis Complete agenesis of the liver is incompatible with life. The congenital absence of an entire liver lobe is extremely rare, with fewer than 100 cases reported in the literature. Agenesis of the right liver lobe is regarded to be a consequence of a developmental anomaly of the right portal vein branch or a growth failure of the hepatic diverticulum (see Chapter 1). The absence of a hepatic segment or lobe results in compensatory hypertrophy of the remaining liver tissue. In agenesis of the right liver lobe the gallbladder is located above the liver. Rare cases of hypoplasia of the right liver lobe have also been described.
Atrophy Atrophy of the entire liver occurs in very old age and in severe chronic hunger disease. Atrophy of a singe lobe or a segment is observed in approximately 5% of diagnostic laparoscopies and in 75% of cases affects the left liver lobe. It is usually due to localized circulatory disturbances or to chronic obstruction of bile flow [2].
Zahn’s Grooves These are deep grooves (pressure atrophy) of the upper liver surface, predominantly of the right liver lobe. They are caused by pressure of hypertrophied diaphragmatic muscle bundles, predominantly in chronic obstructive pulmonary disease, on the liver parenchyma. Zahn’s grooves are found in approximately 10% of all autopsies.
“Corset Liver” Corset liver denotes flat, transverse indentations of the right liver lobe that are caused by deformations of the thoracic cage or are due to chronic strangling by a tight corset. Like Zahn’s grooves these transverse grooves represent pressure atrophy of hepatic parenchyma.
References
References 1. Desmet VJ, Eyken P (1995) Embryology, malformations, and malpositions of the liver. In: Haubrich WS, Schaffner F (eds) Bockus gastroenterology, 5th edn. W.B. Saunders, Philadelphia, PA, pp 1849–57
623 2. Ham JM (1990) Lobar and segmental atrophy of the liver. World J Surg 14: 457–62 3. Riedel I (1888) Über den zungenförmigen Fortsatz des rechten Leberlappens. Berl Klin Wochenschr 25: 577–84
Bile Duct Anomalies
56
Henryk Dancygier
Chapter Outline Congenital Liver Fibrosis .............................................. 625 Caroli’s Disease and Caroli’s Syndrome ...................... 627 Definition ......................................................................... 627 Pathogenesis ..................................................................... 627 Pathology ......................................................................... 627 Diagnosis.......................................................................... 627 Differential Diagnosis ...................................................... 627 Course and Prognosis....................................................... 627 Therapy ............................................................................ 628 Von Meyenburg Complexes........................................... 628 Biliary Atresia ................................................................ 628 Definition ......................................................................... 628 Epidemiology ................................................................... 629 Etiology and Pathogenesis ............................................... 629 Pathology ......................................................................... 629 Diagnosis.......................................................................... 629 Prognosis and Treatment .................................................. 630 References ....................................................................... 630
See also Chapters 108–110. Anomalies may affect the intra- and/or extrahepatic bile ducts. They are characterized by an excess (e.g. doubling) or by a deficit of ducts, with variously shaped dilatations and strictures [17]. Important shape variants and anomalies of the gallbladder and bile ducts (with the exception of atresia) are reported in Tables 56.1 and 56.2 and depicted in Figs. 108.1, 108.2 and 109.1. The most important anomalies of extrahepatic bile ducts are choledochal cysts. Spindle-shaped dilatations are more common than round cyst-like dilatations of bile duct segments. Congenital bronchobiliary fistulas are rarities. Developmental disturbances of the embryonic ductal plate (“ductal plate malformations”) form the basis for anomalies termed fibropolycystic liver diseases [5, 6]. The bile duct level at which the malformation occurs determines the morphological and clinical picture (Table 56.3). Fibropolycystic diseases of the liver encompass • Autosomal recessive and dominant polycystic liver disease • Congenital hepatic fibrosis • Caroli’s disease • Caroli’s syndrome • von Meyenburg complexes The various diseases may present overlapping features, and are often accompanied by renal cysts. Polycystic liver disease is discussed in Chapter 57.
Congenital Liver Fibrosis Congenital liver fibrosis (CLF) is an autosomal recessive disease. In most cases it is associated with autosomal H. Dancygier, Clinical Hepatology, DOI: 10.1007/978-3-642-04519-6_56, © Springer-Verlag Berlin Heidelberg 2010
625
626
56
Bile Duct Anomalies
Table 56.1 Important anomalies of the gallbladder Abnormal shape • Phrygian cap-like bending of body and fundus • Hour glass gallbladder • Septated gallbladder (longitudinal cystic duplication very rare) • Diverticula: preferentially in neck and fundic region Abnormal position • Left sided gallbladder (e.g. in situs inversus) • Intrahepatic gallbladder • “Pendular gallbladder”: fixation at the level of the cystic duct Numerical aberrations • Agenesia: complete absence of the gallbladder anlage (seen in 0.005–0.065% of autopsies) • Aplasia: gallbladder present, but not developed • Hypoplasia: rudimentary gallbladder • Incomplete duplication (Vesica fellea divisa) • Complete duplication and triplication (Vesica fellea duplex et triplex); single case reports in the literature Heterotopias Preferentially in neck region, gastrointestinal mucosa, pancreas, liver Source: Adapted from [17]
Table 56.2 Important bile duct anomalies Atresia See text Hypoplasia Bile ducts with narrowed, but still present lumen Heterotopias Gastric mucosa Cysts Caroli’s disease and Caroli’s syndrome: see text Diverticula Choledochal diverticula are usually near the papilla Choledochocele Hernia-like evagination of main common bile duct into the duodenum Source: Adapted from [17]
Table 56.3 Fibropolycystic diseases (ductal plate malformations) and level of bile ducts affected Disease Bile duct level Autosomal recessive polycystic disease Autosomal dominant polycystic disease Congenital hepatic fibrosis Caroli’s disease Caroli’s syndrome Von Meyenburg complexes
Interlobular bile ducts Peripheral interlobular bile ducts Interlobular bile ducts Segmental bile ducts Segmental and interlobular bile ducts Peripheral interlobular bile ducts
Source: Adapted from [6]
recessive (occasionally with autosomal dominant) polycystic liver (kidney) disease. Associations with other syndromes such as Meckel–Gruber’s syndrome (polydactylia, occipital encephalocele, renal cysts), Jeune’s and Ivemark’s syndrome (familial dysplasia of kidneys, liver and pancreas), and with vaginal atresia and tuberous sclerosis have also been reported. CLF may be combined with other anomalies of the liver such as von Meyenburg complexes, choledochal cysts and Caroli’s disease. CLF may be associated with a variety of liver tumors (cholangiocellular carcinoma, hepatocellular carcinoma, benign tumors) and be part of COACH (Hypoplasia of Cerebellar vermis, Oligophrenia, congenital Ataxia, Coloboma, Hepatic fibrosis) syndrome [10].
CLF probably does not represent a uniform nosologic entity, but rather encompasses a spectrum of liver and kidney lesions. Ductal plate malformation at the level of interlobular bile ducts (“cholangiodysplasia”) underlies the pathogenesis of CLF. The microscopic aspect of the liver is variable. Fibrous enlargement and bridging of portal tracts containing a variable number of abnormal bile ducts are seen. The bile ducts within the fibrous areas communicate with the remainder of the hepatic bile duct system. The portal venous branches often are hypoplastic, while there is an excess of hepatic artery branches. In some patients the lesions remain stationary for long
Caroli’s Disease and Caroli’s Syndrome
periods of time, while in others fibrosis is progressive, and accompanied by cholangitic exacerbations. The slowly progressive destructive cholangitis finally leads to bile duct loss and to “cholangiodysplastic pseudocirrhosis”. Circumscribed forms of CLF with only one liver lobe affected have been described [5, 6]. Depending on the rapidity and intensity of the fibrosing and cholangitic processes, different clinical forms of CLF may be delineated, i.e. a portal-hypertensive, a cholangitic, and a latent variety. CLF is one of the prototypes of portal hypertension with preserved hepatocellular function. Multiple normal deliveries in a woman with severe portal hypertension due to CLF have been described [13].
Caroli’s Disease and Caroli’s Syndrome Definition Caroli’s disease (CD) is characterized by ectasias of the segmental intrahepatic bile ducts as the sole alteration, while in Caroli’s syndrome (CS) these lesions are associated with CLF [2, 3, 20].
Pathogenesis Pathogenetically, an autosmal recessive ductal plate malformation with consequent dilatation of segmental (and interlobular ducts in CS) intrahepatic bile ducts underlies CD and CS.
627
Diagnosis Clinical Manifestations Although the lesions are congenital, the initial manifestation of the disease may not occur until adulthood [8]. The clinical picture is characterized by relapsing cholangitic exacerbations with obstructive jaundice, upper abdominal pain and fever. Progressive remodeling of the liver leads to portal hypertension and its sequelae.
Technical Examinations The biochemical laboratory parameters show a cholestatic pattern. The aminotransferase levels are either normal or only slightly increased. The diagnosis (cystic dilatations and strictures) is made by abdominal ultrasound and CT, and may be confirmed by MRCP or ERCP. The dilated ducts may contain sludge or stones. In advanced cases morphologic signs of cirrhosis are present.
Differential Diagnosis The multiple strictures and spindle-shaped dilatations of bile ducts in primary sclerosing cholangitis are smaller than the sack-like cysts seen in CD and CS. However, intrahepatic bile duct stones may cause strictures with proximal duct dilatation that may be difficult to differentiate from abortive forms of CD. In Asian patients, bile duct infections with Ascaris and Clonorchis sinensis as well as intrahepatic hepatolithiasis (“oriental cholangiohepatitis,” also known as “recurrent pyogenic cholangitis”) must be excluded.
Pathology The dilatation of the segmental intrahepatic bile ducts generally presents in a diffuse form, but may occasionally involve only a single lobe, commonly the left one. In its simple form, sack-like dilatations of the larger intrahepatic, predominantly segmental, bile ducts are found in CD. The dilated ducts may contain sludge, stones and dysplastic epithelial proliferations [7]. In CS the cysts are accompanied by fibrosis and/or by autosomal recessive polycystic kidney disease. Choledochal cysts are found in approximately 20% of cases.
Course and Prognosis The disease runs a chronic progressive course and approximately 50% of patients succumb to complications such as sepsis, biliary liver abscesses, portal hypertension or liver failure 1–5 years after the diagnosis has been established. In a longstanding course, amyloidosis may supervene. Seven to 14% of patients develop a cholangiocarcinoma. The occurrence of hepatocellular carcinoma has been reported in single cases.
628
Therapy Cholangitis is treated with repeated courses of antibiotics. Ursodeoxycholic acid (UDCA) may be tried to alleviate cholestasis, however the evidence for the effectiveness of UDCA in this clinical setting is very weak [18]. Endoscopic, percutaneous or combined techniques may be used for stone extraction, dilatation of strictures and placement of stents. Liver resection is the treatment of choice for CD confined to a single lobe or segment, as it can provide a durable cure and eliminate the potential for cholangitis, lithiasis and carcinoma. In diffuse progressive disease, orthotopic liver transplantation is the only effective long term therapeutic option.
56
Bile Duct Anomalies
peripherally situated intrahepatic bile ducts and communicate with the remaining bile duct system of the liver. These small (1–2 mm), often multiple lesions are clinically asymptomatic and are usually incidental laparoscopic findings. They may occur in an otherwise normal liver or be associated with CD or CLF.
Biliary Atresia Biliary atresia is an occlusive cholangiopathy that may affect both intra- and extrahepatic parts of the biliary tree.
Definition Von Meyenburg Complexes Von Meyenburg complexes are microhamartomas of the bile ducts, located within the portal tracts or in their immediate vicinity. A variable number of irregularly shaped and varyingly dilated duct structures are embedded in a fibrous, occasionally hyalinized stroma (Fig. 56.1). The lesions represent partially fibrosed remnants of ductal plate malformations of small,
Fig. 56.1 Von Meyenburg complex. The microhamartoma is composed of small, dilated, irregularly shaped bile ducts that are surrounded by fibrous tissue. Masson trichrome (×200)
Extrahepatic biliaray atresia (EBA) is characterized by a complete absence of duct lumen or loss of duct continuity in one duct segment or in all extrahepatic bile ducts. In intrahepatic biliary atresia (IBA) atresia is usually not complete but the number of interlobular bile ducts is reduced. Thus, IBA is more accurately a hypoplasia rather than a true atresia, which is why this entity is also referred to as “paucity of intrahepatic bile ducts.”
Biliary Atresia
Epidemiology EBA occurs in 1:10,000 to 13,000 deliveries, more often in female newborns. EBA is responsible for approximately 30–35% of all neonatal cholestasis and in 20% of cases is associated with CLF. EBA associated with choledochal cyst has recently been suggested to represent a distinct subtype of biliary atresia, characterized by a preponderance of type 1 (see below), by an absence of associated congenital anomalies, and by a relatively good clinical outcome after surgery [15].
Etiology and Pathogenesis Embryonic morphogenetic bile duct defects, peri- and postnatal factors have been implicated in the development of EBA. The etiologic hypotheses comprise viral infections (e.g. cytomegalovirus, hepatitis B and C virus), ischemic lesions, toxic injury by bile acids or reflux of pancreatic juice into the bile duct, and an angiofibromatous process. A reoviral etiology has recently been disputed [19]. Immunologically mediated inflammation of bile ducts, involving both cellular and humoral components of autoimmunity, has been suggested to be operative in EBA, and the progressive bile duct injury has been postulated to be due in part to a bile duct epithelia-specific T cell-mediated immune response [12, 16]. All theories, however, are unproven and the exact etiology and pathogenesis of EBA are still unknown. Ultimately a destructive inflammatory-fibrosing cholangiopathy dominates the clinical picture [1, 14].
Pathology According to Kasai, various types of EBA can be distinguished (see Fig. 109.2) [9]. 10% of all EBA cases fall upon types I, IIa and IIb that are amenable to corrective surgery. Ninety percent fall upon type III in which a hepatoportoenterostomy (Kasai’s procedure) is not possible. In 80% of patients the gallbladder is involved in the atretic process. Each EBA is also accompanied by alterations of the intrahepatic bile duct system and of liver parenchyma. Even though it is primarily a bile duct disease, EBA is a complex disorder that ultimately affects all structures within the portal tract.
629
In the first 3–4 weeks of life centrilobular cholestasis with multinucleated giant cells, scattered throughout the parenchyma is seen. An inflammatory cellular infiltration of lobular parenchyma and portal tracts is still lacking in this early phase. During the further course, usually in the 4th–7th week of life the typical changes of extrahepatic bile duct obstruction become evident, with enlargement and rounding of portal tracts, ductular reaction at the porto-lobular interface and a variably dense inflammatory cell infiltrate consisting of neutrophilic granulocytes and lymphocytes. The epithelium of interlobular bile ducts becomes increasingly damaged. Without treatment the inflammatory-fibrosing lesions progress, resulting in loss of portal bile ducts and leading to the development of biliary cirrhosis within several weeks to months. During progression of EBA the portal vein branches within the portal tracts appear increasingly hypoplastic.
Diagnosis The diagnosis must be established before the advent of cirrhosis, i.e. usually before the 6th week of life, in order to utilize all opportunities of corrective surgery.
Clinical Manifestations EBA presents in two forms, an embryonic-fetal type (10–35% of cases), and a perinatal form (65–90% of cases). The embryonic-fetal type is characterized by an early onset of neonatal cholestasis, with continuing icterus after neonatal jaundice has abated. The children have acholic stools. This form of EBA also is more often than the perinatal form associated with other anomalies such as poly- and asplenia, cardiovascular malformations, abdominal situs inversus, intestinal malrotations, and vascular abnormalities of the liver. The perinatal form of EBA initially is anicteric and presents with cholestasis in the 4th–8th week of life. Unlike the embryonic-fetal variety an increased incidence of anomalies of other organs is not observed in this form of EBA. IBA may occur within the context of Alagille’s syndrome (arteriohepatic dysplasia; see Chapter 85) or as an isolated disease without extrahepatic abnormalities. The nonsyndromatic paucity of bile ducts is a heterogeneous group of disorders and occurs more rarely than Alagille’s syndrome.
630
Technical Examinations The laboratory data show a cholestatic enzyme pattern with elevation of AP and g-GT values. The diagnosis is made with imaging techniques such as abdominal sonography, nuclear imaging, percutaneous transhepatic cholangiography, and MRCP. Liver biopsy is mandatory. A ratio of the number of interlobular bile duct profiles to the number of portal tracts (a biopsy specimen with at least six portal tracts is required) of 1,500 mmol/min/L and combined with cyclophosphamide) Whole body irradiation, especially when combined with cyclophosphamide Non-related donor transplants or related, but HLA-mismatched transplants Methotrexate in the prophylaxis of graftversus-host disease Cytomegalovirus infection
a Very weak association with SOS Source: According to [8]
of SOS within the context of stem cell transplantation strongly depends on the conditioning regimen used prior to the transplant. The new non-myeloablative regimens without cyclophosphamide (e.g., fludarabine with low-dose whole body irradiation) are not hepatotoxic. The pathogenesis of SOS is not well understood. The initial insult appears to be a poorly defined sinusoidal endothelial cell injury that activates a cascade of events leading to non-thrombotic impairment of microcirculation at the sinusoidal level. Biochemically,
sinusoidal endothelial cells are depleted in glutathione. Activation of matrix metalloproteinases with degradation of extracellular matrix and a derivative loss of endothelial cell anchoring may also be pathogenetically relevant [9]. Hypercoagulable states do not seem to be associated with the development SOS.
Pathology The earliest lesion in animal experiments (seen on electron microscopy) is swelling and rounding of sinusoidal endothelial cells with loss of endothelial fenestrations and extravasation of red blood cells into the space of Disse. Trichrome stains are best suited for histologic evaluation. The initial histologically visible change is the edematous expansion of the subendothelial space between the basement membrane and the adventitia of terminal hepatic venules and sublobular veins. Fragmented red blood cells and cell debris are found within this space. These venular lesions are accompanied by dilatation and congestion of sinusoids with hemorrhagic necrosis of pericentral liver parenchyma. The architecture of liver cell plates is lost and individual hepatocytes or groups of liver cells may embolize into the lumen of damaged terminal hepatic venules. Approximately 2 weeks after patients with SOS become symptomatic, activated stellate cells proliferate and extracellular matrix is deposited within the subendothelial and perisinusoidal spaces. The advanced stages of SOS are characterized by collagenization of sinusoids and venules, and progressive and diffuse liver fibrosis. In some cases fibrotic septa bridge terminal venules of neighbouring lobules, imitating cardiac sclerosis. 45% of patients with a mild to moderate SOS and 25% of those with a severe SOS do not show complete occlusion of terminal hepatic venules.
Diagnosis A high index of suspicion in the appropriate clinical context (signs of portal hypertension in a patient exposed to pyrrolizidine alkaloids, bush teas, immununosuppressant
Sinusoidal Obstruction Syndrome
653
agents, post hematopoietic cell transplantation) should lead to the correct diagnosis.
Table 60.4 Different grades of severity of the sinusoidal obstruction syndrome in association with cyclophosphamide based myeloablation for stem cell transplantation Mild Moderate Severe
Signs and Symptoms
Weight gain (%) Maximal bilirubin concentration (mg/dL) Proportion of patients with peripheral edema (%) Proportion of patients with ascites (%) Mortality on day 100 (all causes) (%) Source: Adapted from [6]
Functionally SOS is a disorder of hepatic venous outflow with abdominal distention, ascites, painful hepatomegaly and splenomegaly. The clinical picture varies according to the severity of SOS. Patients may be asymptomatic or develop symptoms and signs of portal hypertension, which typically precede those of parenchymal liver failure. SOS associated with bone marrow transplant usually begins 1–3 weeks after the procedure. The occlusion of centrilobular veins is associated with a more severe clinical picture. However, even 20–30% of patients with occlusion of terminal hepatic venules may be asymptomatic [6, 9].
Laboratory Parameters The rise in serum bilirubin and aminotransferase levels is nonspecific. High aminotransferase concentrations are due to centrilobular necrosis and values greater than 750 U/L are assumed to be associated with a poor prognosis.
Imaging Techniques Ultrasound, CT and MRI contribute little to the specific diagnosis of SOS, but rather show the consequences of hepatic venous outflow. Liver biopsy in SOS is often performed by the transvenous route.
Differential Diagnosis Graft versus host disease, viral infection, drug injury, ischemic hepatitis and sepsis-associated cholestasis are among the most important differential diagnoses. In graft versus host disease cutaneous and intestinal manifestations usually precede hepatic symptoms. Viral infections include primarily those with herpes simplex, varizella zoster, cytomegalovirus, and Epstein-Barr virus. Ischemic hepatitis occurs in the clinical context of systemic circulatory impairment.
7 ± 3.5 10.1 ± 5.3 15.5 ± 9.2 4.7 ± 2.9 7.9 ± 6.6 26 ± 15.2
23
70
85
5
16
48
3
2
98
Course and Prognosis Most patients recover, while some progress to acute liver failure. High serum aminotransferase values, rising creatinine levels, a high hepato-venous pressure gradient, the development of portal vein thrombosis, and diminishing blood oxygen saturation are associated with a poor prognosis. In clinically severe forms mortality rates reach 100%. The patients usually die from renal and cardiac rather than from hepatic failure. In Table 60.4 the different grades of severity of cyclophosphamide-associated SOS are reported. A subclinical course with demonstrable histologic lesions but without associated symptoms has also been described.
Treatment A specific management of SOS is not available and treatment is supportive. All potential causes, such as hepatotoxic conditioning regimens in hematopoietic cell transplantation, must be avoided or eliminated. Protein C and antithrombin III concentrations are often diminished in SOS. However, administration of antithrombin III is ineffective. In mild cases anticoagulation with intravenous or subcutaneous heparin might be helpful, but solid data supporting this approach are lacking. In individual cases intravenous infusion of N-acetyl cysteine (50–150 mg/kg body weight/day) over 2–4
654
weeks has been reported to be beneficial. Data regarding the efficacy of ursodeoxycholic acid in SOS are conflicting. TIPS or surgical portosystemic shunts have no effect on survival.
Changes of Sinusoidal Contents Dilated sinusoids may contain abnormal cells or organic material. Usually these changes are of ancillary clinical importance and can only be demonstrated histologically. Occasionally, however, their presence in a liver biopsy will yield the clue for the diagnosis of a systemic disease. In sickle cell anemia (see Chapter 97) panlobular dilated sinusoids may be packed with deformed red blood cells which often are phagocytosed by Kupffer cells (erythrophagocytosis). Sinusoids filled with acanthocytes hint towards a-b-lipoproteinemia. Neutrophilic granulocytes are seen in the context of systemic leukocytosis and in so-called surgical necroses (i.e. neutophils accumulate in the liver during abdominal operations). Increased numbers of intrasinusoidal eosinophils may be present in generalized allergic reactions to drugs, parasitic infections and in the hypereosinophilic syndrome. Lymphocytes within the sinusoids arranged in a string of pearls-like pattern are typical (but not pathognominic) for infection with Epstein-Barr and cytomegalovirus. Focal groups of ceroid storing macrophages also hint toward viral infections and may be present for months as residual changes after resolution of acute viral hepatitis. Plasma cells are occasionally seen in multiple myeloma and in Waldenström’s disease, mast cells in systemic mastocytosis, and abnormal histiocytes in histiocytosis X. Extramedullary hematopoiesis may persist into neonatal life in neonatal hepatitis. In adults the presence of megakaryocytes and immature white and red blood cells within foci of extramedullary hematopoiesis suggest a myeloproliferative disorder or diffuse metastatic involvement of the bone marrow.
60
Sinusoids
Neoplastic cells within the sinusoids are seen in leukemia, malignant lymphoma, and metastatic carcinoma. An infiltration of sinusoids by tumor cells is typical for angiosarcoma and epithelioid hemangioendothelioma (see Chapter 102). Intrasinusoidal fibrin deposits in zone 1 are characteristic of eclampsia and disseminated intravascular coagulation. Pathogens, such as plasmodia, microfilaria (Wuchereria bancrofti) or worm larvae (Strongyloides stercoralis) may also be encountered within the sinusoids occasionally.
Perisinusoidal Lesions Capillarization of sinusoids denotes the deposition of collagen fibers within the space of Disse, with or without the formation of a basement membrane. It may occur among others in alcoholic hepatitis (predominantly in zone 3), in chronic viral hepatitis with marked inflammatory activity (predominantly in zone 1), and in drug induced liver damage (e.g., in hypervitaminosis A and during azathioprine and methotrexate therapy). The fibrous tissue within the space of Disse may be visualized by the usual trichrome stains. The morphological demonstration of basement membranes requires immunocytochemical techniques using antibodies against laminin and collagen type IV. In patients with long-standing diabetes mellitus a noncirrhotic form of sinusoidal fibrosis not associated with nonalcoholic steatohepatitis may be observed. Recently the term “diabetic hepatosclerosis” has been proposed for this entity and suggested that it represents a form of diabetic microangiopathy affecting the liver [8]. Amyloid may be deposited in the branches of hepatic artery or in the space of Disse leading to progressive atrophy of liver cell plates (see Chapter 87) [5]. It can be confirmed by the classical congo-red stain or by immunohistochemistry. Perisinusoidal deposition of nonamyloidotic light chains is rare, and occurs occasionally in chronic renal failure. The deposits are PAS-positive, but do not stain with the usual amyloid stains. They can be visualized by immunocytochemistry using antibodies against kor l-light chains.
References
References 1. Braden B, Helm B, Fabian T, et al (2000) Bazilläre Angiomatose der Leber, eine sonographische Verdachtsdiagnose? Z Gastroenterol 38: 785–9 2. Bras G, Jelliffe DB, Stuart KL (1954) Veno-occlusive disease of liver with non-portal type of cirrhosis occurring in Jamaica. Arch Pathol 57: 285–300 3. Bruguera M, Aranguibel F, Ros E, et al (1978) Incidence and clinical significance of sinusoidal dilatation in liver biopsies. Gastroenterology 75: 474–8 4. Chojkier M (2003) Hepatic sinusoidal-obstruction syndrome: toxicity of pyrrolizidine alkaloids. J Hepatol 39: 437–46 5. Chopra S, Rubinow A, Koff RS, et al (1984) Hepatic amyloidosis. A histopathologic analysis of primary (AL) and secondary (AA) forms. Am J Pathol 115: 186–93 6. DeLeve LD, Shulman HM, McDonald GB (2002) Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease). Semin Liv Dis 22: 27–41 7. Fajardo LF, Colby TV (1980) Pathogenesis of veno-occlusive liver disease after radiation. Arch Pathol Lab Med 104: 584–8
655 8. Harrison SA, Brunt EM, Goodman ZD, et al (2006) Diabetic hepatosclerosis: diabetic microangiopathy of the liver. Arch Pathol Lab Med 130: 27–32 9. Kumar S, DeLeve LD, Kamath PS, et al (2003) Hepatic veno-occlusive disease (sinusoidal obstruction syndrome) after hematopoietic stem cell transplantation. Mayo Clin Proc 78: 589–98 10. Moore EH, Russell LA, Klein JS, et al (1995) Bacillary angiomatosis in patients with AIDS: multiorgan imaging findings. Radiology 197: 67–72 11. Saadoun D, Cazals-Hatem D, Denninger M-H, et al (2004) Association of idiopathic hepatic sinusoidal dilatation with the immunological features of the antiphospholipid syndrome. Gut 53: 1516–9 12. Shulman HM, Fisher LB, Schoch HG, et al (1994) Venoocclusive disease of the liver after marrow transplantation: histological correlates of clinical signs and symptoms. Hepatology 19: 1171–81 13. Winkler K, Poulsen H (1975) Liver disease with periportal sinusoidal dilatation: a possible complication to contraceptive steroids. Scand J Gastroenterol 10: 699–704
61
Portal Vein Henryk Dancygier
Chapter Outline Portal Vein Thrombosis ................................................. 657 Acute Portal Vein Thrombosis ......................................... 657 Chronic Portal Vein Thrombosis ...................................... 658 Hepatoportal Sclerosis ................................................... 659 Definition ......................................................................... 659 Epidemiology ................................................................... 659 Etiology and Pathogenesis ............................................... 659 Pathology ......................................................................... 659 Diagnosis.......................................................................... 660 Prognosis and Therapy ..................................................... 660 Portal Vein Inflammation .............................................. 660 Pylephlebitis..................................................................... 660 Granulomatous Phlebitis .................................................. 661 Portal Vein Gas Embolism ............................................ 661
Portal Vein Thrombosis Portal vein thrombosis (PVT) is caused by endothelial injury, either alone or in combination with hypercoagulability and slowed blood flow. In Table 61.1 the most important causes of portal vein thrombosis are reported (see also etiology of Budd–Chiari syndrome in Chapter 59) [3, 8, 11, 19, 22]. The leading underlying disease, which is associated with 25–30% of PVT-cases, is liver cirrhosis. In many of these patients the liver harbors a hepatocellular carcinoma. PVT may be completely asymptomatic or present with life-threatening complications, such as gastrointestinal hemorrhage and intestinal infarction [1].
Acute Portal Vein Thrombosis
References ....................................................................... 661
Thrombotic obliteration of the portal vein usually develops insidiously, but may also begin acutely. Acute complete occlusion of the main portal vein trunk is a dramatic clinical event. Due to the abruptness of the process there is no time for the development of collateral vessels and acute PVT may extend to the splenic and mesenteric veins. The clinical picture is characterized by acute diffuse abdominal pain, hemorrhagic small intestinal infarction, and circulatory shock. Acute abdominal pain, fever and the rapid development of new or the increase of preexisting ascites in a patient with known cirrhosis should prompt the search for an acute PVT. The sudden occlusion of the portal vein or of one of its branches may cause a true or a pseudoinfarct in the liver. Acute occlusion of an intraparenchymal portal vein branch with concomitant impairment of arterial flow leads to the formation of a pseudoinfarct of Zahn. H. Dancygier, Clinical Hepatology, DOI: 10.1007/978-3-642-04519-6_61, © Springer-Verlag Berlin Heidelberg 2010
657
658 Table 61.1 Etiology of portal vein thrombosisa Prehepatic • Pylephlebitisb • Compression of portal vein (e.g. tumors, lymph nodes) • Appendicitis • Diverticulitis • Pancreatitis • Perforated peptic ulcer • Tuberculous lymphadenitis Intrahepatic • Liver cirrhosisc • Space occupying liver lesions Hepatocellular carcinoma Granuloma, abscess, cysts Nodular transformation Nodular regenerative hyperplasia • Sinusoidal obstruction syndrome (formerly veno-occlusive disease) • Pylephlebitis • Congenital liver fibrosis • Hepatoportal sclerosis (idiopathic portal hypertension) Posthepatic • Right heart failure • Constrictive pericarditis • Tumors of right atrium • Obstruction of inferior vena cava (above the entrance of hepatic veins) • Occlusion of hepatic veins Hypercoagulability • Protein C and S deficiency • Antiphospholipid syndrome • Antithrombin III deficiency • Factor V Leiden mutation • Factor II (Prothrombin) G20210A mutation • Hyperhomocyteinemia (MTFR mutation) • Increased Factor VIII • Myeloproliferative Diseases (JAK2 mutations) Polycythemia vera Essential thrombocythemia • Paroxysmal nocturnal hemoglobinuria Miscellaneous • Sickle cell anemia • Liver transplantation • Surgical porto-systemic shunt • Malignancy • Blunt trauma • Radiation injury • Antineoplastic chemotherapy • Arsenic intoxication • Oral contraceptives • Pregnancy and potpartum • Neonatal omphalitis Idiopathic a
Endothelial injury, slowed blood flow and hypercoagulability combined are pathogenetically important b All causes of pylephlebitis may also cause portal vein thrombosis c Liver cirrhosis is by far the leading disorder underlying portal vein thrombosis
61 Portal Vein
It consists of a sharply demarcated, red-blue, wedgeshaped area (the tip points towards the occluded portal vein branch) of marked hemostasis. The sinusoids are distended and the hepatocytes are severely atrophic but not necrotic, hence the designation pseudoinfarct. The development of a pseudoinfarct of Zahn is clinically silent. Therefore the process usually goes unnoticed or manifests incidentally by a slight and transient rise of aminotransferase concentrations of unknown etiology.
Chronic Portal Vein Thrombosis Subacute or chronic obliterative lesions of intrahepatic portal vein branches may lead to liver atrophy, with or without nodular regenerative hyperplasia of liver parenchyma [25]. The complete occlusion of a major portal vein branch may result in atrophy of the corresponding segment or lobe of the liver. When PVT develops insidiously, there is usually sufficient time for collateral vessels to develop and a sponge-like, angiomatous network (cavernous transformation of the portal vein) forms that maintains hepatic circulation, albeit at a low level. Portal hypertension results in the formation of esophageal varices and splenomegaly. Interestingly, patients with PVT, even in the absence of cirrhosis, may develop subclinical neurological abnormalities compatible with minimal hepatic encephalopathy [14]. The diagnosis of PVT is made by ultrasound with Doppler flow studies, CT scanning or MR-angiography (Fig. 61.1). Endoscopic ultrasonography with linear probes also has emerged as a sensitive and specific test to diagnose PVT [10]. A high percentage of patients with cavernous transformation of the portal vein may exhibit concomitant bile duct changes, such as dilatation and compression (“cavernoma-associated cholangiopathy”), which may remain clinically silent or lead to cholestasis or obstructive jaundice. Thus, cavernous transformation may be a rare cause of extrahepatic cholestasisis, and MR-portography may be coupled with MR-cholangiography in patients with PVT [6]. In children cavernous transformation of the portal vein is frequently associated with prehepatic portal hypertension and congenital anomalies, particularly atrial septal defects or malformations of the biliary tract or inferior vena cava [23]. Effective therapy of PVT is hampered by the lack of controlled data on which to base clinical decisions. The benefit of local thrombolysis in acute PVT (streptokinase or tissue plasminogen activator) is uncertain.
Hepatoportal Sclerosis
659
Fig. 61.1 Color Doppler ultrasound of portal vein thrombosis. The thrombus is partially surrounded by blood
Recanalization of subacute and chronic PVT during anticoagulation for 4 months has been reported, but the study was not controlled and the data were evaluated retrospectively [4]. Therefore, currently there is no compelling evidence for thrombolysis or anticoagulation in patients with PVT. Considering preexisting liver disease, complications of portal hypertension, and comorbidities in most patients with PVT, the risks and benefits of these therapies should be balanced carefully [5]. Anatomic abnormalities causing extrahepatic portal vein obstruction may be amenable to surgical correction.
Hepatoportal Sclerosis Definition Hepatoportal sclerosis (idiopathic portal hypertension, non-cirrhotic portal hypertension; see also Chapter 53) is a disease of unknown etiology which primarily affects the intrahepatic terminal portal venules and leads to atrophy of liver parenchyma as well as to presinusoidal portal hypertension in the absence of cirrhosis.
Epidemiology Exact data on incidence and prevalence are not available. The disease is very rare in Western countries, and is encountered predominantly in India and in Japan.
The incidence in Japan is declining, which may suggest the role of an infectious etiology. In Japan women are affected three times more frequent than men, while in India men are affected more commonly than women. More than 90% of patients are older than 30 years, with a mean age at presentation of 45–50 years [17, 20].
Etiology and Pathogenesis The cause of hepatoportal sclerosis is unknown. Immunologic alterations, chronic exposure to arsenic compounds, microcirculatory disturbances due to the formation of platelet microthrombi and fibrin emboli, and infectious pathogens (e.g. Schistosoma, HIV) have been incriminated [2, 7, 15, 16, 21, 22]. Pathogenetic relationships to Banti’s disease (idiopathic splenomegaly with noncirrhotic portal hypertension) have been discussed [13, 22].
Pathology The terminal portal venules show fibrous intimal thickening (phlebosclerosis) with muscular hypertrophy and fibrosis of the media. The process leads to luminal stenosis and finally to complete obliteration of portal vein branches. The vascular lesions are particularly well visualized by elastic fiber stains. A high incidence of PVT is observed, which is believed to be secondary to the impairment of intrahepatic microcirculation [12].
660
Obliteration of portal veins is accompanied by marked portal and periportal fibrosis, concentric peribiliary fibroelastosis, sclerosis of the sinusoidal fibrous framework and by parenchymal atrophy. Although obliterative portal venopathy may lead to the formation of nodular regenerative hyperplasia, the basic lobular architecture remains preserved in hepatoportal sclerosis [25]. These changes have to be distinguished from secondary phlebosclerotic changes that may occur in schistosomiasis, primary biliary cirrhosis, and even without an underlying liver disease in old age.
Diagnosis The clinical picture is dominated by signs and symptoms of portal hypertension. The liver enzymes in serum are normal or only slightly elevated. Often a mild hypergammaglobulinemia is observed. Ultrasound, CT scanning and MRI show the sequelae (portal hypertension, liver atrophy) of the obliterative portal venous lesions but do not visualize the primary disease process itself. The hepato-venous pressure gradient is normal or only slightly elevated (presinusoidal portal hypertension). The results of liver biopsy are affected by sampling error since the process does not affect the entire organ uniformly.
Prognosis and Therapy The primary disease process is not amenable to therapy. The prognosis largely depends on the efficacy of prophylaxis and treatment of the sequelae of portal hypertension, especially esophageal variceal bleeding (see Chapter 80).
Portal Vein Inflammation Pylephlebitis Pylephlebitis is a suppurative endophlebitis of the portal vein that may lead to the formation of liver abscesses,
61 Portal Vein
mostly in the right liver lobe. It may be associated with portal vein thrombosis. Pylephlebitis begins as an infective thrombophlebitis of small veins draining an area of infection. Septic thromboemboli lodge in the portal vein and cause inflammation of its wall. The etiology is multifaceted (Table 61.2). The most common blood stream isolates are Bacteroides fragilis, aerobic gram negative bacteria, streptococci, staphylococci, citrobacter and yeasts. Enterococci are found rarely [18]. In newborns septic phlebitis of the umbilical vein may extend into the intrahepatic portal vein branches. Pylephlebitis is a chronic inflammatory disease characterized clinically by prolonged fever, night sweats, fatigue and intense malaise [9]. Abdominal pain, when present, is usually not severe. The diagnosis should be suspected in intraabdominal septic disorders with secondary involvement of the liver. Liver abscess and bowel ischemia may complicate pylephlebitis.
Table 61.2 Causes of suppurative pylephlebitis Gastrointestinal diseases • Appendicitis • Ulcerative colitis • Crohn’s disease • Diverticulitis of small and large intestine • Infected hemorrhoids • Proctitis • Ulcerated intestinal cancers • Infections (e.g. typhoid fever, abdominal tuberculosis, shigellosis, schistosomiasis) • Umbilical cord infections • Perforating and deeply penetrating peptic ulcers • Post gastrectomy Hepatobiliary and pancreatic diseases • Liver abscess • Suppurative cholangitis • Suppurative cholecystitis • Echinococcal cysts • Acute and chronic pancreatitis • Pancreatic abscess (may also result from pylephlebitis) Suppurative urogenital diseases Foreign bodies and trauma Miscellaneous • Subphrenic and subhepatic abscesses • Suppurative mesenterial lymphadenitis • Suppurative retroperitoneal inflammation • Lung abscess, pneumonia, emphysema • Peritoneal carcinomatosis • Bacteremia • Rocky mountain spotted fever
References
The laboratory examinations are nonspecific. Marked elevations of inflammatory parameters (ESR, CRP, neutrophil leukocytosis) are accompanied by a mild to moderate rise of aminotransferases, alkaline phosphatase and lactate dehydrogenase. However, a normal leukocyte count and even neutropenia do not exclude pylephlebitis. Blood cultures are mandatory for diagnosis. The results of imaging are also nonspecific. On ultrasound, echogenicity of the liver is irregular. CT-scanning shows heterogeneous, ill-defined enhancement of parenchyma in the central liver segments. Provided no liver abscess has formed, no space occupying lesions are present. Demonstrating wall irregularities of the portal vein is very difficult. The presence of a thrombus in the portal vein is not sufficient by itself in diagnosing pylephlebitis. Occasionally gas in the portal venous system will be visualized. Prognosis is very severe without adequate treatment. In the preantibiotic era pylephlebitis was universally fatal. Early, targeted antibiotic therapy is the treatment of choice. Empiric broad-spectrum antibiotics should be instituted with one of the following parenteral regimens while culture results and sensitivities are pending [24].
661
Granulomatous Phlebitis Portal vein granulomas may occur in sarcoidosis, schistosomiasis, and in mycobacterium avium intracellulare infection. Mineral oil granulomas are only rarely encountered in the portal vein.
Portal Vein Gas Embolism Gas inclusions within the portal vein in adults are frequently caused by vascular mesenterial occlusion and necrotizing enterocolitis. The common pathogenetic mechanism includes intestinal wall defects through which gas-forming pathogens reach the portal venous circulation. These intravascular gas inclusions are easily distinguished by sonography from air in the bile ducts (pneumobilia) which is regularly present after sphincterotomy. Additionally, patients with portal vein gas emboli usually are severely ill, while pneumobilia occurs in clinically healthy persons.
• Combination therapy Metronidazole 500 mg i.v. tid
References
plus one of the following, Ceftriaxone 2 g i.v qd or Cefotaxime 2 g i.v qid or Ciprofloxacin 400 mg i.v. bid or Levofloxacin 500 mg i.v. qd. or • Monotherapy Piperacillin/tazobactam 4.5 g i.v. qid or Ticarcillin-clavulanate 3.1 g i.v. q4h or Ampicillin-sulbactam 3 g i.v. qid or Imipenem 500 mg i.v. qid or Meropenem 1 g i.v. tid or Ertapenem 1 g i.v. qd. Most liver abscesses will require drainage, either operatively or percutaneously (ultrasound or CT-guided). The treatment plan should also consider the elimination of potential intraabdominal septic foci.
1. Amitrano L, Guardascione MA, Brancaccio V, et al (2004) Risk factors and clinical presentation of portal vein thrombosis in patients with liver cirrhosis. J Hepatol 40: 736–41 2. Andrade ZA, Cheever AW (1971) Alterations of the intrahepatic vasculature in hepatosplenic Schistosomiasis mansoni. Am J Trop Med Hyg 20: 425–32 3. Chamouard P, Pencreach E, Maloisel F, et al (1999) Frequent Factor II G20210A mutation in idiopathic portal vein thrombosis. Gastroenterology 116: 144–8 4. Condat B, Passione F, Denninger MH, et al (2000) Recent portal or mesenteric venous thrombosis: increased recognition and frequent recanalization on anticoagulant therapy. Hepatology 32: 466–70 5. Condat B, Pessione F, Hillaire S, et al (2001) Current outcome of portal vein thrombosis in adults: risk and benefit of anticoagulant therapy. Gastroenterology 120: 490–7 6. Condat B, Vilgrain V, Asselah T, et al (2003) Portal cavernoma-associated cholangiopathy: a clinical and MR cholangiography coupled with MR portography imaging study. Hepatology 37: 1302–8 7. Datta DV, Mitra SK, Chuttani PN, et al (1979) Chronic oral arsenic intoxication as a possible aetiological factor in idiopathic portal hypertension (noncirrhotic potal fibrosis) in India. Gut 20: 378–84
662 8. Denninger MH, Chait Y, Casadevall N, et al (2000) Cause of portal or hepatic venous thrombosis in adults: role of multiple concurring factors. Hepatology 31: 587–91 9. Kasper DL, Sahani D, Misdraji J (2005) Case 25–2005 – A 40-year-old man with prolonged fever and weight loss. N Engl J Med 353: 713–22 10. Lai L, Brugge WR (2004) Endoscopic ultrasound is a sensitive and specific test to diagnose portal venous system thrombosis (PVST). Am J Gastroenterol 99: 40–4 11. Mangia A, Villani MR, Cappucci G, et al (2005) Causes of portal venous thrombosis in cirrhotic patients: the role of genetic and acquired factors. Eur J Gastroenterol Hepatol 17: 745–51 12. Matsutani S, Maruyama H, Akiike T, et al (2005) Study of portal vein thrombosis in patients with idiopathic portal hypertension in Japan. Liver Int 25: 978–83 13. Mikkelsen WP, Edmondson HA, Peters RL, et al (1965) Extra- and intrahepatic portal hypertension without cirrhosis (hepatoportal sclerosis). Ann Surg 162: 602–20 14. Minguez B, Garcia-Pagan JC, Bosch J, et al (2006) Noncirrhotic portal vein thrombosis exhibits neuropsychological and MR changes consistent with minimal hepatic encephalopathy. Hepatology 43: 707–14 15. Morris JS, Schmid M, Newman S, et al (1974) Arsenic and noncirrhotic portal hypertension. Gastroenterology 64: 86–94 16. Okuda K, Omata M (1983) Idiopathic portal hypertension. University of Tokyo Press, Tokyo, pp 1–606
61 Portal Vein 17. Okudaira M, Ohbu M, Okuda K (2002) Idiopathic portal hypertension and its pathology. Semin Liv Dis 22: 59–71 18. Plemmons RM, Dooley DP, Longfield RN (1995) Septic thrombophlebitis of the portal vein (pylephlebitis): diagnosis and management in the modern era. Clin Infect Dis 21: 1114–20 19. Primignani M, Martinelli I, Bucciarelli P, et al (2005) Risk factors for thrombophilia in extrahepatic portal vein obstruction. Hepatology 41: 603–8 20. Ramalingaswami B, Wig HL, Sama SK (1962) Cirrhosis of the liver in northern India. A clinicopathologic study. Arch Med 110: 350–8 21. Schiano TD, Kotler DP, Ferran E, et al (2007) Hepatoportal sclerosis as a cause of noncirrhotic portal hypertension in patients with HIV. Am J Gastroenterol 102: 2536–40 22. Sobhonslidsuk A, Reddy KR (2002) Portal vein thrombosis: a concise review. Am J Gastroenetrol 97: 535–41 23. Sorrentino D, Labombarda A, DeBiase F, et al (2004) Cavernous transformation of the portal vein associated to multiorgan developmental abnormalities. Liver Intern 24: 80–3 24. Spielman D (2008) Pylephlebitis. www.uptodate.com Version 15.3 25. Wanless IR, Das A, Boitnott JK, et al (1990) Hepatic vascular disease and portal hypertension in polycythemia era and agnogenic myeloid metaplasia: a clinicopathological stufy of 145 patients examined at autopsy. Hepatology 12: 1166–74
Hepatic Arteries
62
Henryk Dancygier
Chapter Outline Congentital Anomalies................................................... 663 Hepatic Arteries Occlusion ........................................... 663 Hypoxic Hepatitis ........................................................... 664 Definition ......................................................................... 664 Epidemiology ................................................................... 664 Etiology and Pathogenesis ............................................... 664 Pathology ......................................................................... 664 Diagnosis.......................................................................... 665 Differential Diagnosis ...................................................... 665 Prognosis and Treatment .................................................. 665
Congentital Anomalies The hepatic artery exhibits considerable anatomical variations which usually are not clinically relevant, and therefore are not discussed here. Anomalies of the hepatic artery, however, may attain clinical significance in certain situations such as during operative procedures (inadvertent ligation) or in interpreting angiographic findings (see Chapter 58).
Hepatic Artery Occlusion Ischemic Cholangiopathy .............................................. 665 Aneurysms ...................................................................... 665 Etiology ............................................................................ 666 Diagnosis.......................................................................... 666 Prognosis and Therapy ..................................................... 666 Arterioportal Fistula...................................................... 666 Arteritis ........................................................................... 667 Amyloidosis..................................................................... 668 Vascular Tumors ............................................................ 668 References ....................................................................... 668
Occlusion of the hepatic artery or of one of its branches may be caused by thrombi, emboli, trauma or by inadvertent ligation. Due to the dual blood supply of the liver, arterial occlusion does not necessarily lead to a hepatic infarct. The consequences of impaired arterial inflow depend primarily on the size of the occluded vessel and the effectiveness of the collateral circulation. Ligation of the proper hepatic artery leads to total liver necrosis if arterial blood flow is not sustained by anastomoses from the gastroduodenal or the right gastric artery. Occlusion of smaller arteries results in focal parenchymal necrosis (“hepatocyte dropout”). Infusion of the antineoplastic agent floxuridine into the hepatic artery may cause an arterial thrombosis or an obliterative arterio- and venopathy of the vessels in the portal tracts. Arterial chemoembolization attempts to derive a therapeutic benefit from iatrogenic occlusion of tumor-feeding vessels. Thrombosis of the hepatic artery or of its branches induced by local infusion of antineoplastic agents may also cause bile duct ischemia with consequent bile duct strictures (see Chapter 52).
H. Dancygier, Clinical Hepatology, DOI: 10.1007/978-3-642-04519-6_62, © Springer-Verlag Berlin Heidelberg 2010
663
664
Hyaline fibrin thrombi in small arterial vessels, characteristic of thrombotic thrombocytopenic purpura, may also be found in the liver.
Hypoxic Hepatitis See also Chapters 15 and 49. The term “ischemic hepatitis” was coined in 1979 to refer to a liver injury characterized histologically by centrilobular parenchymal necrosis. Clinically, it is vaguely reminiscent of infectious hepatitis with a sharp increase in serum aminotransferase levels and the presence of anorexia, malaise, jaundice, and tender hepatomegaly [3]. Although the disorder is not due solely to ischemia and is not a hepatitis, the term continues to be used interchangeably with “hypoxic hepatitis” and “shock liver”. In view of the etiology, pathogenesis, pathology and clinical features of the disorder, the general term “hypoxic liver injury” would appear to be more appropriate. Nonetheless, in this chapter, all four terms (ischemic hepatitis, hypoxic hepatitis, shock liver, hypoxic liver injury) will be used synonymously.
Definition Hypoxic hepatitis is defined as an acute liver injury due to an imbalance between hepatic oxygen supply and demand in the absence of other acute causes of liver damage. It is characterized by centrilobular parenchymal necrosis and a massive, but transient, increase in serum aminotransferase levels.
62
Hepatic Arteries
Etiology and Pathogenesis Hypoxic liver injury has been associated with congestive heart failure, chronic respiratory failure, sepsis, profound anemia, carbon monoxide poisoning, heat stroke, cocaine use, ergotamine poisoning, bacterial endocarditis, anaphylactic reaction, extensive burns and hypotensive states [4, 6]. Patients with chronic respiratory failure and chronic liver congestion are particularly prone to development of hepatic ischemia when a superimposed insult, such as decreased perfusion, hypoxia, or contact with endotoxin, occurs. Although hepatocellular ischemia is the common pathogenetic denominator in all the respective conditions, in clinical practice hypoxic hepatitis cannot be ascribed to only one pathogenetic factor, but generally several factors act in concert. In patients with left-sided heart failure and venous congestion secondary to right-sided heart failure hypoxia of the liver results from decreased arterial hepatic blood flow (ischemia). Chronic respiratory failure aggravates liver hypoxia mainly due to marked hypoxemia. The main contributing cause of hypoxic liver injury in patients with sepsis and septic shock is the increased metabolic (oxygen) demand of hepatocytes along with their inability to extract adequate oxygen from the blood [5, 6, 10]. Endotoxemia from bacterial translocation through the gut will promote hypoxic liver injury, as will a hypermetabolic state from alcohol abuse. Acute sickle cell crisis in sickle cell anemia may lead to ischemic hepatic changes due to clogging of the sinusoids with damaged erythrocytes. However, marked sickling may be present in the absence of hepatic parenchymal necrosis [1].
Pathology Epidemiology The incidence of hypoxic liver injury is 0.16% for inpatient admissions, 0.9% for intensive care unit admissions, 2.6% for cardiac care unit (CCU) admissions, and 22% for patients admitted to the CCU with decreased cardiac output [4]. If the cut-off value for serum aminotransferase concentrations defining hypoxic hepatitis is lowered the incidence figures are accordingly higher.
Hypoxic liver injury predominantly affects centrilobular hepatocytes. Shock liver is the most severe form of ischemic liver cell damage. It is a complex disturbance of hepatic blood circulation occurring in circulatory shock, and is characterized initially by compromised arterial blood flow followed by secondary changes in lobular perfusion and venous outflow. The histopathological features of shock liver are hypoxic centrilobular changes such as loss of glycogen, hypoxic vacuoles, ballooning, and in its most severe form extensive zone
Aneurysms
3 hemorrhagic necrosis of liver parenchyma (see Chapter 15). Provided the circulatory compromise has not disrupted the lobular reticulin fiber framework, and periportal cells remain viable, liver regeneration occurs, starting from periportally localized progenitor cells capable of proliferation and differentiation into hepatocytes. Thus, centrilobular ischemic necrosis often does not leave scars behind.
Diagnosis
665
Imaging Techniques Results of hepatic imaging are nonspecific. Hypoechoic and hypodense irregularities are seen on ultrasound and on CT-scanning respectively. Imaging techniques are applied to exclude other causes of liver damage rather than to diagnose hypoxic liver injury itself. On liver biopsy various degrees of centrilobular cell damage are seen and can be as severe as extensive centrilobular necrosis. In patients with low serum aminotransferase levels hypoxic liver injury cannot be diagnosed reliably without a biopsy.
Clinical Manifestations
Differential Diagnosis Generally patients with hypoxic liver disease have multiple severe clinical problems, and symptoms are therefore usually related to the underlying disease and to circulatory failure rather than to ischemic liver injury. Patients may complain of right upper quadrant pain (due to the enlarged, congested liver), weakness and shortness of breath. Hypoxic hepatitis is generally precipitated by an acute event, most commonly arrhythmia, pulmonary edema, and less commonly myocardial infarction. A circulatory shock state, if present, is usually septic or cardiogenic in origin. However, many patients with hypoxic hepatitis have no documented decrease in blood pressure and clinically a shock state is observed in only about 50% of cases [6].
Laboratory Examinations Characteristic of hypoxic hepatitis is a massive, sharp but rapidly reversible increase in serum aminotransferase levels. Twelve to 48 h after the initiating event ALT and AST concentrations in serum rise to values up to 20–50–100 times the upper limit of normal (cut off value not exactly defined). Typically aminotransferase levels decrease by 50% within 2–3 days if the causative disturbance is eliminated (see Fig. 49.1). Elevations of aminotransferase concentrations are accompanied by a rise in LDH (often >5,000 U/L) and GLDH. The latter enzyme is a good indicator of centrilobular injury since it is localized preferentially in mitochondria of zone 3 hepatocytes. Bilirubin values may be slightly elevated but jaundice is not a clinical problem.
The diagnosis of hypoxic hepatitis requires the described laboratory changes and liver alterations in the appropriate clinical setting. Toxin- or drug-induced hepatitis, viral hepatitis, liver trauma, and pancreatobiliary disease must be excluded. Typically, and in contrast to acute viral or drug-induced hepatitis, in hypoxic hepatitis the markedly elevated liver enzymes return to normal within a few days. Hepatitis due to toxins can cause a marked increase in transaminase levels that reverses rapidly after withdrawal of the inciting agent.
Prognosis and Treatment The liver in hypoxic hepatitis is usually an innocent bystander that becomes involved in others problems. Treatment should be directed primarily at the underlying disease. Prognosis depends mainly on the underlying illness [7].
Ischemic Cholangiopathy See Chapter 52.
Aneurysms Hepatic artery aneurysms are usually sac- or spindleshaped, rarely dissecting. Men are affected four times as often as females. 80% of aneurysms are solitary; in
666
20% of cases multiple aneurysms are found. 60% of solitary aneurysms affect the common hepatic artery, 30% the right hepatic artery, and in the remainder cases small arterial vessels at the liver hilum are affected. 75% of hepatic artery aneurysms are extrahepatic. Most aneurysms have a size of 2–10 cm at the time of diagnosis [2].
Etiology Hepatic artery aneurysms may be due to infections (mycotic aneurysms, syphilis, tuberculosis; 90%) neutralizing anti-HBsantibodies are produced which indicate spontaneous resolution of HBV-infection. Clearance of the virus, together with the production of anti-HBs antibodies, is associated with protective immunity for a future HBV infection. Some of the capsid antigens can induce an effective HLA-class II restricted T-cell immune response, which is often associated with HBsantigen seroconversion. However, a T-cell response directed against the HBs-antigen is detectable at very low levels.
Molecular Biology of Hepatitis Viruses
For viral clearance the HLA-class I restricted CD8+-T-cell response directed against HBe/HBcantigens seems to play a major role. Thus, a spontaneous clearance of acute HBV infection is closely related to an early and strong cytotoxic T-cell response. In addition, an activation is observed. The epitopes which are recognized by the cytotoxic T-cells are located in highly conserved regions of the HBV-genome. Therefore, it is unlikely that mutations in these regions which lead to a lack of CD8+-T-cell response are a plausible explanation for the development of chronic HBV infection. Instead of a broad antibody response against the different envelope proteins as observed in HBV infection, vaccination with recombinant vaccines induce an immune response only directed against one epitope within the small envelope proteins.
Immune Response in Chronic Hepatitis B HBV infection is defined as “chronic” if the HBsAg is detectable for more than 6 months. The importance of T-cell response in virus clearance is underlined by the observation that the development of persistent infection is often associated with a defective cellular immune response. Transmission of HBeAg from a pregnant HBV carrier to the fetus in the majority of the cases is followed by the development of chronic HBV infection because HBeAg is recognized as an autoantigen in the thymus of the fetus. In adult patients manifestation of chronic infection is often combined with a lack of CD8+T-cell response. For HBV infection itself no cytopathic effects are detectable, and the histological changes and the grade of inflammation correlate with the extent of the T-cell response. Before HBe/antiHBe seroconversion a characteristic increase in the inflammatory activity can be observed, which is combined with an increase of the liver enzymes caused by an enhanced T-cell response.
Molecular Biology of Hepatitis D Virus Hepatitis-delta virus (HDV) was first described in 1977 in patients with a complicated course of HBV infection. In these patients a new protein was discovered, which was thought to be a new HBV-encoded protein and
683
labeled as the delta antigen. Subsequent research indicated that this antigen was derived from a new virus, named HDV, however, the envelope of HDV is composed of HBV surface antigens. It is known that the HBV surface antigens are part of the HDV envelope and that they are necessary for productive infection. Thus, HDV may be considered to be a satellite virus of HBV. The HDV virion has a spherical structure of approximately 36 nm in diameter and merely differs in the composition of HBV L-, M- or S-proteins. HDV uses the HBV envelope to enter the host cell but the exact receptors are still unknown. The HBV envelope harbors the nucleocapsid consisting of approximately 70 molecules of hepatitis D antigens (HDAg) and the viral RNA genome. The nucleocapsid exists in two different forms, as 24 or 27 kDa capsids. The HDV genome consists of a circular single-stranded RNA molecule of approximately 1.7 kb that displays a high degree of internal base-pairing (approx. 70% of the genome) and a high similarity to plant viroid RNAs (Fig. 63.9). The genome encodes only the HDAg, which is a nuclear, RNA-binding phosphoprotein and which is required for virus replication. Because HDV has no sequence homology with its helper virus and because it also infects animals, being the only animal virus with a circular RNA genome, it constitutes a unique entity and is assigned to a separate genus, called Deltaviridae. The evolution rate of HDV ranges from approximately 2 × 10−2 to 7 × 10−3 point mutations per nucleotide per year. Multiple ORFs of different length are present on the genomic and on the antigenomic strand of HDV-RNA, but most of their potential gene products have not been detected. The only ORF (ORF5) located on the antigenome, that is preserved among all known isolates, encodes the HDAg [48, 85]. The HDVRNA can be divided into two domains. One domain represented on both, the genomic and antigenomic RNA, is related to other viroids and displays ribozyme activity. This domain autocatalytically cleaves and ligates itself. Additionally, it shows UV-induced crosslinking of two uracil-nucleotides (U712 and U865) which is a common feature observed in other viroids. The other domain, which is the major part, is located on the antigenome and includes the HDAg encoding ORF (Fig. 63.9). Recently, a novel system for studying HDV genome replication in cultured cell lines in the absence of HBV was described by stable transfection of a cell line (293-dAg) with a complementary DNA of the HDV sequence [14].
684
63
Viral Infections by Hepatotropic Viruses
HDV-genome 795
1638
viroid-like region
1/1638 ribozyme domaine 725
680 688/689
autocatalytic cleavage 903/904 HDV-antigenome
867 912 ribozyme domaine
795
viroid-like region
27 kDa delta-antigen 24 kDa delta-antigen
1638 1/1638
Fig. 63.9 Schematic graphs of the HDV-RNA structure. The circular HDVgenome (clockwise orientation) and the antigenome (counterclockwise orientation) are shown. The localiza-
tion of the large and the small HDV-antigens on the antigenome are indicated. Numbers represent nucleotide positions
Genotypes
the C-terminus of the L-HDAg 19 additional amino acids may be found because some of the mRNAs are altered at the amber termination codon (from TGA to TGG) and therefore the ORF extends for the additional amino acids. Interestingly, these mutations can be induced by interferon-therapy. Both proteins contain several structural domains: One domain has a coiled-coiled structure with classical features of a leucin–zipper sequence, which is important for the dimerization of both proteins to form a nucleocapsid of approximately 70 delta-proteins and a diameter of 19 nm. A second important domain encompasses the nuclear localization sequence which is responsible for the transport of HDAg into the nucleus. The third domain is the RNA-binding domain which confers the ability to HDAg to bind to RNA molecules. The C-terminal extension of the L-HDAg encompasses an isoprenylation signal. Isoprenylation of the C-terminus enables the L-HDAg to interact with the HBV envelope proteins and it might confer the ability to interact with the membrane. In addition, the L-HDAg has been shown to be more phosphorylated than the S-HDAg, but the phosphorylation sites are not yet determined. The L-HDAg is only detectable in later stages of the infection cycle. It
Based on sequence homologies, the different HDV isolates can be classified into three different genotypes. Genotype 1 is found in all parts of the world and the sequence homology within this genotype is more than 80%. Genotype 2 is predominantly present in Japan and shares sequence homology of less than 80% with genotype 1. Genotype 3 is mainly present in Peru and Columbia. The sequence similarity is about 60–65% compared to the other genotypes. Infection with HDV genotype 1 might lead more often to the development of liver cirrhosis and hepatocellular carcinoma but the responsibility of sequence heterogeneity for the clinical outcome is still unclear.
Hepatitis Delta Antigen HDAg is a RNA-binding phosphoprotein and the major component of the nucleocapsid. It is known to exist as 27 kDa protein referred to as large (L)-HDAg, and as 24 kDa protein, termed small (S)-HDAg. Both proteins have the same amino acid composition although they are translated from two different mRNA-species. At
Molecular Biology of Hepatitis Viruses
685
was shown to function as a dominant-negative inhibitor of HDV replication.
RNA. The relative ratio of genomic and antigenomic RNA is approximately 15:1 and each infected cell contains approx. 300,000 copies of HDV-RNA [17]. The replication cycle is shown in Fig. 63.10.
Replication After infection of the host cell via still unknown receptors and entry mechanisms, the HDV-RNA is translocated to the nucleus where RNA replication takes place. The RNA is replicated by use of cellular transcription machineries, and cellular RNA-dependent RNA-polymerase II (RNA-Pol II) has been implicated as the key enzyme for HDV-RNA replication. HDVRNA replicates, as known for plant viroids, by a “double-rolling-circle” mechanism. In this model, the circular negative sense RNA is used as template for the synthesis of antigenomic RNA which is copied multiple times. This RNA intermediate, consisting of several HDV genomes, is self cleaved by HDV ribozyme activity into monomeric RNA-strands which are ligated to yield antigenomic, circular RNA. In a second round of rolling circle the antigenomic RNA serves as a template for the synthesis of genomic HDV-
Fig. 63.10 (a–f) Replication of HDV – the double rollingcircle model of HDV-RNA replication. The circular negative sense RNA genome is used as template for the synthesis of a linear antigenomic RNA (a) which contains multiple copies of the genome. This RNA intermediate is self cleaved by HDV ribozyme activity into monomeric RNAstrands (b) which are ligated to yield antigenomic, circular RNA (c). In a second round of rolling circle the antigenomic RNA serves as template for the synthesis of a linear genomic RNA (d). This genome intermediate is self cleaved into monomeric RNAstrands (e) which are ligated to yield circular genomic RNA (f)
Immunology Basically, the immune response in HDV infection is similar to that of HBV infection (see above). Various IgG- and IgM-antibodies can be detected during chronic HDV infection. A decreasing amount of IgMantibodies in the acute stage of infection is associated with decreasing inflammatory activities and is often an indication of virus clearance, while persistent IgM-antibody levels are characteristics of a chronic infection. However, the main criterion for acute HDVinfection is the detection of HDV-RNA in serum samples. Caused by a not well-known interaction of the HBV replication and gene-expression, the HBV/HDV co-infection typically leads to the suppression of HBV replication with often low or even undetectable levels of HBV-RNA. Consequently, the HBV specific
circular genomic monomeric (Ð)-strand-RNA (genome) a + b + c
linear complementary multimeric (+)-strand-RNA linear complementary monomeric (+)-strand-RNA
+ circular complementary monomeric (+)-strand-RNA (antigenome)
d Ð e Ð
linear genomic multimeric (Ð)- strand-RNA linear genomic monomeric (Ð)- strand-RNA
f Ð circular genomic monomeric (Ð)-strand-RNA (genome)
686
mRNA is suppressed and fewer HBV proteins are synthesized. The severe damage to hepatocytes which is often associated with HDV infection may refer to the direct cytopathic effect observed for HDAg. In chronic HBV carriers a specific T-cell response to HDAg in the peripheral blood of individuals with hepatitis delta is related to the decrease of HDVinduced disease activity [56]. HBV and HDV HDV infection occurs either as simultaneous co-infection or as superinfection in HBV carriers but, despite its helper function, HDV replicates independently from HBV. Some clinical studies have shown that HDV coinfection influences HBV progression. For chimpanzees it is shown that HDV infection leads to undetectable HBV capsid proteins in liver tissue and decreasing HBV surface protein levels. In some patients HBeAg and even HBsAg may become undetectable after HDV superinfection. In addition, there is some evidence that a co-infection with HDV may suppress molecular markers of HBV infection. In clinical studies it has been shown that the majority of patients with chronic hepatitis B/D have detectable amounts of HBVantibodies but have undetectable or low HBV-RNA concentrations. Even in liver tissue no significant amounts of HBV-DNA were detectable. These findings need to be confirmed by the use of currently available, more sensitive assays for HBV-DNA detection.
Molecular Biology of Hepatitis C Virus Since the 1970s there was neither epidemiological nor clinical doubt that additional hepatotropic viruses beside hepatitis A and B existed (“Non-A-Non-B hepatitis”). Numerous attempts to isolate the Non-ANon-B hepatitis pathogen with classical methods of microbiology were not successful. Experimental data indicated the existence of an RNA virus responsible for an often chronically progressing post transfusion hepatitis. Epidemiologically and clinically this NonA-Non-B hepatitis entity was differentiated from an enterically transmissible, non chronic Non-A-Non-B acute hepatitis, whose pathogen was already identified in 1980 and termed hepatitis E virus (HEV).
63 Viral Infections by Hepatotropic Viruses
In 1988 isolation of the genome of the parenterally transmissible hepatitis C virus succeeded due to the use of extensive biomolecular techniques. Initially, large amounts of plasma from a chimpanzee artificially infected with the Non-A-Non-B hepatitis pathogen were used for complete RNA extraction. After reverse transcription of the entire RNA, a gene library from cDNA sequences in lambda bacteriophages was established and subsequently suitable proteins were expressed in E. coli. Through the screening of more than 1 million of these in vitro expressed proteins with sera from patients with clinical and histological proven chronic Non-A-Non-B hepatitis, one clone (5–1–1) was finally found, which apparently expressed viral nucleic acids. This clone was then used as a probe to identify the complete HCV genome. HCV is classified in the family Flaviviridae. Recently a new genus, Hepaciviridae, was established for HCV. Unlike other viruses of the Flaviviridae (Dengue virus, yellow fever virus, Tick-borne encephalitis virus), HCV is not transmitted through arthropods and a chronic infection is established in the majority of cases.
Genome Organisation Hepatitis C virus (HCV) is an enveloped, approximately 9.6 kb, positive-sense, single-stranded RNA virus. After translation from a single large open reading frame (ORF), the polyprotein precursor is cleaved by viral and host peptidases (signal peptidases of the endoplasmic reticulum), resulting in three structural proteins, termed core (p21), envelope 1 (E1, gp31), and envelope 2 (E2, gp70), a protein named p7, which probably forms an ion channel, and six non-structural (NS) proteins, termed NS2 (NS2–3 cysteine protease, p23), NS3 (serine protease/helicase, p70), NS4A (NS3 protease cofactor, p8), NS4B (transmembrane anchor protein, p27), NS5A (replication factor, p58), and NS5B (RNA-dependent RNA-polymerase, p68) (Fig. 63.11). The F protein has been described as being a result of a ribosomal frameshift of the coreencoding genomic region [87]. There is a noncoding region of 324 to 341 nucleotides at the 5’-non coding end (5’NC) containing the internal ribosome entry site (IRES) and a 3’-noncoding (3’NC) region of variable length. The 3’NC region is composed of three sequence elements, a nonconserved highly variable
Molecular Biology of Hepatitis Viruses
687
Fig. 63.11 (a, b) HCV genome organisation. (a) HCV genome composition with structural and nonstructural genes. There are non-coding regions at the 5’end and at the 3’end as well. The translated structural and non-structural proteins are displayed. (b) Localization of the epitopes used for antibody detection in commercially assays. In enzyme immunoassays of the 1st generation antibodies against C100 were detected. In tests of the 2nd and 3rd generation antibodies against C22 and C33 and C22, C33 and NS5 were additionally detected, respectively. (C core, E envelope, NS non-structural proteins)
region (30 – 50 nucleotides), a poly(U • C) tract of variable length (20 – 200 nucleotides), and a highly conserved 98 nucleotide sequence, designated the 3’ X region. The latter forms a three stem-loop structure (SL1 – SL3). An RNA 5’ - 3’ end interaction for initiation of RNA minus-strand synthesis and translation stimulation is supposed for the HCV-RNA, even though it lacks a cap structure at the 5’ end and a poly(A) tail at the 3’ end, which are typical for many viral RNAs. This interaction can also play a role in switching from RNA translation to negative-strand RNA synthesis. However, the IRES-dependent translation in human hepatoma cell lines is strongly stimulated by the 3’NC region.
HCV-Quasispecies A hepatitis C infection in vivo is characterized by a heterogeneous population of closely related isolates, the so called quasispecies. The spectrum of quasispecies can change during the normal course of the disease or during treatment. The variability of the virus is due to a high replication rate and a lack of proofreading activity of the RNA-dependent RNA-polymerase. Selection of the isolates in vivo occurs as a result of the replication competence of the viruses and through immune selection of the host.
Methodologically, the population of quasispecies from an infected person is best displayed with the hypervariable region 1 (amino acid position 1 – 27 of E2) of the hepatitis C virus genome. Spontaneous resolution of hepatitis C has been associated with a low quasispecies complexity, whereas a chronic course correlates with early genetic evolution of high quasispecies heterogeneity during the acute phase of infection. Different studies have shown higher virologic response rates to interferon-based HCV treatment in patients with a small quasispecies heterogeneity compared to patients with a high quasispecies diversity and complexity. During antiviral therapy, certain isolates appear to be interferon-sensitive while others are resistant. Conventional cloning and sequencing of the isolates of HCV-quasispecies is the gold standard but time consuming and costly. An alternative method to analyze HCV-quasispecies is the electrophoretic separation of PCR products from the hypervariable region 1. This so called single-stranded conformation polymorphism (SSCP) analysis enables differentiation of DNA fragments with equal length due to sequence specific conformations. In addition to the investigation of the importance of the HCV-quasispecies of hypervariable region 1 in correlation to interferon-based treatment response, most recently clonal analysis of the HCV-quasispecies was used to characterize potential resistance mutations in
688
patients undergoing direct antiviral therapies with HCV protease and polymerase inhibitors. Detection of these resistance mutations may be introduced in the routine diagnostic workup after these new treatment options are approved for standard treatment of hepatitis C.
Interferon-sensitivity Determining Region in the NS5A Gene Infection with hepatitis C virus genotype 1 is associated with inferior virologic response rates to an IFN-a-based treatment in comparison with HCV genotypes 2 and 3. Sequence comparisons from Japanese interferon-sensitive and -resistant HCV 1b isolates showed that amino acid sequences between codon 2209 and 2248 of the ORF within the non-structural (NS)-5A protein are associated with treatment response. HCV-1b-isolates with four or more mutations in this interferon-sensitivity determining region (ISDR) named area, compared to the HCV 1b prototype sequence, were sensitive to interferon while the HCV 1b prototype isolates were resistant to interferon. Isolates with one to three amino acid changes showed a variable response to IFN-a. In addition, an inverse correlation between an increasing number of mutations within the ISDR and the HCV-RNA concentration at baseline was observed. Subsequently, the correlation of ISDR mutations with treatment response was investigated from different groups in Japan, Europe and the United States. Studies from Japan generally were able to confirm the strong correlation between ISDR mutations and treatment response. Groups from Europe, and the U.S. initially were not able to verify the importance of ISDR mutations for IFN alfa sensitivity and it turned out in subsequent studies that HCV 1b isolates with multiple mutations within the ISDR are rare in Europe and the U.S. as compared with those found in Japan. In further studies with larger patient cohorts, as well as in a meta-analysis, the positive correlation of an increasing number of ISDR mutations with sustained virologic response to IFN alfa-based therapy could be confirmed. However, the functional background for this correlation still is unknown.
63 Viral Infections by Hepatotropic Viruses
obtain the highly basic core (C) protein and glycoproteins E1 and E2. The C protein is an approx. 21 kDa RNA-binding phosphoprotein needed for encapsidation, which is localized near the endoplasmic reticulum. The core protein is essential for expression of E1 and E2. Recently, the new HCV F protein has been described. Its expression results of a ribosomal frameshift within the capsid-encoding sequence. The function of the F protein is not yet known. The envelope proteins E1 and E2 are 30 – 35 and 70 kDa glycoproteins forming a stable heterodimer. A 27 amino acid hyper variable region (HVR1) is located at the amino-terminus of E2 and the HVR1 is assumed to be important for establishment of chronic HCV infection. Despite the high level of amino acid variability in HVR1, there is an overall conservation of basic residues that are important for viral entry [11]. Epitopes for specific binding of neutralizing antibodies were found within the HVR1. Due to the lack of proofreading activity of the HCV RNA-dependent RNA-polymerase and a continuous immunologic pressure, isolates with changing amino acid sequences within the HVR1 develop during HCV infection. Antibodies directed against the HVR1 from previous HCV isolates cannot bind to subsequently produced modified HVR1 sequences, resulting in a selection process which is termed immune-escape. The hypothesis of immune selection is supported by the finding of a lower HVR1 variability in immune suppressed patients with HCV infection than in immune competent patients. Chimpanzees with cured HCV infection could be re-infected with the same HCV isolate. However, in chimpanzees infected with a single consensus HCV clone, no mutations within the HVR1 were detected within a 1 year follow-up period. Thus, further mechanisms of persistence of HCV infection have to be assumed. For both E1 and E2, hydrophobic anchor domains are located at the carboxy-terminal end of the proteins. These domains are important for integration in the membrane of the endoplasmic reticulum. The 7 kDa protein p7 is supposed to form an ion channel and is probably involved in several steps of virus production [6].
Non-structural HCV Proteins Structural HCV Proteins The amino-terminal one third of the polyprotein encodes the HCV structural proteins. They are proteolytically cleaved through host signal peptidases to
The NS2/3 junction is cleaved by the NS2 autoprotease while all other non-structural proteins are processed by the NS3/4A serine protease. The carboxy-terminal two thirds of the hydrophobic 23 kDa NS2 protein contains
Molecular Biology of Hepatitis Viruses
the catalytic triad of a cysteine protease. These residues are necessary for NS2/3 cleavage as well as for the downstream expression of the NS3 serine protease domain, although NS3–4A protease activity is dispensable for NS2/3 processing [44]. NS3 is a 70 kDa multifunctional protein, with an N-terminal serine protease domain and a C-terminal RNA helicase/NTPase domain. The NS3 serine protease is involved in the autocatalytic NS3/4A cleavage. For cleaving of NS4A/B, NS4B/5A, and NS5A/B the NS3 protein has to form a complex with the NS4A protein. NS4A is a small protein of 54 amino acids and represents an important cofactor for the NS3/4A protease. In addition, it is involved in phosphorylation of the NS5A protein. The integral membrane protein NS4B is involved in the membranous web formation and has been proposed to serve as a scaffold for replication complex assembly. Several adaptive mutations for replication efficiency in the replicon model have been mapped to this protein, and NS4B has been found to encode a GTPase activity that may be related to its membranealtering ability. NS5A is a mainly hydrophilic phosphoprotein. It can be detected in a phosphorylated (56 kDa) and a hyperphosphorylated (58 kDa) form. NS5A possesses an N-terminal amphipathic a-helix that mediates membrane association. In addition, it is supposed to be involved in protein–protein interactions required for composition of a functional replication complex. This helix is followed by three domains (I–III). Domain I (N-terminal) coordinates a single zinc atom per protein molecule. Its crystal structure has recently been resolved, and reveals a novel protein fold, a zinc coordination motif, and a dimerization interface. In addition, the ISDR within the NS5A protein was clinically shown to be involved in sensitivity to interferon-based antiviral therapy (see above). The cytoplasmic perinuclear located NS5B protein (68 kDa) exhibits highly conserved motifs which are typical for its function as RNA-dependent RNA-polymerase. A non-HCVspecific RNA polymerase activity was shown in vitro. Genotypes and Subtypes Up to now a minimum of eight HCV isolates were sequenced completely and several other isolates were sequenced partially. Due to sequence comparisons worldwide, six HCV genotypes (type 1–6) with nucleotide sequence differences of more than 30% were distinguished. Inside these groups several subtypes can be
689
defined (subtype a, b, c, etc.). The homology of subtypes is between 80–90%. Between isolates of the HCV quasispecies in a given patient, amino acid sequence differences of a maximum of approximately 10% are detectable. In Europe the prevalent genotypes are HCV-1b, HCV-1a, HCV-2b, and HCV-3a. HCV-1a is the main genotype in the U.S. followed by HCV-1b, HCV-2a, and HCV 3a. An obvious difference in the distribution of HCV genotypes exists between Japan and Western countries. In Japan the prevalence of HCV-1a is less than 1 – 2% and HCV-3 genotypes are rare as well, with HCV-1b and HCV-2 dominating. Genotypes HCV-5 and HCV-6 are detected mainly in South Africa and Hong Kong, while HCV-4 appears in Egypt and the Middle East. Co-infections with several HCV genotypes and superinfections with heterologous HCV genotypes are described especially in polytransfused, hemophilic patients, and IV drug abusers. While there is no evidence of a different natural course of HCV infection in patients infected with different subtypes or genotypes, diagnosis of hepatitis C virus genotypes is important for predicting response to antiviral therapy. Replication Cycle During replication of the hepatitis C virus the genomic (+)-strand RNA is first transcribed to a (−)-strand RNA. Based on this (−)-strand RNA several (+)-strand RNAs can be retranscribed (Fig. 63.12). The replication takes place in a membrane-associated complex derived from the endoplasmic reticulum (ER) and has been designated “membranous web”. All HCV proteins are associated with this web-structure directly or indirectly. While the major location of replication are the hepatocytes in the liver, additional extrahepatic replication in B- and T-lymphocytes was suspected. HCV entry in host cells is a clathrin-dependent process which requires a low pH compartment. The HCV envelope protein E2 binds the tetraspanin CD81 which is expressed in hepatocytes and B lymphocytes amongst others and CD81 was shown to be an essential receptor for HCV entry. However, CD81 is present on multiple cell types which can not be infected with HCV and so further receptors must be involved in HCV entry. One of them is the low density lipoprotein (LDL) receptor. The receptor binds to virus associated LDL particles and mediates internalization. This is a common process in the Flaviviridae family. A
690 Fig. 63.12 Viral entry and replication cycle of HCV
63 Viral Infections by Hepatotropic Viruses
Hepatitis C virus
CLDN1 CLDN6 CLDN9
a
SR-B1
HCV proteins
CD81 ss (+) strand RNA virus
LDL/HDL LDLr
binding of the hepatitis C virus envelope glycoprotein E2, independent from the virus isolate, is mediated by the human scavenger receptor class B type I (SR-BI). SR-BI enhances HCV entry in a high density lipoprotein (HDL) dependent manner [74]. Another HCV coreceptor, which functions in a later step of entry, is the integral membrane protein Claudin-1 (CLDN1) [21]. Two further members of the Claudin family, namely CLDN6 and CLDN9, function as additional co-receptors for HCV [90]. They are expressed in liver and peripheral blood mononuclear cells (PBMCs) unlike CLDN1, which is expressed only in liver (Fig. 63.12). Recently, occludin was described as the last essential receptor for HCV entry. The transcription accuracy of the HCV polymerase is low and leads to a high variability of newly generated HCV isolates (HCV quasispecies). The mutation rate is approx. 2 × 10−3 mutations/nucleotide position/year similar to other RNA viruses. Despite the high genetic variability, functions of HCV proteins remain stable. For proper function of the internal ribosome entry site of the 5’NC region a high sequence identity is mandatory, which most likely is ensured through negative selection of dysfunctional isolates during replication.
Diagnostics of Hepatitis Viruses Hepatitis A Clinical routine diagnostics of HAV infection are based on detection of anti-HAV-antibodies in serum samples. Serological markers during the natural course of HAV
infection are shown in Fig. 63.13. In addition, highly sensitive detection of HAV-RNA by nucleic acid amplification methods (standard RT-PCR, real-time RT-PCR, hybridization techniques) can be performed. Analysis of faecal samples is possible by using electron microscopy, and antigen assays. However, while HAV antigens are easily detectable during the incubation phase of HAV-infection, detection rates are less than 50% after clinical symptoms become apparent and HAV virions are excreted in faeces. Diagnosis of HAV infection is reviewed in detail by Nainan et al. [55].
Anti-HAV-Antibodies and Nucleic Acid Amplification Detection of anti-HAV-IgM antibodies is used as the primary marker of an acute infection. Resolved HAVinfection is characterized by anti-HAV IgG antibodies in the absence of IgM antibodies. In addition, after successful vaccination anti-HAV IgG antibodies are detectable which are directed against structural HAV proteins expressed during vaccination. Antibody levels after vaccination are typical significantly lower than after resolved HAV infection. Assays for total antiHAV antibodies have a sensitivity of 10 – 20 IU/L. Several commercial test systems from various companies (Abbott, Roche Diagnostics, Organon, Technica, Sorin) are available. A number of methods are used to detect the virus-specific antibody classes (IgG, IgM), including radioimmunoassay, immunochemical staining, enzyme-linked immunosorbent assay, immunoblotting, and dot blot immunogold filtration.
Diagnostics of Hepatitis Viruses
691
Fig. 63.13 Serological and clinical progression of an infection with HAV HAV-RNA
Anti-HAV-IG Anti-HAV-IgM Timepoint of infection
Nucleic acid detection assays are more sensitive than immunoassays for viral antigens or antibody detection systems. The virus can be detected by Southern blotting, nucleic acid hybridization, reverse transcription-PCR (RT-PCR) and antigen-capture RT-PCR. More recently, a real-time RT-PCR assay (TaqMan assay) has been developed for the rapid detection of all human HAV genotypes using highly conserved sequences within the 5’UTR [35]. This assay detects HAV in environmental, food, and clinical samples with a sensitivity of 0.5 infectious units per milliliter (IU/mL) of HAV and 40 copies of a synthetic transcript.
Conclusion for HAV Diagnosis For routine purposes HAV infection is diagnosed by anti-HAV-antibodies (IgM and IgG) in serum samples. Presence of anti-HAV IgM antibodies indicate acute HAV infection. Anti-HAV IgM antibodies are detectable with the beginning of clinical symptoms of acute hepatitis A. Antibody concentrations increase during the first month of clinically overt hepatitis A and may be detectable for a maximum of 1 year. In rare cases persistent detection of (low level) anti-HAV IgM antibodies have been reported. Anti-HAV-IgGantibody levels increase together with IgMconcentration and in the majority of cases remain detectable the whole life. In patients with resolved HAV infection, and after active or passive immunization, only anti-HAV IgG antibodies are detectable. Before HAV vaccination is performed, blood screening for total HAV antibodies is recommended.
Aminotransferases
Assays for detection of HAV antigens and HAVRNA (radioimmunoassay, immunochemical staining, enzyme-linked immunosorbent assay, electron microscopy, hybridization methods, RT-PCR) are not used for routine diagnosis but are important for epidemiological investigations of routes of infections during epidemics and for detection of HAV in water and blood products
Hepatitis E Diagnosis of HEV is possible by detection of HEVantibodies (IgA, IgM, and IgG) and viral RNA in serum and fecal samples. In addition, electron microscopy is a possible tool to detect HEV. Currently only the antibody-detection systems are relevant for routine clinical purposes. In Fig. 63.14 the serological and molecular patterns of HEV infection are illustrated.
Anti-HEV Antibodies and Nucleic Acid Amplification For routine diagnosis, HEV antibody detection systems like enzyme immunoassays, western blots or indirect immunoassays are used. Recombinant or synthesized HEV antigens with immune-dominant epitopes derived from the structural proteins of two isolates from Burma and Mexico are typically used in these assays. In patients with acute HEV infection these assays have a sensitivity of 90 – 95%. Anti-HEV IgM antibodies become positive during the early stage of clinical overt acute hepatitis E and after 1 year of infection are still detectable in approximately
692
63 Viral Infections by Hepatotropic Viruses
Fig. 63.14 Progression of HEV infection
HEV-RNA in stool samples HEV-antigen in liver tissue HEV-RNA in serum samples Aminotransferases
anti-HAV-IgG anti-HAV-IgM
40% of patients. IgG antibodies become detectable some days after the IgM antibodies during acute hepatitis E, and IgG antibodies remain detectable for many years (47% after 14 years). The presence of HEV-IgG antibodies either indicates acute or resolved HEV infection. For epidemiological purposes the use of highly sensitive assays is important because antibodyconcentrations may already be very low after some months of infection. The direct detection of HEV-RNA from serum and fecal samples using a “nested-RT-PCR” system has been shown to be highly sensitive. Detection of HEVRNA is possible during the incubation phase and within the first days of clinically overt hepatitis E. Direct detection of HEV by electron microscopy is also only possible before clinical evidence of acute hepatitis E and during the first days of icteric hepatitis. A minimal concentration of at least 107 particles/mL is necessary. Electron microscopy is not used for routine diagnostics.
Conclusion for HEV Diagnosis In western countries HEV infection typically is suspected in patients with acute hepatitis and negative markers for HAV, HBV/HDV, and HCV infection. In addition, a history of traveling to endemic areas should be sought. However, numerous cases of acute hepatitis E have been reported without a travel history. Similar to hepatitis A, diagnosis of acute hepatitis E is easily confirmed by specific detection of anti-HEV-IgM antibodies. Chronic courses of infections are unknown. Positive test results for HEV-IgG antibodies indicate either an acute or a resolved infection. In addition, the
presence of an ongoing HEV infection can be confirmed by HEV-RNA detection in serum samples.
Hepatitis B Diagnosis of hepatitis B infection is based on serological and molecular test systems. Over the last few years the measurement of HBV-DNA levels has become the most reliable method used for accurate diagnosis and prognosis of acute and chronic HBV infection. The recently introduced real-time PCR technique represents the method of choice compared to previous, conventional endpoint PCR due to a very sensitive quantification of the viral load over a wide dynamic range. Molecular-based methods are used to aid in the management of HBV infection, and are helpful for monitoring patients during therapy. An infection with HBV should be excluded in all patients with acute or chronic liver diseases, in particular in patients with liver cirrhosis. Table 63.2 summarizes the serological and molecular parameters used in HBV diagnosis. The serological features during different courses of hepatitis B virus infection are shown in Fig. 63.15.
Serological Diagnosis of HBV During the natural course of HBV infection antibodies against different virus antigens are produced, i.e. HBc-, HBe-, and HBs-antibodies. In addition to these serological markers used in clinical practice, there are some antigens with their respective antibodies which have no clinical relevance (e.g. preS1Ag/anti-preS1-antibodies,
Diagnostics of Hepatitis Viruses
693
Table 63.2 Meaning of serological and molecular virus markers for HBV diagnosis Anti-HBs Resolved hepatitis B or successful vaccination Anti-HBc-IgM Acute or passed HBV infection; sometimes in acute episodes of chronic infection Anti-HBc-IgG Acute or past HBV infection, well established screening parameter for HBV Anti-HBe In wild type HBV infection: change between the high-replication stage to the low-level replication stage of HBV infection HBsAg Early marker of acute HBV infection, indication for chronic infection. Screening parameter for HBV infection HBeAg Indirect parameter of high virus replication and high infectivity HBV-DNA (quantitative) Direct parameter of virus replication and infectivity HBV-DNA (qualitative) No use for diagnosis
a
HBV-DNA HBeAg HBsAg anti-HBc-IgG
anti-HBe infection
anti-HBs
anti-HBcIgM
b
HBV-DNA HBeAg HBsAg anti-HBc-IgG anti-HBc-IgM
anti-HBe
infection
c
HBV-DNA HBeAg
Fig. 63.15 a–c Serological progression of the HBV infection. (a) Acute HBV infection with virus clearance. (b) Chronic HBV infection with seroconversion from HBeAg to antibody-production. (c) Chronic HBV infection without HBeAg seroconversion
HBsAg anti-HBc-IgG
infection
anti-HBc-IgM
694
preS2Ag/anti-preS2-antibodies, HBxAg/anti-HBxantibodies, and HBpolAg/anti-HBpol-antibodies). During HBV infection the production of certain antibodies indicates elimination of the respective antigens from serum, an event dubbed “seroconversion.” After HBV infection occurs, nearly all patients develop antiHBc-antibodies. HBc-antibodies may remain detectable over several years or decades after HBV infection and are therefore used as a screening marker. For discrimination between acute, resolved or chronic HBV infection in anti-HBc-positive patients, analysis of additional parameters e.g. HBsAg, anti-HBs-antibodies, HBeAg, and anti-HBe-antibodies should be performed. Different forms of HBV progression and the presence of HBV mutants often hamper serological diagnosis.
HBsAg and Anti-HBs-Antibodies In acute HBV infection, surface antigens are detectable several weeks after infection and its appearance coincides with the onset of clinical symptoms. HBsAg is incorporated into complete HBV particles as well as into non-infectious particles. It can be found in almost all body fluids. Hepatitis B surface antigens are a very early serological marker of HBV infection. They are already detectable in the incubation period of the infection. In only a few HBV infected patients surface antigens remain undetectable, e.g. in patients with fulminant hepatic failure and in HBs-antigen escape mutants. The quantification of surface-protein-concentrations after 4 weeks of infection may allow for a prediction of HBV progression. Chronic HBV infection is defined by the persistence of HBs-antigens for more than 6 months. Different immunological based systems (immune diffusion, enzyme immunoassay, enzyme-linked immunosorbent assay, radioimmunoassay) are available to detect HBsAg. Commercially available assays are highly sensitive and specific for surface antigens. The test reproducibility is higher than 99%. At present, monoclonal antibodies used in the different assays are directed against different HBsAg-epitopes. In patients with very high HBs-antigen serum concentrations (above 100 ng/mL) the saturation of detector-antibodies is a limitating factor in the exact quantification; also, the specificity of some antibodies to the different HBV genotypes may cause problems. In addition to the simple HBsAg detection, it is also possible to determine HBV-stereotypes (adw, ayw, adr, ayr) which is only important for epidemiological research and is not
63 Viral Infections by Hepatotropic Viruses Table 63.3 Anti-HBs titer: control and refreshing of vaccination Anti-HBs Refreshing < 10 IE/L < 100 IE/L < 1,000 IE/L < 10,000 IE/L > 10,000 IE/L
Immediately 3–6 months 1 year 3 years 5 years
performed in routine clinical practice. The respective test systems are based on serotype-specific monoclonal antibodies. Commercial assays are not available. The immune response against the hepatitis B surface antigens is, due to the different forms of HBsantigens (preS1, preS2, S) and the presence of numerous epitopes (a, d-y, w-r, etc.), highly heterogeneous. During the initial course of HBV infection a subtypespecific immunity is detectable which subsequently is extended to other HBV subtypes. Anti-HBs antibody response is an important parameter to distinguish between ongoing and resolved infection as well as to determine the success of vaccination (see Table 63.3). Presence of anti-HBs-antibodies which are produced typically 2 – 3 months after disappearance of HBsantigen, indicates spontaneous resolution. In patients with past HBV infection anti-HBs-antibody titer can fall below the assay’s limit of detection. Multiple different assays for detection of anti-HBs antibodies are commercially available. Most of them have a detection limit between 2 and 10 IU anti-HBs/L. False positive results may be obtained in approx. 2% of cases. PreS-Ag and Anti-PreS-Antibodies During acute HBV infection, virus replication is associated with expression of both preS-antigens, while development of anti-preS antibodies is an early indicator of viral clearance. During resolution of HBV infection, preS1Ag is eliminated initially, followed by the preS2- and the S-Ag. Subsequently the respective antibodies are produced in the same order. Measurement of preS-Ag is clinically irrelevant while the detection of anti-preS1 and anti-preS2 antibodies maybe useful to narrow the diagnostic window between HBsAg elimination and production of anti-HBs-antibodies. Both preS antigens are detectable by monoclonal antibodies. Anti-preS1 and anti-preS2 are recognized on the basis of sequential epitopes by recombinant peptides in immunoblot assays. Commercial assays for anti-preS1 or anti-preS2 are not available.
Diagnostics of Hepatitis Viruses
Anti-HBc-Antibodies Detection of anti-HBc-antibodies is used as a screening parameter for HBV in blood-samples and body fluids. Anti-HBc-antibodies are produced early after HBV infection and typically are lifelong persistent. In addition, no anti-HBc-antibodies are produced after hepatitis B vaccination. Rarely, especially in immunosuppressed patients and in cases with assayspecific escape mutations, no anti-HBc-antibodies may be detectable. During acute infection, it is possible that due to a diagnostic window between HBsAg elimination and anti-HBs-antibody production, antiHBc-antibodies but neither HBsAg nor anti-HBsantibodies are detectable. A similar situation with anti-HBc as the only marker of hepatitis B is possible many years after resolved HBV infection when HBsantigen is undetectable and anti-HBs titers fell below the detection limit of the assay. Routine diagnostics of numerous available anti-HBc detection assays is based on immunological technologies using recombinant HBcAg. Anti-HBc-IgM antibodies are already detectable in the incubation period and maximum concentrations typically are observed in the third week after infection. Six months after HBV infection anti-HBc-IgM antibodies become undetectable. In addition, anti-HBcIgM antibodies may be present during acute episodes of chronic HBV infection. In asymptomatic HBV carriers typically no anti-HBc-IgM antibodies are detectable. Quantitative and qualitative measurement of anti-HBc-IgM antibodies can be performed by several enzyme immunoassays.
HBeAg and Anti-HBe-Antibodies Detection of HBeAg usually is associated with high HBV-DNA concentrations. Accordingly, seroconversion from HBeAg to anti-HBe-antibody production typically indicates a change from a high-replicative to low-replicative HBV infection. However, due to a number of HBe-antigen mutants (precore/core promoter mutation), detection of anti-HBe-antibodies cannot be used to determine low-replicative HBV infection with low HBV-DNA levels. For monitoring of the activity of HBV infection and response to antiviral therapy, measurement of HBV-DNA concentration represents the only reliable parameter. In patients with
695
HBeAg positive HBV infection, monitoring of HBeAg and anti-HBe-antibody production nevertheless is an important tool to determine durable response to antiviral therapy. Several highly sensitive and specific quantitative and qualitative detection immunoassays for HBe-Ag and anti-HBe-antibodies are commercially available.
Molecular Diagnosis of HBV HBV-DNA is a direct marker of viremia, hence of potential infectivity. In addition, in the early stage of infection the HBV-DNA can be observed two to four weeks before HBsAg is detectable. Furthermore, HBV-DNA is used to determine the activity of HBV infection, to select patients for antiviral therapy, and to monitor treatment response. Qualitative and quantitative detection of HBV-DNA in peripheral blood is performed by signal amplification (‘branched DNA’ technology) or target amplification (including standard and real-time PCR as well as transcriptionmediated amplification [TMA]) based assays. Commercial assays include semi-automated bDNA signal amplification (Versant HBV-DNA 3.0 (bDNA) former Bayer now Siemens Diagnostics), semi-automated quantitative PCR (Cobas Amplicor HBV Monitor, Roche Diagnostics) and real time PCR (Abbott RealTime HBV test, Abbott; Artus HBV PCR Kit, Qiagen and Cobas TaqMan 48 HBV Assay, Roche Diagnostics). Real-time PCR technology schematically is shown in Fig. 63.22 and is explained in detail below. The real-time PCR technology represents the reliable method for HBV-DNA measurement compared to previous, conventional endpoint PCR due to a very sensitive quantification of the viral load over a wide dynamic range.
Qualitative HBV-PCR Qualitative PCR is a highly sensitive method to detect HBV-DNA without determination of HBV-DNA viral load (Fig. 63.16). The assay basically consists of three main steps: (i) sample preparation (ii) target amplification and (iii) detection. Sample preparation involves detergent lysis of the virus followed by the hybridization of the free viral nucleic acid with capture oligonucleotides complementary to highly conserved regions
696
63 Viral Infections by Hepatotropic Viruses Detection of amplification
PCR amplification
denaturation
denaturation annealing extension 5Õ
3Õ
Primer 3Õ
5Õ
5Õ
cycle 1 3Õ
Primer
3Õ
hybridization with capture oligonucleotides
5Õ
biotin 5Õ 3Õ
Primer
3Õ
5Õ
5Õ
Primer 3Õ
3Õ
cycle 2
5Õ TMB cycle 3...
detection
Av-HRP biotin + Stopsolution
Fig. 63.16 Diagram of a qualitative polymerase-chain reaction (PCR). The three major steps of a PCR consist of denaturation, annealing and extension. In the denaturation step single stranded DNA is generated by melting the DNA double-strand with high temperatures up to 96°C. In the annealing step two short oligonucleotides (primer) which are complement to the 3’- and 5’-terminus of the target gene bind with high affinity to the nucleotide sequence. The extension step is performed by a heat resistance DNA-polymerase. By adding desoxynucleotidtriphoshates (dNTPs) the bases (complementary to the template) are coupled to the primer on the 3’ side of each nascent strand. Because both strands are copied during PCR, the number of copies per cycle of the target gene increases exponentially. For RNA
amplification it is necessary to convert the RNA to complementary DNA (cDNA) in a one-step process using dNTPs and the enzyme reverse transcriptase. After PCR, the amplified DNA can be detected by several methods, e.g. electrophoretic DNA separation and staining with ethidiumbromide or detection using enzyme-labeled-synthetic oligonucleotides and chemiluminescent substrates that result in a detectable light emission. Here, the primers are labeled with biotin which is detected by avidin conjugated horseradish peroxidase (AV-HRP). The analysis is based on the oxidation of the chromogenic substrate 3,5,3’,5’-tetramethylbenzidine (TMB) by the AV-HRP which results in an intermediate compound with an absorbance maximum at a wavelength of 450 nm
of the HBV genome. Positive results by qualitative HBV-DNA PCR may be obtained in almost all HBsAgcarriers as well as in 5 – 10% of patients with resolved infection. Differentiation between HBV infection with high- and low-level replication, is impossible by qualitative HBV-DNA assays.
Cobas Amplicor™ HBV-Monitor
Quantitative Methods for HBV-DNA Measurement Several assays for quantitative measurement of HBVDNA have been developed. However, until recently results of the different assays (pg/mL, copies/mL, genome equivalents/mL) were not directly comparable due to the lack of adjustment to an international HBVDNA standard and differences in the dynamic ranges of the assays.
The first standardized commercially available and CE-marked test system, based on quantitative PCR was the Cobas Amplicor™ HBV Monitor assay (CAHBM, Roche Diagnostics). This assay is calibrated to international units (IU/mL) on the basis of the first WHO HBV international standard code 79/796. The CAHBM assay encompasses the co-amplification of HBV template together with an internal standard (QS) added at known concentrations during the nucleic acid extraction step. Detection of the template is performed in a subsequent enzyme-linked immunosorbent assay (Fig. 63.17). The system involves a manual DNA extraction. The assay has a sensitivity of approx. 74 IU/ mL (200 copies/mL) with a linear range up to 38,000 IU/ mL (200,000 copies/mL).
Diagnostics of Hepatitis Viruses Fig. 63.17 Quantitative PCR (Amplicor HBV monitor). The Amplicor HBV MONITOR test is an in vitro nucleic acid amplification test for the quantification of HBV-DNA in human serum or plasma. The amplified DNA is hybridized with dinitrophenyl- (DNP) oligonucleotides. After binding of DNP to alkaline phosphatase conjugated antibodies against DNP (anti-DNP-AP), the addition of a substrate results in a light emission that is directly related to the amount of HBV-DNA. As a reference, an internal standard with known HBV-DNA concentration is used
697 Detection of amplification
PCR amplification
denaturation annealing extension 5Õ
3Õ
Primer 3Õ
5Õ
5Õ
cycle 1 3Õ
Primer
3Õ
3Õ
(
)
5Õ denaturation
biotin 5Õ
binding to streptavidin
Primer
3Õ
3Õ
5Õ
5Õ
Primer 3Õ
cycle 2
DNP conjugated oligonucleotides
5Õ
cycle 3...
anti-DNP-AP
+ substrate detection
Branched HBV-DNA (bDNA) Assay The bDNA assay (Versant HBV-DNA 3.0 Assay, Siemens Diagnostics) is based on a signal amplification technology (Fig. 63.18). The branched DNAcomplex is generated by a sandwich nucleic acid
AP target oligonucleotides linker
HBV-DNA
capture oligonucleotides
Fig. 63.18 The Versant HBV-DNA 3.0 (bDNA) technology. The bDNA-complex is generated by a sandwich nucleic acid procedure. The negative-sense DNA strand binds to immobilized capture-oligonucleotides. The oligonucleotides are complement to a 3’-region of the HBs-gene. In a second step, several targetoligonucleotides bind to the HBV-DNA strand. In a last step multiple copies of an alkaline phosphatase (AP)-labeled probe are then hybridized to the immobilized complex. Detection is achieved by incubating the alkaline phosphatase-bound complex with a chemiluminescent substrate. Light emission is directly related to the amount of HBV-DNA in each sample
procedure. After lysis of the HBV virions and release of nucleic acids the negative-sense HBV-DNA strand binds to immobilized capture-oligonucleotides. The oligonucleotides bind to conserved DNA regions throughout the entire HBV genome. In a second step, several target-oligonucleotides bind to the free ends of HBV-DNA strands. Finally, multiple copies of an alkaline phosphatase-labeled probe are hybridized to the immobilized complex. Detection is achieved by incubating the alkaline phosphatase-bound complex with a chemiluminescent substrate. Light emission directly is related to the amount of HBV-DNA in each sample. The HBV bDNA assay is highly specific, however, the assay has a limited sensitivity with a limit of detection of 357 IU/mL (2,000 copies/mL). The upper limit of detection is 18 × 106 IU/mL (1 × 108 copies/mL). The linear range for HBV-DNA quantification is from 357 IU/mL to 18 × 106 IU/mL. Real Time PCR: Cobas Ampliprep/Cobas TaqMan Assay HBV-DNA extraction from plasma-samples is performed fully automated using the Cobas Ampliprep instrument and the quantification of DNA is performed by real time PCR using the Cobas TaqMan. Recently, an evaluation of this CE-labeled assay showed a nearly 7 log IU/mL dynamic range up to 1.1 × 108 IU/mL, an assay sensitivity (95% hit-rate) of 4 – 12 IU/mL and an
698
equivalent detection of genotypes A - G including a prevalent pre-core mutant [2, 31]. The manufacturers of new diagnostic molecular assays use the international standard for quantitation of HBV-DNA. Therefore, the results obtained by the new Cobas Ampliprep/Cobas TaqMan Assay are solely expressed as international units of HBV-DNA per milliliter. Real Time PCR: Abbott RealTime HBV Assay In 2007 a further real time based assay, called Abbott RealTime HBV test (North Chicago, IL, USA), for monitoring HBV viral load in patients was approved with the CE label in Europe. The Abbott RealTime HBV test, developed for use on the Abbott m2000™ automated instrument system, is designed for the quantitation of HBV in human plasma or serum from patients known to be infected with the virus and is suitable to measuring all known HBV genotypes A - H. The quantitation of mutations within the polymerase, the precore/ core are not yet included. The sensitivity of the assay is 10 IU/mL with up to 8.5 log IU/mL linear range. Real Time PCR: Artus HBV PCR Kit The artus HBV PCR Kit (CE labeled) constitutes a ready-to-use system for the detection of HBV-DNA by real time PCR. For detection, different instruments are available: (i) the LightCycler® 1.1/1.2/1.5/2.0 (artus HBV LC PCR KIT), (ii) the artus 3000™ or Rotor Gene™ 3000 (artus HBV RG PCR KIT) or, the (iii) ABI Prism® (artus HBV TM PCR KIT). The artus HBV Kit contains reagents and enzymes for the specific amplification of a 134 bp region of the HBV genome and for the direct detection of the specific amplicon with the different instruments. The test is suitable to detect all known HBV genotypes A-H with high sensitivity. The sensitivity of the kit depends on the DNA purification method and the analytical instrument used for detection. The linear range of the assay performed with the Rotor Gene™ 3000 is 0.02 IU/mL to 1 × 108 IU/mL.
Conclusion for HBV Diagnosis Acute HBV Infection The most important serological marker for acute HBV infection is the presence of anti-HBc-IgM antibodies. Anti-HBc-IgM antibodies are produced by all patients
63 Viral Infections by Hepatotropic Viruses
with acute hepatitis B and are already detectable during the incubation period of infection. In patients with fulminant acute hepatitis B, anti-HBc-antibodies may be the only serological marker. Usually, anti-HBc-IgM antibodies become undetectable 6 months after HBV infection. HBeAg typically appears together with the first clinical symptoms and intra-individually a good correlation with the HBV-DNA concentration is observed. HBsAg also appears during the incubation period and together with anti-HBc-IgM antibodies represents a marker of an early-stage of infection. In contrast to HBeAg, HBs-antigens are detectable throughout the entire course of ongoing hepatitis B and only disappear together with resolution of HBV infection. The period between the disappearance of the hepatitis B surface antigens and the production of the respective antibodies (anti-HBs) is called the diagnostic window. With the exception of rare mutants which may lead to the production of HBsAg and anti-HBs-antibodies at the same time, the detection of surface antibodies is a reliable marker for spontaneous resolution of HBV infection.
Chronic HBV Infection Definition of chronic HBV infection is based on the detection of HBs-antigen for more than 6 months. Thus, HBsAg is a useful screening parameter for diagnosis of chronic hepatitis B. However, the presence of HBsantigen alone is insufficient to predict the progression of HBV infection. For differentiation of highly active and low active chronic hepatitis B, quantification of HBV-DNA needs to be performed (Table 63.4). In patients with highly replicative chronic hepatitis B, alanineaminotransferase activity is increased and inflammation in liver histology can be observed. In highly replicative wild type HBV infection HBeAg is detectable while anti-HBe-antibodies are negative. A seroconversion from HBeAg to anti-HBe-antibodies is associated with a decrease of HBV-DNA concentrations from a high to low replication level. However, a significant number of patients are infected with HBe-antigen negative HBV-precore/core promotor-mutants. These mutants are associated with high HBV-DNA levels and elevated liver enzymes. Many of these mutants bear a stop-codon in the precore region blocking the synthesis of HBeAg. Initially these mutants were considered to be limited to the Mediterranean area but epidemiological studies have shown an increasing presence of these mutants also in northern European countries [37].
Diagnostics of Hepatitis Viruses
699
Table 63.4 Different forms of chronic HBV infection DNA (PCR) DNA Serology HBsAg HBeAg HBV HBV (qualitative) quantitative (virus copies/mL) Low-replication Level
+
< 104
+
−
+c High-replication level
+
> 104
+
Transaminases
Histology
Therapy indication
Normal, sometimes marginal or slightly increased increased
Normal, minimal inflammatory
−a,b
Inflammatory activity, fibrosis Inflammatory activity, fibrosis Low activity
+a
−d +/−e
normal
−a
a
The decision to start antiviral therapy should be made predominantly by considering the clinical presentation, the transaminase levels and the histological changes. Treatment may be also indicated in patients with low viral load ( 17 mg/ dL, serum ALT < 2,600 IU/L, prothrombin time > 25 s, creatinine > 2.0 mg/dL, and the need for intubation and administration of pressors [14].
Prevention HAV infected patients are contagious from 1 to 2 weeks before the onset of jaundice up until 1 week after. Infection with HAV is best avoided by adhering to sanitation and hygienic measures, such as thorough handwashing after defecation, heating foods appropriately and avoiding water and foods from endemic areas. Vaccination against hepatitis A and B is the most effective means of preventing sexual transmission of hepatitis A and B. Disease reporting is required of physicians, laboratories, and school officials and should trigger investigation to determine the source of infection, identify exposed persons, and provide postexposure prophylaxis without delay.
Passive Immunization Standard immune globulin obtained from pooled human plasma of more than 1,000 donors contains HAV antibody levels (approximately 100 IU/L) sufficient to provide short-term protection against infection
63 Viral Infections by Hepatotropic Viruses
with HAV. Pregnancy and lactation are not contraindications for the administration of immune globulin. In persons with selective IgA deficiency, anaphylaxis may occur after repeated intramuscular applications of immune globulin. Passive immunization should be avoided within 2–3 weeks after administration of live, attenuated vaccines because it decreases their immunogenicity. On the other hand, vaccines based on live attenuated viruses (e.g. measles, mumps, rubella, varicella) should be delayed until 3–5 months after intramuscular immune globulin injection. Preexposure Prophylaxis. Preexposure prophylaxis is recommended for travelers to countries with intermediate (10–19 diseases/100,000 inhabitants: Eastern Europe, Greece, Turkey, countries of the former Soviet Union) and high prevalence of hepatitis A (≥ 20 diseases/100,000 inhabitants: Mexico, Central and South America, Greenland, Africa, Middle East, Asia [except Japan]). Immune globulin, 0.06 mL/kg (corresponding to approximately 5 mL in adults and 2 mL in children up to 20 kg body weight), is administered intramuscularly before the start of travel. When using hyperimmune hepatitis A immune globulin, 2 mL for adults and 1 mL for children up to 20 kg body weight will suffice. The peak anti-HAV titer achieved by passive immunization is 150 IU/L. Preexposure prophylaxis is effective in 80–85% of cases and the protection provided by immune globulin 0.06 mL/kg lasts for 3–5 months [7]. Immune globulin should be administered by intramuscular injection into either the deltoid or gluteal muscle. Prophylaxis is recommended for persons traveling to any part of the world except Canada, Western Europe, Japan, New Zealand and Australia. If the departure is scheduled within 4 weeks, preexposure passive immunization and vaccination should be administered concomitantly. If the sojourn in an endemic area is continued for longer than 3 months or if repeated travels lead to renewed exposures, intramusucular immune globulin 0.06 mL/kg is repeated after 4–5 months. Further administration of immune globulin is not necessary, since by that time most travelers will have acquired natural immunity through contact with HAV. One dose of hepatitis A vaccine administered at any time before traveling to an endemic area also provides adequate protection (see below) [17]. Postexposure prophylaxis. Administration of immune globulin within 2 weeks after close contact with an infected person is 69–89% effective
Hepatitis A
in preventing symptomatic infection or attenuating symptoms and reducing viral transmission. Previously unimmunized contacts of a patient with acute hepatitis A should receive intramuscular globulin without delay and serologic testing for anti-HAV antibodies. Household contacts of patients with acute hepatitis A are protected against infection by intramuscular administration of immune globulin 0.02 mL/kg. Since 2–3 weeks after the onset of illness the patient is no longer contagious, injection of immune globulin does not need to be repeated. The duration of protection provided by 0.02 mL/kg immune globulin is 1–2 months. Recommendations for postexposure prophylaxis are summarized in Table 63.15.
Active Immunization Despite the presence of at least three genotypes, HAV expresses only one single serotype of limited antigenic variability. This allowed the development of a formalin inactivated whole virus vaccine that confers immunity against all probable HAV strains. Active immunization with inactivated whole virus vaccines further reduces the incidence of HAV infection and eliminates the need for passive pre- and postexposure prophylaxis. Antibodies elicited by the vaccine have the same neutralizing capacity as antibodies acquired during natural infection. They are directed against a three dimensional conformation created by juxtapositioning of binding sites on two capsid-polypeptides. The production of a recombinant vaccine is hampered by the fact that the resultant capsidpolypeptides do not arrange in the desired three-dimensional conformation. Work on the development of a recombinant vaccine by cloning HAV is in progress. Two types of vaccines for HAV, introduced in 1995 and 1996 are presently available in the United States in pediatric/adolescent and adult formulation [1, 10]. VAQTA®. Each 0.5 mL dose contains approximately 25 Units of formalin-inactivated hepatitis A virus antigen adsorbed onto aluminium hydroxyphosphate sulphate, in 0.9% NaCl. The formulation does not contain a preservative. Vaccination schedule consists of two doses, administered on a 0, 6–18 months schedule. VAQTA® is contraindicated in persons with known hypersensitivity to any component of the vaccine. Havrix®. A 0.5 mL pediatric dose contains 360 or 720 ELISA Units of formalin-inactivated hepatitis A
741 Table 63.15 Recommendations for postexposure prophylaxis in contacts of patients with hepatitis A Postexposure prophylaxis should be considered in persons who: • Live in the same house, share a room, care for the patient • Are engaged in intimate contacts with the patient • Share illicit drugs with the patient • Are in contact with the patient in a food service establishment, in which the patient handled foods served without further cooking during the time the patient was infective • Work at or attend a child care center, where hepatitis A has been diagnosed in an employee, in a child, or in household contacts of two or more enrolled children • Work at or attend a school or a health care setting in which multiple persons with hepatitis A virus have been identified Postexposure prophylaxis is not recommended in: • Casual contacts of the patient • Hospital staff members • Persons with immunoglobulin A deficiency • Persons in the same school, work, or health care setting in which only one case of hepatitis A has been identified, unless otherwise indicated in the recommendations above Source: Adapted from [3]
viral antigen adsorbed to aluminium hydroxide. The adult dose contains 1,440 ELISA Units/mL. The formulation contains 0.5% 2-phenoxyethanol as a preservative. Vaccination schedule consists of two doses, administered on a 0, 6–12 month schedule. Havrix® is contraindicated in persons with known hypersensitivity to any component of the vaccine. Table 63.16 summarizes the information on VAQTA® and Havirx®. The indications for HAV vaccination are summarized in Table 63.17. In addition to HAV mono-vaccines, a combined inactivated hepatitis A and recombinant hepatitis B vaccine is approved in the United States for persons ≥ 18 years old (Twinrix®). A formulation for children is available in many other countries. 1 mL of the vaccine contains 720 ELISA Units hepatitis A antigen and 20 mg HBsAg. The vaccination schedule is 0, 1 and 6 months (see chapter “Hepatitis B”). Hepatitis A vaccines are highly immunogenic with 97–100% of children, adolescents and adults having protective levels of antibody within 1 month after receiving the first dose and 100% after the second dose. Post-vaccination testing is not recommended. Antibodies persist for at least 5–8 years; protection, however, lasts for at least 20 years. Thus, it seems that in addition to specific protective antibodies other mechanisms, such
742
63 Viral Infections by Hepatotropic Viruses
Table 63.16 Recommended dosages of hepatitis A vaccines Vaccine Age (years) Dose Volume (mL) Havrix
®
VAQTA®
2–18 > 18 2–18 > 18
720 (ELISA Units) 1,440 (ELISA Units) 25 (Units) 50 (Units)
0.5 1.0 0.5 1.0
Application
Dose schedule
i.m. (s.c.)
2 doses, 6–12 mo apart 2 doses, 6–12 mo apart 2 doses, 6–18 mo apart 2 doses, 6–18 mo apart
i.m.
Table 63.17 Persons at increased risk for hepatitis A who should be vaccinated against hepatitis A (According to [3, 4, 7]) • Persons traveling to or working in countries with high or intermediate prevalence of hepatitis A (Central and South America, Mexico, Asia (except Japan), Africa, Eastern Europe)a • Universal hepatitis A vaccination should be implemented and integrated into routine childhood immunization schedule at age 1–2 years. As of 2006 vaccination is mandatory for school entry in Alaska, Arizona, Nevada, New Mexico, Oklahoma, Texas, and Utah. • Unimmunised persons, especially children in communities where outbreaks of hepatitis A are occurring, e.g. day-care centers • Men who have sex with men • Illicit drug users • Persons receiving clotting factor concentrates • Persons with chronic liver disease (hepatitis B, hepatitis C) or who have received or will receive a liver transplant • Laboratory personnel who work with HAV-infected primates or who work with HAV in research laboratories a
Further information is available at http://www.cdc.gov/ncidod/diseases/hepatitis/a/vax/index.htm and at http://www.cdc.gov/ ncidod/diseases/hepatitis/a/prevalence.htm
as cellular memory, contribute to protection against HAV infection. Decreased seroconversion rates are seen in old and immunosuppressed persons, e.g. organ transplant recipients and patients on dialysis. Vaccination against HAV is well tolerated. The most common side effects are tenderness at the injection site (50%), headache (15%) and malaise (7%). No special precautions for immunocompromised persons are needed. Inactivated vaccines generally do not interfere with the immune response to other inactivated or live vaccines and vaccination against HAV infection can be administered concomitantly with M-M-R II (measles, mumps, and rubella live vaccine). Recent data also confirm the protective efficacy of hepatitis A vaccine in postexposure prophylaxis when administered within 8–14 days after exposure to HAV [11, 17]. Thus for healthy persons under age 40, immunoglobulin is no longer required in this setting [17]. In older patients hepatitis A vaccine still should be administered simultaneously with passive immunization.
Therapy Since acute hepatitis A resolves completely without sequelae in nearly all patients, a specific antiviral
therapy is neither necessary nor available. Treatment is supportive. Rigorous bed rest and a “liver diet” do not have an impact on the clinical course of the disease. The patient should observe a balanced diet. Avoidance of hepatotoxins such as alcohol and acetaminophen is axiomatic. Patients with signs of fulminant hepatitis and with hepatic failure require immediate hospitalization and evaluation for liver transplant.
References 1. Bader TF (1996) Hepatitis A vaccine. Am J Gastroenterol 91: 217–22 2. Brown KE, Tisdale J, Barrett AJ, et al (1997) Hepatitisassociated aplastic anemia. N Engl J Med 336: 1059–64 3. Brundage SC, Fitzpatrick AN (2006) Hepatitis A. Am Fam Physician 73: 2162–8 4. Craig AS, Schaffner W (2004) Prevention of hepatitis A with the hepatitis A vaccine. N Engl J Med 350: 476–81 5. Elinav E, Ben-Dov IZ, Shapira Y, et al (2006) Acute hepatitis A infection in pregnancy is associated with high rates of gestational complications and preterm labor. Gastroenterology 130: 1129–34 6. Fiore AE (2004) Hepatitis A transmitted by food. Clin Infect Dis 38: 705–15 7. Fiore AE, Wasley A, Bell P (2006) Prevention of hepatitis A through active or passive immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 55: 1–30
Hepatitis B 8. Hutin YJF, Pool V, Cramer EH, et al (1999) A multistate, foodborne outbreak of hepatitis A. N Engl J Med 340: 595–602 9. Koff RS (1998) Hepatitis A. Lancet 351: 1643–9 10. Lemon SM, Thomas DL (1997) Vaccines to prevent viral hepatitis. N Engl J Med 336: 196–204 11. Sagliocca L, Amoroso P, Stroffolini T, et al (1999) Efficacy of hepatitis A vaccine in prevention of secondary hepatitis A infection: a randomised trial. Lancet 353: 1136–9 12. Shim M, Khaykis I, Park J, et al (2005) Susceptibility to hepatitis A in patients with chronic liver disease due to hepatitis C virus infection: missed opportunities for vaccination. Hepatology 42: 688–95 13. Spada E, Genovese D, Tosti ME, et al (2005) An outbreak of hepatitis A virus infection with a high case-fatality rate among injecting drug users. J Hepatol 43: 958–64 14. Taylor RM, Dave MT, Munoz S, et al (2006) Fulminant hepatitis A virus infection in the Unites States: incidence, prognosis, and outcome. Hepatology 44: 1589–97 15. Tassopoulos NC, Papatheodoridis GV, Delladetsima I, et al (2008) Clinicopathological features and natural history of acute sporadic non-(A-E) hepatitis. J Gastroenterol Hepatol 23: 1208–15 16. Vento S, Garofano T, Renzini C, et al (1998) Fulminant hepatitis associated with hepatitis A superinfection in patients with chronic hepatitis C. N Engl J Med 338: 286–90 17. Victor JC, Monto AS, Surdina TY, et al (2007) Hepatitis A vaccine versus immune globulin for postexposure prophylaxis. N Engl J Med 357: 1685–94 18. Wasley A, Samandari T, Bell BP (2005) Incidence of hepatitis A in the United States in the era of vaccination. JAMA 294: 194–201 19. Wheeler C, Vogt TM, Armstrong GL, et al (2005) An outbreak of hepatitis A associated with green onions. N Engl J Med 353: 890–7
743
Hepatitis B The hepatitis B virus (HBV) is a hepatotropic virus that belongs to the family of Hepadnaviridae (Flaviviridae). It may cause acute and chronic hepatitis as well as cirrhosis and hepatocellular carcinoma (HCC) [139].
Definition Acute hepatitis B is the initial infection of the liver by HBV with biochemical, virological and histological evidence of liver injury. Chronic hepatitis B is an infection of the liver caused by HBV, persisting for more than 6 months, and charactarized by biochemical and virological evidence of active viral infection and histologic liver injury.
Epidemiology HBV was discovered in 1966. It represents one of the most prevalent infectious agents in man and is a global health problem with approximately 2 billion people infected worldwide, and 350–400 million (representing 5–7% of the total world population) suffering from chronic HBV infection [138]. Worldwide, chronic HBV infection is a leading cause of cirrhosis, HCC (60% of all cases of liver cancer worldwide are caused by viral hepatitis B), and death, particularly in moderate and highly endemic countries. Between 1979 and 1998 a fourfold increase in age-adjusted death rates due to HBV was reported [117]. Approximately one million deaths worldwide are attributable annualy to HBV infection [139, 227]. Although the incidence of acute HBV infection in the general US population has declined by 70% over the last decade, approximately 70,000 people have acute hepatitis B each year and an estimated 1.25 million persons are infected with HBV [171]. In Western countries HBV is acquired primarily in adulthood, whereas in Asia and most of Africa, the virus is acquired perinatally or in childhood. In highly endemic regions in Africa, the Far East as well as in large parts of South America more than half of the entire population is expected to be infected with HBV during their lifetime. The prevalence of HBV infection
744
63 Viral Infections by Hepatotropic Viruses
in these geographical areas lies between 10% and 20%, and 8% of the population are chronic HBV carriers due to perinatal (vertical) transmission from the mother and horizontal transmission from child to child. Chronic HBV infection is highly endemic in most Asian countries. In the USA Asians make up 3.6% of the US population, or approximately ten million people. Asian immigrants from endemic areas have a high prevalence of HBV infection comparable to their native country, whereas those born in the United States have a reported prevalence of 1.6%. Among the Asian American population in New York City 23% have detectable serum HBsAg. By contrast, the prevalence of HBV infection is 3–5% in Southern Europe and 0.2–0.5% in Central Europe, Scandinavia, Australia and in the USA. HBV prevalence is substantially higher (circa 30%) in patients with Down syndrome, lepromatous leprosy, polyarteritis nodosa, leukemias, Hodgkin’s lymphoma, i.v. drug users, and in patients on renal dialysis. In nonvaccinated health care workers HBV prevalence rates are approximately 15%. Different HBV genotypes (see Section 63.1) have distinct geographical distributions (Table 63.18). HBV genotypes B and C are most prevalent in highly endemic areas where vertical transmission is the primary means Table 63.18 Hepatitis B virus genotypes, subtypes and their geographic distribution Genotype Subtypes Distribution A
adw2, ayw1
B
adw2, ayw1
C
adw2, adqr +, adrq-
D
ayr
E F
ayw2, ayw3 ayw4
G
adw4q-, adw2, ayw4, adw2
Northwestern Europe, Spain, Poland, North America, India, Central Africa, Brazil East and Far East Asia, Indonesia, Pacific Islands Eats and Far East Asia, Pacific Islands, Australia, USA, Brazil Globally distributed with highest prevalence in Mediterranean, Middle East, Iran, India, Africa, North America West and South Africa South and Central America, Polynesia, Alaska France, USA
Recently, a new strain has been described in one American and two Nicaraguan patients, and the designation of genotype H has been proposed. Source: Adapted from [154, 245]
of transmission. In contrast, HBV genotypes A, D, E, F, and G are found in areas where horizontal or sexual transmission of HBV is more common. HBV circulates in high concentrations in blood, but HBsAg has been demonstrated in nearly all body fluids of infected persons, including saliva, tears, vaginal secretion, urine, semen and breast milk. Stool is probably not infectious. HBV antigens and HBV DNA have been demonstrated in lymph nodes, bone marrow, circulating lymphocytes, spleen and pancreas. Although HBV is not cytopathic and does not injur these tissues and cells, these extrahepatic sites may become a source of reinfection and reappearance of HBV infection in the transplanted liver. Health care workers (surgeons, pathologists, dentists, laboratory workers, renal dialysis technicians, etc.) are markedly at risk for acquiring acute hepatitis B, and in this group of persons hepatitis B is currently the most important occupational disease ahead of tuberculosis, hepatitis A and C. HBsAg positive medical personnel observing the usual protective measures do not seem to pose a danger of transmitting HBV to patients. Transmission is parenteral from mother-to-child (vertical or perinatal transmission) or by percutaneous or mucosal exposure to infectious bodily fluids (horizontal transmission). Perinatal infection of infants from infected mothers and horizontal infection early in childhood from exposure to HBsAg–positive family members are the main routes of HBV transmission in highly endemic areas. Perinatal transmission occurs mainly with HBsAg carriers and women with acute hepatitis B in late pregnancy or in the early postpartal period. The likelihood of transmission correlates with the viral load. Approximately 10% of infections are already acquired in utero. In regions such as subSaharan Africa, tribal rituals, such as scarifications, might also be a potent source of infection. In regions of low endemicity, such as Western countries, hepatitis B is primarily a disease of adolescents and adults as a result of high-risk sexual behavior and injection drug use. Sexual transmission is ascribed to minute mucosal injuries, which are always present and allow the virus to gain entrance to the circulation. Especially in regions with low HBV endemicity sexual transmission represents one of the major routes of infection. The risk of sexual transmission is much higher for HBV than for HCV. Direct inoculation by accidental needle-stick injury with contaminated syringes, tattoos, piercing, and acupuncture represent
Hepatitis B
other routes of aquiring HBV. Transfusion related hepatitis B is extremely rare since screening for hepatitis B is routine in most transfusion centers. The risk of transmitting HBV with blood or blood-products is estimated to be 1:100,000–1:1,000,000. Droplet infection does not play a role in HBV transmission. Different HBV genotypes may be preferentially transmitted by different modes. Thus, genotype C may have been responsible for most perinatal transmission, given that seroconversion from HBeAg occurs decades later than in other genotypes [156]. Due to the parenteral route of transmission and the relatively low rate of endemic infection, hepatitis B in the US and in Europe is a disease that affects primarily certain risk groups, such as medical personnel, patients with Down syndrome, frequent recipients of blood or blood products (hemophiliacs), persons with infectious or malignant diseases (leukemias, malignant lymphomas, polyarteritis nodosa), patients on hemodialysis, organ transplant recipients, drug addicts, prisoners, men having sex with men, and prostitutes. Spouses and family members of acutely infected persons are also at increased risk. The majority of infections coincide with the start of sexual contact, i.e. juveniles and young adults with no typical risk behaviour are affected (see indications for vaccination). HBV can survive in the environment for 7 days or more [9]. The incubation period is 6 weeks to 6 months and depends primarily on the dose of infectious HBV particles. The patient remains contagious from the time of infection until complete healing of hepatitis B (loss of HBsAg and development of anti HBs).
Pathogenesis The molecular biology and the life cycle of HBV are discussed in Section 63.1. HBV entry into hepatocytes requires the initial attachment of HBV envelope protein-derived lipopeptides to the carbohydrate side chains of hepatocyte-associated heparan sulfate proteoglycans as attachment receptors. This interaction initializes the multistep entry process [56, 209]. Key steps in the replication of HBV are illustrated in Fig. 63.6. HBV is noncytopathic for hepatocytes. It is the dynamic interplay between HBV, hepatocytes and the
745
host’s innate and adaptive immune responses that determines the outcome of HBV infection. The efficacy of virus-specific T cells determines whether viral clearance or viral persistence will prevail. Vigorous HBV immune clearance is mirrored by liver damage and clinically acute hepatitis. Recovery from hepatitis B is associated with long-term persistence of cytotoxic T lymphocytes (CTL) that actively maintain CTL responses for life. Patients with weak or totally undetectable HBV specific T cell responses will progress to chronic hepatitis B. Thus, inadequate innate and adaptive immune response (inadequate clearance) accounts for persistent HBV infection [250]. However, even after resolution of acute or chronic hepatitis B, replicative HBV intermediates can persist in the liver under immunologic control, conferring a risk of reactivation following immunosuppressive or chemotherapy [240]. In acute hepatitis B CD4+ and CD8+ T cell responses are strong and multispecific. A few weeks after the infection virus specific CD4+ and CD8+ T cells appear in the peripheral blood and accumulate in the liver. Activated CD4+ T cells recognize viral fragments in association with HLA class II antigens on the surface of antigen presenting cells, secrete cytokines and stimulate macrophages, CD8+ T cells and B-cells to proliferate. Resolution of hepatitis B is characterized by the appearance of neutralizing and protective antibodies against HBsAg. CD8+ T cells are the primary immune effector cells in hepatitis B. Intrahepatic HBV-specific CD8+ T cells remain detectable in the liver after HBsAg seroconversion [217]. Several HBV peptide fragments, after being processed within the cell, are expressed on the surface of hepatocytes in association with HLA class I antigens and are recognized by HLA class I restricted CD8+ T cells. This interaction between HBV infected hepatocytes and CTL activates death receptors, such as Fas-ligands, stimulates the secretion of cytokines and perforin by CD8+ T cells and results in apoptosis of the infected hepatocytes (see Chapters 18 and 23). In addition, HBV itself enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) cytotoxixity by increasing its TRAIL/death receptor expression [110]. CD8+ T cells also secrete cytokines that impair the replicative cycle of HBV by purging HBV replicative intermediates from the cytoplasm and covalently closed circular viral DNA from the nucleus of infected cells. This noncytopathic antiviral mechanism contributes
746
to viral clearance. The differences in cytokine production by HBV-specific T cells in blood and liver may explain the capacity of HBV to persist in the absence of significant hepatic destruction [28, 84, 85]. Acute hepatitis is the clinical expression of a vigorous immune response which is associated histologically with a marked, self-limited necroinflammatory activity that in the majority of patients results in the elimination of HBV infected hepatocytes and resolution of acute hepatitis. Chronic hepatitis B is characterized by T cell failure with weak mono- or oligospecific T cell responses. Impaired T cell immune control fails to eliminate HBV and results in viral persistence and protracted hepatic necroinflammation. Not infrequently in chronic hepatitis B, T cell immune responses are missing completely, except for episodes of acute exacerbation. The mechanisms contributing to T cell failure and viral persistence are poorly understood. Quantitative and qualitative T cell defects occur. Primary inability of T cells to mount a virus specific response, T cell dysfunction, T cell exhaustion, insufficient accumulation (homing) of T cells in the liver, deranged secretion of antiviral cytokines by T cells, the occurrence of viral escape mutants, genetic factors and immune tolerance in perinatally acquired HBV infection are some of the mechanisms currently discussed [178]. In addition, regulatory T cells might suppress HBV-specific T helper cells and impair dendritic cell function (crucial for antigen presentation), and contribute thereby to the evasion of HBV from an adequate immune response, leading to viral persistence and to disease chronicity [218, 235]. HBV covalently closed circular (ccc) DNA plays a key role in viral persistence. It is a replicative form of HBV DNA that is incorporated into the nucleosome to form a non-integrated mini-chromosome (see Section 63.1). It persists as a stable episome, but may be reactivated and act as a template for the transcription of viral genes. Clearance of cccDNA reservoirs is thought to be the limiting factor for complete elimination of HBV from infected cells [276].
63 Viral Infections by Hepatotropic Viruses
• • • •
Immune tolerant phase Immune clearance phase Low or non-replicative phase and Reactivation phase (Fig. 63.43) [65]
The immune tolerant phase is characterized by a lack of or a very weak immune response against infected hepatocytes and by high viral replication (high serum HBV DNA levels). Liver biopsy shows only minimal changes with low histologic necroinflammatory activity, no or only very mild fibrosis, and serum ALT values are normal or only slightly increased. The patients are generally asymptomatic. The immune tolerant phase is seen primarily in patients with perinatally acquired chronic hepatitis B, and may last with minimal to absent hepatic necroinflammatory activity for the first 20–30 years of HBV infection; this quiescence may be related to the acquisition of core deletions. Loss of tolerance is characterized by clearance of HBV or by a rapid transition to an inactive carrier state in two-thirds of patients, and to chronic hepatitis in one third of patients [3]. Patients who acquire the disease during adolescence or adulthood have no immune tolerant phase. Instead the disease progresses directly to immune clearance. Thus, in adult-acquired disease, the early phase of infection often is accompanied by marked disease activity, with increased ALT levels, whereas in perinatally acquired disease, patients tend to be immune tolerant with normal ALT levels. Chronic hepatitis is much more likely to follow infection acquired in the neonatal period and in childhood (90%) than in adult life (< 5%). During the immune clearance phase, immune mediated lysis of infected hepatocytes takes place mirrored
Hepatitis B Stages Based on the interaction between the patient’s immune response and HBV infected hepatocytes, HBV infection may be subdivided into various phases:
Fig. 63.43 Stages of HBV infection (Adapted from [65])
Hepatitis B
by clinical reactivation with increased and fluctuating serum ALT levels and declining HBV DNA concentrations in serum. Marked necroinflammatory activity is present and there is evidence of fibrogenesis on liver histology. This phase may last for months to years and successful viral clearance is usually marked by seroconversion from HBeAg to antiHBe and by loss of HBV DNA from serum. Most patients who mount a successful immune reaction against HBV infected hepatocytes proceed to the low or nonreplicative phase characterized by seroconversion from HBeAg to anti-HBe, by a further decline of HBV DNA to low or undetectable levels and normalization of serum ALT levels. These biochemical changes are accompanied by resolution of liver necroinflammation. The persistence of HBsAg characterizes the “asymptomatic HBsAg carrier” (inactive HBsAg carrier state) while conversion from HBsAg to antiHBs denotes “healing of hepatitis B”. The low or nonreplicative phase may last for a lifetime, but in some patients reactivation of HBV replication occurs. Levels of HBV DNA, with or without HBeAg seroreversion, and ALT concentrations rise again. Even in patients with resolved infection and undetectable serum levels of HBV, the virus may persist for decades and become the source of reactivation, for example during severe immune suppression, such as cancer chemotherapy or after organ transplantation. HBV cccDNA is responsible for viral persistence in the natural course of chronic HBV infection and serves as the template for the production of new HBV (see above and Section 63.1). The levels of both HBV cccDNA, a marker of HBV persistence, and pregenomic RNA, an indicator of viral replication, in the liver of chronically infected patients correlate with viral activity and the phase of HBV infection [136].
Clinical Manifestations Acute Hepatitis B The acute disease begins with a nonspecific prodromal stage characterized by fatigue, malaise, fever and anorexia, occasionally accompanied by arthralgias and right upper quadrant pain. The symptoms and signs correspond to those of hepatitis A (Table 63.11). In
747
5–10% of patients a serum sickness-like syndrome develops with skin rash, urticaria, angioedema, arthritis, high fevers (39.5–40°C) and infrequent hematuria and proteinuria. After a few days, while the patient begins to feel better, jaundice develops, accompanied by darkening of urine and discoloration of stool. In approximately two thirds of adult patients the disease runs an inapparent or anicteric course. In perinatally infected newborns and in immunosuppressed individuals the prevalence of asymptomatic HBV infections is even higher. Acute HBV infection in children may rarely present with lymphadenopathy and a non-pruritic skin rash on the face, extremities and buttocks, a condition known as acrodermatitis papulosa (eruptiva) infantum or Gianotti-Crosti syndrome. The laboratory findings in acute hepatitis B are similar to those of hepatitis A and are summarized in Table 63.13. For immune serologic parameters see Section 63.1. Elevated aminotrasferase levels usually normalize gradually within several weeks.
Chronic Hepatitis B Persistence of hepatitis B surface antigen (HBsAg) in the circulation for more than 6 months defines chronic hepatitis B, which is more likely to follow infections acquired in childhood than those acquired in adult life. Liver damage in chronic hepatitis B may vary from mild chronic inflammation to severe hepatitis progressing to cirrhosis or hepatocellular carcinoma. The patient with chronic HBV infection may be asymptomatic or may complain of mild nausea, decreased appetite, and fatigue. A mild hepatomegaly may be the only pathologic finding on physical examination. The serum aminotransferase levels are slightly elevated (usually less than ten times the upper limit of normal; concentration of ALT is typically higher than that of AST; with the development of cirrhosis AST levels become greater than ALT levels). Serum levels of alkaline phosphatase are generally within normal limits or only slightly elevated. Acute exacerbations may manifest by intermittent elevations of serum bilirubin levels (up to 3–10 mg/dL), and in patients with established cirrhosis may lead to hepatic decompensation with the development of ascites, edema, gastrointestinal bleeding and hepatic encephalopathy. In both acute and in chronic hepatitis B autoantibodies, e.g. ANA, AMA, SMA, rheumatoid factor may appear
748
in up to 50% of patients. In contrast to autoimmune hepatitis, autoantibody titers in HBV infection are low and they represent immunologic epiphenomena [48]. The aminotransferase levels do not correlate with necroinflammatory activity and stage of fibrosis, and approximately one third of patients with persistently normal or only mildly elevated ALT levels in chronic HBV infection have significant fibrosis and inflammation on liver biopsy [132, 229]. Noninvasive predictive models of liver fibrosis based on serum biochemical markers have been developed, but have not gained wide clinical acceptance, and liver biopsy remains the gold standard for grading and staging of chronic hepatitis B [99, 176, 273].
Extrahepatic Manifestations Extrahepatic manifestations may occur in the prodromal phase of acute disease and are seen in 10–20% of patients in the chronic phase of HBV infection [251]. The main extrahepatic manifestations are HBV associated glomerulonephritis and polyarteritis nodosa. However, cutaneous leucocytoclastic vasculitis with palpable purpura, synovitis, urticaria, polyneuropathy with sensory-motor deficiency, sicca syndrome, aplastic anemia, autoimmune thyroiditis or ulcerative colitis may also be seen rarely in association with hepatitis B. A mixed cryoglobulinemia occurs in up to 15% of cases, but is mainly seen in chronic HCV infection. NonHodgkin’s lymphoma has been reported to develop nearly three times more likely in chronic HBV-infected patients than in those without HBV infection [232]. There seems to be an independent association between HBV infection with gestational diabetes mellitus and HBsAg carriers have increased risk of antepartum hemorrhage, and threatened preterm labor [135, 230]. There seems to be no relationship between HBV genotypes and the presence of extrahepatic manifestations [20].
HBV-associated Glomerulonephritis This is a rare immune complex disease occuring predominantly in HBV endemic areas. Patients mostly present with signs and symptoms of the nephrotic syndrome. Rarely the initial presentation is that of acute
63 Viral Infections by Hepatotropic Viruses
renal failure accompanied by signs of cutaneous vasculitis, polyarteritis nodosa or cryoglobulinemia. Three forms of glomerulonephritis are associated with HBV infection: (1) membranous glomerulonephritis, (2) membranoproliferative glomerulonephritis, and (3) immunoglobulin A nephropathy [130, 131]. Membranous glomerulonephritis (MGN) is the most common form and primarily affects children. It is rare in children without HBV infection or systemic lupus erythematosus. But in adult white Americans, membranous nephropathy is the most common pattern of idiopathic nephrotic syndrome. Deposition of subepithelial antigen-antibody-complexes (mainly HBeAg and anti-HBe) is thought to be pathogenetically responsible for the clinical manifestations of HBV-associated MGN. After several months to years, HBV-associated MGN heals in nearly all (95%) affected children. This is usually accompanied by seroconversion of HBeAg to anti-HBe. Resolution of renal disease, however, is relatively uncommon in adults. Membranoproliferative glomerulonephritis (MPGN) occurs more often in adults, with 80% of MPGN cases being associated with chronic hepatitis C rather than HBV infection. HBV-associated MPGN is characterized by immune-complex deposits (containing HBsAg and HBeAg) in the mesangium and subepithelial space. Some of the capillary loops appear normal, with thin basement membranes, while the basement membranes of other capillary loops appear fragmented. Having both abnormal and normal segments of the glomerulus is typical of secondary forms of MPGN and is usually caused by HBV or HCV. MPGN is generally associated with activation of the complement pathway with reduced serum levels of C3 and C4. Rheumatoid factor may be present in serum. The typical clinical presentation is with nephrotic range proteinuria. In a few cases HBV-associated MPGN may run a rapidly progressive course to renal insufficiency, but there is limited information on the natural course of HBVassociated MPGN in adults. The impact of antiviral therapy on the prognosis of HBV-associated renal disease is uncertain. A meta-regression analysis, however, showed a significant link between HBeAg clearance and proteinuria remission after interferon therapy, supporting the role of HBV in the pathogenesis of renal disease [60]. Immunoglobulin A nephropathy is seen most often in children and in Asians.
Hepatitis B
Polyarteritis Nodosa Fewer than 1% of HBV infected patients present with signs of polyarteritis nodosa (PAN), but 20–30% of patients with PAN are HBsAg positive. It typically occurs within 4 months after the onset of HBV infection and the presence of HBV-related disease is suggested by finding HBsAg, HBeAg, and HBV DNA in serum. Deposits of HBsAg, immunoglobulins and complement components are present in the vessel walls of small and medium-sized arterioles. These immune deposits activate the complement pathway which leads to injury of the vessel wall with formation of fibrinoid necrosis and perivascular cellular infiltrates, ultimately resulting in vessel obstruction and organ ischemia. The cardinal clinical features are arterial hypertension, arthralgias, arthritis, skin rash, abdominal pain, fever and eosinophilia. In severe cases the disease may progress to a diffuse necrotizing multisystem vasculitis affecting the kidneys, the gastrointestinal tract, the peripheral and central nervous system. The clinical manifestations are the same as in PAN not associated with HBV [86]. There is no association between the severity of liver disease and that of HBVassociated PAN. Patients with HBV-related PAN may benefit from antiviral therapy.
Diagnosis HBV infection is usually diagnosed by the detection of HBsAg in serum. Hepatitis B viremia is established by detecting HBV-DNA or by demonstrating HBeAg in serum. However, the presence of anti-HBe does not indicate absence of viral replication. Acute HBV infection is usually diagnosed by the presence of HBsAg and anti HBc-IgM in serum. The serologic and molecular diagnosis of HBV infection is discussed in Section 63.1 (Fig. 63.15). Liver biopsy is not required to diagnose acute hepatitis B. Serum aminotransferases are markedly elevated (up to several thousends U/mL) with ALT usually being higher than AST in acute hepatitis B. They gradually normalize over several weeks in uncomplicated cases. Typically the levels of aminotransferases are raised only moderately (less than ten times the upper limit of normal) in patients with chronic hepatitis B, but
749
patients may also have near normal or persistently normal values, despite ongoing inflammation in the liver. Chronic hepatitis B is a dynamic disease and the levels of aminotransferases usually fluctuate. As in acute hepatitis B, the levels of ALT are higher than those of AST. However, with progression to cirrhosis, the ALT/ AST ratio may reverse. Imaging modalities, such as ultrasound, CT-scanning and MRI do not play a role in the diagnosis of acute or chronic hepatitis, except in the differential diagnosis of elevated liver enzymes, excluding for example spaceoccupying lesions, and in demonstrating progression to cirrhosis. In chronic hepatitis B, enlarged perihepatic lymph nodes have been reported to be an indicator for histologic and biochemical inflammatory activity in the liver [39]. Liver biopsy still is the gold standard in grading and staging of chronic hepatitis. Recent attempts at predicting necroinflammation, significant fibrosis, and cirrhosis with noninvasive methods in patients with chronic HBV infection are encouraging. Thus, noninvasive markers, such as HBV DNA levels, AST, alkaline phosphatase, and platelet count reliably predicted hepatic necroinflammation and significant fibrosis, and the age-spleen-platelet ratio index (ASPRI) was accurate in predicting cirrhosis in patients with chronic hepatitis B [118, 174]. If these data are confirmed, these simple noninvasive models have the potential to reduce the number of liver biopsies in patients with chronic hepatitis B (see also Chapter 28).
Differential Diagnosis The differential diagnosis includes hepatitis caused by other hepatotropic (HAV, HEV, HDV, HCV) and nonhepatotropic (EBV, CMV, HSV, Coxsackie-virus) viruses. Of particular importance is the recognition of concomitant HDV infection (coinfection, superinfection), since HDV may have an impact on the natural course of HBV infection. Acute exacerbations of chronic hepatitis B, deteriorating liver function in HBV infected patients or persistent liver injury, despite HBeAg loss, should prompt one to consider an accompanying HDV infection. Around 25% of patients with autoimmune hepatitis have an acute clinical onset of the disease with signs and symptoms that may mimick acute viral hepatitis. Cholestatic liver
750
diseases, e.g. drug, toxin and alcohol-induced liver injury, acute cholecystitis, obstructive jaundice due to common bile duct stone(s) and an ascending, suppurative cholangitis fall into the broader range of differential diagnoses of acute viral hepatitis (Table 63.14).
Major Patterns of Chronic Hepatitis B The definitions, diagnostic criteria and clinical terms used in HBV infection are summarized in Table 63.19. The major patterns of chronic hepatitis B comprise • • • •
HBeAg-positive chronic hepatitis B HBeAg-negative chronic hepatitis B Inactive HBsAg carrier state Occult HBV infection
HBV replicates via an RNA intermediate, using a reverse transcriptase that appears to lack a proofreading function. Therefore, HBV exhibits a higher mutational frequency than most DNA viruses, and individulas chronically infected with HBV harbor the virus as a mixture of viral quasispecies with a dominant strain (see Section 63.1) [80]. These natural polymorphisms of HBV are called “variants” as they describe variations observed within an individual and between populations compared with published wild type strains. Thus, HBV variants are naturally occurring HBV subspecies that are present in a large proportion of patients independent of external selection pressures. The most common HBV variants are the pre-core stop codon (G1896A) and core-promoter variants (A1762T + G1764A) that lead to reduced or abolished HBeAg secretion. In contrast, point mutations in the HBV genome arising from internal or external selection pressure, for example the host immune response or exerted by a drug, give rise to HBV mutants. These mutants may be resistant to the pressure inducing agent(s) and may “escape” the drug’s action. A variety of precore/core mutants have been described. The two well-defined precore mutations include a stop codon mutation at nucleotide (nt) 1,896 (or codon 28) (resulting in the cessation of HBeAg expression) and mutations in the basal core promoter (BCP) at nt 1,762 and nt 1,764 (resulting in diminished production of HBeAg and a resultant increased host immune response).
63 Viral Infections by Hepatotropic Viruses
Marked geographic differences in the prevalence of precore stop mutant viruses have been noted. 12–27% of isolates from US and European patients with chronic active hepatitis B, and 47–60% of patients in Asia, Africa, Southern Europe, and the Middle East exhibit these precore stop mutations [104]. Precore stop codon variants can be found in patients with a wide spectrum of liver disease, and they may or may not be pathogenic. There is no general agreement whether or not precore stop codon variants are associated with more severe liver disease than wild-type strains. Core promoter mutations appear to cause more serious liver disease and have been implicated with the development of HCC [262]. Although testing for precore and core promoter variants is becoming more widespread in research studies, it is not recommended for routine clinical management as the role of these variants in the natural history of HBV and the response to antiviral therapy remains unclear.
HBeAg-Positive Chronic Hepatitis B Patients with HBeAg-positive chronic hepatitis B usually present in the third or fourth decade of life. HBeAg-positive chronic hepatitis B typically is associated with high levels of circulating HBV-DNA (> 105–7 copies/mL, up to 1010 copies/mL), variable elevations of ALT and histological activity. HBeAg seroconversion occurs at an annual rate of 10–15% in adults with elevated ALT. Approximately 65% of patients eventually undergo seroconversion from HBeAg to anti-HBe associated with reduction of HBVDNA replication [66a]. Spontaneous and treatmentinduced seroconversion rates are higher in patients with raised ALT and genotype B (vs C) and genotype D (vs A) (see below). Frequently an acute exacerbation, lasting 2 to 4 months, precedes HBeAg seroconversion. Seroconversion from HBeAg to anti-HBe with significant reduction of HBV replication (to less than 104 copies/mL) marks the transition of chronic hepatitis B to the inactive HBsAg carrier state and is usually associated with biochemical and histologic remission, and a diminished risk of disease progression. However, in a small percentage of patients ALT and HBV DNA levels remain elevated. These patients as well as those undergoing reactivation of hepatitis B after HBeAg seroconversion constitute the group of patients with HBeAg-negative chronic hepatitis B.
Hepatitis B
751
Table 63.19 Definitions, diagnostic criteria and clinical terms used in HBV infectiona Definitions Diagnostic criteria Chronic hepatitis B Chronic necroinflammatory liver disease caused by persistent HBV infection Chronic hepatitis B may be subdivided into: HBeAg positive chronic hepatitis B HBeAg negative chronic hepatitis B
1. HBsAg positive > 6 months 2. Serum HBV DNA > 20,000 IU/mL (> 105 copies/mL) 3. Persistent or intermittent elevations of ALT/AST levels 4. Liver biopsy showing chronic hepatitis (necroinflammatory score ≥ 4)b
HBeAg positive, anti HBe negative HBeAg negative, anti HBe positivec
Inactive HBsAg carrier state Persistent HBV infection of the liver without significant ongoing necroinflammatory activity
1. HBsAg positive > 6 months 2. HBeAg negative, anti HBe positive 3. Serum HBV DNA < 20,000 IU/mL (< 105 copies/mL) 4. Persistently normal ALT and AST levels 5. Liver biopsy showing absence of significant hepatitis (necroinflammatory score < 4)b
Resolved hepatitis B Previous HBV infection without further virological, biochemical, or histological evidence of active virus infection or disease
1.
Reactivation of hepatitis B
Reappearance of active necroinflammatory disease of the liver in a person known to have the inactive HBsAg carrier state or resolved hepatitis B
Acute exacerbation or flare of hepatitis B
Intermittent elevations of aminotransferase activity to more than ten times the upper limit of normal and more than two times the baseline valuee
HBeAg clearance
Loss of HBeAg in a person who was previously HBeAg positive
HBeAg seroconversion
Loss of HBeAg and detection of anti HBe in a person who was previously HBeAg positive and anti HBe negative, associated with a decrease in serum HBV DNA levels to less than 20,000 IU/mL (< 105 copies/mL)
HBeAg reversion
Reappearance of HBeAg in a person who was previously HBeAg negative and anti HBe positive; occurs rarely (< 5%)
Primary treatment failure
Reduction of serum HBV DNA levels by less than 1 log10 IU/mL from baseline at week 12
Complete virologic responsef
Negative HBV DNA by a sensitive assay (< 60 IU/mL or < 300 copies/mL)
Previous known history of acute or chronic hepatitis B or the presence of anti HBc ± anti HBs 2. HBsAg negative 3. Undetectable serum HBV-DNAd 4. Normal ALT levels
Partial virologic response
HBV DNA levels < 2,000 IU/mL (4 log10 copies/mL)
Inadequate virologic response
HBV DNA levels ≥ 2,000 IU/mL (4 log10 copies/mL)
a
Adapted from references 114 and 115 Liver biopsy optional c Most of these patients have precore or core promoter variants d Very low levels (10 IU/mL) can be detected using molecular assays e Most clinicians would regard elevations of ALT levels > 5 times ULN compatible with an acute exacerbation of chronic hepatitis B f Measurement of the HBV DNA levels at week 24 is considered essential to characterize virologic responses as complete, partial, or inadequate b
HBeAg-negative Chronic Hepatitis B Over the course of the last two decades an increasing prevalence of HBeAg negative chronic hepatitis B has been recognized. Nowadays, as many as 50% of patients with chronic HBV infection worldwide have undetectable HBeAg, and 70–90% of unselected adult
chronic HBV carriers from Italy and France are HBeAg negative at diagnosis [66a]. Patients with HBeAgnegative chronic hepatitis B are HBsAg positive and anti-HBe positive. HBeAg-negative chronic hepatitis usually represents a late phase in the natural history of chronic HBV infection rather than a de novo infection with naturally occuring HBV variants that do not
752
produce HBeAg. Acute infection with the precore mutant rarely, if ever, leads to chronicity [34]. For reasons that are not yet known, replication-competent HBV variants with mutations in the precore or core promoter regions preventing or down-regulating HBeAg production may be selected during or after HBeAg seroconversion. The precore variant is usually found in association with HBV genotype D. Therefore, HBeAg negative chronic hepatitis is common in the Mediterranean and in the Middle East, where genotype D predominates. Basic core promoter mutations are not genotype dependent and are seen in Asia, where both genotypes B and C are common. Absence of HBeAg in serum is due to genotypic changes preventing expression of HBeAg. The most common mutation that prevents HBeAg production is a guanine (G) to adenine (A) change at nucleotide 1,896 (G1896A) which creates a stop codon in the precore region of the HBV genome that prematurely terminates synthesis of HBeAg as well as mutations in the basic core promoter region which down-regulate HBeAg synthesis at the transcriptional level. Despite their inability to synthesize HBeAg, these patients may display a high HBV replicative activity. Compared to patients with HBeAg-positive chronic hepatitis, those with HBeAg-negative chronic hepatitis are usually older and have lower levels of serum HBV DNA (104–108 copies/mL). Males predominate and the reported male/female ratio ranges from 3.9 to 17 [65]. However, many patients with HBeAg-negative chronic hepatitis have wide fluctuations in both HBV DNA and serum ALT levels. Despite lower HBV DNA levels, HBeAg-negative patients may have histologically severe and progressive chronic hepatitis, which is more active and advanced than in patients with HBeAgpositive chronic hepatitis. HBeAg-negative patients also are more likely to have cirrhosis at the time of their first presentation. Spontaneous sustained remissions of disease activity are rare. Viremia and necroinflammatory changes improve on treatment, but sustained antiviral responses are difficult to achieve in HBeAg-negative chronic hepatitis B.
Inactive HBsAg Carrier State The inactive HBsAg carrier state denotes a remission in disease activity, and is diagnosed by the absence of HBeAg, the presence of anti-HBe, undetectable or low levels of HBV DNA in PCR-based assays, repeatedly
63 Viral Infections by Hepatotropic Viruses
normal ALT levels, and minimal or no necroinflammation, slight fibrosis, or even normal histology on biopsy. Health related quality of life in asymptomatic carriers is comparable to healthy people, and prognosis is usually benign [181]. Spontaneous reactivation, however, may occur with a very low risk of progression to cirrhosis and HCC, which is strongly related to ongoing high levels of HBV replication independently of HBeAg status [66]. Thus, HBeAg-negative patients are not a homogeneous group and seroconversion to anti-HBe is not necessarily a marker of remission [151]. It may be accompanied by HBV genomic variability and by varying degrees of HBV replication. Long-term longitudinal studies (up to 23 years) of adult inactive carriers have reported that 15–24% developed HBeAg negative chronic hepatitis and 1–17% had sustained reversion back to HBeAg positivity [44, 66]. Since patients with HBeAg-negative chronic hepatitis have wide fluctuations in serum ALT and 20–30% of patients with histologically documented chronic inflammation have persistently normal ALT levels, the distinction between inactive carriers and HBeAgnegative, anti-HBe positive patients with progressive disease can be difficult without longitudinal follow-up studies and liver biopsy [19, 122]. Apoptotic caspases are activated in viral hepatitis and serum caspase activity has been suggested as a sensitive marker of early liver injury. Recently it has been shown that serum caspase activity is strongly associated with the presence of liver injury in patients with HBeAg-negative chronic HBV infection. Measurements of caspase-generated fragments of cytokeratin-18 seem to be a useful marker for differentiation between the inactive HBV carrier state and HBeAg-negative chronic inflammation [183]. These data, however, must be confirmed, before they can be implemented into clinical practice.
Occult Hepatitis B Virus infection The long-lasting persistence of HBV genomes (HBV DNA detectable only by ultrasensitive HBV DNA amplification techniques; < 200 IU/mL) in liver tissue or in serum in HBsAg negative individuals is termed occult HBV infection [196]. On the basis of the HBV antibody profile, occult HBV infection may be distinguished as seropositive (anti-HBc and/or anti-HBs positive) or seronegative (anti-HBc and anti-HBs negative). Eighty percent of occult HBV infections are seropositive, 20% are negative for all serum markers of HBV infection.
Hepatitis B Fig. 63.44 Natural course of HBV infection. Infection acquired during the perinatal/ neonatal period leads to chronic hepatitis in approximately 90% of patients, while HBV infection acquired in adult life is followed by chronic hepatitis in less than 5% of patients
753
60 Ð 70 % Asymptomatic Infection Infection Ð Blood/Blood Products Ð Sexual Contacts
3 months
30Ð40 % Acute Icteric Hepatitis
80Ð >90 %
0,5 Ð1%
Immunity
Fulminant Hepatitis 80 %
5% Neonatal Infection
90%
Chronic Hepatitis 20Ð30% Cirrhosis 2Ð7%/year HCC
In a study in a North American community-based population the prevalence of occult HBV infection was 18% in those with serologic evidence of previous HBV infection and 8.1% in HBV seronegative individuals. Age, gender and liver biochemistry findings did not identify those with occult HBV, and S-variants were present in the majority of individuals with occult HBV [173]. By examining liver tissue from a large series of HBsAg negative Italian individuals with no clinical and biochemical evidence of liver disease, occult HBV infection was revealed in approximately 16% of the Italian general population (!), and was significantly associated with the anti-HBc positive status [197]. HCV infected patients are considered the group of individuals with the highest prevalence of occult HBV infection. Data on occult HBV prevalence in HIV positive individuals are wildly divergent. Occult HBV infection is mostly due to a strong suppression of viral replication and gene expression, but in some cases may be associated with mutant viruses undetectable by HBsAg assays. The exact mechanisms responsible for the inhibition of HBV genome are unknown. The host’s immune surveillance, coinfection with other agents and virus interference as well as epigenetic factors suppressing HBV replication and transcription at the level of nuclear HBV cccDNA might be important in causing occult HBV infection. The stability and long-term persistence of viral cccDNA molecules together with the long half-life of hepatocytes imply that HBV infection, once it has occurred, may possibly continue for life. Occult HBV infection has important clinical implications. Despite HBsAg unreactivity, multiple replication-competent HBV variants accumulate in the liver of occult HBV infected patients and HBV in serum and
liver maintains its infectious and pro-oncogenic properties [190, 191]. Patients with occult HBV infection may transmit HBV by blood transfusion or organ transplantation. Any patient with occult HBV receiving systemic chemo-, radio- or immunosuppressive therapy is potentially at risk for HBV reactivation. Moreover, there is evidence to suggest that, despite the lack of overt infection, the persistence of even small amounts of HBV can enhance the progression to liver fibrosis, is common among patients with cryptogenic liver cirrhosis, and can favor the development of HCC [22, 195].
Natural Course and Prognosis The natural course of HBV infection is outlined in Fig. 63.44. Infections acquired during adulthood usually follow a benign course, with less than 5% progressing to chronic hepatitis B, whereas 90% of perinatally and neonatally acquired infections become chronic and carry the risk of further progression to liver cirrhosis and HCC [66a].
Acute Hepatitis B In 95% of immunocompetent adult patients acute hepatitis B is a self-limited disease and heals without sequelae after 3–4 months, conferring lifelong immunity. Only up to 5% of adult patients develop chronic hepatitis. Perinatally acquired HBV infection is mostly subclinical and asymptomatic, but 90–95% of children develop chronic hepatitis. However, even after serologic recovery with loss of HBsAg and development of
754
63 Viral Infections by Hepatotropic Viruses
anti-HBs and complete clinical recovery from acute self-limited hepatitis B, in some patients occult HBV infection may persist in the liver accompanied by abnormal liver histology for years [272]. Fulminant Hepatitis B Fulminant hepatic failure is defined as the onset of coagulopathy and encephalopathy within 8 weeks of presentation of acute hepatitis. An overly exuberant immune response to HBV antigens is believed to account for the rapid and severe lysis of infected hepatocytes. A fulminant course of acute hepatitis B is very rare and is observed in approximately 0.1–0.5% of patients (1% in hospitalized patients). On the other hand, acute HBV % 50 40 30 decompensation 20 HCC
10 0
0
12
24
36
48
a % 100
60 72 months
84
96
108 120
96
108 120
survival
80 60 40 20 0 b
infection accounts for 8.6% of cases of acute liver failure in the United States [224]. The risk increases with age and with preexisting morbid conditions. Coinfection with hepatitis D is a particularly frequent association. The role of HBV genotypes in fulminant hepatitis B is controversial. A fulminant exacerbation of chronic HBV infection can occur after abrupt discontinuation of immunosuppressive therapy for other conditions or of nucleos(t)ide treatment of chronic hepatitis B, and is considered to result from a rebound immune response of the host. Clinical features and laboratory parameters are those of acute liver failure (see Chapter 78). The prothrombin time is considered to be the best prognostic marker.
Chronic Hepatitis B The natural course of hepatitis B infection is variable and is determined by many factors. Once established, chronic hepatitis B is a potentially serious disease with a severe long-term prognosis (Fig. 63.45). Twenty to 30% of chronically HBV infected patients progress to liver cirrhosis within 5–10 years, which, after decompensation has a cumulative 5 year survival probability of only approximately 30% [65]. Age at infection, mode of transmission, host and viral factors (ongoing viral replication, genotype), as well as cofactors, e.g. alcohol abuse and coinfection with other viruses, are important determinants of whether or not an acute HBV infection will become chronic. Persisting symptoms, failure of aminotransferase, bilirubin and g-globulin serum levels to normalize within 6 months after onset of acute disease and the presence of HBsAg and HBeAg for more than 6 months are strong indicators for progression to chronic HBV infection. Risk of chronicity is low for transmission through sexual contact, intravenous drug use, acupuncture, and transfusion as compared to perinatal (vertical) transmission.
survival after decompensation
Age 0
12
24
36
48
60 72 months
84
Fig. 63.45 Natural history of chronic hepatitis B. (a) Cumulative incidence of hepatocellular carcinoma (HCC) and decompensation of liver disease. (b) Cumulative probability of survival and survival after the appearance of the first episode of decompensation (From [65])
The risk of chronicity varies greatly with the age at which the infection is acquired. Generally the younger the age at infection, the higher the probability of chronicity. Overall the chronicity rate in adults is approximately 5%. In immunocompetent, otherwise healthy young adults the prevalence of chronic disease
Hepatitis B
is less than 5%. Neonates and children who acquire the infection in the first year of life have a 90% risk of the infection becoming chronic. The presence of HBeAg and a high maternal HBV DNA level is associated with increased risk of chronic infection in the infant. Fewer than 10% of babies born to HBeAg-negative/anti HBepositive mothers become persistently infected [65]. For children aged 1–5 years at infection, the risk is about 30%, and for children older than 5 years the risk is less than 5% [105].
Immunosuppression In immunosuppressed patients (hemodialysis, organ transplantation, cancer chemotherapy), in children with Down syndrome, in patients with leukemia, and in HIV coinfected homosexual men a chronic course of hepatitis B is observed 5 times as often as in HBV infected patients without these cofactors. Reactivation of an apparently healed hepatitis B with seroreversion of HBeAg is also observed more frequently in immunosuppressed individuals. Viral factors, such as HBV genotype, baseline HBV DNA levels, duration of HBV replication, persistent HBV replication viral load, and coinfections also have an impact on the course and outcome of HBV infection.
HBV Genotype Growing evidence suggests that HBV genotype may affect HBeAg seroconversion, the presence of HBV variants, and the natural history of liver disease (Table 63.20). These effects seem to be influenced by geographical and ethnic factors. Due to the unique distribution of HBV genotypes in Asia and the West, natural history studies of HBV can only reliably compare genotype B to C or genotype A to D [245]. Recombination between HBV genotypes is also possible, but the clinical significance of recombinant strains remains unclear. Patients infected with genotype B have a significantly lower prevalence of HBeAg at presentation (53% versus 69%, p < 0.01) and a significantly higher rate of spontaneous HBeAg seroconversion. Furthermore, HBeAg seroconversion occurs nearly 10 years earlier in patients with genotype B than in patients infected with genotype C [41]. Asian patients with
755 Table 63.20 Clinical and virologic differences between HBV genotypes B and C Features Genotype B Genotype C HBeAg positivity HBeAg seroconversion Immunoclearance phase HBsAg clearance Histological activity Serum HBV DNA level Precore stop codon mutation Basal core promoter mutation Cirrhosis and HCC
Less Earlier Shorter More Lower Lower More
More Later Longer Less Higher Higher Less
Less
More
Less (Japan, China)
More
Source: According to [154].
genotype C infection are more likely to experience prolonged HBV replication, delayed HBeAg seroconversion, more rapid progression to cirrhosis. They also have a higher risk of development of HCC than patients infected with HBV genotype B [245]. The reasons for why genotype C is more aggressive than genotype B are unclear. The higher prevalence of detectable HBeAg and core promoter mutations in genotype C may, at least in part, account for the more aggressive disease [266]. Sustained biochemical remission, clearance of HBV DNA as well as the rate of HBsAg clearance are more frequent in infection with genotype A than D or F [154, 203]. However, few data comparing genotypes A and D are available, and no definite conclusions as to their impact on the natural course of HBV infection are presently possible. In Europe most patients with genotype A have chronic hepatitis, whereas most patients with genotype D have acute hepatitis. Despite the potential impact of HBV genotypes on outcome and treatment (see below), HBV genotyping has limited clinical application to the study of the natural history and treatment of HBV infection, and contrary to HCV genotyping testing for HBV genotypes remains a research tool for now.
Viral Load The viral burden also has an impact on the course of HBV infection. Overall, patients with a highly replicative chronic hepatitis B (> 105 copies/mL in HBeAg positive and > 104 copies/mL in HBeAg negative chronic HBV infection) seem to develop progressive
756
disease, decompensation and HCC at higher rates than patients with low replicative HBV infection [33]. However, other authors failed to define exact baseline HBV DNA levels as predictors of decompensation or of development of HCC [268].
Coinfections Cofactors, such as alcohol consumption, intravenous drug abuse and coinfection with other viruses appear to confer an increased risk of disease progression to liver cirrhosis and HCC and may have important ramifications on choice of antiviral treatment regimen [63, 146, 172]. HBV shares routes of transmission with other viruses, such as hepatitis C virus (HCV) and hepatitis D virus (HDV), and with systemic retroviral infections. It is therefore not surprising that coinfection with other viral pathogens is not uncommon [213]. Coinfection of HBV and HDV. There are two scenarios for HDV presentation. (1) Coinfection, i.e. transmission of HDV simultaneously with HBV, and (2) superinfection, i.e. HDV transmission in a patient already infected with HBV. HDV co- and superinfection increases the risk of fulminant hepatitis in acute hepatitis B. The genotype of the infecting HDV appears to play a major role in determining the severity of liver disease, with HDV genotype I being associated with more frequent fulminant hepatitis in acutely HBV infected individuals. Chronic HBV/HDV coinfection has an unfavourable course compared to HBV monoinfection. Progression to liver cirrhosis is faster and liver cirrhosis develops 10–15 years earlier than in chronic hepatitis B alone. Once cirrhosis has supervened, the presence of HDV increases the risk for HCC, hepatic decompensation, and mortality by 3.2-, 2.2-, and 2.0-fold, respectively, compared with HBV monoinfected cirrhotic patients [63]. The mechanism of viral interference seen in HBV/HDV coinfection is unclear. The presence of HDV appears to suppress HBV replication. With suppression of HBV replication, it is likely that HDV is the major factor in liver damage as it is believed to be directly cytopathic. Coinfection of HBV and HCV. The reported prevalence rates of HBV/HCV coinfection vary between 10% to 35% depending on the population studied. In coinfected patients the phenomenon of viral interference is observed with each virus affecting the
63 Viral Infections by Hepatotropic Viruses
replication of the other. Thus, coinfection with HCV may decrease the replicative activity of HBV, resulting in an increased prevalence of “silent HBV infection.” In addition to reduced serum concentration of HBsAg, HBsAg production may be delayed in coinfected patients compared to patients infected with HBV alone. On the other hand, HBV may also inhibit HCV replication. Generally, however, it is assumed that HCV inhibits HBV replication more than vice versa. Despite this interaction, liver disease is usually more severe and the prognosis worse among patients with dual HBV and HCV infection than in those infected with a single virus. Thus, coinfection with HCV does appear to significantly alter the natural history of HBV related liver disease. Acute HCV superinfection in patients with chronic HBV infection is clinically severe during its acute phase and the long-term prognosis is much worse than that following active hepatitis B in terms of continuing hepatitis activity after HBsAg loss and the development of cirrhosis or HCC [148]. The rate of HCC per 100 person-years follow-up was 3.7 in patients with HCV alone, 2.0 in those positive for HBsAg alone, and 6.4 in patients with HCV/ HBV coinfection [35]. Coinfection of HBV and HIV. Up to 90% of patients infected with HIV have serologic markers of past HBV infection. The prevalence of chronic HBV infection was 7.6% among HBV unvaccinated HIV positive subjects [116]. With the impressive improvements in survival in HIV-infected patients, treatment of viral hepatitis has assumed greater importance. In HIV/HBV coinfected individuals, diminished anti-HBV immune surveillance reduces spontaneous clearance rates for HBsAg and HBeAg compared with non-HIV infected patients. HIV/HBV coinfection is also associated with lower ALT levels and higher HBV DNA serum levels, indicating more active viral replication. Increasing HIV-induced immunosuppression also amplifies the risk of quiescent HBV. Improvement of an HIV-infected patient’s immune response with highly active antiretroviral therapy (HAART) may induce spontaneous HBeAg to anti HBe seroconversion. On the other hand, HAARTinduced immune reconstitution may also be associated with a flare of acute clinical hepatitis, presumably due to increased recognition and destruction of HBVinfected hepatocytes. Coinfection of HBV and Parvovirus B19. In Vietnamese patients HBV/human parvovirus B19 coinfection was reported to occur in 21% of HBV
Hepatitis B
infected individuals. Coinfected patients had a greater likelihood of progression to more severe HBVassociated liver disease. The impact of parvovirus B19-infection on HBV-associated pathogenesis is poorly understood [226]. Spontaneous Resolution HBeAg Seroconversion Spontaneous HBeAg seroconversion to anti-HBe is a crucial event in the natural history of chronic hepatitis B and a prerequisite for HBsAg seroconversion. It is most common during the immune active phase of the disease when ALT levels are increased and serum HBV DNA levels are falling to levels less than 20,000 IU/mL (105 copies/mL). In Central Europe and in the USA spontaneous HBeAg seroconversion occurs in 8–15% of untreated patients per year and usually portends a favorable prognosis with loss of HBV DNA, biochemical and histological improvement followed by clinical remission [65, 102]. A recent longitudinal study has reported that up to 90% of white (“caucasian”) adults with chronic hepatitis B clear HBeAg within 10 years of follow-up, with an incidence rate of 18 per 100 person years [66]. Older age, higher ALT levels (> 5 × ULN), HBV genotypes B (versus C) and A (versus D) and ethnicity other than Asian are associated with higher rates of spontaneous seroconversion. Among Asian children, most of whom have normal ALT, spontaneous HBeAg seroconversion occurs at a very low rate, less than 2% during the first 3 years of age and 4–5% in children older than 3 years. Spontaneous HBeAg seroconversion is sustained in approximately two thirds of patients. However, despite HBeAg seroconversion in some patients occult disease may persist (see above) [190]. Seroreversion (reappearance of HBeAg) may occur in some patients, while in others HBeAg remains undetectable but high serum levels of HBV DNA reappear accompanied by persistent or intermittent increases of ALT levels. These patients have a naturally occurring mutant form of HBV in the precore or core promoter region that abolishes or down-regulates HBeAg production. HBsAg Seroconversion In contrast to HBeAg seroconversion, spontaneous HBsAg seroconversion occurs in only aproximately
757
1% of patients per year, although recent studies suggest that HBsAg seroclearance rates in asymptomatic carriers of high endemic areas may be higher during a long-term follow-up, amounting to approximately 40% after 25 years [43, 44]. Serological clearance of HBsAg is of paramount importance in the natural history of chronic hepatitis B as its development and the advent of anti HBs is generally referred to as resolution of HBV infection. However, in some patients occult HBV may persist, and in a minority of cases HCC may develop [1, 271].
Hepatitis Flares Hepatitis flares or acute exacerbations are particularly frequent in HBeAg positive patients and are defined as intermittent elevations of aminotransferase activity over 200 U/L or more than 5–10 times the upper limit of normal or more than twice the baseline value [147]. Hepatitis flares may be spontaneous (virus induced) or drug induced (particularly if the drug has immunomodulating effects), such as ALT flares during the second to third month of interferon (IFN)a therapy, after abrupt withdrawal of a short course of corticosteroid therapy, or during or after lamivudine therapy (see below). Acute flares of chronic hepatitis B should be differentiated from superinfection with other hepatotropic viruses. As many as 20–30% of these acute exacerbations may be caused by superinfection with HDV, HCV, or HAV. Severe exacerbations occur with equal frequency in patients who are HBeAg positive and in those with antibodies against HBeAg, and there is no single cutoff HBV DNA value to differentiate whether patients with anti HBe will have inactive disease or continue to have exacerbations [42]. Genotype C and male sex are independent factors predictive of reactivation of hepatitis B [44]. Acute exacerbation of hepatitis B is the result of CTLmediated immune response against HBV antigen(s) and its downstream apoptotic mechanisms. In addition to CTL induced destruction of HBV containing hepatocytes, cytokines secreted by CTL, such as IFNg and TNFa inhibit HBV gene expression and viral replication. A hepatitis flare is therefore a frequent event within 3 months before spontaneous HBeAg seroconversion and occurs in approximately two thirds of spontaneous HBeAg seroconversions. However, less
758
than 25% of hepatitis flares are followed by spontaneous HBeAg/HBV DNA seroclearance within this short time span. Histologically, hepatitis flares are characterized by marked lobular necroinflammatory activity that may lead to bridging hepatic necrosis. The cellular infiltrate at the site of necroinflammatory reaction consists mainly of cytotoxic CD8+ T cells. The clinical spectrum varies from asymptomatic to typical symptoms of acute hepatitis to hepatic decompensation and hepatic failure. Twenty-three to 38% of patients with chronic hepatitis B in Taiwan and Hong Kong experienced icteric flare-ups with decompensating liver function, and significantly increased mortality rates [23]. Generally however, symptoms of hepatitis flares are less severe than those of acute hepatitis or acute superinfections. The laboratory parameters, in addition to elevated serum ALT levels, may show increases of bilirubin concentration and prolongation of prothrombin time. More severe acute exacerbations are associated with a rise in serum AFP levels, usually 1–2 weeks after the peak levels of ALT. AFP levels correlate with bridging hepatic necrosis and AFP levels > 100 ng/mL may be used as a marker of severe parenchymal necrosis. The elevation of ALT levels is usually followed by a decrease in serum HBV DNA concentration and in HBeAg positive patients by seroclearance of HBeAg and appearance of HBe antibodies. Generally, the more severe the hepatitis flare the greater the likelihood of spontaneous HBeAg seroconversion. However, if repeated spontaneous flares of disease activity are not followed by HBV DNA clearance fibrosis can develop at a significant rate. In addition to seroconversion, acute flares of chronic hepatitis B may be associated with mutations in the HBV genome, and patients with acute flares of disease may have reappearance of IgM antiHBc. Not all therapy-related hepatitis flares are followed by HBeAg seoconversion. There is some evidence to suggest that in addition to stimulation of cytotoxic cells, the activation of Th1 immunity with induction of a Th1 cytokine response with non-cytolytic HBV suppression is a prerequisite for a successful HBV clearance [228].
Liver Fibrosis and Cirrhosis Untreated chronic hepatitis B is a potentially serious disease that may progress to liver cirrhosis and
63 Viral Infections by Hepatotropic Viruses
hepatocellular carcinoma. The incidence of cirrhosis ranges from 2 to 5 per 100 person-years and the 5-year cumulative incidence of progression to cirrhosis ranges from 8% to 20%. A higher rate of cirrhosis occurs in patients with HBeAg-negative than HBeAg-positive chronic hepatitis B. Overall, approximately 20–30% of patients with high replicative chronic HBV infection will develop liver cirrhosis. Among the various risk factors identified for the progression to cirrhosis and HCC, a high level of HBV replication has been identified as the most important factor [255]. The cumulative incidence of cirrhosis increased from 4.5% for patients with HBV DNA levels of less than 300 copies/mL to 36.2% for patients with HBV DNA levels of 106 or more copies/mL [106]. In Asian patients HBV genotype C is associated with a higher risk of developing cirrhosis than genotype B [42]. Development of cirrhosis is associated with accumulation of complex HBV variants, which exhibit an altered phenotype combining enhanced replication with defects in protein expression. This phenotype results from major mutations in the core promoter and C gene but is considerably influenced by additional mutations throughout the genome [169]. Progression of chronic hepatitis B to cirrhosis is insidious and only a minority (24%) of patients are symptomatic. The 5-year cumulative incidence of hepatic decompensation is 16%, and the first episode of decompensation is usually (49%) caused by ascites [64]. Patients who have more advanced disease at presentation, men, and patients older than 40 years have a higher risk of decompensation. The 5-year survival of compensated HBV-cirrhosis is 80–86%. Once decompensation occurs, the prognosis is poor. The probability of survival ranges from 55% to 70% at 1 year and from 14% to 28% at 5 years (Fig. 63.45). Active HBV replication is a negative prognostic factor, whereas viral clearance and ALT normalization correlate with increased survival [49, 61, 64, 199].
Hepatocellular Carcinoma The risk of HCC in patients with chronic hepatitis B increases with time (Fig. 63.45). In the USA up to 5,000 people die each year from HBV associated cirrhosis and HCC [192]. The risk of developing HCC in chronic HBV infection is 100–200 times that in noninfected individuals, particularly if the infection was
Hepatitis B
acquired during childhood. Wthin the HBsAg-positive group, HBeAg-positive carriers have the highest risk of HCC, but even carriers with anti-HBe antibodies have a substantial risk of cancer [255]. As in cirrhosis, a high level of HBV replication has also been identified as the most important factor for the development of HCC [270]. The cumulative incidence of HCC was 1.3% in persons with serum HBV DNA levels of less than 300 copies/mL and increased to an incidence of 14.9% for those with HBV DNA levels of 106 or more copies/ mL. Elevated serum HBV DNA above the cut off level ≥ 104 copies/mL was a strong predictor of HCC independent of HBeAg, serum aminotransferase level, and liver cirrhosis [33]. In Asia, genotype C HBV infection is associated with an increased risk of HCC [24]. In most patients HCC develops on the background of liver cirrhosis after a latency period of 25–30 years after infection. After perinatal infection the risk of HCC is 0.1–0.6% per year, even in noncirrhotic livers, and approximately 25 % of patients infected as neonates die prematurely from cirrhosis or liver cancer [139]. HCC usually arises in the setting of compensated cirrhosis, which may be clinically silent. The incidence of HCC in HBV-cirrhosis is 2–7% per year and is 3–6 times higher in males than in females. Older age, alcohol and concurrent infection with HCV or HDV also increase the risk of HCC [64]. However, not all patients with chronic HBV infection develop cirrhosis or HCC. Long-term follow-up studies of HBsAg-positive blood donors and asymptomatic chronic HBsAg carriers with normal ALT levels showed a favorable prognosis that did not differ from that of an uninfected control population [164, 241]. Given the risk of HCC, twice-a-year screening of chronically HBV infected patients, and especially those with cirrhosis, with measurement of alpha fetoprotein (excellent negative predictive value but positive predictive value ranges from 9–30%) and hepatic ultrasonography is warranted [80].
Prevention Patients with chronic HBV infection should be counseled regarding lifestyle modifications and prevention of transmission. Household members and sexual partners are at increased risk of HBV infection. Persons who are HBsAg-positive should have sexual contacts
759
vaccinated, use condoms during sexual intercourse if their partner has not been vaccinated or is not naturally immune, not share toothbrushes or razors, cover open cuts and scratches, clean blood spills with detergent or bleach, and not donate blood, organs or sperms. HBsAg-positive individuals can participate in all activities including contact sports, should not be excluded from daycare or school participation, should not be isolated from other children, can share food, utensils and kiss others [159]. HBV infected health care workers may rarely transmit the virus to patients. Therefore, HBV infected HBeAg-positive health care workers should not perform exposure prone procedures without prior counseling from an expert review panel, and notify prospective patients of their HBV status prior to procedures. Several European countries use a threshold level varying from 103–105 copies/mL (200–20,000 IU/mL) to determine if HBsAg-positive health care workers are allowed to perform exposure prone procedures [15, 21, 87]. Pharmacologic prevention of HBV disease is achieved by • Immune prophylaxis (passive and active immunization), and by • Suppression of HBV-reactivation
Passive Immunization The anti-HBs titer of regular immune globulin (1:100 to 1:512 in radio-immunoassay) is not sufficient to prevent HBV infection. Therefore, passive immunization is carried out by administering hepatitis B immune globulin (HBIG) that has an anti-HBs titer of at least 1:100,000. HBIG is used nearly exclusively for postexposure prophylaxis. Indications for HBIG (in non-immune individuals) are accidental needle stick injuries with contaminated needles, mucocutaneous contact with or ingestion of HBV-containing material, prevention of perinatal HBV transmission from a HBsAg-positive mother, and the prevention of endogenous reinfection after liver transplantation in an HBV carrier. Postexposure prophylaxis with HBIG, 0.06 mL/kg body weight i.m. should be given as soon as possible (within the first 12 h, not later than 48 h; HBIG is unlikely to provide benefit if the time from exposure is
760
longer than 14 days) and as a rule be combined with the first dose of vaccine in a contralateral site, followed by the other two doses of vaccine according to the usual schedule (see below). The risk of becoming a chronic HBV carrier is reduced by approximately 70% in patients receiving only passive immunization, and by 90–95% in those receiving vaccination. Neonates of HBsAg-positive mothers are given both HBIG (0.5 mL i.m.) and hepatitis B vaccine within 12 h of delivery at two different sites.Two additional doses of HBV vaccine are given after 1–2 and 6–12 months. HBIG and concurrent hepatitis B vaccine have been shown to be 95% efficacious in the prevention of perinatal transmission of HBV (except for maternal carriers with very high serum HBV DNA levels). For the prophylaxis of endogenous HBV reinfection after liver transplantation, the patient receives HBIG 10,000 IU (200 mL) i.v. in the anhepatic phase and 2,000 IU (40 mL) i.v. daily for seven consecutive days. During the further course an anti-HBs level in serum of at least 100 IU/L has to be maintained over 6–12 months. The administration of HBIG after transfusion of HBV-infected blood generally cannot prevent the development of a post-transfusion hepatitis, but usually reduces the frequency of clinically severe disease. The administration of HBIG is well-tolerated. In immune individuals (documented by anti-HBs or anti-HBc) no postexposure prophylaxis is required. If there is any doubt about the patient’s immune status, HBIG should be administered. In non-responders to vaccination, two doses of HBIG, 1 month apart, should be given.
63 Viral Infections by Hepatotropic Viruses
The seroconversion rate is age dependent. Healthy children up to 10 years old seroconvert in nearly 100% of cases. Adults up to 40 years old seroconvert in 95% and those older than 40 years in approximately 90% of cases. A successful vaccination provides nearly 100% protection against infection and disease with all HBV subtypes. Successful vaccination against hepatitis B also provides protection against HDV infection, since infection and replication with HDV is dependent on the presence of HBV. In HCV-infected persons the same seroconversion rates are obtained as in non HCVinfected individuals. Seroconversion rates are lower in smokers, the obese, the elderly, and in immunocompromised individuals (patients on dialysis, patients receiving immunosuppressive drugs, HIV infected persons) [144].These groups require higher and more frequent doses. Anti-HBs titers ≥ 10 IU/mL are considered protective. Booster vaccination is recommended before the titer falls below this level. After complete vaccination Table 63.21 Individuals that should be vaccinated against HBV infection • • • • • • • • • • • •
Active Immunization (Vaccination)
•
All vaccines currently available in industrialized countries are obtained by recombinant techniques using cloned HBV S gene expression. The indications for vaccination and the recommended vaccination schedule are reported in Tables 63.21 and 63.22. Prevaccination screening for anti-HBs is generally not recommended except for adults in high-risk groups. In health care and public safety workers postvaccination seroconversion to anti-HBs should be documented. Annual testing of hemodialysis patients is recommended since immunity wanes rapidly in these individuals who are at a high risk of continued exposure to HBV.
All newborns, children and adolescents Health care workers Public safety workers Men who have sex with men Intravenous drug users HIV-infected individuals (preferably with helper cells ≥ 400/mL) Promiscuous persons Sexual partners of HBsAg-positive persons Patients on dialysis Patients receiving blood components regularly (for example hemophiliacs) Persons traveling to endemic areas Persons with close contact with chronically HBV infected patients (family members) HCV-infected persons
Table 63.22 Hepatitis B virus vaccination recommendations
a
Group
Schedule (mo)a
Recombivax HB®b
Engerix-B®b
Children/ Adolescentsc
0, 1 and 6
5 mg (0.5 mL)
10 mg (0.5 mL/1 mL)
Adults Adults on dialysis
0, 1 and 6 0, 1, 2 and 6
10 mg (1 mL) 40 mg (1 mL)
20 mg (1 mL) 40 mg (2 mL)
Protective antibodies may be demonstrated already after the second injection in approximately 80–90% of healthy individuals b Given intramuscularly into the deltoid muscle c Children: 1–10 years, Adolescents: 11–19 years
Hepatitis B
(3 dose vaccine regimen) in children the anamnestic response is highly effective, and a booster dose is usually not necessary at least for up to 15–18 years after the primary vaccination [161, 264]. Approximately 5% of healthy, immunologically unremarkable individuals do not respond at all (“nonresponder”) to vaccination, or only with anti-HBs titers less than 10 IU/mL (“hyporesponder”). In these persons HLA and immunoregulatory cytokine gene polymorphisms may contribute to the variable immune response to recombinant HBV vaccines [246]. Three additional vaccine injections in approximately 3 month intervals will lead to the production of protective antiHBs titers in approximately 60–75% of primarily nonand hyporesponding individuals. Those who do not respond to these additional vaccine doses must receive HBIG upon potential contact with HBV (see above). Large HBV vaccination programs in endemic regions have revealed a 2–3% incidence of vaccine escape mutants resulting from alterations in the HBsAg protein (typically, the substitution of glycine for arginine at aa 145, which makes this epitope unlikely to bind to antibodies generated to wild-type HBsAg) [104].
Suppression of HBV-Reactivation HBV reactivation is a well-recognized complication of HBV-infection. It typically occurs in asymptomatic HBsAg carriers undergoing immunosuppressive therapy, for example after organ transplantation, treatment with TNFa-blockers (infliximab, adalimumab), chemotherapy of malignant lymphoma, and of HBV associated HCC [27, 59, 98, 177]. Patients receiving chemotherapy regimens that include glucocorticoids appear to have the highest rates of HBV reactivation, and HBV reactivation has been reported more than 1 year after completion of chemotherapy. Since this complication may be life threatening, physician awareness is essential, and patients undergoing cytotoxic therapy should be checked routinely for HBV serologic markers and HBV DNA levels. Prophylactic administration of a nucleoside or nucleotide analog during chemotherapy should be strongly considered. The available data show a four- to sevenfold decrease in the incidence and a reduction in the severity of chemotherapy-related HBV reactivation in patients who receive lamivudine prophylaxis [170]. HBV reactivation is more likely to occur in patients with high pre-chemotherapy HBV
761
DNA after withdrawal of pre-emptive lamivudine. A more prolonged course of antiviral therapy may be necessary in these patients after completion of chemotherapy in order to reduce post-chemotherapy HBV reactivation [100]. Thus, all HBsAg carriers should receive lamivudine 100 mg p.o. qd, or a comparable anti-viral agent, as prophylaxis, starting 7 days prior to the initiation of immunosuppressive or chemotherapy until at least 1 year following its completion [98, 120, 202]. Preemptive lamivudine therapy should also be considered in HBV associated HCC patients with an HBV DNA level of more than 104 copies/mL undergoing transarterial chemo-lipiodolization [206].
Treatment Treatment of Acute Hepatitis B In the vast majority of adult patients acute hepatitis B is a self-limited disease that results in viral elimination and complete healing. Fewer than 5% of immunecompetent adult patients with acute hepatitis B progress to chronic hepatitis. Compared to placebo, patients with acute hepatitis B treated for 4 weeks with lamivudine show a more rapid decline of serum HBV DNA levels. However, the significance of this rapid decrease in viral load is unknown and it is not accompanied by a significantly greater biochemical and clinical improvement compared to untreated patients. The administration of lamivudine to patients with acute hepatitis B may slow the development of protective anti-HBs titers [121]. Therefore, antiviral treatment is not recommended in patients with uncomplicated acute viral hepatitis B. Fewer than 1% of patients with acute hepatitis B have a fulminant clinicial course with acute liver failure. In these few patients the administration of nucleos(t)ide analogs might be considered, although at present there are no data to support this approach. There is no place for herbal drugs in the treatment of acute and chronic hepatitis B.
Treatment of Chronic Hepatitis B In the majority of patients chronic hepatitis B is a controllable but not curable disease. Direct antiviral agents
762
effectively suppress HBV replication, but have little impact on host immune response, as reflected by a low rate of HBeAg seroconversion and negligible HBsAg seroconversion (i.e. viral elimination). Thus, most patients treated with antiviral agents will need prolonged or possibly life-long therapy. Antiviral treatment of chronic hepatitis B has undergone major changes in the last few years and new medications continue to be evaluated. There are no universally accepted guidelines for the treatment of chronic hepatitis B and the best treatment still has to be defined. The following paragraphs reflect current (summer 2009) treatment practices in this highly dynamic area. Which patients should be treated? When to start treatment? How to treat? How to monitor treatment? When to end treatment? These are the key questions that have to be addressed in treating patients chronically infected with HBV and for which the answers are not readily at hand. The natural history of chronic HBV infection is variable with patients whose prognosis does not differ substantially from that of the uninfected population and others who progress to cirrhosis and HCC. Selecting patients for therapy should be based on an integrated approach, taking into account the determinants of substantial risk of progressive liver disease, the immune status of the patient, virological markers, such as viral load and genotype, and the necroinflammatory activity and degree of fibrosis. Interferons (IFNs) and nucleos(t)ide analogs are currently approved for the treatment of chronic HBV infection. Compared with the IFNs, oral nucleos(t)ide analogs have excellent safety and tolerability profiles that allow treatment for prolonged periods of time. The therapeutic responses to nucleoside/nucleotide analogs seem to be comparable among patients with different HBV genotypes, while HBV genotype may be an important predictor of response to interferon (see below) [46, 111, 154, 275]. The criteria for starting treatment are not clearly defined and guidelines vary among different countries. In daily clinical practice treatment often is begun in the immunotolerant phase, characterized by increased serum HBV DNA levels with low histological disease activity and normal ALT levels. These patients have very low chances of a sustained therapeutic response, but a high probability of developing drug resistance. Serological and virological markers, rather than patient characteristics, are currently used as parameters for monitoring treatment. Serum HBV DNA is presently the best non-invasive marker for the assessment
63 Viral Infections by Hepatotropic Viruses
of antiviral drug efficacy and the detection of emerging drug-resistant HBV [175]. Quantitative assessment of covalently closed circular (ccc) DNA, the highly stable, integrated form of HBV DNA in the liver and serum, would be a more sensitive end point for antiviral treatment, but measurement is difficult and the technique is not yet widely available [248].
Goals of Therapy Responses to antiviral therapy for chronic hepatitis B should be categorized as clinical, biochemical, virological, or histological, and as on-therapy or sustained off-therapy [107, 150, 158, 159]. The clinical goals of therapy are improving quality of life and ultimately survival. These goals are achieved by preventing progression of chronic hepatitis to cirrhosis and HCC. In patients with established HBV cirrhosis, therapy aims at preventing decompensation, hepatic failure and HCC. The virological goals of treatment are the seroconversion of HBeAg to antiHBe and/or the persistent reduction of viral load as determined by a significant fall in serum levels of HBV DNA (partial therapeutic response). The ultimate virological goal is the complete eradication of HBV as evidenced by clearance of HBV DNA from serum (by sensitive PCR-based and molecular assays) and disappearance of HBV DNA from liver, clearance of HBsAg and the development of antiHBs (complete therapeutic response). Unfortunately a complete sustained therapeutic response is seldom achieved. In the rare patient who loses HBsAg or develops anti-HBs, therapy should be discontinued [76]. One should keep in mind, however, that serologic clearance of HBsAg does not always imply clearance of viremia. It may rarely be caused by a point mutation in the S gene during therapy, which results in detection failure. In such patients, further verification and followup using a sensitive HBV-DNA test is advised [97]. The goals of therapy vary according to the HBeAg status of the patient. In HBeAg-positive patients treatment aims for suppression of HBV DNA to undetectable levels on PCR-based assays (PCR-based and molecular assays can detect as little as 40 IU/mL [200 copies/mL] and 10 IU/mL [50 copies/mL], respectively), normalization of serum ALT levels, and sustained clearance of HBeAg with seroconversion to anti-HBe [114, 184]. HBeAg seroconversion is a prerequisite for HBsAg seroconversion. In HBeAg-negative patients the goal of treatment is suppression of HBV DNA to undetectable
Hepatitis B
763
levels and normalization of serum ALT levels. Longterm suppression of HBV DNA to undetectable levels is significantly correlated with histologic improvement, HBeAg seroconversion, stabilization of the clinical status, and improvement of clinical outcome. Indications Selecting patients for antiviral therapy relies on a combination of biochemical (serum ALT levels), virological (serum HBV DNA levels), histological (necroinflammation and fibrosis) and clinical (compensated or decompensated liver disease) findings. HBV replication is reflected by the presence in serum of detectable HBeAg and by viral load (1 IU = 5 copies). The pretherapeutic serum ALT level is the strongest determinant for HBeAg seroconversion during therapy, and should be considered in selecting patients for treatment. HBeAg seroconversion correlates highly with pretherapeutic serum ALT levels, the highest HBeAg seroconversion rates being observed in patients with pretreatment ALT levels geater than 5 times the upper limit of normal (ULN). Patients with serum ALT levels ≤ 2 × ULN have very low chances of HBeAg seroconversion [36]. There is no international consensus as to the cutoff level of HBV DNA at which treatment should be started. Based on the REVEAL studies that demonstrated that a viral load of 104 copies/mL (2,000 IU/ mL) predicts the risk of cirrhosis and the risk of HCC the German guidelines suggest to start treatment (in patients without marked fibrosis or cirrhosis), as soon as the viral load is > 104 copies/mL (2 × 103 IU/mL) and the serum ALT levels are > 2 × ULN or the histology score is > A1/F1, irrespective of the HBeAg status. When marked fibrosis or cirrhosis is present, treatment is started whenever HBV DNA is detectable,
irrespective of the level of viral load [33, 47, 106]. The American guidelines take into consideration the HBeAg status (as long as no cirrhosis is present) and suggest a cutoff value for HBV-DNA of > 105 copies/mL (> 20,000 IU/mL) in most cases [55, 159]. The US treatment guidelines are outlined in Table 63.23, the indications for therapy according to the German guidelines are shown in Fig. 63.46 (note that cutoff levels of HBV DNA differ). Antiviral treatment is not recommended • In patients with acute HBV infection. • In patients who have received postexposure prophylaxis. • In chronic HBV-carriers with normal serum ALT levels. • In patients with serum ALT levels ≤ 2 × ULN or with low replicative disease or minimal to mild histologic disease on liver biopsy, unless they are undergoing chemotherapy or immunosuppression. These patients should be observed, monitoring regularly clinical signs and laboratory parameters.
Drugs Used in the Treatment of Hepatitis B The following drugs are currently licensed for the therapy of chronic hepatitis B • Interferons Standard interferon Pegylated interferon • Nucleoside and nucleotide analogs Lamivudine Adevofir Dipivoxil Entecavir Telbivudine Tenofovir
Table 63.23 United States treatment guidelines for HBV infection HBeAg Status HBV DNA IU/mL ALT × ULN
Potential First-Line Therapy
≤2 No treatment >2 Treat with IFN, pegIFN, or nucleoside analoguea >2 Treat with IFN, pegIFN, or nucleoside analoguea 1 to > 2 Consider liver biopsy to help in treatment decision ≤1 Observe Cirrhosis with See text; paragraph on special therapeutic problems. ≤ 1 to > 2 Positive or negative Approximately < 10 to 100 Cirrhosis with If compensated, observe: if decompensated refer for liver ≤ 1 to > 2 transplantation a Adefovir or entecavir suggested, because of high rate of resistance to lamivudine and telbivudine. IFN interferon, pegIFN pegylated interferon Source: From [55]. With permission Positive Positive Negative Negative Negative Positive or negative
> 20,000 > 20,000 > 20,000 > 2000 ≤ 2000 Approximately ≥ 10 to 100
764
63 Viral Infections by Hepatotropic Viruses
Fig. 63.46 Indications for therapy of chronic hepatitis B (According to the German guidelines [47])
Many nucleos(t)ide analogs, such as emtricitabine, clevudine, famciclovir, ganciclovir, alamifovir are currently being studied, and probably will be approved for clinical use in the near future. Direct antiviral agents, such as nucleoside and nucleotide analogs are well-tolerated and suppress viral replication effectively. However, they have little impact on the immune response, as reflected by a low rate of HBeAg seroconversion and negligible HBsAg seroconversion, and must be given for years (lifelong?). Their use is limited by the emergence of drug resistant mutants. The advantage of immune modulatory drugs, such as the interferons is their finite duration of treatment and the absence of selection of resistant viral mutants. Although they elicit effective antiviral responses only in a minority of patients, in responders the antiviral effect usually is durable.
Interferons Standard Interferon Interferons (IFNs) are a heterogeneous family of glycoproteins that are produced by nucleated cells. Three main classes (a, b, g) and many subclasses (16 with IFNa) are distinguished.
Mechanisms of action. Interferons have antiviral, antiproliferative and immunomodulatory properties (Table 63.24). The exact mechanisms of action are still poorly understood. IFNs bind to surface receptors on target cells and stimulate a series of complex intracellular reactions. Primarily, however, they induce the Table 63.24 Actions of interferons
• Increased expression of membrane proteins – HLA-class I and II – Beta-2-microglobulin – Fc-receptor • Antiviral effects – Decreased cellular viral uptake – Inhibition of intracellular viral processing – Decreaed synthesis of (viral) mRNA – Decreased protein synthesis • Antineoplastic/antiproliferative effects – Inhibition of cell division (arrest of G1/G0-S-transition) – Decreased oncogene expression – Direct cytotoxicity • Immunomodulatory effects – Cytokine induction – Complement induction (C2 and B) – Activation of macrophages, NK-cells and cytotoxic T-cells
Hepatitis B
synthesis of various proteins and enzyme systems, such as 2', 5'-oligoadenylate synthetase, that degrade viral RNA. The intrahepatic CD8+ T-lymphocyte, but not the CD4+ T-lymphocyte or NK/NKT-cell response, is important for HBV clearance during IFNa therapy, and the antiviral effect may be mediated by both cytolytic and non-cytolytic mechanisms [222]. Pharmacology. The bioavailability after subcutaneous administration is 90%. Peak serum values are reached after approximately 6–8 h for IFNa2a and 3–12 h for IFNa2b. The half-life is 5 h for IFNa2a and 3 h for IFNa2b. Elimination is primarily renal by glomerular filtration, tubular resorption and tubular degradation. Interactions. IFNs inhibit cytochrome P4501A2. They can enhance the unwanted effects of ACEinhibitors, in particular the development of granulocytopenia and aggravate the anticoagulatory actions of warfarin and phenprocoumon. Adverse reactions. The multiple potential side effects of IFNs are summarized in Table 63.25 Acute side effects, particularly flu-like symptoms, begin 1–4 h after the first IFN injection and gradually diminish after the 3rd or 4th application of IFN. These side effects are usually well-controlled by administering IFN at bedtime combined with paracetamol 1 g p.o. Thrombo- and granulocytopenia appear already after one week and persist during the entire duration of IFN-therapy. After discontinuation of IFN platelets and leukocytes normalize again. Patients with IFN-induced leukopenia up to approximately 2500–3000/mL do not appear to have an increased incidence of infections. Anemia starts to appear after 6–10 days of IFN treatment and reaches its peak level after approximately 14 days. Despite continuation of IFN-therapy hemoglobin values return to normal in most cases. A dose reduction due to untoward side effects is necessary in 5–20% of patients treated with IFN, while withdrawal of therapy is required in only 4% of patients. As opposed to nucleos(t)ide analogs, HBV resistance to IFN does not develop and therapy with IFN may be stopped abruptly, without the risk of an acute hepatitis flare. Contraindications. IFN is contraindicated in the conditions listed in Table 63.26. Dosing. IFNa may be applied daily or three times a week. The most effective dosing schedule is either 5–6 MU s.c. qd or 9–10 MU s.c. tiw. Duration of treatment. IFN treatment is usually performed for 3–6 months. HBeAg-negative patients may require 1–2 years of therapy.
765
Pegylated Interferon (See also Section 63.3 "Treatment of Chronic Hepatitis C".) Dosing. PegIFNa-2a is given once weekly 180 mg s.c. (1 or 0.5 mL prefilled syringe). At the time of writing PegIFNa-2b is not yet approved for the treatment of chronic hepatitis B. Duration of treatment. Forty-eight weeks, although a lower dose and/or shorter duration of therapy may also be effective. HBeAg-negative patients may require 1–2 years of therapy. Adverse reactions. As with standard IFN the most common dose dependent side effects of pegIFN are flulike symptoms. These occur mostly during the initial phase of therapy, subside during the course of IFN treatment and do not require the pegIFN dose to be reduced. In case of severe side effects, e.g. marked hematologic changes, psychiatric problems, dose reduction or discontinuing therapy should be considered (see also Section 63.3 “Treatment of Chronic Hepatitis C”). Dose reductions, mostly because of neutropenia, may be necessary in up to 50% of patients. Low neutrophil count at baseline and cirrhosis are independent predictors of dose reduction or therapy discontinuation [238]. Results of treatment of standard and pegylated interferons. Standard IFNa was the first treatment approved for chronic HBV infection. In 1993 a meta-analysis confirmed the efficacy of IFN compared to placebo in chronic HBV infection [252]. Treatment with IFN led to more frequent loss of viral replication markers (HBeAg seroconversion: 33% versus 12%), more frequent loss of HBV DNA (37% versus 17%), and more frequent loss of HBsAg (7.8% versus 1.8%) within 12 months after ending IFN therapy. In approximately 80% of patients showing a favourable response to IFN treatment, the sustained response rates are durable. HBeAg reactivation (relapse) occurs in only 13% of responders. In HBeAg negative patients relapse is common after discontinuation of treatment. Prolonged treatment courses are more effective in obtaining sustained response. The abrupt discontinuation of IFN treatment is not associated with the risk of hepatitis flare (in contrast to nucleos(t)ide analogs). IFN-induced serological clearance of HBeAg and HBV is associated with improvement of liver histology and of clinical outcome. IFN therapy in HBeAg positive chronic hepatitis and in HBeAg positive compensated cirrhosis increases the rate of HBeAg seroconversion, significantly lowers the incidence of decompensation of
766
63 Viral Infections by Hepatotropic Viruses
Table 63.25 Adverse reactions of interferons
Gastrointestinal and hepatic Anorexia (30–70%) Nausea (30–50%) Vomiting (generally mild; 10–30%) Diarrhea (22–34%) Elevation of AST (80%) Elevation of bilirubin (30%) Elevation of alkaline phosphatase (48%) Dysgeusia to loss of taste (13%) Pancreatitis (< 5%) Xerostomia Abdominal cramps Flatulence
Local inflammatory reaction at the site of application (30%)a Flu-like symptoms (90%) Lassitude, malaise Fever Myalgias Arthralgias Headaches Cardiovascular (10%) Chest pain Edema Hypertension Hypotension Heart failure Arrhythmias (primarily supraventricular tachycardia) Cyanosis
Hematologic Bone marrow suppression (30–70%) Granulocytopenia (30–70%) Thrombocytopenia (22–70%) Anemia (25–65%)
Psychiatric-neurologic Depression, suicidal tendencies (15%) Fatigue (90%) Headache (50%) Dizziness (20%) Irritability (15%) Insomnia (15%) Confusion (10%) Hallucinatory psychosis Paresthesias (7%) Epileptic seizures Tinnitus, hearing loss Peripheral neuropathy Cramps of calf muscles
Immunologic Exacerbation of autoimmune diseases, e.g. thyroiditis Formation anti IFN antibodies Urogenital Proteinuria (15–25%) Interstitial nephritis, nephrotic syndrome Erectile dysfunction (6%) Irregularities of menstrual bleeding Pulmonary Cough (27%) Oropharyngeal irritation (14%) Dyspnea (7%) Bronchiolitis obliterans organizing pneumonia (cryptogenic organizing pneumonia) Interstitial pneumonia
Dermatologic Maculo-papular rash (7–18%) Alopecia (20%) Pruritus (13%) Diffuse erythema Urticaria Endocrine and metabolic Hypocalcemia (10–50%) Hyperglycemia (33–39%) Hyperphosphatemia (2%) Hyponatremia (SIADHb) (< 1%) Hypertriglyceridemia (< 1%)
cirrhosis and progression to HCC, and prolongs survival [62, 151–153, 179, 237]. Thus, responders to IFN have an improved long-term prognosis with a significant reduction of liver-related mortality. However, IFN therapy lacks efficacy in approximately 40–60% of patients (non-responders). In contrast to chronic hepatitis C adding ribavirin to IFN does not increase the effi-
Ocular Retinopathy Subconjunctival and retinal hemorrhages Loss of vision Conjunctivitis Ear, Nose and Throat Epistaxis (4%) Rhinitis (3%) a
The numbers in parenthesis relate to the frequency of side effects SIADH syndrome of inappropriate ADH secretion
b
cacy of IFN in patients with chronic hepatitis B [155]. The therapeutic response to standard IFN is modulated by a variety of factors and influenced by genetic polymorphisms in IFN metabolic pathways [119]. HBV genotypes are independent predictors of IFN responsiveness. Sustained response rates to standard IFN are better in patients with genotype A than those
Hepatitis B Table 63.26 Contraindications for interferons • Decompensated liver cirrhosis (Child-Pugh B or C) • Marked thrombo- (< 50,000/ml) and/or leukopenia (< 2000/ mL) • Cerebral seizures • Depression • Pregnancy • Immunosuppression (AIDS, organ transplantation, drugs) • Autoimmune diseases (e.g. thyroiditis, autoimmune hepatitis) • Heart diseases (heart failure, coronary heart disease, especially tachycardic arrhythmias) • Marked renal insufficiency • Severe bacterial infections
with D, and with genotype B better than those with C [57, 275]. In a multicenter study, the overall response rates according to HBV genotype were: genotype A, 47%; genotype B, 44%; genotype C, 28%; and genotype D, 25% [111]. In order to obtain optimal treatment results, patients receiving IFN therapy must be carefully selected. IFN is most likely to benefit patients with replicative infection and active liver disease. HBsAg positive, HBeAg negative, HBV DNA negative patients with normal serum ALT values are carriers with no evidence of active virus replication or ongoing liver damage and should not be treated. HBV DNA positive patients with decompensated cirrhosis carry a high risk of IFN-induced serious infections and hepatic failure and therefore should not receive IFN. Thirty to 50% of patients treated with IFN exhibit a transient rise in serum aminotransferase levels. This flare should not be misinterpreted for relapse of hepatitis and erroneously lead to discontinuation of IFN therapy. Instead, IFN treatment should be continued, since the rise in aminotransferases in this case is evidence of IFN induced stimulation of immune response with consequent lysis of virally infected hepatocytes. In the Mediterranean Basin, Middle and Far East about 20% of HBsAg carriers with antibodies against HBeAg have detectable serum levels of HBV DNA and necroinflammation on liver biopsy. These anti HBe positive patients with chronic HBV infection should receive IFN [14]. Table 63.27 summarizes the predictive factors for response to IFN therapy. The major limitations of immmunomodulatory therapy with IFN, in addition to its lack of efficacy in 40–60% of patients, are the numerous contraindications,
767 Table 63.27 Predicitive factors for response to interferon therapy Positive determinants of response (response rate 40%; in 80% of responders response is durable) • Short duration of chronic hepatitis B • Infection acquired in adult age • High pre-treatment serum ALT levels (> 5 × ULN) • Low viral load • Active liver disease • Female gender • HBV genotype A • White (“Caucasian”) Negative determinants of response • Long duration of chronic hepatitis B • Perinatally acquired HBV infection • Advanced cirrhosis (Child-Pugh stage B or C) • High viral load • HBeAg negative chronic hepatitis • Low ALT levels (≤ 2 × ULN) • Male gender • HBV genotype D • Asian extraction • Immunosuppression (e.g. HIV infection) • Coinfection with HDV or HCV
the profile of untoward effects, and the fact that it cannot be given to patients with decompensated liver cirrhosis. In 2003 pegylated interferon (pegIFN) has been demonstrated to be effective in patients with chronic hepatitis B [46]. Both pegIFNa-2a and pegIFNa-2b are safe and effective in HBeAg positive and HBeAg negative chronic hepatitis B [16, 17, 46, 111, 137, 166]. Non-responders to standard IFN or lamivudine may be successfully treated with pegIFN [68]. Sustained HBeAg seroconversion 6 months after the end of 48 weeks of therapy with pegIFN is seen in approximately 30% of patients [137]. The factors predictive of a response to pegIFN correspond to those reported in Table 63.27 for standard IFN [11]. Quantitative HBeAg determination may be a useful adjunctive measurement for predicting HBeAg seroconversion in patients treated with pegIFN [73]. Patients with HBV genotype A have higher HBeAg seroconversion rates than those with genotype D, and those with genotype B higher than those with genotype C following treatment with pegIFN [46]. HBsAg seroconversion was observed in 7% of patients infected with HBV genotype A after 1 year of pegIFN therapy [69]. However, taken together, data regarding the reponse of various HBV genotypes to pegIFN are limited and conflicting, and whether HBV genotypes (as in treatment
768
with standard IFN) correlate with the response to pegIFN therapy awaits further examination [154]. There are some some data to suggest that combination therapy with pegIFN and adefovir may lead to marked decreases in serum HBV DNA and in intrahepatic cccDNA levels [253]. The evidence, however, still is too weak to recommend this regimen. Virus induced flares, which occur after an increase in HBV DNA level and most probably are indicative for increased expression of viral antigens, do not lead to treatment response. In contrast, host induced flares, which are followed by a decrease in HBV DNA levels, are associated with treatment response [67]. Discontinuing pegIFN is generally necessary in less than 10% of patients, and the most frequent reasons for early discontinuation of therapy are psychiatric sideeffects (depression, psychosis) and flu-like symptoms.
Nucleosides and Nucleotides Lamivudine Lamivudine (LAM), a nucleoside analog, the (−) enantiomer of 2’,3’-dideoxy 3’-thiacytidine (3TC), originally used for the treatment of patients with HIV infection, was the first oral antiviral agent licensed for the treatment of chronic hepatitis B. Mechanism of action. Lamivudine is phosphorylated to the triphosphate (3TC-TP) which competes with dCTP for incorporation into growing DNA chains, causing chain termination. LAM inhibits the reverse transcriptase action of HBV DNA polymerase thus inhibiting viral replication. LAM monophosphate is incorporated by HBV DNA polymerase into the viral DNA, resulting in DNA chain termination. Lamivudine also may exert immunologic effects and can reverse the T cell hyporesponsiveness to HBV, restoring antiviral T cell activity [10]. This immunologic effect, however, is probably of subordinate importance compared to its direct antiviral activity. Pharmacology. After oral application LAM is well absorbed. Ingestion of food does not affect the AUC. Protein binding is < 36%, the half-life in adults is 5–7 h. LAM is eliminated by the kidneys and is found unchanged in the urine. Interactions. Trimethoprim/Sulfamethoxazole reduces the renal clearance of LAM. Concomitant use of ribavirin and nucleoside analogs may increase
63 Viral Infections by Hepatotropic Viruses
the risk of developing hepatic decompensation or other signs of mitochondrial toxicity, including pancreatitis or lactic acidosis. Adverse reactions. Lamivudine 100 mg once daily is very well tolerated, the side effects being comparable to placebo. Long term treatment for up to 6 years has an excellent safety profile in patients with compensated liver disease [157]. Pancreatitis, lactic acidosis and neuropathy seen in lamivudine treated HIV patients are extremely rare events in lamivudine treated patients with chronic hepatitis B. This is probably related to the higher lamivudine doses administered in HIV infected patients. In children lamivudine may impair glucose metabolism as determined by the oral glucose tolerance test [58]. Upon abrupt discontinuation of lamivudine acute exacerbation of hepatitis B may occur. Flares of hepatitis during therapy should not be confused with side effects of lamivudine (check for lamivudine resistant mutants). Contraindications. Hypersensitivity to lamivudine or any component of the formulation. Low dose (100 mg daily) lamivudine monotherapy of chronic HBV infection in an HIV infected patient is contraindicated, since it will lead to rapid development of HIV lamivudine resistance. Dosing. 100 mg p.o. qd. The dose of lamivudine should be increased to 150 mg twice daily in patients who have HIV coinfection to prevent the development of HIV resistance. Dose adjustment is required in renal insufficiency (Table 63.28). Duration of treatment. In HBeAg positive patients duration of therapy usually is 1 year. If HBeAg seroconversion does not occur, therapy should be extended, monitoring for the emergence of drug resistant mutants. For almost all patients with HBeAg negative chronic hepatitis B a year of therapy is insufficient. In the absence of emergence of lamivudine resistant mutants, treatment should be continued for several years, regularly monitoring serum ALT levels and HBV DNA concentration, and the appearance of viral resistance, Table 63.28 Dose adjustment of lamivudine to renal function (creatinine clearance) ClCr (mL/ Lamivudine-initial Lamivudine-subsequent minute) dose (mg p.o. qd) doses (mg p.o. qd) ≥ 50 30–49 15–29 5–14 20 mg/dL [37, 231]. Important predictors of response to lamivudine therapy are the histologic activity of disease, the pretreatment ALT levels, the magnitude of decline in HBV DNA concentration, the duration of therapy, the age of the patient and HBV genotype. High levels of necroinflammation in liver biopsy are associated with a higher probability of initial virological and biochemical response. Rates of HBeAg seroconversion correlate with the pretherapeutic serum ALT levels [36]. High baseline ALT levels (> 5 × ULN) are associated with seroconversion rates of approximately 42%, whereas in patients with ALT levels < 2 × ULN seroconversion rates range between 2% and 7% [186]. The HBeAg seroconversion rate is also determined by the magnitude of the initial viral load decline and by the duration of therapy. A pronounced initial response, characterized by a decrease in serum HBV DNA levels at week 12 of therapy by at least 1 log10 copies/mL compared with the baseline value has been reported to be associated with increased response rates [201]. Recent data suggest that even earlier measurements of HBV DNA may predict the long-term outcome of lamivudine therapy. A fall of HBV DNA concentration to levels of less than 4 log copies/mL (2,000 IU/mL) at week 4 of lamivudine treatment predicts a favorable outcome, while the addition of or switch to an alternative antiviral agent should be considered for patients who fail to achieve this early target [269]. Continuing lamivudine treatment for 3–5 years may lead to an increase in HBeAg seroconversion in 30–50% of patients. However, prolonged therapy is limited by the development of lamivudine resistance in a progressively increasing number of patients. Thus,
770
the potential benefit of extending treatment beyond 1 year may be offset by the selection of resistant mutants, negating the initial benefits of therapy. In addition, HBV genotype and patient age seem to be important factors in determining sustained HBeAg response. Patients with genotype A and B and those younger than 36 years have higher HBeAg seroconversion rates than patients with genotype C and D [38, 111]. The durability of HBeAg seroconversion to anti HBe is sustained in only 30–80% of cases after lamivudine is stopped [52, 150]. The sustained response rate following lamivudine treatment is significantly lower than that following IFN. The durability of response is particularly low in patients with HBV genotype C infection, in older patients and if treatment is maintained for less than 4–8 months after HBeAg seroconversion [38, 140, 216, 236]. Lamivudine retreatment for reappearance of hepatitis B markers can achieve resumption of viral suppression [53]. The pretherapeutic viral load is a predictor of viral breakthrough during treatment. Patients with baseline serum HBV DNA concentrations of greater than 106 copies/mL are more likely to develop virologic breakthrough because of drug-resistant mutations compared to patients with low replicative chronic HBV infection [163]. There is also a direct correlation between the level of HBV DNA reduction achieved during nucleos(t)ide treatment and the probability of development of drug resistance, i.e. a rapid and profound viral suppression is associated with a lower probability of drug resistance and viral breakthrough. The clinical outcome is related to the virological response. Loss of virological response or treatment withdrawal leads to clinical deterioration in approximately 30% patients after 18 months [78]. HBeAg negative cirrhotic patients with a sustained decrease of serum HBV DNA to undetectable levels by PCR are significantly less likely than those with viral breakthrough to develop decompensated cirrhosis or HCC. Maintaining virological response leads to a longer survival in patients with Child-Pugh stage A cirrhosis compared to patients with virological breakthrough [51]. Overall, in patients who do not develop resistant viral mutants long-term lamivudine therapy significantly improves survival and reduces the risk of major complications of chronic hepatitis B and cirrhosis [182]. Abrupt discontinuation of treatment should be avoided, since it can provoke necroinflammatory flares and in rare cases fatal acute liver failure. 90% of these
63 Viral Infections by Hepatotropic Viruses
flares occur withing 6 months after stopping lamivudine therapy. In many patients on lamivudine the appearance of YMDD mutants is heralded by hepatitis flares. Such flares may be more severe than those observed during the natural course of wild-type HBV chronic infection and may be associated with hepatic decompensation. Although such hepatitis flares may be followed by HBeAg seroconversion and HBV seroclearance, new and distinct mutant HBV may also be selected and other hepatitis exacerbations may be elicited.
Adefovir Dipivoxil Adefovir dipivoxil (ADV) is an acyclic nucleotide (adenosine) analog. Mechanism of action. ADV inhibits RNAdependent HBV DNA polymerase resulting in inhibition of viral replication. Pharmacology. Adefovir is a prodrug that is rapidly converted in the intestine to its active metabolite ADV. Bioavailability after oral application is 59%, protein binding is ≤ 4%. Peak concentrations in plasma are reached 1.7 h after ingestion. Half-life is 7.5 h. ADV is excreted by the kidney with 45% recovered in urine as active metabolite within 24 h. Interactions. Aminoglycosides, vancomycin, NSAID and other potentially nephrotoxic medications may increase the risk of renal damage due to ADV. Concomitant use of ribavirin and nucleoside analogs may increase the risk of mitochondrial toxicity and result in hepatic decompensation, pancreatitis or lactic acidosis. Adverse reactions. ADV is well-tolerated and for a majority of adverse reactions the incidence is similar or even less than that observed in patients treated with placebo. The most common adverse events are asthenia, headache, and abdominal pain. An increase in serum ALT levels and the occurrence of hematuria (11% grade ≥ 3) are seen especially in patients with daily doses greater than 10 mg. The most serious side effect is renal dysfunction (rise in serum creatinine, glycosuria, renal insufficiency), which occurs in fewer than 10% of patients. In liver transplant patients with baseline renal dysfunction, prevalence of increased serum creatinine has been observed to be as high as 32–53%. However, it is doubtful whether all these changes in the liver transplant patient can be attributed to ADV. Upon abrupt discontinuation acute exacerbation
Hepatitis B
771
of hepatitis B may occur. Contraindications. Hypersensitivity to ADV or any component of the formulation. Dosing. 10 mg p.o. qd. In renal insufficiency the dose has to be adjusted according to the creatinine clearance (ClCr): ClCr 20–49 mL/min: 10 mg every 48 h ClCr 10–19 mL/min: 10 mg every 72 h Hemodialysis: 10 mg every 7 days (following dialysis) Results and duration of treatment. ADV monotherapy, 10 mg daily for 48 weeks, is safe and effectively suppresses HBV replication in patients with HBeAg positive and HBeAg negative chronic hepatitis B [89, 90, 165, 247, 274]. Compared to placebo ADV leads to a significant decrease in the necroinflammatory activity, to improvement of fibrosis, to significant reduction in serum HBV DNA levels, loss of HBeAg and increased HBeAg seroconversion rates in HBeAg positive patients, and to normalization of serum ALT values after 48 weeks of therapy [89, 90, 165, 274]. The initial drop of HBV DNA titer in serum at week 12 of ADV therapy appears to be predictive of subsequent HBeAg seroconversion. The ADV induced
decrease in serum HBV DNA levels seems to be independent of HBV genotype [249]. Although the initial antiviral effect of ADV seems to be slower and the degree of HBV DNA reduction less than with LAM and entecavir, its antiviral effect increases over time and in the majority of patients HBeAg seroconversion is durable. Loss of HBsAg with appearance of antiHBs during ADV therapy is very rare (1.6%). The optimal duration of therapy is unknown, but higher rates of HBeAg seroconversion (up to 43% after 3 years) can be achieved by continuing treatment. Extending treatment for 4–5 years is associated with maintained virus suppression, ALT normalization, and improved liver histology in 65 to 80% of patients. As with other nucleos(t)ide analogs, abrupt discontinuation of treatment should be avoided. In up to 25% of patients a flare up of hepatitis (ALT > 5–10 × ULN) will occur within 3 months after abrupt stop of ADV treatment. In HBeAg positive patients treatment with ADV beyond 48 weeks is well-tolerated and produces long-term virological, biochemical, serological, and histological improvement [168]. Therapy may be stopped 6 months after HBeAg seroconversion has been achieved (“consolidation phase”).
Table 63.29 Comparison between interferon a, lamivudine und adefovir dipivoxil in patients with HBeAg positive chronic hepatitis B Parameter Interferon (untreated) Lamivudine (Placebo) Adefovir Dipivoxil (Placebo) 12–24 weeks 52 weeks 48 weeks HBV DNA loss (%)a HBV DNA reduction (log10) HBeAg loss (%) HBeAg seroconversion (%)
37 (17) No data 33 (12) 18b
HBsAg loss (%)
11–25 after 5 years (in white patients) 23b 80–90 after 4–8 years
ALT normalization (%) Durability of response after HBeAg seroconversion (%) Emergence of drug resistant mutants Use in decompensated liver cirrhosis Efficacy with normal ALT levels Efficacy in precore mutants Efficacy with high viral load Abrupt discontinuation
44 (16) No data 32 (11) 16–18 (4–6), 50 after 5 years Not enough data
21 (0) 3,52 log (0,55) 24 (11), 44 after 72 weeks 12 (6), 23 after 72 weeks
41–72 (7–24) 77 after 3 years
48 (16) No data
No
Yes
Yes (less often than lamivudine)
Contraindication
Possible
Possible
No Yes Less effective Possible without fear of acute exacerbation of hepatitis
No Yes Effective Risk of acute exacerbation of HBeAgpositive chronic hepatitis
Probably no Yes Effective Risk of acute exacerbation of HBeAg-positive chronic hepatitis
Not enough data
a Interferon and lamivudine, hybridization assay (lower limit of detection 105 copies/mL); Adefovir dipivoxil PCR (lower limit of detection 400 copies/mL) b Difference between treated and untreated
772
In patients with no HBeAg seroconversion but with satisfactory viral suppression (HBV DNA undetectable) ADV therapy should be extended for 3 to 4 (to 5) years. Monitoring renal function and the possible emergence of drug resistant mutants is mandatory. Compared to HBeAg-positive patients it is difficult to establish when therapy can safely be discontinued in HBeAg-negative patients. If ADV treatment is stopped after 1 year, more than 90% of HBeAg negative patients will have a virological and biochemical relapse. Therefore, treatment of HBeAg negative patients should continue as long as HBV DNA suppression is achieved. Treatment for up to 5 years is well-tolerated and produces significant, increasing improvement in necroinflammation and hepatic fibrosis, durable suppression of HBV replication and normalization of ALT in 67–83% of patients [91]. In Table 63.29 important parameters of IFN, LAM and ADV effects in patients with chronic hepatitis B are summarized
Entecavir Entecavir (ENT) is a guanosine nucleoside analog with potent activity against HBV. The corresponding equivalent antiviral dose is approximately 20–100 times lower than that for adefovir dipivoxil and 200–1,000 times lower than the dose for lamivudine. Mechanism of action. ENT is intracellularly phosphorylated to guanosine triphosphate, the active form, which competes with the natural substrate thereby suppressing effectively the activity of HBV polymerase (reverse transcriptase). ENT suppresses the activity of HBV polymerase at three levels: base priming, reverse transcription of the negative strand from the pregenomic messenger RNA and the synthesis of the positive strand of HBV DNA. Pharmacology. The oral bioavailability of the solution is 100%. Solution and tablet can be used interchangeably. Food delays oral absorption. Peak levels in plasma are reached 0.5–1.5 h after oral administration. Protein binding is 13%. ENT undergoes minor hepatic conjugation with glucuronide and sulphate and does not inhibit or induce the cytochrome P450 enzyme system. The half-life is 5–6 days (risk of accumulation). Entecavir is predominantly excreted by the kidneys with 60–70% of the dose recovered as unchanged drug in the urine. Interactions. Ganciclovir and valganciclovir may
63 Viral Infections by Hepatotropic Viruses
increase the adverse effects of entecavir and other nucleoside reverse transcriptase inhibitors. Concomitant use of ribavirin and nucleoside analogs may increase the risk of hepatic decompensation or other signs of mitochondrial toxicity, including pancreatitis or lactic acidosis. Adverse reactions. ENT is well tolerated and the safety profile is similar to lamivudine. In approximately 10% of patients elevations of ALT are observed. In most patients mild-to-moderate adverse reactions including headache, upper respiratory tract infection, cough, nasopharyngitis, fatigue and upper abdominal pain are observed. However, the drug has to be discontinued because of side effects in only 1% of patients [215]. Upon abrupt discontinuation acute exacerbation of hepatitis B may occur. Contraindications. Hypersensitivity to ENT or any component of the formulation. Dosing. 0.5 mg p.o. qd on an empty stomach, i.e. at least 2 h before or after a meal. In lamivudine-resistant patients: 1 mg p.o. qd. Dose adjustment is required in renal impairment: ClCr 30–49 mL/min: 50% of usual dose ClCr 10–29 mL/min: 30% of usual dose ClCr < 10 mL/min (including dialysis): 10% of usual dose (after hemodialysis). Results and duration of treatment. Entecavir seems to be the most potent inhibitor of HBV replication, with a mean of 6.8 log10 and 5.0 log10 reduction in HBV DNA levels at 1 year in HBeAg-positive and HBeAg-negative patients, respectively. ENT 0.5 mg daily is superior to LAM 100 mg daily with regard to rates of histologic improvement, mean reduction in serum HBV DNA levels, undetectable serum HBV DNA levels (determined by PCR) and normalization of serum ALT levels in chronic hepatitis B patients irrespective of the HBeAg status. HBeAg seroconversion rates following short-term treatment do not exceed those achieved by lamivudine. At week 48 the rate of HBeAg-seroconversion is similarly low in entecavir and lamivudine treated HBeAg-positive patients, 21% and 18%, respectively [31, 128, 129]. The optimal duration of treatment is unknown. Entecavir treatment through 96 weeks results in continued benefit for patients with HBeAg-positive chronic hepatitis B, and long-term treatment is probably required to obtain and sustain virological, histological and clinical benefits [83]. No evidence of viral resistance
Hepatitis B
to entecavir is to be expected during a relatively short treatment period of 48–52 weeks. The emergence of entecavir resistance over a 2-year treatment period in previously nucleoside naïve patients is also rare, occurring mostly in patients with lamivudine resistant HBV variants [45]. Long-term treatment with entecavir will probably lead to the development of appreciable viral resistance albeit at a reduced rate compared to lamivudine. Entecavir resistant strains are sensitive to adefovir. Telbivudine Telbivudine is a synthetic thymidine nucleoside analog with strong activity against HBV. Mechanism of action. Telbivudine inhibits HBV DNA polymerase. It is phosphorylated by cellular kinases to the active triphosphate form. Incorporation of telbivudine 5’-triphosphate into viral DNA causes DNA chain termination, which results in inhibition of HBV replication. Pharmacology. Absorption is not affected when administered with food. Peak serum concentrations are achieved 1–4 h after an oral dose. Telbivudine is neither a substrate nor an inhibitor of the cytochrome P450 enzyme system. It is eliminated primarily by renal excretion of unchanged drug. The terminal elimination half-life is 40–49 h. Interactions. Drugs that alter renal function may alter plasma concentrations of telbivudine. Adverse reactions. Abdominal pain, arthralgia, back pain, cough, nausea, vomiting, loose stools, influenza-like symptoms, and insomnia may occur. Occasionally a peripheral neuropathy was observed in patients treated with telbivudine. The risk of peripheral neuropathy is increased when telbivudine is combined with pegylated interferon. Contraindications. Sensitivity to telbivudine or to any component of the product. Dosing. 600 mg p.o. qd with or without food. In patients with renal impairment: ClCr ≥ 50 mL/min: no dosage adjustment is necessary. ClCr 30–49 mL/min: 600 mg p.o. once every 48 h. ClCr < 30 mL/min (not requiring dialysis): 600 mg p.o. once every 72 h. ClCr < 30 mL/min (requiring dialysis): 600 mg p.o.
773
once every 96 h (to be administered after hemodialysis). Results and duration of treatment. Telbivudine is one of the most potent antiviral agents for HBV currently available, and there is evidence for marked doserelated antiviral activity [126]. Data from phase 2 trials indicate that telbivudine is more effective than lamivudine with improved tolerability [265]. Among patients with HBeAg-positive chronic hepatitis B, the rates of therapeutic and histologic response at 1 year are significantly higher in patients treated with telbivudine than in patients treated with lamivudine. In both the HBeAg-negative and the HBeAg-positive groups, telbivudine demonstrates greater HBV DNA suppression with less resistance than does lamivudine [96, 125]. The efficacy of telbivudine for HBV strains resistant to either lamivudine or adefovir has not been clearly defined. There are presently no large scale studies investigating the optimal duration of treatment with telbivudine. However, it can be deduced from the experience with other nucleoside analogs that long-term treatment will be optimal, provided the drug is tolerated and no viral resistance develops.
Tenofovir, Emtricitabine, Clevudine Tenofovir, emtricitabine and clevudine are also potent anti HBV drugs, although the latter two have not yet been approved by the FDA for the treatment of chronic hepatitis B. Tenofovir. Tenofovir is an acyclic nucleotide analog of adenosine monophosphate. It is available as a prodrug, tenofovir disoproxil fumarate (TDF). Tenofovir inhibits viral reverse transcriptase and acts as a DNA chain terminator. After uptake by cells TDF undergoes phosphorylation to its active metabolite TDF diphosphate that inhibits RNA- and DNAdirected reverse transcriptase and causes premature DNA termination. Oral bioavailability of tenofovir from TDF 300 mg is 25% in the fasted state. Administration of TDF following a high-fat meal (roughly 700–1,000 kcal containing 40–50% fat) increases the oral bioavailability. Protein binding of tenofovir is negligible. The intracellular half-life ranges between 15–50 h. Following a single, orally administered dose, the terminal
774
elimination half-life of tenofovir is approximately 17 h. Neither TDF nor tenofovir are substrates of cytochrome P450 enzymes. TDF is eliminated by a combination of glomerular filtration and active renal tubular secretion. Seventy to 80% of the dose is recovered in the urine as unchanged drug. The usual daily dose is 300 mg p.o. with or without food, but recent data show that low-dose TDF monotherapy (75 mg qd) can also control HBV viremia for an extended period of time without the emergence of viral resistance [50]. TDF at a daily dose of 300 mg has superior antiviral efficacy with a similar safety profile as compared with ADV at a daily dose of 10 mg [168a]. TDF is effective against LAM-resistant HBV. In patients with LAM-resistant hepatitis B, treatment with tenofovir is well-tolerated and results in significant virological, serological, and biochemical improvements on par with those seen with high-dose ADV (30 mg/day) therapy, without the complication of renal toxicity (see below) [123]. TDF may be particularly useful as part of combination therapy in HBV-HIV coinfected LAM resistant patients [6, 7, 189]. If treatment for HIV infection with tenofovir is discontinued in a patient co-infected with HBV, the patient should be closely monitored for several months for signs and symptoms of worsening hepatitis infection. Tenfovir is also effective in HBV patients with virologic breakthrough or suboptimal response to ADV in the absence of ADV-resistant mutations [221]. Due to its antiviral efficacy, its safety profile and the lack of resistant mutations at least up to week 48 of treatment TDF has the potential to be used as a first-line drug in patients who have not received treatment. Emtricitabine. Emtricitabine (also referred to as FTC) is a nucleoside analog of cytosine. It is phosphorylated by cellular enzymes to emtricitabine 5’-triphosphate, inhibits viral reverse transcriptase and acts as a chain terminator of nascent viral DNA. The optimal dose appears to be 200 mg po qd. The mean absolute bioavailability after an oral dose is 93% and peak plasma concentrations occur at 1–2 h postdose. Its plasma half-life is approximately 10 h, but the metabolite, emtricitabine-triphosphate, has an intracellular half-life of approximately 39 h. Food has no clinically significant effect on emtricitabine’s systemic exposure. The drug does not undergo hepatic enzyme metabolism, and is excreted renally.
63 Viral Infections by Hepatotropic Viruses
Emtricitabine 200 mg once daily is well tolerated and demonstrates a potent antiviral response for up to 2 years in patients with chronic hepatitis B infection [82]. Safety and efficacy of treatment have not yet been established in patients co-infected with HBV and HIV. Clevudine. Clevudine is a new pyrimidine analog with potent anti-HBV activity in vitro. A dose-escalation study evaluated clevudine at 10, 50, 100, and 200 mg once daily for 28 days. The drug was well tolerated, with no dose-limiting toxicities [167] A dose of 30 mg p.o. qd shows potent and sustained antiviral efficacy in patients with HBeAgpositive and HBeAg-negative chronic hepatitis B [259, 260]. Importantly, the suppression of antiviral activity is maintained at 12 and 24 weeks post treatment [101].
Combination Therapy The rationale for antiviral combination therapy is to increase efficacy of treatment by additive or synergistic antiviral effects and to delay, reduce or prevent the selection of drug resistant mutants. Significantly higher rates of sustained viral response (HBV DNA nondetectable 6 months after end of treatment) have been reported with pegIFNa than with lamivudine. In HBeAg-positive patients the post-therapeutic rates of HBeAg seroconversion with pegIFNa compared to lamivudine were 32% and 19%, respectively. The combination of pegIFNa with lamivudine did not yield better results than monotherapy with pegIFNa [137]. In patients with chronic HBeAg-negative hepatitis the rate of undetectable HBV DNA 24 weeks after discontinuation of therapy with pegIFNa and lamivudine was 19% and 7%, respectively. Again the combination of pegIFNa with lamivudine did not improve the results of monotherapy with pegIFNa [166]. The response rates may vary by HBV genotype (A 47%, B 44%, C 28%, D 25%), but there is no evidence that the combination with lamivudine confers additional benefit to monotherapy with pegIFNa [111, 207, 220, 239]. Thus, adding lamivudine to pegIFN does not improve the results of pegIFN monotherapy. There are indications, however, that combination therapy may delay the selection of lamivudineresistant variants and may reduce viral breakthrough during long-term lamivudine therapy [109, 111, 180]. At present the combined use of pegIFNa and oral antivirals is not recommended in clinical practice outside of clinical trials.
Hepatitis B
Adefovir dipivoxil may be combined with lamivudine after the emergence of lamivudine resistant mutants. Combination of lamivudine and ADV in treatment naïve patients is not associated with an antiviral, biochemical or serologic benefit compared to monotherapy. The seroconversion rate achieved by combination therapy is not better than that by LAM monotherapy [219]. However, the emergence of lamivudine resistant mutants and the rates of viral breakthrough are higher in patients receiving lamivudine monotherapy. The combination of ADV plus emtricitabine resulted in more potent suppression of HBV DNA over 96 weeks of therapy. More patients in the combination group had normalization of ALT and HBV DNA < 300 copies/mL at week 96 when compared with the ADV monotherapy group [103]. Further studies are required before ADV/ FTC combination therapy can be recommended. The combination of lamivudine and famciclovir is effective in suppressing HBV replication [210]. However, there is no information yet whether both drugs combined reduce or delay the emergence of resistant viral mutants. Telbivudine exhibits a significantly greater virological and biochemical response than lamivudine. The efficacy of a combination of both antivirals is similar to that of telbivudine alone [127]. The strategy of sequential, staggered therapy, using an antiviral initially to decrease HBV DNA levels before adding pegIFNa is appealing. Preliminary results suggest that the sustained viral response rates are higher and the relapse rates after discontinuation therapy might be lower than after lamivudine monotherapy [25, 26, 205, 206]. Another novel approach for treating patients with chronic hepatitis B aims at combining the antiviral effect of lamivudine with the immune modulator activity of vaccine therapy. First results in a small group of patients were encouraging with HBeAg seroconversion rates of 56% and no viral breakthrough after 1 year of combination therapy [95].
Special Therapeutic Problems Liver Cirrhosis Patients with Child’s class A cirrhosis may benefit from treatment with IFN-a or pegIFN, thereby
775
reducing the rate of decompensation and obviating or delaying the need for liver transplant. Patients with Child’s class B or C cirrhosis have minimal benefit from IFN therapy, and IFN induced ALT flares may ignite necroinflammatory activity, precipitate hepatic decompensation and potentially cause liver failure. In addition IFNs may deteriorate the already existing leukopenia and thrombocytopenia, and increase the risk of bacterial infections (e.g. spontaneous bacterial peritonitis) or of bleeding complications. IFNs are contraindicated in decompensated cirrhosis. Lamivudine is well tolerated in patients with decompensated liver cirrhosis and can stabilize or improve liver function. ADV has not been evaluated in patients with decompensated liver cirrhosis. Studies with entecavir are ongoing. Both entecavir and adefovir are effective in patients with compensated HBV cirrhosis. In patients with HBV cirrhosis with previous lamivudine resistance, “adefovir salvage” appears more effective and less expensive than “entecavir salvage” [113].
Coinfection with Other Viruses The primary endpoint of treatment in patients with HBV/HDV coinfection is the suppression of HDV replication. Currently, the only approved treatment of chronic hepatitis D is IFN-a. 9 MU 3 times a week (or pegIFN once weekly) for 1 year is recommended. The addition of ribavirin to pegIFN does not improve outcome. Lamivudine is ineffective in inhibiting HDV replication. Due to limited information firm recommendations on treatment of HBV/HCV coinfected patients cannot be made presently [159]. In one study the combination therapy with pegIFN-a2b and ribavirin was highly effective in inducing a virological response concerning HCV in patients with HBV/HCV coinfection. However, HBV replication may increase after the clearance of HCV and thus both viruses must be closely monitored even in patients with initially undetectable HBV-DNA [193]. The decision to treat HBV infection in HBV/HIV coinfected patients should be based on whether or not HIV treatment is ongoing or planned. HBV infection should be treated with pegIFNa, adefovir or entecavir in patients in whom HAART is not planned in the near future. Monotherapy with lamivudine should be
776
avoided in these patients, since it leads to selection of HIV resistant mutants. If HAART is planned, a regimen containing drugs active against both viruses should be used. Lamivudine, emtricitabine, entecavir and tenofovir have activity against both HIV and HBV. Lamivudine plus tenofovir or emtricitabine plus tenofovir are preferred. ADV has negligible activity against HIV. The rate of HBV resistance to lamivudine in HBV/HIV coinfected patients is high, reaching 90% at 4 years. In patients resistant to lamivudine adding tenofovir is the preferred option. Patients who are already on HAART that does not include a drug active against HBV may be treated with pegIFNa, adefovir or entecavir [159].
63 Viral Infections by Hepatotropic Viruses
Asian Patients Asian patients usually respond poorly to IFNs and oral antivirals [140, 141, 216]. The rates of durable responses are lower, and relapses more frequent. This probably is due to a higher percentage of immunotolerant patients with perinatally acquired HBV infection. A frequent profile, found particularly in Asian children infected perinatally consists of HBeAg positivity, elevated serum levels of HBV DNA and normal ALT values. The response rate in this group of patients is less than 10% and treatment is not warranted. However, the response in patients with elevated ALT is similar to that in Caucasian patients. Therefore, Asian patients with elevated ALT values should be offered IFN treatment.
HBV-Induced Glomerulonephritis HBV-induced glomerulonephritis, with the exception of membranous nephropathy only rarely remits spontaneously. Corticosteroids and cytotoxic agents for HBV-induced glomerular disease are of little benefit, and may increase viral persistence and replication. Uncontrolled data suggest that IFNa (5 MU s.c. qd for 16 weeks) is beneficial, and patients who show HBeAg clearance will also have an improvement in their renal function. Treatment with oral antivirals, for example lamivudine and entecavir, (dose should be adjusted for level of kidney function; adefovir should probably be avoided because of potential nephrotoxicity) that is associated with diseappearance of HBV DNA also will result in a reduction in proteinuria. The optimal choice of an agent and duration of therapy in HBV-induced glomerulonephritis are unclear.
Children The response rates to IFNa of children in central Europe and in the USA with active HBV infection and elevated aminotransferases correspond to those of adult patients. However, in Asia most children acquire HBV infection perinatally, and have normal ALT levels. Fewer than 10% of these children respond to IFNa by clearing HBeAg. Lamivudine is safe and effective in children. With increasing duration of treatment, however, the number of drug resistant mutants increases up to 64% of patients after 3 years of treatment [214].
Liver Transplantation (see Chapter 103) The precore stop mutation does not appear to influence the posttransplantation outcome, and no significant difference in posttransplantation HBV recurrence (47– 57%), graft failure (20–23%), or death are observed in patients harboring HBV with or without precore stop mutants. Surface gene mutations have been noted in patients after liver transplantation who exhibit HBV recurrence despite receiving hepatitis B immune globulin (immune escape mutant). Fibrosing cholestatic hepatitis (FCS). FCS is a severe, rapidly progressive variant of chronic hepatitis B and C in the transplanted liver. It is due to HBV reactivation during immunosuppressive therapy and “flooding” of the transplanted hepatocytes with HBsAg. The disease is characterized histologically by the absence of a marked necroiinflammatory reaction. Instead portal fibrosis with periportal fibrous septa extending into the liver lobule stand out (see Fig.63.36). In addition, extensive ductular reaction, hepatocyte ballooning and bilirubinostasis in hepatocytes, and widespread HBcAg-immunoreactivity of hepatocyte nuclei are observed (see Chapter 63.2). It has been postulated that hepatocellular alterations in FCS, in contrast to the usual pathogenesis of HBV infection, are caused by a direct cytopathic effect of HBV on hepatocytes [71]. FCS rapidly progresses to liver failure without specific therapy.
Hepatitis B
Nonresponders and Drug Resistance Nonresponders. Long-term benefit of IFN therapy is unsatisfactory in approximately 50% of patients with chronic HBV infection, be it because of a primary non-response to IFNs or because of a relapse after an initial response. The benefit of a second course of IFN has not been consistently demonstrated. It appears that retreatment is more successful in patients who relapse after an initial response to IFN than in primary IFN nonresponders. Retreatment with a higher IFN dose may lead to seroconversion in approximately 30% of patients who initially responded to IFN, but then relapsed. Retreatment of primary nonresponders with IFN alone is associated with a very low rate of sustained response, and is not warranted. Response of IFNa nonresponders to oral antivirals is similar to treatment of naïve patients [207]. Limited data suggest that retreatment with a combination of IFN and an oral antiviral is not more effective compared to retreatment with antiviral monotherapy, e.g. lamivudine. Drug Resistance. The development of resistance is determined by an interplay of viral, host, and drug characteristics. The reverse transcriptase activity of HBV DNA polymerase gene lacks a proofreading capability. Therefore, HBV exhibits a mutation rate more than tenfold higher than other DNA viruses, and a large number of mutant strains of HBV are generated daily. Drug-resistant mutant strains of HBV containing point mutations of the polymerase gene usually emerge after several months to years of oral antiviral therapy [81]. Development of specific point mutations also may confer cross-resistance to other antiviral drugs. Patients treated with IFNs do not develop drug resistant HBV strains. When using oral antiviral agents in clinical practice, an awareness of the incidence, clinical manifestations and drugs with cross resistance to mutant HBV is necessary. The detection of point mutations in the HBV polymerase gene that confer enhanced replication of mutant HBV strains in the presence of the drug in in vitro assays defines genotypic resistance. Phenotypic resistance is defined by the redetection of HBV DNA on two consecutive occasions in a compliant patient who had previously suppressed HBV DNA. Phenotypic resistance is associated with viral rebound and with serum ALT elevations in many patients. Genotypic resistance is usually followed after several weeks to months by virological
777 Table 63.30 Suggested management of patients with drug resistant HBV mutantsa Resistance to Action Lamivudineb
Adefovir Dipivoxil
Entecavir
Telbivudine
Tenofovir
Add adefovir or Add or switch to tenofovir or Switch to entecavir Add lamivudine or Add telbivudine or or Add entecavir Add adefovir or Add tenofovir Add adefovir or Add tenofovir or Switch to entecavir Add entecavir or Add telbivudine or Add lamivudine
a
Not all suggestions are based on controlled studies Telbivudine and emtricitabine show cross-resistance with lamivudine resistant mutant HBV Source: Adapted from [47, 76] b
breakthrough, i.e. a rise in serum HBV-DNA levels of 1 log10 copies/mL compared to the lowest value during therapy. Virological breakthrough is followed by a rise of serum ALT levels and a worsening of liver histology after a period of several weeks (clinical breakthrough) [72, 76, 160]. Resistant HBV can be detected either phenotypically with an increase in serum HBV DNA levels in a previously suppressed patient or by a confirmatory assay (currently, the most sensitive confirmatory test for genotypic resistance is the lineprobe assay). The clinical consequences following the emergence of drug resistant HBV range from asymptomatic viremia to serum ALT flares, progressive liver disease with worsening liver histology, hepatic decompensation with liver failure and rare instances of death [149]. Cirrhotic patients developing HBV drug resistance are significantly more likely to develop HCC on long-term follow-up [4]. Table 63.30 summarizes the suggested management of patients with drug resistant HBV mutants. Resistance to Lamivudine. Lamivudine therapy may be limited by the emergence of drug resistant mutants.
778
The development of drug resistance leads to HBV DNA breakthrough, compromises therapeutic success as determined by liver histology, reduction in HBV DNA levels and HBeAg seroconversion rates, and ultimately accelerates disease progression [53, 54, 149]. The amount of ccc DNA in the serum is reported to be higher in patients who develop YMDD mutants than in those without mutants [93]. The most important mutation conferring lamivudine resistance involves the substitution of methionine by valine or isoleucine in domain C (tyrosin-methionineaspartate-aspartate (YMDD) motif; rtM204V/I) of the HBV reverse transcriptase (“escape mutants”). The probability of YMDD mutations after 1 year of therapy is related to the magnitude of early viral suppression. The more effective the viral suppression at weeks 12 and 24 after the onset of treatment, the lesser the chance of developing drug resistant mutants. A satisfactory response is characterized by a decrease in viral load at week 12 of therapy by at least 1 log10 copies/mL, and at week 24 by 2 log10 copies/mL compared with the baseline value. Patients with primary treatment failure, i.e. those who fail to achieve a 2 log10 decline in HBV DNA after 24 weeks of treatment seem to be at greater risk of developing drug-resistant HBV. Patients with HBV DNA levels of more than 103 copies/mL after 6 months of lamivudine therapy have a 63% chance of subsequently developing lamivudine resistant YMDD variants [263]. After 1, 2, 3, 4 and 5 years of treatment, lamivudine resistant mutants emerge in 16%, 36%, 56%, 75% and approximately 80% of treatment naïve patients, respectively [76]. Further determinants for the occurrence of lamivudine-resistant HBV mutants during therapy are HBeAg status, HBV DNA and ALT levels. Patients with HBeAg seropositivity, high HBV DNA levels and low pretherapeutic serum ALT levels (< 5 × ULN) have a significantly increased incidence of lamivudine resistance [29]. Recently serum HBV RNA (indicating active transcription and virus particle formation) was reported to be a predictor of early emergence of the YMDD mutant in patients treated with lamivudine [93]. Immunosuppressed patients are at particular risk of developing drug resistance. The association of increased body mass index with lamivudine resistance may be caused by inadequate drug dosing or the adverse impact of fatty liver disease. There are no convincing data that the presence of pre-core/core-promoter variants or a particular
63 Viral Infections by Hepatotropic Viruses
HBV genotype predisposes a patient to lamivudine resistance [2]. The initial assumption that lamivudine resistant mutant viruses are less pathogenic than the HBV wildtype cannot be corroborated. During longer treatment periods lamivudine resistant mutants adapt and facilitate the selection of increasingly more pathogenic viruses. Management of patients with lamivudine resistant hepatitis B virus. Lamivudine resistant HBV remains susceptible to adefovir, entecavir and tenofovir (Table 63.30). Telbivudine and emtricitabine show cross resistance with lamivudine resistant mutant HBV. Adefovir suppresses HBV replication of lamivudine resistant HBV mutants, is well-tolerated, and is associated with virological and biochemical improvement [7, 184, 187, 188, 254, 277]. Factors associated with virologic response to ADV in lamivudine resistant patients are female gender, HBeAg-negative status, low baseline serum HBV-DNA levels, and genotype D HBV [18]. Upon emergence of genotypic viral resistance lamivudine therapy should not be discontinued. Instead, adefovir should be added to lamivudine [32, 133, 188]. “Add-on-therapy” is more effective in maintaining long-term biochemical and virological remission than switching-to adefovir monotherapy, and patients with lamivudine resistant hepatitis B are unlikely to develop genotypic resistance to adefovir [79, 134, 198, 256]. However, despite combined treatment with adefovir and lamivudine the emergence of adefovir resistance in lamivudine resistant patients may present early [257]. A daily dose of 20 mg is safe and seems to be superior to the regular dose of ADV of 10 mg p.o. qd [94]. Add-on salvage therapy with adefovir has also been shown to be cost-effective [112]. Sequential monotherapy is associated with an increased rate of drug resistance to adevofir and should be avoided [75, 258]. Tenofovir is an effective alternative to adefovir for the treatment of patients with lamivudine resistant HBV infection [233, 244]. Tenofovir is superior to adefovir and entecavir in the treatment of lamivudine resistant HBV. The 300 mg dose of tenofovir provides significantly higher concentrations than the minimal inhibitory concentration for HBV replication. Therefore, it might be assumed that the incidence of drug resistance with tenofovir will be lower than with other agents. A final assessment, however, is not yet possible and large-scale trials are still ongoing.
Hepatitis B
Entecavir has potent antiviral activity against lamivudine-resistant HBV and may be given to patients with known lamivudine resistance or who develop resistance during lamivudine therapy. The proportion of patients with undetectable HBV DNA by PCR and normalization of ALT levels increases with continued entecavir treatment. Through 96 weeks of treatment, entecavir resulted in continued clinical benefit in lamivudine-refractory HBeAg-positive chronic hepatitis B patients with a safety profile comparable to lamivudine [212]. However, the optimal duration of treatment is not known and up to 10% of lamivudine resistant patients may develop genotypic resistance to entecavir at 2 years of treatment. In contrast to adevofir ("add-on"), the lamivudine resistant patient should be switched to entecavir; i.e., lamivudine should be discontinued. The adult dose of entecavir in lamivudine resistant patients is 1 mg daily compared to 0.5 mg daily in nucleoside naive patients. Although entecavir is beneficial in lamivudine resistant patients, its antiviral activity is substantially lower compared to wild type HBV in previously untreated patients even if the higher dose of 1 mg daily is given [30, 211]. Data on the impact of pegIFN on chronic hepatitis B resistant to lamivudine are controversial. They range from only marginal efficiency of pegIFNa to response rates of approximately 30% [68, 143]. Resistance to Adefovir Dipivoxil. Resistance to adefovir does occur albeit at a slower rate compared to lamivudine. Mutations known to confer resistance to ADV include an asparagine-to-threonine change in domain D (rtN236T) and an alanine-to-valine or -threonine change in domain B (rtA181V/T) [5]. Resistance is usually not detected during the first 48 weeks of treatment. Thereafter the cumulative probability of adefovir resistant mutations increases. After 3 and 5 years of treatment resistance rates amount to 11% and 29%, respectively. However, the rate of documented adefovir resistance depends on the sensitivity of the investigational techniques applied and studies using more sensitive techniques to detect antiviral-resistant mutants reported rates of adefovir resistance of 19 to 32% at 48 weeks and 58% at 96 weeks [75, 142]. Adefovir resistance can be associated with significant viral rebound and fatal hepatic decompensation [74]. Risk factors for the development of adefovir resistance have not been well-defined, although it seems reasonable to anticipate that they probably will correspond to those described for lamivudine. Patients
779
who have lamivudine-resistant HBV seem to be at increased risk of adefovir resistance when adefovir is used alone (see above). Rare cases of variant hepatitis B virus with primary resistance to adefovir have also been described [208]. Management of adefovir resistant HBV. Adefovir resistant HBV remains sensitive to lamivudine, telbivudine, entecavir, tenofovir, and emtricitabine in vitro [74]. However, clinical experience with salvage therapy in ADV resistant patients is very limited. It is important to distinguish primary treatment failure with adefovir (i.e., lack of a 2 log10 decline in HBV DNA) that occurs in 25% of treatment-naive patients at 1 year versus the emergence of adefovir-resistant HBV, because management recommendations differ. Upon emergence of ADV-resistant HBV, treatment should be continued by adding either lamivudine, telbivudine or entecavir. Some concern has been voiced for the potential emergence of mutant strains of HBV with resistance to both drugs upon adding lamivudine to adefovir in ADV resistant patients [12, 13]. In patients with primary treatment failure a combination of tenofovir (300 mg daily) and emtricitabine (200 mg daily) resulted in undetectable HBV viral DNA levels. Thus, tenofovir, in combination with emtricitabine, may be an alternative treatment for those with detectable HBV DNA on adefovir [204]. Resistance to Entecavir. Resistance to entecavir is rare compared to lamivudine. No cases of genotypic resistance were observed in treatment-naive patients after 1 year [45]. The specific point mutations that confer resistance to entecavir include the rtI169T, rtT184G, rtS202I, and rtM250V mutants in the presence of a lamivudine-resistant strain of HBV. Entecavir monotherapy does not lead to the selection of these mutants of HBV unless there is a subpopulation of HBV quasispecies in the host that are already resistant to lamivudine. Thus, resistance to entecavir requires the presence of preexisting lamivudine-resistant strains of HBV along with the emergence of additional mutations [76]. Based on in vitro data, entecavir-resistant HBV is also resistant to lamivudine, emtricitabine, and telbivudine, but should remain susceptible to adefovir and tenofovir. Resistance to Telbivudine. The rtM204I (domain C) mutation confers cross-resistance to lamivudine as well as to telbivudine. Resistance to telbivudine is 5% at 1 year in telbivudine monotherapy and 10% in combination with lamivudine [127].
780
Resistance to Emtricitabine. The rates of development of resistant mutants are similar in emtricitabine and lamivudine. Resistance is conferred by the rtM204V/I mutation with or without the accompanying rtL180M mutation. Emtricitabine-resistant strains of HBV retain susceptibility to adefovir, tenofovir, and entecavir, but are cross resistant with lamivudine and telbivudine. Chronic hepatitis B, once a purely diagnostic field, has become now a highly dynamic and complex clinical and research subject with rapidly emerging new therapies. New nucleos(t)ide analogs are already beginning to replace the first generation drugs, such as lamivudine and adefovir. The aim of the preceding discussion was to lay the foundation for a rational decision making process in patients with chronic hepatitis B. The indication for antiviral therapy should take into careful consideration the patient’s wish, contraindications and accompanying diseases, the urgency of treatment and the chances of HBV elimination. As a rule, there is no need for ad hoc therapeutic decisions and the clinician has enough time to observe the patient and the course of hepatic and viral parameters before deciding on the appropriate therapeutic approach (with the exception of patients with decompensated HBV-cirrhosis). Antiviral treatment should not be offered to patients who have persistently normal ALT levels or mild disease on liver biopsy unless they are undergoing chemotherapy or immunsuppression. In patients who are undergoing antiviral treatment careful monitoring and surveillance for early recognition of the emergence of drug resistant HBV (except in IFN treated patients) is mandatory. The awareness for the potential cross-resistance among the available oral antiviral agents is important when performing salvage or combination therapy.
References 1. Ahn SH, Park YN, Park JY, et al (2005) Long-term clinical and histological outcomes in patients with spontaneous hepatitis B surface antigen seroclearance. J Hepatol 42: 188–94 2. Akuta N, Suzuki F, Kobayashi M, et al (2003) The influence of hepatitis B virus genotype on the development of lamivudine resistance during long-term treatment. J Hepatol 38: 315–21 3. Andreani T, Serfaty L, Mohand D, et al (2007) Chronic hepatitis B virus carriers in the immunotolerant phase of infection: histologic findings and outcome. Clin Gastroenterol Hepatol 5: 636–41
63 Viral Infections by Hepatotropic Viruses 4. Andreone P, Gramenzi A, Cursaro C, et al (2004) High risk of hepatocellular carcinoma in anti-HBe positive liver cirrhosis patients developing lamivudine resistance. J Viral Hepat 11: 439–42 5. Angus P, Vaughan R, Xiong S, et al (2003) Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase. Gastroenterology 125: 292–7 6. Benhamou Y, Tubiana R, Thibault V (2003) Tenofovir disoproxil fumarate in patients with HIV and lamivudine-resistant hepatitis B virus. N Engl J Med 348: 177–8 7. Benhamou Y, Fleury H, Trimoulet P, et al (2006) Antihepatitis B virus efficacy of tenofovir disoproxil fumarate in HIV-infected patients. Hepatology 43: 548–55 8. Benhamou Y, Thibault V, Vig P, et al (2006) Safety and efficacy of adevofir dipivoxil in patients infected with lamivudine-resistant hepatitis B and HIV-1. J Hepatol 44: 62–7 9. Bond WW, Favero MS, Petersen NJ, et al (1981) Survival of hepatitis B virus after drying and storage for one week. Lancet 1 (8219): 550–1 10. Boni C, Penna A, Ogg GS, et al (2003) Lamivudine treatment can overcome cytotoxic T-cell hyporesponsiveness in chronic hepatitis B: new perspectives for immune therapy. Hepatology 33: 963–71 11. Bonino F, Marcellin P, Lau GK, et al (2007) Predicting response to peginterferon (alpha)-2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B. Gut 56: 699–705 12. Brunelle MN, Jacquard AC, Pichoud C, et al (2004) Susceptibility to antivirals of a human HBV strain with mutations conferring resistance to both lamivudine and adefovir. Hepatology 41: 1391–8 13. Brunelle MN, Jacquard AC, Pichoud C, et al (2005) Susceptibility to antivirals of a human HBV strain with mutations conferring resistance to both lamivudine and adefovir. Hepatology 41: 1391–8 14. Brunetto MR, Oliveri F, Coco B, et al (2002) Outcome of anti-HBe positive chronic hepatitis B in alpha-interferon treated and untreated patients: a long term cohort study. J Hepatol 36: 263–70 15. Buster EH, van der Eijk AA, Schalm SW (2003) Doctor to patient transmission of hepatitis B virus: implications of HBV DNA levels and potential new solutions. Antiviral Res 60: 79–85 16. Buster EH, Hansen BE, Buti M, et al (2007) Peginterferon alpha-2b is safe and effective in HBeAg-positive chronic hepatitis B patients with advanced fibrosis. Hepatology 46: 388–94 17. Buster EH, Flink HJ, Cakaloglu Y, et al (2008) Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg-positive patients treated with peginterferon alpha2b. Gastroenterology 135: 459–67 18. Buti M, Elefsiniotis I, Jardi R, et al (2007) Viral genotype and baseline load predict the response to adefovir treatment in lamivudine-resistant chronic hepatitis B patients. J Hepatol 47: 366–72 19. Cacciola I, Spatari G, Pollicino T, et al (2005) Virological profiles in hepatitis B virus inactive carriers: monthly evaluation in 1-year follow-up study. Liver Int 25: 555–3 20. Cacoub P, Saadoun D, Bourliere M, et al (2005) Hepatitis B virus genotypes and extrahepatic manifestations. J Hepatol 43: 764–70
References 21. CDC (1991) Recommendations for preventing transmission of human immunodeficiency virus and hepatitis B virus to patients during exposure-prone invasive procedures. MMWR 40: 1–7 22. Chan HL, Tsang SW, Leung NW, et al (2002) Occult HBV infection in cryptogenic liver cirrhosis in an area with high prevalence of HBV infection. Am J Gastroenterol 97: 1211–5 23. Chan HL, Tsang SWC, Wong ML, et al (2002) Genotype B hepatitis B virus is associated with severe icteric flare-up of chronic hepatitis B virus infection in Hong Kong. Am J Gastroenterol 97: 2629–33 24. Chan HL, Hui AY, Wong ML, et al (2004) Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma. Gut 53: 1494–8 25. Chan, HL, Hui, AY, Wong, VW, et al (2005) Long-term follow-up of peginterferon and lamivudine combination treatment in HBeAg-positive chronic hepatitis B. Hepatology 41: 1357–64 26. Chan HL, Leung NW, Hui AY et al (2005) A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-alpha2b and lamivudine with lamivudine alone. Ann Intern Med 142: 240–50 27. Chan TM, Fang GX, Tang CSO, et al (2002) Preemptive lamivudine therapy based on HBV DNA in HBsAg-positive kidney allograft recipients. Hepatology 36: 1246–52 28. Chang JJ, Thompson AJ, Visvanathan K, et al (2007) The phenotype of hepatitis B virus-specific T cells differ in the liver and blood in chronic hepatitis B virus infection. Hepatology 46: 1332–40 29. Chang ML, Chien RN, Yeh CT, et al (2005) Virus and transaminase levels determine the emergence of drug resistance during long-term lamivudine therapy in chronic hepatitis B. J Hepatol 43: 72–7 30. Chang TT, Gish RG, Hadziyannis SJ, et al (2005) A doseranging study of the efficacy and tolerability of entecavir in lamivudine-refractory chronic hepatitis B patients. Gastroenterology 129: 1198–209 31. Chang TT, Gish RG, de Man R, et al (2006) A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med 354: 1001–10 32. Chen CH, Lee CM, Lu SN, et al (2004) Comparison of clinical outcome between patients continuing and discontinuing lamivudine therapy after biochemical breakthrough of YMDD mutants. J Hepatol 41: 454–461 33. Chen CJ, Yang HE, Su J, et al (2006) Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 295: 65–73 34. Chen M, Sälberg M, Hughes J, et al (2005) Immune tolerance split between hepatitis B virus precore and core proteins. J Virol 79: 3016–27 35. Chiaramonte M, Stroffolini T, Vian A, et al (1999) Rate of incidence of hepatocellular carcinoma in patients with compensated cirrhosis. Cancer 85: 2132–7 36. Chien RN, Liaw YF, Atkins M, et al (1999) Pretherapy alanine transaminase level as a determinant for hepatitis B e antigen seroconversion during lamivudine therapy in patients with chronic hepatitis B. Hepatology 30: 770–4 37. Chien RN, Lin CH, Liaw YF (2003) The effect of lamivudine therapy in hepatic decompensation during acute exacerbation of chronic hepatitis B. J Hepatol 38: 322–7
781 38. Chien RN, Yeh CT, Tsai SL, et al (2003) Determinants for sustained HBeAg response to lamivudine therapy. Hepatology 38: 1267–73 39. Choi MS, Lee JH, Koh KC, et al (2001) Clinical significance of enlarged perihepatic lymph nodes in chronic hepatitis B. J Clin Gastroenterol 32: 329–32 40. Chu CJ, Husssain M, Lok ASF (2002) Quantitative serum HBV DNA levels during different stages of chronic hepatitis B infection. Hepatology 36: 1408–15 41. Chu CJ, Hussain M, Lok ASF (2002) Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C. Gastroenterology 122: 1756–62 42. Chu CM, Liaw YF (2005) Genotype C hepatitis B virus infection is associated with a higher risk of reactivation of hepatitis B and progression to cirrhosis than genotype B: a longitudinal study of hepatitis B e antigen-positive patients with normal aminotransferase levels at baseline. J Hepatol 43: 411–7 43. Chu CM, Liaw YF (2007) HBsAg seroclearance in asymptomatic carriers of high endemic areas: appreciably high rates during a long-term follow-up. Hepatology 45: 1187–92 44. Chu CM, Liaw YF (2007) Predictive factors for reactivation of hepatitis B following hepatitis B e antigen seroconversion in chronic hepatitis B. Gastroenterology 133: 1458–65 45. Colonno RJ, Rose R, Baldick CJ, et al (2006) Entecavir resistance is rare in nucleoside naïve patients with hepatitis B. Hepatology 44: 1656–65 46. Cooksley, WG, Piratvisuth, T, Lee, SD, et al (2003) Peginterferon alpha-2a (40 kDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B. J Viral Hepat 10: 298–305 47. Cornberg M, Protzer U, Dollinger MM, et al (2007) Prophylaxe, Diagnostik und Therapie der Hepatitis-B-Virus-(HBV-) Infektion. Z Gastroenterol 45: 525–74 48. Czaja AJ (1997) Extrahepatic immunologic features of chronic viral hepatitis. Dig Dis 15:125–44 49. de Jongh FE, Janssen HL, de Man RA, et al (1992) Survival and prognostic indicators in hepatitis B surface antigen-positive cirrhosis of the liver. Gastroenterology 103: 1630–5 50. Del Poggio P, Zaccanelli M, Oggionni M, et al (2007) Lowdose tenofovir is more potent than adefovir and is effective in controlling HBV viremia in chronic HBeAg-negative hepatitis B. World J Gastroenterol 13: 4096–9 51. Di Marco V, Marzano A, Lampertico P, et al (2004) Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological response to lamivudine. Hepatology 40: 883–91 52. Dienstag JL, Schiff ER, Wright TL, et al (1999) Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 341:1256–63 53. Dienstag JL, Cianciara J, Karayalcin S, et al (2003) Durability of serologic response after lamivudine treatment of chronic hepatitis B. Hepatology 37: 748–55 54. Dienstag JL, Goldin RD, Heathcote EJ, et al (2003) Histological outcome during long-term lamivudine therapy. Gastroenterology 124: 105–17 55. Dienstag JL (2008) Hepatitis B virus infection. N Engl J Med 359: 1486–500 56. Engelke M, Mills K, Seitz S, et al (2006) Characterization of a hepatitis B and hepatitis delta virus receptor binding site. Hepatology 43: 750–60
782 57. Erhardt A, Blondin D, Hauck K, et al (2005) Response to interferon alfa is hepatitis B virus genotype dependent: genotype A is more sensitive to interferon than genotype D. Gut 54: 1009–13 58. Ertekin V, Selimoglu MA, Orbak Z (2005) Effects of lamivudine therapy on the glucose metabolism in children with chronic hepatitis B: first year follow-up results. Eur J Gastroenterol Hepatol 17: 655–9 59. Esteve M, Saro C, Gonzalez-Huix F, et al (2004) Chronic hepatitis B reactivation following infliximab therapy in Crohn’s disease patients: need for primary prophylaxis. Gut 53: 1363–5 60. Fabrizi F, Dixit V, Martin P (2006) Meta-analysis: antiviral therapy of hepatitis B virus-associated glomerulonephritis. Aliment Pharmacol Ther 24: 781–8 61. Fattovich G, Giustina G, Schalm SW, et al (1995) Occurrence of hepatocellular carcinoma and decompensation in Western patients with cirrhosis type B. The EUROHEP Study Group on hepatitis B virus and cirrhosis. Hepatology 21: 77–82 62. Fattovich G, Giustina G, Realdi G, et al (1997) Long-term outcome of hepatitis B e antigen-positive patients with compensated cirrhosis treated with interferon alfa. European concerted action on viral hepatitis (EUROHEP). Hepatology 26:1338–42 63. Fattovich G, Giustain G, Christensen E, et al (2000) Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B. Gut 46: 420–6 64. Fattovich G, Pantalena M, Zagni I, et al (2002) Effect of hepatitis B and C virus infection on the natural history of compensated cirrhosis: a cohort study of 297 patients. Am J Gastroenterol 97: 2886–95 65. Fattovich G (2003) Natural history and prognosis of hepatitis B. Semin Liver Dis 23: 47–58 66. Fattovich G, Olivari N, Pasino M, et al (2008) Long-term outcome of chronic hepatitis B in Caucasian patients: mortality after 25 years. Gut 57: 84–90 66a. Fattovich G, Bortolotti F, Donato F (2008) Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol 48: 335–52 67. Flink HJ, Sprengers D, Hansen BE, et al (2005) Flares in chronic hepatitis B patients induced by the host or the virus? Relation to treatment response during Peg-interferon {alpha}-2b therapy. Gut 54: 1604–9 68. Flink HJ, Hansen BE, Heathcote EJ, et al (2006) Successful treatment with peginterferon alfa-2b of HBeAg-positive HBV non-responders to standard interferon or lamivudine. Am J Gastroenterol 101: 2523–9 69. Flink HJ, van Zonneveld M, Hansen BE, et al (2006) Treatment with Peg-interferon alpha-2b for HBeAgpositive chronic hepatitis B: HBsAg loss is associated with HBV genotype. Am J Gastroenterol 101: 297–303 70. Fontana RJ (2003) Management of patients with decompensated HBV cirrhosis. Semin Liver Dis 23: 89–100 71. Foo NC, Ahn BY, Hyun W, et al (2002) Cellular vacuolization and apoptosis induced by hepatitis B virus large surface protein. Hepatology 36: 1400–7 72. Fournier C, Zoulim F (2007) Antiviral therapy of chronic hepatitis B: prevention of drug resistance. Clin Liver Dis 11: 869–92
63 Viral Infections by Hepatotropic Viruses 73. Fried MW, Piratvisuth T, Lau GK, et al (2008) HBeAg and hepatitis B virus DNA as outcome predictors during therapy with peginterferon alfa-2a for HBeAg-positive chronic hepatitis B. Hepatology 47: 428–34 74. Fung SK, Andreone P, Han SH, et al (2005) Adefovirresistant hepatitis B can be associated with viral rebound and hepatic decompensation. J Hepatol 43: 937–43 75. Fung SK, Chae HB, Fontana RJ, et al (2006) Virologic response and resistance to adefovir in patients with chronic hepatitis B. J Hepatol 44: 283–90 76. Fung SK, Fontana RJ (2006) Management of drug-resistant chronic hepatitis B. Clin Liver Dis 10: 275–302 77. Fung SK, Lok ASF (2005) Management of patients with hepatitis B virus-induced cirrhosis. J Hepatol 42: S54–64 78. Fung SK, Wong F, Hussain M, et al (2004). Sustained response after a 2-year course of lamivudine treatment of hepatitis B e antigen-negative chronic hepatitis B. J Viral Hepat 11: 432–8 79. Gaia S, Barbon V, Smedile A, et al (2008) Lamivudineresistant chronic hepatitis B: an observational study on adefovir in monotherapy or in combination with lamivudine. J Hepatol 48: 540–7 80. Ganem D, Prince AM (2004) Hepatitis B virus infection – natural history and clinical consequences. N Engl J Med 350: 1118–29 81. Ghany M, Liang TJ (2007) Drug targets and molecular mechanisms of drug resistance in chronic hepatitis B. Gastroenterology 132: 1574–85 82. Gish RG, Trinh H, Leung N, et al (2005) Safety and antiviral activity of emtricitabine (FTC) for the treatment of chronic hepatitis B infection: A two-year study. J Hepatol 43: 60–6 83. Gish RG, Lok AS, Chang TT, et al (2007) Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B. Gastroenterology 133: 1437–44 84. Guidotti LG, Rochford R, Chung J, et al (1999) Viral clearance without destruction of infected cells during acute HBV infection. Science 284: 825–9 85. Guidotti LG, Chisari FV (2000) Cytokine-mediated control of viral infections. Virology 273: 221–7 86. Guillevin L, Lhote F, Cohen P, et al (1995) Polyarteritis nodosa related to hepatitis B virus. A prospective study with long-term observation of 41 patients. Medicine (Baltimore) 74: 238–53 87. Gunson RN, Shouval D, Roggendorf M, et al (2003) Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in health care workers (HCWs): guidelines for prevention of transmission of HBV and HCV from HCW to patients. J Clin Virol 27: 213–30 88. Hadziyannis SJ, Papatheodoridis GV, Dimou E, et al (2000) Efficacy of long-term lamivudine monotherapy in patients with hepatitis B e antigen-negative chronic hepatitis B. Hepatology 32: 847–51 89. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al (2003) Adefovir dipivoxil for the treatment of hepatitis B e antigen–negative chronic hepatitis B. N Engl J Med 348: 800–7 90. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al (2005) Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B. N Engl J Med 352: 2673–81
References 91. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al (2006) Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology 131: 1743–51 92. Hann HW, Fontana RJ, Wright T, et al (2003) A United States compassionate use study of lamivudine treatment in nontransplantation candidates with decompensated hepatitis B virus-related cirrhosis. Liver Transpl 9: 49–56 93. Hatakeyama T, Noguchi C, Hiraga N, et al (2007) Serum HBV RNA is a predictor of early emergence of the YMDD mutant in patients treated with lamivudine. Hepatology 45: 1179–86 94. Hezode C, Chevaliez S, Bouvier-Alias M, et al (2007) Efficacy and safety of adefovir dipivoxil 20 mg daily in HBeAg-positive patients with lamivudine-resistant hepatitis B virus and a suboptimal virological response to adefovir dipivoxil 10 mg daily. J Hepatol 46: 791–6 95. Horiike N, Fazle Akbar SM, et al (2005) In vivo immunization by vaccine therapy following virus suppression by lamivudine: a novel approach for treating patients with chronic hepatitis B. J Clin Virol 32: 156–61 96. Hou J, Yin YK, Xu D, et al (2008) Telbivudine versus lamivudine in Chinese patients with chronic hepatitis B: Results at 1 year of a randomized, double-blind trial. Hepatology 47: 447–54 97. Hsu CW, Yeh CT, Chang ML, et al (2007) Identification of a hepatitis B virus S gene mutant in lamivudine-treated patients experiencing HbsAg seroclearance. Gastroenterology 132: 543–50 98. Hsu C, Hsiung CA, Su IJ, et al (2008) A revisit of prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in non-Hodgkin’s lymphoma: a randomized trial. Hepatology 47: 844–53 99. Hui AY, Chan HL, Wong VW, et al (2005) Identification of chronic hepatitis B patients without significant liver fibrosis by a simple noninvasive predictive model. Am J Gastroenterol 100: 616–23 100. Hui CK, Cheung WW, Au WY, et al (2005) Hepatitis B reactivation after withdrawal of pre-emptive lamivudine in patients with haematological malignancy on completion of cytotoxic chemotherapy. Gut 54: 1597–603 101. Hui CK, Lau GK (2005) Clevudine for the treatment of chronic hepatitis B virus infection. Expert Opin Investig Drugs 14: 1277–1284 102. Hui CK, Leung N, Shek TW, et al (2007) Sustained disease remission after spontaneous HBeAg seroconversion is associated with reduction in fibrosis progression in chronic hepatitis B Chinese patients. Hepatology 46: 690–8 103. Hui CK, Zhang HY, Bowden S, et al (2008) 96 weeks combination of adefovir dipivoxil plus emtricitabine vs. adefovir dipivoxil monotherapy in the treatment of chronic hepatitis B. J Hepatol 48: 714–20 104. Hunt C, McGill LM, Allen MIA, et al (2000) Clinical relevance of hepatitis B viral mutations. Hepatology 31: 1037–44 105. Hyams KC (1995) Risks of chronicity following acute hepatitis B virus infection: a review. Clin Infect Dis 20: 992–1000 106. Iloeje UH, Yang HI, Su J, et al (2006) Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 130: 678–86
783 107. International European Association for the Study of the Liver (2003) Consensus conference on hepatitis B: consensus statement. J Hepatol 38: S90–103 108. Jang JW, Choi JY, Bae SH, et al (2006) A randomized controlled study of preemptive lamivudine in patients receiving transarterial chemo-lipiodolization. Hepatology 43: 233–40 109. Jang MK, Chung YH, Choi MH, et al (2004) Combination of alpha-interferon with lamivudine reduces viral breakthrough during long-term therapy. J Gastroenterol Hepatol 19:1363–8 110. Janssen HL, Higuchi H, Abdulkarim A, et al (2003) Hepatitis B virus enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) cytotoxicity by increasing TRAIL-R1/death receptor 4 expression. J Hepatol 39: 414–20 111. Janssen HL, van Zonneveld M, Senturk H, et al (2005) Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet 365: 123–9 112. Kanwal F, Gralnek IM, Martin P, et al (2005) Treatment alternatives for chronic hepatitis B virus infection: a costeffectiveness analysis. Ann Intern Med 142: 821–31 113. Kanwal F, Farid M, Martin P, et al (2006) Treatment alternatives for hepatitis B cirrhosis: a cost-effectiveness analysis. Am J Gastroenterol 101: 2076–89 114. Keefe EB, Dieterich DT, Han SB, et al (2006) A treatment algorithm for the management of chronic hepatitis B virus infection in the United States. Clin Gastroenterol Hepatol 4: 936–62 115. Keeffe EB, Zeuzem S, Koff RS, et al (2007) Report of an international worshop: roadmap for management of patients receiving oral therapy for chronic hepatitis B. Clin Gastroenterol Hepatol 5: 890–7 116. Kellerman SE, Hanson DL, McNaghten AD, et al (2003) Prevalence of chronic hepatitis B and incidence of acute hepatitits B infection in human immunodeficiency virusinfected subjects. J Infect Dis 188: 571–7 117. Kim WR, Ishitani MB, Dickinson ER (2002) Rising burden of hepatitis B in the United States: Should the other virus be forgotten? Hepatology 36: A222 118. Kim BK, Kim SA, Park YN, et al (2007) Noninvasive models to predict liver cirrhosis in patients with chronic hepatitis B. Liver Int 27: 969–76 119. King JK, Yeh SH, Lin MW, et al (2002) Genetic polymorphisms in interferon pathway and response to interferon treatment in Hepatitis B patients: a pilot study. Hepatology 36: 1416–24 120. Kohrt HE, Ouyang DL, Keeffe EB (2006) Systematic review: lamivudine prophylaxis for chemotherapy-induced reactivation of chronic hepatitis B virus infection. Aliment Pharmacol 24: 1003–16 121. Kumar M, Satapathy S, Monga R, et al (2007) A randomized controlled trial of lamivudine to treat acute hepatitis B. Hepatology. 45: 97–101 122. Kumar M, Sarin SK, Hissar S, et al (2008) Virologic and histologic features of chronic hepatitis B virus-infected asymptomatic patients with persistently normal ALT. Gastroenterology 134: 1376–84 123. Kuo A, Dienstag JL, Chung RT (2004) Tenofovir disoproxil fumarate for the treatment of lamivudine-resistant hepatitis B. Clin Gastroenterol Hepatol 2: 266–72
784 124. Lai CL, Chien RN, Leung NW, et al (1998) A one-year trial of lamivudine for chronic hepatitis B. N Engl J Med 339: 61–8 125. Lai CL, Gane E, Liaw YF, et al (2007) Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med 357: 2576–88 126. Lai CL, Lim SG, Brown NA, et al (2004) A dose-finding study of once-daily oral telbivudine in HBeAg-positive patients with chronic hepatitis B virus infection. Hepatology 40: 719–26 127. Lai CL, Leung N, Teo EK, et al (2005) A 1-year trial of telbivudine, lamivudine, and the combination in patients with hepatitis B e antigen-positive chronic hepatitis B. Gastroenterology 129: 528–36 128. Lai CL, Rosmawati M, Lao J, et al (2002) Entecavir is superior to lamivudine in reducing hepatitis B virus DNA in patients with chronic hepatitis B infection. Gastroenterology 123: 1831–8 129. Lai CL., Shouval D., Lok A S., et al (2006) Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med 354: 1011–20 130. Lai KN, Lai FM (1991) Clinical features and the natural course of hepatitis B virus-related glomerulopathy in adults. Kidney Int (Suppl) 35: S40–5 131. Lai KN, Li PK, Lui SF, et al (1991) Membranous nephropathy related to hepatitis B virus in adults. N Engl J Med 324: 1457–63 132. Lai M, Hyatt BJ, Nasser I, et al (2007) The clinical significance of persistently normal ALT in chronic hepatitis B infection. J Hepatol 47: 760–7 133. Lampertico P, Vigano M, Manenti E, et al (2005) Adefovir rapidly suppresses hepatitis B in HBeAg-negative patients developing genotypic resistance to lamivudine. Hepatology 42: 1414–9 134. Lampertico P, Vigano M, Manenti E, et al (2007) Low resistance to adefovir combined with lamivudine: a 3-year study of 145 lamivudine-resistant hepatitis B patients. Gastroenterology 133: 1445–51 135. Lao TT, Chan BC, Leung WC, et al (2007) Maternal hepatitis B infection and gestational diabetes mellitus. J Hepatol 47: 46–50 136. Laras A, Koskinas J, Dimou E, et al (2006) Intrahepatic levels and replicative activity of covalently closed circular hepatitis B virus DNA in chronically infected patients. Hepatology 44: 694–702 137. Lau GKK, Piratvisuth T, Luo KX, et al (2005) Peginterferon alfa-2a, lamivudine, and the combination for HBeAgpositive chronic hepatitis B. N Engl J Med 352: 2682–95 138. Lavanchy D (2004) Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat 11: 97–107 139. Lee WM (1997) Hepatitis B virus infection. N Engl J Med 337: 1733–45 140. Lee CM, Ong GY, Lu SN, et al (2002) Durability of lamivudine-induced HBeAg seroconversion for chronic hepatitis B patients with acute exacerbation. J Hepatol 37: 669–74 141. Lee KM, Cho SW, Kim SW, et al (2002) Effect of virological response on post-treatment durability of lamivudine-induced HBeAg seroconversion. J Viral Hepat 9: 208–12
63 Viral Infections by Hepatotropic Viruses 142. Lee YS, Suh DJ, Lim YS, et al (2006) Increased risk of adefovir resistance in patients with lamivudine-resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy. Hepatology 43:1385–91 143. Leemans WF, Flink HJ, Janssen HL, et al (2006) The effect of pegylated interferon-alpha on the treatment of lamivudine resistant chronic HBeAg positive hepatitis B virus infection. J Hepatol 44: 507–11 144. Lemon SM, Thomas DL (1997) Vaccines to prevent viral hepatitis. N Engl J Med 336: 196–204 145. Liaw YF, Tai DI, Chu CM, et al (1988) The development of cirrhosis in patients with chronic type B hepatitis: a prospective study. Hepatology 8: 493–6 146. Liaw YF (1995) Role of hepatitis C virus in dual and triple hepatitis virus infection. Hepatology 22: 1101–8 147. Liaw YF (2003) Hepatitis flares and hepatitis B e antigen seroconversion: implication an anti-hepatitis B virus therapy. J Gastroenterol Hepatol 18: 246–52 148. Liaw YF, Chen YC, Sheen IS, et al (2004) Impact of acute hepatitis C virus superinfection in patients with chronic hepatitis B virus infection. Gastroenterology 126: 1024–9 149. Liaw YF, Sung JJ, Chow WC, et al (2004) Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 351: 1521–31 150. Liaw YF, Leung NW, Guan R, et al (2005) Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2005 update. Liver Int 25: 472–89 151. Lin CL, Liao LY, Liu CJ, et al (2007) Hepatitis B viral factors in HBeAg-negative carriers with persistently normal serum alanine aminotransferase levels. Hepatology 45: 1193–8 152. Lin SM, Sheen IS, Chien RN, et al (1999) Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection. Hepatology 29: 971–5 153. Lin SM, Yu ML, Lee CM, et al (2007) Interferon therapy in HBeAg positive chronic hepatitis reduces progression to cirrhosis and hepatocellular carcinoma. J Hepatol 46: 45–52 154. Liu CJ, Kao JH, Chen DS (2005) Therapeutic implications of hepatitis B virus genotypes. Liver International 25: 1097–107 155. Liu CJ, Lai MY, Chao YC, et al (2006) Interferon alpha-2b with and without ribavirin in the treatment of hepatitis B e antigen-positive chronic hepatitis B: A randomized study. Hepatology 43: 742–9 156. Livingston SE, Simonetti JP, Bulkow LR, et al (2007) Clearance of hepatitis B e antigen in patients with chronic hepatitis B and genotypes A, B, C, D, and F. Gastroenterology 133: 1452–7 157. Lok ASF, Lai CL, Leung N, et al (2003) Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology 125: 1714–22 158. Lok ASF, McMahon BJ (2004) American Association for the Study of Liver Diseases practice guidelines. Chronic hepatitis B: update of recommendations. Hepatology 39: 857–61 159. Lok ASF, McMahon BJ (2007) AASLD Practice Guidelines. Chronic Hepatitis B. Hepatology 45: 507–39 160. Lok ASF, Zoulim F, Locarnini S, et al (2007) Antiviral drug-resistant HBV: standardization of nomenclature and assays and recommendations for management. Hepatology 46: 254–65 161. Lu CY, Chiang BL, Chi WK, et al (2004) Waning immunity to plasma-derived hepatitis B vaccine and the need for
References boosters 15 years after neonatal vaccination. Hepatology 40: 1415–20 162. Manolakopoulos S, Karatapanis S, Elefsiniotis J, et al (2004) Clinical course of lamivudine monotherapy in patients with decompensated cirrhosis due to HBeAg negative chronic HBV infection. Am J Gastroenterol 99: 57–63 163. Manolakopoulos S, Bethanis S, Elefsiniotis J, et al (2006) Lamivudine monotherapy in HBeAg-negative chronic hepatitis B: prediction of response-breakthrough and long-term clinical outcome. Aliment Pharmacol Ther 23: 787–95 164. Manno M, Camma C, Schepis F, et al (2004) Natural history of chronic HBVcarriers in Northern Italy: morbidity and mortality after 30 years. Gastroenterology 127: 756–63 165. Marcellin P, Chang TT., Lim SG, et al (2003) Adefovir dipivoxil for the treatment of hepatitis B e antigen–positive chronic hepatitis B. N Engl J Med 348: 808–16 166. Marcellin, P, Lau GK, Bonino F, et al (2004) Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 351: 1206–17 167. Marcellin P, Mommeja-Marin H, Sacks SL, et al (2004) A phase II dose-escalating trial of clevudine in patients with chronic hepatitis B. Hepatology 40: 140–8 168. Marcellin P, Chang TT, Lim SG, et al (2008) Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. Hepatology 48: 750–8 168a. Marcellin P, Heathcote EJ, Buti M, et al (2008) Tenefovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med 359: 2442–55 169. Marschenz S, Endres AS, Brinckmann A, et al (2006) Functional analysis of complex hepatitis B virus variants associated with development of liver cirrhosis. Gastroenterology 131: 765–80 170. Martyak LA, Taqavi E, Saab S (2008) Lamivudine prophylaxis is effective in reducing hepatitis B reactivation and reactivation-related mortality in chemotherapy patients: a meta-analysis. Liver Int 28: 28–38 171. Mast EE, Mahoney FJ, Alter MJ, et al (1998) Progress toward elimination of hepatitis B virus transmission in the United States. Vaccine 16: S48–51 172. McMillan JS, Shaw T, Angus PW, et al (1995) Effect of immunosuppressive and antiviral agents on hepatitis B virus replication in vitro. Hepatology 22: 36–43 173. Minuk GY, Sun DF, Uhanova J, et al (2005) Occult hepatitis B virus infection in a North American community-based population. J Hepatol 42: 480–5 174. Mohamadnejad M, Montazeri G, Fazlollahi A, et al (2006) Noninvasive markers of liver fibrosis and inflammation in chronic hepatitis B-virus related liver disease. Am J Gastroenterol 101: 2537–45 175. Mommeja-Marin H, Mondou E, Blum R, et al (2003) Serum HBV DNA as a marker of efficacy during therapy for chronicHBVinfection: analysis and review of the literature. Hepatology 37: 1309–19 176. Myers RP, Tainturier MH, Ratziu V, et al (2003) Prediction of liver histological lesions with biochemical markers in patients with chronic hepatitis B. J Hepatol 39: 222–30 177. Nathan DM, Angus PW, Gibson PR (2006) Hepatitis B and C virus infections and anti-tumor necrosis factor-a therapy:
785
178.
179.
180.
181.
182.
183.
184. 185.
186.
187.
188.
189.
190.
191.
192. 193.
194.
guidelines for clinical aproach. J Gastroenterol Hepatol 21: 1366–71 Neumann-Haefelin C, Blum HE, Thimme R (2006) Immunantwort bei der Hepatitis-B und -C-Virusinfektion. Der Gastroenterologe 1: 109–16 Niederau C, Heintges T, Lange S, et al (1996) Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med 334:1422–7 Nikolaidis NL, Giouleme OI, Tziomalos KA, et al (2005) Interferon/long-term lamivudine combination therapy in antiHBe positive chronic hepatitis B patients. J Gastroenterol Hepatol 20: 1721–5 Ong SW, Mak B, Aung MO, et al (2008) Health-related quality of life in chronic hepatitis B patients. Hepatology 47: 1108–17 Papatheodoridis GV, Dimou E, Dimakopoulos K, et al (2005) Outcome of hepatitis B e antigen-negative chronic hepatitis B on long-term nucleos(t)ide analog therapy starting with lamivudine. Hepatology 42: 121–9 Papatheodoridis GV, Hadziyannis E, Tsochatzis E, et al (2008) Serum apoptotic caspase activity as a marker of severity in HBeAg-negative chronic hepatitis B virus infection. Gut 57: 500–6 Pawlotsky J (2003) Molecular diagnosis of viral hepatitis. Gastroenterology 122: 1554–68 Perrillo R, Schiff E, Yoshida E, et al (2000) Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants. Hepatology 32: 129–34 Perrillo RP, Lai CL, Liaw YF, et al (2002) Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B. Hepatology 36: 186–94 Perrillo R, Hann HW, Mutimer D, et al (2004) Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus. Gastroenterology 126: 81–90 Peters MG, Hann HW, Martin P, et al (2004) Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B. Gastroenterology 126: 91–101 Peters MG, Andersen J, Lynch P, et al (2006) Randomized controlled study of tenofovir and adefovir in chronic hepatitis B virus and HIV infection: ACTG A5127. Hepatology 44: 1110–6 Pollicino T, Squadrito G, Cerenzia G, et al (2004) Hepatitis B virus maintains its pro-oncogenic properties in the case of occult HBV infection. Gastroenterology 126: 102–10 Pollicino T, Raffa G, Costantino L, et al (2007) Molecular and functional analysis of occult hepatitis B virus isolates from patients with hepatocellular carcinoma. Hepatology 45: 277–85 Poterucha JJ, Wiesner RH (1997) Liver transplantation and hepatitis B. Ann Intern Med 126: 805–7 Potthoff A, Wedemeyer H, Boecher WO, et al (2008) The HEP-NET B/C co-infection trial: A prospective multicenter study to investigate the efficacy of pegylated interferona2b and ribavirin in patients with HBV/HCV co-infection. J Hepatol 49: 688–94 Poynard T, Zoulim F, Ratziu V, et al (2005) Longitudinal assessment of histology surrogate markers (FibroTestActiTest) during lamivudine therapy in patients with chronic hepatitis B infection. Am J Gastroenterol 100: 1970–80
786 195. Raimondo G, Pollicino T, Cacciola I, et al (2007) Occult hepatitis B virus infection. J Hepatol 46: 160–70 196. Raimondo G, Allain JP, Brunetto MR, et al (2008) Statements from the Taormina espert meddting on occult hepatitis B virus infection. J Hepatol 49: 652–7 197. Raimondo G, Navarra G, Mondello S, et al (2008) Occcult hepatitis B virus in liver tissue of individuals without hepatic disease. J Hepatol 48: 48: 743–6 198. Rapti I, Dimou E, Mitsoula P, et al (2007) Adding-on versus switching-to adefovir therapy in lamivudine-resistant HBeAg-negative chronic hepatitis B. Hepatology 45: 307–13 199. Realdi G, Fattovich G, Hadziyannis S, et al (1994) Survival and prognostic factors in 366 patients with compensated cirrhosis type B: a multicenter study. J Hepatol 21: 656–66 200. Rizzetto M (2002) Efficacy of lamivudine in HBeAgnegative chronic hepatitis B. J Med Virol 66: 435–51 201. Rizzetto M, Tassopoulos NC, Goldin RD, et al (2005) Extended lamivudine treatment in patients with HBeAgnegative chronic hepatitis B. J Hepatol 42: 173–9 202. Saab S, Dong MH, Joseph TA, et al (2007) Hepatitis B prophylaxis in patients undergoing chemotherapy for lymphoma: a decision analysis model. Hepatology 46: 1049–56 203. Sánchez-Tapias JM, Costa J, Mas A, et al (2002) Influence of hepatitis B virus genotype on the long-term outcome of chronic hepatitis B in western patients. Gastroenterology 123: 1848–56 204. Santos SA, Uriel AJ, Park JS, et al (2006) Effect of switching to tenofovir with emtricitabine in patients with chronic hepatitis B failing to respond to an adefovir-containing regimen. Eur J Gastroenterol Hepatol 18: 1247–53 205. Sarin SK, Kumar M, Kumar R, et al (2005) Higher efficacy of sequential therapy with interferon-alpha and lamivudine combination compared to lamivudine monotherapy in HBeAg positive chronic hepatitis B patients. Am J Gastroenterol 100: 2463–71 206. Sarin SK, Sood A, Kumar M, et al (2007) Effect of lowering HBV DNA levels by initial antiviral therapy before adding immunomodulator on treatment of chronic Hepatitis B. Am J Gastroenterol 102: 96–104 207. Schiff ER, Dienstag JL, Karayalcin S, et al (2003) Lamivudine and 24 weeks of lamivudine/interferon combination therapy for hepatitis B e antigen-positive chronic hepatitis B in interferon nonresponders. J Hepatol 38: 818–26 208. Schildgen O, Sirma H, Funk A, et al (2006) Brief report: Variant of hepatitis B virus with primary resistance to adefovir. N Engl J Med 354: 1807–12 209. Schulze A, Gripon P, Urban S (2007) Hepatitis B virus infection initiates with a large surface protein-dependent binding to heparan sulfate proteoglycans. Hepatology 46: 1759–68 210. Shen H, Alsatie M, Eckert G, et al (2004) Combination therapy with lamivudine and famciclovir for chronic hepatitis B infection. Clin Gastroenterol Hepatol 2: 330–6 211. Sherman M, Yurdaydin C, Sollano J, et al (2006) Entecavir for treatment of lamivudine-refratctory, HBeAg-positive hepatitis B. Gastroenterology 130: 2039–49 212. Sherman M, Yurdaydin C, Simsek H, et al (2008) Entecavir therapy for lamivudine-refractory chronic hepatitis B:
63 Viral Infections by Hepatotropic Viruses
213.
214.
215.
216.
217.
218.
219.
220.
221.
222.
223.
224.
225.
226.
227. 228.
improved virologic, biochemical, and serology outcomes through 96 weeks. Hepatology 48: 99–108 Shukla NB, Poles MA (2004) Hepatitis B virus infection: co-infection with hepatitis C virus, hepatitis D virus, ans human immunodeficiency virus. Clin Liver Dis 8: 445–60 Sokal EM, Kelly DA, Mizerski J, et al (2006) Long-term lamivudine therapy for children with HBeAg-positive chronic hepatitis B. Hepatology 43: 225–32 Sollano, J, Schiff, E, Carrilho, F, et al (2004) Entecavir is well-tolerated for treatment of chronic hepatitis B: phase III safety analysis in nucleoside-naive and lamivudinerefractory patients. Hepatology 40(Suppl 1): 665A Song BC, Suh DJ, Lee HC, et al (2000) Hepatitis B e antigen seroconversion after lamivudine therapy is not durable in patients with chronic hepatitis B in Korea. Hepatology 32: 803–6 Sprengers D, Molen RG, Kusters JG, et al (2006) Analysis of intrahepatic HBV-specific cytotoxic T-cells during and after acute HBV infection in humans. J Hepatol 45: 182–9 Stoop JN, van der Molen RG, Baan CC, et al (2005) Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection. Hepatology 41: 771–8 Sung JJY, Lai JY, Zeuzem S, et al (2008) Lamivudine compared with lamivudine and adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B. J Hepatol 48: 728–35 Sypsa VA, Mimidis K, Tassopoulos NC, et al (2005) A viral kinetic study using pegylated interferon alfa-2b and/ or lamivudine in patients with chronic hepatitis B/HBeAg negative. Hepatology 42: 77–85 Tan J, Degertekin B, Wong SN, et al (2008) Tenofovir monotherapy is effective in hepatitis B patients with antiviral treatment failure to adefovir in the absence of adefovirresistant mutations. J Hepatol 48: 391–8 Tang TJ, Kwekkeboom J, Mancham S, et al (2005) Intrahepatic CD8(+) T-lymphocyte response is important for therapy-induced viral clearance in chronic hepatitis B infection. J Hepatol 43: 45–52 Tassopoulos NC, Volpes R, Pastore G, et al (1999) Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B. Lamivudine precore mutant study group. Hepatology 29: 889–96 Teo EK, Ostapowicz G, Hussain M, et al (2001) Hepatitis B infection in patients with acute liver failure in the United States. Hepatology 33: 972–6 ter Borg MJ, van Zonneveld M, Zeuzem S, et al (2006) Patterns of viral decline during PEG-interferon alpha-2b therapy in HBeAg-positive chronic hepatitis B: Relation to treatment response. Hepatology 44: 721–7 Toan NL, Song le H, Kremsner PG, et al (2006) Co-infection of human parvovirus B19 in Vietnamese patients with hepatitis B virus infection. J Hepatol 45: 361–9 Tran TT, Martin P (2004) Hepatitis B: epidemiology and natural history. Clin Liver Dis 8: 255–66 Tsai SL, Sheen IS, Chien RN, et al (2003) Activation of Th1 immunity is a common immune mechanism for the successful treatment of hepatitis B and C. J Biomed Sci 10: 120–35
References 229. Tsang PSY, Trinh H, Garcia RT, et al (2008) Significant prevalence of histologic disease in patients with chronic hepatitis B and mildly elevated serum alanine aminotransferase levels. Clin Gastroenterol Hepatol 6: 569–74 230. Tse KY, Ho LF, Lao T (2005) The impact of maternal HBsAg carrier status on pregnancy outcomes: a case-control study. J Hepatol 43: 771–5 231. Tsubota A, Arase Y, Suzuki Y, et al (2005) Lamivudine monotherapy for spontaneous severe acute exacerbation of chronic hepatitis B. J Gastroenterol Hepatol 20: 426–32 232. Ulcickas YM, Quesenberry CP Jr, Guo D, et al (2007) Incidence of non-Hodgkin’s lymphoma among individuals with chronic hepatitis B virus infection. Hepatology 46: 107–12 233. van Bommel F, Wunsche T, Mauss S, et al (2004) Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection. Hepatology 40: 1421–5 234. van Bommel F, Zollner B, Sarrazin C, et al (2006) Tenofovir for patients with lamivudine-resistant hepatitis B virus (HBV) infection and high HBV DNA level during adefovir therapy. Hepatology 44: 318–25 235. van der Molen RG, Sprengers D, Binda RS, et al (2004) Functional impairment of myeloid and plasmacytoid dendritic cells of patients with chronic hepatitis B. Hepatology 40: 738–46 236. van Nunen AB, Hansen BE, Suh DJ, et al (2003) Durability of HBeAg seroconversion following antiviral therapy for chronic hepatitis B: relation to type of therapy and pretreatment serum hepatitis B virus DNA and alanine aminotransferase. Gut 52: 420–4 237. van Zonneveld M, Honkoop P, Hansen BE, et al (2004) Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B. Hepatology 39: 804–10 238. van Zonneveld M, Flink HJ, Verhey E, et al (2005) The safety of pegylated interferon alpha-2b in the treatment of chronic hepatitis B: predictive factors for dose reduction and treatment discontinuation. Aliment Pharmacol Ther 21: 1163–71 239. van Zonneveld M, Zondervan PE, Cakaloglu Y, et al (2006) Peg-interferon improves liver histology in patients with HBeAg-positive chronic hepatitis B: no additional benefit of combination with lamivudine. Liver Int 26: 399–405 240. Vierling JM (2007) The immunology of hepatitis B. Clin Liver Dis 11: 727–59 241. Villeneuve JP, Desrochers M, Infante-Rivard C, et al (1994) A long-term follow-up study of asymptomatic hepatitis B surface antigen positive carriers in Montreal. Gastroenterology 106: 1000–5 245. Wai CT, Fontana RJ (2004) Clinical significance of HBV genotypes, variants, and mutants. Clin Liver Dis 8: 321–52 246. Wang C, Tang J, Song W, et al (2004) HLA and cytokine gene polymorphisms are independently associated with responses to hepatitis B vaccination. Hepatology 39: 978–88 247. Werle B, Cinquin K, Marcellin P, et al (2004) Evolution of hepatitis B viral load and viral genome sequence during adefovir dipivoxil therapy. J Viral Hepat 11: 74–83 248. Werle-Lapostolle B, Bowden S, Locarnini S, et al (2004) Persistence of cccDNA during the natural history of chronic
787
249.
250.
251. 252.
253.
254.
255.
256.
257.
258.
259.
260.
261.
262.
263.
264.
265.
hepatitis B and decline during adefovir dipivoxil therapy. Gastroenterology 126:1748–58 Westland C, Delaney W 4th, Yang H, et al (2003) Hepatitis B virus genotypes and virologic response in 694 patients in phase III studies of adefovir dipivoxil. Gastroenterology 125: 107–16 Wieland S, Thimme R, Purcell RH, et al (2004) Genomic analysis of the host response to hepatitis B virus infection. Proc Natl Acad Sci USA 101: 6669–74 Willson RA (1997) Extrahepatic manifestations of chronic viral hepatitis. Am J Gastroenterol 92: 4–17 Wong DK, Cheung AM, O’Rourke K, et al (1993) Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis. Ann Intern Med 119: 312–23 Wursthorn K, Lutgehetmann M, Dandri M, et al (2006) Peginterferon alpha-2b plus adefovir induce strong cccDNA decline and HBsAg reduction in patients with chronic hepatitis B Hepatology 44: 675–84 Xiong X, Flores C, Yang H, et al (1998) Mutations in hepatitis B DNA polymerase associated with resistance to lamivudine do not confer resistance to adefovir in vitro. Hepatology 28:1669–73 Yang HI, Lu SN, Liaw YF, et al (2002) Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med 347: 168–74 Yatsuji H, Suzuki F, Sezaki H, et al (2008) Low risk of adefovir resistance in lamivudine-resistant chronic hepatitis B patients treated with adefovir plus lamivudine combination therapy: two-year follow-up. J Hepatol 48: 923–31 Yeon JE, Yoo W, Hong SP, et al (2006) Resistance to adefovir dipivoxil in lamivudine resistant chronic hepatitis B patients treated with adefovir dipivoxil. Gut 55: 1488–95 Yim HJ, Hussain M, Liu Y, et al (2006) Evolution of multidrug resistant hepatitis B virus during sequential therapy. Hepatology 44: 703–12 Yoo BC, Kim JH, Chung YH, et al (2007) Twenty-fourweek clevudine therapy showed potent and sustained antiviral activity in HBeAg-positive chronic hepatitis B. Hepatology 45: 1172–8 Yoo BC, Kim JH, Kim TH, et al (2007) Clevudine is highly efficacious in hepatitis B e antigen-negative chronic hepatitis B with durable off-therapy viral suppression. Hepatology 46: 1041–8 Yu MW, Yeh SH, Chen PJ, et al (2005) Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study. J Natl Cancer Inst 97: 265–72 Yuan HJ, Yuen MF, Ka-Ho WD, et al (2005) Impact of precore and core promoter mutations on hepatic histology in patients with chronic hepatitis B. Aliment Pharmacol Ther 22: 301–7 Yuen MF, Sablon E, Hui CK, et al (2001) Factors associated with hepatitis B virus DNA breakthrough in patients receiving prolonged lamivudine therapy. Hepatology 34: 785–91 Yuen MF, Lim WL, Chan AO, et al (2004) 18-year followup study of a prospective randomized trial of hepatitis B vaccinations without booster doses in children. Clin Gastroenterol Hepatol 2: 941–5 Yuen MF, Lai CL (2005) Telbivudine: an upcoming agent for chronic hepatitis B. Expert Rev Anti Infect Ther 3: 489–94
788 266. Yuen MF, Tanaka Y, Ng IO, et al (2005) Hepatic necroinflammation and fibrosis in patients with genotypes Ba and C, core-promoter and precore mutations. J Viral Hepat 12: 513–8 267. Yuen MF, Wong DK, Sum SS, et al (2005) Effect of lamivudine therapy on the serum covalently closed-circular (ccc) DNA of chronic hepatitis B infection. Am J Gastroenterol 100: 1099–103 268. Yuen MF, Yuan HJ, Wong DKH, et al (2005) Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications. Gut 54: 1610–4 269. Yuen MF, Fong DY, Wong DK, et al (2007) Hepatitis B virus DNA levels at week 4 of lamivudine treatment predict the 5-year ideal response. Hepatology 46: 1695–703 270. Yuen MF, Tanaka Y, Shinkai N, et al (2008) Risk for hepatocellular carcinoma with respect to hepatitis B virus genotypes B/C, specific mutations of enhancer II/core promoter/ precore regions and HBV DNA levels. Gut 57: 98–102 271. Yuen MF, Wong DK, Fung J, et al (2008) HBsAg seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma. Gastroenterology 135: 1192–9 272. Yuki N, Nagaoka T, Yamashiro M, et al (2003) Long-term histologic and virologic outcomes of acute self-limited hepatitis B. Hepatology 37: 1172–9 273. Zeng MD, Lu LG, Mao YM, et al (2005) Prediction of significant fibrosis in HBeAg-positive patients with chronic hepatitis B by a noninvasive model. Hepatology 42: 1437–45 274. Zeng M, Mao Y, Yao G, et al (2006) A double-blind randomized trial of adefovir dipivoxil in Chinese subjects with HBeAg-positive chronic hepatitis B. Hepatology 44: 108–16 275. Zhang X, Zoulim F, Habersetzer F, et al (1996) Analysis of hepatitis B virus genotype and pre-core region variability during interferon treatment of HBe antigen negative chronic hepatitis B. J Med Virol 48: 8–16 276. Zoulim F (2005) New insights on hepatitis B virus persistence from the study of intrahepatic viral cccDNA. J Hepatol 42: 302–8 277. Zoulim F, Parvaz P, Marcellin P, et al (2009) Adefovir dipivoxil is effective for the treatment of cirrhotic patients with lamivudine failure. Liver Int 29: 420–6
63 Viral Infections by Hepatotropic Viruses
Hepatitis C The virus causing non-A, non-B-hepatitis was identified as an RNA virus in 1989 and named hepatitis C virus (HCV).
Epidemiology Chronic hepatitis C represents one of the biggest healthcare problems worldwide. Approximately 170 million people had contact and 130 million people are chronically infected with HCV, which corresponds to a worldwide prevalence of chronic hepatitis C of approximately 3%. It is the most common cause of hepatocellular carcinoma (HCC) in Europe, and the majority of liver transplants performed in Europe and in the United States are for chronic hepatitis C. Hepatitis C is an important cause of premature mortality, especially in persons aged 55–64 years [253]. Epidemiological parameters (prevalence, incidence, disease transmission patterns and genotype distribution) have changed substantially in Western Countries over the last 15 years. Increased blood transfusion safety, improvement of healthcare conditions, expansion of intravenous drug use and immigration to Europe and to the USA from endemic areas are the main factors responsible for this change. The prevalence rate of chronic HCV infection in Europe shows a north-south gradient. Prevalence in Scandinavia is 0.1–0.2%, in Germany 0.6% (figure probably too low due to under-reporting), while in Southern Europe prevalence rates of 2.5%–3.5% are registered. In isolated areas in Greece and Southern Italy prevalence rates of 7–20% have been reported [52]. The overall incidence in the USA in 2006 was estimated to be 0.3 per 100,000 [248]. The prevalence of antibodies to HCV in the US is approximately 1.6% (equating to about 4.1 million anti-HCV positive persons), while the prevalence of positive HCV RNA is 1.3% [5]. The region with the highest prevalence of HCV worldwide is the Middle East and Africa, particularly Egypt, with prevalence rates up to 20% [113]. In the US HCV infection is more prevalent among African Americans and Hispanics than among non-Hispanic Whites. The course of chronic hepatitis C in Latinos is more aggressive, with higher risk of
Hepatitis C
developing cirrhosis than any other ethnic group or race. Both African Americans and Latinos also have inferior treatment responses, compared to those of nonHispanic whites. The causes of this more aggressive progression are complex, and, in addition to genetic factors, decreased efficacy of treatment is probably related to the metabolic syndrome, insulin resistance, and hepatic steatosis [173, 196, 241]. The distribution of HCV-genotypes and subtypes (see Section 63.1) varies worldwide. In Germany and in the USA genotype 1b is most frequent, responsible for approximately 50% of HCV infections, followed by genotype 1a (approximately 20%) and 3a (approximately 15%). HCV genotype 4 is the most common variant of HCV in the Middle East and Africa. In Egypt more than 90% of infections are due to genotype 4. Recent studies suggest that HCV-4 infection is spreading beyond its strongholds in Africa and the Middle East to Western Europe [113].
Transmission Even before HCV was discovered, approximately 90% of cases of posttransfusion hepatitis were classified as non-A, non-B-hepatitis, suggesting parenteral transmission as an important route of acquiring hepatitis C. In the 1990s risk groups with a high prevalence of HCV infection were hemophiliacs (70–90%), injection drug users (50–90%), HIV-infected patients (90%), alcoholics (30%), and patients on chronic hemodialysis (5–30%) [143]. Coinfections of HCV with HBV or HIV were particularly prevalent among hemophiliacs or injection drug users. Currently the most important sources of infection for persons with hepatitis C in Western countries are injection drug use (60%), sexual (15%), nosocomial, health-care work, perinatal (5%), and unknown (10– 20%). The risk of nosocomial spread of HCV is emphasized by a recent outbreak of HCV infection during sclerotherapy of varicose veins [41]. Blood transfusion was a major risk factor for HCV infection in the past. The incidence of post transfusion hepatitis C has declined sharply after the introduction of reliable and sensitive HCV tests. The risk of acquiring the infection through infected blood stored for transfusion nowadays is approximately 1:120,000 units, which is lower than the prevalence of HCV in the
789
general population. New tests detecting minute amounts of HCV genetic material will further decrease the risk of transfusion-transmitted HCV to a range between 1:500,000 and 1:1,000,000 units. Forty to 60% of cases of HCV transmission occur by contaminated needles in injection drug users, in persons receiving tattoos or by accidental needle stick injury (especially healthcare workers, manifestation rate 5.4%). Healthcare workers adhering to general hygienic measures are not at an increased risk of acquiring HCV infection. Only in approximately 5–10% of cases transmission is sexual, perinatal or via breast milk. The risk of sexual transmission is much lower than for HBV. It probably depends on the number of sexual intercourses and the degree of HCV viremia. HCV antibodies occur in approximately 2% of the spouses [228]. Vertical perinatal HCV transmission occurs in approximately 5% of infants born to anti HCV positive mothers. It increases to up to 40% in HCV/HIV coinfection. No risk factors for HCV infection can be identified in up to 45% of cases (“community acquired”/“sporadic” HCV infection). HCV infection in endemic countries has a strong familial component (clustering of HCV cases) explained, at least partly, by specific modes of intrafamilial viral transmission and supporting the role of host genes predisposing to HCV infection [181]. A rare, but important route of transmitting HCV is by infected organs during transplantation (liver, kidney, heart, bone marrow). A chronic HCV infection develops in approximately 50% of these initially HCV negative transplant recipients. Infection of an originally HCV negative donor liver by persistent HCV in the extrahepatic tissues of the recipient has also to be kept in mind. A recent study from Spain suggests that hospital admission per se is a risk factor for acquiring HCV infection [141]. The incubation period of acute hepatitis C in symptomatic patients is between 2–12 weeks [169].
Pathogenesis HCV-induced liver injury is primarily mediated by immunologic mechanisms rather than by direct HCV cytotoxicity. HCV is taken up by hepatocytes with the help of the low-density lipoprotein receptor, is
790
63 Viral Infections by Hepatotropic Viruses
Phagocytosis APC Extracellular viral antigens IL-12 CD4+
+ CD8+
IL-2 IFN-γ TNF-α/β
cytotoxic
CD4+ TH1
CD4+ TH2
IL-4 IL-5 IL-10
antiviral B cells
Infected hepatocytes APC = antigen presenting cell HLA-molecules class I
class II
Antibody production
... with antigen
T-cell receptor
Fig. 63.47 Immune pathogenesis of hepatitis C. See text
processed intracellularly and is actively secreted by infected cells through a Golgi-dependent mechanism while bound to very low density lipoprotein (Fig. 63.12) [156]. Processed viral peptides are expressed on the surface of hepatocytes in association with HLAclass I molecules where they are recognized by the T cell receptor of HLA-class I restricted cytotoxic CD8+ T-cells (CTL) (Fig. 63.47). Virus-specific CTL induce increased hepatocyte loss by apoptosis (via FAS ligand) and play an important role in viral clearance, i.e. in the outcome of acute HCV infection [122]. In addition to direct virus specific cytotoxicity, antibody mediated cytotoxicity (ADCC) may play a role in hepatocyte death. The HCV envelope E2 protein expressed on the hepatocyte surface has been shown to be able to mediate ADCC [161a]. While a prerequisite for CTL action is their direct interaction with the infected cell, virus specific CD4+ T-helper cells (Th1 and Th2) do not require a direct contact with HCV infected hepatocytes in order to unfold their activities. They recognize antigen-presenting cells that have taken up, processed and expressed viral antigens in association with HLA class II molecules on their surface. This reaction not necessarily has
to take place in the liver, but may also occur in extrahepatic sites, for example the lymph nodes. The ability of HCV to infect, replicate in, and produce progeny virus in perihepatic lymph nodes and peripheral blood mononuclear cells is interesting in this regard [30, 170]. The main antigen presenting cells (APC) are macrophages, dendritic cells and Kupffer cells. The interaction of T-helper cells with APC leads to the release of cytokines that both stimulate T-cell proliferation and increase expression of HLA-molecules on the hepatocyte surface resulting in a reduced viral replication. Based on their cytokine profile various types of CD4+ T-helper cells are differentiated. Th1-cells produce interleukin (IL)-2, interferon (IFN) g, tumor necrosis factor (TNF) a and b and stimulate cell-mediated immune reactions. Th2-cells secrete IL-4, -5 and -10 and primarily control the humoral immune response. Therefore, a strong Th-immune response and a vigorous CTL-response are always linked. Patients in whom acute hepatitis C resolves completely have a stabile and strong Th1immune response that in cooperation with CTL leads to complete HCV clearance. Notably a strong IFNg response is associated with efficient viral clearance that primarily results from antigen-driven selection/ survival of HCV-specific T cells expressing high-avidity T-cell receptors [165]. The development of chronic HCV infection is often associated with impaired innate and adaptive immune responses. Broadly reactive neutralizing antibodies and multispecific T-cell responses are generated during chronic HCV infection but are too weak to clear the virus. Despite the presence of intrahepatic virusspecific CTL, HCV persists, apparently due to an ineffective antiviral T-cell response [164, 226]. The precise mechanisms underlying the failure of intrahepatic HCV-specific CTL to control the virus during persistent infection are not fully understood. Deranged ability to secrete IFNg and impaired cooperation with T-helper cells may contribute to this failure [223]. In addition, HCV itself has been shown to inhibit IFNa secretion by primary hepatocytes and human hepatic cell lines in vitro. Silencing IFNa gene expression results in increased HCV replicon expression [265]. Continued generation of HCV escape mutants due to selection pressure from both humoral and cellular immunity represents another mechanism of HCV persistence [244]. Non-immunologic mechanisms probably also contribute to the pathogenesis of hepatocyte injury in HCV
Hepatitis C
infection. HCV has been shown to induce the accumulation of autophagosomes in hepatocytes by stimulating the unfolded protein response without enhancing autophagic protein degradation, thereby perturbating the normal autophagic response [221]. Furthermore, HCV may limit hepatocyte regeneration by causing hepatocyte arrest in the G1 phase, thereby impairing hepatocellular function [140]. Steatosis and factors related to the metabolic syndrome, such as insulin resistance, also appear to play a role in the pathogenesis of chronic hepatitis C. The prevalence of steatosis in chronic hepatitis C is approximately 40–55%, about twice that in chronic hepatitis B [134, 233]. The pathogenesis, prevalence and the severity of steatosis varies according to the infecting HCV genotype. Steatosis is more frequent and usually more severe in patients with HCV genotype 3 infection and experimental evidence suggests that HCV core protein components are capable of inducing triglyceride accumulation [1]. Virus induced dysfunction of liver microsomal triglyceride transfer protein may interfere with very low density lipoprotein assembly, thus enhancing intracellular lipid accumulation (see also Chapter 89) [154]. In addition, it has been shown recently that specific amino acid residues of the HCV-3 core protein directly up-regulate fatty acid synthase expression and thus alter the cellular lipid profile [103, 255]. The severity of steatosis in genotype 3 infection correlates with the level of HCV RNA in serum and the liver and steatosis is significantly reduced or even disappears in patients with sustained virological response to antiviral therapy [124, 162, 186]. While HCV genotype 3 has a direct steatogenic effect, lipid accumulation in patients with genotype non-3 HCV infection is mostly due to metabolic and toxic factors, such as obesity, insulin resistance and alcohol abuse [28, 158, 234, 258]. Steatosis not only is a histologic characteristic of HCV infection, but also appears to play an important role in the pathogenesis of disease progression. Most studies have shown a correlation between presence and severity of steatosis and stage of fibrosis [57, 80, 127, 199]. Steatosis in chronic hepatitis C may contribute to the progression of liver injury via upregulation of mediators in hepatocyte apoptosis, such as Fas, TNFR1 and active caspase-3, and by activating NF-kB [95, 247]. Evidence is accumulating, however, that it is not the fat per se, but rather the pathogenetic mechanisms
791
underlying steatosis that are the pacemaker of accelerated fibrogenesis in chronic hepatitis C. Thus, the level of insulin resistance has been shown to be associated with the stage of fibrosis, and insulin resistance has been reported to be an independent predictor of advanced fibrosis in chronic HCV infection [22, 49, 58, 90, 158]. In addition, steatosis negatively influences the rate of response to antiviral treatment. Steatosis and factors related to the metabolic syndrome, particularly obesity and insulin resistance are associated with a decreased efficacy of interferon-based therapies, which may partly be overcome by adjusting the dose to the weight of the patient (see below) [31, 35, 83, 232]. Hepatic fibrosis in chronic hepatitis C infection may also be advanced by the interaction between HCV and stellate cells. HCV E2 glycoprotein has been shown to bind to the cell surface of human hepatic stellate cells and to up-regulate matrix metalloproteinase-2 [148]. HCV nonstructural genes may also directly induce profibrogenic mediators, such as transforming growth factor b1 in infected hepatocytes [211]. These findings would explain the frequent observation of progressive liver fibrosis despite a low level of inflammation. The role of iron overload as a cofactor in the progression of chronic hepatitis is controversial. Most studies support a role of HFE mutations with consequent iron loading as risk factors for fibrogenesis and disease progression in chronic hepatitis C [72, 73, 235]. Heterozygosis for b-globin mutations has recently been described as a novel risk factor for both hepatic iron accumulation and progression of fibrosis in patients with chronic HCV infection [209]. Other investigators, however, failed to document iron overload in chronically HCV-infected patients and were unable to demonstrate a relation between hepatic iron content and the liver damage process in HCV infection [220].
Clinical Manifestations and Diagnosis The diagnosis of HCV infection is based on clinical manifestations, but above all on laboratory tests. Imaging techniques, such as ultrasound, CT and MRI play a role in excluding other liver disorders and in the diagnosis of architectural changes leading to cirrhosis. Liver biopsy is still the gold standard in grading the necroinflammatory reaction and in staging fibrosis.
792
However, noninvasive techniques, such as transient elastography are becoming more important in assessing fibrosis and cirrhosis. For serologic diagnosis see Section 63.1; for histopathology see Section 63.2.
Acute Hepatitis C Most patients with acute hepatitis C are asymptomatic. Therefore, detection of HCV infection and diagnosis are difficult [17, 206]. Symptoms develop in approximately 20–30% of patients. The incubation period ranges from 2 to 12 weeks [169]. The most common symptoms are fatigue, jaundice, dyspepsia with vague abdominal pain and flulike complaints. As an indication of hepatic injury, serum ALT levels rise up to approximately 500 IU/L 4–12 weeks after viral exposure. After exposure to HCV, there is a window of 1–3 weeks before serum HCV RNA can be detected. Detection of anti HCV IgM in the early phase of the illness may help in the diagnosis of acute hepatitis C [202]. Proposed criteria for the diagnosis of acute hepatitis C infection are listed in Table 63.31.
Chronic Hepatitis C Patients with chronic hepatitis C are either asymptomatic or complain of nonspecific symptoms, such as fatigue, right upper quadrant pain, nausea, anorexia, dyspepsia or diffuse muscle aches. Although usually mild and nonspecific, these symptoms often markedly impair the quality of life [224]. Mild to moderate fluctuating elevations of serum ALT levels between 50–500 IU/L are characteristic. ALT flares with an increase in serum levels up to ten times the ULN occur in approximately 20% of patients. On the other hand, approximately 25–30% of patients have persistently normal ALT activity (PNALT), despite ongoing liver damage [2, 262]. PNALT has been defined as at least two ALT measurements within the normal range taken during a period of at least 6 months. However, levels fluctuate, therefore more determinations and longer time intervals might be more meaningful. Currently, no strict consensus exists on the definition of ALT flare or of PNALT. Gender, viral factors (genotype, HCV-RNA titer) and indicators of metabolic syndrome (body mass
63 Viral Infections by Hepatotropic Viruses
index, blood pressure, blood glucose, cholesterol and triglyceride concentration) affect ALT levels in patients with chronic hepatitis C [187]. Once cirrhosis develops, aminotransferases are only mildly elevated (usually < 100 IU/L) and AST levels are higher than ALT levels. Among patients with advanced chronic hepatitis C, mild elevations of serum a1-fetoprotein values occur in 17% of cases, even in the absence of HCC [46]. Increased serum gGT levels in patients with chronic hepatitis C are associated with liver steatosis and fibrosis, and indicate more advanced liver disease rather than reflecting cholestasis [9]. Hyperferritinemia is encountered in 20–27% and is associated with liver iron deposits in 39–46% of cases of chronic hepatitis C. Hepatic iron deposits are usually associated with a more advanced stage of fibrosis [81, 212]. The extent of apoptotic activity, steatosis and of fibrotic liver injury in patients with chronic hepatitis C has been reported to be mirrored by caspase activity in serum [8, 213]. Determinations of serum caspase levels, however, have not yet been adopted into clinical practice. Retinol-binding protein 4 (RBP4) is an adipocytokine associated with insulin resistance. It has been shown recently that serum RBP4 levels were independently linked to steatosis in patients with chronic HCV genotype 1 infection [177]. Chronic hepatitis C is often associated with autoimmune reactions. Various autoantibodies (ANA [32%], SMA [11%], LKM-1 [5%], thyroid antibodies Table 63.31 Proposed criteria for diagnosis of acute hepatitis C infection Primary criteria
Secondary criteria
Additional considerations
Presence of HCV RNA in serum of a previously HCV-negative patient. Seroconversion from anti HCVnegative to anti HCV-positive. Elevated aminotransferase levels ≤ 10–20 times the ULN. Known or suspected exposure to HCV within the preceding 6 months. All other causes of acute liver damage excluded. Sudden onset of liver disease. Repetition of recombinant immunoblot assay testing to demonstrate eventual increase in the number of reactive proteins.
Source: From [206]. With permission
Hepatitis C
[21%] or rheumatoid factor [29%], antibodies against basal membranes, thymic cells and laminin A and C) occur in up to 65% of patients with chronic HCV infection. Their serum titers are usually low and, in contrast to autoimmune hepatitis, they represent nonspecific immune phenomena. Their prevalence rises with increasing age, especially in women, and is not influenced by interferon therapy. Anti LKM-1 autoantibodies are considered specific markers of type 2 autoimmune hepatitis (see Chapters 36 and 72), but are also found in 5% of patients with chronic hepatitis C. They are directed against a 33 amino acid sequence of cytochrome P4502D6 (CYP2D6). This conformational epitope on CYP2D6 shares a sequence homology with the HCV NS3 and NS5a proteins. Crossreactivity due to molecular mimicry could explain the presence of anti-LKM1 in patients chronically infected with HCV [139]. Antibodies against cytochrome P4502E1 occur in 40% of patients with chronic hepatitis C [242]. Recently, a subset of HCV patients with positive AMA have been described who presented with a broad spectrum of clinical features, including liver, autoimmune and neoplasic manifestations. Two-thirds of these patients presented an associated systemic autoimmune disease, mainly Sjögren’s syndrome or systemic sclerosis, together with a high frequency of multiple autoantibodies and an increased prevalence of cirrhosis and neoplasia [191]. The hallmark of progression of chronic hepatitis C is fibrosis. Various panels of non-invasive serum markers to differentiate mild from moderate-to-advanced liver fibrosis in chronic hepatitis C patients have been devised [29, 66, 82, 118, 128, 172, 237]. Most of them, however, are unreliable and cumbersome to calculate. They render liver biopsy unnecessary in only a minority of patients and have not gained wide acceptance in clinical practice [125]. Measurements of expression profile of genes involved in extracellular matrix turnover are emerging as new techniques in determining hepatic fibrosis, but they have not yet been adopted into clinical practice [6]. Transient elastography (see also Chapter 28) reflects “elasticity of tissue” and is increasingly used as a non-invasive technique to determine “liver stiffness”, i.e. fibrosis. It is suitable for the diagnosis of advanced fibrosis/cirrhosis but cannot reliably discriminate lower grades of fibrosis [4, 71, 115, 266]. Liver biopsy still is the method of choice to evaluate liver fibrosis.
793
Extrahepatic Manifestations of Chronic Hepatitis C There is a growing body of evidence to suggest that HCV can replicate in extrahepatic tissues and cells, including peripheral blood mononuclear cells, dendritic cells, granulocytes, B lymphocytes, and monocytes/macrophages [17]. Extrahepatic manifestations in chronic HCV infection are quite common. The association of HCV infection with autoimmune and hematologic processes is well documented. The sialotropism of HCV may explain the association with Sjögren’s syndrome, and its lymphotropism links the virus to cryoglobulinemia, autoimmune cytopenias, and lymphoma [190]. In a large prospective cohort study 74% of patients chronically infected with HCV had a least one clinical extrahepatic manifestation. The most common were mixed cryoglobulinemia (40%), arthritis and arthralgia (23%), peripheral neuropathy and paresthesia (17%), myalgia (15%), pruritus (15%), and sicca syndrome (11%) [24]. Furthermore, an association of HCV infection with polyarteritis nodosa, glomerulonephritis, porphyria cutanea tarda, cutaneous vasculitis, lichen planus, erythema nodosum, erythema exsudativum multiforme, urticaria, immune thyroid disorders, corneal ulcers, diabetes mellitus, malignant non-Hodgkin’s lymphomas, idiopathic thrombocytopenia and idiopathic pulmonary fibrosis has been demonstrated [189]. The association between some of these disorders and HCV may not be direct, but rather mediated by cryoglobulins.
Mixed Cryoglobulinemia Cryoglobulins are serum immunoglobulins that precipitate reversibly upon cooling. This reaction results in an increased blood viscosity, in red blood cell clumping, and in functional impairment of platelets ultimately leading to circulatory disturbances. Three types of cryoglobulinemia are differentiated. In mixed cryoglobulinemia (Type II) generation of immune complexes and cryoprecipitation involves polyclonal IgG- and mono- or polyclonal IgM-antibodies. Rheumatoid factor activity (monoclonal IgM-antibody against IgG) commonly is present. The pathogenetic mechanisms of HCV-associated mixed cryoglobulinemia are unclear. Immune complexes consist of HCV-RNA, anti-HCV antibodies and IgM rheumatoid factor. The concentration of HCVRNA in cryoprecipitates may be 10–1,000 times higher
794
than the serum HCV-RNA level. Cryoglobulinemia more often occurs in patients with long-standing HCV infection, high serum g-globulin levels and liver cirrhosis. An association with a specific HCV genotype cannot be demonstrated. Cryoglobulins are more common in women. The overall prevalence of mixed cryoglobulins in various liver diseases is 41%, with the highest values being observed in chronic hepatitis C (47–54%) compared to 15% in chronic HBV infection. HCV-RNA may be demonstrated in 42–95% of patients presenting clinically with cryoglobulinemia. Cryoglobulinemia is symptomatic in about 1% of HCV infected patients. Clinical manifestations include signs and symptoms of vasculitis with Raynaudtype symptoms, erythemas, palpable purpura and hyperpigmented skin (Fig. 63.48). Synovitis, arthralgias and arthritis, peripheral neuropathies, marked fatigue, membranoproliferative glomerulonephritis, renal failure and hepatic involvement may occur. The development of renal injury is associated with a severe prognosis. The impact of cryoglobulins on the natural history of liver disease is not clear. While there appears to be an independent association between cryoglobulinemia and steatosis as well as advanced fibrosis, a recent report failed to identify an influence of cryoglobulins on the clinical course of hepatitis C [200, 243]. The overall risk of non-Hodgkin’s lymphoma in patients with HCV related cryoglobulinemic syndrome is about 35 times higher than in the general population [157]. HCV-associated mixed cryoglobulinemia usually responds to treatment with pegylated interferon and ribavirin [147].
63 Viral Infections by Hepatotropic Viruses
Glomerulonephritis Membranoproliferative glomerulonephritis (MPGN) is the most common renal manifestation of HCV infection, representing 70–80% of HCV-associated glomerulonephritis. HCV-associated MPGN may be cryoglobulin related and non-cryoglobulin related. The prevalence of HCV infection in MPGN is 10–20% in the United States [17]. Most of the remaining HCV-associated glomerulonephritides fall upon membranous glomerulonephritis (MGN). MPGN and MGN are rare immune complex diseases that are characterized clinically by hematuria, proteinuria and renal dysfunction. Only 15% progress to end-stage renal disease. HCV glomerulonephritis is rare in children and most often develops in infected adults in their 40s and 50s after a long history of HCV infection. Many patients have symptoms of cryoglobulinemia [111]. In HCV-associated MPGN, immune complexes with cryoglobulin-like ultrastructure are deposited in the mesangium and in the subendothelial space of glomerular capillaries. These complexes consist of HCV-RNA, anti-HCV IgG, IgM (rheumatoid factor) and complement component C3. HCV replication within renal epithelia is not known to occur. Serum complement factors C3, C4, CH50 are diminished, the rheumatoid factor often is positive and commonly cryoglobulins and circulating cryoprecipitates are demonstrable. In contrast, patients with HCV-associated MGN have normal serum complement levels and no circulating rheumatoid factor or cryoglobulins. HCV-core antigen, however, may be demonstrated immunohistochemically in the glomeruli. Treatment with plasmapheresis (removes cryoglobulins), corticosteroids, cytotoxic drugs/rituximab and pegylated interferon/ribavirin has proven to be effective in some patients.
Polyarteritis Nodosa
Fig. 63.48 Mixed cryogobulinemic purpura in a patient with chronic hepatitis C
Polyarteritis nodosa (PAN) may be associated with many viral diseases (HAV, HBV, HCV, HIV, Varicella zoster, CMV, EBV, parvovirus, human T-cell leukemia virus type I). Anti-HCV antibodies may be demonstrated in 20% of patients with PAN, while HCV-RNA is demonstrable in only 5% of patients. The pathogenesis is characterized by the deposition of immune complexes
Hepatitis C
of HCV antigens and cryoglobulins (?) in the vessel walls. The consequent binding and activation of complement results in a narrowing of the vessel lumen and leads to ischemic tissue injury.
795
secondary to HCV infection have positive anti-Ro/ SS-A and/or anti-La/SS-B antibodies [191]. These antibodies react with salivary and lacrimal gland epithelia.
Sarcoidosis Porphyria Cutanea Tarda The association of porphyria cutanea tarda (PCT) with chronic liver disease, especially of alcoholic origin, is well known. The disease is characterized by a defect in uroporphyrinogen-III-decarboxylase (see Chapter 84). Symptoms include fragile skin with blister formation, cutaneous bleeding tendency, de- and hyperpigmentation, and hirsutism. Patients with PCT have an increased incidence of liver disease. Extrinsic factors, such as excessive sun exposure, ethanol, estrogens, and iron trigger disease symptoms. The prevalence of markers of HCV infection in patients with PCT exhibits geographical variations. While the prevalence of HCV in patients with PCT in the mediterranean area (Spain, Italy) amounts to 70–80%, HCV prevalence in central and northern Europe is less than 10% [56]. Overall, HCV prevalence in patients with PCT is approximately 50%, much higher than that reported in the general population [77]. Although this strong association suggests a possible etiopathogenic role of HCV in PCT this has not been substantiated yet. It appears that HCV-induced liver injury contributes to the manifestation of PCT symptoms in persons with an inborn deficiency of uroporphyrinogen-III-decarboxylase.
Sjögren’s Syndrome Sjögren’s syndrome (SS) is characterized by a diminished secretory activity of salivary and lacrimal glands (sicca syndrome). Sicca syndrome secondary to liver disease is often associated with primary biliary cirrhosis and chronic HCV infection. In addition to reduced salivation and lacrimation approximately 60% of patients present with a systemic process with diverse extraglandular manifestations, with articular involvement (44%), vasculitis (20%), and neuropathy (16%) being the most frequent features observed. The main immunologic features are antinuclear antibodies (65%), hypocomplementemia (51%), and cryoglobulinemia (50%). Only approximately 25% of patients with SS
Sarcoidosis is a systemic disease that may be associated with HCV infection. It is triggered (initial manifestation or reactivation) by interferon in 75%, and is unrelated to interferon treatment in 25% of cases. Two thirds of patients who develop interferon associated sarcoidosis do so during the first 6 months after starting therapy [192].
Thyroid Disorders Approximately 10% of HCV infected persons (predominantly women) have thyroid antibodies already prior to interferon therapy. On the other hand antibodies to HCV are more frequent in patients with thyroiditis compared to the general population. Five percent of patients with chronic hepatitis C have a history of thyroid disorder. It is unclear if there is a direct pathogenetic link between HCV infection and thyroid dysfunction, mainly autoimmune hypothyroidism (Hashimoto’s thyroiditis). Patients receiving interferon therapy for hepatitis C may develop thyroid dysfunction. Up to 15% of patients with hepatitis C receiving interferon develop clinical thyroid disease, in up to 40% with thyroid antibodies. Patients seropositive for LKM1 antibodies seem to be particularly susceptible to developing autoimmune thyroid disease during interferon treatment [135, 160]. Interferon induced thyroiditis (autoimmune type and non-autoimmune type) may be a major clinical problem resulting in discontinuation of interferon therapy. Non-autoimmune interferon induced thyroiditis can manifest as destructive thyroiditis or as hypothyroidism with negative thyroid antibodies.
Dermatologic Disorders Dermatologic disorders associated with chronic HCV infection encompass the cutaneous manifestations of
796
mixed cryoglobulinemia, porphyria cutanea tarda, lichen planus, erythema exsudativum multiforme, erythema nodosum, cutaneous vasculitis, urticaria, Behcet’s disease and vitiligo [13]. Many dermatologic manifestations are due to deposits of cryoglobulin immune complexes in the vessel walls. Cutaneous vasculitis manifests clinically with palpable purpura, predominantly of lower extremities (Fig. 63.48). The occurrence of generalized lichen planus in patients with chronic hepatitis C is well known. Lichen planus may also be triggered by interferon therapy [161]. The causal association of oral lichen planus with HCV infection recently has been put in doubt in an Italian case-control study and it has been suggested that the concomitant occurrence of both disorders may be due mainly to the frequency of each disease in the population [52].
Metabolic Manifestations HCV infection is associated with the metabolic syndrome, and compared to the general population patients with HCV infection have a higher prevalence of type 2 diabetes mellitus. Chronic infection with HCV can induce insulin resistance in a genotype-dependent fashion, thus contributing to steatosis and progression of fibrosis (see paragraph on “Pathogenesis”) [94, 214, 257]. Possibly there is a direct correlation between the viral load and the presence of insulin resistance in HCV patients [93]. The metabolic effects of HCV also have a negative impact on the response of HCV to antiviral treatment. On the other hand, clearance of HCV improves insulin resistance, b-cell function and parameters of glucose metabolism [114, 183, 198].
Hematologic-Oncologic Disorders HCV has been demonstrated to occur in bone marrow cells, lymphocytes and peripheral blood mononuclear cells. Among the hematological disorders associated with HCV infection are idopathic thrombocytopenia, anemia, lymphadenopathy and malignant nonHodgkin’s lymphomas. Immune thrombocytopenic purpura (ITP). Patients with ITP show markers of HCV infection in
63 Viral Infections by Hepatotropic Viruses
approximately 10% of cases, and up to 80% of patients with chronic hepatitis C have platelet antibodies, in comparison to approximately 45% of those with hepatitis B. HCV-RNA may be demonstrated within the platelets of some patients with HCV-associated ITP. Eltrombopag is an orally active thrombopoietin-receptor agonist that stimulates thrombopoiesis. It has been shown to increase platelet counts in patients with thrombocytopenia due to HCV-related cirrhosis [151]. However, at the time of writing it has not yet been approved for clinical use in cirrhosis induced thrombocytopenia. Recombinant interleukin-11 (rIL-11), which has both thrombopoietic and anti-inflammatory properties, was recently evaluated in 12 patients with HCV associated ITP. At high dose (50 mg/kg daily) mean platelet counts rose from initial 54 × 109/L to 103 × 109/L and at low dose (15–35 mg/kg tiw) from an initial 51 × 109/L to 74 × 109/L. Side effects of rIL-11 were common and troublesome, but could be reduced by lowering the dose [68]. Anemia. Hemoglobin concentrations in patients with chronic HCV infection decrease mainly as a result of ribavirin-induced hemolysis. Although ribavirin-associated anemia can be reversed by dose reduction or discontinuation, this approach compromises outcomes by significantly decreasing sustained viral response rates. Recombinant human erythropoietin has been used with varying success to manage ribavirin-associated anemia. Viramidine, a liver-targeting prodrug of ribavirin, has the potential to maintain the virologic efficacy of ribavirin while decreasing the risk of hemolytic anemia in patients with chronic hepatitis C [150]. Aplastic anemia, usually severe and irreversible may occur several weeks or months following acute viral hepatitis C. Lymphadenopathy. Enlarged hepatic hilar lymph nodes occur in up to 40% of patients with chronic hepatitis C. Non-Hodgkin’s lymphoma (NHL). The prevalence of NHL is increased among patients with chronic HCV infection. HCV infection confers a 20–30% increased risk of NHL overall, and a threefold higher risk of Waldenström’s macroglobulinemia, a low-grade lymphoma [76]. The prevalence of HCV infection in NHL ranges between 7.4% and 37.0%. The spectrum of HCV induced lymphomas includes the intermediate to highgrade lymphoma, and the more common indolent, low-grade lymphoma, preceded by long-standing
Hepatitis C
symptomatic mixed cryoglobulinemia Type II (diffuse large B-cell lymphoma, marginal zone lymphoma, and lymphoplasmacytic lymphoma) [42, 146, 166]. HCV has also been ascribed a role in the development of gastrointestinal MALT lymphoma [130]. HCV has oncogenic potential, but the intimate pathogenetic mechanism involved in HCV-related tumorigenesis remains unknown. Regression of HCV associated low-grade NHL after treatment with pegylated interferon plus ribavirin has been reported [145]. Viral reactivation may occur during chemotherapy and complicate the underlying liver disease. In addition to NHL a Swedish study also showed a significantly increased prevalence of malignant melanoma in patients with HCV infection [50].
Nervous System and Psychiatric Disorders Neuropathy. Neurologic manifestations in HCVinfected patients occur predominantly in the peripheral nervous system. The prevalence of peripheral nerve involvement in patients with mixed cryoglobulinemia ranges between 20% and 35%. Clinical manifestations result from immune complex deposits within the vasa nervorum of the peripheral nerves leading to vasculitis. Eighty percent of cases of HCV-associated peripheral neuropathy manifest as a very painful symmetrical distal polyneuropathy that involves the legs [25]. Mononeuritis multiplex occurs more rarely. In addition to polyneuropathy cerebral infarcts, cerebral nerve palsies and a poyradiculitis manifesting in the form of a Guillain-Barré syndrome have been described in chronic HCV infection. Electrophysiologic investigations confirm axonal degeneration, and histology shows a vasculitis. The response to antiviral therapy and plasmapheresis is discouraging. Psychiatric disorders. There is growing evidence that HCV may have a direct effect on neuropsychiatric function [129, 249]. HCV involvement of the central nervous system may manifest as fatigue, depression and result in a markedly diminished quality of life [37]. Depression also is a major side effect of interferon treatment and may lead to discontinuing therapy. The 5-hydroxytryptamine receptor type 3 antagonist ondansetron has been reported to have a significant positive effect on fatigue in chronic hepatitis C
797
[179]. Citalopram treatment is highly effective in HCV patients with interferon-induced depression [120].
Others Arthritis and arthralgias are often associated with cryoglobulinemia of viral hepatitis. The condition is probably mediated by immune complexes. Gallbladder disease. Chronic hepatitis C was strongly associated with gallbladder disease (gallstones or cholecystectomy) among men but not women in the United States in a study of more the 13,000 persons [15]. Cardiovascular disease. Of all HIV-infected individuals in the United States, approximately 15–30% are co-infected with HCV. It has been suggested that hepatitis C may be independently associated with cardiovascular disease in HIV-infected individuals. HCV/ HIV coinfection was associated with a > 4.5-fold increased prevalence of cardiovascular disease after controlling for age and other confounders [69]. Lung disease. There are case reports and small series suggesting an association between idiopathic pulmonary fibrosis and chronic hepatitis C. HCV-RNA has been demonstrated in bronchoalveolar lavage in some of these patients [3, 19, 100]. Sexual dysfunction. Sexual dysfunction as assessed by a questionaire evaluating sexual drive, erection, ejaculation, sexual problem assessment, and overall sexual satisfaction is highly prevalent among men with chronic hepatitis C, and is independent of depression [38]. It is not surprising that this contributes to the HCV-associated reduction in quality of life.
Differential Diagnosis The discussion on the differential diagnosis of hepatitis B pertains also to hepatitis C (see Section 63.3 “Hepatitis B”). Chronic HCV infection associated with anti-LKM antibodies must be distinguished from autoimmune hepatitis (see Chapter 72).
Natural Course and Prognosis The natural course of hepatitis C is influenced by a number of host factors (age, gender, immune status,
798
genetic susceptibility, alcohol use, smoking, hepatotoxic drugs, accompanying diseases), by coinfections with other hepatotropic viruses, and by viral factors (HCV genotype, viral load). In patients with acute hepatitis C who successfully clear the virus, HCVRNA concentrations already decline prior to the rise in serum aminotransferase levels. Patients with icteric acute hepatitis C seem to have a better prognosis and do eliminate the virus more often than anicteric patients. Host related factors, in particular female sex and cell mediated immunity (HCV specific T cell response, i.e. virus-specific CD4 function and maturation of antiviral memory CD8 response), play an important role in the spontaneous clearance of HCV [236]. A negative HCV-RNA test and broad cell mediated immunity within the first month after onset of the symptoms represent efficacious predictors of viral clearance [222]. Alcohol and HIV coinfections are negatively associated with viral clearance [178]. HCV genotype 1b infection signals an unfavorable prognosis with a chronic course. There is recent evidence that even after serological eradication of HCV (HCV-RNA negative, HCV antibodies positive) the virus may persist at low levels and affect the natural history and liver histology. Nonviremic HCV antibody-positive patients may present fibrosis and inflammatory activity similar to viremic cases. The presence of a CD8+ rich inflammatory infiltrate suggests an ongoing immune response in the liver, supporting the view that HCV may persist in the liver in the majority of HCV RNA-negative cases [91]. Fulminant hepatitis occurs in less than 1% of cases of acute hepatitis C and may be more common in patients with underlying chronic hepatitis B virus infection, or be associated with hepatitis A superinfection in patients with chronic hepatitis C [32, 240]. HVC infection results in a high frequency (approximately 80%) of chronic disease. Twenty to 30% of patients with chronic hepatitis C insiduously progress to cirrhosis (Fig. 63.49). The most important process on the road to cirrhosis is progressive fibrosis. Duration of infection is the most consistent factor significantly associated with progression of fibrosis. It is important to realize that the progression of fibrosis is not linear, and requires evaluation over long follow-up periods. The majority of fibrosis progression occurs in patients aged 50 years or older [75, 185, 231]. In a large metaanalysis of 111 studies of 33,121 individuals with
63 Viral Infections by Hepatotropic Viruses
Hepatitis C-Infection
Acute Hepatitis C
Healing (20 %)
Chronic Course (80 %)
inactive (20 %)
active (60 %)
Cirrhosis (20Ð30 %)
HCC (4 %)
Fig. 63.49 Natural course of hepatitis C
chronic HCV infection the estimated prevalence of cirrhosis at 20 years after the infection was 16% [231]. Host factors predictive of disease progression are (1) acquisition of HCV infection after the age of 40–55, (2) a high body mass index and hepatic steatosis, (3) even a relatively low alcohol intake (30–50 g/day in men and 20–50 g/day in women), justifying the recommendation that alcohol intake should be avoided in all patients with chronic HCV infection, and (4) smoking (nicotine and cannabis) [45, 54, 87–89, 96, 101, 127, 176]. Progression of liver fibrosis in women may be affected by hormonal factors. Menopause appears to be associated with accelerated liver fibrosis progression. Since estrogens may have an antifibrotic effect, progression of fibrosis possibly may be delayed or even prevented by hormone replacement therapy [48]. Hepatocellular carcinoma may develop on the background of liver cirrhosis after a mean latency period of 20–25 years. HCV accounts for approximately one third of HCC cases in the United States. The risk of developing HCC once cirrhosis has developed is up to 3% per year. In contrast to HBV infection, HCV associated HCC occurs almost exclusively in patients with cirrhosis [39]. Overweight, diabetes mellitus, chronic HBV coinfection and HCV genotype 1b are associated with an increased risk of HCC occurrence in patients with HCV-related cirrhosis [20, 99, 167, 239].
Hepatitis C
Thus, the natural course of chronic hepatitis C implies on one hand that in most patients chronic hepatitis C has a relatively benign clinical course over years; on the other hand persons infected for years or decades are diagnosed not until advanced liver disease with its complications becomes manifest. The serum levels of aminotransferases do not mirror viral replication in the liver, and in immunosuppressed patients low serum aminotransferases are associated with high HCV-RNA concentrations. Survival of patients with chronic hepatitis C is generally not impaired until cirrhosis has developed. The 3, 5, and 10-year survival rates in 384 patients with compensated cirrhosis were 96%, 91%, and 79%, respectively [60]. In a more recent study a cohort of 214 patients with compensated cirrhosis due to HCV were followed for 17 years. HCC developed in 68 (32%), ascites in 50 (23%), jaundice in 36 (17%), upper gastrointestinal bleeding in 13 (6%), and encephalopathy in 2 (1%), with annual incidence rates of 3.9%, 2.9%, 2.0%, 0.7%, and 0.1%, respectively. HCC was the main cause of death (44%) and the first complication to develop in 58 (27%) patients, followed by ascites in 29 (14%), jaundice in 20 (9%), and upper gastrointestinal bleeding in 3 (1%). The annual mortality rate was 4.0% [204].
Chronic Hepatitis C with Persistently Normal Aminotransferases Patients with PNALT usually have a higher viral load but a more favorable histology with a slower rate of fibrosis progression when compared with patients with persistently elevated ALT levels [2, 70, 215]. The potential for progression to advanced liver disease, however, still exists [70]. Spontaneous resolution of HCV infection in patients with PNALT may occur, but is a very rare event, and on long-term follow-up 30% of such carriers become candidates for antiviral therapy within 5 years [33, 168, 260].
799
Spontaneous improvement of chronic hepatitis C during pregnancy has been reported, but there is evidence of deterioration of hepatitis C after delivery [65]. Vertical transmission of HCV is much less efficient than for HBV, occurring in approximately 5–10% of infants born to HCV-RNA positive mothers.
Hepatitis C in Children Chronic hepatitis C in children usually is associated with lower ALT and HCV-RNA levels in serum combined with only mild histopathological alterations. Children appear to have a relatively decreased risk of disease progression. Only a few children, however, clear viremia spontaneously (most likely infected with genotype 3) and persistent viral replication may lead to end-stage liver disease in a small subgroup characterized by perinatal exposure, maternal drug use, and infection with HCV genotype 1a [18].
Coinfection with HBV Coinfection with HBV usually is associated with a more severe course with a high risk of progression to end-stage liver disease and development of HCC. Interferon therapy might be less effective in preventing HCC among patients with chronic hepatitis C who are anti-HBc-positive than in those with chronic hepatitis C who are anti-HBc-negative [99]. One should also be aware of occult HBV infection present in patients with chronic HCV liver disease, i.e. many coinfected patients lack serologic markers of HBV infection. In one study HBV-DNA sequences were detected in the liver in one third of patients despite the absence of HBsAg, and patients with HCV were significantly more likely to be positive for HBV-DNA than controls (33% versus 14%) [23]. HCV infection, however, may also inhibit HBV replication and result in seroconversion with loss of HBsAg in some coinfected patients.
Hepatitis C and Pregnancy Coinfection with GBV-C/HGV Women chronically infected with HCV can have an uneventful pregnancy without worsening of liver disease or other adverse effects on the mother or fetus.
A concomitant GBV-C/HGV infection does not appear to impact the natural course of HCV infection.
800
Coinfection with HIV Effect of HIV on chronic hepatitis C. In the preHAART era, coinfection of HCV patients with HIV was a significant factor for accelerated progression of chronic hepatitis C to cirrhosis, but was not associated with the development of HCC (probably because most patients succumbed to AIDS prior to the appearance of HCC) [119]. HIV coinfection reduced considerably the survival of patients with HCV-related end stage liver disease independently of other markers of poor prognosis [180]. The introduction of HAART has changed this scenario dramatically. HCV infection in successfully treated HIV patients has a course similar to that in HIV negative patients. Once immunodeficiency is advanced with T helper cells < 100/mL HCV infection may run a rapidly progressive, occasionally cholestatic course and patients may die from liver related complications (bleeding, hepatic insufficiency). When interpreting elevated liver enzymes in HIV/ HCV coinfected patients, one should also be aware of the hepatotoxic potential of antiretroviral drugs (see Chapter 71). Effect of HCV on HIV infection. HCV coinfection does not seem to affect adversely the course of HIV infection. In a recent epidemiological study coinfection with HCV was even associated with a significant decrease in the mortality of HIV-infected patients [51].
a1-Antitrypsin Deficiency The concomitant occurrence of a1-antitrypsin deficiency and HCV infection results in an increased risk of cirrhosis and a shortened life expectancy.
Porphyria Cutanea Tarda Patients with porphyria cutanea tarda and HCV infection have an accelerated progression of liver disease.
Diabetes Mellitus Type 2 diabetes mellitus and the metabolic syndrome have profound effects on HCV infection (see above). Diabetic patients with HCV cirrhosis have been
63
Viral Infections by Hepatotropic Viruses
reported to have a more severe hepatic encephalopathy compared to patients without diabetes mellitus [218]. For patients with chronic hepatitis C and advanced cirrhosis, diabetes mellitus increases the risk of developing HCC [167, 239].
Prevention Currently immune prophylaxis, neither active nor passive is available for hepatitis C. Prevention of hepatitis C relies on identifying and counselling uninfected persons at risk for hepatitis C (e.g., injection-drug users) regarding ways to protect themselves from infection and on identifying and preventing transmission of HCV in healthcare settings.
Approach to Accidental Exposure (Needle Stick Injury) There are no guidelines as how to proceed after accidental needle stick exposure to HCV infected material. The approach practiced at the author’s institution is outlined here. After accidental injury with HCV infected blood immediate cleaning and disinfection of injured skin seems reasonable, although not proven by studies. Thereafter the potentially HCV positive person (“blood donor”) and the injured person (in order to document HCV negativity) are tested immediately for the presence of HCV antibodies and HCV RNA, and aminotransferase levels in serum are determined in both. The accident should be documented carefully and the risk of transmission (depth of the wound, needle type, clinical and virological state of the potentially contagious person) should be estimated. During the first 2 months after exposure aminotransferases are determined in intervals of 2 weeks, thereafter once monthly for 4 months. During this period careful attention is to be given to the appearance of nonspecific symptoms of viral hepatitis. Measuring HCV RNA in serum 2, 4 and 12 weeks after the injury allows one to determine whether or not an infection has occurred. After 3 and 6 months, testing for anti HCV (in addition to measuring aminotransferases) is recommended. If aminotransferases rise, measurement of HCV antibodies and HCV RNA in serum should occur in any case.
Hepatitis C
Postexposure prophylaxis with immunoglobulin or the immediate administration of interferon is not indicated. Only if acute infection is documented treatment with standard or pegylated interferon should be started (see below).
801
viremic patients with HCV antibodies may have persistent hepatic HCV infection the author prefers the early approach to therapy [91]. Taking into account the excellent sustained viral responses of IFN or pegIFN monotherapy there is no compelling evidence to include ribavirin in the treatment of acute hepatitis C.
Therapy The goal of treatment is sustained clearance of HCV. In the case of acute hepatitis C chronicity is prevented, in chronic hepatitis C sustained elimination of HCV is followed by disappearance of necroinflammatory activity and prevention of the development of cirrhosis and HCC. Therapy of Acute Hepatitis C There are no established treatment guidelines for acute hepatitis C. Interferon a (IFN) and more recently pegylated interferon a (pegIFN) monotherapy have been shown to be effective in patients with acute hepatitis C. Treatment regimens used are IFN 2a/2b 5 MU s.c. daily for 4 weeks followed by 5 MU s.c. three times weekly for 20 more weeks (total duration of therapy 24 weeks) or pegIFN a-2a (180 mg once weekly) or pegIFN a-2b (1.5 mg/kg once weekly) for 12–24 weeks. If treatment is started within 8 to 12 weeks after the onset of symptoms of acute hepatitis or the appearance of HCV RNA, end-of-treatment and sustained virological response rates in patients who strictly adhere to the treatment regimen are > 90% and approximately 90%, respectively [44, 108, 112, 206, 250, 251]. There is some controversy as to when to start antiviral therapy. In view of the high rate (up to 68%) of spontaneous viral clearance within 12 weeks after the onset of symptomatic disease some authors advocate treating only those patients who remain HCV RNA positive for more than 3 months after the onset of disease [74, 131, 205]. Others, however, recommend early initiation of treatment within 8–12 weeks after the appearance of HCV RNA [44, 112, 251]. Considering recent data that suggest that even non-
Therapy of Chronic Hepatitis C IFN combined with ribavirin was introduced as the standard treatment of chronic hepatitis C in 1999. In November 2000 standard IFN has been replaced by pegIFN in chronic HCV infection [26, 40, 86, 132, 138, 149, 184, 259]. Current developments are characterized by attempts to predict early the viral response to therapy in the individual patient, thus allowing for the indvidualization of treatment. In addition, new substances are being developed. Definitions of Response to Treatment Patients responding to therapy usually show normalization of elevated aminotransferase levels within 4–6 weeks (biochemical response) with HCV RNA becoming non-detectable (virologic response). The end-oftreatment response describes results of HCV RNA testing at the end of treatment, while sustained viral response is defined by negative HCV RNA status ≥ 6 months after the end of therapy. If initially normalized aminotransferases rise again after the end of treatment, biochemical relapse is said to be present, while renewed HCV RNA positivity characterizes virologicl relapse. Breakthrough phenomenon describes the renewed elevation of initially normalized aminotransferase levels (biochemical breakthrough) or the reappearance of initially nondetectable HCV-RNA (virologic breakthrough) during therapy. If aminotransferase levels do not normalize and HCV-RNA remains detectable during treatment the patient is a nonresponder. The definition of terms based on HCV-RNA during therapy is summarized in Table 63.32. Drugs used in the Treatment of Chronic Hepatitis C Interferons. For actions, pharmacology and side effects of interferons see this Chapter, Section on “Hepatitis B”.
802 Table 63.32 Definition of terms based on HCV-RNA during therapy Term HCV-RNA Non-response Relapse
Positive at all times during therapy Negative during therapy, positive after end of treatment Rapid Virologic Negative (< 10–30 IU/mL) after 4 Response weeks of treatment Complete Early Negative (< 10–30 IU/mL) after 12 Virologic Response weeks of therapy Partial Early ≥ 2-log reduction after 12 weeks Virologic Response of therapy Sustained Viral Negative 24 weeks after end of Response therapy
Standard IFN is not used anymore in the therapy of chronic hepatitis C. Coupling polyethyleneglycol to IFNa (pegylation) results in the formation of pegylated interferons. They have improved pharmacokinetic and pharmacodynamic characteristics compared to standard IFN, and are therefore easier to use. Pegylation of IFNa leads to an increased solubility in water, to a reduced antigenicity and to a prolonged half life and duration of action due to slowed renal clearance [78]. Currently 2 pegylated interferons (peg-interferon a-2b [12 kD]) and peg-interferon a-2a [40 kD]) are available for treatment of chronic hepatitis C. PegIFN a-2b is administered at a weight-based dose of 1–1.5 mg/kg s.c. once weekly while pegIFN a-2a is given at a flat dose of 180 mg s.c. once weekly. In patients infected with HCV genotype 1 ( probably also with others genotypes ) the rates of sustained virologic response do not differ significantly between the two peginterferon – ribavirin regimes ( see below ) [151a]. Consensus interferon (interferon-alfacon-1) combines the most frequent amino acid sequences of naturally occuring IFNs-a to one “consensus protein”. Its biological activity in vitro is approximately ten times higher than that of IFN a-2a or 2b. Response rates to consensus IFN are comparable to those of standard IFN [85]. The vast majority of specialized centers do not use consensus interferon in patients with HCV infection. Albinterferon a-2b is a novel recombinant 85.7kDa protein consisting of IFN a-2b genetically fused to human albumin. It has been shown to retain the antiviral properties of IFNa. Due to its longer half life it can be administered with an improved dosing schedule, once every 2 or 4 weeks, at a dose of 900 mg or 1,200 mg s.c., respectively, offering comparable
63 Viral Infections by Hepatotropic Viruses
efficacy to pegIFN a-2a (at the time of writing albinterferon a-2b has not yet been approved for clinical use) [7, 264]. Ribavirin. Ribavirin is a purine nucleoside analog that inhibits the replication of a wide range of RNA and DNA viruses. In patients with chronic hepatitis C it is administered orally, adapted to the patient’s weight (< 75 kg: 500 mg bid; ≥ 75 kg: 600 mg bid). In obese patients weighing 105–125 kg its dose should be increased to 1,400 mg/day. Amantadine. Most authors agree that adding amantadine to pegIFN/ribavirin combination therapy (triple therapy) does not improve significantly virologic response rates in patients with chronic hepatitis C [43, 62, 171, 246].
Combination Treatment The treatment of chronic hepatitis C is outlined in Table 63.33. Patients with genotype 1 or 4 infections are treated for 48 weeks. Treatment duration of 24 weeks compared with 48 weeks does not impair sustained viral response rates in patients with HCV genotype 2 or 3 infection. Thus, treatment for 24 weeks with pegIFN and ribavirin is sufficient in HCV genotype 2 or 3 infected patients [225, 261]. In contrast to genotype 1 or 4, in patients with HCV genotype 2 or 3 infection, Table 63.33 Standard treatment of chronic hepatitis C with pegylated interferon and ribavirin Genotype Duration (1) PegIFN a-2a Ribavirina of Therapyb (2) PegIFN a-2b 1 or 4c
(1) 180 mg s.c. qw (2) 1–1.5 mg/kg s.c. qw
2 or 3d
≥ 75 kg: 600 mg bid < 75 kg: 500 mg bidc 400 mg bid
48 weeks
(1) 180 mg s.c. 24 weeks qw (2) 1–1.5 mg/kg s.c. qw a Ribavirin dose should be adjusted to 1,400 mg/day in obese patients (105–125 kg) with HCV genotype 1 infection b HCV-RNA should be tested already 4 weeks after the start of therapy in order to recognize rapid viral responders c In patients with HCV genotype 1 or 4 infection, quantification of the viral load is mandatory at baseline and during therapy d Patients with HCV genotype 2 or 3 infection are sufficiently treated with combination therapy for 24 weeks regardless of baseline viral load
Hepatitis C
flat doses of 800 mg ribavirin daily are proven to be sufficient. A treatment algorithm for chronic hepatitis C is outlined in Fig. 63.51 (for individualizing treatment see below). In order to avoid unnecessary therapy (costs, side effects), stopping rules must be taken into account. Response to antiviral therapy should be assessed after 12 weeks of treatment. Therapy should be stopped in patients who do not show at least a 2 log decline of baseline viral load after 12 weeks of treatment, since these patients with all likelihood will not attain a sustained viral response with continued therapy. This stopping rule, however, is not absolute as treatment decisions always must be individualized (see paragraph on “Nonresponders”). Side effects of and contraindications for combination therapy. The numerous potential adverse effects of and contraindications for IFNs are listed in Tables 63.25 and 63.26, respectively. The contraindications for ribavirin treatment are reported in Table 63.34. The time course of the major side effects occuring during combination therapy is depicted in Fig. 63.50. Flu-like symptoms regularly occur during the first weeks of treatment and then subside. They are usually well controlled by paracetamol 1 g p.o. prior to the application of pegIFN. Systemic ribavirin causes dose-related reversible hemolytic anemia and bone marrow suppression. Anemia is usually mild and only about 10% of patients have a hemoglobin level of less than 10 g/dL. Occasionally, however, anemia may be so severe as to necessitate discontinuation of treatment. For patients with no cardiac disease who experience significant anemia during therapy dose reduction of ribavirin to 600 mg/day is recommended for Hb levels of 8.5–10 g/ dL. If Hb falls to less than 8.5 g/dL, ribavirin should
Table 63.34 Contraindications for treatment with ribavirin • • • • • • • • • •
Severe hepatic dysfunction, decompensated liver cirrhosis Anemia (Hb < 10 mg/dL) Hemoglobinopathies (e.g. thalassemia, sickle cell anemia) Severe cardiac diseases (e.g. coronary heart disease, myocardial infarction) Pregnancy or inadequate contraception Breastfeeding Allergies Renal failure (creatinine clearance < 50 mL/min) Ongoing alcohol or substance abuse Poor compliance
803
Anemia, Neutropenia, Thrombocytopenia
Fatigue
Flu-like Symptoms 4 weeks
Psychologic Symptoms, e.g. Depression 12 weeks
Fig. 63.50 Major side effects of interferon therapy in relation to duration of treatment
be discontinued. If a patient with stable cadiac disease experiences a > 2 g/dL Hb drop in any 4-week period, the dose of ribavirin should be reduced by 600 mg/ day. Ribavirin should be discontinued permanently if patients have a Hb level < 12 g/dL 4 weeks at the reduced dose of ribavirin [227]. Ribavirin alternatives with a lower risk for hemolytic anemia are therefore desirable. Viramidine is the amidine prodrug of ribavirin, which is taken up preferentially by hepatocytes during first-pass metabolism and has less drug available for entry into erythrocytes. Erythropoetin (epoetin alpha) 40,000–60,000 units s.c. once weekly leads to an increase in Hb levels of 2.3–2.8 g/dL. It may, however, worsen pegIFN induced thrombocytopenia [92]. Erythropoetin treatment of anemia in HCV infected patients has not been approved by the FDA. Due to its teratogenic and mutagenic potential pregnancy and breastfeeding are contraindications for ribavirin therapy. Women in childbearing age treated with ribavirin should be advised to practice effective anticonception that should continue up to 4–6 months after end of treatment. Men treated with ribavirin should not procreate during and up to 7 months after end of ribavirin therapy. Over the course of pegIFN treatment, nearly 50% of subjects experience a grade 3 or 4 neutropenia. 4–5% of patients experience an absolute neutrophil count less than 0.5 × 109/L (500/mm3) (grade 4 neutropenia). With neutropenia of 0.5–1.5 × 109/L the dose of pegIFN should be reduced by 50% with an absolute neutrophil count of < 0.5 × 109/L pegIFN should be discontinued. Human granulocyte colony-stimulating
804
factor (G-CSF) (filgrastim) 300 mg s.c. biw–tiw should be considered. With thrombocytopenia < 50 × 109/L the dose of pegIFN should be reduced by 50%. With platelet numbers < 25 × 109/L pegIFN should be discontinued. Eltrombopag is promissing but not yet approved for clinical use in IFN-indnced thrombocytopenia [151]. The only product approved by the FDA for the management of cancer chemotherapy-related thrombocytopenia is interleukin-11 (oprelvekin). Recombinant interleukin-11 appeared useful in the treatment of HCV associated immune thrombocytpenic purpura (see above) [67]. No data are available on interleukin-11 in ribavirin induced thrombocytpenia. Depression may be severe and a cause for poor compliance and discontinuation of therapy. Antidepressants, such as citalopram (20 mg/day), which may also be used prophylactically, are effective in treating IFN induced depression and restoring compliance [120, 210].
63 Viral Infections by Hepatotropic Viruses
treatment cessation [144]. Clinical relapse is extremely rare in patients who achieve an SVR and these patients may be deemed clinically cured of chronic HCV. Elevated liver enzymes normalize, quality of life improves, the risk of cirrhosis and HCC diminishes [14, 98, 238]. Although achieving SVR is associated with a lowering of long-term liver related mortality, residual HCV-RNA may persist at very low levels in the liver, the serum and peripheral lymphoid cells, and the risk of complications and development of HCC is not completely abolished. Therefore, careful long-term observation of these patients (especially elderly male HCV cirrhotics) even after achieving SVR is advisable [21, 117, 188]. The beneficial effects of pegIFN/ribavirin therapy on liver histology are closely related to virologic response [27]. Successful treatment may result in regression of fibrosis. Full-blown cirrhosis, however, is irreversible, despite claims to the contrary by some [144].
Results of Treatment Individualizing Treatment Treatment results have improved constantly over the last years and overall sustained viral response rates (SVR) after treatment for 48 weeks currently are approximately 50% in patients with HCV genotype 1 or 4 infection, and around 80% for those with genotype 2 or 3 infection. Factors associated with high SVR are • • • • • • • • •
Non-1 genotype Baseline viral load ≤ 2 × 106 copies/mL Weight ≤ 75 kg Age ≤ 40 years Non–African American No or minimal fibrosis Body mass index < 30 kg/m2 Absence of steatosis or metabolic syndrome Female sex [254]
IFN-based therapies are conducted over longer periods of time and are associated with potentially serious adverse effects. Thus, patient motivation and guidance are essential in initiating and maintaining treatment and key to the success of therapy. Adherence to the treatment protocol is essential in achieving optimal results. Ninety percent of patients who achieve an SVR remain HCV-RNA undetectable at a mean of 4.1 years of follow-up and SVR is durable up to 18 years after
The response to pegIFN/ribavirin treatment is influenced by patient and virus related factors. Current attempts try to predict response to therapy in order to be able to tailor treatment to the needs of the individual patient [12]. The major patient related factors associated with impaired response to combination therapy are • Advanced fibrosis or cirrhosis (SVR in 8–44% of patients), ethnic factors (African Americans have less favorable response to treatment [19–26%] than whites) • Male gender • Older age • Obesity • Metabolic syndrome (insulin resistance) • Elevated pretreatment gGT levels (probably a surrogate marker for hepatic steatosis, fibrosis and intrahepatic expression of TNF a) [53, 84, 102, 197, 219, 229] The major viral factors associated with impaired response are • HCV genotype 1 and • High viral load.
Hepatitis C
Individualizing treatment based on patient related factors is difficult. Weight-based ribavirin, i.e. increasing the dose to 1,400 mg/day in obese patients weighing 105–125 kg has been shown to be more effective than flat-dose ribavirin [106]. However, even with weightbased dosing, response rates in African Americans are lower than reported in other ethnic groups [107]. Since patient related factors are unreliable in predicting the individual response to treatment, viral factors are being increasingly analyzed. Viral kinetic analysis, i.e. quantification of HCV-RNA during early therapy is becoming increasingly important in individual treatment decisions. Viral kinetic analysis can be used as an early predictive marker for SVR and on the other hand may allow for early detection of nonresponders and early treatment discontinuation [175]. HCV-RNA reduction during reduction antiviral therapy typically shows a biphasic pattern with a rapid first phase during the initial 24–48 h and a less rapid second phase of viral decline thereafter [153, 163]. The more rapidly HCV-RNA declines during therapy the higher is the chance to achieve SVR. Identifying patients with a rapid virologic response (RVR), i.e. non-detectable HCV-RNA by PCR after 4 weeks of treatment allows for a shortened treatment without compromising SVR rates [61]. Thus, irrespective of genotype HCV RNA should be tested 4 weeks after initiation of therapy in order to recognize RVR. HCV genotype 1 and 4. Shortening of treatment from 48 to 24 weeks in HCV genotype 1 patients with a low baseline viral load (< 600,000–800,000 IU/mL) and a RVR does not impair SVR. In patients with genotype 4 achieving RVR, 24 weeks of treatment are sufficient irrespective of the baseline viral load [36, 64, 110, 136, 137, 245, 256, 263]. On the other hand, extending the treatment duration from 48 weeks to 72 weeks in HCV genotype 1 infected patients who fail to achieve a RVR significantly improves SVR rates. Treatment extension does not seem to increase the rate of side effects induced dose reduction or therapy discontinuation [174, 203]. HCV genotype 2 and 3. Shortening of treatment from 24 to 16 weeks in patients with low pretreatment viremia (≤ 400,000 IU/mL) in patients with RVR does not impair SVR [36, 136, 137, 217]. When administered for 24 weeks with pegIFN, ribavirin doses of 400 and 800 mg/day produce equivalent outcomes in patients infected with HCV genotype 3 [63]. An individualized genotype-specific treatment algorithm of chronic hepatitis C is outlined in Fig. 63.51.
805
New Approaches to Treatment Despite the improvements achieved over the last years, treatment of chronic hepatitis C still is unsatisfactory. Intense research efforts to develop new antiviral drugs are ongoing. Among them are serine protease inhibitors (telaprevir, boceprevir), polymerase inhibitors, NS5A inhibitors, cyclophilin inhibitors and antiapoptotic caspase inhibitors [123, 182]. Some of these emerging drugs are currently tested in phase 2 studies. Serine protease inhibitors intensify the action of standard combination therapy and telaprevir has an increased antiviral effect when combined with pegIFN [68, 116, 207]. The combination of telaprevir, pegIFN, and ribavirin is generally well tolerated [126]. The problem of protease inhibitors is the emergence of viral resistance. Long-acting interferons currently tested in phase 2 studies are locteron, interferon-omega, and an oral interferon (belerofon). Albinterferon a-2b (see above) is already tested in phase 3 studies
Therapeutic Problems in Special Patient Populations Patients with Persistently Normal Aminotransferase Levels (PNALT) Most patients with PNALT have a slow rate of fibrosis progression and a favorable natural history of HCV infection. However, the potential for progression to advanced liver disease persists and 10% of the PNALT patients have stage 3 bridging fibrosis on liver biopsy [70]. Patients with PNALT treated with pegIFN/ribavirin have a rate of SVR comparable to that in patients with elevated ALT and should not be excluded from treatment on the basis of ALT alone [104, 260]. The decision to initiate combination therapy should be individualized based on the severity of liver disease by liver biopsy.
Nonresponders and Relapsers The lack of response of chronic hepatitis C to current antiviral therapy may have many reasons which have been discussed above. It may be treatment-related (drug efficacy, dosing, side effects), host-related (adherence to treatment protocol, alcohol use, accompanying
806
63 Viral Infections by Hepatotropic Viruses Genotype 1 Start of therapy (HCV-RNA concentration) Week 4 HCV-RNA measurement Week 12 HCV-RNA measurement
Stop therapy Week 24 HCV-RNA measurement
HCV-RNA 60 g/day HLA-DR 3 or HLA-DR 4 Concurrent immune disease (any nonhepatic disease of an immune nature) Histologic features Interface hepatitis Plasmacellular infiltrate Rosettes None of above Biliary changes (includes destructive and nondestructive cholangitis, ductopenia) Atypical features (steatosis, iron or copper overload, alcohol-induced hepatitis, granulomas, ground-glass hepatocytes, viral inclusions) Treatment response Complete remission Remission with relapse
+2 0
Interpretation
Score
Pretreatment Definite diagnosis Probable diagnosis Posttreatment Definite diagnosis Probable diagnosis ULN upper limit of normal
−2 0 +2 +3 +2 +1 0
+3 +2 +1 0 −4 +2
−3 +3 −4 +1 +2 −2 +1 +2
+3 +1 +1 −5 −3 −3
+2 +3
> 15 10–15 > 17 12–17
and 4% in the USA fall upon AIH type II. Compared to AIH type I AIH type II more often clinically manifests as an acute hepatitis. Extrahepatic immune diseases, especially type 1 diabetes mellitus, vitiligo and autoimmune thyroiditis are also more common with AIH type II. AIH type II is characterized by the presence of antibodies against microsomes from liver and kidney (anti-LKM1). These antibodies react with the epithelia of proximal tubules and liver cell cytoplasm of rodents and may be demonstrated by immunocytochemistry. They must be distinguished on immunofluorescence microscopy from antimitochondrial antibodies (AMA). The target antigen of anti-LKM1 is cytochrome P450 IID6 (CYP2D6) and less often uridine 5′-diphosphate glucuronyl transferase [7, 7, 51, 81]. Anti-liver cytosol autoantibody (anti-LC1) may be associated, and occurs predominantly in children. Anti-LC1 may be the only autoimmune marker of AIH type II in children [11]. Ten to 15% of patients with autoimmune polyglandular syndrome type 1 (APS1) have also AIH type II. Patients with APS1 have autoantibodies against CYP1A2 and CYP2A6 [13]. However, while anti-CYP1A2 are associated with AIH, antibodies against CYP2A6 also occur in patients with APS1 without liver disease. Antibodies against CYP1A2 are specific for AIH associated with APS1, and are not encountered in APS1-patients without hepatitis, nor do they occur in any other autoimmune liver disease. Approximately 50% of patients with APS1 and 90% of those with APS1 and AIH type II have antibodies against aromatic L-amino decarboxylase. The knowledge of AIH type II as part of the APS1 is important since in these patients the course of AIH is more aggressive with acute and fulminant presentations and the response to corticosteroids is worse than in AIH without APS1. APS1 is an autosomal recessive disease caused by mutations in a single gene. The gene is located on the long arm of chromosome 21 and is called autoimmune regulator (AIRE) [75]. It is assumed that AIRE is involved in establishing and maintaining immune tolerance. Patients with APS1 have a defective immune response to Candida albicans and present with recurrent mucocutaneous candidiasis, and with many organ specific autoimmune diseases, leading especially to hypothyroidism, hypoparathyroidism and ovarian insufficiency. In addition, ectodermal dystrophies such as keratopathy, enamel hypoplasia and nail dystrophy are observed.
886
72
Table 72.2 Different types of autoimmune hepatitis [4, 38] Feature AIH type I Characteristic autoantibodies Associated autoantibodies ↑ Gamma-globulin Age at onset of disease Female Other immune diseases
HLA association
Target antigens
ANA, SMA p-ANCA, anti-actin, anti-ASGPR +++ All age groups; bimodal (10–20 and 45–70 years) 80% Autoimmune thyroiditis, ulcerative colitis (rare), synovitis
B8, DR3, DR4 DRB1*0301 and DRB1*0401 (Northern Europeans), DRB1*1501 (protective), DRB1*0404 (Middle American), DRB1*0405 (Japanese), DRB1*1301 (South American) ANA: Centromere, ribonucleoproteins (not precisely defined)
Autoimmune Hepatitis
AIH type II
AIH type IIIa
anti-LKM1 anti-LC1, anti-ASGPR
Anti-SLA/LP ANA, SMA, antiASGPR
++ 2–14 years 90% Vitiligo, Diabetes mellitus type 1, autoimmune thyroiditis, autoimmune polyendocrine syndrome 1 B 14, DR3, C4A-QO, DRB1*07
As AIH type I As AIH type I As AIH type I
Not precisely defined
LKM1: P-450 IID6 SLA/LP: UGA(CYP2D6), P-450 IA2 suppressor (APS1), P-450 IA6 tRNA-associated (APS1) LC1: protein Formiminotransferase cyclodeaminase ASGPR: Asialoglycoprotein receptor, LC1: Liver cytosol type 1, SLA/LP: Soluble liver antigen/liver pancreas, APS 1: Autoimmune polyendocrine syndrome 1, p-ANCA: perinuclear antibodies against neutrophil cytoplasm a The distinct existence of AIH type III is controversial. Probably AIH type III may be allocated to AIH type I
Autoimmune Hepatitis Type III AIH type III is the most uncommon and immunologically less well characterized AIH. Ninety percent of affected patients are women between the ages of 20 and 40 years. AIH type III is characterized by antibodies against soluble antigen from liver and pancreas (anti-SLA/LP) [43, 76]. Contrary to previous views, the target antigens are neither cytokeratins nor glutathion-S-transferases, but the cytosolic UGA-suppressor transfer RNAassociated protein [78, 80]. Anti-SLA/LP cannot be visualized by immunofluorescence; instead, they are demonstrated by standardized immunoassays based on recombinant antigen [6]. Patients with AIH type III do not differ from those with classic AIH type I with respect to age, gender, presence of different autoantibodies (except for antiSLA/LP) and the response to corticosteroids. Therefore,
antibodies against SLA/LP do not define a clinically discrete form of AIH, but they may be regarded as a specific diagnostic marker for AIH, occurring in approximately 20% of patients with AIH [35]. Thus, the search for anti-SLA/LP attains special importance in patients with chronic hepatitis of unknown cause. Approximately 25% of these patients present with antiSLA/LP in serum, allowing for a change in diagnosis from previously cryptogenic hepatitis to AIH in which conventional autoantibodies are absent [42].
Clinical Presentation The presentation of AIH is heterogeneous with nonspecific symptoms common to all autoimmune liver diseases. Patients complain of fatigue, lethargy, malaise, anorexia, nausea, weight loss, myalgias, arthralgias involving small joints, fever, skin rashes, itching
Diagnosis
and noncharacteristic upper abdominal discomfort. The spectrum of presentations ranges from no symptoms (with the diagnosis made incidentally by finding elevated serum aminotransferase levels and hypergammaglobulinemia) to an acute onset even with fulminant hepatic failure [44]. The majority of patients have an insiduous course, but in 25–30% of cases presentation is acute. Acute onset AIH may be difficult to diagnose by serological data alone and liver biopsy with histologic evidence of chronic disease might be helpful in this situation [1]. In acute onset AIH the diagnosis of AIH may be made on the initial presentation without awaiting the period of 6 months required for the diagnosis of a chronic hepatitis. Physical examination may be unremarkable, but it may also reveal hepatomegaly, splenomegaly, jaundice, and signs and symptoms of chronic liver disease (see Chapters 79 and 80). Table 72.3 Extrahepatic diseases in autoimmune hepatitis [47, 52]
• • • • • • • • • • • • • • • • • • • • • • • • •
Hemolytic anemias Immune thrombocytopenic purpura Glomerulonephritis Lupus erythematosus Immune thyroid disease Immune vasculitis Celiac disease (more common with primary biliary cirrhosis) Ulcerative colitis (rare) Iridocyclitis Fibrosing alveolitis Raynaud’s disease Localized scleroderma Sjögren’s syndrome CREST-Syndrome Synovitis Rheumatoid arthritis Primary adrenal insufficiency Diabetes mellitus type 1 Autoimmune polyendocrine syndrome 1 Polymyositis Febrile panniculitis Vitiligo Lichen planus Alopecia Nail dystrophy
887
Extrahepatic immune mediated diseases are associated with AIH in 10–50% of patients and may be one clue to diagnosing AIH (Table 72.3) [45].
Laboratory Findings Aminotransferase levels in serum are markedly elevated (AST > ALT) while parameters of cholestasis (alkaline phosphatase and gGT) are normal or only slightly increased. The level of aminotransferase elevation does not always correlate with the histological activity of the disease (possibly GLDH levels reflect intralobular inflammatory activity better than aminotransferases). A polyclonal hypergammaglobulinemia with a marked increase in IgG levels is characteristic for AIH. IgA levels might be decreased [20]. Once cirrhosis develops, the synthetic parameters of liver function decrease. Laboratory diagnosis of AIH is based on the demonstration of autoantibodies in serum, which is done increasingly by ELISA using recombinant, well defined antigens, rather than by immunofluorescence microscopy (see above and Chapter 36). While the measurement of routine antibodies such as ANA and AMA is standardized, assays for many other antibodies, for example anti-actin and anti-ASGPR (asialo glycoprotein receptor) are available in specialized laboratories only. They are not always standardized and, because of different measurement systems, results from different laboratories are not always comparable. One must therefore be very critical in drawing conclusions regarding the course and prognosis of AIH based on these determinations alone. The dictum that the level of antibody titers does not correlate with the activity of hepatitis still holds true. It is possible, however, that antibodies against ASGPR are an exception to this rule. They may be regarded as general markers of all AIH and their presence might be associated with a more severe histological and clinical activity. The prevalence of autoantibodies in AIH is summarized in Table 72.4. Note that in up to 10% of patients with AIH no autoantibodies in serum are found. These patients, however, are hypergammaglobulinemic with predominant elevation of IgG. Very rarely patients with AIH, in the absence of the typical antibody profile, and no histological or clinical evidence for primary biliary cirrhosis, are AMA positive. An
888
72
Table 72.4 Prevalence of autoantibodies in autoimmune hepatitis [7] Autoantibody Prevalence in AIH ANAa SMA LKM1 SLA/LP No standard autoantibody
40–60% 40–50% 0–5% 15–30% Up to 10%
a The combined prevalence of ANA and SMA in AIH type I is about 80%
algorithm for the rational use of serum autoantibodies in autoimmune liver disease is presented in Fig. 72.2.
Imaging Tools Imaging techniques (ultrasound, CT scanning, MRI) are of subordinate importance in the diagnosis of AIH. Only liver biopsy is diagnostically useful. Although the microscopic findings are not disease specific, only histology allows one to reliably assess the degree of inflammatory activity and the stage of fibrosis (see Chapters 28 and 29). Liver biopsy is mandatory in the initial diagnosis of AIH. Liver biopsy should also be performed before
ANA, AMA, SMA, anti-LKM 1 positive
negative
ANA/ SMA
antiLKM 1
AMA
AIH 1
AIH 2
PBC
antiSLA/LP
pANCA
AIH
PSC
AIH 3
pANCA anti-SLA/LP anti-PDH-E2
antiPDH-E2
PBC
negative Cryptogenic chronic hepatitis
AIC
Fig. 72.2 Suggested algorithm for the use of autoantibodies in the diagnosis of autoimmune liver disease. AIH autoimmune hepatitis, PSC primary sclerosing cholangitis, PBC primary biliary cirrhosis, AIC autoimmune cholangiopathy, PDH-E2 pyruvate dehydrogenase E2
Autoimmune Hepatitis
scheduled withdrawal of immunosuppressive therapy. In this clinical situation the histological findings are crucial in deciding whether treatment may be terminated or should proceed (see below). On laparoscopy the liver is swollen in the early stage of AIH, displaying a fine fibrotic rim at its lower margin. During the further course the consistency of the organ increases. The subcapsular lobular architecture becomes increasingly blurred, the number of vessels increases, and fibrotic scars and dilated lymph vessels become visible. The stage of AIH may be diagnosed reliably by an experienced laparoscopic examiner. However, despite the diagnostic value of laparoscopy, the procedure is nowadays rarely performed and not necessary in the diagnosis of AIH. Signs of cirrhosis and portal hypertension may be seen on ultrasound examination. CT scanning and MRI do not provide significant additional information. They are useful, however, in addition to ultrasound in characterizing focal lesions that develop in a cirrhotic liver.
Differential Diagnosis The differential diagnosis of AIH includes all chronic hepatitides, and cryptogenic liver cirrhosis. In addition, in every acute hepatitis (especially in the elderly) AIH has to be excluded, since a significant proportion of patients with AIH have an acute onset. The definitive diagnosis of AIH is established after the exclusion of metabolic, hereditary, viral, drug-induced and cholestatic liver diseases. The measurement of anti-SLA/LP in patients with cryptogenic chronic hepatitis or cirrhosis of unknown origin, negative for ANA, AMA and anti-LKM1 yields positive results in up to 25% of cases, allowing for the reassignment of the disease to the group of autoimmune disorders. The delineation of AIH from variant (overlap) syndromes is discussed in Chapter 77 [8]. The differentiation of AIH from virus-associated autoimmunity is relevant clinically, since it has a direct impact on treatment. Anti-LKM1 antibodies are present in 2–12% of cases of chronic viral hepatitis C and D. The titers of anti-LKM1 are lower, and the antibodies in virus associated autoimmunity are directed against different LKM-epitopes on recombinant CYP2D6 than in AIH type II. The basis for autoantibody production in chronic hepatitis C and D is a genetic predisposition of
Therapy
the host and homologies between CYP2D6 and the viral genome (molecular mimicry) [32]. Differentiating between autoimmune liver disease and virus-induced autoimmunity is therapeutically important, since patients with autoimmune liver disorders receive immunosuppressive treatment, while those with chronic hepatitis C (with or without autoantibodies) are treated with pegylated interferon (contraindicated in autoimmune disease) and ribavirin. The simultaneous occurrence of a chronic viral hepatitis and AIH has been documented anecdotally, but is extremely rare. Up to 25% of patients with nonalcoholic fatty liver disease present with low titer (≤ 1: 320) ANA, which might lead to misdiagnosing NAFLD for AIH with consequent corticosteroid treatment of steatosis. The astute clinician will avoid this error, and in dubious cases liver biopsy should be performed.
Course and Prognosis AIH often is an aggressive and progressive disease that, without adequate immunosuppressive treatment leads to death in many patients. If a marked inflammatory activity with bridging necrosis and fibrosis is present already on initial diagnosis, without treatment 50% and 90% of patients will die within 3 and 10 years, respectively. In contrast, patients with mild disease have 5 year survival rates comparable to the normal population and the risk of having cirrhosis 5 years after diagnosis is 17%.With adequate treatment the 5 and 20 years survival rates are > 90% and 80%, respectively [20, 63, 69]. Patients with AIH who are asymptomatic at presentation have a good prognosis and may not require immunosuppressive therapy [31]. Thus, course and prognosis of AIH crucially depend on the activity of the inflammatory process, the degree of liver cell death and on timely adequate therapy in patients with active disease. Certain autoantibodies may have relevant prognostic value. Antibodies against actin identify a subgroup of SMA-positive patients with AIH type I in whom the disease starts at an earlier age and who respond less well to corticosteroids than anti-actin negative patients. Antibodies against ASGPR seem to correlate with the histological and clinical activity, and the presence of anti-ASGPR possibly identifies patients who will relapse after withdrawal of therapy.
889
There are only few data on the impact of gender and ethnicity on the natural history of AIH. Men with AIH appear to have a higher relapse rate and younger age of disease onset which may relate to increased prevalence of HLA A1-B8-DR3. Despite this, men have been reported to have a significantly better longterm survival and outcomes than women [3]. Blacks, especially black men with AIH, have more aggressive disease at the initial presentation, are less likely to respond to conventional immunosuppression, and have a worse outcome than non-blacks [74]. A recent report describes Somalian men with AIH presenting with cholestatic features and responding poorly to standard immunosuppressive regimens [29]. AIH may influence pregnancy outcome, and pregnancy may affect the activity of AIH. A rate of 26% of adverse pregnancy outcome in AIH has been reported, and unexplained adverse pregnancy outcomes were highly associated with the presence of anti-SLA/LP [67]. The course of AIH in pregnancy is variable, but liver tests often improve, assumed to be due to a state of immune tolerance during pregnancy. Post-partum flare-ups and AIH first presenting in the early post partum period are well documented [12, 64].
Therapy All types of AIH are treated by immunosuppression for several years and some patients must receive lifelong therapy. AIH patients with no autoantibodies in serum (up to 10%) respond to immunosuppressive therapy like patients with classical AIH. Patients with AIH and bile duct injury but lacking features of primary biliary cirrhosis respond as well to corticosteroid therapy as patients with classical disease. Background bile duct changes should not alter the treatment of AIH [23]. The absolute and relative indications for therapy are listed in Table 72.5. Histologically inactive AIH without fibrosis only rarely proceeds to cirrhosis. Therefore, immunosuppressive treatment in these patients must be pondered critically, since the side effects of corticosteroids may offset their slight therapeutic benefit in this clinical situation. Examination of liver tissue remains the best method of evaluating both treatment response and need for treatment in patients who have little biochemical activity [34]. Immunosuppressive therapy also should not be administered to patients with inactive cirrhosis and only
890
72
Table 72.5 Indications for treatment of autoimmune hepatitis [4, 20, 39] Absolute Relative Serum AST ≥ 10 × ULN Serum AST ≥ 5 × ULN and g-globulin level ≥ 2 × ULN Marked inflammatory activity with bridging necrosis or multiacinar necrosis on histologic examination
Table 72.6 Standard treatment of autoimmune hepatitis [53] Initial therapy
Symptoms (fatigue, arthralgia, jaundice) Serum AST and/or g-globulin increased, but less than absolute criteria Interface hepatitis
1. Predniso(lo)ne Monotherapy
2. Predniso(lo)ne
plus Azathioprinea Therapy of relapse
mildly elevated aminotransferase levels [53]. However, liver cirrhosis is not a contraindication for immunosuppressive treatment.
Two treatment regimens are comparable with each other in the management of severe AIH in adults: (1) monotherapy with prednisone or (2) the combined administration of prednisone and azathioprine irrespective of the serological subtype of AIH [9, 20, 52]. Prednisone is transformed in the liver to its active moiety prednisolone. Since this metabolic step is not impaired even in advanced chronic liver disease, there is no advantage to administer prednisolone instead of prednisone [66]. Various treatment strategies are outlined in Table 72.6. Prednisone in combination with azathioprine is the preferred initial treatment because of its lower frequency of side effects [20, 39, 70]. Phenotyping and genotyping of thiopurine methyltransferase activity (key enzyme in azathioprine transformation to its active metabolites) before institution of azathioprine therapy does not predict response of AIH to the drug [46]. The clinical picture in addition to aminotransferase and g-globulin levels are the initial parameters of determining treatment response. Ninety percent of adults have improvements in the serum aminotransferase, bilirubin, and g-globulin levels within 2 weeks [24]. Normalization of increased IgG levels in > 90% of cases correlates with histologic improvement. Although there is no prescribed minimum or maximum duration of treatment, experience has shown that
Duration 1 week 1 week 2 weeks Maintenance
30 mg 20 mg
1 week 1 week
15 mg 10 mg or less
2 weeks Maintenance
50 mg
1. Repeat initial therapy or
The goals of therapy are Induction of remission Maintaining complete remission Preventing relapse, and if necessary Management of relapse after drug withdrawal
Daily oral dose 60 mg 40 mg 30 mg 15–20 mg or less
or
AST: aspartate aminotransferase level, ULN: upper limit of normal
• • • •
Autoimmune Hepatitis
2. Predniso(lo)ne plus
30 mg
Azathioprine
150 mg
4 weeks
or 3. Predniso(lo)ne 60 mg Treatment to maintain remission may also be performed with azathioprine monotherapy (2 mg/kg per day) sparing corticosteroids. Induction therapy with azathioprine monotherapy is not promising a
usually 2–4 years of therapy are required to maintain complete remission and to avoid relapses after cessation of treatment. The most common error made in treating patients with AIH is too early withdrawal of therapy. The administration of prednisone every other day during the induction phase aiming at reducing corticosteroid side effects is not recommended, since this practice reduces the rate of histological remissions. On the other hand, enforcing a rapid and early remission by increasing drug doses also has no advantage with respect to the overall success rate of treatment. After reaching complete remission, the prednisone dose is slowly and continuously tapered to a daily maintenance dose of 2.5–10 mg. The dose should be adjusted to the minimal dose required to maintain remission. After complete remission is stable for 6–12 months prednisone usually can be withdrawn completely and therapy may be continued with azathioprine alone at a daily dose of 50 mg for approximately 2 more years [41]. Treatment withdrawal should not be based on biochemical parameters only. Before complete treatment withdrawal a liver biopsy should be performed. Histological improvement lags approximately 3–6
Therapy
months after clinical and biochemical improvement. In addition to inflammatory changes, fibrosis also commonly improves, and if it is not too far progressed may even regress to a certain degree during corticosteroid therapy of AIH [16]. Fibrosis progresses in only a minority of patients during immunosuppressive therapy, and progression is associated with HLADR3/DR4 [17]. If histological and biochemical findings are normal, treatment may be terminated. Despite normal histology, relapses after drug withdrawal occur in approximately 20% of cases. Inflammatory portal infiltrates are associated with a relapse rate of 50% and virtually every patient with a continuing interface hepatitis and/or progression to cirrhosis during drug treatment will experience a relapse after drug withdrawal. Thus, the histological findings after approximately 6–12 months of clinical and biochemical remission are essential in deciding whether therapy may be terminated or not. Conventional treatment regimens should be continued in adults until remission, treatment failure, incomplete response, or drug toxicity. Once disease remission (criteria: disappearance of symptoms, normal serum bilirubin and g-globulin levels, serum aminotransferase level normal or less than twice normal, normal hepatic tissue or minimal inflammation and no interface hepatitis within 1 year of treatment and for at least 6 months) has been achieved, drug withdrawal should be attempted. Overall, complete remission rates of 60–70% are reached. Despite treatment, 30–40% of patients proceed to cirrhosis within 10 years. Treatment failure (criteria: worsening clinical, laboratory, and histologic features despite compliance with therapy; increase of serum aminotransferases by 67%; development of jaundice, ascites, or hepatic encephalopathy) is observed in approximately 10% of cases. Onset at an early age, acute presentation, hyperbilirubinemia, and presence of HLA DRB1*03 characterize patients who fail corticosteroid treatment [58]. In these patients prednisone dose should be increased to 60 mg daily or to 30 mg daily combined with azathioprine, 150 mg daily, for at least one month, then slowly tapering the prednisone dose over months to 2–2.5 mg daily and azathioprine to 25–50 mg daily. Despite dose escalation, only 20% of patients with treatment failure achieve histological remission, and maintenance dose probably has to be given lifelong. Relapses occur most commonly within the first 6 months after treatment withdrawal and are characterized by an increase of serum AST to ≥ 3 times the upper
891
limit of normal, reappearance of symptoms, and inflammatory lesions on liver histology. However, liver biopsy is not required to document a relapse. Prolonged time to complete clinical and biochemical remission and increased numbers of portal plasma cells prior to treatment withdrawal are associated with > 90% probability of relapse [73]. Treatment of a relapse corresponds to the standard initial regimen as outlined in Table 72.6. Long-term maintenance therapy with azathioprine helps to spare corticosteroids. However, with each relapse the probability of side effects of drugs increases and that of a new remission decreases. Lifelong combination therapy with prednisone (e.g. 7.5–10 mg daily) and azathioprine (50 mg daily) may be necessary. In patients receiving long-term corticosteroid therapy supporting measures, such as the administration of vitamins D and K, and bisphosphonates should not be forgotten. In patients with AIH not responsive or intolerant to standard immunosuppressive therapy, prednisone monotherapy at a dose of 60 mg daily or another immunosuppressive drug may be tried. Encouraging results have been reported for cyclosporine (5–6 mg daily), tacrolimus (3 mg bid), mycophenolate mofetil (1 g bid), 6-mercaptourine (1.5 mg/kg daily), and budesonide (3 mg tid). These drugs, however (possibly with the exception of budesonide), should be regarded as investigational in AIH and should therefore be used only in controlled trials [34, 37, 53, 61, 79]. Ursodeoxycholic acid (UDCA) should not be used in patients with classical AIH. Possibly, UDCA has some value in cholestatic variants of AIH. With multiple relapses, in treatment failure not responding to drug therapy, and in decompensating cirrhosis liver transplantation should be considered [65]. AIH presenting as acute liver failure and a failure of elevated serum bilirubin to fall in a patient with multiacinar necrosis on histologic examination within 2 weeks of corticosteroid therapy is considered an absolute indication for liver transplantation. The 5-year survival rates after transplantation for AIH are 80–90% and 75% after 10 years. Recurrence of AIH in the transplanted liver occurs in approximately 17–41% of patients followed for more than 10 years after the procedure, mainly in those with HLA-DR3 and/or HLA-DR4. Recurrence is usually relatively mild and can be mastered by adjusting immunosuppressive therapy. Histological recurrence precedes clinical and biochemical recurrence, thus, regular liver biopsy is
892
warranted after orthotopic liver transplantation for AIH [30, 60].
References 1. Abe M, Onji M, Kawai-Ninomiya K, et al (2007) Clinicopathologic features of the severe form of acute type 1 autoimmune hepatitis. Clin Gastroenterol Hepatol 5: 255–8 2. Al-Chalabi T, Boccato S, Portmann BC, et al (2006) Autoimmune hepatitis (AIH) in the elderly: a systematic retrospective analysis of a large group of consecutive patients with definite AIH followed at a tertiary referral centre. J Hepatol 45: 575–83 3. Al-Chalabi T, Underhill JA, Portmann BC, et al (2008) Impact of gender on the long-term outcome and survival of patients with autoimmune hepatitis. J Hepatol 48: 140–7 4. Al-Khalidi JA, Czaja AJ (2001) Current concepts in the diagnosis, pathogenesis, and treatment of autoimmune hepatitis. Mayo Clin Proc 76: 1237–52 5. Alvarez F, Berg PA, Bianchi FB, et al (1999) International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 31: 929–38 6. Baeres M, Herkel J, Czaja AJ, et al (2002) Establishment of standardized SLA/LP immunoassay: specificity for autoimmune hepatitis, worldwide occurrence, and clinical characteristics. Gut 51: 259–64 7. Bayer EM, Schramm C, Kanzler S, et al (2004) Autoimmune Lebererkrankungen: Diagnose und Therapie. Z Gastroenterol 42: 19–30 8. Ben-Ari Z, Czaja AJ (2001) Autoimmune hepatitis and its variant syndromes. Gut 49: 589–94 9. Beuers U, Wiedmann KH, Kleber G, et al (1997) Therapie der autoimmunen Hepatitis, primär biliären Zirrhose und primär sklerosierenden Cholangitis. Konsensus der Deutschen Gesellschaft für Verdauungs- und Stoffwechselkrankheiten. Z Gastroenterol 35: 1041–49 10. Bogdanos DP, Choudhuri K, Vergani D (2001) Molecular mimicry and autoimmune liver disease: vituous intentions, malign consequences. Liver 21: 225–32 11. Bridoux-Henno L, Maggiore G, Johanet C, et al (2004) Features and outcome of autoimmune hepatitis type 2 presenting with isolated positivity for anti-liver cytosol antibody. Clin Gastroenterol Hepatol 2: 825–30 12. Buchel E, van Steenbergen W, Nevens F, et al (2002) Improvement of autoimmune hepatitis during pregnancy followed by flare-up after delivery. Am J Gastroenterol 97: 3160–5 13. Clemente MG, Meloni A, Obermayer-Straub P, et al (1998) Two cytochromes P450 are major hepatocellular autoantigens in autoimmune polyglandular syndrome type 1. Gastroenterology 114: 324–8 14. Czaja AJ (2001) Understanding the pathogenesis of autoimmune hepatitis. Am J Gastroenterol 96: 1224–31 15. Czaja AJ (2008) Genetic factors affecting the occurrence, clinical phenotype, and outcome of autoimmune hepatitis. Clin Gastroenterol Hepatol 6: 379–88
72
Autoimmune Hepatitis
16. Czaja AJ, Carpenter HA (2004) Decreased fibrosis during corticosteroid therapy of autoimmune hepatitis. J Hepatol 40: 646–52 17. Czaja AJ, Carpenter HA (2004) Progressive fibrosis during corticosteroid therapy of autoimmune hepatitis. Hepatology 39: 1631–8 18. Czaja AJ, Cassani F, Cataleta M, et al (1996) Frequency and significance of antibodies to actin in type 1 autoimmune hepatitis. Hepatology 24: 1068–73 19. Czaja AJ, Doherty DG, Donaldson PT (2002) Genetic bases of autoimmune hepatitis. Dig Dis Sci 47: 2139–50 20. Czaja AJ, Freese DK (2002) AASLD practice guidelines: diagnosis and treatent of autoimmune hepatitis. Hepatology 36: 479–97 21. Czaja AJ, Kruger M, Sanrach PJ, et al (1997) Genetic distinctions between types 1 and 2 autoimmune hepatitis. Am J Gastroenterol 92: 2197–200 22. Czaja AJ, Manns MP (1995) The validity and importance of subtypes of autoimmune hepatitis: a point of view. Am J Gastroenterol 90: 1206–11 23. Czaja AJ, Muratori P, Muratori L, et al (2004) Diagnostic and therapeutic implications of bile duct injury in autoimmune hepatitis. Liver Int 24: 322–9 24. Czaja AJ, Rakela J, Ludwig J (1985) Features reflective of early prognosis in corticosteroid-treated severe autoimmune chronic active hepatitis. Gastroenterology 95: 448–53 25. Dienes HP, Popper H, Manns M, et al (1989) Histologic features in autoimmune hepatitis. Z Gastroenterol 27: 325–30 26. Dienes HP (2000) Autoimmune hepatitis. In: Denk H, Dienes HP, Düllmann J, et al (eds) Pathologie der Leber und Gallenwege, Springer Verlag, pp 379–89 27. Doherty DG, Donaldson PT, Underhill JA, et al (1994) Allelic sequence variation in the HLA class II genes and proteins in patients with autoimmune hepatitis. Hepatology 19: 609–15 28. Donaldson P, Doherty D, Underhill J, et al (1994) The molecular genetics of autoimmune liver disease. Hepatology 20: 225–9 29. D’Souza R, Sinnott P, Glynn MJ, et al (2005) An unusual form of autoimmune hepatitis in young Somalian men. Liver Int 25: 325–30 30. Duclos-Vallée JC, Sebagh M, Rifai K, et al (2003) A 10 year follow up study of patients transplanted for autoimmune hepatitis: histological recurrence precedes clinical and biochemical recurrence. Gut 52: 893–7 31. Feld JJ, Dinh H, Arenovich T, et al (2005) Autoimmune hepatitis: effect of symptoms and cirrhosis on natural history and outcome. Hepatology 42: 53–62 32. Gerotto M, Pontisso P, Giostra F, et al (1994) Analysis of the hepatitis C virus genome in patients with anti-LKM-1 autoantibodies. J Hepatol 21: 273–6 33. Gish RG, Mason A (2001) Autoimmune liver disease: current standards, future directions. Clin Liver Dis 5: 287–314 34. Heneghan MA, McFarlane IG (2002) Current and novel immunosuppressive therapy for autoimmune hepatitis. Hepatology 35: 7–13 34a.Hennes EM, Zeniya M, Czaja AJ, et al (2008) Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 48: 169–76 35. Herkel J, Heidrich B, Nieraad N, et al (2002) Fine specificity of autoantibodies to soluble liver antigen and liver/pancreas. Hepatology 35: 403–8
References 36. Hiraide A, Imazeki F, Yokosuka O, et al (2005) Fas polymorphisms influence susceptibility to autoimmune hepatitis. Am J Gastroenterol 100: 1322–9 37. Inductivo-Yu I, Adams A, Gish RG, et al (2007) Mycophenolate mofetil in autoimmune hepatitis patients not responsive or intolerant to standard immunosuppressive therapy. Clin Gastroenterol Hepatol 5: 799–802 38. Invernizzi P, Lleo A, Podda M (2007) Interpreting serological tests in diagnosing autoimmune liver disease. Semin Liver Dis 27: 161–72 39. Ishibashi H, Komori A, Shimoda S, et al 2007) Guidelines for therapy of autoimmune liver disease. Semin Liv Dis 27: 214–26 40. Johnson PJ, McFarlane IG (1993) Meeting report of the International Autoimmune Hepatitis Group. Hepatology 18: 998–1005 41. Johnson PJ, McFarlane IG, Williams R (1995) Azathioprine for long-term maintenance of remission in autoimmune hepatitis. N Engl J Med 333: 958–63 42. Kanzler S, Weidemann C, Gerken G, et al (1999) Clinical significance of autoantibodies to soluble liver antigen in autoimmune hepatitis. J Hepatol 31: 635–40 43. Kernebeck T, Lohse AW, Grötzinger J (2001) A bioinformatical approach suggests the function of the autoimmune hepatitis target antigen soluble liver antigen/liver pancreas. Hepatology 34: 230–3 44. Kessler WR, Cummings OW, Eckert G, et al (2004) Fulminant hepatic failure as the initial presentation of acute autoimmune hepatitis. Clin Gastroenterol Hepatol 2: 625–31 45. Krawitt EL (2006) Autoimmune hepatitis. N Engl J Med 354: 54–66 46. Langley PG, Underhill J, Tredger JM, et al (2002) Thiopurine methyltransferase phenotype and genotype in relation to azathioprine therapy in autoimmune hepatitis. J Hepatol 37: 441–7 47. Leuschner U (2001) Autoimmunkrankheiten der Leber und Overlapsyndrome. Uni-Med Verlag AG, Bremen 48. Lohr H, Manns MP, Kyriatsoulis A, et al (1991) Clonal analysis of liver-infiltrating T cells in patients with LKM-1 antibody-positive autoimmune chronic active hepatitis. Clin Exp Immunol 84: 297–302 49. Longhi MS, Ma Y, Bogdanos DP, et al (2004) Impairment of CD4+CD25+ regulatory T-cells in autoimmune liver disease. J Hepatol 41: 31–7 50. Mackay IR, Weiden S, Hasker J (1965) Autoimmune hepatitis. Ann N Y Acad Sci 124: 767–80 51. Manns MP, Griffin KJ, Sullivan KF, et al (1991) LKM-1 autoantibodies recognize a short linear sequence in P450IID6, a cytochrome P-450 monooxygenase. J Clin Invest 88: 1370–8 52. Manns MP, Strassburg CP (2001) Autoimmune hepatitis: clinical challenges. Gastroenterology 120: 1502–17 53. Manns MP, Strassburg CP (2002) Autoimmunhepatitis. Z Gastroenterol 40: 39–42 54. Manns MP, Vogel A (2006) Autoimmune hepatitis, from mechanisms to therapy. Hepatology 43(2 Suppl 1): S132–44 55. McFarlane IG (1999) Pathogenesis of autoimmune hepatitis. Biomed Pharmacother 53: 255–63 56. Michitaka K, Durazzo M, Tillmann HL, et al (1994) Analysis of hepatitis C virus genome in patients with autoimmune hepatitis type 2. Gastroenterology 106: 1603–10
893 57. Montano-Loza AJ, Carpenter HA, Czaja AJ (2006) Clinical significance of HLA DRB103-DRB104 in type 1 autoimmune hepatitis. Liver Int 26: 1201–8 58. Montano-Loza AJ, Carpenter HA, Czaja AJ (2007) Features associated with treatment failure in type 1 autoimmune hepatitis and predictive value of the model of end-stage liver disease. Hepatology 46: 1138–45 59. Muratori L, Parola M, Ripalti A, et al (2000) Liver/kidney microsomal antibody type 1 tarhets CYP2D6 on hepatocyte plasma membrane. Gut 46: 553–61 60. Neuberger J, Portmann B, Calne R, et al (1984) Recurrence of autoimmune chronic active hepatitis following orthotopic liver grafting. Transplantation 37: 363–5 61. Pratt DS, Flavin DP, Kaplan MM (1996) The successful treatment of autoimmune hepatitis with 6-mercaptopurine after failure with azathioprine. Gastroenterology 110: 271–4 62. Pratt DS, Fawaz KA, Rabson A, et al (1997) A novel histological lesion in glucocorticoid-responsive chronic hepatitis. Gastroeneterology 113: 664–8 63. Roberts SK, Therneau TM, Czaja AJ (1996) Prognosis of histological cirrhosis in type I autoimmune hepatitis. Gastroenterology 110: 848–57 64. Samuel D, Riordan S, Strasser S, et al (2004) Severe autoimmune hepatitis first presenting in the early post partum period. Clin Gastroenterol Hepatol 2: 622–4 65. Sanchez-Urdazpal L, Czaja AJ, van Hoek B, et al (1992) Prognostic features and role of liver transplantation in severe corticosteroid-treated autoimmune chronic active hepatitis. Hepatology 15: 215–21 66. Schalm SW, Summerskill WHJ, Go VLW (1977) Prednisone for chronic active liver disease: pharmacokinetics, including conversion to prednisolone. Gastroenterology 72: 910–3 67. Schramm C, Herkel J, Beuers U, et al (2006) Pregnancy in autoimmune hepatitis: outcome and risk factors. Am J Gastroenterol 101: 556–60 68. Singh R, Nair S, Farr G, et al (2002) Acute autoimmune hepatitis presenting with centrizonal liver disease: case report and review of the literature. Am J Gastroenterology 97: 2670–3 69. Summerskill WHJ (1974) Chronic active liver disease reexamined: prognosis hopeful. Gastroenterology 66: 450–64 70. Summerskill WHJ, Korman MG, Ammon HV, et al (1975) Prednisone for chronic active liver disease: dose titration, standard dose, and combination with azathioprine compared. Gut 16: 876–83 71. Tahiri F, Le Naour F, Huguet S, et al (2008) Identification of plasma membrane autoantigens in autoimmune hepatitis type 1 using a proteomics tool. Hepatology 47: 937–48 72. Te HS, Koukoulis G, Granger DR (1997) Autoimmune hepatitis: a histological variant associated with prominent centrilobular necrosis. Gut 41: 269–71 73. Verma S, Gunuwan B, Mendler M, et al (2004) Factors predicting relapse and poor outcome in type I autoimmune hepatitis: role of cirrhosis development, patterns of transaminases during remission and plasma cell activity in the liver biopsy. Am J Gastroenterol 99: 1510–6 74. Verma S, Torbenson M, Thuluvath PJ (2007) The impact of ethnicity on the natural history of autoimmune hepatitis. Hepatology 46: 1828–35 75. Vogel A, Liermann H, Harms A, et al (2001) Autoimmune regulator AIRE: evidence for genetic differences between
894 autoimmune hepatitis and hepatitis as part of the autoimmune polyglandular syndrome type 1. Hepatology 33: 1047–52 76. Volkmann M, Martin L, Bäurle A, et al (2001) Soluble liver antigen: isolation of a 35-kd recombinant protein (SLA-p35) specifically recognizing sera from patients with autoimmune hepatitis. Hepatology 33: 591–6 77. Waldenström J (1950) Leber, Blutproteine und Nahrungseiweisse. Dtsch Ges Verd Stoffw 15:113–9 78. Wesierska-Gadek J, Grimm R, Hitchman E, et al (1998) Members of the glutathione S-transferase gene family are antigens in autoimmune hepatitis. Gastroenterology 114: 329–35 79. Wiegand J, Schuler A, Kanzler S, et al (2005) Budesonide in previously untreated autoimmune hepatitis. Liver Int 25: 927–34
72
Autoimmune Hepatitis
80. Wies I, Brunner S, Henninger J, et al (2000) Identification of target antigen for SLA/LP autoantibodies in autoimmune hepatitis. Lancet 355: 1510–5 81. Yamamoto AM, Cresteil D, Homberg JC, et al (1993) Characterization of the anti-liver-kidney microsome antibody (anti-LKM1) from hepatitis C virus-positive and -negative sera. Gastroenterology 104: 1762–7 82. Yokosawa S, Yoshizawa K, Ota M, et al (2007) A genomewide DNA microsatellite association study of Japanese patients with autoimmune hepatitis type 1. Hepatology 45: 384–90 83. Zauli D, Ghetti S, Grassi A, et al (1997) Anti-neutrophil cytoplasmic antibodies in type 1 and 2 autoimmune hepatitis. Hepatology 25: 1105–7
Primary Biliary Cirrhosis
73
Henryk Dancygier
Chapter Outline Definition......................................................................... 895 Epidemiology .................................................................. 895 Etiology and Pathogenesis ............................................. 896 Genetic Factors ................................................................ 896 Environmental Factors ..................................................... 896 Immunologic Factors ....................................................... 896 Pathology ........................................................................ 897 Diagnosis ......................................................................... 897 Clinical Presentation ........................................................ 897 Laboratory Findings ......................................................... 899 Imaging Tools .................................................................. 900
“Chronic idiopathic obstructive jaundice” occurring chiefly in middle-aged women has been already noted by Hanot in 1876. Denominated later “primary biliary cirrhosis,” this entity continued to puzzle clinicians throughout the following century, as it was extremely difficult to differentiate from jaundice due to obstruction of the main bile ducts [2, 115]. In a landmark study published in 1965 a close association between anti-mitochondrial antibodies and primary biliary cirrhosis was demonstrated [132].
Definition
Differential Diagnosis .................................................... 900 Natural Course and Prognosis ...................................... 900 Therapy ........................................................................... 901 References ....................................................................... 903
Primary biliary cirrhosis (PBC) is an autoimmune cholestatic liver disease characterized by progressive, non-suppurative, inflammatory destruction of interlobular bile ducts resulting in ductopenia, and leading to cirrhosis. Synonym: chronic non-suppurative destructive cholangitis.
Epidemiology There is a striking female predominance with 80–90% of affected patients being women between 20 and 60 years of life. Anecdotal cases of pediatric-onset PBC have also been reported [17]. PBC is more common than assumed previously, and incidence and prevalence show geographical variations [40]. The incidence in the USA and in Germany is approximately 2.7–3.5/105 persons per year. The incidence for women older than 40 years is 10/105 persons per year. The prevalence rates are 25–40/105 H. Dancygier, Clinical Hepatology, DOI: 10.1007/978-3-642-04519-6_73, © Springer-Verlag Berlin Heidelberg 2010
895
896
persons and for women older than 40 years 65–100/105 persons [55]. The highest prevalence rates are reported from Northern Europe, while low prevalence rates are found in Australia.
Etiology and Pathogenesis Etiology and pathogenesis are not exactly known. Immune mechanisms based on a genetic susceptibility and triggered by environmental factors appear to be operative.
Genetic Factors The concordance rate of PBC in monozygotic twins is 63%. First-degree relations of index PBC patients have a PBC prevalence of 4–6% [124]. The incidence of AMA in first-degree relatives of patients with PBC is increased to 13% [59]. An enhanced X monosomy has been reported in women with PBC [78]. This preferential involvement of X chromosome gene products might be one explanation for the female predisposition to PBC. There is supporting evidence for the genetic association of PBC with major histocompatibility complex-encoded genes. PBC is associated with the DRB1*08 family of alleles. HLADR8 positive persons have a 2–7 times higher risk of developing PBC. However, the presence of HLA DR8 is neither a necessary nor a sufficient condition for PBC to develop [48]. A protective association has been described with DRB1*11 and DRB1*13. Significant variation is seen, however, between different ethnic groups both in susceptibility and in protective associations. To date, none of the genetic associations identified in PBC have proved sufficiently strong to be useful clinically in the prediction of disease risk [38, 44].
Environmental Factors Geographical clustering (“hot spots”) of PBC cases in urban, former industrial and/or coal mining areas and in the environs of highly toxic federal waste disposal sites may reflect environmental factors in the
73
Primary Biliary Cirrhosis
etiology of PBC [3, 103]. Chemicals contained in cigarette smoke, may induce PBC in genetically susceptible individuals [26]. Exposure to infectious organisms may represent another environmental factor involved in triggering the autoimmune process in PBC. Retroviral antibodies have been demonstrated in the serum of patients with PBC [73]. Recently a human betaretrovirus was identified both in liver tissue and draining lymph nodes from PBC patients [136, 137]. Bacteria may contain amino acid sequence homologies with PDC-E2 (see below) which by molecular mimicry may cause immunologic crossreactivity. There is epidemiological evidence of infection with Escherichia coli, Mycobacterium gordonae, Novosphingobium aromaticovorans (an ubiquitous xenobiotic-metabolizing bacterium), Paracoccus denitrificans, and Chlamydia pneumoniae in PBC patients [1, 10, 27, 67, 109, 111]. Although these epidemiological data are attractive there is no objective evidence confirming a role of bacteria or viruses in the pathogenesis of PBC.
Immunologic Factors It is widely accepted that liver damage in PBC ultimately results from an “immunologic attack” on portal bile ducts, despite the triggering factors being still largely unknown. Autoreactive T cells (against PDCE2) occur in high concentrations in the liver and in the hepatic hilar lymph nodes in patients with PBC, and aberrant expression of mitochondrial autoantigens on biliary epithelia has been described. Autoreactive T cell-mediated cholangiocyte injury leads to the destruction of interlobular bile ducts. The diagnostically defining anti-mitochondrial antibodies (AMA) are neither cytotoxic nor do they damage the cholangiocytes [87]. Innate immune mechanisms may also play a role in the induction and persistence of abnormal humoral immune responses in PBC. The increase in serum IgM levels that is present in patients with PBC is the result of chronic B-cell activation induced via the Toll-like receptor signaling pathway. Bacterial molecules have been shown to induce hyper-IgM production in CD27+ memory B cells in PBC [53]. Additional factors may contribute to bile duct damage in PBC, such as (1) the secretion by eosinophils of
Diagnosis
897
eosinophilic cationic protein, (2) apoptosis of biliary epithelial cells, secondary to the invasion of inflammatory cells or induced by dimeric IgA, and (3) ischemia due to loss of peribiliary vessels commonly seen in the early stages of PBC and probably secondary to the inflammatory process [75, 128, 133].
Pathology The denomination “chronic non-suppurative destructive cholangitis” and PBC already indicates that the disease starts as a cholangitis and terminates as cirrhosis. The development of PBC is characterized by different histological stages that are distributed irregularly throughout the liver. They cannot always be sharply separated from each other and overlap is common (Table 73.1) [72, 110]. On histological examination a dense lympho-plasmacytic infiltrate of portal tracts is seen, occasionally arranged in a lymph follicle like pattern. In the early stages it is often accompanied by epithelioid granulomas (Fig. 73.1). The portal tract inflammatory infiltrate is mixed in phenotype, T cells ([CD4 and CD8], with the latter predominating in the periductal areas), B cells, natural killer cells, macrophages, eosinophils and mast cells [22, 24, 44, 126]. The portal inflammation spills over to the neighbouring lobular parenchyma (interface hepatitis) resulting in damage and destruction of periportal hepatocytes (“biliary piece meal necrosis”) [96]. Occasionally, Mallory-Denk bodies may be found predominantly in periportal and periseptal liver cells.
Table 73.1 Histopathologic stages of primary biliary cirrhosis According to According to Scheuer (1967) Ludwig (1978) Stage 1
Stage 2
Stage 3
Stage 4
Florid Duct Lesion Bile duct lesion Portal hepatitis Ductular Reaction Periportal (interface) hepatitis Ductular proliferation Scarring Bridging necrosis Septal fibrosis Ductopenia Cirrhosis
Portal Stage Portal hepatitis Periportal Stage Periportal (interface) hepatitis Septal Stage Bridging necrosis Septal fibrosis Cirrhosis
Continuing inflammatory activity is associated with increasing portal and periportal fibrosis. The typical stage I lesion is the inflammatory injury of interlobular bile ducts (florid bile duct lesion) characterized by a breach in continuity of ductal basal membranes, ectasia and rupture of bile ducts, intraepithelial lymphocytic infiltrates and cholangiocyte injury (Fig. 73.2). At the edges of the portal tracts ductular proliferation is present. Ultimately the continuing inflammatory process leads to the loss of bile ducts (ductopenia). Focal scars within the portal tracts represent remnants of previously destroyed interlobular bile ducts. With continuing disease the inflammatory infiltrate and the number of interlobular bile ducts diminish. Progression of periportal hepatocellular damage leads to septum formation. Incomplete septa from the enlarged portal tracts and portal to portal bridges appear first, while portal to central septa form later [85]. Finally the process results in cirrhosis.
Diagnosis PBC must be excluded in every patient with longstanding increased serum levels of enzymes indicating cholestasis and normal appearing bile ducts on ultrasound or CT scan. The most sensitive diagnostic parameter is serum AMA. The diagnosis of PBC is made when two of three following criteria are fulfilled. • Presence of serum AMA • Increased levels of enzymes (e.g. alkaline phosphatase) indicating cholestasis for longer than 6 months, and • Compatible or diagnostic liver histology
Clinical Presentation The disease begins insidiously with the patient being asymptomatic despite ongoing hepatic inflammation. The appearance of symptoms lags months (to years?) behind the development of histological lesions, and the increase in levels of cholestatic liver enzymes usually lags behind the appearance of symptoms. Thus, once symptoms develop the inflammatory process probably
898
73
Primary Biliary Cirrhosis
Fig. 73.1 Primary biliary cirrhosis (stage 1). Portal inflammatory infiltrate containing an epithelioid granuloma. The interlobular bile duct is damaged. Masson trichrome (× 400)
Fig. 73.2 Primary biliary cirrhosis (stage 1). A portal lymphocytic infiltrate damages an interlobular bile duct. Domagk stain (× 400)
has been active already for a long time. Symptoms are nonspecific. Initially the patient barely notices a mild fatigue which with time, however, may become so severe as to compromise markedly his quality of life, long before the development of cirrhosis and hepatic encephalopathy [23, 101, 119]. The overall quality of life deteriorates mainly due to the decrease in energy and emotional reactions, and increased vulnerability to emotional stress, all associated with fatigue [8]. Noncharacteristic upper abdominal discomfort and bloating may supervene. The prevalence of a depressive
disorder in patients with PBC is not higher than in the general population, and fatigue cannot be explained by depression [130]. Fatigue, which is seemingly unrelated to the severity of the underlying liver disease usually is accompanied by a generalized pruritus that may become excruciating. Both, fatigue and pruritus may precede the elevation of serum AP and g-GT and the diagnosis of PBC by months or even years. Thus, the first symptoms in PBC are not equivalent to symptoms of early disease. In a patient with fatigue and pruritus of unknown origin, even with normal serum levels of
Diagnosis
enzymes indicating cholestasis, AMA in serum should be determined. Jaundice is a symptom of advanced disease. However, occasionally it may occur in non-cirrhotic but ductopenic patients [131]. As a consequence of chronic cholestasis xanthomas and xanthelasms, vitamin deficiencies (A, D, E, K), steatorrhea and bone loss may develop (see Chapter 80) [36]. Additional genetic factors probably contribute to the development of PBC associated osteopathy.
Extrahepatic Diseases PBC may be associated with extrahepatic immunemediated diseases. Conjunctivitis, myalgias, arthralgias, scleroderma, sicca syndrome, Sjögren’s syndrome and Hashimoto’s thyroiditis have been reported. Liver disease seems to have a slower progression in patients with PBC and systemic sclerosis compared with matched patients with PBC alone [108]. The cause for this interaction is unclear. Seven to 9% of patients with PBC have CREST (calcinosis cutis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly, telangiectasia)syndrome. Celiac disease, often asymptomatic, is encountered in 6% of patients with PBC, and patients with celiac disease have an increased risk of developing PBC [56]. PBC and autoimmune pancreatitis (AIP) may coexist, but AIP is more often associated with primary sclerosing cholangitis than with PBC. Skin and nail lesions, particularly plantar mycoses, onychomycoses, and interdigital mycoses are reported to be significantly more common in patients with PBC than in the general population [57]. Autonomic dysfunction (reduced heart rate variability and baroreflex sensitivity, orthostatic dysregulation of blood pressure) is found at all stages of PBC and correlates with fatigue severity [88–90]. Despite increased serum cholesterol levels PBC does not confer an increased risk for cardiovascular disease [71].
Laboratory Findings Serum levels of alkaline phosphatase and g-glutamyl transpeptidase rise continuously over the years, while aminotransferase concentrations remain only slightly
899
elevated. A polyclonal hypergammaglobulinemia is primarily due to increased IgM levels (also in AMAnegative patients). As a nonspecific sign of cholestasis, serum cholesterol level is increased. The nonspecific laboratory alterations of liver cirrhosis of all etiologies are found in the cirrhotic stage of PBC (see Chapter 79). A platelet count of less than 140,000/mm3 and/or a Mayo-Risk-Score of 4.5 or greater (see below) appears to identify PBC patients with esophageal varices [65]. The serologic diagnosis of PBC is made by demonstrating high titer antibodies against mitochondria (AMA) [121]. Serum AMA at titers higher than 1:40 are considered the most specific marker for the diagnosis of PBC, being present in the sera of > 90% of patients who have PBC when tested using routine indirect immunofluorescence. Serum AMA include all three major immunoglobulin isotypes, IgG, IgM, and IgA, but the AMA activity resides predominantly in the IgG1 and IgG3 subclasses. Elevated AMA titers in serum (> 1:40) occur already prior to the clinical manifestations, histological changes and to a rise of serum levels of alkaline phosphatase. Thus, the finding of an AMA titer greater than or equal to 1:40 is strongly suggestive of PBC even in the absence of symptoms and in the presence of a normal alkaline phosphatase concentration [79]. The M2 subtype of AMA is the most sensitive and specific diagnostic marker. It is present in > 95% of cases and regarded as pathognomonic for PBC [87, 121]. The mitochondrial antigens for AMA are heterogeneous. AMA are directed primarily against components of the 2-oxoacid dehydrogenase multienzyme complex on the inner mitochondrial membrane, including the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), the branched chain 2-oxoacid dehydrogenase complex (BCOADC-E2), and the oxoglutarate dehydrogenase complex (OGDC-E2), as well as the dihydrolipoamide dehydrogenase (E3)-binding protein (E3BP) and the E1a subunit of pyruvate dehydrogenase complex (PDC-E1a) [25]. Autoantibodies against individual members of this complex (especially anti PDC-E2) represent the anti-M2 subtype of AMA. Approximately 5% (according to some authors up to 15%) of PBC patients are consistently AMA-negative on immunofluorescence microscopy, yet they share the same clinical, biochemical and histological features of AMA-positive PBC, raising the question of the existence of a separate AMA-negative PBC [82, 112]. However, most patients who are initially
900
AMA-negative, become AMA-positive when investigated with more sensitive immunoblot techniques based on recombinant antigens [91]. Thus, the number of truly AMA-negative patients diminishes with increasing sensitivity of the detection assay used. The very few “true” AMA-negative cases might represent patients with autoimmune cholangitis (especially when ANA are positive) (see Chapter 74). AMA are not the only disease specific autoantibodies in PBC. In addition, highly specific (99%) antinuclear antibodies (ANA) directed against the lamin B receptor (nuclear envelope), centromeres and the nuclear pore complex (gp210, Sp100, p62) have been described in up to 25% of PBC patients (on immunofluorescence a “nuclear rim” or a “multiple nuclear dots” pattern is usually seen). These autoantibodies are highly indicative of PBC and are associated with more serious liver disease with a significantly higher rate of progression to end-stage liver disease with hepatic failure. Thus, in addition to their high specificity these antibodies seem to have prognostic significance in patients with PBC [31, 37, 81, 83, 84, 139]. Recently, small ubiquitin-related modifiers (SUMO), a novel class of nuclear autoantigens has been described in PBC [41]. The significance of autoantibodies against SUMO is unclear. Measurement of PBC specific antibodies against nuclear components is still restricted to specialized laboratories and has not gained entrance into general clinical practice.
Imaging Tools A liver biopsy is not mandatory in diagnosing PBC. Nevertheless, biopsy is recommended to grade and stage the disease with regard to inflammatory activity and fibrosis. In order to minimize sampling error several large biopsy specimen are better suited than a wedge biopsy. These may easily and safely be obtained during laparoscopy, which in addition is a highly sensitive technique in visualizing cirrhotic alterations of the liver surface. A liver biopsy is also helpful in disclosing histological changes of PBC in AMA-positive patients with (still) normal serum levels of alkaline phosphatase. Nearly all these patients will develop elevated cholestasis parameters during a follow-up of 10–15 years. Ultrasound and CT-scanning only yield nonspecific findings. Since biliary cirrhosis is micronodular, both
73
Primary Biliary Cirrhosis
methods are not sensitive in diagnosing cirrhotic transformation in PBC. Sequelae of portal hypertension, such as splenomegaly and ascites, however, are well documented by both methods. Endoscopic and magnetic retrograde cholangiography yield normal findings in the early stages of the disease. In end-stage PBC nonspecific secondary alterations of intrahepatic bile ducts due to cirrhosis are seen.
Differential Diagnosis The differential diagnosis of PBC includes all autoimmune hepatobiliary diseases. In addition, metabolic, drug-induced, viral and cholestatic liver diseases must be excluded. The demonstration of the PBC specific antibody profile will make diagnosis straightforward in the vast majority of patients. Diagnostic difficulties often arise in patients with AMA-negative PBC, with overlap syndromes or with a switch in diagnosis during long-term follow-up (see Chapter 77). Involvement of the interlobular bile ducts in chronic viral hepatitis C, to the less experienced pathologist, may sometimes cause confusion with a primary biliary disorder. However, in chronic HCV infection, unlike in PBC, interlobular bile ducts show only reactive but no destructive changes, and chronic hepatitis C does not lead to ductopenia. The cholangiographic bile duct changes seen in end-stage PBC may mimic those of primary sclerosing cholangitis (PSC). However, AMA are not a feature of PSC. Bile duct damage associated with epithelioid granulomas may be observed in conditions such as sarcoidosis and infection with Fasciola hepatica.
Natural Course and Prognosis PBC is a chronic, slowly progressive disease, often unnoticed for years by the patient and the physician. Smoking may accelerate the progression of PBC [140]. Nowadays, diagnosis is increasingly made in asymptomatic AMA-positive patients with still normal serum levels of alkaline phosphatase. Patients with AMA but no other signs or symptoms of PBC
Therapy
eventually develop symptoms over an 11- to 24-year follow-up period [112]. AMA profiles do not predict prognosis, while anti-nuclear core complex antibodies identify patients likely to experience an unfavorable clinical course [47]. The mean time of progression from stage 1 or 2 to cirrhosis among patients receiving no medical treatment is reported to be four to six years [15, 69]. The mean life expectancy of symptomatic PBC patients (without treatment) may be estimated to be approximately 10–15 years from diagnosis. In a communitybased study (which might reflect the overall situation better than most studies reported from tertiary referral centers) which included treated and untreated PBC patients the median time until death or referral for liver transplantation was only 9.3 years from diagnosis. Patient age, the presence of fatigue, alkaline phosphatase, albumin, and bilirubin levels at diagnosis independently predicted survival [43, 104]. As in cirrhosis of other etiologies, the risk of developing hepatocellular carcinoma (HCC) in patients with PBC is also increased to approximately 6%, with men having a relatively higher risk [42]. HCC develops mostly in old male patients with advanced-stage PBC, and often does not affect the patient’s survival [117, 122]. It is now appreciated that there is a subgroup of patients within the PBC population who have a low risk of disease progression and who are unlikely to develop end-stage disease during a normal lifetime [45, 134]. The most reliable prognostic parameters of PBC are serum bilirubin and the Mayo-Risk-Score (www.mayo.edu/int-med/gi/model/mayomodl.htm), a model based on patient age, total serum bilirubin and serum albumin concentrations, prothrombin time and severity of edema [20, 58, 114]. Factors that decrease survival are jaundice, irreversible loss of bile ducts, cirrhosis, and the presence of other autoimmune diseases. Neither the presence nor the titer of AMA affect disease progression, patient survival, or response to treatment [129]. Since the early 1980s, significant changes in mortality from PBC have occurred in the USA. The most noticeable change was an increase in the age of death, which indicates prolongation of survival. These changes may be attributable to earlier diagnosis and treatment with liver transplantation or ursodeoxycholic acid (UDCA) [51, 76, 77, 95, 118]. One should be aware that in some patients with PBC autoimmune hepatitis (AIH) may develop and
901
result in rapid progression toward cirrhosis and liver failure. Superimposed AIH necessitates a change in treatment adding immunosuppressive therapy to UDCA (see Chapter 72) [102].
Therapy Many immunosuppressive, antiinflammatory and antifibrotic drugs have been used alone or in combination in PBC. Healing of the disease, however, is still not in sight. Current evidence indicates that treatment of early stage PBC with UDCA probably prolongs life [4, 33, 64, 68, 97]. Drugs and drug combinations that have been used in PBC are listed in Table 73.2. The results of treatment with corticosteroids, azathioprine, methotrexate, cyclosporine, D-penicillamine and colchicine have been disappointing [6, 7, 11, 12, 29, 35, 49–52, 66, 70, 80]. Monotherapy with these drugs is no longer warranted, and at present, there are insufficient data to support the use of immunosuppressive therapy for PBC [33]. The current drug of choice in PBC is UDCA, 13–15 (−20) mg/kg p.o. daily in two divided doses. Treatment should begin at an early stage, and is lifelong [16, 64, 98, 99]. UDCA is a physiologic tertiary bile acid that is nontoxic due to its hydrophilia and polarity, and has virtually no serious side effects. An interesting “side effect” might be the observation (awaiting confirmation in controlled trials) that prolonged administration of UDCA significantly decreases the probability of colorectal adenoma recurrence following removal [113]. Its mechanism of action in limiting bile duct injury is unclear, and hypotheses include membrane stabilizing effects, immune modulatory functions, and inhibition of eosinophil degranulation [14, 138]. Although some metaanalyses failed to show a benefit of UDCA in the treatment of PBC, the majority of studies confirmed the long-term beneficial effect of UDCA, especially if treatment is begun in the early stages of the disease [13, 16, 28, 30, 39, 46, 92, 93, 116, 125]. In approximately 30% of patients with PBC who are treated with UDCA a complete response is observed, characterized by normalization of liver enzymes, reduction of increased IgM levels up to 30–40% from baseline values, and stabilized or improved histologic findings [63]. In the remaining 70%, especially in
902
73
Table 73.2 Drugs that have been used in primary biliary cirrhosis Drug(s) Comments Glucocorticoid monotherapy
Azathioprine monotherapy Methotrexate monotherapy Chlorambucil monotherapy D-Penicillamine monotherapy Colchicine monotherapy
Cyclosporine A monotherapy Tacrolimus monotherapy Ursodeoxycholic acid (UDCA) UDCA plus colchicine UDCA plus methotrexate UDCA plus prednisolone UDCA plus budesonide
Indication in PBC
May improve some laboratory parameters and have a positive effect on liver histology. Aggravates osteoporosis. No survival benefit. Mortality and transplantation rate 2.9 times higher than under placebo! Lowers serum bilirubin levels. Long-term treatment leads to bone marrow suppression. No effect on PBC. Improvement of some laboratory parameters, such as albumin and bilirubin. No effect on liver histology. High rates of therapy withdrawal. No survival benefit. Many side effects. Too few data. See text. Too few data. Only few data. No clinical or biochemical benefit. Few data. Possibly better effect on liver histology than UDCA monotherapy. See text.
UDCA plus prednisolone plus azathioprine
Fee data.
Antiretroviral therapy (lamivudine plus zidovudine) Statins
Preliminary results in pilot studies suggest some histological and biochemical improvement, but too few data. Atorvastatin effectively reduces serum cholesterol levels, but no effect on cholestatic parameters in PBC patients. Only anecdotal data [107]
Tamoxifen
patients with high initial AP and g-GT concentrations, response to UDCA is incomplete, i.e. AP and g-GT levels fall, but do not normalize. UDCA has no impact on AMA-titers. UDCA therapy influences the process leading to bile duct destruction. A 2-year UDCA treatment reduced periportal necroinflammation and improved ductular proliferation, and when initiated at the earlier stages I-II of the disease also delayed the progression of histologic stage [19, 100]. UDCA treatment was associated with a fivefold lower progression rate from early stage disease to extensive fibrosis or cirrhosis (7% per year under UDCA vs. 34% per year under placebo) [15]. Overall, UDCA seems to improve the 10-year prognosis for most UDCA-treated patients with PBC as manifested by increased survival rates and prolonged survival free of liver transplantation. Ten year survival of UDCA-treated PBC patients with normal bilirubin and albumin serum concentration is
Primary Biliary Cirrhosis
Not indicated.
Not indicated. Not indicated. Not indicated. Not indicated. Not indicated.
Not indicated. Not indicated. Indicated. Not indicated. Not indicated. Possibly indicated. Further studies required. Possibly indicated. Further studies required. Possibly indicated as second line therapy in UDCA non-responders.Further studies required. Not indicated.
Not indicated.
Not indicated.
comparable to that of a matched general population [93, 125]. There is some evidence, but no proof that combining UDCA with antiinflammatory and immunosuppressive agents might improve treatment results compared to UDCA monotherapy. In one study, after 1 year therapy with UDCA and prednisolone, improvement of liver histology was more pronounced in the combination group than in patients treated with UDCA only [61]. Corticosteroid related side effects, especially osteoporosis limit long-term treatment. Budesonide is characterized by a high hepatic firstpass effect, with 90% of the drug being metabolized in the liver and only 10% reaching the systemic circulation. In cirrhotic patients with PBC the pharmacokinetics and pharmacodynamics of budesonide are altered, and administration of budesonide leads to markedly elevated plasma levels with serious adverse
References
drug reactions [34]. This effect is not present in earlier stages of PBC nor do multidrug resistance 1 gene polymorphisms affect disposition of budesonide in early PBC [21, 105]. The effects of combination therapy with UDCA and budesonide are controversial. In one US study oral budesonide appeared to add minimal, if any, additional benefit to UDCA in patients with prior suboptimal response to UDCA, and was associated with a significant worsening of osteoporosis [5]. In another European trial the combination of UDCA (10– 15 mg/kg p.o. daily) and budesonide (3 mg p.o. tid) improved liver histology and laboratory findings compared to UDCA monotherapy [62]. However, patients with a suboptimal initial response to UDCA benefited only marginally from the later addition of budesonide. Thus, combined treatment with budesonide and UDCA may be considered in early-stage PBC but not in cirrhotic patients [106]. It is recommended that bone mass density is monitored during budesonide therapy. Whether or not adding prednisone and azathioprine to UDCA has an additional beneficial effect on symptoms and biochemical, fibrogenetic and histological parameters is controversial. It remains to be determined whether or not this triple therapy represents a second line option in UDCA nonresponders [135]. Azathioprine may be substituted for mycophenolate mofetil since azathioprine is a potential risk factor for the development of nodular regenerative hyperplasia. One must remember, however, that the evidence supporting this combination treatment is very weak. Two studies suggested histological and biochemical improvements with antiretroviral therapy combining lamivudine 150 mg p.o. bid and zidovudine 300 mg p.o. bid (Combivir®) [73, 74]. However, this approach is experimental and should not be used in clinical practice. Statin therapy may target both hypercholesterolemia and cholestasis in PBC. However, despite effectively reducing serum cholesterol levels atorvastatin does not improve cholestasis in PBC patients with an incomplete biochemical response to UDCA [120]. Pruritus in PBC patients may be severe and agonizing, and therapeutic options are very limited. Recently improvements of pruritus with sertraline and extracorporeal albumin dialysis were described in two small trials [9, 94]. In a placebo controlled trial alendronate (70 mg p.o. per week over 1 year) significantly improved PBCrelated bone loss and was more effective than etidro-
903
nate for increasing bone mass in osteopenic patients with PBC [32, 141]. (For treatment of pruritus, osteoporosis and vitamin substitution in chronic cholestatic liver disease see also Chapter 52.) Fatigue remains a major clinical problem in patients with PBC and no specific therapies are available. In recent trials only modafinil (started at a dose of 100 mg/day and titrated according to tolerability and response) showed some improvement in excessive daytime somnolence and associated fatigue in PBC [45]. Ondansetron and fluoxetine did not improve fatigue in PBC [123, 127]. Even with optimal drug treatment PBC is a progressive disease and in most younger patients liver transplantation must be considered, which is the treatment of choice in end-stage PBC. A Mayo-RiskScore of 7.8 seems to correlate best with the optimal timing for transplantation [54]. Intractable pruritus and severe osteoporosis also are indications for transplantation. Recurrence rates of PBC in the transplanted liver increase with time after transplantation, from 8–18% at 5 years to 22–30% at 10 years after transplantation [18, 86]. Progression of PBC in the transplanted liver, however, is very slow. Thus, the concern of disease recurrence in the liver graft should not deprive the patient from this valuable treatment option. Interestingly, the need for liver transplantation in PBC decreased in the last 10–15 years, despite an increase in the total number of liver transplants and no change in transplant rates for primary sclerosing cholangitis [60, 86]. The reasons for the fall in numbers transplanted for PBC are unclear, but it is tempting to speculate that this trend might be due to the efficacy of UDCA treatment.
References 1. Abdulkarim AS, Petrovic LM, Kim WR, et al (2004) Primary biliary cirrhosis: an infectious disease caused by Chlamydia pneumoniae? J Hepatol 40: 380–4 2. Ahrens EH Jr, Payne MA, Kunkel HG, et al (1950) Primary biliary cirrhosis. Medicine (Baltimore) 29: 299–364 3. Ala A, Stanca CM, Bu-Ghanim M, et al (2006) Increased prevalence of primary biliary cirrhosis near superfund waste sites. Hepatology 43: 525–31 4. Angulo P, Batts KP, Therneau TM, et al (1999) Long-term ursodeoxycholic acid delays histological progression in primary biliary cirrhosis. Hepatology 29: 644–7
904 5. Angulo P, Jorgensen RA, Keach JC, et al (2000) Oral budesonide in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid. Hepatology 31: 318–23 6. Bach N, Thung SN, Schaffner F (1998) The histologic effects of low-dose methotrexate therapy for primary biliary cirrhosis. Arch Pathol Lab Med 122: 342–5 7. Bach N, Bodian C, Bodenheimer H, et al (2003) Methotrexate therapy for primary biliary cirrhosis. Am J Gastroenterol 98: 187–93 8. Blackburn P, Freeston M, Baker CR, et al (2007) The role of psychological factors in the fatigue of primary biliary cirrhosis. Liver Int 27: 654–61 9. Browning J, Combes B, Mayo MJ (2003) Long-term efficacy of sertraline as a treatment for cholestatic pruritus in patients with primary biliary cirrhosis. Am J Gastroenterol 98: 2736–41 10. Burroughs AK, Butler P, Sternberg MJ, et al (1992) Molecular mimicry in liver disease. Nature 358: 377–8 11. Christensen E, Neuberger J, Crowe J, et al (1985) Beneficial effect of azathioprine and prediction of prognosis in primary biliary cirrhosis: final results of an international trial. Gastroenterology 89: 1084–91 12. Combes B, Emerson SS, Flye NL, et al (2005) Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis. Hepatology 42: 1184–93 13. Combes B, Luketic VA, Peters MG, et al (2004) Prolonged follow-up of patients in the U.S. multicenter trial of ursodeoxycholic acid for primary biliary cirrhosis. Am J Gastroenterol 99: 264–8 14. Combes B, Markin RS, Wheeler DE, et al (1999) The effect of ursodeoxycholic acid on the florid duct lesion of primary biliary cirrhosis. Hepatology 30: 602–5 15. Corpechot C, Carrat F, Bonnand AM, et al (2000) The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis. Hepatology 32: 1196–9 16. Corpechot C, Carrat F, Bahr A, et al (2005) The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. Gastroenterology 128: 297–303 17. Dahlan Y, Smith L, Simmonds D, et al (2003) Pediatric-onset primary biliary cirrhosis. Gastroenterology 125: 1476–9 18. Davern TJ, Lake JR (1998) Recurrent disease after liver transplantation. Semin Gastrointest Dis 9: 86–109 19. Degott C, Zafrani ES, Callard P, et al (1999) Histopathological study of primary biliary cirrhosis and the effect of ursodeoxycholic acid treatment on histology progression. Hepatology 29: 1007–12 20. Dickson E, Grambsch PM, Fleming TR, et al (1989) Prognosis in primary biliary cirrhosis: model for decision making. Hepatology 10: 1–7 21. Dilger K, Cascorbi I, Grunhage F, et al (2006) Multidrug resistance 1 genotype and disposition of budesonide in early primary biliary cirrhosis. Liver Int 26: 285–90 22. Farrell DJ, Hines JE, Walls AF, et al (1995) Intrahepatic mast cells in chronic liver diseases. Hepatology 22: 1175–81 23. Forton DM, Patel N, Prince M, et al (2004) Fatigue and primary biliary cirrhosis: association of globus pallidus magnetisation transfer ratio measurements with fatigue severity and blood manganese levels. Gut 53: 587–92
73
Primary Biliary Cirrhosis
24. Galperin C, Gershwin ME (1996) Immunopathology of primary biliary cirrhosis. Baillieres Clin Gastroenterol 10: 461–81 25. Gershwin ME, Mackay IR, Sturgess A, et al (1987) Identification and specificity of a cDNA encoding the 70 kd mitochondrial antigen recognized in primary biliary cirrhosis. J Immunol 138: 3525–31 26. Gershwin ME, Selmi C, Worman HJ, et al (2005) Risk factors and comorbidities in primary biliary cirrhosis: A controlled interview-based study of 1032 patients. Hepatology 42: 1194–202 27. Gershwin EM, Mackay IR (2008) The causes of primary biliary cirrhosis: convenient and inconvenient truths. Hepatology 47: 737–45 28. GongY, Huang Z, Christensen E, et al (2007) Ursodeoxycholic acid for patients with primary biliary cirrhosis: an updated systematic review and meta-analysis of randomized clinical trials using bayesian approach as sensitivity analyses. Am J Gastroenterol 102: 1799–807 29. Gong Y, Klingenberg SL, Gluud C (2006) Systematic review and meta-analysis: D-Penicillamine vs. placebo/no intervention in patients with primary biliary cirrhosis–Cochrane Hepato-Biliary Group. Aliment Pharmacol Ther 24: 1535–44 30. Goulis J, Leandro G, Burroughs AK (1999) Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis. Lancet 354: 1053–60 31. Granito A, Muratori P, Muratori L, et al (2006) Antinuclear antibodies giving the ‘multiple nuclear dots’ or the ‘rim-like/ membranous’ patterns: diagnostic accuracy for primary biliary cirrhosis. Aliment Pharmacol Ther 24: 1575–83 32. Guanabens N, Parés A, Ros I, et al (2003) Alendronate is more effective than etidronate for increasing bone mass in osteopenic patients with primary biliary cirrhosis. Am J Gastroenterol 98: 2268–74 33. Heathcote EJ (2000) AASLD guideline: management of primary biliary cirrhosis. Hepatology 31: 1005–13 34. Hempfling W, Grunhage F, Dilger K, et al (2003) Pharmacokinetics and pharmacodynamic action of budesonide in early- and late-stage primary biliary cirrhosis. Hepatology 38: 196–202 35. Hendrickse M, Rigney E, Giaffer MH, et al (1999) Low-dose methotrexate in primary biliary cirrhosis: long-term results of a placebo controlled trial. Gastroenterology 117: 400–7 36. Hodgson SF, Dickson ER, Wahner HW, et al (1985) Bone loss and reduced osteoblast function in primary biliary cirrhosis. Ann Intern Med 103: 855–60 37. Invernizzi P, Podda M, Battezzati PM, et al (2001) Autoantibodies against nuclear pore complexes are associated with more active and severe liver disease in primary biliary cirrhosis. J Hepatol 34: 366–72 38. Invernizzi P, Selmi C, Mackay IR, et al (2005) From bases to basis: linking genetics to causation in primary biliary cirrhosis. Clin Gastroenetrol Hepatol 3: 401–10 39. Jackson H, Solaymani-Dodaran M, Card TR, et al (2007) Influence of ursodeoxycholic acid on the mortality and malignancy associated with primary biliary cirrhosis: a population-based cohort study. Hepatology 46: 1131–7 40. James OFW, Bhopal R, Howel D, et al (1999) Primary biliary cirrhosis once rare, now common in the United Kingdom? Hepatology 30: 390–4
References 41. Janka C, Selmi C, Gershwin ME, et al (2005) Small ubiquitin-related modifiers: a novel and independent class of autoantigens in primary biliary cirrhosis. Hepatology 41: 609–16 42. Jones DEJ, Metcalf JV, Collier JD, et al (1997) Hepatocellular carcinoma in primary biliary cirrhosis and its impact on outcomes. Hepatology 26: 1138–42 43. Jones DEJ, Bhala N, Burt J, et al (2006) Four year follow up of fatigue in a geographically defined primary biliary cirrhosis patient cohort. Gut 55: 536–541 44. Jones DEJ (2007) Pathogenesis of primary biliary cirrhosis. Gut 56: 1615–24 45. Jones DEJ, Newton JL (2007) An open study of modafinil for the treatment of daytime somnolence and fatigue in primary biliary cirrhosis. Aliment Pharmacol Ther 25: 471–6 46. Jorgensen R, Angulo P, Dickson ER, et al (2002) Results of long-term ursodiol treatment for patients with primary biliary cirrhosis. Am J Gastroenterology 97: 2647–50 47. Joshi S, Cauch-Dudek K, Heathcote J, et al (2002) Antimitochondrial antibody profiles: are they valid prognostic indicators in primary biliary cirrhosis? Am J Gastroenterol 97: 999–1002 48. Kaplan MM (1996) Primary biliary cirrhosis. N Engl J Med 335: 1570–80 49. Kaplan MM, Alling DW, Zimmerman HJ, et al (1986) A prospective trial of colchicine for primary biliary cirrhosis. N Engl J Med 315: 1448–54 50. Kaplan MM, Cheng S, Price LL, et al (2004) A randomized controlled trial of colchicine plus ursodiol versus methotrexate plus ursodiol in primary biliary cirrhosis: ten year results. Hepatology 39: 915–23 51. Kaplan MM, Gershwin ME (2005) Primary biliary cirrhosis. N Engl J Med 353: 1261–73 52. Kaplan MM, Schmid C, Provenzale D, et al (1999) A prospective trial of colchicine and methotrexate in the treatment of primary biliary cirrhosis. Gastroenterology 117: 1173–80 53. Kikuchi K, Lian ZX, Yang GX, et al (2005) Bacterial CpG induces hyper-IgM production in CD27+ memory B cells in primary biliary cirrhosis. Gastroenterology 128: 304–12 54. Kim WR, Wiesner RH, Therneau TM, et al (1998) Optimal timing of liver transplantation for primary biliary cirrhosis. Hepatology 28: 33–8 55. Kim WR, Lindor KD, Locke III GR, et al (2000) Epidemiology and natural history of primary biliary cirrhosis in a U.S. community. Gastroenterology 119: 1631–6 56. Kingham JG, Parker DR (1998) The association between primary biliary cirrhosis and coeliac disease: a study of relative prevalences. Gut 42: 120–2 57. Koulentaki M, Ioannidou D, Stefanidou M, et al (2006) Dermatological manifestations in primary biliary cirrhosis patients: a case control study. Am J Gastroenterol 101: 541–6 58. Krzeski P, Zych W, Kraszewska E, et al (1999) Is serum bilirubin concentration the only valid prognostic marker in primary biliary cirrhosis? Hepatology 30: 865–9 59. Lazaridis KN, Juran BD, Boe GM, et al (2007) Increased prevalence of antimitochondrial antibodies in first-degree relatives of patients with primary biliary cirrhosis. Hepatology 46: 785–92
905 60. Lee J, Belanger A, Doucette JT, et al (2007) Transplantation trends in primary biliary cirrhosis. Clin Gastroenterol Hepatol. 5: 1313–5 61. Leuschner M, Güldütüna S, You T, et al (1996) Ursodeoxycholic acid and prednisolone versus ursodeoxycholic acid and placebo in the treatment of early stages of primary biliary cirrhosis. J Hepatol 25: 49–57 62. Leuschner M, Maier KP, Schlichting J, et al (1999) Oral budesonide and ursodeoxycholic acid for treatment of primary biliary cirrhois: results of a prospective double blind trial. Gastroenterology 117: 918–25 63. Leuschner M, Dietrich CF, You T, et al (2000) Characterization of patients with primary biliary cirrhosis responding to long-term ursodeoxycholic acid therapy. Gut 46: 121–6 64. Leuschner U, Güldütüna S, Imhof M, et al (1994) Effect of ursodeoxycholic acid after 4 to 12 years of therapy in early and late stages of primary biliary cirrhosis. J Hepatol 21: 624–33 65. Levy C, Zein CO, Gomez J, et al (2007) Prevalence and predictors of esophageal varices in patients with primary biliary cirrhosis. Clin Gastroenterol Hepatol 5: 803–8 66. Lindor KD, Dickson ER, Jorgensen RA, et al (1995) The combination of ursodeoxycholic acid and methotrexate for patients with primary biliary cirrhosis: the results of a pilot study. Hepatology 22: 1158–62 67. Lindor KD, Hoofnagle J, Maddrey WC, et al (1996) Primary biliary cirrhosis clinical research single-topic conference. Hepatology 23: 639–44 68. Lindor KD, Therneau TM, Jorgensen RA, et al (1996) Effects of ursodeoxycholic acid on survival in patients with primary biliary cirrhosis. Gastroenterology 110: 1515–18 69. Locke GR III, Therneau TM, Ludwig J, et al (1996) Time course of histological progression in primary biliary cirrhosis. Hepatology 23: 52–6 70. Lombard M, Portmann B, Neuberger J (1993) Cyclosporin A treatment in primary biliary cirrhosis: results of a long-term placebo controlled trial. Gastroenterology 104: 519–26 71. Longo M, Crosignani A, Battezzati PM, et al (2002) Hyperlipidaemic state and cardiovascular risk in primary biliary cirrhosis. Gut 51: 265–9 72. Ludwig J, Dickson ER, McDonald GS (1978) Staging of nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis). Virchows Arch A Pathol Anat Histol 379: 103–12 73. Mason AL, Xu L, Guo L, et al (1998) Detection of retroviral antibodies in primary biliary cirrhosis and other idiopathic biliary disorders. Lancet 351: 1620–4 74. Mason AL, Farr GH, Xu L, et al (2004) Pilot studies of single and combination antiretroviral therapy in patients with primary biliary cirrhosis. Am J Gastroenterol 99: 2348–55 75. Matsumura S, Van De Water J, Leung P, et al (2004) Caspase induction by IgA antimitochondrial antibody: IgA-mediated biliary injury in primary biliary cirrhosis. Hepatology 39: 1415–22 76. Mendes FD, Kim WR, Pedersen R, et al (2008) Mortality attributable to cholestatic liver disease in the United States. Hepatology 47: 1241–7 77. Metcalf JV, Mitchison HC, Palmer JM, et al (1996) Natural history of early primary biliary cirrhosis. Lancet 348: 1399–402
906 78. Miozzo M, Selmi C, Gentilin B, et al (2007) Preferential X chromosome loss but random inactivation characterize primary biliary cirrhosis. Hepatology 46: 456–62 79. Mitchison HC, Bassendine MF, Hendrick A, et al (1986) Positive antimitochondrial antibody but normal alkaline phosphatase: is this primary biliary cirrhosis? Hepatology 6: 1279–84 80. Mitchison HC, Palmer JM, Bassendine MF, et al (1992) A controlled trial of prednisolone treatment in primary biliary cirrhosis. Three-year results. J Hepatol 15: 336–44 81. Muratori P, Muratori L, Ferrari R, et al (2003) Characterization and clinical impact of antinuclear antibodies in primary biliary cirrhosis. Am J Gastroenterol 98: 431–7 82. Muratori P, Muratori L, Gershwin ME, et al (2004) ‘True’ antimitochondrial antibody-negative primary biliary cirrhosis, low sensitivity of the routine assays, or both? Clin Exp Immunol 135: 154–8 83. Nakamura M, Kondo H, Mori T, et al (2007) Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis. Hepatology 45: 118–27 84. Nakamura M, Shimizu-Yoshida Y, Takii Y, et al (2005) Antibody titer to gp210-C terminal peptide as a clinical parameter for monitoring primary biliary cirrhosis. J Hepatol 42: 386–92 85. Nakanuma Y (1991) Pathology of septum formation in primary biliary cirrhosis: a histological study in the non-cirrhotic stage. Virchows Arch A Pathol Anat Histopathol 419: 381–7 86. Neuberger J (2003) Liver transplantation for primary biliary cirrhosis: indications and risk of recurrence. J Hepatol 39: 142–8 87. Neuberger J, Thomson R (1999) PBC and AMA–What is the connection? Hepatology 29: 271–6 88. Newton JL, Allen J, Kerr S, et al (2006) Reduced heart rate variability and baroreflex sensitivity in primary biliary cirrhosis. Liver Int 26: 197–202 89. Newton JL, Davidson A, Kerr S, et al (2007) Autonomic dysfunction in primary biliary cirrhosis correlates with fatigue severity. Eur J Gastroenterol Hepatol 19: 125–32 90. Newton JL, Pairman J, Sutcliffe K, et al (2008) A predictive model for fatigue and its etiologic associations in primary biliary cirrhosis. Clin Gastroenterol Hepatol 6: 228–33 91. Oertelt S, Rieger R, Selmi C, et al (2007) A sensitive bead assay for antimitochondrial antibodies: chipping away at AMA-negative primary biliary cirrhosis. Hepatology 45: 659–65 92. Papatheodoridis GV, Hadziyannis ES, Deutsch M, et al (2002) Ursodeoxycholic acid for primary biliary cirrhosis: final results of a 12-year, prospective, randomized, controlled trial. Am J Gastroenetrol 97: 2063–70 93. Parés A, Caballeria L, Rodes J (2006) Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic Acid. Gastroenterology 130: 715–20 94. Parés A, Cisneros L, Salmeron JM, et al (2004) Extracorporeal albumin dialysis: a procedure for prolonged relief of intractable pruritus in patients with primary biliary cirrhosis. Am J Gastroenterol 99: 1105–10 95. Parés A, Rodes J (2003) Natural history of primary biliary cirrhosis. Clin Liver Dis 7: 779–94
73
Primary Biliary Cirrhosis
96. Portmann B, Popper H, Neuberger J, et al (1985) Sequential and diagnostic features in primary biliary cirrhosis based on serial histologic study in 209 patients. Gastroenterology 88: 1777–90 97. Poupon RE, Bonnand AM, Chrétien Y, et al (1999) Tenyear survival in ursodesoxycholic acid-treated patients with primary biliary cirrhosis. Hepatology 29: 1668–71 98. Poupon RE, Poupon R, Balkau B, et al (1994) Ursodiol for the long-term treatment of primary biliary cirrhosis. N Engl J Med 330: 1342–7 99. Poupon RE, Lindor KD, Cauch-Dudek K, et al (1997) Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology 113: 884–90 100. Poupon RE, Lindor KD, Parés A, et al (2003) Combined analysis of the effect of treatment with ursodeoxycholic acid on histologic progression in primary biliary cirrhosis. J Hepatol 39: 12–6 101. Poupon RE, Chretien Y, Chazouilleres O, et al (2004) Quality of life in patients with primary biliary cirrhosis. Hepatology 40: 489–94 102. Poupon RE, Chazouilleres O, Corpechot C, et al (2006) Development of autoimmune hepatitis in patients with typical primary biliary cirrhosis. Hepatology 44: 85–90 103. Prince MI, Chetwynd A, Diggle P, et al (2001) The geographical distribution of primary biliary cirrhosis in a welldefined cohort. Hepatology 34: 1083–8 104. Prince MI, Chetwynd A, Newman W, et al (2002) Survival and symptom progression in a large geographically based cohort of patients with primary biliary cirrhosis: follow-up for up to 28 years. Gastroenterology 123: 1044–51 105. Rautiainen H, Färkkila M, Neuvonen M, et al (2006) Pharmacokinetics and bone effects of budesonide in primary biliary cirrhosis. Aliment Pharmacol Ther 24: 1545–52 106. Rautiainen H, Karkkainen P, Karvonen AL, et al (2005) Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: a three-year randomized trial. Hepatology 41: 747–752 107. Reddy A, Prince MI, James OF, et al (2004) Tamoxifen: a novel treatment for primary biliary cirrhosis? Liver Int 24: 194–7 108. Rigamonti C, Shand LM, Feudjo M, et al (2006) Clinical features and prognosis of primary biliary cirrhosis associated with systemic sclerosis. Gut 55: 388–94 109. Sayers TJ, Baum H (1976) Possible cross-reactivity of human anti-mitochondrial antibodies with membrane vesicles of Paracoccus denitrificans. Biochem Soc Trans 4: 138–9 110. Scheuer PJ (1967) Primary biliary cirrhosis. Proc R Soc Med 60: 1257–60 111. Selmi C, Balkwill DL, Invernizzi P, et al (2003) Patients with primary biliary cirrhosis react against a ubiquitous xenobiotic-metabolizing bacterium. Hepatology 38: 1250–7 112. Selmi C, Zuin M, Bowlus CL, et al (2008) Antimitochondrial antibody-negative primary biliary cirrhosis. Clin Liver Dis 12: 173–85 113. Serfaty L, De Leusse A, Rosmorduc, O et al (2003) Ursodeoxycholic acid therapy and the risk of colorectal adenoma in patients with primary biliary cirrhosis: an observational study. Hepatology 38: 203–9
References 114. Shapiro JM, Smith H, Schaffner F (1979) Serum bilirubin: a prognostic factor in primary biliary cirrhosis. Gut 20: 137–40 115. Sherlock S (1959) Primary biliary cirrhosis (chronic intrahepatic obstructive jaundice). Gastroenterology 37: 574–86 116. Shi J, Wu C, Lin Y, et al (2006) Long-term effects of middose ursodeoxycholic acid in primary biliary cirrhosis: a meta-analysis of randomized controlled trials. Am J Gastroenterol 101: 1529–38 117. Shibuya A, Tanaka K, Miyakawa H, et al (2002) Hepatocellular carcinoma and survival in patients with primary biliary cirrhosis. Hepatology 35: 1172–8 118. Springer J, Cauch-Dudek K, O’Rourke K, et al (1999) Asymptomatic primary biliary cirrhosis: a study of its natural history and prognosis. Am J Gastroenterol 94: 47–53 119. Stanca CM, Bach N, Krause C, et al (2005) Evaluation of fatigue in U.S. patients with primary biliary cirrhosis. Am J Gastroenterol 100: 1104–9 120. Stojakovic T, Putz-Bankuti C, Fauler G, et al (2007) Atorvastatin in patients with primary biliary cirrhosis and incomplete biochemical response to ursodeoxycholic acid. Hepatology 46: 776–84 121. Strassburg CP, Jaeckel E, Manns MP (1999) Antimitochondrial antibodies and other immunological tests in primary biliary cirrhosis. Eur J Gastroenterol Hepatol 11: 595–601 122. Suzuki A, Lymp J, Donlinger J (2007) Clinical predictors for hepatocellular carcinoma in patients with primary biliary cirrhosis. Clin Gastroenterol Hepatol 5: 259–64 123. Talwalkar JA, Donlinger JJ, Gossard AA, et al (2006) Fluoxetine for the treatment of fatigue in primary biliary cirrhosis: a randomized, double-blind controlled trial. Dig Dis Sci 51: 1985–91 124. Tanaka A, Borchers AT, Ishibashi H, et al (2001) Genetic and familial considerations of primary biliary cirrhosis. Am J Gastroenterol 96: 8–15 125. ter Borg PC, Schalm SW, Hansen BE, et al (2006) Prognosis of ursodeoxycholic acid-treated patients with primary biliary cirrhosis. Results of a 10-yr cohort study involving 297 patients. Am J Gastroenterol 101: 2044–50 126. Terasaki S, Nakanuma Y, Yamazaki M, et al (1993) Eosinophilic infiltration of the liver in primary biliary cirrhosis: a morphological study. Hepatology 17: 206–12 127. Theal JJ, Toosi MN, Girlan L, et al (2005) A randomized, controlled crossover trial of ondansetron in patients with primary biliary cirrhosis and fatigue. Hepatology 41: 1305–12 128. Tinmouth J, Lee M, Wanless IR, et al (2002) Apoptosis of biliary epithelial cells in primary biliary cirrhosis and primary sclerosing cholangitis. Liver 22: 228–34
907 129. Van Norstrand MD, Malinchoc M, Lindor KD, et al (1975) Quantitative measurement of autoantibodies to recombinant mitochondrial antigens in patients with primary biliary cirrhosis: relationship of levels of autoantibodies to disease progression. Hepatology 25: 6–11 130. van Os E, van den Broek WW, Mulder PG, et al (2007) Depression in patients with primary biliary cirrhosis and primary sclerosing cholangitis. J Hepatol 46: 1099–103 131. Vleggaar FP, van Buuren HR, Zondervan PE, et al (2001) Jaundice in non-cirrhotic primary biliary cirrhosis: the premature ductopenic variant. Gut 49: 276–81 132. Walker JG, Doniach D, Roitt IM, et al (1965) Antimitochondrial antibodies in primary biliary cirrhosis. Lancet i: 827–31 133. Washington K, Clavien PA, Killenberg P (1997) Peribiliary vascular plexus in primary sclerosing cholangitis and primary biliary cirrhosis. Hum Pathol 28: 791–5 134. Wesierska-Gadek J, Penner E, Battezzati PM, et al (2006) Correlation of initial autoantibody profile and clinical outcome in primary biliary cirrhosis. Hepatology 43: 1135–44 135. Wolfhagen FHJ, van Hoogstraten HJF, van Buuren HR, et al (1998) Triple therapy with ursodeoxycholic acid, prednisone and azathioprine in primary biliary cirrhosis: a 1-year randomized, placebo-controlled study. J Hepatol 29: 736–42 136. Xu L, Sakalian M, Shen Z, et al (2004) Cloning the human betaretrovirus proviral genome from patients with primary biliary cirrhosis. Hepatology 39: 151–6 137. Xu L, Shen S, Guo L, et al (2003) Does a betaretrovirus infection trigger primary biliary cirrhosis? Proc Natl Acad Sci USA 100: 8454–9 138. Yamazaki A, Suzuki K, Nakamura A, et al (1999) Ursodeoxycholic acid inhibits eosinophil degranulation in patients with primary biliary cirrhosis. Hepatology 30: 71–8 139. Yang WH, Yu JH, Nakajima A, et al (2004) Do antinuclear antibodies in primary biliary cirrhosis patients identify increased risk for liver failure? Clin Gastroenterol Hepatol 2: 1116–22 140. Zein CO, Beatty K, Post AB, et al (2006) Smoking and increased severity of hepatic fibrosis in primary biliary cirrhosis: A cross validated retrospective assessment. Hepatology 44: 1564–71 141. Zein CO, Jorgensen RA, Clarke B, et al (2005) Alendronate improves bone mineral density in primary biliary cirrhosis: A randomized placebo-controlled trial. Hepatology 42: 762–71
Autoimmune Cholangitis
74
Henryk Dancygier
In 1987 Brunner and Klinge have described three women with the clinical, biochemical and histological features of primary biliary cirrhosis (PBC) without, however, the presence of serum antimitochondrial antibodies (AMA) [2]. Instead, these patients had antinuclear antibodies (ANA) in serum. The authors have called this condition “immune cholangitis”. Currently, autoimmune cholangitis (AIC) denotes a disease displaying the clinical and pathological features of PBC with absent AMA, but with positive tests for ANA [7, 13, 19]. More recently, a broader definition has been suggested that includes: (1) serum ANA and/or smooth muscle (SMA) positivity and/or hypergammaglobulinemia, (2) serum AMA negativity by immunofluorescence, (3) biochemical and/or histologic features of cholestatic and hepatocellular injury, and (4) exclusion of chronic viral, metabolic, or toxic liver disease [5, 17]. However, these definitions and the term autoimmune cholangitis is problematic, since they imply the existence of a distinct cholangiopathy (autoimmune cholangitis), while PBC, small-duct primary sclerosing cholangitis and idiopathic adulthood ductopenia may also be considered as (auto)immune cholangiopathies [10]. There is evidence to suggest that AIC is not a separate disease entity, but rather an AMA-negative PBC [11, 17, 18]. The epidemiological, clinical and histopathological features, as well as the response to treatment are similar in AIC and PBC [9, 12, 15]. AIC, like PBC may also be associated with extrahepatic immune disorders, such as systemic lupus erythematosus, antiphospholipid antibody syndrome and celiac disease [8, 14, 16]. The AST and bilirubin levels in serum seem to be higher, while the serum IgM concentrations lower in AIC than in PBC. However, the most important distinguishing feature is the autoantibody profile (see discussion of AMA-negative PBC in Chapter 73). Most PBC patients, initially negative for
AMA on immunofluorescence turn out to be AMA positive as soon as more sensitive techniques for their demonstration are applied. Thus, the question – is it AIC or AMA-negative PBC? – may be focused on the sensitivity of the technique used in detecting AMA. Moreover, approximately 40% of patients with PBC have also PBC-specific ANA (see Chapter 73). As long as an etiologic classification of immune cholangiopathies is not available, AIC should not be regarded as a distinct entity but rather a variant of PBC or a disease of the spectrum of overlap syndromes (see Chapter 77) [1, 3, 4, 6]. Thus, for the time being patients lacking detectable AMA, especially when indirect immunofluorescence is used, but otherwise presenting signs and symptoms of PBC should be regarded as affected by “AMA-negative PBC” or having an overlap between PBC and autoimmune hepatitis [9, 17].
References 1. Ben-Ari Z, Dhillon AP, Sherlock S (1993) Autoimmune cholangiopathy: part of the spectrum of chronic active hepatitis. Hepatology 18: 10–5 2. Brunner G, Klinge O (1987) Ein der chronisch-destruierenden nichteitrigen Cholangitis ähnliches Krankheitsbild mit antinukleären Antikörpern (Immuncholangitis). Dtsch Med Wschr. 112: 1454–8 3. Carrougher JG, Shaffer RT, Canales LI, et al (1991) A 33-yearold woman with an autoimmune syndrome. Semin Liv Dis 11: 256–62 4. Colombato LA, Alvarez F, Coté J, et al (1994) Autoimmune cholangiopathy: the result of consecutive primary biliary cirrhosis and autoimmune hepatitis? Gastroenterology 107: 1839–43 5. Czaja AJ, Carpenter HA, Santrach PJ, et al (2000) Autoimmune cholangitis within the spectrum of autoimmune liver disease. Hepatology 31: 1231–8 6. Goodman ZD, McNally PR, Davis DR, et al (1995) Autoimmune cholangitis: a variant of primary biliary cirrhosis.
H. Dancygier, Clinical Hepatology, DOI: 10.1007/978-3-642-04519-6_74, © Springer-Verlag Berlin Heidelberg 2010
909
910 Clinicopathologic and serologic considerations in 200 cases. Dig Dis Sci 40: 1232–42 7. Heathcote J (1997) Autoimmune cholangitis. Gut 40: 440–2 8. Heyman SN, Spectre G, Aamar S, et al (2002) Autoimmune cholangiopathy associated with systemic lupus erythematosus. Liver 22: 102–6 9. Invernizzi P, Crosignani A, Battezzati PM, et al (1997) Comparison of the clinical features and clinical course of antimitochondrial antibody-positive and -negative primary biliary cirrhosis. Hepatology 25: 1090–5 10. Kinoshita H, Omagari K, Whittingham S, et al (1999) Autoimmune cholangitis and primary biliary cirrhosis – an autoimmune enigma. Liver 19: 122–8 11. Lacerda MA, Ludwig J, Dickson ER, et al (1995) Antimitochondrial antibody-negative primary biliary cirrhosis. Am J Gastroenterol 90: 247–9 12. Mohr L, Heintges T, Hensel F, et al (1998) Treatment of autoimmune cholangitis. Dis Dis Sci 43: 2160–3 13. Michieletti P, Wanless IR, Katz, et al (1994) Antimitochondrial negative primary biliary cirrhosis: a distinct clinical syndrome of autoimmune cholangitis. Gut 35: 260–5
74
Autoimmune Cholangitis
14. Murdaca G, Colombo BM, Sprecacenere B, et al (2007) Autoimmune intrahepatic cholangiopathy associated with antiphospholipid antibody syndrome. Eur J Gastroenterol Hepatol 19: 910–2 15. Nakanuma Y, Harada K, Kaji K, et al (1997) Clinicopathological study of primary biliary cirrhosis negative for antimitochondrial antibodies. Liver 17: 281–7 16. Sedlack RE, Smyrk TC, Czajy AJ, et al (2002) Celiac disease-associated autoimmune cholangitis. Am J Gastroenterol 97: 3196–8 17. Selmi C, Zuin M, Bowlus CL, et al (2008) Anti-mitochondrial antibody-negative primary biliary cirrhosis. Clin Liv Dis 12: 173–85 18. Sherlock S (1998) Autoimmune cholangitis. A unique entity? Mayo Clin Proc 73: 184–90 19. Taylor SL, Dean PJ, Rieley CA (1994) Primary autoimmune cholangitis: an alternative to antimitochondrial antibodynegative primary biliary cirrhosis. Am J Surg Pathol 18: 91–9
Primary Sclerosing Cholangitis
75
Henryk Dancygier
Chapter Outline Definition......................................................................... 911 Epidemiology .................................................................. 911 Etiology and Pathogenesis ............................................. 912 Pathology ........................................................................ 912 Diagnosis ......................................................................... 913 Clinical Manifestations .................................................... 913 Laboratory Findings ......................................................... 914 Imaging Tools .................................................................. 914
Definition Primary sclerosing cholangitis (PSC) is a chronic fibro-obliterative inflammation of intra-and/or extrahepatic bile ducts of unknown origin. Small duct primary sclerosing cholangitis (formerly called pericholangitis) is an intrahepatic variant of PSC in patients with chronic cholestasis and hepatic histology compatible with PSC, but normal findings on endoscopic retrograde or magnetic resonance cholangiography.
Differential Diagnosis .................................................... 915 Course and Prognosis .................................................... 916
Epidemiology
Therapy ........................................................................... 917 References ....................................................................... 917
Since it was first described by Delbet in 1924, fewer than 80 cases of PSC had been reported in the literature up to the mid-1970s. Not until the introduction and increasing use of endoscopic retrograde cholangiography (ERC) did the numbers of patients diagnosed with PSC began to rise continuously. The epidemiological characteristics of PSC vary somewhat between different countries. A recent study in white Americans reported an incidence of PSC in men of 1.25 per 105 person years compared with 0.54 per 105 person years in women. The prevalence of PSC was 20.9 per 105 men and 6.3 per 105 women. Both incidence and prevalence of PSC were approximately one third of those previously described for primary biliary cirrhosis in the same population [4]. In a populationbased study from Scandinavia the incidence of PSC was 1.3 per 105 person years and the prevalence 8.5 per 105 persons [12]. A recent epidemiological study from the UK reported an incidence of 0.4 per 105 person years and a prevalence of 3.8 per 105 [15]. All epidemiological investigations agree that approximately two thirds of
H. Dancygier, Clinical Hepatology, DOI: 10.1007/978-3-642-04519-6_75, © Springer-Verlag Berlin Heidelberg 2010
911
912
the affected patients are men, most commonly in their third and fourth decade at presentation. PSC, however, is also recognized in children and adolescents [20]. Firstdegree relatives of patients with PSC have a disease prevalence of 0.7%, equivalent to a nearly 100-fold increased risk of developing PSC compared with the general population [8]. Approximately 70–80% of PSC cases are associated with inflammatory bowel disease (IBD), particularly (up to 90%) with ulcerative colitis [4]. On the other hand 5–6% of patients with ulcerative colitis have concurrent PSC. Generally IBD precedes PSC. There seems to be no close association between the inflammatory activity of IBD and the severity of PSC.
Etiology and Pathogenesis The etiology and pathogenesis of PSC are unknown. Toxic, infectious, genetic and (auto)immune factors have been discussed widely but their role remains speculative [1, 41, 52]. Hypotheses incriminating chronic portal bacteremia and/or toxic bile acids in damaging the biliary system have not been confirmed. The markedly increased copper concentration in liver tissue found in patients with PSC does not seem to trigger the disease process but rather is a secondary storage phenomenon that may be observed regularly in chronic cholestatic liver disease. Animal experiments and serological findings in neonates with biliary atresia suggest that viral infections (reovirus type 3, cytomegalovirus) may elicit a fibroobliterative cholangiopathy. AIDS-cholangiopathy is another example of infectious agents (cryptosporidium parvum, microsporidia, cytomegalovirus) causing a PSClike cholangiopathy. However, a direct causal relationship between an infectious agent and PSC has not yet been established. Various immunological findings may be recorded in PSC patients. A wide variety of nonspecific autoantibodies may be detected in serum of patients with PSC [2]. Increased levels in blood and bile of circulating immune complexes and secretory immunogobulins, a prolonged clearance of immune complexes from the circulation, decreased numbers of circulating T lymphocytes particularly due to diminished CD8 cells, and a reduced CD4/CD8 ratio within the liver tissue have also been documented in PSC patients. Inhibition of leukocyte
75
Primary Sclerosing Cholangitis
migration by bile duct epithelial constituents and an increased expression of HLA-DR antigens on bile duct epithelia in the early stages of PSC also corroborate the idea of PSC as an immune-mediated disease. All these findings, however, are nonspecific and represent immunologic epiphenomena in chronic inflammation rather than pathophysiologically significant reactions. The importance of genetic factors is underscored by the increased prevalence of PSC among first-degree relatives (see above) [8]. MHC-haplotypes with an increased risk of PSC include several risk alleles such as MHC class I chain-like a-molecules (MICA)*008, DRB1*0301, DRB1*1301 or DRB1*1501, with the strongest association being found for the MICA*008-homozygosity [52]. Combinations of killer immunoglobulin-like receptors and HLA class I ligands that reduce natural killer (NK) cell inhibition have been shown to increase the risk for autoimmune diseases. Particular variants of ligands for NK cell receptors encoded at three neighbouring genes in the HLA complex may contribute to the HLA associated risk of PSC [23].
Pathology PSC may affect the entire biliary system from interlobular bile ducts to the ampulla of Vater. Macroscopically the bile ducts appear thickened with their lumen being irregularly narrowed. Bile duct ectasias of various degree occur even without the presence of nearby duct strictures. The chronic inflammatory process may also involve the gallbladder, with dysplasia and carcinoma of the gallbladder being more prevalent in the PSC population [43]. PSC probably initiates as an inflammation of the interlobular bile ducts. This small duct variant of PSC (formerly called pericholangitis) was first recognized in 1985 [51]. It is characterized by a marked periductal edema and a dense portal inflammatory infiltrate consisting of plasma cells, lymphocytes and polymorphonuclear leukocytes. Not uncommonly the portal inflammatory process leads to interface hepatitis with the formation of so-called piece meal necroses which may be difficult to differentiate from chronic hepatitis of autoimmune or viral origin [29, 31]. The inflammatory changes in PSC are irregularly distributed, portal and periportal inflammation being focal with varying severity in different locations. Like in the early stages of primary biliary
Diagnosis
913
Fig. 75.1 Concentric peribiliary fibrosis in primary sclerosing cholangitis. The histological finding is nonspecific and does not allow for differentiating from secondary sclerosing cholangitis. Hematoxylin and Eosin
cirrhosis (PBC) the portal tracts in PSC may also contain lymphoid follicles. Portal granulomas occur much more rarely in PSC than in PBC. Despite PSC being primarily a mural inflammatory process, the cholangiocytes as well may display alterations ranging from degenerative and atrophic changes to cell death [18]. Loss of peribiliary vascular plexus has been described in the early stages of PSC and is probably secondary to the inflammatory process [50]. It is unknown whether or not ischemia contributes to the formation of bile duct strictures in PSC. During the further course of the disease, portal cellular infiltrates diminish with a concentric, onion-skin like, peribiliary fibrosis becoming increasingly prominent (Fig. 75.1). Finally, the chronic fibro-obliterative process transforms the bile ducts into fibrous cords which are either solid or contain remnants of bile duct epithelium. Complete focal loss of bile ducts may be observed in advanced stages of PSC [30]. The final stage of PSC is represented by secondary biliary cirrhosis. A histological staging system for PSC is reported in Table 75.1 [29].
Table 75.1 Staging of primary sclerosing cholangitis Stage 1 Stage 2 Stage 3 Stage 4
Portal cholangitis Periportal hepatitis and/or fibrosis Septal fibrosis and /or bridging necrosis Cirrhosis
Source: According to Ludwig et al. [29]
Diagnosis The diagnosis of PSC is based on the typical cholangiographic appearance of the bile ducts in a patient with a cholestatic laboratory profile, and on the exclusion of secondary causes of chronic cholangitis. If small duct PSC is suspected liver biopsy is required.
Clinical Manifestations PSC usually develops insidiously as a chronic smouldering disease initially unnoticed by the patient and may be in an advanced stage by the time it becomes clinically apparent. The main signs and symptoms are reported in Table 75.2. Increasing fatigue, malaise and
Table 75.2 Symptoms and signs in primary sclerosing cholangitis Jaundice Pruritus RUQ-pain Weight loss Fever Hepatomegaly Esophageal variceal bleeding Ascites Asymptomatic RUQ Right upper quadrant
61% 49% 42% 38% 36% 48% 9% 6% 19%
914
75 Primary Sclerosing Cholangitis
pruritus are usually followed by the appearance of jaundice. On average at the time of diagnosis the symptoms date back 2 years in 80% of patients. With the increasing use of cholangiography (ERC and MRC) in patients with a chronic cholestatic laboratory profile, the proportion of PSC patients who are asymptomatic at diagnosis has increased from 7–10% to 25–44% [37, 53]. While PSC is a chronic disease with protean symptoms in the vast majority of patients, in approximately 1% of all patients it can present with acute liver failure [9]. In long-standing PSC signs and symptoms of malabsorption of fat soluble vitamins and of chronic hepatic failure may supervene.
Extrahepatic Diseases Like other autoimmune diseases PSC also may be associated with extrahepatic diseases. Immune thyroiditis, rheumatic disorders, sicca syndrome, and retroperitoneal fibrosis have been reported [1, 37, 53]. Occasionally, irregularly narrowed lesions of the pancreatic duct may also be observed. In these cases an autoimmune pancreatitis should be considered (see below). The association of PSC with IBD, particularly ulcerative colitis has been mentioned above. In addition to an increased prevalence of cholangiocarcinoma, patients with longstanding PSC also have an increased risk for colorectal, pancreatic, gallbladder and hepatocellular carcinoma compared with that of the general population (see below) [7].
Laboratory Findings The main laboratory findings in patients with PSC are reported in Table 75.3. A marked and long-standing increase in alkaline phosphatase and g-glutamyl Table 75.3 Serum laboratory findings in primary sclerosing cholangitis Alkaline phosphatase Aminotransferases Bilirubin Immunoglobulin M ¯ Albumin pANCA positive ANA positive AMA positive
98% 90% 57% 39% 28% 20–80% 25% 15%
transpeptidase serum levels with only minimally elevated serum aminotransferase concentrations is a typical but nonspecific finding. In very few patients with typical bile duct changes on ERC, serum alkaline phosphatase levels remain normal while aminotransferase concentrations are mildly elevated. The erythrocyte sedimentation rate, although a very nonspecific indicator of systemic inflammation, together with anemia of chronic disease, can provide an indication of PSC activity. Four percent of PSC patients have a peripheral blood eosinophilia. Patients with PSC have increased antibody titers to a wide range of autoantigens (Table 75.3). Antinuclear antibodies have been described in 7–77%, anticardiolipin antibodies in 4–66%, anti-smooth muscle antibodies in 13–20%, anti-thyroid peroxidase antibodies in 16% and rheumatoid factor in 15% of patients with PSC [2]. pANCA occurs in 20–80% of patients and has been thought of as more specific for PSC than other autoantibodies. However, all the serum autoantibodies are nonspecific and are not required for diagnosing PSC. Moreover, there is no correlation between the titers of autoantibody (including pANCA) and clinical parameters, so they are not helpful in clinical management.
Imaging Tools ERC is the diagnostic technique of choice and despite the rapid advancement of magnetic resonance technology it is still regarded in many centers worldwide as the gold standard in the diagnosis of PSC. One should be aware, however, that even mild cholangiographic bile duct changes are not equivalent to early disease but rather represent long-standing cholangitis. The typical cholangiographic pattern presents as irregularly placed multiple bile duct strictures and ectasias of varying length and severity (Figs. 75.2 and 75.3). The hepatic bifurcation is the region that is most often and most severely affected. An increasingly diffuse rarefaction of bile ducts may be observed in advanced stages. So-called high grade dominant stenoses may be superimposed on diffuse bile duct sclerosis in approximately 10% of cases. If cholangiography is technically adequate, lesions of intrahepatic bile ducts may be visualized in virtually all patients, while the extrahepatic bile ducts are spared in up to 20% of PSC patients. Cholangiographic classification systems have not attained relevance in the management of patients with PSC.
Differential Diagnosis
Fig. 75.2 Endoscopic retrograde cholangiography in primary sclerosing cholangitis. Multiple irregularities of intra- and extrahepatic bile ducts are seen
Transcutaneous and endoscopic ultrasound, intraductal ultrasound, CT scanning, MRI of the liver, and nuclear functional imaging with 99m-technetium
Fig. 75.3 Magnetic resonance cholangiography. Mild primary sclerosing cholangitis
915
imidoacetate show no characteristic changes and yield nonspecific findings. These techniques contribute little, if at all, to the diagnosis of pre-cirrhotic PSC, but ultrasound, CT and MRI are helpful in ruling out space occupying lesions as a cause for elevated alkaline phosphatase levels. These methods also are not helpful in the early detection of cholangiocellular carcinoma that may develop as a complication of PSC. Recently, FDGPET has been reported superior to conventional imaging techniques for both the detection and exclusion of cholangiocellular carcinoma in patients with advanced PSC, but further studies must be conducted before this costly imaging modality can be recommended in the routine diagnostic work-up of patients with PSC [39]. There is no specific histological picture of PSC and, as mentioned above, the inflammatory changes are irregularly distributed. Therefore, with the exception of small duct PSC, the diagnostic importance of liver biopsy in PSC generally is limited [29]. However, laparoscopy and (laparoscopic or percutaneous) liver biopsy are helpful in staging PSC.
Differential Diagnosis The differential diagnosis of PSC includes all chronic cholestatic liver disorders, particularly those leading to secondary sclerosing cholangitis (see Chapter 52, Table 52.1). Due to their relatively high prevalence, however, first and foremost intraductal stones, postoperative bile duct strictures, cholangiocarcinoma (Klatskin tumor), and PBC have to be excluded. Ischemic cholangiopathy in critically ill patients following circulatory shock (e.g., in polytraumatized and septic patients) should be considered increasingly more often in the differential diagnosis [21]. Isolated small duct PSC is diagnosed in patients with inflammatory bowel disease showing a cholestatic laboratory profile, biopsy features compatible with PSC, but a normal cholangiogram [31]. If ductopenia (absence of interlobular bile ducts in ³50% of portal tracts) is found histologically in the absence of PSC, inflammatory bowel disease, and other specific cholestatic syndromes such as drug reaction or sarcoidosis, the most likely diagnosis is idiopathic adulthood ductopenia (see Chapter 76) [26].
916
Drug-induced liver injury usually does not present with a PSC-like pattern on cholangiography. Bile duct lesions due to local intraarterial (hepatic artery) infusional chemotherapy with 5-fluorouracil and floxuridine are exceptions and may lead to the formation of ischemic bile duct strictures. The bile duct lesions on ERC in PBC stage IV may resemble PSC-induced changes. PBC primarily affects women, while two thirds of PSC patients are men. Moreover, the characteristic antibody profile of PBC is absent in PSC. Biliary infections in AIDS patients, for example with cryptosporidia, microsporidia and cytomegalovirus may lead to cholangiographic bile duct changes identical to those of PSC. The clinical constellation of a cholestatic laboratory profile with bile duct irregularities on ERC in a patient with a known HIV-infection is characteristic of AIDS-cholangiopathy. Immunglobulin G4 associated cholangitis (IAC) appears to be a newly emerging clinical entity that often is associated with autoimmune pancreatitis (AIP), and patients with unexplained biliary strictures associated with elevated serum IgG4 concentrations should also be examined for the presence of AIP [22, 33, 49]. Patients with IAC more often have a rather abrupt clinical presentation with obstructive jaundice in comparison with patients with classic PSC [10]. Portal inflammation with or without interface hepatitis, portal sclerosis, and large bile-duct obstructive features may be present. Corticosteroid therapy reduces IgG4-bearing plasma cell infiltration in the liver, and in the majority of patients requiring biliary stents these can be removed after successful corticosteroid treatment. Biliary strictures occurring after orthotopic liver transplantation may resemble ischemic type biliary lesions. They are, however, not caused by ischemia but probably result from bile duct damage induced by biliary debris and biliary casts. Rare differential diagnoses include, for example, Langerhans cell histiocytosis, mast cell cholangiopathy, angioimmunoblastic lymphadenopathy, local irradiation and congenital immune deficiency syndromes that may lead to a PSC-like bile duct pattern in children (see Table 52.1) [5, 6, 40]. Differentiating a central cholangiocarcinoma (Klatskin tumor) spreading along the bile ducts from PSC may be extremely difficult.
75 Primary Sclerosing Cholangitis
Course and Prognosis PSC is a chronic, progressive disease that leads to secondary biliary cirrhosis and chronic hepatic failure without adequate treatment. It carries an increased risk of recurrent bacterial and fungal (candida species) biliary infections, of forming intraductal stones and, most notably, of developing malignancies [1, 4, 7, 14, 15, 27, 37, 48]. Survival among children, adolescents and adults with PSC is significantly less than expected for the general population of similar age and gender [4, 20]. In a recent (2008) epidemiological study from the United Kingdom, mortality rate was increased three-fold in people with PSC compared to the general population [15]. The estimated median survival from the time of diagnosis to death or liver transplantation of patients who are symptomatic at the time of diagnosis is approximately 10–12 years, while 93% of patients who are asymptomatic at the time of diagnosis still live longer than 10 years. Age, low albumin, persistent bilirubin elevation for longer than 3 months (>4 times the upper limit of normal), hepatomegaly, splenomegaly, dominant bile duct stenosis, and intra- and extrahepatic ductal changes at the time of diagnosis are independent risk factors correlating with poor prognosis [48]. A Mayo model for predicting survival in PSC is available at http://www.mayoclinic.org/gi-rst/mayomodel3.html. The most important complication of PSC is cholangiocarcinoma (CCA). It occurs in 6–20% of patients after a mean follow-up of approximately 11–15 years, with a yearly incidence of approximately 1%. The prevalence of CCA in autopsy studies is as high as 30–40% [1, 4, 14, 37, 48]. Approximately one third of biliary malignancies are diagnosed within 1 year after the diagnosis of PSC [7]. The early detection of a CCA associated with PSC is a diagnostic challenge and even with a high index of suspicion is extremely difficult, as the numerous inflammatory bile duct strictures are indistinguishable from CCA on cholangiography. Rapidly developing dominant bile duct strictures and a worsening of the general state of the patient may be clues to the development of a biliary malignancy. Screening patients with PSC with serum tumor markers (e.g., carcinoembryonic antigen, carbohydrate antigen 19-9) is not helpful. Brush cytology from dominant strictures and
References
bile cytology yield unsatisfactory results with low sensitivities and predictive values. There is also no additional diagnostic benefit from p53 immunocytochemistry and K-ras mutation analysis [38]. High resolution (12.5–20 MHz) intraductal ultrasound with miniprobes introduced into the bile ducts also is not able to differentiate between benign and malignant strictures. In addition to CCA, the risk of hepatocellular carcinoma is increased 40 times, that of pancreatic carcinoma 14 times, and that of colorectal carcinoma 10 times in patients with PSC compared to the general population [7, 15]. The natural history of small duct PSC (SD-PSC) differs from that of large duct PSC. SD-PSC is a disease of progressive potential but associated with a better long-term prognosis. The survival of patients with isolated SD-PSC is similar to that of the general population, and the risk of CCA in these patients is not increased. In a small proportion of patients SD-PSC may progress to large duct PSC. SD-PSC may also recur after liver transplantation [3, 11].
Therapy Biliary tract infections in patients with PSC are treated with antibiotics or antifungals. Deficiency states due to malabsorption are corrected appropriately (see Chapters 52 and 80). An effective drug treatment for PSC is not available. Corticosteroids, colchicine, methotrexate, azathioprine, mycophenolate mofetil, tacrolimus, penicillamine, and metronidazole have no effect on the natural course of the disease [19, 46, 47]. Only ursodeoxycholoic acid (UDCA) has shown some promise. UDCA 13–15 mg/kg p.o. daily reduces the serum levels of cholestatic liver enzymes in some patients. However, a beneficial effect of UDCA on the natural course of PSC is not proven [28, 35]. The administration of high-dose UDCA (20–30 mg/ kg p.o. daily) is well tolerated, safe and leads to biliary enrichment of UDCA [42]. Although results are not uniform, high-dose UDCA may be of clinical benefit in PSC and may be associated with an improvement in survival. However, trials with a large number of participants
917
and of long duration are currently lacking and are required to establish whether the effect of high-dose UDCA on liver biochemistry, histology, and cholangiography in patients with PSC is translated into improved long-term survival [17, 34, 36]. UDCA also improves liver biochemistries in SD-PSC. As in large duct PSC it is not clear whether UDCA delays disease progression in SD-PSC [16]. Results of endoscopic or percutaneous dilatation of dominant stenoses are promising and repeated dilatation with opening of dominant stenoses appears to slow the progression of PSC [44, 45]. However, a beneficial effect on survival has yet to be demonstrated. The only life saving procedure for patients with PSC associated cirrhosis is orthotopic liver transplantation. The 5-year survival rates are approximately 75% and even PSC patients with CCA have a 35% 5-year survival following transplantation [13]. Xanthogranulomatous cholangiopathy (XGC) at the hilum of the native liver occurs in 20–30% of patients with PSC and negatively impacts graft and patient survival. Unfortunately there are no clinical features or laboratory tests to identify the presence of XGC prior to transplantation [24, 25]. Compared to patients with PBC, PSC patients have higher retransplantation and lower survival rates. Preemptive liver transplantation in PSC, for example, aiming to prevent the development of a CCA, is not recommended [32]. For treatment of CCA see Chapter 116.
References 1. Angulo P, Lindor KD (1999) Primary sclerosing cholangitis. Hepatology 30: 325–32 2. Angulo P, Peter JB, Gershwin ME, et al (2000) Serum autoantibodies in patients with primary sclerosing cholangitis. J Hepatol 32: 182–7 3. Angulo P, Maor-Kendler Y, Lindor KD (2002) Small-duct primary sclerosing cholangitis: a long-term follow-up study. Hepatology 35: 1494–500 4. Bambha K, Kim WR, Talwalkar J, et al (2003) Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a united states community. Gastroenteroogy 125: 1364–9 5. Baron TH, Koehler RE, Rodgers WH, et al (1995) Mast cell cholangiopathy: another cause of sclerosing cholangitis. Gastroenterology 109: 1677–81
918 6. Bass NM, Chapman RW, O’Reilly A, et al (1983) Primary sclerosing cholangitis associated with angioimmunoblastic lymphadenopathy. Gastroenterology 85: 420–4 7. Bergquist A, Ekbom A, Olsson R, et al (2002) Hepatic and extrahepatic malignancies in primary sclerosing cholangitis. J Hepatol 36: 321–7 8. Bergquist A, Lindberg G, Saarinen S, et al (2005) Increased prevalence of primary sclerosing cholangitis among first-degree relatives. J Hepatol 42: 252–6 9. Bergquist A, Glaumann H, Lindberg B, et al (2006) Primary sclerosing cholangitis can present with acute liver failure: report of two cases. J Hepatol 44: 1005–8 10. Björnsson E, Chiari ST, Smyrk TC, et al (2007) Immunoglobulin G4 associated cholangitis: description of an emerging clinical entity based on review of the literature. Hepatology 45: 1547–54 11. Björnsson E, Olsson R, Bergquist A, et al (2008) The natural history of small-duct primary sclerosing cholangitis. Gastroenterology 134: 975–80 12. Boberg KM, Aadland E, Jahnsen J, et al (1998) Incidence and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a Norwegian population. Scand J Gastroenterol 33: 99–103 13. Brandsaeter B, Isoniemi H, Broome U, et al (2004) Liver transplantation for primary sclerosing cholangitis; predictors and consequences of hepatobiliary malignancy. J Hepatol 40: 815–22 14. Burak K, Angulo P, Pasha TM, et al (2004) Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol 99: 523–6 15. Card T, Solaymani-Dodaran M, West J (2008) Incidence and mortality of primary sclerosing cholangitis in the UK: a population-based cohort study. J Hepatol 48: 939–44 16. Charatcharoenwitthaya P, Angulo P, Enders FB, et al (2008) Impact of inflammatory bowel disease and ursodeoxycholic acid therapy on small-duct primary sclerosing cholangitis. Hepatology 47: 133–42 17. Cullen SN, Rust C, Fleming K, et al (2008) High dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis is safe and effective. J Hepatol 48: 792–800 18. Dienes HP, Lohse AW, Gerken G, et al (1997) Bile duct epithelia as target cells in primary biliary cirrhosis and primary sclerosing cholangitis. Virchows Arch 431: 119–24 19. Farkkila M, Karvonen AL, Nurmi H, et al (2004) Metronidazole and ursodeoxycholic acid for primary sclerosing cholangitis: a randomized placebo-controlled trial. Hepatology 40: 1379–86 20. Feldstein AE, Perrault J, El-Youssif M, et al (2003) Primary sclerosing cholangitis in children: a long-term follow-up study. Hepatology 38: 210–7 21. Gelbmann CM, Rümmele P, Wimmer M, et al (2007) Ischemiclike cholangiopathy with secondary sclerosing cholangitis in critically ill patients. Am J Gastroenterol 102: 1221–9 22. Ghazale A, Chari ST, Zhang L, et al (2008) Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy. Gastroenterology 143: 706–15 23. Karlsen TH, Boberg KM, Olsson M, et al (2007) Particular genetic variants of ligands for natural killer cell receptors may contribute to the HLA associated risk of primary sclerosing cholangitis. J Hepatol 46: 899–906
75
Primary Sclerosing Cholangitis
24. Keaveny AP, Gordon FD, Goldar-Najafi A, et al (2004) Native liver xanthogranulomatous cholangiopathy in primary sclerosing cholangitis: impact on posttransplant outcome. Liver Transpl 10: 115–22 25. Khettry U, Keaveny A, Goldar-Najafi A, et al (2003) Liver transplantation for primary sclerosing cholangitis: a longterm clinicopathologic study. Hum Pathol 34: 1127–36 26. Kim WR, Ludwig J, Lindor KD (2000) Variant forms of cholestatic diseases involving small bile ducts in adults. Am J Gastroenterol 95: 1130–8 27. Kulaksiz H, Rudolph G, Kloeters-Plachky P, et al (2006) Biliary candida infections in primary sclerosing cholangitis. J Hepatol 45: 711–6 28. Lindor KD (1997) Ursodiol for primary sclerosing cholangitis. N Engl J Med 336: 691–5 29. Ludwig J, Barham SS, LaRusso NF, et al (1981) Morphologic features of chronic hepatitis associated with primary sclerosing cholangitis and chronic ulcerative colitis. Hepatology 1: 632–40 30. Ludwig J, MacCarty RL, LaRusso NF, et al (1986) Intrahepatic cholangiectases and large-duct obliteration in primary sclerosing cholangitis. Hepatology 6: 560–8 31. Ludwig J (1991) Small-duct primary sclerosing cholangitis. Semin Liver Dis 11: 11–7 32. Maheshwari A, Yoo HY, Thuluvath PJ (2004) Long-term outcome of liver transplantation in patients with PSC: a comparative analysis with PBC. Am J Gastroenterol 99: 538–42 33. Mendes FD, Jorgensen R, Keach J, et al (2006) Elevated serum IgG4 concentration in patients with primary sclerosing cholangitis. Am J Gastroenterol. 101: 2070–5 34. Mitchell SA, Bansi DS, Hunt N, et al (2001) A preliminary trial of high-dose ursodeoxycholic acid in primary sclerosing cholangitis. Gastroenterology 121: 900–7 35. Okolicsanyi L, Groppo M, Floreani A, et al (2003) Treatment of primary sclerosing cholangitis with low-dose ursodeoxycholic acid: results of a retrospective Italian multicentre survey. Dig Liver Dis 35: 325–31 36. Olsson R, Boberg KM, Schaffalitsky de Muckadell O, et al (2005) High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study. Gastroenterology 129: 1464–72 37. Ponsioen CY, Tytgat GNJ (1998) Primary sclerosing cholangitis: a clinical review. Am J Gastroenterol 93: 515–23 38. Ponsioen CY, Vrouenraets SME, van Milligen de Wit AWM, et al (1999) Value of brush cytology for dominant strictures in primary sclerosing cholangitis. Endoscopy 31: 305–9 39. Prytz H, Keiding S, Björnsson E, et al (2006) Dynamic FDG-PET is useful for detection of cholangiocarcinoma in patients with PSC listed for liver transplantation. Hepatology 44: 1572–80 40. Ramos FJ, Perez-Arellano JI, Lopez-Borrasca A (1987) Primary sclerosing cholangitis in histiocytosis X. Am J Med 82: 191 41. Rösch T, Dancygier H (1988) Primär sklerosierende Cholangitis. Leber Magen Darm 18: 184–96 42. Rost D, Rudolph G, Kloeters-Plachky P, et al (2004) Effect of high-dose ursodeoxycholic acid on its biliary enrichment in primary sclerosing cholangitis. Hepatology 40: 693–8 43. Said K, Glaumann H, Bergquist A (2008) Gallbladder disease in patients with primary sclerosing cholangitis. J Hepatol 48: 598–605
References 44. Stiehl A, Rudolph G, Sauer P, et al (1997) Efficacy of ursodeoxycholic acid treatment and endoscopic dilatation of major duct stenoses in primary sclerosing cholangitis. An 8-year prospective study. J Hepatol 26: 560–6 45. Stiehl A, Rudolph G, Klöters-Plachky P, et al (2002) Development of dominant bile duct stenoses in patients with primary sclerosing cholangitis treated with ursodeoxycholic acid: outcome after endoscopic treatment. J Hepatol 36: 151–6 46. Talwalkar JA, Angulo P, Keach JC, et al (2005) Mycophenolate mofetil for the treatment of primary sclerosing cholangitis. Am J Gastroenterol 100: 308–12 47. Talwalkar JA, Gossard AA, Keach JC, et al (2007) Tacrolimus for the treatment of primary sclerosing cholangitis. Liver Int 27: 451–3 48. Tischendorf JJW, Hecker H, Krüger M, et al (2007) Characterization, outcome, and prognosis in 273 patients with primary sclerosing cholangitis: a single center study. Am J Gastroenterol 102: 107–14
919 49. Umemura T, Zen Y, Hamano H, et al (2007) Immunoglobin G4-hepatopathy: association of immunoglobulin G4-bearing plasma cells in liver with autoimmune pancreatitis. Hepatology 46: 463–71 50. Washington K, Clavien PA, Killenberg P (1997) Peribiliary vascular plexus in primary sclerosing cholangitis and primary biliary cirrhosis. Hum Pathol 28: 791–5 51. Wee A, Ludwig J (1985) Pericholangitis in chronic ulcerative colitis: primary sclerosing cholangitis of the small bile ducts? Ann Intern Med 102: 581–7 52. Weismüller TJ, Wedemeyer J, Kubicka S, et al (2008) The challenges in primary sclerosing cholangitis–aetiopathogenesis, autoimmunity, management and malignancy. J Hepatol 48: S38–S57 53. Wiesner RH, Grambsch PM, Dickson ER, et al (1989) Primary sclerosing cholangitis: natural history, prognostic factors and survival analysis. Hepatology 10: 430–6
Biliary Ductopenia (Vanishing Bile Duct Syndrome)
76
Henryk Dancygier
Chapter Outline Definition......................................................................... 921 Epidemiology .................................................................. 921 Etiology and Pathogenesis ............................................. 921 Pathology ........................................................................ 923 Diagnosis ......................................................................... 924 Clinical Manifestations .................................................... 924 Laboratory Findings ......................................................... 924 Imaging Techniques ......................................................... 924 Differential Diagnosis .................................................... 924
Definition Vanishing bile duct syndrome (VBDS) encompasses a group of different cholestatic liver diseases characterized by the destruction and permanent loss of predominantly interlobular bile ducts. If more than 50% of portal tracts in an adequately large biopsy specimen do not contain a bile duct, then VBDS is present. VBDS may be idiopathic or secondary to other causes.
Epidemiology
Course and Prognosis .................................................... 924 Therapy ........................................................................... 924 References ....................................................................... 924
Due to the rarity of idiopathic VBDS reliable data on the incidence and prevalence of idiopathic adulthood ductopenia (IAD) is not available. An analysis of approximately 2,000 patients with small bile duct disease gives an idea of the frequency of ductopenia. Sixtyfive percent of cases fell upon primary biliary cirrhosis, 28% on primary sclerosing cholangitis, 1.2% on idiopathic VBDS and 0.5% on drug-induced biliary ductopenia [8]. The median age at diagnosis is in the third and fourth decade of life and IAD occurs with a distinct male preponderance [6–8, 14]. Manifestations of IAD late in life, however, have also been reported [10].
Etiology and Pathogenesis The causes of VBDS are reported in Table 76.1. The common pathophysiological denominator of all conditions is the progressive loss of interlobular bile ducts. The pathophysiological pathways leading to bile duct loss, however, differ according to the underlying condition. H. Dancygier, Clinical Hepatology, DOI: 10.1007/978-3-642-04519-6_76, © Springer-Verlag Berlin Heidelberg 2010
921
922
76 Biliary Ductopenia (Vanishing Bile Duct Syndrome)
Table 76.1 Causes of biliary ductopenia (vanishing bile duct syndrome) Cause/disease Comment Congenital, developmental and genetic Biliary atresia Alagille’s syndrome a1-Antitrypsin deficiency Cystic fibrosis Progressive familial intrahepatic cholestasis Zellweger syndrome Trisomy [17, 18, 21] Immunologic Primary biliary cirrhosis Primary sclerosing cholangitis Cholestatic overlap syndromes Sarcoidosis
Acute and chronic hepatic cellular rejection
Chronic graft versus host disease Stevens–Johnson syndrome Macrophage activating syndrome [1] Vascular (ischemic/hypoxic) Thrombosis of hepatic artery Traumatic injury Intraarterial infusion Vasculitis
Ischemic cholangiopathy [3] Infectious Cytomegalovirus Reovirus 3 Rubella virus Cryptosporidium parvum Echinococcus granulosus Hepatitis B virus Hepatitis C virus Epstein-Barr virus Drug-induced Neoplastic Langerhans’ cell histiocytosis Hodgkin’s disease Idiopathic Idiopathic adulthood ductopenia
See Chapter 56 See Chapter 85 See Chapter 83 See Chapter 86 See Chapter 85 Congenital absence of peroxisomes. Anomalies in bile acid metabolism
See Chapter 73 See Chapter 75 See Chapter 77 Granulomas occur preferentially in the portal and periportal areas. In a few cases granulomatous destruction of interlobular bile ducts occurs. The clinical manifestations in these patients resemble those of primary biliary cirrhosis The bile ducts are the targets of immune defense. The bile duct lesions usually are reversible with adequate immunosuppressive therapy. However, in a small percentage of patients destruction of bile ducts continues despite immunosuppression. Ischemic factors, in addition to immune reactions possibly are also implicated in bile duct injury After bone marrow transplantation a few patients develop progressive bile duct loss Usually drug-related Histologically, liver involvement is characterized by acute lobular hepatitis, marked hepatocyte apoptosis and small bile duct injury (see Chapters 52 and 97)
Anti-tumor chemotherapy (5-FU, FUDR), transarterial chemoembolization (TACE) 1. Collagen vascular disease, for example, polyarteritis nodosa 2. Irradiation damages the endothelium of peribiliary arterial plexuses leading to secondary bile duct injury. A direct damage of small bile ducts by irradiation seems also possible Rarely sclerosing cholangitis like lesions following septic shock may result in loss of bile ducts and rapidly progress to cirrhosis Neonatal exposure has been implicated in biliary ductopenia
AIDS-cholangiopathy Rupture of hydatid cysts may lead to a circumscribed loss of bile ducts, not to a true VBDS Fibrosing cholestatic hepatitis in patients after liver transplantation Questionable. Only anecdotal reports in renal transplant recipients with HCV infection Very rare See Table 76.2 see Chapter 97 Hepatic involvement in Hodgkin’s disease is seen in up to 50% of autopsy cases. Cholestasis with bile duct loss is a very rare presentation of Hodgkin’s disease
Pathology Table 76.2 Drugs reported to cause chronic cholestasis and ductopenia [2, 11] • Ajmaline • Amineptine • Amitryptyline • Amoxicillin/clavulanic acida • Ampicillin • Androgenic anabolic steroids • Arsenic derivatives • Azathioprine • Barbiturates • Carbamazepine • Carbutamide • Chlorothiazide • Chlorpromazine • Cimetidine • Clindamycin • Co-trimoxazole • Cromolyn sodium • Cyamemazine • Cyclohexyl proprionate • Cyproheptadine • Diazepam • Erythromycin • Estradiol • Flucloxacillin • Glibenclamide • Glycyrrhizin • Haloperidol • Ibuprofen • Imipramine • Methyltestosterone • Norandrostenolone • Phenylbutazone • Phenytoin • Prochlorperazine • Tetracyclines • Thiabendazole • Tiopronin • Tolbutamide • Trioleandomycin • Xenalamine a Cholestasis may appear after the drug has been withdrawn
In newborns and infants, developmental and genetic factors as well as malformations of the ductal plate predominate, possibly due to viral infections or metabolic factors [13]. Immune mechanisms, hypoxic/ischemic factors and drugs predominate in adults. While (auto)immune cholangiopathies, such as primary biliary cirrhosis and primary sclerosing cholangitis are well recognized causes of VBDS, permanent loss of bile ducts in
923
chronic ascending bacterial cholangitis is rather the exception. In contrast to hepatocytes, which receive a dual blood supply via the hepatic artery and the portal vein, the bile ducts are supplied solely by the branches of the hepatic artery. Cholangiocytes are therefore more susceptible to ischemic injury than hepatocytes [13]. Individual drugs only rarely lead to VBDS. Due to their frequent worldwide use, however, drugs always must be taken into consideration as a potential cause of VBDS (Table 76.2) [2, 11]. It is possible that viral infections and immune reactions in genetically susceptible individuals are important in IAD [12, 14]. White probands with the DRB1*1502 allele seem to have an increased susceptibility to VBDS and multiple HLA-DRB1 alleles (*04, *11, *15) occur more often in VBDS patients [4].
Pathology A portal inflammatory and fibrotic process leading to the destruction and loss of interlobular bile ducts is the histological hallmark of ductopenia (see paragraphs on Pathology in Chapters 73 and 75) [5]. By definition, VBDS is present if interlobular bile ducts are absent in at least 50% of portal tracts (normally each hepatic arterial branch is accompanied by at least one portal bile duct profile) [7]. The irregular distribution of lesions may impair the diagnostic accuracy of a liver biopsy and an adequately large tissue sample is mandatory for the diagnosis of VBDS. In order to avoid a sampling error, at least 11–20 portal tracts are required for accurate semiquantitative assessment, paying special attention to bile duct(s) accompanying the hepatic artery branches. An adequate biopsy size is 3 cm in length and 16 gauge in caliber. Diagnostic accuracy declines with specimen size, especially when smaller than 2 cm in length [11]. Alternatively, several biopsies may be easily obtained during diagnostic laparoscopy (see Chapter 45). The diagnosis can be established on routine hematoxylin and eosin sections. However, on PAS stained sections after pretreatment with diastase, the basement membranes of bile ducts (which are PAS positive and diastase resistant) are well visualized and even small bile ducts lying within an inflammatory infiltrate may be discerned easily. Immunocytochemical demonstration of cytokeratins 7 and 19 also allows for
924
an excellent identification of interlobular bile ducts. Ductular proliferation may coexist with interlobular duct loss, and ductules must be distinguished from bile ducts [11].
Diagnosis Clinical Manifestations A literature review of 39 cases of IAD reported a median age at diagnosis of 27 years (range 15–67 years), and most patients presented with a progressive cholestatic clinical picture with fatigue, episodic jaundice, pruritus and occasional fever [6]. A mild apparently nonprogressive clinical course with no symptoms of liver disease has also been reported [9].
Laboratory Findings Nonspecific elevations of alkaline phosphatase, g-glutamyl transpeptidase and alanine aminotransferase levels are observed. There is no specific autoantibody profile of VBDS.
Imaging Techniques The diagnosis of VBDS is made histologically on large liver biopsy specimen (see above) or in the explanted liver. Ultrasound, CT scanning and MRI do not yield significant diagnostic findings in the precirrhotic stages.
Differential Diagnosis The differential diagnosis has to consider all the conditions listed in Table 76.1.
Course and Prognosis Apparently two different clinical courses of IAD exist. While one half of the patients progresses relatively rapidly to cirrhosis and liver failure, the other half has
76 Biliary Ductopenia (Vanishing Bile Duct Syndrome)
a long lasting benign course with only mildly abnormal cholestatic parameters in serum and a cholangitic histologic picture, but with subjective well-being.
Therapy If the cause of VBDS is known, then the underlying illness is treated. Potentially incriminating drugs should be withdrawn. Some cases respond to lifelong, high dose (10–25 mg/kg) UDCA. Patients with rapidly progressive VBDS must undergo liver transplantation.
References 1. Bihl F, Emmenegger U, Reichen J, et al (2006) Macrophage activating syndrome is associated with lobular hepatitis and severe bile duct injury with cholestasis. J Hepatol 44: 1208–12 2. Desmet VJ (1997) Vanishing bile duct syndrome in druginduced liver disease. J Hepatol 26 (Suppl 1) 31–5 3. Engler S, Elsing C, Flechtenmacher, et al (2003) Progressive sclerosing cholangitis after spetic shock: a new variant of vanishing bile duct disorders. Gut 52: 688–93 4. García-Jiménez ME, Quiroga JA, Gutiérrez ML, et al (2001) Association of HLA-DR genes with mild idiopathic adulthood ductopenia. Am J Gastroenterol 96: 1178–82 5. Hübscher SG (1999) Pathology of vanishing bile duct syndromes. In: Neuberger J (ed.) Primary biliary cirrhosis. West End Studios, Eastbourne, pp 41–52 6. Kim WR, Ludwig J, Lindor KD (2000) Variant forms of cholestatic diseases involving small bile ducts in adults. Am J Gastroenterol 95: 1130–8 7. Ludwig J, Wiesner RH, LaRusso NF (1988) Idiopathic adulthood ductopenia: a cause of chronic cholestatic liver disease and biliary cirrhosis. J Hepatol 7: 193–9 8. Ludwig J (1998) Idiopathic adulthood ductopenia: an update. Mayo Clin Proc 73: 285–91 9. Moreno A, Carreno V, Cano A (1997) Idiopathic biliary ductopenia in adults without symptoms of liver disease. N Engl J Med 336: 835–8 10. Müller C, Ulrich W, Penner E (1995) Manifestation late in life of idiopathic adulthood ductopenia. Liver 15: 213–8 11. Reau NS, Jensen DM (2008) Vanishing bile duct syndrome. Clin Liv Dis 12: 203–17 12. Woolf GM, Vierling JM (1993) Disappearing intrahepatic bile ducts: the syndromes and their mechanisms. Semin Liv Dis 13: 261–75 13. Xia X, DeMorrow S, Francis H, et al (2007) Cholangiocyte injury and ductopenic syndromes. Semin Liv Dis 27: 401–12 14. Zafrani ES, Metreau JM, Douvin C, et al (1990) Idiopathic biliary ductopenia in adults: a report of five cases. Gastroenterology 99: 1823–8
Autoimmune Overlap Syndromes
77
Henryk Dancygier
Chapter Outline Overlap Between AIH and PBC ................................... 926 Overlap Between AIH and PSC.................................... 926 Overlap Between PBC and PSC ................................... 926 References ....................................................................... 927
The advancement of immunological, molecular biological, and morphological techniques as well as the introduction of diagnostic scoring systems allows for precisely allocating the majority of patients to one of the three major hepatobiliary (auto)immune diseases, i.e. autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC). Up to 20% of these patients, however, share overlapping clinical, histological, and immunological features that do not allow for establishing a precise diagnosis [12]. These patients are said to suffer from a variant or overlap syndrome [10, 23]. The clinician should be aware, though, that this term does not define an exact diagnosis, but rather results from our still unsatisfactory understanding of the precise etiology and pathogenesis of autoimmune liver diseases. The degree of overlap may be minor with signs and symptoms of one disease clearly prevailing, or major with the clinical, serological and histological features of two diseases fully overlapping. In addition to coexistence, two diseases may appear sequentially during follow up. The evolution of one autoimmune liver disease to another does not represent a true overlap, but a sequential syndrome. The knowledge of variant (overlap) syndromes of autoimmune liver disease is not only interesting diagnostically, but also has therapeutic implications. Predominantly cholestatic overlap syndromes are generally more responsive to ursodeoxycholic acid (UDCA) than to immunosuppressive therapy, while hepatitic overlap syndromes respond to immunosuppressive treatment with corticosteroids and azathioprine. If both components, cholestatic and hepatitic, are present in equal measure combination therapy of UDCA and immunosuppressive drugs is warranted.
H. Dancygier, Clinical Hepatology, DOI: 10.1007/978-3-642-04519-6_77, © Springer-Verlag Berlin Heidelberg 2010
925
926
Overlap Between AIH and PBC PBC–AIH overlap syndrome is a clinical entity characterized by the occurrence of both conditions at the same time in the same patient. It occurs in approximately 5–13% of patients with AIH, and in approximately 19% of patients diagnosed with PBC [7, 9, 12, 17]. In addition to the serological features of AIH (elevation of alanine aminotransferase > 5 × the upper limit of normal (ULN), IgG > 2 × ULN, typical autoantibody profile), these patients have elevated alkaline phosphatase and IgM levels in serum and bile duct lesions on histologic examination. In two thirds of cases ANA and SMA occur in addition to AMA. Moreover, the presence of antiSLA/LP in patients with PBC is highly specific for AIH-PBC overlap [15]. Patients with true AIH–PBC overlap syndrome usually respond well to immunosuppressive therapy (prednisone plus azathioprine) combined with UDCA [8]. In addition to PBC–AIH overlap syndrome, a rare sequential syndrome of AIH superimposed on PBC can occur. In a Mayo Clinic series of 1,476 patients with PBC who had no features of AIH, only eight patients developed AIH over a 9-year period [14]. The development of superimposed AIH cannot be predicted from baseline characteristics and initial response of PBC to UDCA therapy. If not detected and treated early, superimposed AIH can result in rapid progression toward cirrhosis and liver failure in PBC patients. Most patients respond well to treatment with prednisone plus azathioprine [19, 21]. Autoimmune cholangitis may be regarded as an overlap between PBC and AIH, a subtype of AIH type I with cholestatic features, or a distinct variant of PBC (AMA-negative PBC) (see Chapter 74) [3, 18].
Overlap Between AIH and PSC AIH–PSC overlap syndrome is rarer than overlap between AIH and PBC. The diagnosis is established in a patient with AIH and concomitant features of PSC, such as typical bile duct changes on ERCP or MRCP [1, 13]. The presence of an inflammatory bowel disease hints at the diagnosis of PSC.
77
Autoimmune Overlap Syndromes
If the scoring system for the diagnosis of AIH is applied to patients with PSC confirmed by cholangiography, a diagnosis of definite or probable AIH is made in approximately 1.4%–8% of cases, respectively [5, 6, 16, 22]. Patients with AIH-PSC overlap syndrome benefit from immunosuppression (prednisone and azathioprine) combined with UDCA [11]. AIH and PSC may also be sequential in their appearance, whereby patients have features of AIH and then after an average duration of 4–5 years develop clear features of PSC on ERCP. There are no specific features at presentation that can predict this sequence of events [2].
Overlap Between PBC and PSC PBC–PSC overlap syndrome is very rare, with only anecdotal reports being found in the literature [20]. In the early stages, the distinction between these two disorders is easier to discern than in advanced stages, where it may be difficult to distinguish both diseases even with the help of histological and immunological changes. Secondary alterations of bile ducts in PBC stage IV may be indistinguishable from PSC on ERCP/MRCP. Some differentiating features between AIH, PBC and PSC are summarized in Table 77.1, and a diagnostic and therapeutic algorithm in AIH-overlap syndromes is depicted in Fig. 77.1. Table 77.1 Some differentiating features between autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC) PBC PSC AIH Occurrence in childhood No (only anecdotal cases) Percentage females 90% HLA B8, DR3 (+) IBD (+) Predominant immune IgM globulin in serum Autoantibodies AMA Alteration of major − bile ducts Response to − corticosteroids IBD Chronic inflammatory bowel disease
Yes
Yes
40% + +++ (IgG)
60% +++ (+) IgG
(pANCA) ANA +++ − −
+++
References
Fig. 77.1 Diagnostic and therapeutic algorithm in autoimmune hepatitis overlap syndromes [4]. AIH Autoimmune hepatitis, PBC primary biliary cirrhosis, AIC autoimmune cholangitis, IBD chronic inflammatory bowel disease, N upper limit of normal, UDCA ursodeoxycholic acid
References 1. Abdalian R, Dhar P, Jhaveri K, et al (2008) Prevalence of sclerosing cholangitis in adults with autoimmune hepatitis: evaluating the role of routine magnetic resonance imaging. Hepatology 47: 949–57 2. Abdo AA, Bain VG, Kichian K, et al (2002) Evolution of autoimmune hepatitis to primary sclerosing cholangitis: a sequential syndrome. Hepatology 36: 1393–9 3. Ben Ari Z, Dhillon AP, Sherlock S (1993) Autoimmune cholangiopathy: part of the spectrum of autoimmune chronic active hepatitis. Hepatology 18: 10–5 4. Ben Ari Z, Czaja AJ (2001) Autoimmune hepatitis and its variant syndromes. Gut 49: 589–94 5. Boberg KM, Fausa O, Haaland T, et al (1996) Features of autoimmune hepatitis in primary sclerosing cholangitis: an evaluation of 114 primary sclerosing cholangitis patients according to a scoring system for the diagnosis of autoimmune hepatitis. Hepatology 23: 1369–76 6. Chazouillieres O (2000) Diagnosis of primary sclerosing cholangitis–autoimmune hepatitis overlap syndrome: to score or not to score? J Hepatol 33: 661–3
927 7. Chazouillieres O, Wendum D, Serfaty L, et al (1998) Primary biliary cirrhosis–autoimmune hepatitis overlap syndrome: clinical features and response to therapy. Hepatology 28: 296–301 8. Chazouilleres O, Wendum D, Serfaty L, et al (2006) Long term outcome and response to therapy of primary biliary cirrhosis-autoimmune hepatitis overlap syndrome. J Hepatol 44: 400–6 9. Czaja AJ (1996) The variant forms of autoimmune hepatitis. Ann Intern Med 125: 588–98 10. Czaja AJ (1998) Frequency and nature of the variant syndromes of autoimmune liver disease. Hepatology 28: 360–5 11. Floreani A, Rizzotto ER, Ferrara F, et al (2005) Clinical course and outcome of autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome. Am J Gastroenterol 100: 1516–22 12. Gheorghe L, Iacob S, Gheorghe C, et al (2004) Frequency and predictive factors for overlap syndrome between autoimmune hepatitis and primary cholestatic liver disease. Eur J Gastroenterol Hepatol 16: 585–92 13. Gohlke F, Lohse AW, Dienes HP, et al (1996) Evidence for an overlap syndrome of autoimmune hepatitis and primary sclerosing cholangitis. J Hepatol 24: 699–705 14. Gossard AA, Lindor KD (2007) Development of autoimmune hepatitis in primary biliary cirrhosis. Liver Int 27: 1086–90 15. Kanzler S, Bozkurt S, Herkel J, et al (2001) Nachweis von SLA/LP-Autoantikörpern bei Patienten mit primär biliärer Zirrhose als Marker für eine sekundäre autoimmune Hepatitis (Overlapsyndrom). Dtsch med Wschr 126: 450–6 16. Kaya M, Angulo P, Lindor KD (2000) Overlap of autoimmune hepatitis and primary sclerosing cholangitis: an evaluation of a modified scoring system. J Hepatol 33: 537–42 17. Lohse AW, Meyer zum Büschenfelde KH, Franz B, et al (1999) Characterization of the overlap syndrome of primary biliary cirrhosis (PBC) and autoimmune hepatitis: evidence for it being a hepatitic form of PBC in genetically susceptible individuals. Hepatology 29: 1978–84 18. Michieletti P, Wanless IR, Katz A, et al (1994) Antimitochondrial antibody negative primary biliary cirrhosis: a distinct syndrome of autoimmune cholangitis. Gut 35: 260–5 19. Poupon R, Chazouilleres O, Corpechot C, et al (2006) Development of autoimmune hepatitis in patients with typical primary biliary cirrhosis. Hepatology 44: 85–90 20. Rubel LR, Seeff LB, Patel V (1984) Primary biliary cirrhosis–primary sclerosing cholangitis overlap syndrome. Arch Pathol Lab Med 108: 360–1 21. Silveira MG, Talwalkar JA, Angulo P, et al (2007) Overlap of autoimmune hepatitis and primary biliary cirrhosis: longterm outcomes. Am J Gastroenterol 102: 1244–50 22. Van Buuren HR, van Hoogstraten HJF, Terkivatan T, et al (2000) High prevalence of autoimmune hepatitis among patients with primary sclerosing cholangitis. J Hepatol 33: 543–8 23. Woodward J, Neuberger J (2001) Autoimmune overlap syndromes. Hepatology 33: 994–1002
Acute Liver Failure
78
Alexander Koch and Christian Trautwein
Chapter Outline Definition......................................................................... 931 Epidemiology .................................................................. 931 Etiology ........................................................................... 931 Prognosis ......................................................................... 932 General Considerations ................................................. 933 Special Entities ............................................................... 934 Acetaminophen Intoxication ............................................ 934 Mushroom Poisoning ....................................................... 934 Drug-Induced Liver Injury ............................................... 935 Viral Hepatitis .................................................................. 935 Wilson’s Disease .............................................................. 936 Autoimmune Hepatitis ..................................................... 937 Acute Fatty Liver of Pregnancy ....................................... 937 Budd-Chiari Syndrome .................................................... 937 Indeterminate Etiology..................................................... 937 Therapy ........................................................................... 937 General Considerations .................................................... 937 Encephalopathy and Cerebral Edema .............................. 938 Infections in Acute Liver Failure ..................................... 940 Multi-Organ-Failure in Acute Liver Failure .................... 941 Metabolic Disorders in Acute Liver Failure..................... 942 Basic Aspects of Nutrition in Acute Liver Failure ........... 942 Liver Replacement Therapies .......................................... 943 Liver Transplantation and Prognosis................................ 943 References ....................................................................... 944
Definition Acute liver failure (ALF) is defined by loss of liver function in patients with no pre-existing chronic liver disease. This definition differentiates ALF from endstage liver disease, which can also result in terminal loss of liver function. Acute liver failure is characterized by a related group of typical findings, which include severe liver insufficiency clinically presenting with coagulation disorders (usually an INR ≥ 1.5) and any degree of mental alteration caused by hepatic encephalopathy. The poor prognosis of ALF is due to the combination of liver insufficiency and hepatic encephalopathy. Depending on the length of illness, ALF has been historically differentiated into fulminant or hyperacute (< 7 days), acute (7–21 days) and subacute (> 21 days and < 26 days) liver failure [74]. Duration of the clinical course has, unlike the cause of the illness, no prognostic significance.
Epidemiology The worldwide incidence of ALF is uncertain. Approximately 2,000 cases of ALF occur yearly in the United States, representing 0.1% of all deaths and around 6% of liver-related deaths [27].
Etiology The major causes of ALF are medication toxicity, viral hepatitis and indeterminate causes. Data collected by the Acute Liver Failure Study Group revealed that H. Dancygier, Clinical Hepatology, DOI: 10.1007/978-3-642-04519-6_78, © Springer-Verlag Berlin Heidelberg 2010
931
932
during the period of 1998 to 2001 acetaminophen overdose was responsible for 39% of ALF cases, indeterminate causes for 17%, idiosyncratic drug reactions for 13% and acute viral hepatitis A or B for 12% [57]. Amoxicillin-clavulanate has been identified as the most common agent in drug induced liver injury, accounting for almost 13% of cases [1]. ALF is more rarely caused by amanita intoxication, acute Wilson’s disease, and Budd-Chiari syndrome (Table 78.1). Table 78.1 Causes of acute liver failure Infectious (viral) Hepatitis A Hepatitis B Hepatitis D Hepatitis E Hepatitis NANBNC Rare viral causes Herpes simplex virus Herpes virus Type 6 Varicella virus Cytomegalovirus Ebstein-Barr virus Toga virus Paramyxovirus Parainfluenza virus Drugs/Toxins/Chemicals Acetaminophen Amanita phalloides Halothane Isoniazid Valproate NSAIDE Other drugs see Table 78.5 Cardiovascular Budd-Chiari syndrome Hypotension (circulatory shock) Heart failure (e.g. right ventricular) Hyperthermia Veno-occlusive disease Portal vein thrombosis Sepsis Metabolic and infiltrative Wilson’s disease Reye’s syndrome Acute fatty liver of pregnancy HELLP syndrome (hemolysis, elevated liver enzymes, low platelet count) Galactosemia Hereditary fructose intolerance Hereditary tyrosinemia Malignant tumors Anorexia nervosa (with extremely poor nutritional status)
78
Acute Liver Failure
A distinct cause for ALF can be established in approximately 60–80% of cases; identification of the underlying disease directly influences treatment options and determines prognosis [46].
Prognosis The probability of spontaneous hepatic recovery cannot be predicted by any single factor alone. The most important variables for predicting the outcome in ALF are the grade of hepatic encephalopathy, the patient’s age, the underlying etiology and the progression in clinical course. Spontaneous recovery of liver function is more likely with lower grades of hepatic encephalopathy: 65–70%, for grade I–II 40–50% for grade III and < 20% for grade IV [56]. The overall prognosis is determined by different pathophysiological factors of ALF: the metabolic consequences of diminished functional liver cell mass, the release of toxic metabolites from destroyed liver cells and the ability of regeneration of the remaining liver tissue. The potential for liver regeneration is higher in fulminant liver failure than in subacute liver failure due to its sudden occurrence. In patients with fulminant liver failure, intensive care medicine can more often bridge to spontaneous recovery of liver function; acetaminophen toxicity should be considered in most cases of fulminant ALF. In contrast, continuous damage in subacute liver failure reduces the possibility of liver regeneration and leads to a worse prognosis. With regard to its cause, the prognosis of ALF due to Wilson’s disease, Budd-Chiari syndrome and Non A-, B- or C-hepatitis is more severe whereas the clinical course of ALF caused by hepatitis A is more favourable. The overall prognosis of ALF for children younger than 10 years and adults older than 40 years in all underlying diseases is poor. Based on developments in intensive care medicine over the past 20 years the prognosis of ALF has improved; nevertheless, the mortality of ALF with conservative treatment is approximately 40–70% depending on patients’ characteristics and underlying disease. In other words, 50% of patients with ALF will need a liver transplantation.
General Considerations Table 78.2 King’s college criteria Acetaminophen-induced ALF Arterial pH < 7.3 (following adequate volume resuscitation), irrespective of coma grade OR PT > 100 s (INR ≥ 6.5) + serum creatinine > 3.4 mg/dL in patients in grade III/IV coma Non-acetaminophen-induced ALF PT > 100 s irrespective of grade of encephalopathy OR Any three of the following, irrespective of coma grade: Drug toxicity, indeterminate cause of ALF Age < 10 years or > 40 years Jaundice or coma interval > 7 days PT > 50 s (INR ≥ 3.5) Serum bilirubin > 17.5 mg/dL
Survivors of ALF usually recover completely; residual cerebral, renal or hepatic damage is rare. To assess prognosis of ALF, several scoring systems have been developed. Most frequently the King’s College Score is used (Table 78.2). The accuracy of the King’s College Criteria has been evaluated in separate cohorts, proving that fulfillment is associated with an inferior outcome; however, sensitivity of this scoring system is poor. Relatively low negative predictive values indicate that King’s College Criteria are better able to predict prognosis in patients with a poor than those with a good prognosis. The Model for Endstage Liver Disease (MELD) score is suited to predict mortality in patients with chronic liver disease; currently, its use cannot be recommended in patients with ALF [80]. In patients with acute acetaminophen intoxication APACHE-II-Score > 15 and serum lactate concentration > 3 mmol/l discriminates patients with an adverse prognosis. Liver histology can be an important tool for establishing a diagnosis but its accuracy is not proven for predicting outcome and its routine use is therefore not recommended [26].
General Considerations In all patients with clinical evidence of moderate to severe hepatitis, measurement of prothrombin time and careful evaluation of the mental status should be performed. If the prothrombin time is prolonged, with
933
an INR ≥ 1.5, and alterations in mentation are present, the diagnosis of ALF is established. All patients with the diagnosis of ALF should be treated in an intensive care unit (ICU), preferably in a transplant center, since the condition may progress rapidly. When possible, a detailed history should be obtained from the patient, patient’s family or friends, and/or paramedics, with particular attention to possible exposures to viral infection, medications, illicit drugs and toxins. On admission, physical examination is important to assess and document the patient’s initial mental status so that any subtle progression can be more accurately detected. Jaundice is a common clinical sign but not always seen at presentation. One should look carefully for signs of cirrhosis such as spider nevi, gynecomastia, atrophic tongue and glabella, so as to exclude underlying chronic liver disease. Due to massive hepatocyte loss the physical examination can reveal a decreased size of the liver. Otherwise an enlarged liver might be observed in cases of early viral hepatitis, malignant infiltration, congestive heart failure or Budd-Chiari syndrome. In order to evaluate the etiology and severity of ALF, initial laboratory examination must be immediate and extensive. Laboratory examination should include coagulation parameters, routine chemistries (glucose, electrolytes, AST, ALT, AP, gGT, bilirubin, albumin, creatinine, urea nitrogen), arterial blood gas measurement, complete blood count, blood typing, toxicology screening and acetaminophen level. Arterial ammonia at presentation is predictive of outcome in patients with acute liver failure and may be an independent risk factor for the development of both hepatic encephalopathy and intracranial hypertension. ALF due to hepatitis A and B, Wilson’s disease and autoimmune hepatitis should be excluded. To identify the underlying etiology of ALF, liver biopsy, preferably via transjugular route because of coagulopathy, might be useful, especially in cases of suspected autoimmune hepatitis, malignancy or lymphoma (see Chapter 44). All women of child-bearing age with ALF should undergo pregnancy tests. According to ALF etiology specific therapeutic procedures should be initiated and the indication for transplantation should be evaluated as early as possible and considered continuously.
934
Special Entities Acetaminophen Intoxication Acetaminophen toxicity is a typical example of a doserelated toxicity. Severe hepatotoxicity and ALF has to be expected after ingestion of > 10 g per day. However, severe liver injury can occur rarely when doses as low as 3–4 g per day are taken, especially in patients consuming regularly ethanol (see Table 93.3) [67]. Medical history can reveal excessive ingestion either in the intention of suicidal overdose or in accidental overdose as pain medication. Medical history provided by relatives (e.g. preexisting depression, conflict in partnership) and information from paramedics (blister packages or empty bottles at location) can be helpful. Very high levels of aminotransferases are a typical laboratory finding of acetaminophen intoxication. In therapeutic doses acetaminophen is detoxified in the liver by glucoronidation or sulfation. High acetaminophen dosage and liver enzyme induction can lead to metabolism by cytochrome P450 IIE1 pathway which results in production of n-acetyl-p-benzoquinone-imine (NAPQI). As long as there are adequate hepatic glutathione reserves NAPQI is detoxified; otherwise, NAPQI binds covalently to cellular proteins. These NAPQIprotein-complexes induce hepatocellular apoptosis. N-acetylcysteine (NAC) replenishes diminished hepatic glutathione reserves so that NAC given in high dosage can inhibit the progression of ALF due to acetaminophen toxicity. As NAC is a very safe and easily administered drug, it should be given early on suspicion of acetaminophen intoxication, though it may still be of value 48 h or more after ingestion [36]. If NAC is administered early, the full extent of ALF can be nearly always avoided (Table 78.3). Additional activated charcoal (1 g/kg p.o.) may be useful for gastrointestinal decontamination as long as 3–4 h after ingestion [25]. Because acetaminophen is the leading cause of ALF in the United States and Western Europe and NAC is an adaptive antidote, acetaminophen levels should be measured wherever applicable to confirm the diagnosis of acetaminophen intoxication. High serum drug levels and rising aminotransferases indicate imminent liver injury or ALF. If acetaminophen levels are below 200 mg/mL 4 h after ingestion, administration of NAC can be deferred.
78
Acute Liver Failure
Table 78.3 N-acetyl-cysteine treatment of acetaminophen intoxication Oral administration Initial: 140 mg/kg b.w. by mouth or nasogastric tube Following: q4h × 17 doses: 70 mg/kg by mouth or nasogastric tube Intravenous administration 150 mg/kg b.w. in 200 mL 5% glucose over 15 min, followd by 50 mg/kg b.w. in 500 mL 5% glucose over 4 h, followed by 100 mg/kg b.w. in 1000 mL 5% glucose over 16 h Primary gastrointestinal decontamination Up to 4 h after ingestion using activated charcoal 1 g/kg b.w. orally administered
Patients at particular risk for acetaminophen toxicity (e.g. alcohol abuse, long-term fasting, enzyme-induction by tuberculostatic and anti-epileptic medications) and with laboratory-confirmed serum concentrations greater than 100 mg/mL should be treated. A recently published study shows that the measurement of serum acetaminophen-protein adducts can reliably identify acetaminophen toxicity in cases of acute liver failure in which no clinical or historic data are given to reveal the cause of acute liver failure [12].
Mushroom Poisoning Amanita phalloides poisoning is an uncommon cause of acute liver failure with an especially rapid course (see Table 93.3). Amatoxins of Amanita phalloides are hepato- and nephrotoxic. One mushroom of the species Amanita phalloides (50–100 g) contains 8–20 mg amatoxin; LD50 is about 0.2 mg/kg b.w. amatoxin. In Germany, returned settlers from Russia are at particular potential danger because Amanita phalloides looks similar to edible mushrooms in their country of origin. As there are no typical laboratory findings and no commercially available blood tests to confirm the presence of amatoxins, the diagnosis has to be based on clinical symptoms and a detailed history. In the typical clinical course severe diarrhea, vomiting and abdominal cramps start approximately 6–10 h after mushroom ingestion. The climax of liver deterioration takes place after 2–3 days; at that time, gastrointestinal symptoms usually have already subsided. An interval between ingestion and diarrhea of < 8 h is a very early predictor of a fatal outcome [19].
Special Entities
There are no controlled clinical studies for proper treatment of Amanita phalloides intoxication. Recommendations are based on case reports, experts’ opinion and experimental data. The main goal after (suspected) ingestion of Amanita phalloides is primary gastrointestinal decontamination by gastrointestinal lavage, administration of activated charcoal and laxatives and forced diuresis to prevent toxin absorption in the small intestine. Fluid resuscitation is also fundamental. Amanita intoxication frequently necessitates liver transplantation, but complete recovery has been described with supportive care and medical treatment [40, 60]. Liver transplantation should be strongly considered in patients with evolving clinical symptoms (diarrhea, vomiting, abdominal cramps) less than 8 h after mushroom ingestion. From day 4 after ingestion, INR ≥ 6 is a reliable tool for deciding emergency transplantation [19]. Specific antidotes for Amanita phalloides are silibinin and penicillin G, despite no controlled trials proving their efficacy [28, 40, 60]. Silibinin is not available as a licensed drug in the United States, although it is widely available in Europe and has been reported to be more effective than penicillin G in Amanita poisoning [19]. Silibinin is administered in a dosage of 30–50 mg/kg (intravenously or orally) for an average period of 3–4 days (Table 78.4). Penicillin G is given intravenously in doses of 300,000– 1,000,000 UI/kg/day. Charcoal plasma perfusion and MARS (see below) have been described as effective procedures in combination with conservative therapies within the first 36–48 h after amanita ingestion [10, 32]. There is no distinct scientific evidence for the effectiveness of other substances, such as a-liponic acid, cortisone, cephalosporins and cimetidine. Future clinical Table 78.4 Therapy of Amanita phalloides intoxication Fluid resuscitation Primary gut decontamination: – Gastric lavage (up to 36 h after ingestion) – Activated charcoal 1 g/kg b.w. p.o. In proof of Amanita phalloides ingestion Antidot-therapy: – Silibinin i.v. 20 mg/kg b.w. in 4 doses over 2 h (diluted in 5% glucose or 0,9% NaCl) – Additive i.v. NAC-therapy as in acetaminophenintoxication Secondary gut decontamination: – Hourly application of 0.25–0.5 g/kg b.w. activated charcoal
935
research has to concentrate on the efficacy of silibinin, N-acetylcysteine, and detoxification procedures.
Drug-Induced Liver Injury Drug-induced liver injury (DILI) is caused by direct hepatotoxic effects of a drug, or a reactive metabolite of a drug (see Section XVIII). Parenchymal cell injury induces activation of immune cells, which produce proinflammatory and tissue hepatotoxic mediators and may lead to acute liver failure. In clinical practice medication history should be taken carefully to reveal type, duration and quantity of all substances ingested over the past year. Attention has to be paid to the fact that ALF can result from therapeutic doses in patients with underlying liver disease (particularly with ongoing alcohol abuse) and in patients who are taking medications known to induce the cytochrome P450 system such as anti-convulsants. In contrast to dose-related acetaminophen toxicity, a variety of drugs can cause idiosyncratic liver injury which may lead to ALF. Idiosyncratic drug toxicity usually occurs within the first 6 months of intake. Drugs used for more than 1–2 years are unlikely to cause de novo liver damage. Drug-induced ALF is a diagnosis of exclusion; all other causes for ALF have to be ruled out. In addition to prescribed medications, non-prescription over-the-counter-drugs, herbal preparations and nutritional supplements can also cause liver injury [70]. “Usual suspects” for drug-induced liver injury are antibiotics, non-steroidal anti-inflammatory agents (NSAID) and anti-convulsants, especially isoniazid, valproic acid, phenytoin and amoxicillin-clavulanate. Table 78.5 gives an overview of drugs which are known to cause drug-induced liver injury. There are no specific therapies or antidotes for idiosyncratic drug injuries; discontinuation of all but essential medication is necessary. Unless allergic drug-reactions are suspected, there is no indication for corticosteroids in drug-induced liver injury.
Viral Hepatitis In the United States, acute viral hepatitis is causative in approximately 12% of ALF (hepatitis B 8%, hepatitis A
936 Table 78.5 Selected drugs which may cause liver injury Isoflurane Isoniazid/Rifampicina Trimethoprim-sulfamethoxazole Lisinopril Amoxicillin-clavulanate Nicotinic acid Sulfonamides Ofloxacin Phenytoin Dapsone Statins Imipramine Propylthiouracil Etoposid Halothane Allopurinol Disulfiram Methyldopa Valproic acid Ketoconazole Amiodarone Efavirenz Diclofenac Metformin a bold: combination agents with enhanced toxicity
4%) [57, 66]. Implementation of hepatitis B vaccination has led to a striking reduction in the occurrence of HBVrelated ALF. Nevertheless, acute hepatitis B still is a significant cause of fulminant hepatitis. Acute hepatitis due to precore or pre-S mutant hepatitis B viruses may be difficult to diagnose by routine serology; thus, liver failure in this group may be misinterpreted as non A, B or C hepatitis or of cryptogenic etiology. In unclear cases hepatitis B infection can be detected by polymerase chain reaction (PCR) [83]. Acute hepatitis C alone seems not to cause ALF [21]. In countries where hepatitis E is endemic (e.g. Russia, Pakistan, India or Mexico) it is a significant cause of ALF; especially in pregnant women [37, 66]. Acute hepatitis E infection has to be considered in patients with ALF and recent travels to endemic areas. In acute hepatitis B virus infection related ALF the nucleoside analog lamivudine in doses of 100 mg per day was used – rather based on case reports and experts’ opinion than on distinct scientific data – to improve liver function and reduce the necessity of liver transplantation [44]. In a randomized controlled clinical trial the efficacy of lamivudine 100 mg daily was compared to placebo. The lamivudine group showed a greater decrease in levels of HBV-DNA but no significantly greater biochemical or clinical improvement compared to placebo could be demonstrated [41]. Therapy in viral hepatitis A- and B- and E-related ALF is based on supportive care, as no virus-specific treatment has been proven effective. Chemotherapy or immunosuppression can lead to reactivation or acute flare of hepatitis B and by this means even to ALF. Therefore patients found to be positive for HBsAg should be treated prophylactically
78
Acute Liver Failure
with a nucleoside analog before initiating immunosuppressive therapy. Prophylaxis should be continued for 6 months after cessation of immunosuppression [48]. Herpes and varizella zoster, Epstein-Barr virus and cytomegalovirus infections rarely cause ALF. While herpes virus ALF has been reported in healthy individuals, it is typically immunocompromized patients and pregnant woman who are at increased risk [34, 58]. The diagnosis is established by clinical presentation usually with high fever and direct virus detection via PCR; typical skin lesions are only present in 50%. Liver biopsy can be helpful to clarify the diagnosis. Recommended therapy for herpes infection is intravenous treatment with acyclovir, which should be initiated immediately on suspicion.
Wilson’s Disease ALF due to Wilson’s disease typically occurs in young patients (see Chapter 81). Patients typically present with acute-onset jaundice and hemolytic anemia, with serum bilirubin levels > 20 mg/dL (mainly indirectreacting bilirubin). Hemolysis is induced by copper ions leaking from necrotic hepatocytes into the circulation and causing lysis of red blood cells [38]. Laboratory diagnostic tests for establishing the diagnosis of Wilson’s disease should include measurement of serum ceruloplasmin which is typically low, but can be normal in up to 15% of cases, and high serum and urinary copper levels. Indirect indicators of the presence of Wilson’s disease are very low serum alkaline phosphatase or uric acid levels, and a bilirubin to alkaline phosphatase ratio > 2 [62]. Slit lamp examination reveals Kayser-Fleischer rings in about 50% of cases [18]. Measurement of hepatic copper concentration is a powerful diagnostic tool as long as (transjugular) liver biopsy is feasible in the acute situation (Table 78.6). To acutely lower serum copper concentrations albumin dialysis, continuous veno-venous hemofiltration and especially plasmapheresis and plasma exchange are recommended [62]. These procedures lead to amelioration of hemolytic anemia and provide clinical stabilization until liver transplantation can be performed; recovery without transplantation is unusual. In ALF due to Wilson’s disease d-penicillamine is not indicated. Family members of patients with ALF due to Wilson’s disease need genetic counseling and screening.
Therapy Table 78.6 Diagnostic characteristics in ALF due to Wilson’s disease Clinical presentation: young patients, acute onset, jaundice Laboratory findings: • Hemolysis (LDH, haptoglobin) • Hyperbilirubinemia (indirect > direct) • Low serum ceruloplasmin • High serum and urinary copper levels (urine Cu > 600 nmol/day) • Very low serum alkaline phosphatase levels • Very low serum uric acid levels • Bilirubin (mg/dL) to alkaline phosphatase (IU/L) ratio > 2.0 • Renal impairment due to tubular copper toxicity Examination: • Slit lamp: Kayser-Fleischer ring (50% of cases) Liver biopsy: • High hepatic copper levels (> 250 mg/g dry weight) and compatible histology
Autoimmune Hepatitis If autoimmune hepatitis is assumed to be the underlying cause of ALF, liver biopsy should be performed to establish this diagnosis. Without histological findings, making a definite diagnosis might be difficult, especially if autoantibodies are absent. If feasible in the clinical setting, therapy with prednisone, starting with doses of 40–60 mg daily is indicated as a therapeutic trial; nevertheless, the anticipatory clinical course frequently necessitates listing for transplantation.
Acute Fatty Liver of Pregnancy
937
Budd-Chiari Syndrome Depending on the progression of the disease, BuddChiari syndrome may result in acute liver failure when sudden obstruction of all three main liver veins occurs (see Chapter 59). Clinically, the acute Budd-Chiari syndrome presents with ascites, abdominal pain, jaundice and hepatomegaly [20]. Budd-Chiari syndrome is frequently associated with primary myeloproliferative disorders and hypercoagulable states, such as a factor V Leiden mutation, anti-cardiolipin antibodies, or protein C and S deficiency [14]. In general, acute Budd-Chiari syndrome necessitates liver transplantation [52]. Transjugular portosystemic acute stent shunt (TIPSS) or percutaneous transjugular direct portocaval shunt, in patients with inaccessible hepatic veins, seems to be a therapeutic option to decrease portal pressure gradient, improve synthetic function, reduce elevated aminotransferase levels and control ascites [39].
Indeterminate Etiology As long as a clear-cut diagnosis cannot be established by routine evaluation, liver biopsy has to be considered as it can be helpful in diagnosing malignancy, autoimmune hepatitis, viral infection and Wilson’s disease. Furthermore, unidentified toxins or drug ingestions have to be reconsidered.
Therapy General Considerations
Acute fatty liver of pregnancy is associated with increased maternal and fetal mortality and affects a small number of women usually in the last trimester (see Chapter 99) [59]. The clinical triad of jaundice, coagulopathy and low platelet count is commonly associated with signs of pre-eclampsia such as hypertension and proteinuria. Obstetrical services should always be consulted immediately. Early recognition of the symptoms and expeditious delivery is crucial and directly affects outcome. After delivery liver function usually is completely restored. All fertile female patients with ALF should undergo pregnancy tests.
The clinical course and prognosis of ALF is determined by the underlying disease. Different etiologies necessitate differentiated therapeutic approaches. There is no proven conservative therapy for ALF in general, so management consists of supportive intensive care and, as far as available, specific treatments. Main challenges of intensive care medicine in ALF are fluid management and hemodynamic stabilisation, treatment of hepatic encephalopathy and coagulation disorders, maintenance of metabolic homeostasis, prevention and treatment of complications, adequate
938
nutrition, as well as surveillance for and therapy of infection [50]. The only therapy documented to improve patient outcome in ALF is orthotopic liver transplantation, which is associated with 1-year survival rates of greater than 80% [46]. Patients with ALF should therefore always be transferred early to and managed in an intensive care unit at a facility capable of performing liver transplantation, since transportation may be hazardous if complications develop [45].
78
Table 78.7 Grades of hepatic encephalopathy I. Prodrome
II. Impending coma
III. Stupor
IV. Coma
Encephalopathy and Cerebral Edema Hepatic encephalopathy is one of the major clinical findings in ALF and directly influences outcome. Cerebral edema, resulting increased intracranial pressure and cerebral herniation, is the main cause of death in ALF [77]. The pathophysiology of hepatic encephalopathy is multifactorial and not completely understood [13, 75]. Ammonia increasingly produced from nitrogenous substances in the gut lumen is of particular importance in the development of hepatic encephalopathy [61]. Therefore treatment has been directed towards reducing the production and absorption of ammonia via administration of lactulose, oral neomycin, and a low protein diet. Ammonia causes osmotic derangements in astrocytes, changes in cellular metabolism and alteration in cerebral blood flow [3]. These factors mainly determine clinical course and prognosis of encephalopathy and cerebral edema. Brainstem herniation as the most advanced stage of cerebral edema correlates with arterial ammonia concentration. Ammonia measurements could possibly be a tool for risk stratification for hepatic encephalopathy and intracranial hypertension, which might help to identify patients for ammonialowering therapies and invasive monitoring. The level of hepatic encephalopathy has prognostic impact (Table 78.7). Prognosis is favorable, if the patient is accessible and orientated (encephalopathy grade I and II). With higher levels of encephalopathy the prognosis is generally worse and unpredictable. The risk of multi-organ failure and the danger of cerebral edema directly correlate with the grade of encephalopathy. Independent from the etiology of ALF, 65–75% of patients with ALF and encephalopathy grade IV develop cerebral edema [53].
Acute Liver Failure
Mild confusion, slurred speech, slowness of mentation, disordered sleep rhythm, euphoria/depression Accentuation of grade 1: drowsy but speaking, inappropriate behavior, incontinence Sleeps most of the time but arousable to vocal stimuli, incoherent or no speech, marked confusion Comatose, unresponsive to pain
Younger patients and patients with rapidly developing clinical symptoms are at particular risk. Arterial ammonia at presentation is predictive for outcome in patients with acute liver failure. Patients with encephalopathy grade III and IV show significantly higher serum ammonia levels than patients with lower grade encephalopathy. It may be possible to use a serum ammonia cut-off value of ≥ 124 mmol/L to predict the presence or development of advanced cerebral dysfunction. Ammonia levels can be used for risk stratification [2].
Diagnosis of Increased Intracranial Pressure Cerebral hypertension causes diminished cerebral perfusion. Cerebral perfusion pressure (CPP) is defined as the difference between intracranial pressure (ICP) and mean arterial pressure (MAP). Hence, in the situation of rising cerebral pressure and falling MAP, the CPP rapidly decreases. Critical values of CPP are about 60 mmHg; conditions with CPP under 40 mmHg can rarely be survived. Maintaining CPP above 70 mmHg may improve neurological outcome. Indication for lowering cerebral pressure is given at intracranial pressure above 25 mmHg. As clinical signs of elevated ICP, such as hypertension, bradycardia and irregular respirations are not present in either case, ICP measuring devices are the only effective tools to detect rising ICP in early stages. Neurological manifestations of intracranial hypertension (ICH) include increased muscle tone, hyperreflexia and altered papillary responses; however, in the early course they may be absent or difficult to detect [45].
Therapy
939
The risks of insertion of intracranial devices, especially infection and bleeding, have to be balanced accurately against the anticipated benefits. In the majority of cases, intracranial pressure measuring devices are inserted in patients with hepatic encephalopathy grade III and IV and concomitant indication for liver transplantation. In higher grade encephalopathy and especially following transplantation, measuring intracranial pressure can be very useful due to possible fluctuations of intracranial pressure during operation [47]. Four different types of catheters have been used to measure ICP: epidural, subdural, parenchymal and intraventricular devices (Table 78.8). The advantage of epidural catheters is that they are less invasive and therefore they cause fewer complications, but they cannot be used to drain cerebrospinal fluid to lower ICP. Before an ICP monitor is placed, any existing coagulopathy should be corrected. The number of complications in the use of modern epidural ICD measuring devices is about 4% compared to significantly higher rates of subdural (20%) and parenchymal catheters (22%) [4]. Invasive ICP monitoring with epidural catheters is safe and reliable though it is unclear whether the use of such devices improves overall survival. Besides invasive monitoring of intracranial pressure, the cranial computed tomography (CCT) is a useful tool to diagnose cerebral edema or intracranial bleeding; however, it does not reliably demonstrate evidence of edema, especially in early stages. Repeated use of transcranial doppler ultrasound and measurement of serum S-100 protein and neuronal specific enolase have not been proven reliable and adequate tools in examination of ICP and cerebral edema [43, 72]. By relating oxygen concentration of jugular venous to arterial oxygen concentration, evaluation of cerebral oxygen consumption is possible. Also, elevated lactate levels in jugular venous blood can be a sign of inadequate cerebral oxygen supply.
Table 78.8 Monitoring intracerebral pressure: different types of catheters Epidural Subdural Parenchymal Intraventricular
Placed outside the dura mater Placed beneath the dura mater Placed directly into the brain parenchyma Placed within a cerebral ventricle
General Therapeutic Measures in Cerebral Hypertension Patients at risk for cerebral edema should be cared for in a silent environment, and direct manipulation of the patient should be minimized to avoid agitation. Although induced sedation should be used carefully, distinct agitation can be treated with short-acting benzodiazepines in small doses. The upper part of the body should be positioned at a 30–45 degree elevated angle, and the mental status should be checked frequently [16]. Unconscious or comatose patients (encephalopathy grade III and IV) should be electively intubated and mechanically ventilated to prevent aspiration and to facilitate hyperventilation to lower intracranial pressure. Propofol is often used for sedation, because it may reduce cerebral blood flow [81]. An increased cerebral blood flow due to loss of cerebrovascular autoregulation is a typical phenomenon during the various stages of hepatic encephalopathy before overt cerebral edema supervenes. By the use of gut lavage, the additional systemic impact of intestinal toxins can be reduced. Lactulose and intravenous application of L-ornithin and L-aspartate can decrease serum ammonia levels, but there is lack of clinical data proving that lowering ammonia levels leads to prevention of cerebral edema. Lactulose therapy in ALF is associated with a small increase in survival time but has no effect on severity of hepatic encephalopathy or overall outcome [29].
Drug Therapy of Intracranial Hypertension Mannitol is an important drug for osmotic therapy of cerebral edema. It is especially effective in early and middle grades of cerebral edema but loses its efficacy in higher grades. Mannitol is usually administrated at a dose of 0.5–1.0 g per kg body weight, given intravenously over a period of 30 min. The administration of mannitol can be repeated as long as serum osmolarity does not exceed 320 mosmol/L. In renal failure the usage of mannitol is limited due to the insufficient elimination by extracorporal renal replacement therapies. Maintaining serum sodium in patients with ALF at levels of 145–155 mmol/L via administration of 30%
940
hypertonic NaCl-solution can possibly control ICP [54]. Induced hypernatremia might have a potential role in the prophylaxis of intracranial hypertension or cerebral edema. Preliminary neurosurgical data validate that hypertonic saline is a safe and effective treatment for elevated ICP in patients after traumatic brain injury [78]. Further studies are needed to prove the clinical impact especially in ALF. Thiopental is a widely used agent in refractory intracranial hypertension in neurology and neurosurgery. In hepatic encephalopathy grade IV, administration of thiopental can reduce cerebral oxygen consumption. Systemic hypotension is a classic adverse reaction which can necessitate the use of systemic catecholamines [22]. Phenobarbital sedation is usually induced using a bolus of 3–5 mg/kg b.w. intravenously. Although corticosteroids are regularly used for therapy of intracranial hypertension due to cerebral tumors, they have not been proven effective in patients with intracranial hypertension in ALF and should not be used [5].
Supportive Therapy in Intracranial Hypertension Hyperventilation to CO2 levels of 25–30 mmHg can provide a short-term amelioration of intracranial pressure by cerebral vasoconstriction and subsequently decreased cerebral perfusion [42]. In patients with ALF the loss of autoregulation of cerebral blood flow can be restored after a short time of mechanical hyperventilation [71]. Hyperventilation should be initiated if intracranial hypertension or cerebral edema is proved and mannitol infusion is ineffective; continuous prophylactic hyperventilation in ALF showed no reduced incidence of cerebral edema or intracranial hypertension [17]. Attention should be paid to the fact that long-term hyperventilation carried out in grades of progressive intracranial pressure with already reduced cerebral perfusion can furthermore impair oxygen delivery [79]. Few uncontrolled studies have shown a protective effect of mild hypothermia in acute liver failure and cerebral edema [30, 31, 63]. Hypothermia (32–35°C) can be applied safely and easily. The risk of complications (arrhythmias, myocardial ischemia, infections, coagulopathy) increases with the degree and duration of hypothermia mainly with body temperatures below
78
Acute Liver Failure
32°C. Hypothermia reduces intracranial pressure and re-establishes disturbed autoregulation of cerebral blood flow. Some animal studies suggest that hypothermia can reduce the extent of liver injury in acute liver failure [23]. In contrast, hypothermia might also lead to impaired liver regeneration. Further research and controlled clinical studies are required to clarify the significance of hypothermia in acute liver failure.
Infections in Acute Liver Failure Patients in ALF show severe disturbances in immunological defense which become apparent in deranged function of neutrophils and Kupffer cells and a lack of opsonins (complement-factors and fibronectin). In ALF bacterial infiltration via the portal vein is commonly observed, with subsequent activation of neutrophils and Kupffer cells by endotoxins, resulting in the increased synthesis of cytokines like IL-6 and TNF. Infections are the second most common cause of death in ALF. Positive cultures are observed in 80% of patients with ALF and 32% have laboratory-confirmed mycosis. Mortality of systemic mycosis is about 50% in ALF. Most common are infections of the respiratory tract (approximately 50% of all cases) followed by infections of the urogenital tract and infections of inserted foreign materials (e.g. central-venous catheters, urinary catheters and intracranial pressure measurement devices). Typical clinical findings of infection – fever and leucocytosis – are infrequently found in ALF. Therefore a regular microbiological screening of all reachable visceral cavities and body fluids should be provided to obtain maximum information about the actual bacterial flora and resistance in order to not only detect bacterial and fungal infection as soon as possible, but also to provide the most appropriate and effective antimicrobial therapy. By administration of a prophylactic intravenous antibiotic regimen, the general rate of infections can be lowered to about 20%. Concurrently the progression of hepatic encephalopathy towards higher grades and coma can be significantly reduced; but there is no evidence of improved overall outcome, so prophylactic antibiotic therapy in ALF can not be recommended generally [64, 76]. Enteral administration of amphotericin B has shown to be able to minimize the rate of fungal infections to 4%.
Therapy
Prophylactic application of fluconazole is also effective in prevention of invasive mycosis. Based on these data in all patients with ALF a prophylactic treatment with antibiotic and antimycotic drugs should be discussed. Attention has to be paid to the potential hepatotoxicity of these substances. For enteral gut decontamination, neomycin and paromomycin plus amphotericin B can be used, however systemic antibiotic therapy showed no benefit in overall survival [76].
Multi-Organ-Failure in Acute Liver Failure ALF patients typically can rapidly develop multi-organfailure (MOF). A distinct dysfunction of immune defence occurs early in the clinical course of the disease. Amongst others this is caused by diminished production of opsonins by damaged hepatocytes. As a consequence bacterial infection and endotoxemia are common. This leads to activation of macrophages and release of cytokines like interleukin-6 (IL-6) and tumor-necrosis-factoralpha (TNFa). The clinical situation is similar to sepsis with peripheral vasodilation and consecutive hypotension up to shock and disturbances in microcirculation. Intravascular volume deficits on admission are often due to decreased oral intake resulting from altered mental status, fluid shift in the extracellular space and possibly blood loss. Cardiac output is increased to compensate for reduced vascular filling; initial fluid resuscitation is crucial. Due to tissue hypoxemia secondary deterioration of extrahepatic organs, as gut with bacterial translocation and admittance of toxic substances, emerges. This may result in accelerating hepatic damage. The extent of deterioration in the function of kidney, lung and central nervous system (CNS) determines the patient’s prognosis. Histological findings in ALF are confluent hepatic necrosis and loss of hepatocytes; the histological extent of hepatic necrosis does not significantly correlate with the anticipated prognosis [15].
Aspects of Cardiovascular System and Hemodynamics Similar to the situation in sepsis and septic shock, patients with ALF present with hypovolemic hyperdynamic
941
circulation and low intravascular pressure (CVP, PAP, PCWP). Patients with hepatic encephalopathy grade III-IV and high risk for intracranial pressure should obtain extensive hemodynamic monitoring. In comparison to the classic pulmonary catheter (Swan-Ganz catheter) the PiCCO-System yields a lower rate of infections and complications [9]. Using invasive hemodynamic monitoring, patients can be hydrated in an optimal manner and the hemodynamic situation can be accurately controlled and be properly influenced by the administration of catecholamines. Agents that promote vasoconstriction should generally be avoided unless significant systemic hypotension is present. Refractory shock despite optimal hydration is associated with poor prognosis. The following benchmarks concerning the hemodynamic situation should be obtained for a favorable outcome: cardiac index (CI) > 4.5 L/min/m2, peripheral systemic resistance (PSVR) > 700 dyn/s/cm5, and oxygen consumption (VO2) > 170 mL/min/m2. Fluid resuscitation is performed with colloids and crystalloids. Additionally, plasma albumin and, especially in severe coagulopathy, fresh frozen plasma can be used. Systemic vasopressors like norepinephrine, epinephrine and dopamine are catecholamines of choice in severe shock due to peripheral vasodilation following adequate volume replacement; vasopressin should be avoided.
Renal Failure Acute renal failure (ARF) complicates the clinical course in about 30–70% of patients with ALF and significantly affects overall prognosis [51]. ARF in ALF is mainly caused by dehydration, hepatorenal syndrome or acute tubular necrosis [82]. Especially in acetaminophen intoxication – depending on the dose ingested – ARF can occur due to direct toxicity [6]. Renal failure in hepatic failure is typically characterized by extreme intrarenal vasoconstriction, with very low urine sodium concentration and fractional excretion. In early stages vasoconstriction is reversible; in prolonged courses kidney damage is permanent. Renal replacement therapy should be started early before conventional indications in order to avoid complications of hyperhydration such as pulmonary edema and cerebral edema.
942
78
Acute Liver Failure
Due to the often attending cardiovascular instability of patients with ALF, continuous-veno-venous-hemodialysis/hemofiltration (CVVHF/CVVHD) is superior to intermittent renal replacement therapies in terms of hemodynamical parameters [11]. To protect kidney function, nephrotoxic drugs such as aminoglycosides, non-steroidal anti-inflammatory drugs (NSAID) and intravenous contrast agents should be avoided as far as possible. Terlipressin has been used effectively in treating hepatorenal syndrome in chronic liver disease, but clinical data indicate worsening of cerebral hyperemia and hypertension by administration of terlipressin in ALF with high-grade hepatic encephalopathy [69]. At present there is no indication for terlipressin to treat ARF in acute liver failure.
Vitamin K should be given routinely, despite existing malnutrition, in a dose of 5–10 mg per day subcutaneously or intravenously, usually over a period of 3 days. The main origin of bleeding with relevant loss of blood is the mucosa of the upper intestine. The most important identifiable risk factors for intestinal bleeding in all critically ill patients are mechanical ventilation for more than 48 h and coagulopathy [8]. Additional risk factors are hepatic and renal failure, sepsis and shock [49]. Therefore patients with ALF should receive, balancing potential hepatotoxicity, H2-receptor blockers – which are well studied – or proton-pump inhibitors (PPI) as prophylactic measure to prevent bleeding [7]. Sucralfate can be used additionally as second-line therapy.
Coagulation Disorders
Metabolic Disorders in Acute Liver Failure
Severe coagulation disorders define the clinical presentation of ALF and are the major cause for bleeding complications in ALF. The nature of coagulation disorders is complex and includes a lack of pro-coagulation factors as well as a deficit in inhibitors of coagulation and fibrinolysis. Due to consumption, platelet counts are often below 100,000 /mm3. With no evident signs of bleeding correction of coagulation disorders is generally not recommended [24]. Using a threshold platelet count of < 10,000 /mm3 in the absence of bleeding seems to be safe although some experts suggest more conservative levels of 15–20,000 /mm3. When invasive procedures are planned or in setting of severe coagulopathy, substitution of fresh frozen plasma (FFP), single factors or platelets can be useful and should be taken into consideration. Invasive procedures can be safely performed with platelet counts of 50,000–70,000 /mm3. In the setting of severe coagulopathy and hemorrhage, transfusion of platelets is recommended at levels below 50,000 /mm3 and administration of FFP is indicated if prothrombin time is prolonged (INR ≥ 1.5). Excessive substitution of FFP can lead to volume overload, resulting in pulmonary and cerebral edema. If correction of coagulopathy is necessary and cannot be achieved adequately with FFP, particularly in patients with prominent volume overload, substitution with recombinant activated factor VII (rFVIIa, 40 mg/kg b. w. i.v.) has been shown to be effective in improving prothrombin time and controlling bleeding [33, 68].
As a result of diminished gluconeogenesis and reduced release of glycogen, ALF patients often develop severe hypoglycemia. Therefore, blood glucose concentrations have to be monitored carefully and glucose should be administered early. Disturbances of acid-base balance are common. In acute liver failure both acidosis and alkalosis might be present. Metabolic alkalosis is more frequent in early stages of ALF as impaired urea synthesis of the liver results in the accumulation of the two precursor substrates bicarbonate and ammonium. Alkalosis is associated with hypokalemia that is further aggravated by high sodium reabsorption in patients with acute liver failure. As ALF progresses patients can develop metabolic acidosis due to lactic acidosis, which portends an unfavorable prognosis. Nearly 30% of the patients with acetaminophen intoxication display metabolic acidosis. Metabolic acidosis considerably worsens prognosis; dropping of arterial pH below 7.3 on day 2 or later after ingestion of acetaminophen is associated with 90% mortality.
Basic Aspects of Nutrition in Acute Liver Failure Nutrition in ALF strives for two main goals: first, catabolism should be minimized, since loss of body
Therapy
cell mass worsens spontaneous recovery and negatively influences the outcome of potential liver transplantation; secondly, liver regeneration should be supported and homeostasis of glucose should be assured. In the catabolic stage an energy input of 30 kcal/ kg body weight should be achieved. Glucose infusions are essential to prevent hypoglycemia and to reach a blood glucose concentration of 8–10 mmol/L. According to glucose control in severe sepsis blood glucose levels should not exceed 140 mg/dL. Careful monitoring and exact administration of insulin is crucial. The demand of protein and amino acids is about 1–1.2 g/kg b.w. and should be calculated independent of ammonia levels. Substitution of branched-chain amino acids has not been proven superior to other preparations in ALF [55]. Lipids are an important energy source in ALF, and the use of lipids is particularly indicated during longterm (>3 days) parenteral nutrition. Serum triglyceride concentrations and cholesterol levels should be monitored daily to avoid fatty degeneration of the remaining liver parenchyma due to disturbed hepatic lipid utilization. Minimal enteral nutrition is reasonable to avoid atrophy of intestinal mucosa and to prevent consecutive bacterial translocation from the gut into bloodstream. Besides monitoring energy demands, the surveillance and substitution of electrolytes is important. Prevention of hypophosphatemia is crucial as it is an independent risk factor in critical care medicine. Vitamins and micronutrients have to be substituted, generally in standardized forms of application.
Liver Replacement Therapies The liver captures multiple functions in the human organism. The role of the liver in homeostasis of acidbase balance, glucose metabolism or protein synthesis can be partially replaced by therapeutical interventions. A pending problem is to replace detoxification function of the liver. In the early 1970s initial approaches were undertaken to imitate and support detoxification function of the liver. At this time extended dialysis therapies were studied. The rationale for extracorporal systems in ALF is to provide an environment facilitating recovery or the opportunity for transplantation.
943
Actually besides the renal replacement therapies such as hemodialysis, hemofiltration, plasmapheresis and hemadsorption via activated charcoal, two procedures to cover partially liver function in ALF are used in studies: molecular adsorbents recirculation systems (MARS) and Prometheus-System. Both use albumin as a scavenging molecule. These liver support systems can transiently improve hepatic encephalopathy and biochemical markers but studies showing significant improvement of hepatic function or long-term benefit are pending [35]. One of the main clinical problems of both systems is the loss of platelets and worsening of coagulation parameters across the device [21]. There is lack of well-designed controlled studies with homogeneous patient populations. The practices of different specialized centers with regard to synthetic function, detoxification and homeostasis are too different; hence liver replacement therapies should only be used in prospective controlled clinical trials. Therefore, at present it is unclear if these devices will become clinically relevant to treat patients with ALF.
Liver Transplantation and Prognosis Orthotopic liver transplantation (OLT) is the only definitive therapy for patients with ALF who are unable to achieve regeneration of sufficient hepatocyte mass. Due to the fact that outcome in ALF is hard to predict, early referral to a transplant center is important to offer the best chance for a favorable outcome. Without liver transplantation patients with ALF will either have recovery of liver function or die from the underlying disease; hence patients with ALF are given highest priority on the transplant list [57]. Contraindications to listing for transplantation are center-dependent. Severe cardiopulmonary disease which cannot be ameliorated acutely and influences surgical mortality, extrahepatic malignancy and active alcohol or drug abuse are contraindications for liver transplantation at most centers. Relative contraindications such as advanced age and HIV disease are commonly considered center-specific on a case-by-case basis. During intensive care management in ALF uncontrolled extrahepatic sepsis, MOF, irreversible brain damage or intractable cerebral edema with sustained elevation of ICP > 50 mmHg are contraindications for liver transplantation [65].
944
Limited organ availability, specific risk of transplant surgery in ALF and lifelong immunosuppression necessitate an accurate evaluation of indication for OLT. Actually, there are no single prognostic indicators or even scoring systems to predict outcome in ALF precisely. Therefore the decision on listing a patient for transplantation might be difficult and should be based on regard of the clinical course and a variety of clinical and biochemical parameters. Patient age and etiology of the underlying disease have shown a correlation with patient survival. Survival rates in patients with ALF between the ages of 10 and 40 years are approximately 30–35%, whereas survival rate in patients older than 40 years or younger than 10 years is less than 10%. ALF due to drug-induced liver injury and cryptogenic causes is associated with poor prognosis, while higher survival rates are observed in patients with hepatitis B and D virus infection. Acute hepatitis A and acetaminophen toxicity usually lead to a favorable outcome. Clinical and biochemical parameters which are routinely used to predict outcome of ALF include level of hepatic encephalopathy, prothrombin time, factor V level, serum bilirubin, serum creatinine and arterial pH [56]. While in chronic liver disease severity of illness is assessed by using the MELD system, this score currently cannot be recommended in ALF. Timing of OLT in ALF is critical, as a delay in the availability of the donor organ may often result in the onset of hazardous infections or sepsis and severe neurological damage, and therefore poor outcome. Considering clinical data and individual variables, the indication for liver transplantation in ALF has to be continuously re-evaluated, particularly in patients who fail to show clinical and biochemical improvement despite appropriate intensive care management. The advance in intensive care medicine and advent of transplantation resulted in survival rates of > 60% in ALF (from 15% in the pre-transplant area). Post-transplant short-term survival rates for ALF are as high as 80–90%. The long-term survival rate for ALF 5 years after transplantation is about 60%, which is 5–10% inferior to outcomes in elective transplantation in chronic liver disease [57]. Hepatocyte transplantation might be a new approach for “bridging to transplantation” in ALF. In a study with 11 patients who underwent hepatocyte transplantation in ALF, 6 patients could be successfully bridged
78
Acute Liver Failure
to liver transplantation. One patient even showed regeneration of sufficient hepatocyte mass with no further need for transplantation [73]. Follow-up studies are needed to prove the clinical impact of this technology. In the future, patient survival might be improved by developing prognostic indicators for early identification of patients who benefit from liver transplantation. Enhancements in artificial liver support systems and hepatocyte transplantation in combination with evidence-based accurate intensive care management could help to optimize “bridging” to transplantation and improve outcomes in ALF.
References 1. Andrade RJ, Lucena MI, Fernandez MC, et al (2005) Druginduced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 129: 512–21 2. Bhatia V, Singh R, Acharya SK (2006) Predictive value of arterial ammonia for complications and outcome in acute liver failure. Gut 55: 98–104 3. Blei AT (2005) The pathophysiology of brain edema in acute liver failure. Neurochem Int 47: 71–7 4. Blei AT, Olafsson S, Webster S, et al (1993) Complications of intracranial pressure monitoring in fulminant hepatic failure. Lancet 341: 157–8 5. Canalese J, Gimson AE, Davis C, et al (1982) Controlled trial of dexamethasone and mannitol for the cerebral oedema of fulminant hepatic failure. Gut 23: 625–9 6. Cobden I, Record CO, Ward MK, et al (1982) Paracetamolinduced acute renal failure in the absence of fulminant liver damage. Br Med J (Clin Res Ed) 284: 21–2 7. Cook D, Guyatt G, Marshall J, et al (1998) A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. Canadian Critical Care Trials Group. N Engl J Med 338: 791–7 8. Cook DJ, Fuller HD, Guyatt GH, et al (1994) Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group. N Engl J Med 330: 377–81 9. Cottis R, Magee N, Higgins DJ (2003) Haemodynamic monitoring with pulse-induced contour cardiac output (PiCCO) in critical care. Intensive Crit Care Nurs 19: 301–7 10. Covic A, Goldsmith DJ, Gusbeth-Tatomir P, et al (2003) Successful use of Molecular Absorbent Regenerating System (MARS) dialysis for the treatment of fulminant hepatic failure in children accidentally poisoned by toxic mushroom ingestion. Liver Int 23(Suppl 3): 21–7 11. Davenport A, Will EJ, Davidson AM (1993) Improved cardiovascular stability during continuous modes of renal replacement therapy in critically ill patients with acute hepatic and renal failure. Crit Care Med 21: 328–38
References 12. Davern TJ, James LP, Hinson JA, et al (2006) Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. Gastroenterology 130: 687–94 13. Dbouk N, McGuire BM (2006) Hepatic encephalopathy: a review of its pathophysiology and treatment. Curr Treat Options Gastroenterol 9: 464–74 14. Deltenre P, Denninger MH, Hillaire S, et al (2001) Factor V Leiden related Budd-Chiari syndrome. Gut 48: 264–8 15. Donaldson BW, Gopinath R, Wanless IR, et al (1993) The role of transjugular liver biopsy in fulminant liver failure: relation to other prognostic indicators. Hepatology 18: 1370–6 16. Durward QJ, Amacher AL, Del Maestro RF, et al (1983) Cerebral and cardiovascular responses to changes in head elevation in patients with intracranial hypertension. J Neurosurg 59: 938–44 17. Ede RJ, Gimson AE, Bihari D, et al (1986) Controlled hyperventilation in the prevention of cerebral oedema in fulminant hepatic failure. J Hepatol 2: 43–51 18. Eisenbach C, Sieg O, Stremmel W, et al (2007) Diagnostic criteria for acute liver failure due to Wilson disease. World J Gastroenterol 13: 1711–4 19. Escudie L, Francoz C, Vinel JP, et al (2007) Amanita phalloides poisoning: reassessment of prognostic factors and indications for emergency liver transplantation. J Hepatol 46: 466–73 20. Faust TW (1999) Budd-Chiari Syndrome. Curr Treat Options Gastroenterol 2: 491–504 21. Faybik P, Bacher A, Kozek-Langenecker SA, et al (2006) Molecular adsorbent recirculating system and hemostasis in patients at high risk of bleeding: an observational study. Crit Care 10: R24 22. Forbes A, Alexander GJ, O’Grady JG, et al (1989) Thiopental infusion in the treatment of intracranial hypertension complicating fulminant hepatic failure. Hepatology 10: 306–10 23. Fu T, Blei AT, Takamura N, et al (2004) Hypothermia inhibits Fas-mediated apoptosis of primary mouse hepatocytes in culture. Cell Transplant 13: 667–76 24. Gazzard BG, Henderson JM, Williams R (1975) Early changes in coagulation following a paracetamol overdose and a controlled trial of fresh frozen plasma therapy. Gut 16: 617–20 25. Green R, Grierson R, Sitar DS, et al (2001) How long after drug ingestion is activated charcoal still effective? J Toxicol Clin Toxicol 39: 601–5 26. Hanau C, Munoz SJ, Rubin R (1995) Histopathological heterogeneity in fulminant hepatic failure. Hepatology 21: 345–51 27. Hoofnagle JH, Carithers RL, Shapiro C, et al (1995) Fulminant hepatic failure: summary of a workshop. Hepatology 21: 240–52 28. Hruby K, Csomos G, Fuhrmann M, et al (1983) Chemotherapy of Amanita phalloides poisoning with intravenous silibinin. Hum Toxicol 2: 183–95 29. Jalan R (2003) Intracranial hypertension in acute liver failure: pathophysiological basis of rational management. Semin Liver Dis 23: 271–82 30. Jalan R, Olde Damink SW, Deutz NE, et al (2001) Restoration of cerebral blood flow autoregulation and reactivity to carbon dioxide in acute liver failure by moderate hypothermia. Hepatology 34: 50–4 31. Jalan R, Olde Damink SW, Deutz NE, et al (2004) Moderate hypothermia in patients with acute liver failure and uncontrolled intracranial hypertension. Gastroenterology 127: 1338–46
945 32. Jander S, Bischoff J (2004) Treatment of Amanita phalloides poisoning: I. Retrospective evaluation of plasmapheresis in 21 patients. Ther Apher 4: 303–7 33. Kalicinski P, Kaminski A, Drewniak T, et al (1999) Quick correction of hemostasis in two patients with fulminant liver failure undergoing liver transplantation by recombinant activated factor VII. Transplant Proc 31: 378–9 34. Kang AH, Graves CR (1999) Herpes simplex hepatitis in pregnancy: a case report and review of the literature. Obstet Gynecol Surv 54: 463–8 35. Karvellas CJ, Gibney N, Kutsogiannis D, et al (2007) Benchto-bedside review: Current evidence for extracorporeal albumin dialysis systems in liver failure. Crit Care 11: 215 36. Keays R, Harrison PM, Wendon JA, et al (1991) Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. BMJ 303: 1026–9 37. Khuroo MS, Kamili S (2002) Aetiology and prognostic factors in acute liver failure in India. J Viral Hepat 10: 224–31 38. Kiss JE, Berman D, Van Thiel D (1998) Effective removal of copper by plasma exchange in fulminant Wilson’s disease. Transfusion 38: 327–31 39. Klein AS (2006) Management of Budd-Chiari syndrome. Liver Transpl 12: S23–8 40. Klein AS, Hart J, Brems JJ, et al (1989) Amanita poisoning: treatment and the role of liver transplantation. Am J Med 86: 187–93 41. Kumar M, Satapathy S, Monga R, et al (2007) A randomized controlled trial of lamivudine to treat acute hepatitis B. Hepatology 45: 97–101 42. Laffey JG, Kavanagh BP (2002) Hypocapnia. N Engl J Med 347: 43–53 43. Larsen FS, Hansen BA, Ejlersen E, et al (1996) Cerebral blood flow, oxygen metabolism and transcranial Doppler sonography during high-volume plasmapheresis in fulminant hepatic failure. Eur J Gastroenterol Hepatol 8: 261–5 44. Lee WC, Wu MJ, Cheng CH, et al (2001) Lamivudine is effective for the treatment of reactivation of hepatitis B virus and fulminant hepatic failure in renal transplant recipients. Am J Kidney Dis 38: 1074–81 45. Lee WM (1993) Acute liver failure. N Engl J Med 329: 1862–72 46. Lidofsky SD (1993) Liver transplantation for fulminant hepatic failure. Gastroenterol Clin North Am 22: 257–69 47. Lidofsky SD, Bass NM, Prager MC, et al (1992) Intracranial pressure monitoring and liver transplantation for fulminant hepatic failure. Hepatology 16: 1–7 48. Lok ASF, McMahon BJ (2004) AASLD Practice Guideline, Chronic Hepatitis B: Update of Recommendations. Hepatology 39: 1–5 49. Martin LF, Booth FV, Reines HD, et al (1992) Stress ulcers and organ failure in intubated patients in surgical intensive care units. Ann Surg 215: 332–7 50. Mas A, Rodes J (1997) Fulminant hepatic failure. Lancet 349: 1081–5 51. Mendoza A, Fernandez F, Mutimer DJ (1997) Liver transplantation for fulminant hepatic failure: importance of renal failure. Transpl Int 10: 55–60 52. Mentha G, Giostra E, Majno PE, et al (2006) Liver transplantation for Budd-Chiari syndrome: A European study on 248 patients from 51 centres. J Hepatol 44: 520–8
946 53. Munoz SJ (1993) Difficult management problems in fulminant hepatic failure. Semin Liver Dis 13: 395–413 54. Murphy N, Auzinger G, Bernel W, et al (2004) The effect of hypertonic sodium chloride on intracranial pressure in patients with acute liver failure. Hepatology 39: 464–70 55. Naylor CD, O’Rourke K, Detsky AS, et al (1989) Parenteral nutrition with branched-chain amino acids in hepatic encephalopathy. A meta-analysis. Gastroenterology 97: 1033–42 56. O’Grady JG, Alexander GJ, Hayllar KM, et al (1989) Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 97: 439–45 57. Ostapowicz G, Fontana RJ, Schiodt FV, et al (2002) Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 137: 947–54 58. Peters DJ, Greene WH, Ruggiero F, et al (2000) Herpes simplex-induced fulminant hepatitis in adults: a call for empiric therapy. Dig Dis Sci 45: 2399–404 59. Rajasri AG, Srestha R, Mitchell J (2007) Acute fatty liver of pregnancy (AFLP) – an overview. J Obstet Gynaecol 27: 237–40 60. Rengstorff DS, Osorio RW, Bonacini M (2003) Recovery from severe hepatitis caused by mushroom poisoning without liver transplantation. Clin Gastroenterol Hepatol 1: 392–6 61. Riordan SM, Williams R (1997) Treatment of hepatic encephalopathy. N Engl J Med 337: 473–9 62. Roberts EA, Schilsky ML (2003) A practice guideline on Wilson’s disease. Hepatology 37: 1475–92 63. Roberts DR, Manas D (1999) Induced hypothermia in the management of cerebral oedema secondary to fulminant liver failure. Clin Transplant 13: 545–7 64. Rolando N, Gimson A, Wade J, et al (1993) Prospective controlled trial of selective parenteral and enteral antimicrobial regimen in fulminant liver failure. Hepatology 17: 196–201 65. Sass DA, Shakil AO (2003) Fulminant hepatic failure. Gastroenterol Clin North Am 32: 1195–211 66. Schiodt FV, Davern TJ, Shakil AO, et al (2003) Viral hepatitis-related acute liver failure. Am J Gastroenterol 98: 448–53 67. Schiodt FV, Rochling FA, Casey DL, et al (1997) Acetaminophen toxicity in an urban county hospital. N Engl J Med 337: 1112–7 68. Shami VM, Caldwell SH, Hespenheide EE, et al (2003) Recombinant activated factor VII for coagulopathy in fulminant hepatic failure compared with conventional therapy. Liver Transpl 9: 138–43
78
Acute Liver Failure
69. Shawcross DL, Davies NA, Mookerjee RP, et al (2004) Worsening of cerebral hyperemia by the administration of terlipressin in acute liver failure with severe encephalopathy. Hepatology 39: 471–5 70. Stedman C (2002) Herbal hepatotoxicity. Semin Liver Dis 22: 195–206 71. Strauss G, Hansen BA, Knudsen GM, et al (1998) Hyperventilation restores cerebral blood flow autoregulation in patients with acute liver failure. J Hepatol 28: 199–203 72. Strauss GI, Christiansen M, Moller K, et al (2001) S-100b and neuron-specific enolase in patients with fulminant hepatic failure. Liver Transpl 7: 964–70 73. Strom SC, Chowdhury JR, Fox IJ (1999) Hepatocyte transplantation for the treatment of human disease. Semin Liver Dis 19: 39–48 74. Trey C, Davidson CS (1970) The management of fulminant hepatic failure. Prog Liver Dis 3: 282–98 75. Vaquero J, Chung C, Cahill ME, et al (2003) Pathogenesis of hepatic encephalopathy in acute liver failure. Semin Liver Dis 23: 259–69 76. Vaquero J, Polson J, Chung C, et al (2003) Infection and the progression of hepatic encephalopathy in acute liver failure. Gastroenterology 125: 755–64 77. Ware AJ, D’Agostino AN, Combes B (1971) Cerebral edema: a major complication of massive hepatic necrosis. Gastroenterology 61: 877–84 78. Ware ML, Nemani VM, Meeker M, et al (2005) Effects of 23.4% sodium chloride solution in reducing intracranial pressure in patients with traumatic brain injury: a preliminary study. Neurosurgery 57: 727–36 79. Wendon JA, Harrison PM, Keays R, et al (1994) Cerebral blood flow and metabolism in fulminant liver failure. Hepatology 19: 1407–13 80. Wiesner R, Edwards E, Freeman R, et al (2003) Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology 124: 91–6 81. Wijdicks EF, Nyberg SL (2002) Propofol to control intracranial pressure in fulminant hepatic failure. Transplant Proc 34: 1220–2 82. Wilkinson SP, Blendis LM, Williams R (1974) Frequency and type of renal and electrolyte disorders in fulminant hepatic failure. Br Med J 1: 186–9 83. Wright TL, Mamish D, Combs C, et al (1992) Hepatitis B virus and apparent fulminant non-A, non-B hepatitis. Lancet 339: 952–5
79
Liver Cirrhosis Henryk Dancygier
Chapter Outline Definition......................................................................... 949 Epidemiology .................................................................. 949 Etiology and Pathogenesis ............................................. 950 Cell Death ........................................................................ 950 Fibrosis and Circulatory Disturbances ............................. 951 Disturbances in Hepatocyte Growth and Proliferation .... 951
Definition Cirrhosis is the end-stage manifestation of every chronic progressive liver disease. It is a diffuse process characterized by loss of hepatic parenchyma, formation of fibrous septa and structurally abnormal nodules, resulting in the distortion of the normal architecture and of gross vascular anatomy and microcirculation [2, 3].
Pathology ........................................................................ 952 Macroscopical Findings ................................................... 952 Histological Findings ....................................................... 954
Epidemiology
Diagnosis ......................................................................... 955 Clinical Manifestations .................................................... 955 Laboratory Findings ......................................................... 959 Imaging Techniques ......................................................... 960 Differential Diagnosis .................................................... 961 Course and Prognosis .................................................... 962 Therapy ........................................................................... 963 References ....................................................................... 964
Liver cirrhosis is a leading cause of death worldwide. It is the end result of a long-lasting process, usually clinically silent and unnoticed by the patient and the physician for years. Therefore, incidence and prevalence are not exactly known. In the past, up to 30–40% of cases have been discovered at autopsy [28]. Due to the widespread use of imaging techniques, such as ultrasound and computed tomography it may be assumed that currently most cirrhotic livers are discovered earlier. Moreover, geographical differences in causes, variations in incidence and prevalence from one country to another, and even between different regions in the same country, make an accurate epidemiological estimate very difficult. Several reports suggest that coffee drinking is associated with a reduced risk of cirrhosis, supporting the hypothesis that there may be an ingredient in coffee that protects against cirrhosis, especially alcoholic cirrhosis [33, 49].
H. Dancygier, Clinical Hepatology, DOI: 10.1007/978-3-642-04519-6_79, © Springer-Verlag Berlin Heidelberg 2010
949
950
Etiology and Pathogenesis The many causes of cirrhosis are summarized in Table 79.1. Approximately 40–60% of cases of liver cirrhosis in Europe and North America are due to alcohol abuse, while 25–30% result from chronic viral hepatitis. On a global scale, chronic hepatitis B and C, with more than 400 million people infected worldwide, Table 79.1 Causes of liver cirrhosis Infectious Virus hepatitis B, C, D Schistosomiasis Autoimmune Autoimmune hepatitis Primary biliary cirrhosis Autoimmune cholangitis Overlap syndromes Metabolic-toxic Ethanol Nonalcoholic fatty liver disease (insulin resistance; metabolic syndrome) Indian childhood cirrhosis Drug-induced e.g. CCl4, arsenic, methotrexate, isoniazid, amiodarone, a-methyldopa Genetic–hereditary Hereditary hemochromatosis Wilson’s disease a1-antitrypsin-deficiency Porphyria cutanea tarda Glycogen storage diseases Galactosemia Tyrosinemia Urea cycle disturbances Abetalipoproteinemia Cystic fibrosis Biliary Secondary biliary cirrhosis (gallstones, strictures) Primary sclerosing cholangitis IgG4-associated cholangitis Ischemic cholangiopathy Ductopenia, bile duct atresia Alagille's syndrome Vascular Chronic right heart failure (“cirrhose cardiaque”) Constrictive pericarditis Budd-Chiari syndrome Sinusoidal obstruction syndrome (venoocclusive disease) Hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber disease) Cryptogenica a Approximately 70% of cryptogenic cirrhoses develop in the context of insulin resistance and the metabolic syndrome
79 Liver Cirrhosis
represent the most important problem. Hereditary hemochromatosis is not as rare as assumed in the past. The genetic defect occurs with a frequency of 1:20 in its heterozygous form and in 1:400 in the homozygous form in the general population. Despite intensive diagnostic efforts the cause of cirrhosis remains unknown in approximately 10% of cases (cryptogenic cirrhosis) [25]. Approximately 70% of hitherto cryptogenic cases are nowadays believed to result from nonalcoholic fatty liver disease within the context of insulin resistance and metabolic syndrome, while the remainder are possibly due to as yet unknown viruses, metabolic derangements or (auto)immune mechanisms. Liver disease in metabolic syndrome is responsible for the majority of cases of cryptogenic cirrhosis among Hispanics and European Americans, and is unexpectedly rare among African Americans, supporting the evidence that ethnic factors play a role in the development of cirrhosis [8]. Several etiologic factors, such as hemochromatosis and alcohol, or alcohol and hepatitis C may also act in concert and accelerate the progression to cirrhosis. The following pathophysiological mechanisms are important in the development of liver cirrhosis • Hepatocyte death with loss of hepatic parenchyma • Fibrosis • Changes in cell growth (hyperplasia, regeneration) and • Vascular and circulatory alterations
Cell Death Chronic loss of hepatocytes is regarded as the primary stimulus and perpetuating factor in the development of liver cirrhosis. In order for cirrhosis to develop, liver cell loss must be sustained and long-lasting. Short-lived parenchymal losses, for example in acute necrotizing viral hepatitis or in acetaminophen toxicity, usually heal completely. If parenchymal loss is extensive, the tissue defects heal by scar formation with broad fibrous septa and regenerative nodules, but do not result in a progressive process leading to cirrhotic transformation of the liver. Continuous liver cell loss represents a stimulus for proliferation and growth of hepatocytes and for fibrogenesis. Different pathogenetic mechanisms may underly hepatocyte injury and liver cell death (see Section III). Liver injury may be mediated by immune mechanisms (for example cytotoxic lymphocytes attacking virally
Etiology and Pathogenesis
infected hepatocytes), inflammatory reactions (mediated by neutrophils and macrophages) or toxic factors (for example via oxidative stress and calcium-mediated cytotoxicity). Ischemic parenchymal necrosis of large regenerative nodules may occur especially after massive gastrointestinal bleeding and be in turn a stimulus for further nodule growth.
Fibrosis and Circulatory Disturbances Fibrosis plays a crucial role in nodular transformation of the liver. However, it represents just one facet of liver cirrhosis and must not be equated with cirrhosis [20]. Isolated fibrosis, even if extensive, does not necessarily result in cirrhosis. Cirrhosis is more than just widespread liver fibrosis. Further pathogenetic factors, such as liver cell loss and circulatory disturbances, must supervene in order for cirrhosis to develop. The development of liver cirrhosis is accompanied by a marked increase in collagen content and by deposition of extracellular matrix, both produced mainly by stellate cells, which are activated and transformed into myofibroblasts (see Chapter 3). During this activation process the spectrum of proteins and enzymes secreted by stellate cells changes. More collagens, but also matrix metalloproteinases (MMPs) and their inhibitors (TIMPs), are expressed [35]. Progressive disease is characterized by increasing fibrosis with fibrous tissue surrounding islands of hepatic parenchyma, thus leading to the formation of pseudolobuli. These are called so, because the normal lobular architecture has been destroyed and the normal vascular relationship between portal vessels and central veins has been obliterated. Depending on the etiology and pathogenesis of cirrhosis connective tissue deposits may assume various aspects. Broad fibrous septa, chicken-wire fibrosis and perisinusoidal fibrosis may occur separately or combined. Fibrous septa may form bridges between portal tracts (portal-portal septa) and between portal tracts and central veins (portal-central septa). These remodeling processes are accompanied by hemodynamic alterations. Vascular channels within the fibrous septa lead to the establishment of intrahepatic vascular shunts between afferent (portal vein and hepatic artery) and efferent (hepatic vein) vessels of the liver, which are significant for the development of the sequelae of liver cirrhosis (see Chapter 80). The
951
deposition of an increasingly dense extracellular matrix within the space of Disse results in the formation of pseudomembranes located underneath the sinusoidal endothelium and in the capillarization of sinusoids. Thus, an additional barrier is created between the sinusoidal lumen and hepatocytes, lengthening the diffusion pathway and impeding the exchange of substances between sinusoidal blood and parenchymal cells, rendering hepatocytes in a cirrhotic liver vulnerable to nutritive and ischemic injury. Hemodynamic alterations are not only secondary to structural distortion of normal anatomy, but may be due to primary vascular and circulatory changes. Thus, an obliterative portal venopathy, for example, may occur and initiate a process leading to fibrosis and nodular transformation. Small (< 1 cm in 75% of cases) focal nodular hyperplasia (FNH)-like nodules have been described in 15% of 130 cirrhotic explant livers, believed to result from vascular alterations in the cirrhotic liver. Unlike in FNH, (considered to be a hyperplastic response to increased blood flow in normal liver) the ß-catenin pathway is not activated in cirrhotic FNH-like nodules [34, 47]. Generally fibrogenesis in liver cirrhosis is considered to represent a repair mechanism triggered by continuous loss of liver parenchyma. However, fibrogenesis may also be a primary process, initiated by stimulation of stellate cells without prior loss of liver tissue, which occurs for example in hypervitaminosis A.
Disturbances in Hepatocyte Growth and Proliferation Changes in hepatocellular growth combined with parenchymal destruction, fibrotic strangulation of liver tissue and vascular alterations contribute to the nodular transformation of the liver. How exactly cirrhotic nodules form, however, is still poorly understood. Several mechanisms probably act in concert, such as tissue growth after parenchymal destruction, partitioning of nodules by fibrotic septa, and remodeling due to vascular and circulatory alterations. The proliferation of hepatocytes in a cirrhotic liver is viewed as a reactive regenerative process after cell loss. Regeneration, however, is incomplete, since complete restoration of normal hepatic architecture does not occur and the parenchymal defects are replenished by surrogate tissue (see Chapter 13).
952
Hepatocyte growth in a cirrhotic liver manifests itself by thickened hepatocyte plates, containing more than one cell layer, by an increased number of bi- and multinucleated hepatocytes and by nuclear size variation (anisonucleosis). Lipofuscin in proliferating hepatocytes is absent and growing parenchymal nodules compress adjacent structures. The proliferative activity of hepatocytes can be highlighted by immunostaining of proliferation markers, such as Ki-67 (labelled with the antibody MIB-1) or proliferating cell nuclear antigen (PCNA). Generally, with advancing cirrhosis and increasing Child-Pugh stage the proliferation of hepatocytes decreases. However, there is no strict correlation between the proliferative activity of hepatocytes and the functional reserve of the liver or the prognosis of cirrhosis [15]. Nodular transformation in cirrhosis of biliary origin is not pronounced until the late stages of the disease. In alcoholic cirrhosis, hepatocyte proliferation is inhibited which possibly contributes to the micronodular aspect of alcoholic cirrhosis (see below).
79 Liver Cirrhosis
the clinician who informs the pathologist about the etiology of liver disease, and not vice versa. Therefore, in addition to etiologic and pathophysiological interpretation the pathologist should primarily provide a detailed descriptive anatomical-pathological diagnosis. A simple, i.e. reproducible and comprehensible, macroscopical description of cirrhosis is its classification according to the size of nodules, specifically • Micronodular • Macronodular, and • Mixed forms These three categories do not describe different diseases, but rather may represent different developmental stages of one disease process.
Macroscopical Findings Micronodular Cirrhosis
Pathology Liver cirrhosis represents the advanced stage of nodular transformation of the organ. The normal lobular structure is absent in cirrhotic nodules which is the reason why they are called pseudolobuli [2, 3]. In the past, numerous terms were used to characterize cirrhosis, such as Laennec type, nutritive, postnecrotic, post-hepatitic, post-collapse, portal, septal, regular, and irregular, to name just a few [3, 20, 53]. A precise definition of these categories, however, was lacking and etiologic, pathogenetic and morphological criteria were widely overlapping. Thus, the multitude of terms did not testify to a differentiated etiopathogenetic perspective but was rather evidence of our conceptual confusion. The macroscopic aspect of a cirrhotic liver does not allow for drawing firm conclusions regarding its etiology and pathogenesis. What appears morphologically identical may be due to various causes and pathogenetic mechanisms. Thus, etiologic, pathogenetic and morphological criteria of liver cirrhosis are separate but complementary categories. The pathologist should use terms, such as alcoholic or post-hepatitic cirrhosis, only if the morphological aspect unequivocally permits it, which, as mentioned above, often is not the case. Anyway, in today’s clinical practice it is generally
A liver cirrhosis in which nearly all nodules measure less than 3 mm in diameter is called micronodular (Figs. 79.1 and 79.2). A noticeable feature is the uniformity of the nodules. Typical causes for micronodular cirrhotic transformation are chronic alcohol abuse, bile duct obstruction, chronic venous outflow tract obstruction, hereditary hemochromatosis, Indian childhood cirrhosis, and many
Fig. 79.1 Laparoscopic appearance of micronodular alcoholic liver cirrhosis. At first glance the liver surface looks smooth. However, the light reflexes are split and the margin of the liver is finely undulated. As a rule such findings are underdiagnosed on ultrasonography as fatty liver without cirrhotic change
Pathology
953
Fig. 79.2 Biopsy specimen of the liver shown in Fig. 79.1. The pseudolobular cirrhotic transformation is easily recognizable in connective tissue staining. Domagk Staining (× 50)
hereditary metabolic diseases in pediatric hepatology. In micronodular cirrhosis the pseudolobuli usually contain portions of only one acinus (“monoacinar cirrhosis”). Portal tracts (for example in venous outflow obstruction) and efferent veins (for example in biliary obstruction) are only rarely found in micronodules. The fibrous septa contain new blood vessels that form a “fibrovascular compartment” which bypasses the sinusoids and shunts the blood through portal-venous bridges (connections between portal tracts and centrilobular veins) directly into the systemic circulation. The ratio of extracellular matrix to liver parenchyma is higher than in macronodular cirrhosis, which is why micronodular cirrhosis usually has a more firm consistency than macronodular cirrhosis. The early stages of alcoholic cirrhosis, the most frequent cirrhosis in Europe and North America, are an exception. Due to marked steatosis in the early stages alcoholic cirrhosis presents with an enlarged and relatively soft liver. Since alcohol inhibits hepatocyte proliferation, the nodules remain uniformly small at first. During the further course the nodules become irregular, and mixed forms (micro- and macronodular) are common. The micronodular transformation is best appreciated on the cut surface of the organ, while the liver surface, as seen on ultrasound and CT-scanning may appear smooth. The cut surface of the liver in alcoholic cirrhosis has a yellowish appearance (fat in hepatocytes), in hereditary hemochromatosis a reddish-brown (iron overload), and in biliary obstruction a greenishbrown (bile retention) aspect.
Macronodular Cirrhosis Macronodular cirrhosis is characterized by nodules greater than 3 mm in size (Fig. 79.3). The size of the nodules may vary considerably and nodules several centimeters in diameter are not uncommon. The pseudolobuli of macronodular cirrhosis consist of several acini, which is why it is also called “multiacinar cirrhosis”. The pseudolobuli contain portal tracts and centrilobular veins, however, their architectural relationship is deranged. Most diseases leading to cirrhosis ultimately result in macronodular cirrhosis. Overlap between micro- and macronodular forms, however, is
Fig. 79.3 Macronodular liver cirrhosis
954
frequent. Liver cirrhosis due to chronic viral hepatitis and autoimmune hepatitis is macronodular from the outset. The growth activity within the nodules is recognizable by thickened liver cell plates consisting of several cell layers and by increased variation in hepatocyte nuclear sizes. The expansive proliferation of hepatocytes may lead to compression and pressure atrophy of adjacent parenchymal cells. Regional variation in circulation probably contributes to the non-uniform growth activity in different parts of the nodules, which results in variously shaped nodules and may lead to a “nodulein-nodule” pattern. With progressive disease the broad fibrous septa cause increasingly deep grooves of the liver surface. Typical end-stage macronodular cirrhosis is small and hard (“shrunken liver”). Assuming that broad fibrous septa result from prior extensive parenchymal necrosis, this form of cirrhosis was designated previously as “postnecrotic” or “postcollaptic cirrhosis”. A special form of macrodular cirrhosis is “incomplete septal cirrhosis”. It is seen most commonly in “burnt out” inflammation due to chronic viral hepatitis B. Its pathogenesis is unclear. Parenchymal necrosis and circulatory disturbances due to obliterative portal venopathy are assumed to play a role in its development [57]. Slender, incomplete fibrous septa extend from the portal tracts into the lobular parenchyma, where they often terminate halfway. Inflammatory cellular infiltrates within the septa are sparse or are absent completely. The hypoplastic portal tracts occasionally contain sclerotic veins. In their vicinity, an increased number of central venule profiles are present, but the normal vascular relationships are lost. The expanding parenchymal nodules have a blurred outline and compress the reticulin fiber network at their edges. Diagnosing incomplete septal cirrhosis on liver biopsy may be extremely difficult, and its differentiation from noncirrhotic (idiopathic) portal hypertension may sometimes be impossible. The differential diagnosis should include liver changes associated with diffuse or focal nodularity, such as nodular regenerative hyperplasia and partial nodular transformation. In contrast to cirrhosis, intervening fibrous septa between the nodules are lacking in both conditions. The compression and condensation of sinusoidal collagen bundles at the edges of the nodules by the hyperplastic parenchyma may simulate fibrosis. Special reticulin fiber stains should always be employed in the diagnosis and differential diagnosis of these lesions.
79
Liver Cirrhosis
Mixed Forms If the number of micronodules roughly equals that of macronodules, a mixed form of cirrhosis is said to be present. During the course of the disease micronodular cirrhosis may give way to the macronodular form. Viral superinfections, autoimmune processes and circulatory disturbances account for this transformation. Transformation of macrondular to micronodular cirrhosis does not occur.
Histological Findings Liver histology is the gold standard in the diagnosis of cirrhosis (see below). Histological findings allow for the assessment of inflammatory activity and may provide clues as to the etiology of cirrhosis. Cirrhosis with a marked inflammatory cell infiltrate, usually at the interface between septal connective tissue and parenchyma (interface hepatitis) is said to be active and progressive. Accordingly, fibrous septa that are infiltrated by inflammatory cells have been designated in the older literature as active, in contrast to passive septa lacking such an infiltration. Apoptotic (acidophilic bodies) and necrotic processes may occur throughout the lobular parenchyma. Portal-portal and portal-central fibrous bridging represents previous parenchymal necrosis. It significantly contributes to the structural transformation of the liver and to the progression of cirrhosis. Special stains (in addition to the routine hematoxylin and eosin stain), such as for example Masson Trichrome, Domagk, Ladewig, elastica, reticulin fiber and PAS after digestion with diastase, are helpful in visualizing the architectural transformation of liver tissue. The iron stain should be part of the routine arsenal, while staining of copper and copper-binding protein should be reserved for special diagnostic problems, such as cholestasis and Wilson’s disease. The histological lesions in different liver diseases leading to cirrhosis are discussed in the respective chapters. Following are a few selected examples hinting at histological characteristics which facilitate etiologic interpretation of cirrhosis. In chronic viral hepatitis B infection “ground-glass hepatocytes” may occur that may be highlighted by immunostaining with antibodies against HBsAg (see Fig. 63.34a).
Diagnosis
Lymphocytic aggregates within the portal stroma, often arranged in a follicle like pattern are typical of chronic viral hepatitis C. A marked steatosis may be present in alcoholic cirrhosis. Often, however, in advanced alcoholic cirrhosis hepatocellular fat has disappeared. Damaged, ballooned and necrotic hepatocytes, Mallory-Denk bodies and neutrophilic infiltrates are signs of alcoholic hepatitis. Fibrosis in alcoholic liver disease usually starts in the perivenular areas and has a characteristic “chicken-wire” appearance. Advanced hereditary hemochromatosis is characterized by a marked deposition of iron predominantly in periportal hepatocytes, in liver macrophages and in biliary epithelial cells of interlobular bile ducts (Fig. 79.4). Inflammation is only scant. However, even an extensive iron overload is no proof of hereditary hemochromatosis. A variously intense siderosis may be found in cirrhosis of different etiologies, with the exception of biliary cirrhosis, which usually contains only little iron [37]. Wilson’s disease may produce various histologic patterns, such as steatosis, steatohepatitis, Mallory-Denk bodies, chronic inflammatory cell infiltrates with hepatocyte necrosis and apoptosis and increased deposition of copper in hepatocytes (see Fig. 81.4). Albeit characteristic, the latter, however, is not pathognomonic of Wilson’s disease, and may also be observed in biliary cirrhosis and in longstanding obstructive cholestasis of any cause. PAS-positive round intracytoplasmic inclusions resistant to diastase digestion hint towards a1-antitrypsin deficiency (see Fig. 83.2 and 83.3).
Fig. 79.4 Hereditary hemochromatosis. Massive iron overload of periportal hepatocytes, portal macrophages and biliary epithelial cells. Prussian Blue staining (× 200)
955
In biliary cirrhosis the lobular architecture remains intact for long periods of time. In end-stage secondary biliary cirrhosis, complex pseudolobuli form containing segments of several adjacent liver acini and resembling the pieces of a jigsaw puzzle. The normal vascular relationships remain essentially intact. These complex structural changes, however, usually can only be detected on the cut surface of the liver and not on liver biopsy. The inflammatory and fibrotic lesions in primary biliary cirrhosis (PBC) are not distributed uniformly throughout the liver. Thus advanced stages of PBC and florid duct lesions coexist in the same liver and may even be observed in the same biopsy. Chronic venous outflow obstruction causes perivenular fibrosis, dilatation of zone 3 sinusoids and ultimately “reverse lobulation”. Nodular regenerative hyperplasia also may be a hint to venous outflow obstruction.
Diagnosis Clinical Manifestations The clinical spectrum of liver cirrhosis ranges from asymptomatic patients with normal laboratory findings, in whom the diagnosis of cirrhosis is made incidentally, to patients with decompensated disease and hepatic failure. At the time of diagnosis the majority of patients have compensated cirrhosis and physical
956
examination discloses signs of chronic liver disease (see Section VI). A minority of patients initially present with decompensated disease manifested for example by ascites, esophageal variceal bleeding, signs of hepatic encephalopathy or the systemic manifestations of hepatocellular carcinoma. After the diagnosis of cirrhosis has been established, its cause(s) should be clarified, since even in advanced stages the etiology is crucial in choosing the appropriate therapy. History and physical examination are important in determining the etiology of cirrhosis, but they are not definitive. Clinical and laboratory data should be interpreted conjointly (Table 79.2). In addition to clarifying the etiology, the stage of disease must be determined. The most widely used clinical staging system of cirrhosis is that according to Child-Pugh, which also has prognostic significance (Table 79.3; see also Chapter 30). According to another classification, cirrhosis is classified into 4 stages. Stage 1 is characterized by the absence of esophageal varices and of ascites. Stage 2 patients have esophageal varices without bleeding and no ascites. Stage 3 is characterized by ascites with or without esophageal varices in a patient that has never bled, and stage 4 by gastrointestinal bleeding with or without ascites [14]. The clinical changes in patients with liver cirrhosis derive from the loss of functional parenchyma (liver cell failure) and the sequelae of vascular-parenchymal remodeling (portal hypertension). In the early stages of the disease the patients are asymptomatic. During the further course noncharacteristic complaints, such as fatigue and loss of energy supervene. The patients complain of sleep disturbances, they feel feeble and not well rested in the morning [13]. In this stage of the disease there is still no reversal of day-and-nightrhythm. Mood changes with easy irritability, occasional anxiety and depression may be observed. The history often reveals loss of libido which the patient only rarely mentions spontaneously by himself. Dyspeptic symptoms, bloating, loss of appetite and weight loss may initially divert the attention to the gastrointestinal tract, the more so as up to 10–15% of patients with liver cirrhosis have gastric and/or duodenal peptic ulcers. Disturbances in taste perception quite often occur in cirrhotics and probably are mediated centrally [38]. Increased abdominal girth described as tightness may be the first evidence of developing ascites.The full-blown clinical picture of cirrhosis is impressive and the diagnosis can hardly be missed at this stage (Fig. 79.5).
79 Liver Cirrhosis
Fig. 79.5 Patient with advanced liver cirrhosis, massive ascites and muscle wasting
The extent of physical findings depends on the stage of the disease and on the etiology of liver cirrhosis. Assigning the cause of cirrhosis based on physical finding, however, is not always possible, since findings are usually nonspecific with regard to etiology. One should also be aware that all physical findings typical of cirrhosis represent end-stage lesions common to all etiologies (Table 79.4). Body composition is altered in patients with cirrhosis. Malnutrition is virtually ubiquitous in all types of cirrhosis (see Chapter 91). Liver cirrhosis is characterized by a significant reduction in body cell mass and body fat, and by a redistribution of body water. A pronounced loss of fat occurs already in the initial stages, followed by an accelerated loss of body cell mass in the advanced stages of liver cirrhosis [21]. The patient
Diagnosis
957
Table 79.2 Characteristic findings in patients with liver cirrhosis of various etiologies Disease
Findings
Alcoholic liver disease
History of alcohol intake (often negated by the patient) AST: ALT > 2 Decrease of g-GT levels upon abstinence Alcoholic hepatitis: hepatomegaly, jaundice, fever, leukocytosis, AST and ALT < 500 IU/mL, AST: ALT > 2 Alcoholic cirrhosis: micronodular, surface on ultrasound often appears smooth, hepatomegaly Presence of anti-HCV Presence of HCV-RNA (viral load) Liver biopsy for grading and staging Vasculitic skin lesions (cryoglobulins) Persistence of HBsAg > 6 months after initial infection Liver biopsy for grading and staging “Ground glass” hepatocytes are liver cells with large amounts of HBsAg in their cytoplasm Male: female = 9: 1 Fatigue (early symptom), jaundice, pruritus (late symptoms) Mildly elevated aminotransferases, marked elevation of AP and g-GT levels in serum ↑ serum cholesterol ↑ IgM, poitive AMA (subtype M2 [anti PDC-E2] is confirmatory) Histologically lesions are not distributed uniformly throughout the liver Autoimmune cholangitis: AMA negative, ANA positive, liver histology compatible with PBC Strong association with inflammatory bowel disease, especially with ulcerative colitis. Approximately 70% of patients with PSC have ulcerative colitis Jaundice and pruritus are late symptoms Mildly elevated aminotransferases, marked elevation of AP and g-GT levels in serum pANCA present in 75–80% of patients, but not specific for diagnosis of PSC ERCP is the diagnostic gold standard: strictures and dilatations of intra- and/or extrahepatic bile ducts Liver biopsy not required for diagnosis (exception: small duct PSC) Complication: cholangiocellular carcinoma Female predominance Hypergammaglobulinemia Type 1 (classic): ANA, SMA, anti-SLA, anti-actin, ANCA Type 2: anti-LKM1, ALC-1 Overlap syndrome: AMA Family history HFE gene mutation (heterozygotes usually do not develop cirrhosis) Dark skin tan in late stages Transferrin saturation elevated in approximately 90% of patients (males > 60%, females > 50%) Hepatic Fe-index in liver biopsy ≥ 1.9 (hepatic Fe-concentration in mmol/g: patient age) Family history Neurologic-psychiatric symptoms in young age In each patient < 40 years with acute liver failure Wilson’s disease should be included in the differential diagnosis ↓ Ceruloplasmin in serum in 95% of patients ↑ Copper excretion in urine Liver biopsy: various histologic patterns, for example steatosis, steatohepatitis, chronic hepatitis, cirrhosis ↑ copper concentration in hepatocytes (e.g. rhodanine stain) is not specific for Wilson’s disease. Occurs in all chronic cholestatic liver diseases
Chronic hepatitis C
Chronic hepatitis B
Primary biliary cirrhosis
Primary sclerosing cholangitis
Autoimmune hepatitis
Hereditary hemochromatosis
Wilson’s disease
a1-antitrypsin deficiency
Family history Chronic obstructive lung disease a-globulin band in serum electrophoresis may be flattened or absent a1-antitrypsin concentration in serum decreased Liver biopsy: globular, PAS-positive inclusions in hepatocytes after diastase digestion
AST aspartate-aminotransferase, ALT alanine-aminotransferase, AMA antimitochondrial antibodies, ANCA antibodies against cytoplasm of neutrophils, SLA soluble liver antigen, ANA antinuclear antibodies, ALC antibodies against liver cytosol, LKM liver-kidneymicrosomes, PBC primary biliary cirrhosis, PSC primary sclerosing cholangitis
958
79 Liver Cirrhosis
Table 79.3 Child-Pugh stages of liver cirrhosis Parameter Points 1 2 3 Ascites Encephalopathy a Serum albumin (g/dL) Serum bilirubin (mmoL/L)b in PBC, PSC Prothrombin time (%) INR
0 No > 3.5 < 35
+/ + + grade I/II 2.8–3.5 35–51
+++ grade III/IV < 2.8 > 51
< 69 > 70 < 1.7
69–170 40–70 1.8–2.3
> 170 < 40 > 2.3
Table 79.4 Physical findings in patients with liver cirrhosis Finding Comment Ascites Hepatomegaly Splenomegaly Skin Changes Glazing lips and tongue Oral rhagades Spider angiomas
Scoring occurs by adding the points for the various parameters. 5–6 points: Child A (well compensated disease) 7–9 points: Child B (significant loss of hepatic function) 10–15 points: Child C (decompensated disease) a Stages of hepatic coma according to Trey et al. (1966) N Engl J Med 274: 473–81 (see Section 80.4), b 17 mmoL/L = 1 mg/dL
“Banknote” skin
with advanced and decompensated cirrhosis of viral origin has quite a typical appearance. Due to generalized muscle wasting the extremities are lean and emaciated (just “skin and bones”), the facial fat pads have receded, and the patient is hollow-cheeked and cachectic (Fig. 79.5). The lips are dark red, the tongue is smooth and bright red due to papillary atrophy, and oral rhagades (linear scars at the angles of the mouth) are present. With massive ascites, the abdomen is markedly distended. The tense and atrophic abdominal skin appears glossy due to loss of abdominal hair (abdominal baldness). The superficial abdominal venous vessels are prominent; a caput medusae, however, is a very rare finding. Spider angiomas occur preferentially on the upper part of the body and on the face. Very rarely they also may be present in the rectal mucosa (see Fig. 80.12). Due to hyperdynamic circulation the skin is warm and dry, and the pulse is strong. In this advanced stage of cirrhosis jaundice is usually present and if accompanied by pruritus the skin may show scratch effects. The hands display a palmar erythema and the skin on the back of the hand is thin, atrophic and puckered. Petechiae and ecchymoses preferentially occur on the extremities. Due to hormonal changes, signs of feminization in men, such as gynecomastia, testicular atrophy, decrease of secondary hair-growth, and amenorrhea in women may be observed. With advanced liver cell failure a sweetish, slightly fetid breath (foetor hepaticus) hints towards the presence of hepatic encephalopathy. Possibly it is caused by methymercaptanes generated in the gut. Disturbances of memory, concentration and coordination are further clues of hepatic encephalopathy. In end-stage cirrhosis the liver usually is small, firm and palpable only on deep inspiration. With non-tense
Scratch signs Xanthelasms
Palmar erythema Dupuytren’s disease Jaundice Purpura
↑ Abdominal venous cutaneous vessels Caput medusae Nail Changes White nails Clubbed fingers/hour glass nails Endocrine Changes Abdominal baldness ↓ Terminal hair in men Testicular atrophy Gynecomastia
Portal hypertension Facultative; small liver in posthepatitic cirrhosis Portal hypertension Skin atrophy; papillary atrophy Zinc deficiency Central arteriole with radiating vessels Skin atrophy due to zinc deficiency ↑ estrogen: testosterone (?) Palmar fibromatosis; occurs predominantly in alcoholics Advanced hepatocellular failure Vascular fragility; thrombocytopenia Pruritus Chronic biliary/cholestatic diseases Portal hypertension Very rare; portal hypertension Predominantly thumb and index finger In hepatopulmonary syndrome Feminization in men
Increased ratio of estrogen to free androgen due to decreased testosterone production, and increased peripheral conversion of testosterone to estradiol
Amenorrhea Miscellaneous Foetor hepaticus Kayser Fleischer Ring Muscle atrophy Parotid gland swelling
Intestinal methylmercaptanes (?) Green-brown corneal ring; Wilson’s disease Cytokines (?); malnutrition Malnutrition; predominantly in alcoholics
ascites and thin abdominal wall, its nodular surface occasionally may be palpable. The spleen is enlarged due to portal hypertension, but the degree of splenomegaly correlates poorly with the severity of portal hypertension. In contrast to the patient with cirrhosis of viral origin, the typical patient with alcoholic cirrhosis appears turgid. The face is bloated due to long-standing alcohol
Diagnosis
abuse, the gait is ataxic with a wide-based stance, lateral instability of the trunk and difficulty in maintaining balance when turning. Leg edema may assume enormous (elephantiasis-like) proportions. Dupuytren’s disease (palmar fibromatosis) and bilateral parotid swelling occur more often in alcoholics. The liver in alcoholic cirrhosis is usually enlarged. In addition, the alterations described above may also be present in alcoholics. In biliary cirrhosis signs of long-standing cholestasis dominate the clinical picture, such as scratch signs due to pruritus or xanthelasms and xanthomas.
Laboratory Findings The laboratory changes depend on the stage of the disease and the cause of cirrhosis. The most important nonspecific laboratory changes are listed in Table 79.5. The parameters specific for various etiologies, such as immune-serologic and viral findings are discussed in the chapters dealing with the respective disease. Most cirrhotic patients have a mild normo- to macrocytic anemia. Leuko- and thrombocytopenia are due to hyperspelnism, but platelet numbers < 30,000 /mL are rare and clinically relevant thrombocytopenic bleeding is rather the exception. Elevated serum levels of aminotransferases usually indicate the process still being active. Flares in aminotransferase levels hint at a necroinflammatory process, but there is no strict correlation between the concentration of aminotransferases and the necroinflammatory activity. A predominant increase in aminotransferase levels suggests a hepatocellular cause of cirrhosis, while a preponderance of cholestatic parameters, such as alkaline phosphatase combined with g-glutamyl transpeptidase favors a biliary etiology. Usually, ALT levels are higher than AST concentrations in cirrhosis of viral origin (chronic hepatitis B ± D and C), while in alcoholic cirrhosis AST is higher than ALT. In addition, g-GT levels are often elevated in the latter, and decline during abstinence from alcohol. The significance of these enzymatic patterns, however, in advanced (“burnout”) stages of cirrhosis is reduced, with aminotransferase levels usually being only mildly increased (< 100 IU/L) or even normal. Low or normal aminotransferase levels do not exclude cirrhosis, but rather support the diagnosis in a patient with an appropriate history and physical findings. Serum bilirubin concentration remains normal for a long time or is only slightly increased. The
959 Table 79.5 Laboratory serum findings in patients with liver cirrhosis Laboratory finding Comment Aminotransferases Parameters of Cholestasis Bilirubin Choline esterase
Prothrombin time
Albumin
g-globulins
Blood count
Ammonia
Branched-chain amino acidsa Aromatic amino acidsb
Viral cirrhosis: ALT > AST Alcoholic cirrhosis: AST > ALT Biliary cirrhosis: ↑ AP and gGT Serum level rises in advanced stage of cirrhosis Parameter of hepatocyte synthetic capacity. Serum level decreases in advanced stage of cirrhosis Parameter of hepatocyte synthetic capacity. Prolonged in advanced stage of cirrhosis Parameter of hepatocyte synthetic capacity. Serum level decreases in advanced stage of cirrhosis Serum levels are increased with a broad based g-band on serum electrophoresis in 80% of patients with cirrhosis. g-globulins make up for 20–35% of all proteins Autoimmune hepatitis: g-globulins increased in all patients. g-globulins > 50% of total protein Primary biliary cirrhosis: ↑ IgM Alcoholic cirrhosis: ↑ IgA Viral cirrhosis: ↑ IgG Mild normo- to macrocytic anemia. Leukopenia, thrombocytopenia (hypersplenism) Serum levels increased in advanced stage of cirrhosis. Levels do not correlate with signs and symptoms of hepatic encephalopathy Serum levels decreased in advanced stage of cirrhosis Serum levels increased in advanced stage of cirrhosis
ALT Alanine-aminotransferase, AST Aspartate-aminotransferase, gGT Gamma glutamyl-transpeptidase, AP Alkaline phosphatase a Branched-chain amino acids: valine, leucine, isoleucine, b Aromatic amino acids: phenylalanine, tyrosine, methionine
level of serum bilirubin, especially in biliary cirrhosis is considered to be of prognostic significance. Elevated levels of serum cholesterol and triglycerides, with lowered concentrations of cholesterol esters are also observed predominantly in cirrhosis of biliary origin. The functional reserve capacity of the liver is high. Therefore, reductions in the synthetic capacity of the liver, such as a reduced synthesis of albumin and of hepatic clotting factors with resulting hypoalbuminemia and prolongation of prothrombin time, respectively, and a decrease in serum level of choline esterase occur only
960
in advanced disease stages. In interpreting decreased serum levels of albumin and of choline esterase one should also take into account that these proteins are negative acute phase reactants, whose concentrations therefore also are reduced in acute infections. Ammonia concentration in serum rises in advanced liver failure, usually accompanied by changes in the normal amino acid pattern, i.e. a decrease in branchedchain amino acids (valine, leucine, isoleucine) and a rise in aromatic amino acids (phenylalanine, tyrosine, methionine). The performance of tests of specific liver function, such as indocyanine green, MEGX and caffeine clearance (see Chapter 35) is dispensable in clinical practice. 80% of patients with cirrhosis, and all patients with an autoimmune hepatitis have a hyper-g-globulinemia with a broad based g-band in serum electrophoresis, which is regarded as sign of nonspecific activation of the humoral immune system. Twenty to 35% of all proteins, in autoimmune hepatitis even more than 50% fall upon g-globulins. The distribution of immune globulin classes also to a certain degree permits to draw some conclusions as to the cause of cirrhosis. While in cirrhosis of viral origin usually IgG levels are elevated, in alcoholic cirrhosis IgA, and in primary biliary cirrhosis IgM predominates. The attentive interpretation of serum electrophoresis will not only allow for detection these frequent changes, but in isolated cases will permit one to formulate the presumptive diagnosis of a1-antitrypsin deficiency, in which the a-globulin band may be flattened or completely absent.
Imaging Techniques The diagnosis of advanced and decompensated cirrhosis can be made with sufficient accuracy by interpreting the clinical manifestations and laboratory findings. Imaging techniques play a leading role in the diagnosis of early stages of cirrhosis and in detecting focal (neoplastic) alterations in cirrhotic livers. Sonography, CT-scanning and magnetic resonance imaging are the prime imaging modalities in the diagnosis of cirrhosis, and the reader is referred to Chapters 37 and 38 for a discussion of these techniques. CT and MRI are not superior to ultrasound in the diagnosis of cirrhosis, and all three techniques, when combined with contrast enhancement, are regarded as equivalent in detecting
79
Liver Cirrhosis
and characterizing nodular hepatocellular carcinoma in a cirrhotic liver. Endoscopic ultrasonography (EUS) may visualize parts of the left liver lobe. A systematic examination of the liver is not possible with EUS. Thus, except for selected findings in the left liver lobe that happen to be within the range of the EUS-transducer (and may also be biopsied through the EUS-scope), EUS has no place in the diagnosis of liver disease. A widely underused technique in the diagnosis of cirrhosis is laparoscopy (see Chapter 45). Minilaparoscopy is a very safe procedure, takes only a few minutes to perform, allows diagnosis of cirrhosis at a glance, and permits acquisition of several liver biopsies under direct vision, which further increases safety and diagnostic accuracy. Especially in biliary cirrhosis, which often is micronodular and not uniformly distributed throughout the liver, laparoscopy with biopsy is the best staging method currently available. Nuclear imaging techniques do not play a role in the diagnosis of cirrhosis. Transient elastography is an evolving technique measuring liver elasticity (stiffness) (see also Chapter 28). It has a good diagnostic accuracy for the diagnosis of advanced fibrosis, but a high variation of results is found in earlier stages of fibrosis [24]. Moreover, one should not equate fibrosis with cirrhosis. The diagnosis of cirrhosis, in addition to fibrosis, requires the demonstration of architectural distortion and loss of normal vascular relationships. The gold standard in the diagnosis of cirrhosis is liver biopsy which nowadays should not be performed anymore as a “blind” biopsy, but rather under ultrasound, CT or preferentially under laparoscopic guidance (see Chapters 43, 44, and 45). Liver biopsy not only allows diagnosing pseudolobular remodeling but also may yield clues as to the etiology of cirrhosis (see above). However, the diagnosis of cirrhosis in a biopsy specimen is afflicted with some caveats. Quite often a biopsy cylinder from a cirrhotic liver disintegrates into several fragments, which makes interpretation of architectural remodeling difficult. Percutaneous biopsy in macrododular cirrhosis is affected by sampling variability, which may lead to a false negative diagnosis in up to 30% of cases [39, 54]. Biopsy under laparoscopic guidance reduces sampling error [44]. Therefore, in examining a biopsy specimen the observance of certain changes and criteria is helpful in establishing the diagnosis of cirrhosis [52].
Differential Diagnosis
• The diagnosis of cirrhosis in a biopsy specimen is highly probable if at least one parenchymal nodule, completely surrounded by connective tissue is present. • The diagnosis of cirrhosis is definite if several such pseudolobules are present, or if fibrous septa cross abnormally structured lobules. • The presence of broad fibrous septa without portal tracts and an abnormal architectural relationship between terminal venules and portal tracts, even in the absence of fibrous septa, is highly suggestive but no prove of cirrhosis. • If the biopsy specimen is fragmented, fibrous tissue at the edges of the fragments should be looked for, which often requires special reticulin and connective fiber stains. • A marked variation in size of hepatocytes and hepatocyte nuclei in different areas of the biopsy specimen and changes in growth pattern, mirrored by multicellular liver cell plates or by compression effects at the edges of parenchymal nodules are compatible with cirrhosis.
961 Table 79.6 Different forms of ascitesa • • • • • •
Portal ascites Malignant ascites Inflammatory, bacterial ascites Pancreatogenic ascites Chylous ascites Hypoalbuminemic ascites
a
See Chapter 54
Table 79.7 Causes of non-cirrhotic portal hypertensiona Prehepatic • Portal vein thrombosis • Splenic vein thrombosis • Arterio-venous splanchnic shunts • Marked splenomegaly Intrahepatic • Alcoholic hepatitis (central sclerosis) • Acute liver failure • Drugs/toxins (e.g. vinyl chloride, vitamin A, 6-mercaptopurine) • Budd-Chiari syndrome • Sinusoidal obstruction syndrome (veno-occlusive disease) • Peliosis hepatis • Nodular regenerative hyperplasia • Schistosomiasis • Sarcoidosis • Primary biliary cirrhosis (in precirrhotic stage) • Hepatocellular carcinoma or hepatic metastases • Hemangioendotheliomatosis • Myeloproliferative diseases • Idiopathic Posthepatic • Chronic right heart failure • Obstruction of inferior V. cava
Despite observing all these criteria, it still may be difficult to decide in the individual case whether complete cirrhosis is already present or if the patient has still precirrhotic fibrosis. Characterization of liver cirrhosis nodules by analysis of gene-expression profiles in order to disclose genetic mechanisms involved in the development or progression of hepatocellular carcinoma is still experimental [41]. a
See Chapter 53
Differential Diagnosis The full blown clinical picture of decompensated cirrhosis usually poses little differential diagnostic difficulties. In the first instance the various etiologic forms of cirrhosis, of ascites and the non-cirrhotic causes of portal hypertension must be differentiated (Tables 79.1, 79.6 and 79.7). If on ultrasonography the liver surface appears undulated with nodular lesions in the parenchyma, liver metastases, multiple hemangiomas, a nodular regenerative hyperplasia and a partial nodular transformation must all be excluded (see Section XXII). Hepatic granulomas, for example in sarcoidoisis, or a
chronic thrombosis of hepatic veins, rarely may cause a similar appearance. Indian childhood cirrhosis is a particular form of cirrhosis in children between the ages 6 months and 5 years that was originally described in, but is not confined to India. The pathogenesis is unclear, but the very high copper concentration in the liver is believed to play an important pathogenetic role in the development of cirrhosis. Histologically, steatosis, ballooning of hepatocytes, focal necrosis, Mallory-Denk bodies, inflammatory cell infiltrates (steatohepatitis) and a marked pericellular chicken-wire fibrosis are found, which lead to micronodular cirrhosis [55]. Clinically progressive hepatomegaly accompanied by a splenomegaly are
962
observed. Penicillamine is useful in the initial stages of the diseases, but in the past as a rule patients died due to liver failure. Orthotopic liver transplantation is the only therapeutic option that significantly improves outcome.
Course and Prognosis Advanced cirrhosis is the irreversible end-stage of chronic liver disease. Fibrosis in a cirrhotic liver is not a static condition but rather a dynamic process reflecting continuous formation, degradation and remodeling of extracellular matrix. This process results in qualitative and quantitative changes of the extracellular matrix which may be increased tenfold in a cirrhotic liver. Up to a certain degree, connective tissue may be degraded and fibrosis, including fibrosis in a cirrhotic liver, may regress [16–18, 22, 23]. Cirrhotic structural transformation, however, is permanent, and, despite occasional claims to the contrary, complete reversal of cirrhosis has yet to be demonstrated convincingly. Thus, the old dictum that once cirrhosis is fully established it is irreversible still holds true [16, 57]. Comorbidities affect prognosis and should be kept in mind when caring for patients with cirrhosis. Cirrhotic patients have a higher incidence of gallbladder stones and 10–15% of cases concomitantly have type 2 diabetes mellitus (insulin resistance with hyperinsulinemia) and gastro-duodenal ulcers. Sudden and unexpected deterioration of a minimal hepatic encephalopathy should prompt the search for infections, gastrointestinal bleeding, renal failure, electrolyte disturbances (diuretic therapy!) or a hepatocellular carcinoma (HCC). Patients with long-standing cirrhosis of any etiology have an increased risk of HCC. Of particular importance, because of the high prevalence of these conditions in the general populations, are type 2 diabetes mellitus and obesity. Obesity (body mass index > 30 kg/m2) and type 2 diabetes mellitus represent independent risk factors for the development of both cirrhosis and HCC [11, 19, 42]. Therefore, each patient with liver cirrhosis, particularly obese and diabetic patients, should undergo long-term routine HCC screening with ultrasound (performed by an experienced examiner with a state of the art machine) and by measuring serum a1-fetoprotein levels every 6 months [12, 31, 45]. The majority (90%) of arterially enhancing nodules < 20 mm in cirrhosis, however, are benign (see Chapter 102) [10].
79 Liver Cirrhosis
Mortality rates from cirrhosis show favourable trends in countries following the reduction in alcohol consumption and hepatitis B and C virus infection. In England and central and eastern European countries however, population based mortality rates from liver cirrhosis have sharply increased in the past 35 years. This upward trend in mortality rates is attributed to the persistent increase in the prevalence of alcohol consumption. Increased mortality from accidents, suicides, and mental disorders, particularly among those with alcoholic cirrhosis, indicates that prognosis is influenced by behavioral as well as by physical pathology [6, 48]. Thus, liver cirrhosis remains a disease with a very poor prognosis. The natural history of cirrhosis is characterized by a “compensated phase”, defined by the absence of complications, such as ascites, variceal bleeding, encephalopathy and by preserved synthetic and excretory functions (albumin ≥ 3.5 g/dL, INR ≤ 1.5, total bilirubin ≤ 1.5 mg/dL), followed by a rapidly progressive phase marked by increasing portal pressure and declining liver function, resulting in the development of ascites, portal hypertensive gastrointestinal bleeding, encephalopathy and/ or jaundice. The development of any of these complications defines the transition from a compensated to a “decompensated phase”. Transition from a compensated to a decompensated stage occurs at a rate of 5–7% per year. During a 10 year follow up of compensated viral cirrhosis, HCC develops in 21–32% of cases, followed by ascites (19.5–23%), jaundice (17%), upper gastrointestinal bleeding (4.5–6%), and encephalopathy (1–2%) [4, 51, 56]. Survival of patients with compensated cirrhosis is significantly longer than that of decompensated patients with median survival times of 12 years and 2 years, respectively (Fig. 79.6). The mortality risk increases as the stage and the number of complication episodes increases [14, 30]. The one-year outcome probabilities according to clinical stages (see above) are summarized in Fig. 79.7. While patients remain in stage 1, the mortality rate is as low as 1% per year. Patients exit this status at a cumulative rate of 11.4% per year: 7% because of the development of varices and 4.4% because of the development of ascites (with or without varices). For patients remaining in stage 2, the mortality rate is 3.4% per year. Patients leave this status by developing ascites (6.6% per year) or by developing variceal bleeding before or at the time of development of ascites (rate 4% per year). For patients remaining in stage 3, the mortality rate is
Therapy
963
1.00 Compensated cirrhosis 0.75
0.50
Additional parameters that have been reported to add in assessing the patient prognosis are indices of malnutrition, the presence of diabetes mellitus or a pathological oral glucose tolerance test, and low HDL cholesterol levels (< 30 mg/dL), all correlating with a poor prognosis. HDL cholesterol in noncholestatic cirrhotic patients may be regarded as a liver function test and an indicator of prognosis [26, 27, 43].
0.25 Decompensated cirrhosis
Therapy
0.00 0
12
24
36
48
60
72
84
96
108 120 Months
Fig. 79.6 Survival of patients with compensated and decompensated cirrhosis. (Adapted from [14]. With permission)
20% per year. Patients exit this stage by bleeding (7.6% per year). In stage 4 the 1-year mortality rate is 57%, with nearly half of these deaths occurring within 6 weeks from the initial episode of bleeding. The Child-Pugh stages also correlate quite well (largely independent from etiology) with the 1 and 2 year survival rates: Child A: 100 and 85% Child B: 80 and 60%, Child C: 45 and 35%, respectively. The APACHE III-score (Acute Physiology, Age and Chronic Health Evaluation) appears to be superior to the Child Pugh-classification in estimating the short term outcome – hospital mortality – especially if information regarding ascites and prolongation of prothrombin time is integrated into the APACHE-score [9]. However, the APACHE-score is more cumbersome to determine than the Child-Pugh stage and is not widely used in clinical practice. The MELD score correlates significantly with residual liver function. Increasing MELD score is associated with the onset of ascites and encephalopathy, it reliably predicts the mortality risk in patients with endstage liver disease and is suitable for use as a disease severity index to determine organ allocation priorities [7, 29, 32, 50]. Dilutional hyponatremia (< 126 mEq/L), refractory ascites and the development of hepatorenal syndrome are associated with a poor prognosis. Addition of serum sodium to MELD can improve its prognostic accuracy [1, 5, 36, 46].
The first step in the treatment of cirrhosis aims at eliminating the cause(s), hoping to stop or at least to delay the progression of further architectural transformation of the liver. If the alcoholic patient abstains from ethanol, if replication of hepatitis B or C virus is arrested and the virus eliminated, the necroinflammatory process usually will abate and finally come to a standstill. Due to the high functional reserve capacity of the liver, the remaining vital parenchyma will sustain and improve organ function. However, clinical experience also teaches that despite eliminating the causative stimulus, once a critical point is reached the cirrhotic process may progress. The factors responsible for this continuing cirrhotic transformation (autoimmunity, circulatory disturbances, viral superinfections, viral persistence in liver tissue?) are poorly understood. General measures, such as oral supplementation with branched-chain amino acids that can be administered for a long period improves event-free survival, serum albumin concentration, and quality of life in patients with decompensated cirrhosis with an adequate daily food intake [40]. Therapeutic interference with the fibrotic process, be it by inhibiting fibrogenesis or by stimulating the degradation of extracellular matrix, would be highly desirable, but currently is not possible. Thus, at the present time therapy of cirrhosis essentially is the management of its complications and sequelae (see Chapter 80). A significant progress in the treatment of end stage liver cirrhosis is orthotopic liver transplantation (OLT). Since the first OLT was performed in 1963, this technique has evolved from an experimental intervention to a life saving operation. Current 1 and 5 year overall survival rates after OLT are 80–90% and 70%, respectively. In contrast, with conservative treatment the 5 year survival rate of patients with decompensated
964
Fig. 79.7 Clinical course of cirrhosis: 1 year outcome probabilities according to clinical stages (According to [14]. With permission)
cirrhosis is only 20%. Timely referral to a specialized liver center is mandatory in caring for patients with liver cirrhosis.
References 1. Angeli P, Wong F, Watson H, et al (2006) Hyponatremia in cirrhosis: results of a patients population survey. Hepatology 44: 1535–42 2. Anthony PP, Ishak KG, Nayak NC, et al (1977) The morphology of cirrhosis: definition, nomenclature and classification. Bull World Health Organ 55: 521–40 3. Anthony PP, Ishak KG, Nayak NC, et al (1978) The morphology of cirrhosis. Recommendations on definition, nomenclature, and classification by a working group sponsored by the World Health Organization. J Clin Pathol 31: 395–414 4. Benvegnù L, Gios M, Boccato S, et al (2004) Natural history of compensated viral cirrhosis: a prospective study on the incidence and hierarchy of major complications. Gut 53: 744–9 5. Biggins SW, Rodriguez HJ, Bacchetti P, et al (2005) Serum sodium predicts mortality in patients listed for liver transplantation. Hepatology 41: 32–9 6. Bosetti C, Levi F, Lucchini F, et al (2007) Worldwide mortality from cirrhosis: an update to 2002. J Hepatol 46: 827–39 7. Botta F, Giannini E, Romagnoli P, et al (2003) MELD scoring system is useful for predicting prognosis in patients with liver cirrhosis and is correlated with residual liver function: a European study. Gut 52: 134–9 8. Browning JD, Kumar KS, Saboorian MH, et al (2004) Ethnic differences in the prevalence of cryptogenic cirrhosis. Am J Gastroenterol 99: 292–8 9. Butt AK, Khan AA, Alam A, et al (1998) Predicting hospital mortality in cirrhotic patients: comparison of Child–Pugh and
79
Liver Cirrhosis
acute physiology, age and chronic health evaluation (APACHE III) scoring systems. Am J Gastroenterol 93: 2469–75 10. Byrnes V, Shi H, Kiryu S, et al (2007) The clinical outcome of small (< 20 mm) arterially enhancing nodules on MRI in the cirrhotic liver. Am J Gastroenterol 102: 1654–9 11. Calle EE, Rodriguez C, Walker-Thurmond K, et al (2003) Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348: 1625–38 12. Collier J, Sherman M (1998) Screening for hepatocellular carcinoma. Hepatology 27: 273–8 13. Cordoba J, Cabrera J, Lataif L, et al (1998) High prevalence of sleep disturbance in cirrhosis. Hepatology 27: 339–45 14. D’Amico G, Garcia-Tsao G, Pagliaro L (2006) Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 44: 217–31 15. Delhaye M, Louis H, Degraef C, et al (1999) Hepatocyte proliferative activity in human liver cirrhosis. J Hepatol 30: 461–71 16. Desmet VJ, Roskams T (2004) Cirrhosis reversal: a duel between dogma and myth. J Hepatol 40: 860–7 17. Dufour JF, De Lellis R, Kaplan MM (1997) Reversibility of hepatic fibrosisin autoimmune hepatitis. Ann Int Med 127: 981–5 18. Dufour JF, De Lellis R, Kaplan MM (1998) Regression of hepatic fibrosis in hepatitis C with long-term interferon treatment. Dig Dis Sci 43: 2573–6 19. El-Serag HB, Tran T, Everhart JE (2004) Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 126: 460–8 20. Fifth Pan American Congress of Gastroenterology, Report of the Board for Classification and Nomenclature of Cirrhosis of the Liver (1956) Gastroenterology 31: 213–9 21. Figueiredo FA, De Mello Perez R, Kondo M, et al (2005) Effect of liver cirrhosis on body composition: evidence of significant depletion even in mild disease. J Gastroenterol Hepatol 20: 209–16 22. Friedman SL (2000) Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem 275: 2247–50 23. Friedman SL, Arthur MJ (2002) Reversing hepatic fibrosis. Sci Med 8: 194–205 24. Friedrich-Rust M, Ong MF, Martens S, et al (2008) Performance of transient elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology 134: 960–74 25. Greeve M, Ferrell L, Kim M, et al (1993) Cirrhosis of undefined pathogenesis: absence of evidence for unknown viruses or autoimmune processes. Hepatology 17: 593–98 26. Gunsar F, Raimondo ML, Jones S, et al (2006) Nutritional status and prognosis in cirrhotic patients. Aliment Pharmacol Ther 24: 563–72 27. Habib A, Mihas AA, Abou-Assi SG, et al (2005) Highdensity lipoprotein cholesterol as an indicator of liver function and prognosis in noncholestatic cirrhotics. Clin Gastroenterol Hepatol 3: 286–91 28. Hällen J, Nord J (1965) Liver cirrhosis unsuspected during life: a series of 79 cases. J Chron Dis 17: 951–8 29. Huo TI, Wu JC, Lin HC, et al (2005) Evaluation of the increase in model for end-stage liver disease (DeltaMELD) score over time as a prognostic predictor in patients with
References advanced cirrhosis: risk factor analysis and comparison with initial MELD and Child-Turcotte-Pugh score. J Hepatol 42: 826–32 30. Huo TI, Lin HC, Lee FY, et al (2006) Occurrence of cirrhosis-related complications is a time-dependent prognostic predictor independent of baseline model for end-stage liver disease score. Liver Int 26: 55–61 31. Ioannou GN, Splan MF, Weiss NS, et al (2007) Incidence and predictors of hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol. 5: 938–45 32. Kamath PS, Wiesner RH, Malinchoc M, et al (2001) A model to predict survival in patients with end-stage liver disease. Hepatology 33: 464–70 33. Klatsky AL, Morton C, Udaltsova N, et al (2006) Coffee, cirrhosis, and transaminase enzymes. Arch Intern Med 166: 1190–5 34. Libbrecht L, Cassiman D, Verslype C, et al (2006) Clinicopathological features of focal nodular hyperplasia-like nodules in 130 cirrhotic explant livers. Am J Gastroenterol 101: 2341–6 35. Lichtinghagen R, Breitenstein K, Arndt B, et al (1998) Comparison of matrix metalloproteinase expression in normal and cirrhotic liver. Virchows Arch 432: 153–58 36. Londoño MC, Cárdenas A, Guevara M, et al (2007) MELD score and serum sodium in the prediction of survival of patients with cirrhosis awaiting liver transplantation. Gut 56: 1283–90 37. Ludwig J, Hashimoto E, Porayko MK, et al (1997) Hemosiderosis in cirrhosis. A study of 447 native livers. Gastroenterology 112: 882–88 38. Madden AM, Bradbury W, Morgan MY (1997) Taste perception in cirrhosis: its relationship to circulating micronutrients and food preferences. Hepatology 26: 40–8 39. Maharaj B, Maharaj RJ, Leary WP, et al (1986) Sampling variability and its influence on the diagnostic yield of percutaneous needle biopsy of the liver. Lancet i: 523–25 40. Muto Y, Sato, S, Watanabe A, et al (2005) Effects of oral branched-chain amino acid granules on event-free survival in patients with liver cirrhosis. Clin Gastroenterol Hepatol 3: 705–13 41. Nagai H, Terada Y, Tajiri T, et al (2004) Characterization of liver-cirrhosis nodules by analysis of gene-expression profiles and patterns of allelic loss. J Hum Genet 49: 246–55 42. Nair S, Mason A, Eason J, et al (2002) Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis? Hepatology 36: 150–5
965 43. Nishida T, Tsuji S, Tsujii M, et al (2006) Oral glucose tolerance test predicts prognosis of patients with liver cirrhosis. Am J Gastroenterol 101: 70–5 44. Pagliaro L, Rinaldi F, Craxi A, et al (1983) Percutaneous blind biopsy versus laparoscopy with guided biopsy in diagnosis of cirrhosis. A prospective, randomized trial. Dig Dis Sci 28: 39–43 45. Pateron D, Ganne N, Trinchet JC, et al (1994) Prospective study of screening for hepatocellular carcinoma in caucasian patients with cirrhosis. J Hepatol 20: 65–71 46. Planas R, Montoliu S, Balleste B, et al (2006) Natural history of patients hospitalized for management of cirrhotic ascites. Clin Gastroenterol Hepatol 4: 1385–94 47. Rebouissou S, Couchy G, Libbrecht L, et al (2008) The b-catenin pathway is activated in focal nodular hyperplasia but not in cirrhotic FNH-like nodules. J Hepatol 49: 61–71 48. Roberts SE, Goldacre MJ, Yeates D (2005) Trends in mortality after hospital admission for liver cirrhosis in an English population from 1968 to 1999. Gut 54: 1615–21 49. Ruhl CE, Everhart JE (2005) Coffee and tea consumption are associated with a lower incidence of chronic liver disease in the United States. Gastroenterology 129: 1928–36 50. Said A, Williams J, Holden J, et al (2004) Model for end stage liver disease score predicts mortality across a broad spectrum of liver disease. J Hepatol 40: 897–903 51. Sangiovanni A, Prati GM, Fasani P, et al (2006) The natural history of compensated cirrhosis due to hepatitis C virus: A 17-year cohort study of 214 patients. Hepatology 43: 1303–10 52. Scheuer PJ (1970) Liver biopsy in the diagnosis of cirrhosis. Gut 11: 275–78 53. Sciot R, Staessen D, van Damme B, et al (1988) Incomplete septal cirrhosis: histopathological aspects. Histopathology 13: 593–603 54. Soloway RD, Baggenstoss AH, Schoenfield LJ, et al (1971) Observer error and sampling variability tested in evaluation of hepatitis and cirrhosis by liver biopsy. Dig Dis Sci 16: 1082–86 55. Tanner MS, Portmann B (1981) Indian childhood cirrhosis. Arch Dis Childh 56: 4–6 56. Veldt BJ, Chen W, Heatcote EJ, et al (2008) Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus. Hepatology 47: 1856–62 57. Wanless IR, Nakashima E, Sherman M (2000) Regression of human cirrhosis: morphologic features and the genesis of incomplete septal cirrhosis. Arch Pathol Lab Med 124: 1599–607
80
Complications of Liver Cirrhosis Henryk Dancygier
Chapter Outline 80.1 Ascites, Varices, Portal Hypertensive Gastroenteropathy ................................................ 969 Ascites.............................................................................. 969 General Measures............................................................. 970 Diuretics ........................................................................... 970 Large-Volume Paracentesis .............................................. 972 Refractory Ascites ............................................................ 973 Outlook ............................................................................ 975 Esophageal Varices ........................................................ 976 Definition ......................................................................... 976 Epidemiology ................................................................... 976 Anatomy, Etiology and Pathophysiology......................... 976 Diagnosis.......................................................................... 977 Course and Prognosis....................................................... 978 Predictors of Variceal Bleeding ....................................... 978 Prophylaxis and Therapy ................................................. 979 Gastric Varices ............................................................... 985 Portal Hypertensive Gastropathy ................................. 986 Definition ......................................................................... 986 Epidemiology ................................................................... 986 Etiology and Pathogenesis ............................................... 986 Pathology ......................................................................... 986 Clinical Manifestations and Diagnosis ............................ 986 Differential Diagnosis ...................................................... 987 Course and Prognosis....................................................... 987 Therapy ............................................................................ 988
80.2 Bacterial Infections ............................................... 994 Spontaneous Bacterial Peritonitis................................. 994 Definition ......................................................................... 994 Epidemiology ................................................................... 994 Etiology and Pathogenesis ............................................... 994 Diagnosis.......................................................................... 995 Differential Diagnosis ...................................................... 996 Course and Prognosis....................................................... 996 Prophylaxis and Therapy ................................................. 996 References ....................................................................... 998 80.3 Hepatorenal Syndrome ......................................... 999 Definition ......................................................................... 999 Epidemiology ................................................................... 999 Etiology and Pathogenesis ............................................... 999 Clinical Manifestations and Diagnosis .......................... 1001 Type 1 Hepatorenal Syndrome ................................. 1001 Type 2 Hepatorenal Syndrome ................................. 1001 Differential Diagnosis .................................................... 1002 Course and Prognosis..................................................... 1002 Therapy .......................................................................... 1003 Drug Therapy ........................................................... 1003 TIPS .......................................................................... 1003 Hemodialysis ............................................................ 1004 Liver Transplantation ............................................... 1004 References ..................................................................... 1004
Portal Hypertensive Entero-, Colo- and Biliopathy .... 988 References ....................................................................... 988
H. Dancygier, Clinical Hepatology, DOI: 10.1007/978-3-642-04519-6_80, © Springer-Verlag Berlin Heidelberg 2010
967
968
80
Complications of Liver Cirrhosis
80.4 Hepatic Encephalopathy .................................... 1005
80.6 Cardiovascular Complications........................... 1024
Definition ....................................................................... 1005 Epidemiology ................................................................. 1005 Etiology and Pathogenesis ............................................. 1005 Neurotoxins and Impaired Astrocyte Function ........ 1007 Amino Acid Imbalance and False Neurotransmitters ..................................... 1009 Pathology ....................................................................... 1010 Diagnosis........................................................................ 1010 Clinical Manifestations ............................................ 1010 Technical Investigations ........................................... 1011 Differential Diagnosis .................................................... 1012 Course and Prognosis..................................................... 1012 Therapy .......................................................................... 1012 General Measures and Elimination of Precipitating Factors ............................................ 1012 Ammonia-Lowering Strategies ................................ 1014 Orthotopic Liver Transplantation ............................. 1015
Hyperdynamic Circulation.......................................... 1024 Pathogenesis ................................................................... 1024 Clinical Manifestations .................................................. 1024 Differential Diagnosis .................................................... 1024 Therapy .......................................................................... 1025 Cirrhotic Cardiomyopathy.......................................... 1025 References ..................................................................... 1025 80.7 Endocrine Alterations........................................ 1026 Sexual Dysfunction....................................................... 1026 Thyroid Dysfunction .................................................... 1026 Alterations of Glucose Homeostasis ........................... 1027 References ..................................................................... 1027
References ..................................................................... 1015 80.5 Pulmonary Complications .................................. 1017
80.8 Hematologic Alterations and Hepatic Coagulopathy....................................................... 1028
Hepatopulmonary Syndrome ...................................... 1017
Hematologic Alterations .............................................. 1028
Definition ....................................................................... 1017 Epidemiology ................................................................. 1017 Etiology and Pathogenesis ............................................. 1017 Pathology ....................................................................... 1018 Clinical Manifestations and Diagnosis .......................... 1018 Differential Diagnosis .................................................... 1019 Course and Prognosis..................................................... 1019 Therapy .......................................................................... 1019
Red Blood Cells ............................................................. 1028 White Blood Cells .......................................................... 1028 Platelets .......................................................................... 1028 Hepatic Coagulopathy ................................................. 1029 References ..................................................................... 1029 80.9 Hepatic Osteodystrophy ..................................... 1030
Portopulmonary Hypertension ................................... 1020 Definition ....................................................................... 1020 Epidemiology ................................................................. 1020 Etiology and Pathogenesis ............................................. 1020 Pathology ....................................................................... 1021 Clinical Manifestations and Diagnosis .......................... 1021 Differential Diagnosis .................................................... 1021 Course and Prognosis..................................................... 1021 Therapy .......................................................................... 1021 Hepatic Hydrothorax ................................................... 1022 Definition ....................................................................... 1022 Epidemiology ................................................................. 1022 Pathogenesis ................................................................... 1022 Clinical Manifestations and Diagnosis .......................... 1022 Course and Prognosis..................................................... 1022 Therapy .......................................................................... 1022 References ..................................................................... 1022
Definition ....................................................................... 1030 Epidemiology ................................................................. 1030 Pathogenesis ................................................................... 1030 Clinical Manifestations and Diagnosis .......................... 1030 Therapy .......................................................................... 1030 References ..................................................................... 1031 80.10 Muscular Complications .................................. 1031 References ..................................................................... 1031
Ascites
969
Most complications of liver cirrhosis are either due to portal hypertension and/or to progressive hepatic dysfunction. Hepatocellular carcinoma also may be viewed as a complication of liver cirrhosis especially when it develops in the course of chronic viral infection, hereditary hemochromatosis, a1-antitrypsin deficiency, chronic alcoholic and nonalcoholic fatty liver disease. The malignant tumors of the liver are discussed in Chapter 102.
Cirrhosis Sinusoidal portal hypertension Vasodilating factors (NO, peptides) Splanchnic arterial vasodilation Reduction of effective arterial blood volume Redistribution of arterial blood volume Reduction of effective arterial blood volume
80.1 Ascites, Varices, Portal Hypertensive Gastroenteropathy
Activation of vasoconstrictive and Na+-retaining systems Renal Na+ retention
Gastrointestinal complications in patients with liver cirrhosis are primarily due to portal hypertension (see Chapter 53), with ascites, and gastrointestinal bleeding from esophagogastric varices and/or from portal hypertensive gastroenteropathy being of prime importance.
Ascites This chapter focuses on the therapeutic approach to cirrhotic ascites [15, 25, 31]. For etiology, pathogenesis, diagnosis, differential diagnosis, prognosis and approach to the patient with ascites see Chapter 54. Approximately 25% of patients with compensated cirrhosis develop ascites during a follow up period of 10 years. The development of ascites is a prognostically important event in the natural history of liver cirrhosis. It is associated with a mortality rate of 50% and 80% within 2–5 years respectively after the first ascites episode. A rise in serum creatinine to >1.5 mg% in a patient with cirrhotic ascites is associated with a mortality rate of up to 80% within 6–12 months [7]. A simplified scheme summarizing the pathophysiology of ascites is depicted in Fig. 80.1. Ascites is often complicated by an impairment of free water excretion by the kidneys and by renal vasoconstriction, which may lead to dilutional hyponatremia and to the development of a hepatorenal syndrome. Persistent ascites and low serum sodium (20 mmoL >130 mmoL/L 3.6–4.9 mmol/L 3.5 g/dL
Complicated acitesa Grade 3 + 80 mmol Na+/24 h, in patients whose ascites is not adequately mobilized and who do not lose weight, suggests dietary noncompliance with Na+-restriction. The presence of hepatic encephalopathy, serum sodium concentration 2.0 mg/dL (180 mmol/L) should lead to at least temporary withdrawal of diuretics [32]. Errors in the therapy of cirrhotic ascites are summarized in Table 80.4.
Large-Volume Paracentesis Large volume paracentesis (LVP) is the initial treatment of choice in patients with tense (grade 3) and refractory ascites [10, 12]. Therapeutic paracentesis is the fastest method to mobilize ascites, it shortens the hospital stay and is associated with less complications than therapy with diuretics. In the absence of hepatic encephalopathy, gastrointestinal bleeding or a bacterial infection, LVP may be performed in an outpatient setting (see “Treatment of Refractory Ascites”) [17]. The goal of paracentesis is the complete removal of ascites. This can be attempted in one session. Single total paracentesis is as effective as and generally safer than repeated partial paracenteses. With paracentesis of ≥5 L removed at once, acute reduction of effective blood volume with subsequent activation of the sympathetic nervous system and reninangiotensin-aldosterone-system may lead to circulatory dysfunction with a fall in arterial blood pressure and increased cardiac output and complications, such
Ascites
973
Table 80.4 Errors in the treatment of cirrhotic ascites Finding Wrong action Correct action Marked hyponatremia (≤125 mmol/L)
Infusion of NaCl
Impaired renal function Increase in dose of Serum creatinine diuretics > 2 mg%; creatinineclearance 2.5, but mild coagulapathy need not be corrected with blood products prior to paracentesis. Renal insufficiency might be a risk factor for iatrogenic hemoperitoneum. • Paracentesis should preferably be performed in a single session. This can be done over a period of 1–4 h or much quicker by using vacuum-sealed containers which allow for removal of, for example, 8 L ascites in 30 min. • Paracentesis 90% of patients. With diuretics the recurrence rate of ascites is 18%. Therefore, paracentesis should always be followed with maintenance diuretic therapy and dietary sodium restriction to avoid recurrence of ascites.
Practical Approach to Paracentesis
Refractory Ascites
There is no evidence that spontaneous bacterial peritonitis, renal failure, hepatic encephalopathy, or severe
An ascites refractory to therapy – either diuretic-resistant or diuretic-intractable ascites – occurs in 5–10% of patients
974
with cirrhotic ascites. Once refractory ascites develops, prognosis is extremely severe, with approximately 50% of patients dying within 6–12 months. A diuretic-resistant ascites refers to an ascites that despite maximal diuretic treatment of at least 1 week duration (spironolactone 400 mg/day and furosemide 160 mg/day) and strict dietary Na+-restriction (2 mg/dL in patients with ascites responding to treatment), hyponatremia (decrease of serum Na+concentration by >10 mEq/L to 3/months), who are intolerant of repeated LVP or in whom a LVP cannot be performed, e.g. because of extensive peritoneal
Ascites
Liver vein
975
Right atrium
TIPS Left gastric vein Splenic vein Superior mesenteric vein Portal vein
Fig. 80.3 Transjugular intrahepatic portosystemic shunt (TIPS)
adhesions. TIPS also resolves hepatic hydrothorax in 60–70% of patients (see Section 80.5). TIPS leads to an increase in cardiac output, a rise in right atrial and pulmonary arterial pressure with a secondary fall of systemic vascular resistance, increase of pulmonary vascular resistance and of effective arterial blood volume, improvement of renal function and to an increase in urinary Na+-excretion. It is less effective in patients older than 60 years and in those with a preTIPS creatinine clearance of 3 mg/dL, a Child-Pugh score >11, age over 70 years, or evidence of heart failure (ejection fraction 12 mmHg Variceal characteristics • Size • Wall tension • Intravariceal pressure • Red colour signs Liver function (Child-Pugh-Stage; MELD score) Continuing alcohol abuse
Esophageal Varices
979
Table 80.7 Prognostic significance of endoscopic and functional criteria for variceal bleeding Endoscopic criteria Bleeding risk (%) Red wale markings Absent Mild Moderate Severe
19 33 39 80
Variceal size Small Ø < 3 mm Medium Ø 3–5 mm Large Ø > 5 mm
18 29 49
Cherry-red-spots Absent Mild Moderate Severe
23 32 40 55
Liver function (Child-Pugh-Stage) Child A Child B Child C
17 31 39
Source: According to the North Italian Endoscopic Club (1988)
either by puncturing the vessel or less invasively by a balloon technique with pressure registration by a capsule. Both methods are used in experimental studies but not in clinical practice. The surface appearance of the vessel wall may yield important information regarding impending hemorrhage. Diffuse redness of the vessel, red color signs, such as “cherry red spots” and “red wale marks” (correspond to microtelangiectasia of the varix) and hemocystic spots looking like blood blisters (>4 mm; saccular aneurysm projections), are all thought to indicate a high risk for bleeding (Fig. 80.5). A “white nipple sign” on a varix represents a platelet-fibrin plug and indicates previous bleeding but is not predictive of rebleeding [87]. Every third patient with variceal hemorrhage, however, does not present these endoscopic signs. Thus, hemodynamic parameters are preferable in predicting the risk of variceal bleeding. The level of HVPG is a reliable and independent indicator for esophageal variceal bleeding. The normal value of HVPG is 5 mmHg. Portal hypertension starts at a HVPG > 5 mmHg, but values of >10–12 mmHg are clinically significant. With a HVPG < 10–12 mmHg, varices do not develop, and preexisting varices do not bleed. Once HVPG increases to >12–16 mmHg, the risk of bleeding is high, but the degree of portal pressure
elevation over 12 mmHg does not correlate directly with bleeding.
Prophylaxis and Therapy The management of patients with esophageal varices aims at three goals: • Prevention of first variceal hemorrhage (primary bleeding prophylaxis) • Treatment of acute variceal hemorrhage, and • Prevention of recurrent variceal hemorrhage (secondary bleeding prophylaxis) The outcome of the patients critically depends on the success of these measures. There is an increased array of therapeutic options including pharmacological, endoscopic, mechanically compressing (balloon tamponade), radiologic-invasive (TIPS) and surgical techniques which may be applied according to the clinical situation [24, 25, 27]. Substances that lower the portal pressure are listed in Table 80.8. Most of these substances are not (yet) introduced into clinical practice. Currently b-adrenergic blocking agents, nitrates, vasoconstrictors (e.g. terlipressin) and growth hormone inhibitors, such as somatostatin and octreotide are important. Endoscopic techniques encompass sclerotherapy and band ligation; surgical procedures include the creation of various portal-systemic shunts or the staple-gun transection of the esophagus as a salvage procedure for active variceal bleeding after failure of acute endoscopic therapy [68]. The prophylactic and therapeutic options in patients with esophageal varices are summarized in Table 80.9.
“Preprimary” Prophylaxis “Preprimary” prophylaxis refers to the prevention of the development of esophagogastric varices in patients with liver cirrhosis. The best way to achieve this goal is to successfully treat the underlying disease that leads to cirrhotic transformation. Beta-blockers are ineffective in preventing the development of varices in patients with cirrhosis [50]. For cirrhotic patients without varices, screening endoscopy every 3 years, or sooner if liver function deteriorates, is recommended.
980
80 Complications of Liver Cirrhosis
Table 80.8 Substances that lower portal pressure Substances that diminish portal venous flow • Angiotensin-receptor agonists • V1a-receptor agonists • Endothelin-receptor agonists • a1- and a2-adrenoceptor agonists • b1- and b2-adrenoceptor antagonists • Blockers of ATP-sensitive K+-channels • Activators of Ca++-channels • Inhibitors of NO-synthase Substances that lower the intrahepatic vascular resistance • b2-adrenoceptor agonists • ETA-ETB-receptor antagonists • Nitrates Substances whose mechanism of action is not completely understood • a-adrenoceptor antagonists • AT1 angiotensin-receptor antagonists • Angiotensin converting enzyme inhibitors • Antiglucagon • Ca++-antagonists • Dimethylxanthine • Diuretics • 5-Hydroxytryptamine-receptor antagonists • Somatostatin, octreotide • Natriuretic peptides • Parathyroid hormone • Antagonists of platelet-activating factors Source: According to [61] Table 80.9 Prophylactic and therapeutic options in patients with esophageal varices [17]. See text for use and clinical significance of individual substances and measures Primary prophylaxis
Acute bleeding
Secondary prophylaxis
a
Nonselective b-blockers Oral nitrates Endoscopic variceal ligation Octreotide/somatostatin Vasopressin/nitrates Terlipressin Endoscopic therapy Injection sclerotherapy Band ligation Balloon tamponade Surgical therapya Shunt Devascularization Nonselective b-blockers Oral nitrates Endoscopic variceal ligation (TIPS) Surgical therapya Shunt Devascularizationa Esophageal transectiona
Limited to patients with uncontrollable bleeding, unsuccessful TIPS or thrombosis of portal and splenic vein
Primary Bleeding Prophylaxis Because every episode of variceal hemorrhage is associated with a high mortality rate, patients with cirrhosis and varices should be treated before the first bleeding occurs. Primary prophylaxis refers to the prevention of the first variceal hemorrhage and relies on measures • Lowering portal venous pressure, and • Obliterating varices The first goal can be achieved by pharmacotherapy, the latter by endoscopic techniques. Pharmacotherapy. Nonselective b-blockers reduce portal-venous pressure by reducing cardiac output and splanchnic blood flow. In addition, splanchnic vasoconstriction is enhanced by an uninhibited activation of a-receptors [37]. Nonselective b- adrenergic antagonists are the mainstay of pharmacologic prevention of a first esophageal variceal hemorrhage [23, 74, 77]. The individual dose of b-blockers must be determined for each patient individually by adjusting the dose weekly with the goal of reducing heart rate by 25% from the baseline value without falling below a rate of 55/min or a systolic blood pressure of 90 mmHg (adjust to the maximal tolerated dose). The magnitude of heart rate reduction, however, is not a reliable indicator of portal pressure lowering, which ideally should be assessed by repeated measurements of HVPG during the course of treatment (see Chapter 46). However, invasive targeting of portal pressure is not routine in clinical practice [18, 49, 94]. Treatment with b-blockers is lifelong. Only patients in whom b-blockers lead to a durable decrease of HVPG < 12 mmHg or > 20% from baseline benefit from treatment. Falls in HVPG > 20% are associated with lower mortality [14, 25, 32]. In addition, reduction of HVPG also correlates with a reduced risk of spontaneous bacterial peritonitis or bacteremia [96 ]. The b-blocker of choice is propranolol, 80–160 mg p.o. daily in 3–4 divided doses; alternatively nadolol 20–240 mg p.o. daily can be used (Table 80.10). Nadolol is less lipophilic than propranolol and does not cross the blood–brain barrier. It is better tolerated and leads to less drug withdrawal (4%) due to side effects compared with propranolol (up to 30%). There are no data regarding pharmacologic primary bleeding prophylaxis of gastric fundal varices. Nonetheless, the use of b-blockers also seems warranted in these patients, as fundal and esophageal varices usually occur together.
Esophageal Varices
981
Table 80.10 Pharmacologic characteristics of propranolol and nadolol Substance Half Oral Comments life (h) bioavailability (%) Propranolol 3–5
~25
Nadolol
~35
10–20
Extensive hepatic metabolism (first pass effect). Metabolites are excreted in urine. Marked interindividual variation of plasma concentration after oral application Excreted largely unchanged in urine. Risk of accumulation in renal failure
Depending on Child-Pugh class, the number of patients needed to treat in order to prevent one bleeding episode is 5–14. The primary prophylactic effect of b-blockers seems to be more pronounced in patients with large varices and a high Child-Pugh class, which means that in order to achieve the same effect, fewer patients need to be treated. Primary prophylaxis with propranolol is cost-effective, even if compared with no therapy [80, 92]. Thus, despite their effectiveness in some patients, HVPG does not fall < 12 mmHg or ≥ 20% from baseline in up to two thirds of patients treated with b-blockers despite adequate b-blockade. Possibly Doppler patterns of splanchnic hemodynamics can serve as a non-invasive clue for the a priori identification of good and poor responders to b-blockers. Cirrhotic patients who responded poorly to nadolol, in contrast to good responders, showed a pronounced arterial splanchnic vasodilatation at a baseline echo-color-Doppler study [10]. Therefore, in up to two thirds of patients treated with b-blockers and in 15–25% with contraindications to b-blocker therapy or those who cannot tolerate the required doses because of untoward side effects, the question as to an alternative pharmacologic primary prophylaxis arises. Long-acting oral nitrates, isosorbide mono- or dinitrate, because of their vasolidating effect lower both the systemic, splanchnic and portal pressure. Combined with b-blockers, the drop in pressure is slightly more pronounced than with sole b-blocker therapy [47, 69]. However, the number of studies examining nitrates is relatively small compared to trials with b-blockers, and the efficacy of nitrates in primary bleeding prophylaxis
is controversial [3, 12, 36, 47]. Monotherapy with nitrates may impair renal function and worsen a preexisting ascites. There are even worries that nitrates may increase the mortality rate. Therefore, nitrates should not be used as monotherapy in the prophylaxis of esophageal variceal bleeding [29]. Carvedilol and the long-acting somatostatin analogue octreotide also reduce HVPG but both substances are not used in the long-term prevention of esophageal hemorrhage [62, 89]. Endoscopic Techniques. Endsocopic multiband ligation (EVL) of esophageal varices is safe and effective (Figs. 80.7 and 80.8). It reduces the rate of first bleeding to 30–40% and the hemorrhage related mortality to 30% within 2 years. Patients with compensated Child-Pugh class A cirrhosis benefit most from ligation [58, 64, 82]. Most authors agree that in patients with
Fig. 80.7 Variceal band ligation
Fig. 80.8 Several days after band ligation the ligated variceal nodules detach leaving behind ulcers
982
high-risk esophageal varices, EVL is more effective than propranolol for the primary prevention of variceal bleeding [56, 83, 95]. However, there are also data showing that in patients in whom propranolol lowers HVPG effectively (20%), its efficacy is comparable to ligation [59, 66, 85]. If quality of life is considered, then EVL is similarly cost-effective as b-blockade [55]. EVL is usually performed once every 2 weeks until varices are eradicated. Recent data show that EVL yields good results even if performed at bi-monthly intervals [104]. Postbanding ulcers occur regularly and usually are asymptomatic. Proton pump inhibitors may reduce their size [86]. Endoscopic obliteration of varices is followed by lifelong treatment with b-blockers. Endoscopic injection sclerotherapy is inferior to EVL and should not be performed in primary prophylaxis of esophageal varices. Summarizing the current evidence, the following may be stated: • Cirrhotic patients without varices should not receive b-blockers. • Primary prophylaxis should be performed in patients with a high risk of bleeding (high grade, large varices, “red color signs”, HVPG > 12 mmHg). • The use of b-blockers in patients with small ( 240 U/L and CEA levels > 5 ng/ mL. Ascites pH, lactate, cholesterol, fibronectin and glycosaminoglycan levels are unhelpful. Further differential diagnoses include peritoneal tuberculosis and carcinomatosis. The sensitivity of ascites smear for mycobacteria is 0%, that of ascites culture is approximately 50%. If three still warm ascites
Early diagnosis and prompt treatment have reduced early mortality from approximately 80% to 15–20%. Still today, however, the prognosis of SBP is poor with a recurrence rate of up to 60–70% within 1 year without adequate prophylaxis and a probability of survival at 1 year of 30–50% and 25–30% at 2 years [1, 40]. Pneumococcal peritonitis has a particularly severe prognosis. SBP predisposes to renal dysfunction. Despite resolution of infection patients with SBP may develop a rapidly progressive impairment in systemic hemodynamics, leading to severe renal and hepatic failure, aggravation of portal hypertension, encephalopathy, and death [32].
Prophylaxis and Therapy Primary Prophylaxis Because of the severe prognosis of SBP the question arises whether patients with liver cirrhosis and ascites benefit from primary prophylaxis. Current evidence suggests that not every patient with cirrhotic ascites requires primary prophylaxis. Prophylaxis should be reserved for patients at an increased risk of developing SBP, i.e. those with gastrointestinal bleeding and a protein concentration in ascites < 1–1.5 g/dL. In patients at risk for SBP Norfloxacin 400 mg p.o. qd–bid or Ciprofloxacin 500 mg p.o. qd–bid or Ceftriaxone 2 g i.v. qd (after gastrointestinal bleeding)
should be administered for 7–10 days. They lead to a risk reduction of 9–23% and improve acute survival [3, 13, 20, 22]. Intravenous ceftriaxone is more effective than oral norfloxacin in the prophylaxis of bacterial infections in patients with advanced cirrhosis and hemorrhage [13].
Spontaneous Bacterial Peritonitis
Indiscriminate long-term primary prophylaxis carries the risk of the emergence of resistant gram-negative bacilli. Quinolone-resistant SBP constitutes an emergent problem in patients on long-term norfloxacin prophylaxis, with trimethoprim-sulfamethoxazole not being a valid alternative [9]. Patients with cirrhosis and low protein ascitic levels (250 neutrophils/mm3 ascites, therapy with antibiotics should start without awaiting the culture result. If needed, antibiotic therapy is modified according to the result of the culture. Patients who have culture-negative, neutrocytic ascites and those who are symptomatic with monomicrobial, non-neutrocytic bacterascites are treated in the same way as patients with typical SBP. In asymptomatic patients with monomicrobial, nonneutrocytic ascites watchful waiting is appropriate since in most of these patients ascites turns sterile without treatment. Antibiotics of choice are third generation cephalosporins (they cover 95% of the flora isolated from ascitic fluid), for example Ceftriaxone 2 g i.v. qd or Cefotaxime 2 g i.v. q8h to which 75–90% of patients respond. In asymptomatic cases
997
Ofloxacin 400 mg p.o. bid or Ciprofloxacin 500 mg p.o. bid or Amoxicillin/clavulanic acid 1,000/200 mg p.o. tid may be administered [26, 37]. The routine use of an antibiotic against anaerobic organisms, e.g. metronidazole, is not warranted. It should be given only to patients with culturally proven anaerobic bacteria. Treatment is continued until complete resolution of all clinical signs of SBP and a drop of neutrophil count in ascites to 1 mg/dL should receive albumin 1.5 g/kg body weight i.v. at the time of diagnosis followed by 1 g/kg body weight i.v. after 48 h. Renal impairment is one of the strongest predictors of mortality in patients with SBP. Albumin, but not hydroxyethyl starch, reduces the activation of the renin-angiotensin-aldosterone system, improves circulatory function, reduces the risk of renal failure in patients with SBP, and improves survival in hospital and at 3 months [10, 11, 36].
998
Secondary Prophylaxis Without secondary prophylaxis SBP recurs in up to 70% of patients within 12 months. Therefore, immediately following successful treatment patients should receive continuous secondary prophylaxis with Norfloxacin 400 mg p.o. qd or Ciprofloxacin 500 mg p.o. qd [18, 35]. Alternatively, Ciprofloxacin 750 mg p.o. qw. May be tried Long-term secondary prophylaxis will result in a change of the bacterial spectrum towards Gram positive cocci and carries the risk of emergence of quinolone resistant Gram negative organisms. Given the severity of the prognosis of SBP, patients on secondary prophylaxis should always be considered as potential candidates for liver transplantation.
References 1. Andreu M, Sola R, Sitges-Serra A, et al (1993) Risk factors for spontaneous bacterial peritonitis in cirrhotic patients with ascites. Gastroenterology 104: 1133–8 2. Bahr JM, Manns MP (2001) Funktion des immunsystems bei leberzirrhose. Z Gastroenterol 39: 601–7 3. Bernard B, Grange JD, Khac NE, et al (1999) Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: a meta-analysis. Hepatology 29: 1655–61 4. Bert F, Noussair L, Lambert-Zechovsky N, et al (2005) Viridans group streptococci: an underestimated cause of spontaneous bacterial peritonitis in cirrhotic patients with ascites. Eur J Gastroenterol Hepatol 17: 929–33 5. Butani RC, Shaffer RT, Szyjkowski RD, et al (2004) Rapid diagnosis of infected ascitic fluid using leukocyte esterase dipstick testing. Am J Gastroenterol 99: 532–7 6. Castellote J, Lopez C, Gornals J, et al (2003) Rapid diagnosis of spontaneous bacterial peritonitis by use of reagent strips. Hepatology 37: 893–6 7. Christou L, Pappas G, Falagas ME (2007) Bacterial infectionrelated morbidity and mortality in cirrhosis. Am J Gastroenterol 102: 1510–7 8. Cirera I, Bauer TM, Navasa M, et al (2001) Bacterial translocation of enteric organisms in patients with cirrhosis. J Hepatol 34: 32–7
80
Complications of Liver Cirrhosis
9. Fernandez J, Navasa M, Gomez J, et al (2002) Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis. Hepatology 35: 140–8 10. Fernandez J, Navasa M, Garcia-Pagan JC, et al (2004) Effect of intravenous albumin on systemic and hepatic hemodynamics and vasoactive neurohormonal systems in patients with cirrhosis and spontaneous bacterial peritonitis. J Hepatol 41: 384–90 11. Fernandez J, Monteagudo J, Bargallo X, et al (2005) A randomized unblinded pilot study comparing albumin versus hydroxyethyl starch in spontaneous bacterial peritonitis. Hepatology 42: 627–34 12. Fernández J, Escorsell A, Zabalza M, et al (2006) Adrenal insufficiency in patients with cirrhosis and septic shock: effect of treatment with hydrocortisone on survival. Hepatology 44: 1288–95 13. Fernandez J, Ruiz del Arbol LR, Gomez C, et al (2006) Norfloxacin vs ceftriaxonee in the prophylaxis of infections in patients with advanced cirrhosis and hemorrhage. Gastroenterology 131: 1049–56 14. Fernández J, Navasa M, Planas R, et al (2007) Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology 133: 818–24 15. Frances R, Benlloch S, Zapater P, et al (2004) A sequential study of serum bacterial DNA in patients with advanced cirrhosis and ascites. Hepatology 39: 484–91 16. Garfia C, Garcia-Ruiz I, Solis-Herruzo JA (2004) Deficient phospholipase C activity in blood polimorphonuclear neutrophils from patients with liver cirrhosis. J Hepatol 40: 749–56 17. Gaya DR, David B Lyon T, Clarke J, et al (2007) Bedside leucocyte esterase reagent strips with spectrophotometric analysis to rapidly exclude spontaneous bacterial peritonitis: a pilot study. Eur J Gastroenterol Hepatol 19: 289–95 18. Ginès P, Rimola A, Planas R, et al (1990) Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double blind, placebo-controlled trial. Hepatology 12: 716–24 19. Gonzalez-Suarez B, Guarner C, Villanueva C, et al (2005) Pharmacologic treatment of portal hypertension in the prevention of community-acquired spontaneous bacterial peritonitis. Eur J Gastroenterol Hepatol 18: 49–55 20. Grange JD, Roulot D, Pelletier G, et al (1998) Norfloxacin prophylaxis of bacterial infections in cirrhotic patients with ascites: a double blind randomized trial. J Hepatol 29: 430–6 21. Guarner C, Soriano G (1997) Spontaneous bacterial peritonitis. Semin Liver Dis 17: 203–17 22. Guarner C, Solà R, Soriano G, et al (1999) Risk of a first community-acquired spontaneous bacterial peritonitis in cirrhotics with low ascitic fluid protein levels. Gastroenterology 117: 414–9 23. Haq SM, Dayal HH (2005) Chronic liver disease and consumption of raw oysters: a potentially lethal combination – a review of Vibrio vulnificus septicemia. Am J Gastroenterol 100: 1195–9 24. Kim DY, Kim JH, Chon CY, et al (2005) Usefulness of urine strip test in the rapid diagnosis of spontaneous bacterial peritonitis. Liver Int 25: 1197–201
Etiology and Pathogenesis 25. Lin CY, Tsai IF, Ho YP, et al (2007) Endotoxemia contributes to the immune paralysis in patients with cirrhosis. J Hepatol 46: 816–26 26. Navasa M, Follo A, Llovet JM, et al (1996) Randomized, comparative study of oral ofloxacin versus intravenous cefotaxim in spontaneous bacterial peritonitis. Gastroenterology 111: 1011–7 27. Navasa M, Rimola A, Rodés J (1997) Bacterial infections in liver disease. Semin Liver Dis 17: 323–33 28. Nousbaum JB, Cadranel JF, Nahon P, et al (2007) Diagnostic accuracy of the Multistix 8 SG reagent strip in diagnosis of spontaneous bacterial peritonitis. Hepatology 45: 1275–81 29. Ramachandran A, Balasubramanian KA (2001) Intestinal dysfunction in liver cirrhosis: its role in spontaneous bacterial peritonitis. J Gastroenterol Hepatol 16: 607–12 30. Rimola A, García-Tsao G, Navasa M, et al (2000) Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. J Hepatol 32: 142–53 31. Rolachon A, Cordier L, Bacq Y, et al (1995) Ciprofloxacin and long-term prevention of spontaneous bacterial peritonitis: results of a prospective controlled trial. Hepatology 22: 1171–4 32. Ruiz-del-Arbol L, Urman J, Fernandez J, et al (2003) Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology 38: 1210–8 33. Runyon BA (1993) Bacterial infections in patients with cirrhosis. J Hepatol 18: 272–2 34. Sapey T, Mena E, Fort E, et al (2005) Rapid diagnosis of spontaneous bacterial peritonitis with leukocyte esterase reagent strips in a European and in an American center. J Gastroenterol Hepatol 20: 187–92 35. Singh N, Gayowski T, Yu VL, et al (1995) TrimethoprimSulfamethoxazole for the prevention of spontaneous bacterial peritonitis in cirrhosis: a randomized trial. Ann Intern Med 122: 595–8 36. Sort P, Navasa M, Arroyo V, et al (1999) Effect of intravenous albumin or renal impairment on mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 341: 403–9 37. Such J, Runyon BA (1998) Spontaneous bacterial peritonitis. Clin Infect Dis 27: 669–76 38. Tandon P, Garcia-Tsao G (2008) Bacterial infections, sepsis, and multiorgan failure in cirrhosis. Semin Liver Dis 28: 26–42 39. Terg R, Fassio E, Guevara M, et al (2008) Ciprofloxacin in primary prophylaxis of spontaneous bacterial peritonitis: A randomized, placebo-controlled study. J Hepatol 48: 774–9 40. Thuluvath PJ, Morss S, Thompson R (2001) Spontaneous bacterial peritonitis–In-hospital mortality, predictors of survival, and health care costs from 1988 to 1998. Am J Gastroenterol 96: 1232–6 41. Tsai MH, Peng YS, Chen YC, et al (2006) Adrenal insufficiency in patients with cirrhosis, severe sepsis and septic shock. Hepatology 43: 673–81 42. Wong F, Bernardi M, Balk R, et al (2005) Sepsis in cirrhosis: report on the 7th meeting of the international ascites club. Gut 54: 718–25
999
80.3 Hepatorenal Syndrome Definition Hepatorenal syndrome (HRS) is a potentially reversible functional renal insufficiency in patients with cirrhosis, advanced liver failure and portal hypertension in the absence of shock or an intrinsic parenchymal renal disease. It is characterized by changes in endogenous vasoactive systems with marked renal vasoconstriction while at the same time extrarenal arteriolar vasodilatation, decreased systemic resistance and arterial hypotension predominate [4, 6, 9].
Epidemiology Eighteen percent of patients with decompensated cirrhosis develop HRS within 1 year of decompensation and 40% within 5 years. The incidence of HRS in patients with liver cirrhosis who are admitted to the hospital because of ascites formation is 7–15% [7, 12].
Etiology and Pathogenesis HRS most often occurs in patients with advanced cirrhosis, but may also complicate acute liver failure. Older persons, especially alcoholics are more often affected. It may develop without precipitating factors or be elicited for example by alcoholic hepatitis, spontaneous bacterial peritonitis (SBP), large volume paracentesis without adequate volume replacement, nonsteroidal antiinflammatory drugs (NSAIDS), nephrotoxic medication (e.g. antibiotics) or major surgical procedures. SBP is the most common bacterial infection precipitating HRS. Approximately 30% of patients with SBP develop impairment of renal function – not necessarily a full blown HRS – that cannot be attributed to the administration of nephrotoxic antibiotics or to the presence of circulatory shock. Gastrointestinal bleeding, intensive treatment with diuretics, and diarrheal disease may elicit HRS, but more often cause prerenal insufficiency that occasionally may lead to acute tubular necrosis.
1000
80
Predictive factors for the development of HRS in nonazotemic patients with liver cirrhosis and ascites are • • • • • • • • • • • • • • • •
Previous episodes of ascites Absence of hepatomegaly Poor nutritional status Moderately reduced glomerular filtration rate (> 50 mL/min) Moderately increased BUN (50% from normal) of renal blood flow and glomerular filtration rate with retention of Na+ and reduced perfusion of the outer renal cortex. Intrarenal and systemic circulatory disturbances are closely interrelated in HRS. As in the development of ascites, arterial splanchnic vasodilatation is the primary event with reduced renal perfusion as its extreme sequel. Thus, the pathogenesis of hepatorenal
Complications of Liver Cirrhosis
syndrome according to the “underfilling hypothesis” may be summarized as follows: LIVER CIRRHOSIS ß Portal (sinusoidal) hypertension ß Increased synthesis of NO in splanchnic vessels ß Splanchnic vasodilatation ß Reduction of effective arterial blood volume (“Underfilling”) ß Reflexive (baroceptors) stimulation of vasoconstrictory systems ß Renal vasoconstrictiona ß Reduction of renal perfusion and glomerular filtration ß HEPATORENAL SYNDROME Arterial underfilling with reduction of effective blood volume activates vasoconstrictory systems such as the renin–angiotensin–aldosterone and the sympathetic nervous system that cause arterial vasoconstriction in the kidneys and in other vascular territories (brain, muscles, skin). Very high plasma levels of arginine–vasopressin and endothelin are also found. Primary splanchnic vasodilatation is thought to result from local overproduction of vasodilator substances, predominantly nitric oxide (NO), due to sinusoidal hypertension [5, 9]. In the early stages of HRS local vasodilating renal factors counteract reduced perfusion. Ultimately, however, with continuing arterial underfilling reactive vasoconstrictory systems prevail and lead to diminished renal perfusion. Among the local vasodilating factors in the kidneys are prostaglandins such as PGE2 and prostacyclin and NO. Other vasodilators that counteract the development of HRS belong to the family of natriuretic peptides (atrial and brain natriuretic peptide, urodilatin). NSAIDS reduce renal perfusion and decrease glomerular filtration by inhibiting the
a
Possibly enhanced by diminished synthesis of local vasodilators
Clinical Manifestations and Diagnosis
synthesis of prostaglandins. They may precipitate HRS in patients with advanced liver cirrhosis. The functional nature of HRS is evidenced (1) by normal renal histology, (2) by the fact that transplanted kidneys from patients with HRS function normally in the recipient, and (3) that HRS is reversible after liver transplantation.
Clinical Manifestations and Diagnosis The clinical picture of patients with HRS mirrors renal insufficiency, cardiocirculatory dysfunction and liver failure. It is characterized by a marked retention of water and Na+ with ascites, edema and dilutional hyponatremia. Circulation is hyperdynamic with high cardiac output and reduced total vascular resistance. Clinically two types of HRS are distinguished.
Type 1 Hepatorenal Syndrome Type 1 HRS is rapidly progressive and is characterized by doubling of the initial serum creatinine to >2.5 mg/ dL or by halving of the creatinine clearance to 1.5 mg/dL) progresses more slowly, the decline of glomerular filtration rate is less dramatic, and renal function is more stable. Each HRS that does not meet
1001
the criteria of type 1 HRS is classified as type 2 HRS. Clinically these patients usually are characterized by a diuretic resistant ascites, which is due to a marked stimulation of antinatriuretic systems with pronounced Na+retention, and a diminished glomerular filtration rate. Because of the lack of specific tests, the diagnosis of HRS is based on the demonstration of a reduced glomerular filtration rate in a patient with liver cirrhosis and ascites and on the exclusion of other disorders that can cause renal failure in cirrhosis. Tables 80.13 and 80.14 summarize the International Ascites Club’s diagnostic criteria and the new revised criteria of HRS [4, 23]. The intrarenal hemodynamics in patients with liver cirrhosis and ascites may be assessed with Doppler-Duplex-sonography. This technique may prove useful for the diagnosis of developing HRS. Postrenal causes of renal failure can also be excluded easily with ultrasound. The diagnosis of HRS in patients with spontaneous bacterial peritonitis should only be made after successful treatment of the infection, since improvement of initially reduced renal function after successful therapy of SBP is often observed.
Table 80.13 International Ascites Club’s diagnostic criteria of hepatorenal syndrome [4] Major criteria • Chronic or acute liver disease with advanced hepatic failure and portal hypertension • Low glomerular filtration rate, as indicated by serum creatinine of >1.5 mg/dL or 24-h creatinine clearance < 40 mL/min • Absence of shock, ongoing bacterial infection, and current or recent treatment with nephrotoxic drugs; absence of gastrointestinal fluid losses (repeated vomiting or intense diarrhea) or renal fluid losses (weight loss > 500 g/day for several days in patients with ascites without peripheral edema or 1,000 g/day in patients with peripheral edema) • No sustained improvement in renal function (decrease in serum creatinine to 1.5 mg/dL or less or increase in creatinine clearance to 40 mL/min or more) following diuretic withdrawal and expansion of plasma volume with 1.5 L of isotonic saline • Proteinuria < 500 mg/day and no ultrasonographic evidence of obstructive uropathy or parenchymal renal disease Additional criteria • Urine volume < 500 mL/day • Urine sodium < 10 mEq/L • Urine osmolality greater than plasma osmolality • Urine red blood cells < 50 per high-power field • Serum sodium concentration < 130 mEq/L
1002 Table 80.14 New diagnostic criteria of hepatorenal syndrome in cirrhosis [23] • Cirrhosis with ascites • Serum creatinine > 133 mmol/L (1.5 mg/dL) • No improvement of serum creatinine (decrease to a level of £133 mmol/L) after at least 2 days with diuretic withdrawal and volume expansion with albumin; the recommended dose of albumin is 1 g/kg of body weight/day up to a maximum of 100 g/day • Absence of shock • No current or recent treatment with nephrotoxic drugs • Absence of parenchymal kidney disease as indicated by proteinuria > 500 mg/day, microhematuria (>50 red blood cells per high-power field), and/or abnormal renal ultrasonography
80 Complications of Liver Cirrhosis Table 80.15 Differential diagnosis of renal insufficiency (serum creatinine > 3 mg%) in patients with cirrhosis and ascites Parameter Hepatorenal Prerenal Acute syndrome kidney tubular failure necrosis Na+-concentration in 24 h urine (mEq/L) Urine-to-plasma osmolality ratio Urine-to-serum creatinine ratio Urinary sediment
1
>1
30
15 mmHg), they should be considered to have POPH [32].
Course and Prognosis Prognosis of POPH is poor. Patients die from liver failure or due to right heart insufficiency. Survival rates after 1, 2, and 5 years are 76%, 72% and 50%, respectively [26].
Therapy Clinical Manifestations and Diagnosis In the early stages of POPH the patients are asymptomatic with regard to the lungs and POPH can only be diagnosed by invasive techniques. During the further course exertional dyspnea supervenes and patients may complain of thoracic pain, syncope and hemoptysis. Doppler echocardiography allows screening of patients with portal hypertension for the presence of POPH. An increased right atrial pressure of ≥14 mmHg has a positive predictive value for POPH of 83% [6]. Right heart catheterization is necessary to confirm POPH and frequently identifies other causes of pulmonary hypertension (for example, high flow and increased cen-
Currently, there is no effective therapy for POPH. Improvement in pulmonary hemodynamics has been documented with 24 h continuous intravenous epoprostenol (prostacyclin), but the proof of long-term survival benefit is lacking [20]. b-Adrenergic blockers are associated with a significant worsening in exercise capacity and pulmonary hemodynamics, and are therefore contraindicated in patients with moderate to severe POPH [29]. There is no role for TIPS in the management of POPH. Liver transplantation has been less well studied than in HPS, but transplantation does not seem to be a valid option for patients with severe POPH. Highly selected POPH patients who experience improved pulmonary
1022
hemodynamics with prostacyclins and endothelin antagonists may benefit from liver transplantation [21, 23, 31]. A well functioning right heart ventricle is an absolute precondition for a successful liver transplantation. A combined liver–lung-transplantation has been performed in a few desperate cases, but without evident benefit.
80
Complications of Liver Cirrhosis
Intraperitoneal injection of methylene blue or scanning with 99mtechnetium-labeled colloidal sulfate demonstrates the movement of fluid from the peritoneal to the pleural cavity [24].
Course and Prognosis Hepatic Hydrothorax Definition Hepatic hydrothorax (HH) denotes a pleural effusion that results from a free communication between the peritoneal and pleural cavity in patients with liver cirrhosis and ascites [2, 15].
Epidemiology Most patients with HH have decompensated cirrhosis and refractory ascites. Exact data regarding incidence and prevalence are not available. HH seems to occur in less than 10% of patients with refractory ascites.
Pathogenesis HH is caused by overstretching and rupture of the membranous part of the diaphragm due to tense ascites with high intraabdominal pressure. The relative negative pressure in the pleural cavity and the valve-like effect of the diaphragmatic lesion causes abdominal fluid to flow into the thoracic cavity.
Clinical Manifestations and Diagnosis HH occurs preferentially on the right side. In the vast majority of patients ascites is present at the time of diagnosis. With large diaphragmatic lesions and/or mild ascites production HH may be present in the absence of concomitant ascites. A diagnostic tap discloses the noninflammatory nature of the effusion with results resembling those in ascites.
The prognosis of HH is poor with a high morbidity and mortality rate. Spontaneous bacterial pleurisy (neutrophil count > 400/mL; culture), empyema or a tension hydrothorax through the valve like effect of the diaphragmatic lesion may complicate HH.
Therapy HH usually is a major therapeutic challenge that requires careful planning of therapy and the timely application of all methods. Simply draining HH while marked ascites is present is futile since HH rapidly redevelops. Therapeutic thoracentesis, combined with intensive therapy of ascites (large volume paracentesis with intravenous albumin infusion, diuretics) should be performed in severely symptomatic patients. Patients who require repeated thoracentesis should receive a TIPS (provided that there are no contraindications). The response rates of HH to TIPS are 45–80% [34]. If HH reappears a pleurodesis, combined with surgical repair of the diaphragmatic lesion may be attempted. In refractory HH, orthotopic liver transplantation is the only remaining therapeutic option.
References 1. Abrams GA, Nanda NC, Dubovsky EV, et al (1998) Use of macroaggregated albumin lung perfusion scan to diagnose hepatopulmonary syndrome: a new approach. Gastroenterology 114: 305–10 2. Alberts WM, Salem AJ, Solomon DA, et al (1991) Hepatic hydrothorax: cause and management. Arch Intern Med 151: 2383–88 3. Arguedas MR, Abrams G, Krowka MJ, et al (2003) Prospective evaluation of outcomes and predictors of mortality in patients with hepatopulmonary syndrome undergoing liver transplantation. Hepatology 37: 192–7 4. Arguedas MR, Drake BB, Kapoor A, et al (2005) Carboxyhemoglobin levels in cirrhotic patients with and
References without hepatopulmonary syndrome. Gastroenterology 128: 328–33 5. Arguedas MR, Singh H, Faulk DK, et al (2007) Utility of pulse oximetry screening for hepatopulmonary syndrome. Clin Gastroenterol Hepatol 5: 749–54 6. Benjaminov FS, Prentice M, Sniderman KW, et al (2003) Portopulmonary hypertension in decompensated cirrhosis with refractory ascites. Gut 52: 1355–62 7. Blendis L, Wong F (2003) Portopulmonary hypertension: an increasingly important complication of cirrhosis. Gastroenterology 125: 622–4 8. Fallon MB, Abrams GA, Luo B, et al (1997) The role of endothelial nitric oxide synthase in the pathogenesis of a rat model of hepatopulmonary syndrome. Gastroenterology 113: 606–15 9. Fallon MB, Abrams GA (2000) Pulmonary dysfunction in chronic liver disease. Hepatology 32: 859–65 10. Fuhrmann V, Madl C, Mueller C, et al (2006) Hepatopulmonary syndrome in patients with hypoxic hepatitis. Gastroenterology 131: 69–75 11. Gomez FP, Martinez-Palli G, Barbera JA, et al (2004) Gas exchange mechanism of orthodeoxia in hepatopulmonary syndrome. Hepatology 40: 660–6 12. Gomez FP, Barbera JA, Roca J, et al (2006) Effects of nebulized N(G)-nitro-L-arginine methyl ester in patients with hepatopulmonary syndrome. Hepatology 43: 1084–91 13. Hadengue A, Benhayoun MK, Lebrec D (1991) Pulmonary hypertension complicating portal hypertension: prevalence and relation to splanchnic hemodynamics. Gastroenterology 100: 520–8 14. Herve P, Lebrec D, Brenot F, et al (1998) Pulmonary vascular disorders in portal hypertension. Eur Respir J 11: 1153–66 15. Johnston RF, Loo RV (1964) Hepatic hydrothorax. Ann Intern Med 61: 385–401 16. Kawut SM, Krowka MJ, Trotter JF, et al (2008) Clinical risk factors for portopulmonary hypertension. Hepatology 48: 196–203 17. Khandaker MH, Knoll BM, Arora AS (2008) 63-year-old man with cryptogenic cirrhosis and dyspnea. Mayo Clin Proc 83: 580–3 18. Krowka MJ, Cortese DA (1994) Hepatopulmonary syndrome–current concepts in diagnostic and therapeutic considerations. Chest 105: 1528–37 19. Krowka MJ, Porayko MK, Plevak DJ, et al (1997) Hepatopulmonary syndrome with progressive hypoxemia as an indication for liver transplantation: case reports and literature review. Mayo Clin Proc 72: 44–53 20. Krowka MJ, Frantz RP, McGoon MD, et al (1999) Improvement in pulmonary hemodynamics during intravenous epoprostenol (prostacyclin): a study of 15 patients with moderate to severe portopulmonary hypertension. Hepatology 30: 641–8 21. Krowka MJ, Mandell MS, Ramsay MAE, et al (2004) Hepatopulmonary syndrome and portopulmonary hyperten-
1023 sion: a report of the multicenter liver transplant database. Liver Transpl 10: 174–82 22. Krowka MJ, Swanson KL, Frantz RP, et al (2006) Portopulmonary hypertension: results from a 10-year screening algorithm. Hepatology 44: 1502–10 23. Kuo PC, Plotkin JS, Gaine S, et al (1999) Portopulmonary hypertension and the liver transplantation candidate. Transplantation 67: 1087–93 24. Lazaridis KN, Frank JW, Krowka MJ, et al (1999) Hepatic hydrothorax: pathogenesis, diagnosis, and management. Am J Med 107: 262–67 25. Lima BLG, Franca AVC, Pazin-Filho A, et al (2004) Frequency, clinical characteristics, and respiratory parameters of hepatopulmonary syndrome. Mayo Clin Proc 79: 42–8 26. Mandell MS, Groves BM (1996) Pulmonary hypertension in chronic liver disease. Clin Chest Med 17: 17–34 27. Martínez GP, Barberà JA, Visa J, et al (2001) Hepatopulmonary syndrome in candidates for liver transplantation. J Hepatol 34: 651–7 28. Palma DT, Philips GM, Arguedas MR, et al (2008) Oxygen desaturation during sleep in hepatopulmonary syndrome. Hepatology 47: 1257–63 29. Provencher S, Herve P, Jais X, et al (2006) Deleterious effects of beta-blockers on exercise capacity and hemodynamics in patients with portopulmonary hypertension. Gastroenterology 130: 120–6 30. Rodriguez-Roisin R, Agusti AGN, Roca J (1992) The hepatopulmonary syndrome: new name, old complexities. Thorax 47: 897–902 31. Rodríguez-Roisin R, Krowka, MJ, Hervé P, et al (2004) Pulmonary-hepatic vascular disorders (PHD). Eur Respir J 24: 861–80 32. Rodriguez-Roisin R, Krowka MJ, Herve P, et al (2005) Highlights of the ERS task force on the pulmonary-hepatic vascular disorders (PHD) J Hepatol 42: 924–7 33. Rodríguez-Roisin R, Krowka MJ (2008) Hepatopulmonary syndrome–a liver-induced lung vascular disorder. N Engl J Med 358: 2378–87 34. Rössle M, Siegerstetter V (1998) Der hepatische hydrothorax. empfehlungen für eine rationelle therapie. Dtsch med Wschr 123: 1485–89 35. Schenk P, Madl C, Rezaie-Majd S, et al (2000) Methylene blue improves hepatopulmonary syndrome. Ann Intern Med 133: 701–6 36. Schenk P, Schoniger-Hekele M, Fuhrmann V, et al (2003) Prognostic significance of the hepatopulmonary syndrome in patients with cirrhosis. Gastroenterology 125: 1042–52 37. Swanson KL, Wiesner RH, Krowka MJ (2005) Natural history of hepatopulmonary syndrome: impact of liver transplantation. Hepatology 41: 1122–9 38. Zamirian M, Aslani A, Shahrzad S (2007) Left atrial volume: a novel predictor of hepatopulmonary syndrome. Am J Gastroenterol 102: 1392–6
1024
80.6 Cardiovascular Complications Heart and liver diseases may be associated in many ways: • Hepatic complications of heart failure • Cardiac complications of liver disease • Cardiac and hepatic lesions of common etiology [16] A pericardial effusion, for example may develop in the setting of fluid retention (ascites, edema) in cirrhosis [1]. It may be demonstrated by transthoracic echocardiography in approximately two thirds of patients with decompensated liver cirrhosis, and usually disappears after successful treatment of ascites. Rarely a tense ascites may increase intraabdominal pressure, elevate the diaphragm, impair cardiac filling and result in a decreased cardiac output. In these cases a large volume paracentesis improves cardiac function. Treatment of ascites by a large volume paracentesis without adequate volume replacement may lead to cardiocirculatory dysfunction with a fall in right atrial and pulmonary occlusion pressure, and a consecutive fall in cardiac output (see Section 80.1) [17]. Spontaneous bacterial peritonitis in cirrhotic patients may be associated with severe systemic, renal and hepatic hemodynamic derangement [20]. Hepatic complications of heart failure primarily include liver lesions due to acute or chronic vascular congestion (see Chapter 59). In this chapter the cardiovascular changes typical of cirrhosis are discussed, i.e. hyperdynamic circulation and cirrhotic cardiomyopathy.
80
Complications of Liver Cirrhosis
are also operative in the development of ascites. Vascular endothelial dysfunction and progressive vasodilation are central to the pathogenesis of hyperdynamic circulation in cirrhosis and to the detrimental effects observed in multiple organs with nitric oxide being the primary (but not the only) vasodilator molecule in these effects [10, 11]. Recent data also suggest that in cirrhosis-induced vasodilation, the angiotensin (1)-receptor is desensitized [8]. Vasodilation of muscle districts contributes to the reduced peripheral vascular resistance in advanced cirrhosis [5]. The consequent decrease of effective arterial volume activates the sympatho-adrenergic mechanisms and the renin-angiotensin-aldosterone system (see Chapter 54 and Section 80.1). Experiments in portal hypertensive rats show that central cardiovascular regulatory nuclei initiate hyperdynamic circulation in response to a gut signal associated with portal hypertension via capsaicinsensitive vagal afferent nerves [13]. Patients with liver cirrhosis may also have arterial hypertension. In common with their normotensive counterparts, hypertensive cirrhotic patients are hyperkinetic and central hypovolemic, but vasodilation is reduced and regulation of arterial blood pressure may be less deranged [9].
Clinical Manifestations
A hyperdynamic (hyperkinetic) circulation denotes cardiovascular alterations in patients with liver cirrhosis that are characterized by a decrease in systemic peripheral vascular resistance, peripheral vasodilatation, low arterial blood pressure and a compensatory increase of cardiac output per minute in the presence of a low arterio-venous oxygen gradient. These cardiovascular changes only rarely lead to heart insufficiency.
Tachycardia, low arterial blood pressure with a high amplitude, dry, reddened, warm skin, bouncing peripheral pulses with capillary pulsations at the fingertips, a broadened cardiac apex beat, and occasionally a loud mid-systolic heart murmur at the cardiac base are the clinical signs of hyperdynamic circulation. Delayed repolarisation of the myocardium occurs in a substantial fraction of patients with liver cirrhosis (not only of alcoholic origin) already at a stage with a mild increase in portal pressure. Compared to noncirrhotic patients the QT-interval is prolonged [23]. It correlates with the Child-Pugh stage. Prolongation to greater than 440 ms seems to correlate with a shortened survival [3].
Pathogenesis
Differential Diagnosis
The pathophysiology of hyperdynamic circulation is still understood incompletely, but involves many factors that
The hyperkinetic heart syndrome in cirrhosis has to be differentiated from cardiac changes in thiamine
Hyperdynamic Circulation
Cirrhotic Cardiomyopathy
(vitamin B1) deficiency (“beri beri heart”) and from similar conditions with decreased peripheral vascular resistance, such as extrahepatic arterio-venous communications, severe anemia, hyperthyroidism, Paget’s disease, alcoholic cardiomyopathy and hyperdynamic circulation in late pregnancy. A heart insufficiency with increased cardiac output may be caused by intrahepatic arteriovenous shunts in a non-cirrhotic liver [4]. Giant hemangiomas and hemangioendotheliomas, especially in children may cause a hyperkinetic heart failure due to a significant arteriovenous shunt load. Rarely, a similar clinical picture has been described in adults with Osler-WeberRendu syndrome. Long-term administration of estrogens may aggravate a preexisting vascular disease or lead to peliosis hepatis (see Chapter 60), which in rare cases may cause or precipitate heart failure.
Therapy Specific treatment of hyperdynamic circulation usually is not available. Interestingly, selective intestinal decontamination with norfloxacin, 400 mg p.o. bid for 4 weeks, may partially reverse the hyperdynamic circulatory state in cirrhotic patients [19]. If tachycardia is problematic, non-selective b-adrenergic blockers may be administered. They concomitantly lower portal hypertension. Cardiac failure is treated according to guidelines for non-cirrhotic patients. Following liver transplantation the cardiovascular changes are reversible [21].
Cirrhotic Cardiomyopathy Cirrhotic cardiomyopathy (CC) implies left ventricular systolic and diastolic dysfunction and electrophysiological abnormalities under physiological conditions or under pharmacological stress in patients with liver cirrhosis [12, 14]. Nearly every third cirrhotic patient has elevated serum levels of troponin I as an expression of a subclinical myocardial injury. Being clinically latent CC can be unmasked by physical or pharmacological strain and by stressful procedures, such as large volume paracentesis without adequate plasma volume expansion, transjugular intrahepatic portosystemic shunt
1025
(TIPS) insertion, peritoneovenous shunting and surgery [6, 7, 15]. Diastolic dysfunction does not only occur in cirrhosis but may also be present in non-cirrhotic portal fibrosis. It indicates that portal hypertension is an important factor in the genesis of cardiac dysfunction [7]. Diastolic dysfunction is associated with poor survival in patients with cirrhosis and TIPS [6]. The pathophysiology of CC is multifactorial and includes diminished b-adrenergic receptor signal transduction, cardiomyocyte plasma membrane dysfunction, and increased activity or levels of cardiodepressant substances such as cytokines, endogenous cannabinoids, and nitric oxide [2]. However, if CC is indeed a discrete disease entity or if it just represents left ventricular abnormalities due to an increased work load in hyperkinetic circulation is currently under investigation [18, 22]. Treatment is mainly supportive. Orthotopic liver transplantation appears to improve or normalize the condition, generally after a period of several months.
References 1. Ahah A, Variyam E (1988) Pericardial effusion and left ventricular dysfunction associated with ascites secondary to hepatic cirrhosis. Arch Intern Med 148: 585–8 2. Alqahtani SA, Fouad TR, Lee SS (2008) Cirrhotic cardiomyopathy. Semin Liver Dis 28: 59–69 3. Bernardi M, Calandra S, Colantoni A, et al (1998) Q-T interval prolongation in cirrhosis: prevalence, relationship with severity, and etiology of the disease and possible pathogenetic factors. Hepatology 27: 28–34 4. Brohee D, Franken P, Fievaz M, et al (1984) High-output heart failure secondary to hepatic arteriovenous microfistulae. Selective arterial embolization treatment. Arch Intern Med 144: 1282–4 5. Caraceni P, Dazzani F, Salizzoni E, et al (2008) Muscle circulation contributes to hyperdynamic circulatory syndrome in advanced cirrhosis. J Hepatol 48: 559–66 6. Cazzaniga M, Salerno F, Pagnozzi G, et al (2007) Diastolic dysfunction is associated with poor survival in patients with cirrhosis with transjugular intrahepatic portosystemic shunt. Gut 56: 869–75 7. De BK, Majumdar D, Das D, et al (2003) Cardiac dysfunction in portal hypertension among patients with cirrhosis and noncirrhotic portal fibrosis. J Hepatol 39: 315–9 8. Hennenberg M, Trebicka J, Biecker E, et al (2007) Vascular dysfunction in human and rat cirrhosis: role of receptordesensitizing and calcium-sensitizing proteins. Hepatology 45: 495–506 9. Henriksen JH, Fuglsang S, Bendtsen F, et al (2006) Arterial hypertension in cirrhosis: arterial compliance, volume distribution, and central haemodynamics. Gut 55: 380–7
1026 10. Iwakiri Y, Groszmann RJ (2006) The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule. Hepatology 43: S121–31 11. Iwakiri Y, Groszmann RJ (2007) Vascular endothelial dysfunction in cirrhosis. J Hepatol 46: 927–34 12. Liu H, Lee SS (1999) Cardiopulmonary dysfunction in cirrhosis. J Gastroenterol Hepatol 14: 600–8 13. Liu H, Schuelert N, McDougall JJ, et al (2008) Central neural activation of hyperdynamic circulation in portal hypertensive rats depends on vagal afferent nerves. Gut 57: 966–73 14. Ma Z, Lee SS (1996) Cirrhotic cardiomyopathy: getting to the heart of the matter. Hepatology 24: 451–9 15. Møller S, Henriksen JH (2008) Cardiovascular complications of cirrhosis. Gut 57: 268–78 16. Naschitz JE, Slobodin G, Lewis RJ, et al (2000) Heart diseases affecting the liver and liver diseases affecting the heart. Am Heart J 140: 111–20 17. Panos MZ, Moore K, Vlavianos P, et al (1990) Single, total paracentesis for tense ascites: sequential hemodynamic changes and right atrial size. Hepatology 11: 662–7 18. Pozzi M, Carugo S, Boari G, et al (1997) Evidence of functional and structural cardiac abnormalities in cirrhotic patients with and without ascites. Hepatology 26: 1131–7 19. Rasaratnam B, Kaye D, Jennings G, et al (2003) The effect of selective intestinal decontamination on the hyperdynamic circulatory state in cirrhosis. A randomized trial. Ann Intern Med 139: 186–93 20. Ruiz-del-Arbol L, Urman J, Fernandez J, et al (2003) Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology 38: 1210–8 21. Torregrosa M, Aguade S, Dos L, et al (2005) Cardiac alterations in cirrhosis: reversibility after liver transplantation. J Hepatol 42: 68–74 22. Valeriano V, Funaro S, Lionetti R, et al (2000) Modification of cardiac function in cirrhotic patients with and without ascites. Am J Gastroenterol 95: 3200–5 23. Ytting H, Henriksen JH, Fuglsang S, et al (2005) Prolonged Q-T(c) interval in mild portal hypertensive cirrhosis. J Hepatol 43: 637–44
80
Complications of Liver Cirrhosis
80.7 Endocrine Alterations Sexual Dysfunction Sexual dysfunction, especially in patients with alcoholic liver cirrhosis occurs frequently. It is more pronounced in men and commonly leads to feminization, while signs of ovarian insufficiency predominate in women. Eighty percent of male alcoholic cirrhotics complain of loss of libido, erectile dysfunction or infertility. Hypogonadism manifests with atrophic, small and soft testes. Terminal hair diminishes, and gynecomastia and a female body habitus develop (the most common cause of gynecomastia in patients with liver cirrhosis is spironolactone treatment). Prostatic hyperplasia is less common in patients with alcoholic cirrhosis. Women often have menstrual irregularities, such as amenorrhea and metrorrhagia in advanced cirrhosis with coagulation defects. Libido and sexual behaviour are not altered in women with nonalcoholic liver cirrhosis [1]. The pathophysiology of sexual alteration is complex and multifactorial. The liver plays a major role in metabolism of sex hormones which is usually disturbed in advanced stages of cirrhosis. The lack of a secondary rise in gonadotropins in alcoholic testicular injury hints at a dysfunction of hypothalamic–hypophyseal–gonadal axis. Ethanol induces the enzyme aromatase that catalyzes the transformation of androgens to estrogens, it leads to an increased extragonadal synthesis of estrogens and to an upregulation of estrogen receptors [2]. In hereditary hemochromatosis, hypophyseal iron deposits may lead to secondary hypogonadism which, in contrast to that of patients with alcoholic cirrhosis can be treated by testosterone injections. A reversal of sexual dysfunction following liver transplantation has been reported [5].
Thyroid Dysfunction Patients with liver cirrhosis are usually clinically euthyroid. Laboratory findings of a low-T3 syndrome may be present. The hepatic transformation of T4 in T3 is diminished, while extrahepatic generation of reverse-T3 from
References
T4 is increased. Diminished levels of T3 and increased reverse T3-levels are found in plasma. TSH is within normal limits. Frequently T4 levels also fall in the final stages of liver cirrhosis. Thyroid hormone replacement therapy is not indicated [4]. Hypothyroidism in patients with autoimmune liver diseases, for example primary biliary cirrhosis, autoimmune hepatitis or in hereditary hemochromatosis usually is due to immune thyroiditis (Hashimoto thyroiditis).
Alterations of Glucose Homeostasis Disturbed glucose tolerance, overt diabetes mellitus and hypoglycemia may be observed in patients with liver cirrhosis [7]. Sixty to 80% of patients with liver cirrhosis have disturbed glucose tolerance and approximately 20–30% have diabetes mellitus. The fraction of patients with overt diabetes mellitus is particularly high in patients with hemochromatotic cirrhosis. Increased serum insulin levels in patients with liver cirrhosis are primarily due to decreased hepatic degradation of insulin. The so-called hepatogenous diabetes mellitus is due to insulin resistance with inadequately high serum insulin levels [8, 9]. Cirrhotic patients with still normal glucose tolerance already exhibit peripheral (i.e. muscular) insulin resistance which initially is compensated by increased secretion of insulin by the pancreatic b-cells. Insulin resistance also plays a pivotal pathophysiologic role in nonalcoholic fatty liver disease (see Chapter 89). Liver transplantation may improve or normalize both glucose tolerance and insulin sensitivity [6].
1027
The prevalence of insulin resistance and type 2 diabetes mellitus in patients with chronic hepatitis C and HCV-cirrhosis is above average [3]. The liver has an extraordinary high capacity to produce glucose. Therefore, hypoglycemia in patients with liver cirrhosis is rare and occurs only with extensive loss of hepatic parenchyma. Hypoglycemia seen in patients with alcoholic cirrhosis is usually due to ethanol-induced inhibition of hepatic gluconeogenesis.
References 1. Bach N, Schaffner F, Kapelman B (1989) Sexual behavior in women with nonalcoholic liver diseases. Hepatology 9: 698–703 2. Bannister P, Oakes J, Sheridan P, et al (1987) Sex hormone changes in chronic liver disease: a matched study of alcoholic versus non-alcoholic liver disease. Quart J Med 63: 305–13 3. Caronia S, Taylor K, Pagliaro L, et al (1999) Further evidence for an association between non-insulin-dependent diabetes mellitus and chronic hepatitis C virus infection. Hepatology 30: 1059–63 4. Häussinger D (1995) Leber und endokrines system. In: Gerok W, Blum HE (Hrsg.) Hepatologie. 2. Auflage. Urban & Schwarzenberg, München-Wien-Baltimore, pp 789–809 5. Madersbacher S, Ludvik G, Stulnig T, et al (1996) The impact of liver transplantation on endocrine status in man. Clin Endocrinol 44: 461–6 6. Merli M, Leonetti F, Riggio O, et al (1999) Glucose intolerance and insulin resistance in cirrhosis are normalized after liver transplantation. Hepatology 30: 649–54 7. Nolte W, Hartmann H, Ramadori G (1995) Glucose metabolism and liver cirrhosis. Exp Clin Endocrinol 103: 63–74 8. Petrides AS, Stanley T, Matthews DE, et al (1998) Insulin resistance in cirrhosis: prolonged reduction of hyperinsulinemia normalizes insulin sensitivity. Hepatology 28: 141–9 9. Siegel EG, Gallwitz B, Schmidt WE, et al (1999) Der hepatogene Diabetes–Aktuelle Konzepte zu Pathophysiologie und Therapie. Dtsch med Wschr 124: 1530–5
1028
80.8 Hematologic Alterations and Hepatic Coagulopathy Hematologic Alterations Red Blood Cells Erythrocytic alterations in patients with liver cirrhosis primarily regard changes in cell shape and anemias. Macrocytosis is the most common variant and is especially pronounced in patients with alcoholic liver disease where it may often be aggravated by concomitant vitamin B12 and/or folate deficiency. The target cell which has a central knob of hemoglobin surrounded by an area of pallor and then a peripheral area of hemoglobin (Mexican hat cell; bull’s-eye appearance) is also typical of liver disease. Acanthocytes are erythrocytes that have lost their smooth oval shape and display cytoplasmic projections. Acanthocytosis is primarily observed in approximately 5% of decompensated alcohol induced cirrhosis and provides an indication of a grave prognosis. It is due to an altered lipid composition of the red cell membrane with an abnormally low density lipoprotein and an increase in cholesterol and phospholipids. An increase in plasma volume in patients with decompensated cirrhosis with marked ascites may lead to dilutional anemia. Bleeding esophago-gastric varices, portal hypertensive gastropathy or peptic ulcers may lead to acute or chronic iron deficiency anemia. Dysfunctional hemostasis in cirrhosis promotes this bleeding tendency. A megaloblastic anemia in cirrhotic patients is mostly due to folate deficiency. It occurs primarily in alcoholics. Occasionally a sideroblastic anemia occurs in patients with alcoholic cirrhosis which is due to an alcohol-induced defect of heme synthesis. These patients show a hypochromic anemia with normal or elevated serum iron concentrations, increased transferrin saturation and an increased iron deposition in the bone marrow. An aplastic anemia is usually not part of liver cirrhosis, but may rarely (250 Ð 300 ng/l Gene test (C282Y/C282Y homozygous mutation) Ð
+
Still clinical suspicion of iron overload or liver cirrhosis
Genetic risk for type 1 hemochromatosis
Liver biopsy with quantitative measurement of iron content & search mutation in other genes
Phlebotomy therapy in case of ferritin elevation (see AASLD guidelines)
Fig. 82.2 Diagnosis and treatment algorithm for type 1 hemochromatosis
sensitive and specific than the chemical quantification of the liver iron concentration. In case of a homozygous C282Y gene test, liver biopsy is no longer required for the diagnosis of genetic hemochromatosis (Fig. 82.2). There may, however, be other reasons to perform a liver biopsy in cases of suspected iron overload: (1) subjects with biochemical or clinical evidence of iron overload in the absence of the homozygous C282Y mutation should usually have a liver biopsy to prove iron overload; (2) in C282Y homozygotes the risk for liver fibrosis and cirrhosis is only increased at ferritin values > 1,000 ng/mL [110]. In those patients liver biopsy is recommended because the presence of liver cirrhosis markedly increases the later HCC risk. Thus, all cirrhotic patients should be screened for HCC with ultrasound and measurement of serum a1-fetoprotein (AFP) levels twice a year.
Deferoxamine Testing and Ferrokinetic Measurements Determination of urinary excretion of iron after administration of deferoxamine allows some estimation of total body iron stores. The deferoxamine test, however, often only shows pathological results when serum ferritin and transferrin saturation are markedly increased and does not allow for diagnosis of early disease. Ferrokinetic measurements today are only done for scientific reasons or difficult diagnostic problems.
1050
Computed Tomography (CT), Magnetic Resonance Tomography (MRT) and Biomagnetometry CT density measurements of liver tissue allow a semiquantitative estimation of liver iron concentrations. This method however is associated with radiation and therefore not allowed in many countries when alternative methods are available which do not expose the patient to radiation. MRT in contrast even allows a quite reliable measurement of liver iron content, provided that a special software is used and provided that the equipment is calibrated for such measurement. In clinical practice most MRT machines do not fulfill the criteria required for quantitative iron determination and diagnosis of early iron overload. Biomagnetometry allows the most accurate non-invasive measurement of liver iron concentration. However, this equipment is very expensive and only allows the measurements of iron concentration. Consequently biomagnetometry is done only at a few places worldwide and just useful for scientific studies but not for daily clinical practice. With availability of a reliable and inexpensive genetic testing, CT, MRT, and biomagnetometry do not need to be done for most patients any longer.
Genetic Tests In populations with a celtic origin, the homozygous C282Y mutation accounts for more than 90% of patients with the clinical phenotype of type-1 hemochromatosis [4, 61]. Approximately 5% of patients with the clinical phenotype are C282Y/H63D compound heterozygotes; the prevalence of C282Y or H63D heterozygosity in patients with the clinical phenotype of hemochromatosis is considerably lower than in the general population. Thus, a subject who is heterozygous for C282Y or H63D per se has no risk of iron overload. In subjects homozygous for C282Y, both serum ferritin and transferrin saturation are frequently increased; however, only male subjects had an increased risk for liver disease when compared to subjects without HFE gene alterations in a recent large screening study. It is as yet unknown how many C282Y homozygotes will later develop clinical signs and symptoms due to iron overload. It has become increasingly evident that only a minority of C282Y homozygotes progress to end stage iron overload with liver cirrhosis and diabetes mellitus.
82 Hereditary Hemochromatosis and Iron Overload
In subjects who are not C282Y homozygotes but have laboratory, histological or clinical evidence of iron overload, further genes may be analyzed for mutations such as hemojuvelin, transferrin receptor 2, ferroportin 1 and hepcidin. The types 2–4 of hemochromatosis probably occur mainly in populations without a strong celtic background (many of the rare genetic types have been described in Italy). African subjects may well develop the clinical phenotype of hemochromatosis although they almost never have a C282Y HFE mutation; in the latter subjects the gene responsible for iron overload is as yet unknown.
Early Diagnosis and Screening The prevalence of C282Y homozygotes is 0.5% in celtic populations [4, 61]. The phenotypic expression however is variable and also depends on several non-genetic factors such as dietary iron intake and blood losses. Until 1980 most patients with hemochromatosis were detected with late irreversible complications such as liver cirrhosis and diabetes mellitus. With the better understanding of the disease, the broad use of ferritin and transferrin saturation measurements and the availability of reliable gene tests, diagnostic efforts have concentrated on the detection of early disease in the absence of liver cirrhosis and diabetes mellitus. Several studies have shown that iron removal by phlebotomy is associated with a normal life expectancy in patients diagnosed at such early stages (Fig. 82.3) [63, 128, 129]. Thus, several further studies have focused on screening procedures in order to diagnose more subjects with early disease [57]. These studies include populations with special risks, family members as well as the general population (Table 82.3) (for further literature see [133]). It has also been shown that an increasing number of patients are now diagnosed in early stages and that this trend increases survival (Figs. 82.4 and 82.5). A large number of studies have shown that screening is useful for detection of asymptomatic C282Y homozygotes by using transferrin saturation and serum ferritin as well a genetic test for the C282Y mutation [57, 130, 142]. A broad screening of the general population however is as yet not recommended by WHO and CDC mainly because it is unknown how many of the asymptomatic C282Y homozygotes will later develop clinical disease (for further literature see [195]). The largest
Type 1 HFE Hemochromatosis Fig. 82.3 Survival of 251 patients with genetic hemochromatosis (HC) (with and without cirrhosis) in comparison with a matched general population (Modified from [129])
1051 100
100 Normal population 80
60
Cumulative survival (%)
Cumulative survival (%)
80
HC
40
20
0
Cirrhotic HC 40
20
0
6
12
% asymptomatic % no cirrhosis
60 50
18
24 30 Time (years)
0
600
0
6
12
18
24 30 Time (years)
Screening in the general population not recommended A screening of HFE gene alterationsis is not recommended for the general population because it remains unknown how many of the C282Y homozygotes will develop the clinical phenotype. Such screening would be meaningful only in populations of celtic origin.
40 30 20 10 0
1947 - 69
1970 - 81
1982 Ð 91
Fig. 82.4 Prevalence of early diagnosis in 251 patients with genetic hemochromatosis during three time periods. Early diagnosis was defined either as diagnosis without symptoms or as diagnosis without evidence of liver cirrhosis (Modified from [129])
Diagnosis 19821991 (n=84) General population
100 90 Cumulative survival (%)
60
Table 82.3 Methods for early diagnosis of hemochromatosis
70
(matched to patients diagnosed 19821991)
80 70 60
Diagnosis 19701981 (n=84)
50 40 30
Diagnosis 19471969 (n=83)
20 10 0
Noncirrhotic HC
0
6
12
18
24 30 Time (years)
Fig. 82.5 Cumulative survival in patients with genetic hemochromatosis according to the time of diagnosis (Modified from [129])
Family screening Genetic testing can reliably determine who of the first degree relatives of a hemochromatotic patient is a heterozygote or homozygote. Heterozygotes are healthy and do not need follow-up. C282Y homozygotes should be followed and treated by phlebotomy if ferritin increases > 300 ng/mL in men and > 200 ng/mL in women. Hemochromatosis should be excluded in patients with • Newly diagnosed diabetes mellitus • Chronic liver disease of unknown etiology • Elevation of iron, transferrin saturation or serum ferritin • Cardiomyopathy of unknown etiology • Arthropathy of unknown etiology • Loss of potency/libido and amennorrhea of unknown etiology Every liver biopsy needs to be checked for iron deposits
screening study analyzed HFE gene mutations in almost 100,000 subjects in North America. In white subjects, C282Y homozygosity was found in 0.44%, a value similar to many previous studies in other populations with a celtic/caucasian background. Asian or black people in contrast almost never had a HFE gene mutation. Among the white C282Y homozygotes only males had a significant increase in liver disease when compared to subjects without a HFE gene variation [4]. Only further
1052
prospective follow-up studies will determine how many asymptomatic C282Y homozygotes will develop clinical consequences of iron overload. It is also unknown at which ferritin values phlebotomy treatment should be initiated in asymptomatic C282Y homozygotes (see chapter on treatment for details). The values recommended by the American Association for the Study of Liver Diseases (AASLD) are based more on the judgment of experts than on solid data. The only solid data show that the risk for liver fibrosis and cirrhosis increases above the threshold of 1,000 ng/mL serum ferritin [110]. The value of screening family members is obvious when a firstdegree relative has clinical hemochromatosis. Such family screening is easy to do with the gene test. Heterozygous family members are not at risk for hemochromatosis unless they have additional risk factors. The clinical phenotype of hemochromatosis is detected in 1–2% of patients with newly diagnosed diabetes mellitus und in 3–15% of patients with liver cirrhosis [131]. The latter patients should be screened for iron overload although elevated ferritin levels are common in cirrhosis in the absence of hemochromatosis. Little is known as yet about the prevalence of hemochromatosis in patients with arthropathy or cardiomyopathy of unclear etiology. Several smaller studies indicate that arthropathy may be a rather early clinical sign of iron overload, whereas cardiomyopathy usually only occurs when there is massive iron overload.
82 Hereditary Hemochromatosis and Iron Overload
of the C282Y mutation allows this differentiation to be made without major problems.
Complications of Iron Overload Liver cirrhosis, diabetes mellitus, and increased skin pigmentation are the classic triad of genetic hemochromatosis. Cardiomyopathy, cardiac arrhythmias, and impotence are also typical complications of advanced iron overload. Arthropathy, in contrast, may be an early sign of hemochromatosis which may enable the diagnosis in the precirrhotic stage [129].
Liver cirrhosis The liver is the organ which is affected by genetic iron overload most early and heavily. At early stages, excess iron stores are mainly found in periportal parenchymal cells as ferritin and haemosiderin. When iron excess further increases, there is development of perilobular fibrosis and iron stores are also found in bile ducts and Kupffer cells. Septal fibrosis finally progresses towards complete cirrhosis. The stage of fibrosis is closely associated with the degree of iron excess [110, 129]. In many affected symptomatic patients there are signs of liver disease at the time of diagnosis (Fig. 82.6). Many nonspecific symptoms may as well be a consequence of liver involvement such as abdominal discomfort and
Differential Diagnosis Fatigue
Symptoms and clinical signs determine the differential diagnosis of hemochromatosis. Most often signs of liver disease, diabetes mellitus, and arthropathy lead to suspicion of hemochromatosis. In other patients elevations of serum iron or ferritin initiate a further workup. The use of serum ferritin, transferrin saturation, and genetic testing today enable the diagnosis of hemochromatosis in celtic populations in > 90% of subjects. Previously it was sometimes difficult to distinguish hemochromatosis from alcoholic hepatitis which may also be associated with ferritin elevations and some iron deposits in liver biopsy; today, the determination
ALT increase Hyperpigmentation Diabetes mellitus Arthralgia
at diagnosis
Impotence
after therapy 0
20
40
60
80 100 % of patients
Fig. 82.6 Signs and symptoms in 185 patients with genetic hemochromatosis prior and after iron removal (Modified from [129])
Complications of Iron Overload
1053
Liver Carcinoma
Fatigue Hyperpigmentation EKG alterations Diabetes mellitus Impotence
cirrhosis no cirrhosis
Arthralgia 0
20
40
60
80 100 % of patients
Fig. 82.7 Signs and symptoms in 251 patients with genetic hemochromatosis with and without liver cirrhosis (Modified from [129])
Mobilized iron (g)
30 25 20 15 10 5 0
Cirrhosis absent
Diabetes mellitus
Arthropathy
Liver carcinoma develops in approximately 30% of patients with hemochromatosis and liver cirrhosis independent of iron depletion [129]. The interval between complete iron depletion and diagnosis of liver cancer was approximately 9 years in large cohorts of German patients [128, 129]. The risk of dying from liver cancer is increased in patients with hemochromatosis by 100–200 times when compared to the general population (Fig. 82.9). Among the liver cancers there were hepatocellular carcinomas (HCC) as well as cholangiocellular carcinomas. In the own cohort all liver cancers developed in patients with liver cirrhosis. Thus cancer screening by ultrasound and measurement of serum AFP levels (twice a year) is only recommended for cirrhotic patients although in the literature there are a few published case reports about HCC in patients with hemochromatosis in a noncirrhotic stage. The degree and duration of iron overload are probably the decisive risk factors for the development of liver cancer in hemochromatosis. Patients who develop a liver cancer usually have the largest amount of mobilizable iron among various subgroups [129, 131].
present
Fig. 82.8 Mobilized iron by phlebotomies in 185 patients with documented complete iron removal (Modified from [129])
fatigue. In asymptomatic patients who are often diagnosed by some screening procedure, signs of liver disease are infrequent. Complications due to cirrhosis such as ascites, jaundice and portal hypertension are seen rarely and only in advanced iron overload [128, 129]. Many further complications of hemochromatosis are seen more frequently in patients with cirrhosis when compared to patients without cirrhosis (Fig. 82.7); this reflects the fact that cirrhotic patients have a higher iron burden than noncirrhotic patients (Fig. 82.8). The risk for liver cirrhosis usually increases only at ferritin values > 1,000 ng/mL [110]. Similar to insulin-dependent diabetes, liver cirrhosis cannot be reversed by removal of iron [129]. However, less advanced stages respond well to removal of iron. Survival is significantly reduced in the presence of liver cirrhosis while patients diagnosed in the precirrhotic stage have a normal life expectancy when treated with phlebotomies (Fig. 82.3) [129].
Association of Hemochromatosis with other Liver Diseases Some studies indicate that C282Y heterozygosity may aggravate the progression of other concomitant liver
Liver cancer
n = 19
Cardiomyopathy
n=5
Diabetes mellitus
n=4
Liver cirrhosis
n = 14
Extrahepatic cancer
n=8
Myocardial infarction
n=4
0,1
1
10 100 1000 Relative mortality risk
Fig. 82.9 Relative mortality risk in 251 patients with genetic hemochromatosis in comparison to the general population (Modified from [129])
1054
diseases such as porphyria cutanea tarda, chronic hepatitis C, alcoholic hepatitis, and non-alcoholic steatohepatitis. In the latter patients, one might find slightly elevated liver iron concentrations and serum ferritin levels when they are C282Y heterozygotes (for review see [62]). Many studies however suggest that these associations are of minor importance for the clinical prognosis. Phlebotomy as yet has only been proven meaningful in porphyria cutanea tarda where it also ameliorates the cutaneous manifestations.
Diabetes mellitus “Diabetes mellitus” was actually the most frequent term used to denominate hereditary hemochromatosis in the early descriptions. It reflected the various beliefs as to whether the disease was primarily pancreatic, hepatic, or hematological in origin or whether it was a separate disease entity [82, 163, 192, 193]. Liver cirrhosis, damage to pancreatic beta-cells, and genetic predisposition have been proposed as the major factors causing impaired glucose tolerance and diabetes mellitus in hemochromatosis [126–128, 174, 186]. Early studies reported an almost 80% prevalence of diabetes mellitus in hemochromatosis [25, 66, 177, 208]. In more recent studies the prevalence is reported to be < 50% [129]. In a large series of 474 patients with hemochromatosis from France, 191 patients (40%) had diabetes at the time of diagnosis. The prevalence and stage of diabetes was related to the degree of iron deposition in the pancreas. Patients with diabetes had a twofold higher mobilizable iron content than non-diabetics [209]. In another cohort study which included mostly precirrhotic patients, the prevalence of diabetes was only 21% [2]. Thus, the decrease in the prevalence of diabetes during the last decades is probably due to the fact that many patients are now diagnosed at an early stage when glucose metabolism is still normal or only slightly abnormal. Investigations into the prevalence of unrecognized hemochromatosis in diabetic patients showed some variations in Europe and overseas. Screening revealed a prevalence of 5–8 per 1,000 unrecognized cases in Europe and 9.6 per 1,000 in Australia [143, 182]. Therefore diabetics should always be carefully investigated for iron overload. Diabetes mellitus and impaired glucose tolerance are frequent features in several chronic liver diseases
82
Hereditary Hemochromatosis and Iron Overload
[17, 41]. Because insulin resistance has been established as a major factor causing impairment of glucose metabolism in chronic liver disease, it might also be responsible for impaired glucose metabolism associated with hemochromatosis [159]. Our own studies showed hyperinsulinemia and hence insulin resistance without impaired glucose tolerance in the noncirrhotic stage of hemochromatosis [127]. In contrast to increased insulin concentrations, circulating concentrations of C-peptide were normal in noncirrhotic patients, indicating a normal insulin secretion by pancreatic betacells. Circulating glucagon in response to oral glucose were also normal. The latter results are in accordance with two other studies demonstrating normal glucagon following arginine stimulation in patients with cirrhotic and noncirrhotic hemochromatosis. The observation of normal glucagon concentration also in cirrhotic patients is further substantiated by histological studies showing that the iron depositions in hemochromatosis are almost exclusively found in beta-cells and not in alpha-cells [83]. Since the circulating gastric inhibitory peptide (GIP) in response to oral glucose remained unchanged, insulin secretion by beta-cells, glucagon secretion by alpha-cells, and the enteroinsulinar axis (GIP) are not impaired in noncirrhotic hemochromatosis. The increase in circulating insulin is likely to be due to a decrease in diminished hepatic extraction of insulin. Iron accumulation in hepatocytes may be responsible for the impaired hepatic degradation of insulin. There is a close correlation between the progression of alterations of glucose metabolism and the development of liver cirrhosis. Thus, a part of diabetes may be due to the development of liver cirrhosis. On the other hand, the high frequency of diabetes in advanced iron overload also reflects the advancement of iron deposition in beta-cells. Insulin secretion by pancreatic beta-cells is normal in precirrhotic stages [127]. With the progression of iron overload and destruction of beta-cells in combination with the development of liver cirrhosis, pancreatic insulin secretion becomes impaired [16, 56]. In the end-stage of hemochromatosis, insulin deficiency is associated with severe reduction in the mass of immunoreactive beta-cells [161]. Along with the component of impaired insulin secretion by damaged beta cells, there is an almost obligatory insulin resistance observed in iron overload disease. This is due to an insulin receptor/postreceptor defect in the iron loaded liver, which is, in contrast to the destruction of the betacells, partially reversible after completion of the
Complications of Iron Overload
1055
Table 82.4 Changes in clinical features during initial treatment period in 183 patients with biopsy proven iron depletiona (Modified from [129]) Feature At time of diagnosis After depletion or ironb Improved Unchanged Worsened Percent of group (no. of patients) Diabetes mellitus (n = 81) Insulin-dependent Non-insulin dependent Glucose tolerance (n = 101) Impaired Normal
44 (81) 25 (46) 19 (35) 56 (101) 15 (27) 40 (74)
41 (33) 41 (19)c 40 (14) 10 (10) 37 (10) –
53 (43) 50 (23) 57 (20) 87 (88) 56 (15) 99 (73)
6 (5) 10 (4) 3 (1) 3 (3) 7 (2) 1 (1)
a
From 2 of the 185 patients with biopsy proven iron depletion sufficient follow-up information could not be obtained Data obtained from a 6-months period after the end of the initial phlebotomy period c The daily insulin dose could be reduced in 19 of the 46 insulin-dependent patients, but insulin dependency could be abolished in none of the patients b
phlebotomy therapy [128, 129]. The analysis of patients in whom complete iron depletion could be achieved showed that therapy did not eliminate insulin-dependency (Table 82.4) [129]. However, in 19 of the 46 insulin-dependent patients (41%) in whom complete iron depletion had been achieved, the insulin dose could be reduced. Statistically, hemochromatotic patients without diabetes showed significantly less mobilizable iron compared with patients who had already developed diabetes (Fig. 82.8). Thus, the degree of iron overload reflects the degree of alterations in glucose metabolism. Survival was significantly reduced in patients with diabetes mellitus at entry compared to patients without diabetes [129]. The survival curve for non-diabetic patients was virtually identical to that of a matched normal population.
with severe cardiomyopathy may be affected by juvenile type 2 hemochromatosis. Severe iron overload, hypogonadism, cardiomyopathy, liver cirrhosis, and amenorrhea can be seen at age 15–24 years of age. The type 2 associated cardiomyopathy is often irreversible despite initiation of phlebotomy or chelation therapy and may require a rapid transplantation of the heart and potentially also of the liver [86, 90]. It has been reported that venesection therapy may aggravate cardiomyopathy. In these rare cases therapy with ironchelating agents may be performed instead of or in addition to a cautious phlebotomy treatment. Phlebotomies usually have not to be stopped completely, but their frequency has to be reduced as well as the amount of blood withdrawn with each phlebotomy.
Arthropathy Heart Disease Cardiomyopathy and cardiac arrhythmias are specific complications of hemochromatosis caused by iron deposition in the heart [24, 178, 199]. Clinical or electrocardiographic signs of heart disease may be found in 20–35% of patients with HFE hemochromatosis [128]. Arrhythmias usually respond well to iron removal [129, 178]. In type 1 hemochromatosis cardiomyopathy is rare and usually associated with advanced iron overload at higher ages. However, in particular in young patients who present with cardiac disease, cardiomyopathy is a frequent cause of death [66, 178]. Only recently has it become clear that young patients
Joint changes in genetic hemochromatosis may occur in two different types [56, 128, 129, 176]. The most prevalent changes are seen in the metacarpophalangeal joints II and III in the form of cystic and sclerotic changes, cartilage damage, and narrowing of intraarticular spaces. Sometimes other joints of the hands and feet are also affected. The large joints (knees and hips) can be affected in form of chondrocalcinosis. The pathogenesis of joint changes in hemochromatosis remains unclear. The arthropathy is one of the few complications which is not associated with the degree of iron overload. It has been speculated that iron may inhibit pyrophosphatase and may thereby lead to
1056
crystallization of calcium pyrophosphates. Alternatively, iron may have direct toxic effects on the joints. Arthropathy may be an early sign of hemochromatosis and may help to make the diagnosis in a precirrhotic stage [129]. Hemochromatosis should therefore be considered in all patients with an arthropathy of unknown etiology.
Endocrine Abnormalities In contrast to arthropathic changes, endocrine abnormalities are a late consequence of iron overload. Sexual impotence and loss of libido may occur in up to 40% of male patients [128]. Interestingly, gynecomastia is not frequently associated with the other endocrine abnormalities in contrast to what is seen in alcoholic cirrhosis [97, 98, 128]. The endocrine abnormalities in hemochromatosis have been attributed to primary testicular failure, to secondary pituitary hypogonadism, to impaired metabolism of sex hormones due to liver failure, and to diabetes mellitus which is often associated with alterations of libido and potency [33, 98, 108, 179, 184, 185, 201, 205, 206]. Most studies have demonstrated decreased testosterone concentration in impotent male patients potentially caused by primary gonadal failure or by secondary pituitary failure. Iron deposits have been shown both in testes and pituitary [112, 177]. Later studies have clearly demonstrated that hypogonadism in hemochromatosis is mainly, if not exclusively due to pituitary failure in contrast to alcoholic cirrhosis where testicular failure is predominant [97, 98]. In contrast to alcoholic cirrhosis, where estrogen levels are increased, estrogen levels were found decreased in hemochromatosis [97]. Most endocrine changes are late and irreversible complications of iron overload and do not respond well to phlebotomy treatment [129]. Iron overload only infrequently affects other endocrine organs such as thyroid and adrenal glands. A severe hypogonadism with amennorrhea in young women and impotence in young men is today thought to be due to type 2 hemochromatosis [101].
Skin The increased skin pigmentation is mainly seen in light exposed areas. To a large degree the pigmentation is
82 Hereditary Hemochromatosis and Iron Overload
thought to be due to an increase in melanin and not due to iron excess itself. The increase in skin pigmentation is reversible after iron removal.
Other Potential Complications Iron overload has been speculated to aggravate atherosclerosis; however, the evidence for that speculation is rather weak (for review see [132]). In some reports extrahepatic malignancies were increased in HFE hemochromatosis while other studies did not find such an association [8, 11, 19, 58, 72, 129]. It is not yet clear whether HFE gene mutations are involved in the pathogenesis of porphyria cutanea tarda since the prevalence and association of both risk factors greatly vary in different parts of the world; associations between HFE gene mutations and porphyria have been described in particular for southern Europe but not for northern Europe (for literature see [191]).
Therapy Phlebotomy Phlebotomy treatment is the standard care to remove iron in genetic hemochromatosis. One phlebotomy removes approximately 200–250 mg iron from the body. Since patients with the classical clinical phenotype may have excess iron between 10–30 g, it may take 12–24 months to remove the iron overload when phlebotomies of 500 mL blood are done weekly (Table 82.5). Phlebotomy treatment is generally well tolerated and hemoglobin usually does not drop below 12 g/dL. Complete iron removal usually is seen when hemoglobin becomes decreased; at this time serum ferritin is often reduced to less than 20 ng/mL. Several studies have shown that liver iron is completely removed at such ferritin values; thus the effect of therapy can be checked by following ferritin measurements rather than by liver biopsy. After complete removal of excess iron the intervals of phlebotomies may be increased to 2–3 months; serum ferritin should be kept in the lower normal range between 20–50 ng/mL. Phlebotomy should not be interrupted for longer intervals because otherwise there is a risk of reaccumulation of iron to the genetic defect.
Therapy
1057
Table 82.5 Therapy of iron overload Phlebotomy In symptomatic genetic hemochromatosis Aims: Complete iron depletion in 12–24 months Treatment: 1–2 phlebotomies of 500 mL each week until serum ferritin is in the range of 20–50 ng/ mL Long-term therapy with 4–8 phlebotomies per year to keep ferritin between 20–50 ng/mL and thus to prevent reaccumulation of iron In asymptomatic C828Y homozygotes therapy should be initiated above the following ferritin values: Subjects < 18 years: >200 ng/mL Men: Women (not pregnant): Women (pregnant):
>300 ng/mL >200 ng/mL >500 ng/mL
Therapy with iron chelators in secondary hemochromatosis and anemia Aims: Removal of iron overload by increase of iron excretion in feces and urine In case of further blood transfusions at high frequency stabilization of iron balance and reduction of further iron accumulation are aimed at Treatment: Until recently 25–50 mg deferoxamine/kg as s.c. infusion for 10–12 h daily; today deferoxamine is largely replaced by the oral chelator deferasirox 20 mg/kg deferasirox once daily prevents iron accumulation up to 800 mL erythrocytes concentrates/month Long-term treatment necessary; normalization of ferritin and liver iron concentration is often not possible Diet Recommended: Avoidance of food with very high iron content (e.g. liver) and food with iron supplement A further strict iron-depleted diet is very difficult to perform and not recommended A single phlebotomy of 500 mL blood is as effective for iron removal as a very strict iron-depleted diet for a whole year
Iron Removal by Chelators Therapy of genetic hemochromatosis with deferoxamine is not recommended because phlebotomy is more effective with fewer side-effects and costs. In secondary hemochromatosis, however, phlebotomy treatment is not possible because of the underlying anemia. Until recently, these patients had to be treated by continuous s.c. or i.v. infusions of the chelator deferoxamine for 8–12 h per day (Table 82.5). Deferoxamine chelates iron by increasing its excretion in the urine. Because of its short half-life and low oral bioavailability continuous parenteral application is necessary; these problems reduce the compliance in many patients. Just recently deferasirox, the first orally effective iron chelator, has been approved for secondary hemochromatosis, e.g. caused by poly-transfusions in thalassemia (see page 1064). Deferasirox (20 mg/kg once daily) can assure a neutral iron balance in patients who need up to 800 mL erythrocyte concentrates/month; it can even reduce iron stores when fewer transfusions are required (Table 82.6). Gastrointestinal and cutaneous side-effects of deferasirox are usually mild and
Table 82.6 Dose of deferasirox for secondary hemochromatosis Aims of chelation therapy Balance of Reduction of iron Transfusion rate (unit of erythrocyte iron overload pack) metabolism Low: < 2 units/ months Moderate: 2–4 units/months High: > 4 units/ months
10 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
20 mg/kg
30 mg/kg
reversible. Recently, a phase 2 study has started to look at the safety and efficacy of deferasirox in genetic hemochromatosis. As yet, deferasirox is only approved for secondary hemochromatosis.
Diet An iron-depleted diet is not recommended for patients with genetic hemochromatosis. One phlebotomy of 500 mL blood removes approximately 250 mg iron. A
1058
strict dietary iron restriction, which is difficult to observe, for a whole year would just have the effect of a single phlebotomy. It is thus only recommended that patients do not eat larger amounts of food with very high iron content (such as liver) and that they do not eat food to which iron has been added (Table 82.5).
Liver Transplantation Advanced liver cirrhosis and carcinoma may be indications for liver transplantation in hemochromatosis [20, 99]. The prognosis of patients with a liver transplant for hemochromatosis is markedly worse than that for patients with other liver diseases; a considerable number of patients with hemochromatosis died after transplantation from infectious complications or heart failure [20]. Liver transplantation does not cure the genetic defect.
Prognosis Untreated hemochromatosis often has a lethal prognosis in the presence of liver cirrhosis and diabetes mellitus. The prognosis is markedly worse in patients with cirrhosis when compared to those without cirrhosis at diagnosis; the same is true for diabetes mellitus. It is generally accepted that phlebotomy therapy improves the prognosis. Patients diagnosed and treated in the early noncirrhotic stage have a normal life expectancy (Fig. 82.3) [128, 129]. Thus, early diagnosis markedly improves the prognosis (Figs. 82.4 and 82.5). Iron removal by phlebotomy also improves the outcome in patients with liver cirrhosis. The prognosis of liver cirrhosis due to hemochromatosis is markedly better than in other types of cirrhosis [158]. Hepatomegaly and elevation of aminotransferases often regress after iron removal [128, 129]. Phlebotomy also improves the general well being. Insulin-dependent diabetes mellitus and hypogonadism are irreversible complications despite complete iron removal [129]. Earlier changes in glucose and insulin metabolism, however, may be ameliorated after iron removal (Table 82.4). For unknown reasons arthropathy does not respond well to phlebotomy treatment although it may be a rather early sign of iron overload. The prognosis of asymptomatic C282Y homozygotes is not exactly known. The
82 Hereditary Hemochromatosis and Iron Overload
AASLD consensus guideline recommends starting phlebotomy treatment when serum ferritin values exceed 300 ng/mL in men and 200 ng/mL in women. The risk for liver fibrosis and cirrhosis is increased at ferritin levels exceeding 1,000 ng/mL. Further studies need to determine whether asymptomatic C282Y homozygotes with ferritin values between 300 and 1,000 ng/mL should be treated or followed expectantly with serial ferritin measurements.
Juvenile Hereditary Hemochromatosis Prevalence Juvenile hemochromatosis is very rare. There is probably no specific ethnic background for juvenile hemochromatosis; subjects with such mutations have been identified in most parts of the world. Some clustering of HJV mutations has been identified in Italy and Greece although only a few families account for this phenomenon. Mutations in HJV represent the majority of worldwide cases of juvenile hemochromatosis. Only a small number of patients have been identified with HAMP-related juvenile hemochromatosis (see below).
Pathophysiology Juvenile hemochromatosis is characterized by onset of severe iron overload occurring typically in the first to third decades of life. Both sexes are equally affected since juvenile hemochromatosis is inherited in an autosomal recessive manner. Prominent clinical features include hypogonadotropic hypogonadism, cardiomyopathy, and liver cirrhosis. The main cause of death is cardiomyopathy. Two genes have been shown to be associated with juvenile hemochromatosis: (1) 90% of cases are associated with mutations in hemojuvelin (HJV) (locus name HFE2A) which encodes HJV; (2) 10% of cases are associated with HAMP (locus name HFE2B) which encodes hepcidin. Despite the nomenclature of HFE2A and HFE2B, juvenile hemochromatosis is not associated with HFE mutations. In order to avoid confusion most physicians use the terms type 2A (hemojuvelin mutations) and type 2B (HAMP mutations).
Juvenile Hereditary Hemochromatosis
The hemojuvelin protein has 425 amino acids with a size of 41 kd. The hydrophobic signal peptide is located at the N-terminal. At the C-terminal, there is a transmembrane domain and a glycophosphatidyl inositol sequence. The function of hemojuvelin protein is not fully understood, but it likely regulates the hepcidin pathway and is thought to be upstream of hepcidin [139]. Mutations in hemojuvelin are associated with low levels of hepcidin in urine suggesting that hemojuvelin regulates hepcidin. Twenty-six different HJV mutations, all in the coding region, have been thus far identified in homozygous or compound heterozygous forms. The mutation G320V is the most prevalent mutation (almost 60% of all cases) and has been reported in most Greek individuals with juvenile hemochromatosis, in all individuals with juvenile hemochromatosis from Quebec as well as in Canadian, French, Dutch, Italian, American, Albanian, Romanian, and Chinese families [102, 103, 106, 107, 153]. HAMP encodes the peptide hepcidin. The small 25-amino-acid peptide hepcidin is predominately expressed in liver and excreted by the kidney. Hepcidin is the key regulator of intestinal iron absorption and iron release from macrophages. Hepcidin facilitates ferroportin internalization and degradation. Hepcidin mutations may thereby lead to an increase in ferroportin and thus iron uptake from the intestine. Five different mutations in HAMP causing juvenile hemochromatosis in five independent families have been reported as yet. These individuals had an Italian, Greek, Arab or Portuguese origin [46, 113, 171, 172].
Natural History Juvenile hemochromatosis is characterized by early onset of severe iron overload. In contrast to HFE type 1 hemochromatosis, both sexes are equally affected. Juvenile hemochromatosis most often presents in the first to third decades. In clinical practice, individuals with juvenile hemochromatosis are rarely diagnosed before significant iron overload occurs. This problem will continue to exist unless there is some genetic screening during childhood. Typical features include hypogonadotropic hypogonadism, cardiomyopathy, and liver cirrhosis [51, 196]. The clinical course is severe and many patients die from cardiomyopathy [30, 45]. Severe cardiac failure may be the presenting
1059
finding [65]. Hepatocellular cancer has not been reported in juvenile hemochromatosis, probably because many patients have died prematurely in the past due to cardiac complications [26, 27]. Mortality can, however, be reduced also in juvenile hemochromatosis when it is diagnosed early and treated properly. Phlebotomy in asymptomatic patients can prevent organ damage. The phenotype may be less progressive and severe in individuals with digenic inheritance of heterozygous mutations in HAMP and HFE or heterozygous mutations in HJV and HFE. However, digenic inheritance accounts for only a small proportion of genetic hemochromatosis. The presence of heterozygous HJV or HAMP mutations does not fully explain the variability in the penetrance of HFE-related hemochromatosis. In order to identify other genetic modifiers one needs to further study the effect of HJV, HAMP, HFE, and heme-related alleles on the phenotype [102, 103, 105, 111, 118, 146].
Diagnosis Data are minimal as documented cases are rare; however, the diagnostic procedures may follow the advice given for type 1 HFE hemochromatosis. Serum ferritin concentration in juvenile hemochromatosis is often high and has been reported to range from 1,000 to 7,000 ng/mL. Transferrin saturation often approaches 100%. Mutation scanning will detect most mutations in HJV-related juvenile hemochromatosis. Mutation scanning would only be unable to detect an extensive deletion. To date, the most frequent mutation in HJV is G320, accounting for more than 60% of all mutations.
Treatment Phlebotomy is also the standard therapy in juvenile hemochromatosis and is done similarly as in HFE hemochromatosis. The patients should have 1–2 phlebotomies of 500 mL blood each week because they usually have a large iron excess [188]. In patients with juvenile hemochromatosis and anemia or severe cardiac failure, administration of chelators such as
1060
deferoxamine have been used in attempts to reduce mortality; some case reports suggest that such therapy might improve left ventricular ejection fraction [96].
Transferrin Receptor 2 (TFR2)-Related Type 3 Hemochromatosis Prevalence TFR2-related hereditary hemochromatosis is very rare with about 20 patients reported worldwide who came from Japan, Italy, France and Portugal [103, 114]. Screening for the TFR2 mutation Y250X among Italian blood donors with increased transferrin saturation identified a single Y250X heterozygote, resulting in a carrier frequency of 0.9% in this selected small cohort [45]. In contrast, screening of individuals with nonHFE-associated hemochromatosis worldwide did not show any Y250X mutation [5, 6, 12, 104].
82
Hereditary Hemochromatosis and Iron Overload
organs similar to human iron overload [27, 68, 69]. The TFR2 knockout mouse also shows iron overload and is unable to express hepcidin in response to iron [204]. TFR2 is 21 kb long and consists of 18 exons. Several polymorphisms are either silent or missense mutations [104]. A single nucleotide polymorphism in the non-coding region of TFR2 has also been identified [119]. Nine disease-causing mutations (E60X, R105X, M172K, Y250X, Q317X, L490R, V561X, AVAQ621– 624del, Q690P) have been reported; most are rare or private [170]. The most frequent mutation is Y250X, identified in several Italian families [27, 170]. The Q317X mutation was associated with HFE C282Y/ H63D compound heterozygosity in two siblings with a severe juvenile phenotype and in association with wild-type HFE in a brother with a type 1 disease [148]. Some pathological variants produce a truncated protein (E60X, R105X, Y250X, Q317X, V561X) while others produce an abnormally structured protein (AVAQ motif deletion, L490R, Q690P) [168].
Natural History Pathophysiology TFR2-related hemochromatosis is defined as type 3 and has also been named HFE3; however, the term HFE3 should not be used because the HFE gene is not affected. TFR2-related hemochromatosis is inherited in an autosomal recessive manner. TFR2 is a type II transmembrane glycoprotein; its full length transcript originates an 801-amino-acid transmembrane protein. TFR2 is mainly expressed in hepatocytes and at lower levels also in Kupffer cells [210]. TFR2 binds and internalizes transferrin. However, binding occurs at a 25- to 30-fold lower affinity as compared to that of the transferrin receptor 1 (TFR1) [94]. TFR2 protein shows significant amino acid homology with TFR1 [93]. A finely regulated interaction between TFR2, TFR1 and HFE is now thought to affect the hepcidin pathway [70]. TFR2 may also play an essential role for sensing of the iron status. Hepcidin concentrations in urine are low in TFR2 hemochromatosis [123]. In mice with a TFR2-Y245X targeted mutation and in TFR2-knockout mice hepatic mRNA of hepcidin was also down-regulated [95, 204]. The TfR2deficient mouse homozygous for Y245X (orthologous to human Y250) shows iron overload in liver and other
Age of onset in TFR2-related type 3 hemochromatosis is earlier than in HFE type 1 form [77, 84, 152]. Progression is, however, slower than in juvenile type 2 hemochromatosis [45, 77, 168]. The phenotype is similar to type 1 disease with iron accumulation in liver, heart, pancreas and endocrine organs. Many patients present with fatigue, arthralgia, abdominal pain, decreased libido or with biochemical signs of iron oveload [27, 77, 84, 100, 168]. Complications of type 3 hemochromatosis include cirrhosis, hypogonadism, and arthropathy. Cardiomyopathy and diabetes mellitus appear to be rather rare. Hepatocellular carcinoma has not been observed in the small number of cases diagnosed as yet. Most individuals with type 3 hemochromatosis were of Italian or Japanese origin. Some of the Japanese male subjects affected already had liver cirrhosis at diagnosis [84, 100]. Similar to type 1 hemochromatosis, the penetrance of type 3 hemochromatosis is lower than 100%. One middle-aged woman who was homozygous for the E60X mutation had no evidence of clinical disease; a second female even had iron deficiency [168]. The presence of a H63D allele of HFE has been described in individuals with type 3 hemochromatosis [27, 152].
Type 4 Hemochromatosis–Ferroportin Disease
However, its contribution to the phenotype of iron overload remains unclear. In contrast, inheritance of compound heterozygosity for the HFE mutations C282Y and H63D and homozygosity for the TFR2 mutation Q317X produced a phenotype of severe juvenile hemochromatosis in one family [148].
Diagnosis TFR2-related hemochromatosis may be suspected in patients who present with biochemical or clinical evidence of iron overload but do not have HFE gene mutations. Diagnosis of TFR2-related hemochromatosis is similar to that in type 1 including liver histology and iron content [77]. Only a few mutations have been described in single families [27, 77, 84, 100, 102, 114, 168]. Mutations are spread over the entire gene. A panel of four mutations (E60X, M172K, Y250X, AVAQ621–624del) account for about 50% of mutations in individuals with TFR2-hemochromatosis. Mutation scanning followed by sequencing of variant fragments allows rapid screening of coding sequences and splice junctions and detects almost all mutations [15].
Therapy Standard therapy is iron removal by weekly phlebotomies similar to the management of type 1 disease. Individuals with increased ferritin should be treated in the same manner as HFE hemochromatosis.
Type 4 Hemochromatosis–Ferroportin Disease Prevalence and Pathophysiology Ferroportin-associated iron overload (also named ferroportin disease) was first recognized by Pietrangelo et al. in 1999 who described an Italian family with an autosomal dominant form of non-HFE hemochromatosis [144]. Many family members had iron overload resulting in liver fibrosis, diabetes, impotence, and
1061
cardiac arrhythmias. In addition to autosomal dominant inheritance, features distinguishing this entity from HFE hemochromatosis included early iron accumulation in reticuloendothelial cells and a marked increase in ferritin prior to that in transferrin saturation. Several patients showed a reduced tolerance to phlebotomy and became anemic despite elevated ferritin. In 2001 this form of non HFE hemochromatosis was linked to mutations of ferroportin which had just been identified as the basolateral iron transporter (also termed iron-regulated transporter 1/metal transporter protein 1–IREG-1/ MTP-1) simultaneously by three groups [1, 52, 115, 121, 135]. Thereafter, numerous ferroportin mutations have been implicated in patients from diverse ethnic origins with previously unexplained hemochromatosis. Iron overload due to ferroportin mutations has been defined as type 4 hemochromatosis or ferroportin disease (for review see [147]). Ferroportin shows a high level of expression in human placenta, liver, spleen, and kidney [52]. It is also expressed at the basolateral surface of duodenal enterocytes and required for intestinal iron absorption [52, 115, 116]. Ferroportin mRNA and protein expression are increased when iron absorption is high. In addition, ferroportin stimulated iron efflux following expression in Xenopus oocytes [115]. Thus, ferroportin is the intestinal iron exporter which is upregulated in hemochromatosis. Later it was shown that hepcidin binds to ferroportin in vitro [122]. Following that binding, ferroportin was internalized and degraded, leading to a reduction of the export of iron. Thus, posttranslational regulation of ferroportin by hepcidin completes a feedback loop regulating circulating iron and its tissue distribution [122]. Ferroportin was mapped to human chromosome 2q32 [81]. Then genetic analysis of ferroportin in a Dutch family with hemochromatosis type 4 identified a heterozygous A-to-C transversion at nucleotide 734 in exon 5 in all affected individuals [135]. At the same time Italian groups also mapped the disease locus responsible for autosomal dominant hemochromatosis type 4 to 2q32 and recognized ferroportin as the positional candidate [121, 144]. Several studies corroborated that the distinguishing features of this disorder, in addition to autosomal dominant inheritance, is early iron accumulation in reticuloendothelial cells and a marked increase in serum ferritin before that in transferrin saturation [67]. The iron export is tightly regulated because both iron deficiency and iron excess are harmful. The main
1062
regulator of this mechanism is the peptide hepcidin which binds to ferroportin, induces its internalization and degradation, thereby reducing iron export [122]. Plasma iron levels, in turn, regulate hepcidin production, thus completing the feedback loop. Increase in iron absorption may be caused either by hepcidin deficiency or its ineffective interaction with ferroportin. All recent studies have shown that hepcidin deficiency appears to be the common characteristic of most types of genetic hemochromatosis (mutations in HFE, transferrin receptor 2, hemojuvelin, or hepcidin itself). The remaining cases of genetic iron overload are due to heterozygous mutations in the hepcidin target ferroportin. This phenotype was consistent with a loss-offunction hypothesis [67]. A second model for how mutations could cause disease is a gain of function model whereby overactive ferroportin leads to inappropriately high transport of iron from the diet through enterocytes, resulting in an iron overload phenotype, particularly observed in patients who have mutations at N144 or C326Y [166, 202]. In contrast to patients with loss of function, these patients have high transferrin saturation and serum ferritin, and liver biopsy shows that iron is located also in hepatocytes and not only in macrophages [203]. Ferroportin mutants associated with type 4 hemochromatosis thus fall into two categories, those that traffic poorly to the cell surface and loose iron export function (A77D, V162, and G490D) and those that retain cell-surface expression and export function (Y64N, N144D, N144H, Q248H, C326Y). The loss-of-function mutations probably cause disease by withholding iron from the bone marrow through sequestration within macrophages, subsequently leading to a signal for increased dietary iron uptake being sent from the erythron to the intestine. The second set of mutations may cause disease by resisting negative feedback mechanisms that normally operate to maintain iron homeostasis [175]. Recent studies further support the central role of the hepcidinferroportin interaction in regulating extracellular iron concentrations and to the concept that most iron overload diseases are caused by mutations affecting the production or function of either the ligand hepcidin or its target ferroportin [123]. Ferroportin disease or type 4 hemochromatosis is the most prevalent non-HFE type of hemochromatosis. Type 4 hemochromatosis does not result from deficient hepcidin production (as most other forms) but rather from mutations in ferroportin. In contrast to other forms
82
Hereditary Hemochromatosis and Iron Overload
of hemochromatosis, type 4 (ferroportin disease), is inherited dominantly. All known ferroportin mutations are missense mutations leading to amino acid substitutions or deletions. The phenotype can be classified into two groups, varying in both the severity of tissue iron loading and in the type of tissue affected. One group is characterized by an early rise in ferritin levels with low to normal transferrin saturation and iron accumulation predominantly in macrophages [31]. The other group is more similar to classical hemochromatosis, with high transferrin saturation and at least some parenchymal iron loading. The reason for the phenotypic variability is not completely clear, but it has been speculated that mutant ferroportin can multimerize with normal ferroportin and thus affect its function. Depending on the type of the genetic variation, mutant ferroportin may affect the cellular location of normal ferroportin or its responsiveness to hepcidin [44]. Patients with ferroportin disease often have high serum ferritin despite normal transferrin saturation (at least in early stages of disease) and iron deposits predominantly in the liver macrophages and to a lesser degree also in some hepatocytes [10, 13, 79, 121, 135, 144, 164, 169, 202, 203]. Patients often have a borderline anemia, and these cases do not respond well to phlebotomy [91, 144]. The ferroportin Q248H polymorphism has been associated with increased ferritin also in sub-Saharan Africans and in African Americans [165]. African Americans participants of the HEIRS study who did not have HFE C282Y or H63D but had elevated ferritin were matched to participants with normal ferritin to investigate the association of the Q248H with elevated ferritin. The frequency of Q248H was higher among men with elevated ferritin when compared to those with normal ferritin [165]. At this point the pathophysiology of iron overload in Africans remains rather unclear.
Natural History Little is known about the natural history of ferroportinassociated iron overload. In the first Italian families with ferroportin disease, some family members had clinical signs of iron overload resulting in liver fibrosis, diabetes, impotence, and cardiac arrhythmias [144]. Later it became clear that the clinical penetrance of the genetic defect is rather mild. It has recently been
Secondary Hemochromatosis
reported that patients carrying the A77D mutation of ferroportin may develop relevant iron overload with organ damage and liver cancer [40]. It remains however unclear whether there is a good genotype-phenotype correlation in ferroportin disease.
1063
are similar to those described for other types of genetic hemochromatosis.
Secondary Hemochromatosis Diagnosis
Pathophysiology
Increase in serum ferritin is a common laboratory finding also in the absence of iron overload. In the presence of early-onset bilateral cataracts hereditary hyperferritinemia-cataract syndrome may be suspected; this disease results from a heterozygous mutation in the L ferritin IRE sequence [88]. An analysis of 52 DNA samples from patients referred for suspected hyperferritinemia-cataract syndrome identified 24 samples with a point mutation or deletion in the IRE. The 28 samples without an IRE mutation were then genotyped for mutations in HFE, H ferritin and ferroportin genes showing an increased frequency (12 of 28) of heterozygotes for the H63D mutation but no H ferritin mutations. In addition, three novel ferroportin mutations were identified suggesting that these patients had type 4 hemochromatosis. Thus both L ferritin IRE and ferroportin mutations can cause hyperferritinemia. The knockout of the ferroportin gene in mice results in prenatal death [53]. Heterozygous animals showed mild abnormalities of iron homeostasis. Mice with ferroportin deletion restricted to the intestines developed severe iron deficiency anemia. Thus ferroportin is essential for prenatal and postnatal iron homeostasis [53]. Disease-associated ferroportin mutations include Y64N, A77D, N144D and N144H, N144T, V162, Q248H, C326Y, and G490D in patients with iron overload and N174I, Q182H, and G323V in patients with hyperferritinaemia [10, 12, 49, 79, 88, 91, 121, 135, 164, 166, 169, 202].
Most forms of secondary hemochromatosis are due to hemolytic anemia associated with multiple transfusions, such as thalassemia, sickle cell disease, and myelodysplastic syndrome. Most of these patients need blood transfusion on a regular basis for survival. The transfusions have markedly improved the prognosis and quality of life in patients with thalassemia major [137, 154, 156]. However, in the long run multiple blood transfusions often lead to iron overload if patients are not treated with iron chelators. Each pack of erythrocytes contains 200–250 mg iron, which is approximately 100-fold of the dietary iron daily absorbed from the intestine [137]. Iron from degraded red blood cells is primarily taken up by macrophages; thereafter, iron can be bound by transferrin and may reach various organs. In general, iron overload due to blood transfusions is similar to genetic hemochromatosis; however secondary iron overload develops much faster than the genetic forms, sometimes already after 10–12 blood transfusions [117, 156]. Subsequently, secondary iron overload also results in a more rapid organ damage when compared with genetic hemochromatosis. Secondary iron overload can obviously not be treated by phlebotomies because a marked anemia is the clinical landmark of the disease. Secondary iron overload often limits the prognosis of patients with thalassemia; life expectancy deteriorates with increasing iron concentrations in the liver [190]. Therapy with iron chelator may reduce the transfusional iron burden if the frequency of transfusion is not too high. In severe hemolytic anemia with frequent transfusions, iron chelation may sometimes only reduce the further increase in iron overload. It has also been speculated that iron chelation exerts some beneficial effects by reducing the labile iron pools and thus the non-transferrin bound iron (NTBI) [141, 155]. NTBI is thought to be very toxic and to predominantly cause the damage to cardiomyocytes in secondary hemochromatosis. The development of HFE versus secondary hemochromatosis does not
Therapy Because of the mild clinical penetrance of the genetic defect there had been doubts about the rationale for iron-removal therapy. However, a recent study shows that there may be clinically relevant iron overload with organ damage and liver cancer in patients carrying the A77D mutation of ferroportin [40]. Treatment schemes
1064
only differ in terms of the speed of iron accumulation but also in the type of organ damage; in secondary hemochromatosis cardiomyopathy is often the complication which determines the prognosis [109]. It is interesting that heart disease is also very frequent in juvenile genetic hemochromatosis in which there is also a rapid iron accumulation.
Diagnosis In general, serum ferritin values closely reflect liver iron concentration and may be used to determine the indication and timing of therapy and to check the effects of iron chelation.
Therapy Until recently deferoxamine was the only iron chelator available in most countries. In some countries the drug deferiprone was also approved for patients who did not tolerate deferoxamine [89]. The clinical use of deferiprone was limited due to its side-effects, such as agranulocytosis and neutropenia [7]. Long-term data prove that deferoxamine can reduce iron overload and its organ complications [35, 48, 120, 137]. Deferoxamine, however, needs to be given daily by s.c. route or by i.v. infusion for several hours. Thus, patients with thalassemia often experienced the deferoxamine treatment worse than thalassemia itself [78]. Although deferoxamine in general may improve patients’ prognosis, minor compliance problems often limit the beneficial effects of this iron chelator [23, 36, 156]. Without iron chelation, children with thalassemia often develop severe cardiomyopathy prior to age 15 [37, 60]. After age 15 liver cirrhosis is also a significant complication in secondary iron overload due to thalassemia, while transfusion-associated hepatitis C also plays a major role for the development of liver disease in addition to iron toxicity [34, 211]. Theoretically one might be able to normalize liver iron in patients with thalassemia [22]. In clinical practice, however, the doses of deferoaxmine needed are so high that the chelator has toxic side-effect on nerves and eyes. Thus, in most patients one would tolerate slightly elevated liver iron concentrations [138]. The optimal age at which chelation therapy should be started in patients with
82
Hereditary Hemochromatosis and Iron Overload
severe thalassemia is unclear. In general chelation therapy should start early enough to prevent complications of iron overload. Very early chelation by deferoxamine before age 3 however was associated with metaphysal dysplasia [50, 136, 150]. Already between ages 3–5, liver iron concentration may reach values which are associated with a significant risk for liver fibrosis in severe thalassemia [9]. Children who are younger than 5 years should therefore be cautiously be treated with chelators if they have received transfusions for more than one year in the past [138]. Deferoxamine can reduce the incidence and ameliorate the course of iron associated cardiomyopathy [23, 120, 137, 162]. Deferasirox is a new oral iron chelator with high selectivity for iron III [124]. Deferasirox binds iron in a 2:1 proportion with a high affinity and increases the biliary iron excretion. This chelator is able to reduce iron overload in hepatocytes and cardiomyocytes [87, 124, 125]. Due to its half-time of 11–18 h it needs to be taken only once daily [74, 134]. Deferasirox exerts similar iron chelation when compared with deferoxamine in patients with thalassemia; the effect of 40 mg/ kg deferoxamine was similar to that of 20 mg/ kg deferasirox [151]. In adults with thalassemia and iron overload deferasirox at daily doses of 10, 20 and 40 mg/ kg resulted in a daily loss of 0.12, 0.33, and 0.45 mg iron/ kg body weight. A large phase 3 study analyzed the clinical effects of deferasirox in 287 adults patients (>16 years) and in 299 pediatric patients (2–16 years) with secondary iron overload [29]. Both in adults and children 20–30 mg/kg/day deferasirox reduced liver iron concentration during a 1-year treatment by 0.4 and 8.9 mg Fe/g, respectively, and also reduced serum ferritin by 36 and 926 ng/mL, respectively. At the 20 mg/ kg dose iron balance was neutral despite further transfusions while the 30 mg/kg dose resulted in a net loss of iron. MRT showed that 10–30 mg/day deferasirox reduced iron concentration in the heart after one year of therapy. Deferasirox may cause minor increases in serum creatinine as well as mild gastrointestinal discomfort and skin exanthema which are usually self limiting. The compliance is better for deferasirox when compared with deferoxamine [29]. The chelating effects of deferasirox do not depend on the underlying type of hemolytic or myelodysplastic disease [75, 157, 189, 198]. Considering the compliance problems with deferoxamine, deferasirox also has a better cost-effectiveness [47, 92, 197]. Thus, according to international guidelines deferasirox is now the standard therapy of secondary iron overload diseases [76, 80]. Data pooled from
References
several studies show that the dose of deferasirox should be chosen according to the iron load already documented and according to the rate of transfusions (Table 82.6) [38, 75, 80]. Currently a phase 2 study is analyzing the safety and efficacy of various doses of deferasirox in patients with HFE genetic hemochromatosis.
References 1. Abboud S, Haile DJ (2000) A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem 275:19906–12 2. Adams PC, Speechley M, Kertesz AE (1991) Long-term survival analysis in hereditary hemochromatosis. Gastroenterology 101: 368–72 3. Adams P, Brissot P, Powell LW (2000) EASL International consensus conference on haemochromatosis. J Hepatol 33: 485–504 4. Adams PC, Reboussin DM, Barton JC, et al (2005) Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med 352: 1769–78 5. Aguilar-Martinez P, Esculie-Coste C, Bismuth M, et al (2001) Transferrin receptor-2 gene and non-C282Y homozygous patients with hemochromatosis. Blood Cells Mol Dis 27: 290–3 6. Aguilar-Martinez P, Bismuth M, Picot MC, et al (2001) Variable phenotypic presentation of iron overload in H63D homozygotes: are genetic modifiers the cause? Gut 48: 836–42 7. al Refaie FN, Hershko C, Hoffbrand AV, et al (1995) Results of long-term deferiprone (L1) therapy: a report by the International Study Group on Oral Iron Chelators. Br J Haematol 91: 224–9 8. Ammann RW, Müller E, Bansky J, et al (1980) High incidence of extrahepatic carcinoma in idiopathic hemochromatosis. Scan J Gastroenterol 15: 733–6 9. Angelucci E, Baronciani D, Lucarelli G, et al (1995) Needle liver biopsy in thalassaemia: analyses of diagnostic accuracy and safety in 1184 consecutive biopsies. Br J Haematol 89: 757–61 10. Arden KE, Wallace DF, Dixon JL, et al (2003) A novel mutation in ferroportin1 is associated with haemochromatosis in a Solomon Islands patient. Gut 52: 1215–7 11. Bain C, Bradbear R, Siskind V, et al (1984) Cohort study of the risk of malignancy in haemochromatosis and other nonalcoholic liver diseases. Hepatology 4: A1020 12. Barton EH, West PA, Rivers CA, et al (2001) Transferrin receptor-2 (TFR2) mutation Y250X in Alabama Caucasian and African American subjects with and without primary iron overload. Blood Cells Mol Dis 27: 279–84 13. Barton JC, Acton RT, Rivers CA, et al (2003) Genotypic and phenotypic heterogeneity of African Americans with primary iron overload. Blood Cells Mol Dis 31: 310–9 14. Beutler E, Barton JC, Felitti VJ, et al (2003) Ferroportin 1 (SCL40A1) variant associated with iron overload in AfricanAmericans. Blood Cells Mol Dis 31: 305–9 15. Biasiotto G, Belloli S, Ruggeri G, et al (2003) Identification of new mutations of the HFE, hepcidin, and transferrin
1065 receptor 2 genes by denaturing HPLC analysis of individuals with biochemical indications of iron overload. Clin Chem 49: 1981–8 16. Bierens deHaan B, Scherrer JR, Stauffacher W, et al (1973) Iron excess, early glucose intolerance, and impaired insulin secretion in idiopathic hemochromatosis. Eur J Clin Invest 3: 179–87 17. Blei AT, Robbins DC, Drobny E, et al (1982) Insulin resistance and insulin receptors in hepatic cirrhosis. Gastroenterology 83: 1313–8 18. Bothwell TH, Seftel H, Jocobs P, et al (1964) Iron overload in Bantu subjects. Studies on the availability of iron in Bantu beer. Am J Clin Nutr 14: 47–51 19. Bradbear RA, Bain C, Siskind V, et al (1985) Cohort study of internal malignancy in genetic hemochromatosis and other chronic nonalcoholic liver diseases. J Natl Cancer Inst 75: 81–4 20. Brandhagen DJ, Alvarez W, Therneau TM, et al (2000) Iron overload in cirrhosis-HFE genotypes and outcome after liver transplantation. Hepatology 31: 456–60 21. Brissot P, Troadec MB, Loreal O (2004) The clinical relevance of new insights in iron transport and metabolism. Curr Hematol Rep 3: 107–15 22. Brittenham GM, Farrell DE, Harris JW, et al (1982) Magnetic-susceptibility measurement of human iron stores. N Engl J Med 307: 1671–5 23. Brittenham GM, Griffith PM, Nienhuis AW, et al (1994) Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N Engl J Med 331: 567–73 24. Buja L, Roberts WC (1971) Iron in the heart. Am J Med 51: 209–21 25. Butt HR, Wilder RM (1938) Hemochromatosis: report of 30 cases in which diagnosis was made during life. Arch Pathol 43: 551–4 26. Camaschella C (1998) Juvenile haemochromatosis. Baillieres Clin Gastroenterol 12: 227–35 27. Camaschella C, Roetto A, Cali A, et al (2000) The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet 25: 14–5 28. Camaschella C, Roetto A, De Gobbi M (2002) Juvenile hemochromatosis. Semin Hematol 39: 242–8 29. Cappellini MD, Cohen A, Piga A, et al (2006) A Phase III study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. Blood 107: 3455–62 30. Cazzola M, Ascari E, Barosi G, et al (1983) Juvenile idiopathic haemochromatosis: a life-threatening disorder presenting as hypogonadotropic hypogonadism. Hum Genet 65: 149–54 31. Cemonesi L, Forni GL, Soriani N, et al (2005) Genetic and clinical heterogeneity of ferroportin disease. Brit J Haemat 131: 663–70 32. Centers for Disease Control and Prevention. Iron overload and hemochromatosis: home (2007) http://www.cdc.gov/ ncbddd/hemochromatosis 33. Charbonnel B, Chupin M, LeGrand A, et al (1981) Pituitary function in idiopathic hemochromatosis: hormonal study in 36 male patients. Acta Endocrinologia 98: 178–83 34. Clemente MG, Congia M, Lai ME, et al (1994).Effect of iron overload on the response to recombinant interferon-alfa treatment in transfusion-dependent patients with thalassemia major and chronic hepatitis C. J Pediatr 125: 123–8
1066 35. Cohen A, Martin M, Schwartz E (1981) Response to long-term deferoxamine therapy in thalassemia. J Pediatr 99: 689–94 36. Cohen AR, Mizanin J, Schwartz E (1989) Rapid removal of excessive iron with daily, high-dose intravenous chelation therapy. J Pediatr 115: 151–5 37. Cohen A. Management of iron overload in the pediatric patient (1987) Hematol Oncol Clin North Am 1: 521–44 38. Cohen A, Masera G, Zoumbos N, et al (2005) Effect of iron intake on control of body iron in patients with thalassemia major treated with deferasirox (Exjade®, ICL670). Blood 106: A822 39. Conn HO, Schreiber W, Elkington SG, et al (1969) Cirrhosis and diabetes. I. Increased incidence of diabetes in patients with Laennec’s cirrhosis. Am J Dig Dis 14: 837–45 40. Corradini E, Ferrara F, Pollicino T, et al (2007) Disease progression and liver cancer in the ferroportin disease. Gut 56: 1030–2 41. Creutzfeldt W, Frerichs H, Sickinger K (1970) Liver diseases and diabetes mellitus. Prog Liver Dis 3: 371–407 42. Crosby WH (1966) Hereditary hemochromatosis. In: Ingelfinger FJ (ed) Controversy in internal medicine. Saunders, Philadelphia, pp 261–70 43. De Domenico I, Diane M, Ward DM, et al (2007) Hepcidin regulation: ironing out the details. J Clin Invest 117: 1755–8 44. De Domenico I, Ward DM, Nemeth E, et al (2005) The molecular basis of ferroportin-linked hemochromatosis. Proc Nat Acad Sci 102: 8955–60 45. De Gobbi M, Pasquero P, Brunello F, et al (2000) Juvenile hemochromatosis associated with B-thalassemia treated by phlebotomy and recombinant human erythropoietin. Haematologica 85: 865–7 46. Delatycki MB, Allen KJ, Gow P, et al (2004) A homozygous HAMP mutation in a multiply consanguineous family with pseudo-dominant juvenile hemochromatosis. Clin Genet 65: 378–83 47. Delea E, Sofrygin O, Baladi JF, et al (2006) Sensitivity analysis of the cost-effectiveness of chelation therapy with deferasirox or deferoxamin in transfusion-dependent thalassemia based on European costs. 11th EHA Congress, Amsterdam p. 8 48. Desferal® Basic Prescribing Information (1998) Basel, Switzerland: Novartis Pharma AG, p. 27 49. Devalia V, Carter K, Walker AP, et al (2002) Autosomal dominant reticuloendothelial iron overload associated with a 3-base pair deletion in the ferroportin 1 gene (SLC11A3). Blood 100: 695–7 50. De Virgiliis S, Congia M, Frau F, et al (1988) Deferoxamineinduced growth retardation in patients with thalassemia major. J Pediatr 113: 661–9 51. Diamond T, Stiel D, Posen S (1989) Osteoporosis in hemochromatosis: iron excess, gonadal deficiency, or other factors? Ann Intern Med 110: 430–6 52. Donovan A, Brownlie A, Zhou Y, et al (2000) Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 403: 778–81 53. Donovan A, Lima CA, Pinkus JL, et al (2005) The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab 1: 191–200 54. Drakesmith H, Schimanski LM, Ormerod E, et al (2005) Resistance to hepcidin is conferred by hemochromatosisassociated mutations of ferroportin. Blood 106:1092–7
82
Hereditary Hemochromatosis and Iron Overload
55. Dymock W, Hamilton EBD, Laws JW, et al (1970) Arthropathy of hemochromatosis: clinical and radiological analysis of 73 patients with iron overload. Ann Rheum Dis 29: 469–76 56. Dymock W, Cassar J, Pyke DA, et al (1972) Observations on the pathogenesis, complications, and treatment of diabetes in 115 cases of hemochromatosis. Am J Med 52: 203–10 57. Edwards CQ, Griffen LM, Goldgar D, et al (1988) Prevalence of hemochromatosis among 11,065 presumably healthy blood donors. N Engl J Med 318: 1355–62 58. Elmberg M, Hultcrantz R, Ekbom A, et al (2003) Cancer risk in patients with hereditary hemochromatosis and in their first-degree relatives. Gastroenterology 125: 1733–41 59. EMEA. European Medicines Agency (2005) Ferriprox European Public Assessment Report. www.emea.eu.int. und Exjade product information, Novartis Pharmaceuticals Corporation. 2005. Exjade (deferasirox) Prescribing information online, www.exjade.com 60. Engle MA, Erlandson M, Smith CH (1964) Late cardiac complications of chronic, severe, refractory anemia with hemochromatosis. Circulation 30: 698–705 61. Erhardt A, Niederau C, Osman Y, et al (1999) Demonstration of HFE polymorphism in German patients with hereditary hemochromatosis. Dtsch Med Wochenschr 124: 1448–52 62. Erhardt A, Maschner-Olberg A, Mellenthin C, et al (2003) HFE mutations and chronic hepatitis C: H63D and C282Y heterozygosity are independent risk factors for liver fibrosis and cirrhosis. J Hepatol 38: 335–42 63. Fargion S, Mandelli C, Piperno A, et al (1992) Survival and prognostic factors in 212 Italian patients with genetic hemochromatosis. Hepatology 15: 655–9 64. Feder JN, Gnirke A, Thomas W, et al (1996) A novel MCH class I-like gene is mutated in patients with hereditary haemochromatosis. Nature Genetics 13: 399–407 65. Filali M, Le Jeunne C, Durand E, et al (2004) Juvenile hemochromatosis HJV-related revealed by cardiogenic shock. Blood Cells Mol Dis 33: 120–4 66. Finch SC, Finch CA (1966) Idiopathic hemochromatosis, an iron storage disease. Medicine (Baltimore) 34: 381–430 67. Fleming RE, Sly WS (2001) Ferroportin mutation in autosomal dominant hemochromatosis: loss of function, gain in understanding. J Clin Invest 108: 521–2 68. Fleming RE, Sly WS (2002) Mechanisms of iron accumulation in hereditary hemochromatosis. Ann Rev Physiol 4: 663–80 69. Fleming RE, Ahmann JR, Migas MC, et al (2002) Targeted mutagenesis of the murine transferrin receptor-2 gene produces hemochromatosis. Proc Natl Acad Sci USA 99: 10653–8 70. Fleming RE (2005) Advances in understanding the molecular basis for the regulation of dietary iron absorption. Curr Opin Gastroenterol 21: 201–16 71. Fletcher LM, Halliday JW (2002) Haemochromatosis: understanding the mechanism of disease and implications for diagnosis and patient management following the recent cloning of novel genes involved in iron metabolism. J Intern Med 251: 181–92 72. Fracanzani AL, Conte D, Fraquelli M, et al (2001) Increased cancer risk in a cohort of 230 patients with hereditary hemochromatosis in comparison to matched control patients with non-iron-related chronic liver disease. Hepatology 33: 647–51
References 73. Galanello R, Piga A, Alberti D, et al (2003) Safety, tolerability, and pharmacokinetics of ICL670, a new orally active iron-chelating agent in patients with transfusion-dependent iron overload due to beta-thalassemia. J Clin Pharmacol 43: 565–72 74. Galanello R, Piga A, Forni GL, et al (2006) Phase II clinical evaluationof deferasirox (Exjade, ICL670), a once-daily oral chelating agent, in paediatric patients with beta-thalassaemia major. Haematologica 91: 1343–51 75. Gattermann N, Cazzola M, Greenberg P, et al (2005) The efficacy and tolerability of ICL670, a once-daily oral iron chelator, in patients with myelodysplastic syndrome and iron overload. Leuk Res 29: S67–S74 76. Gattermann N (2005) Consensus statement on iron overload in myelodysplastic syndromes. Hematol Oncol Clin N Am 19: S18–S25 77. Girelli D, Bozzini C, Roetto A (2002) Clinical and pathological finding in hemochromatosis type 3 due to a novel mutation in transferrin receptor 2 gene. Gastroenterology 122: 1295–302 78. Goldbeck L, Baving A, Kohne E (2000) Psychosocial aspects of beta-thalassemia: distress, coping and adherence. Klin Pädiatr 212: 254–9 79. Gordeuk VR, Caleffi A, Corradini E, et al (2003) Iron overload in Africans and African-Americans and a common mutation in the SCL40A1 (ferroportin 1) gene. Blood Cells Mol Dis 31: 299–304 80. Greenberg PL, Baer MR, Bennett JM, et al (2006) Myelodysplastic syndromesclinical practice guidelines in oncology. J Natl Compr Canc Netw 4: 58–77 81. Haile DJ (2000) Assignment of Slc11a3 to mouse chromosome 1 band 1B and SLC11A3 to human chromosome 2q21 by in situ hybridization. Cytogenet Cell Genet 88: 328–9 82. Hanot V, Schachmann M (1886) Sur la cirrhose pigmentaire dans le diabète. sucré. Arch Physiol Norm Pathol 7: 50–72 83. Hartroft WS (1956) Islet pathology in diabetes. Diabetes 5: 98–104 84. Hattori A, Wakusawa S, Hayashi H, et al (2003) AVAQ 594– 597 deletion of the TfR2 gene in a Japanese family with hemochromatosis. Hepatol Res 26: 154–6 85. Hentze MW, Muckenthaler MU, Andrews NC (2004) Balancing acts: molecular control of mammalian iron metabolism. Cell 117: 285–97 86. Herbay von A, Niederau C, Pelichowska M, et al (1996) Kardiomyopathie als Todesursache bei genetischer Hämochromatose. Z Gastroenterol 34: 178–82 87. Hershko C, Konijn AM, Nick HP, et al (2001) ICL670A: a new syntheticoral chelator: evaluation in hypertransfused rats with selective radio iron probes of hepatocellular and reticuloendothelial iron stores and in ironloadedrat heart cells in culture. Blood 97: 1115–22 88. Hetet G, Devaux I, Soufir N, et al (2003) Molecular analyses of patients with hyperferritinemia and normal serum iron values reveal both L ferritin IRE and 3 new ferroportin (slc11A3) mutations. Blood 102: 1904–10 89. Hoffbrand AV, Cohen A, Hershko C (2003) Role of deferiprone in chelation therapy for transfusional iron overload. Blood 102: 17–24 90. Jensen PD, Bagger JP, Jensen FT, et al (1993) Heart transplantation in a case of juvenile hereditary haemochromatosis followed up by MRI and endomyocardial biopsies. Eur J Haematol 51: 199–205
1067 91. Jouanolle AM, Douabin-Gicquel V, Halimi C, et al (2003) Novel mutation in ferroportin 1 gene is associated with autosomal dominant iron overload. J Hepatol 39: 286–9 92. Karron J, Akehurst RL, Papo NL (2006) Cost utility analysis of deferasirox versus deferoxamin for patients requiring chelation therapy in the United Kingdom. 11th EHA Congress, Amsterdam, p A0812 93. Kawabata H, Yang R, Hirama T, et al (1999) Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family. J Biol Chem 274: 20826–32 94. Kawabata H, Germain RS, Vuong PT, et al (2000) Transferrin receptor 2-alpha supports cell growth both in iron-chelated cultured cells and in vivo. J Biol Chem 275: 16618–25 95. Kawabata H, Fleming RE, Gui D, et al (2005) Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis. Blood 105: 376–81 96. Kelly AL, Rhodes DA, Roland JM, et al (1998) Hereditary juvenile haemochromatosis: a genetically heterogeneous life-threatening iron-storage disease. QJM 91: 607–18 97. Kley HK, Stremmel W, Niederau C, et al (1985a) Androgen and estrogen response to adrenal and gonadal stimulation in idiopathic hemochromatosis: evidence for decreased estrogen formation Hepatology 5: 251–6 98. Kley HK, Niederau C, Stremmel W, et al (1985b) Conversion of androgens to estrogens in idiopathic hemochromatosis: comparison with alcoholic cirrhosis. J Clin Endocrinol Metabol 61: 1–6 99. Kowdley K, Hassanein T, Kaur S, et al (1995) Primary liver cancer and survival in patients undergoing liver transplantation for hemochromatosis. Liver Transpl Surg 1: 237–41 100. Koyama C, Wakusawa S, Hayashi H, et al (2005) Two novel mutations, L490R and V561X, of the transferrin receptor 2 gene in Japanese patients with hemochromatosis. Haematologica 90: 302–7 101. Lamon JM, Marynick SP, Rosenblatt R, et al (1979) Idiopathic hemochromatosis in a young female. Gastroenterology 76: 178–84 102. Lanzara C, Roetto A, Daraio F, et al (2004) Spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis. Blood 103: 4317–21 103. Le Gac G, Mons F, Jacolot S, et al (2004) Early onset hereditary hemochromatosis resulting from a novel TFR2 gene nonsense mutation (R105X) in two siblings of north French descent. Br J Haematol 125: 674–8 104. Lee PL, Halloran C, West C, et al (2001) Mutation analysis of the transferrin receptor-2 gene in patients with iron overload. Blood Cells Mol Dis 27: 285–9 105. Lee PL, Gelbart T, West C, et al (2002) Seeking candidate mutations that affect iron homeostasis. Blood Cells Mol Dis 29: 471–87 106. Lee PL, Barton JC, Brandhagen D, et al (2004a) Hemojuvelin (HJV) mutations in persons of European, African-American and Asian ancestry with adult onset haemochromatosis. Br J Haematol 127: 224–9 107. Lee PL, Beutler E, Rao SV, et al (2004b) Genetic abnormalities and juvenile hemochromatosis: mutations of the HJV gene encoding hemojuvelin. Blood 103: 4669–71 108. Levy LC, Carlson HE (1978) Decreased prolactin reserve in hemochromatosis. J Clin Endocrinol Metabol 47: 444–6
1068 109. Liu P, Olivieri N (1994) Iron overload cardiomyopathies: new insights into an old disease. Cardiovasc Drugs Ther 8: 101–10 110. Loreal O, Deugnier Y, Moirand R (1992) Liver fibrosis in genetic hemochromatosis. Respective roles of iron and noniron related factors in 127 homozygous patients. J Hepatol 16: 122–7 111. Majore S, Binni F, Pennese A, et al (2004) HAMP gene mutation c.208T>C (p.C70R) identified in an Italian patient with severe hereditary hemochromatosis. Hum Mutat 23: 400–5 112. MacDonald RA, Mallory GK (1960) Hemochromatosis and hemosiderosis. Study in 211 autopsied cases. Arch Intern Med 105: 686–700 113. Matthes T, Aguilar-Martinez P, Pizzi-Bosman L, et al (2004) Severe hemochromatosis in a Portuguese family associated with a new mutation in the 5'UTR of the hepcidin gene. Blood 104: 2181–3 114. Mattman A, Huntsman D, Lockitch G, et al (2002) Transferrin receptor 2 (TfR2) and HFE mutational analysis in non-C282Y iron overload: identification of a novel TfR2 mutation. Blood 100: 1075–7 115. McKie AT, Marciani P, Rolfs A, et al (2000) A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 5: 299–309 116. McKie AT, Barlow DJ (2004) The SLC40 basolateral iron transporter family (IREG1/ferroportin/MTP1). Pflugers Arch 447: 801–6 117. McLaren GD, Muir WA, Kellermeyer RW (1983) In overload disorders: natural history, pathogenesis, diagnosis, and therapy. Crit Rev Clin Lab Sci 19: 205–66 118. Merryweather-Clarke AT, Cadet E, Bomford A, et al (2003) Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis. Hum Mol Genet 12: 2241–7 119. Meregalli M, Pellagatti A, Bissolotti E, et al (2000) Molecular analysis of the TFR2 gene: report of a novel polymorphism (1878C>T). Hum Mutat 16: 532–9 120. Miskin H, Yaniv I, Berant M, et al (2003) Reversal of cardiac complications in thalassemia major by long-term intermittent daily intensive iron chelation. Eur J Haematol 70: 398–403 121. Montosi G, Donovan A, Totaro A, et al (2001) Autosomaldominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest 108: 619–23 122. Nemeth E, Tuttle MS, Powelson J, et al (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306: 2090–3 123. Nemeth E, Roetto A, Garozzo G, et al (2005) Hepcidin is decreased in TFR2-Hemochromatosis. Blood 105: 1803–6 124. Nick H, Acklin P, Lattmann R, et al (2003) Development of tridentate iron chelators: from desferrithiocin to ICL670. Curr Med Chem 10: 1065–76 125. Nick H, Wong A, Acklin P, et al (2002) ICL670A: preclinical profile. Adv Exp Med Biol 509: 185–203 126. Niederau C, Stremmel W, Strohmeyer G (1981) Eisenüberladung und Hämochromatose. Internist 22: 546–54 127. Niederau C, Berger M, Stremmel W, et al (1984) Hyperinsulinaemia in non-cirrhotic haemochromatosis: impaired hepatic insulin degradation? Diabetologia 26: 441–4
82
Hereditary Hemochromatosis and Iron Overload
128. Niederau C, Fischer R, Sonnenberg A, et al (1985) Survival and causes of death in cirrhotic and noncirrhotic patients with primary haemochromatosis. New Engl J Med 313: 1256–62 129. Niederau C, Fischer R, Pürschel A, et al (1996) Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 110: 1107–19 130. Niederau C, Niederau CM, Littauer A, et al (1998) Screening for iron overload and iron deficiency. Ann Int Med 128: 337–45 131. Niederau C (1999) Diabetes mellitus bei Hämochromatose. Z Gastroenterol 37: 22–32 132. Niederau C (2000) Iron overload and atherosclerosis. Hepatology 32: 569–74 133. Niederau C, Strohmeyer G (2002) Strategies for early diagnosis of haemochromatosis. Eur J Gastroenterol Hepatol 14: 1–5 134. Nisbet-Brown E, Olivieri F, Giardina PJ, et al (2003) Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebocontrolled, dose-escalation trial. Lancet 361: 1597–602 135. Njajou OT, Vaessen N, Joosse M, et al (2001) A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat Genet 28: 213–4 136. Olivieri NF, Koren G, Harris J, et al (1992) Growth failure and bony changes induced by deferoxamine. Am J Pediatr Hematol Oncol 14: 48–56 137. Olivieri NF, Nathan DG, Macmillan JH, et al (1994) Survival in medically treated patients with homozygous beta-thalassemia. N Engl J Med 331: 574–8 138. Olivieri NF, Brittenham GM (1997) Iron-chelating therapy and the treatment of thalassemia. Blood 89: 739–61 139. Papanikolaou G, Samuels ME, Ludwig EH, et al (2004) Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet 36: 77–82 140. Park CH, Valore EV, Waring AJ, et al (2001) Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Bioll Chem 276: 7806–10 141. Parkes JG, Randell EW, Olivieri NF, et al (1995) Modulation by iron loading and chelation of the uptake of non-transferrinbound iron by human liver cells. Biochim Biophys Acta 1243: 373–80 142. Phatak PD, Sham RL, Raubertas RF, et al (1998) Prevalence of hereditary hemochromatosis in 16,031 primary care patients. Ann Intern Med 129: 954–61 143. Phelps G, Chapman I, Hall P, et al (1989) Prevalence of genetic haemochromatosis among diabetic patients. Lancet 2: 233–4 144. Pietrangelo A, Montosi G, Totaro A (1999) Hereditary hemochromatosis in adults without pathogenic mutations in the hemochromatosis gene. N Engl J Med 341: 725–32 145. Pietrangelo A (2002) Physiology of iron transport and the hemochromatosis gene. Am J Physiol Gastrointest Liver Physiol 282: G403–G414 146. Pietrangelo A (2004a) Hereditary hemochromatosis – a new look at an old disease. N Engl J Med 350: 2383–97 147. Pietrangelo A (2004) The ferroportin disease. Blood Cells Mol Dis 32: 131–8 148. Pietrangelo A, Caleffi A, Henrion J, et al (2005) Juvenile hemochromatosis associated with pathogenic mutations of adult hemochromatosis genes. Gastroenterology 128: 470–9
References 149. Pietrangelo A, Dierssen U, Valli L, et al (2007) STAT3 is required for IL-6-gp130-dependent activation of hepcidin in vivo. Gastroenterology 132: 294–300 150. Piga A, Luzzatto L, Capalbo P, et al (1988) High-dose desferrioxamine as a cause of growth failure in thalassemic patients. Eur J Haematol 40: 380–1 151. Piga A, Galanello R, Forni GL, et al (2006) Randomized phase II trial of deferasirox (Exjade, ICL670), a once-daily, orally-administered iron chelator, in comparison to deferoxamine in thalassemia patients with transfusional iron overload. Haematologica 91: 873–80 152. Piperno A, Roetto A, Mariani R, et al (2004) Homozygosity for transferrin receptor-2 Y250X mutation induces early iron overload. Haematologica 89: 359–60 153. Pissia M, Polonifi K, Politou M, et al (2004) Prevalence of the G320V mutation of the HJV gene, associated with juvenile hemochromatosis, in Greece. Haematologica 89: 742–3 154. Pomarede, R, Girot, R, Constant, S, et al (1984) Effect of hematologic treatment on the growth and puberty of children with thalassemia major. Arch Fr Pediatr 41: 255–9 155. Pootrakul, P, Breuer, W, Sametband, M, et al (2004) Labile plasma iron (LPI) as an indicator of chelatable plasma redox activity in iron-overloaded beta-thalassemia/HbE patients treated with an oral chelator. Blood 104: 1504–10 156. Porter JB (2001) Practical management of iron overload. Br J Haematol 115: 239–52 157. Porter J, Borgna-Pignatti C, Baccarani M, et al (2005) Iron chelation efficiency of deferasirox (Exjade®, ICL670) in patients with transfusional hemosiderosis. Blood 106: A2690 158. Powell LW, Mortimer R, Harris OD (1971) Cirrhosis of the liver: A comparative study of the four major aetiological groups. Med J Aust 58: 1941–50 159. Pozza G, Ghidoni A (1968) Studies in the diabetic syndrome of idiopathic hemochromatosis. Diabetologia 4: 83–6 160. Qaseem A, Aronson M, Fitterman N, et al (2005) Screening for hereditary hemochromatosis: a clinical practice guideline from the American College of Physicians. Ann Intern Med 143: 517–21 161. Rahier J, Loozen S, Goebbels RM, et al (1987) The haemochromatosis human pancreas: a quantitative immunochemical and ultrastructural study. Diabetologia 30: 5–12 162. Rahko PS, Salerni R, Uretsky BF (1986) Successful reversal by chelation therapy of congestive cardiomyopathy due to iron overload. J Am Coll Cardiol 8: 436–40 163. Recklinghausen von FD (1889) Über Hämochromatose. Berl Klin Wochenschr 26: 925 164. Rivard SR, Lanzara C, Grimard D, et al (2003) Autosomal dominant reticuloendothelial iron overload (HFE type 4) due to a new missense mutation in the FERROPORTIN 1 gene (SLC11A3) in a large French-Canadian family. Haematologica 88: 824–6 165. Rivers CA, Barton JC, Gordeuk VR, et al (2007) Association of ferroportin Q248H polymorphism with elevated levels of serum ferritin in African Americans in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. Blood Cells Mol Dis 38: 247–52 166. Robson KJ, Merryweather-Clarke AT, Cadet E, et al (2004) Recent advances in understanding haemochromatosis: a transition state. J Med Genet 41: 721–30 167. Roetto A, Totaro A, Cazzola M, et al (1999) Juvenile hemochromatosis locus maps to chromosome 1q. Am J Hum Genet 64: 1388–93
1069 168. Roetto A, Totaro A, Piperno A, et al (2001) New mutations inactivating transferrin receptor 2 in hemochromatosis type 3. Blood 97: 2555–60 169. Roetto A, Merryweather-Clarke AT, Daraio F, et al (2002) A valine deletion of ferroportin 1: a common mutation in hemochromastosis type 4. Blood 100: 733–4 170. Roetto A, Daraio F, Alberti F, et al (2002) Hemochromatosis due to mutations in transferrin receptor 2. Blood Cells Mol Dis 29: 465–70 171. Roetto A, De Braekeleer M, Bechner L, et al (2003) Juvenile hemochromatosis locus maps to chromosome 1q in a French Canadian population. Eur J Hum Genet 11: 585–9 172. Roetto A, Daraio F, Porporato P, et al (2004) Screening hepcidin for mutations in juvenile hemochromatosis: identification of a new mutation (C70R). Blood 103: 2407–9 173. Roy CN, Andrews NC (2001) Recent advances in disorders of iron metabolism: mutations, mechanisms and modifiers. Hum Molec Genet 10: 2181–6 174. Saddi R, Feingold J (1974) Idiopathic hemochromatosis and diabetes mellitus. Clin Gent 5:242–7 175. Schimanski LM, Drakesmith H, Merryweather-Clarke AT, et al (2005) In vitro functional analysis of human ferroportin (FPN) and hemochromatosis-associated FPN mutations. Blood 105:4096–102 176. Schuhmacher HR (1964) Hemochromatosis and arthritis. Arthr Rheum 7: 41–50 177. Sheldon JH (1935) Haemochromatosis. Oxford University Press, London 178. Short EM, Winkle RA, Billingham ME (1979) Myocardial involvment in idiopathic hemochromatosis. Am J Med 70: 1275–9 179. Simon M, Franchimont P, Murie N, et al (1972) Study of somatotrophic and gonadotrophic pituitary function in idiopathic hemochromatosis. Eur J Clin Invest 2: 384–9 180. Simon M, Pawlotsky Y, Bourel M, et al (1975) Hemochromatose idiopathique. Maladie associee a l’antigen HLA-A3? Nouv Press Med 4: 1432 181. Simon M, Bourel M, Genetet B (1977) Idiopathic hemochromatosis: demonstration of recessive transmission and early detection by family HLA typing. N Engl J Med 297: 1017–21 182. Singh BM, Grunewald RA, Press M, et al (1992) Prevalence of haemochromatosis amongst patients with diabetes mellitus. Diabet Med 9: 730–1 183. SMPC. Ferriprox TM (2006) Summary of Product Characteristics. www.emea.eu.int 184. Stocks AE, Martin J (1968) Pituitary function in hemochromatosis. Am J Med 45: 839–45 185. Stocks AE, Powell LW (1972) Pituitary function in hemochromatosis and cirrhosis of the liver. Lancet 2: 298–300 186. Strohmeyer G, Gottesbüren H, Behr C, et al (1976) Diabetes mellitus bei idiopathischer Hämochromatose. Dtsch Med Wschr 101: 1055–60 187. Summers KM, Halliday JW, Powell LW (1990) Identification of homozygous hemochromatosis subjects by measurement of hepatic iron index. Hepatology 12: 20–5 188. Tavill AS (2001) Diagnosis and management of hemochromatosis. Hepatology 33: 1321–8 189. Tchernia G, Vichinsky E, Jeng M, et al (2005) The oncedaily oral ironchelator ICL670 is well tolerated and effective in treating transfusional iron overload in Diamond-Blackfan anaemia patients. Haematologica 90: S192–S199
1070 190. Telfer PT, Prestcott E, Holden S, et al (2000) Hepatic iron concentration combined with long-term monitoring of serum ferritin to predict complications of iron overload in thalassaemia major. Br J Haematol 110: 971–7 191. Toll A, Celis R, Ozalla MD, et al (2006) The prevalence of HFE C282Y gene mutation is increased in Spanish patients with porphyria cutanea tarda without hepatitis C virus infection. J Eur Acad Dermatol Venereol 20: 1201–6 192. Troisier M (1871) Diabete sucre. Bull Soc Anatom (Paris) 16: 231–5 193. Trosseau A (1865) Glucosurie: Diabete sucre. Bull Soc Anatom (Paris) 2: 663 194. Townsend A, Drakesmith H (2002) Role of HFE in iron metabolism, hereditary haemochromatosis, anaemia of chronic disease, and secondary iron overload. Lancet 359: 786–90 195. U.S. Preventive Services Task Force (2007) Screening for Hemochromatosis: Recommendation Statement. Am Fam Phys 75: 11–21 196. Vaiopoulos G, Papanikolaou G, Politou M, et al (2003) Arthropathy in juvenile hemochromatosis. Arthritis Rheum 48: 227–30 197. Vichinsky E, Fischer R, Pakbaz Z, et al (2005) Satisfaction and convenience of chelation therapy in patients with sickle cell disease (SCD): comparison between deferasirox (Exjade®, ICL670) and deferoxamine (DFO). Blood 106: A2334 198. Vichinsky E, Onyekwere O, Porter J, et al (2007) A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease. Br J Haematol 36: 501–8 199. Vigorita VJ, Hutchins GM (1979) Cardiac conduction system in hemochromatosis: clinical and pathologic features of six patients. Am J Cardiol 44: 418–23 200. Vulpe CD, Kuo YM, Murphy TL, et al (1999) Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat Genet 21: 195–9
82
Hereditary Hemochromatosis and Iron Overload
201. Walker RJ, Newton JR, Williams SR (1976) Testicular function and the pituitary-hypothalamic axis in the hypogonadism of primary idiopathic hemochromatosis. Med Chir Dis 5: 67–71 202. Wallace DF, Pedersen P, Dixon JL, et al (2002) Novel mutation in ferroportin1 is associated with autosomal dominant hemochromatosis. Blood 100: 692–4 203. Wallace DF, Clark RM, Harley HA, et al (2004) Autosomal dominant iron overload due to a novel mutation of ferroportin1 associated with parenchymal iron loading and cirrhosis. J Hepatol 40: 710–3 204. Wallace DF, Summerville L, Lusby PE, et al (2005) First phenotypic description of transferrin receptor 2 knockout mouse, and the role of hepcidin. Gut 54: 980–6 205. Walsh CH, Wright AD, Williams JW, et al (1976) A study of pituitary function in patients with idiopathic hemochromatosis. J Clin Endocrinol Metabol 43: 866–72 206. Walton C, Kelly WF, Laing I, et al (1983) Endocrine abnormalities in idiopathic hemochromatosis. Q J Med 205: 99–110 207. Whitington PF, Hibbard JU (2004) High-dose immunoglobulin during pregnancy for recurrent neonatal haemochromatosis. Lancet 364: 1690–8 208. Wöhler F (1964) Pathophysiologie und Therapie der Hämochromatose. Verh Dtsch Ges Inn Med 70: 300–2 209. Yaouanq JM (1995) Diabetes and hemochromatosis: current concepts, management and prevention. Diabete et Metabolisme (Paris) 21: 219–329 210. Zhang AS, Xiong S, Tsukamoto H, et al (2004) Localization of iron metabolism-related mRNAs in rat liver indicate that HFE is expressed predominantly in hepatocytes. Blood 103: 1509–14 211. Zurlo MG, De Stefano P, Borgna-Pignatti C, et al (1989) Survival and causes of death in thalassaemia major. Lancet 2: 27–30
a1 - Antitrypsin Deficiency
83
Henryk Dancygier
Chapter Outline Definition....................................................................... 1072 Epidemiology ................................................................ 1072 Etiology and Pathogenesis ........................................... 1072 Pathology ...................................................................... 1073 Clinical Manifestations ................................................ 1073 Laboratory Findings .................................................... 1075 Differential Diagnosis .................................................. 1075 Course and Prognosis .................................................. 1075 Therapy ......................................................................... 1075 References ..................................................................... 1076
a1-antitrypsin is a 56 kd-glycoprotein (b1-globulin; 394 amino acids with 3 carbohydrate side chains) belonging to the family of serine protease inhibitors also called “serpines”. It is secreted into the circulation primarily by the liver and to a lesser extent by macrophages. Serpines regulate proteolytic cascades, for example in inflammatory processes, blood coagulation and complement activation. a1-antitrypsin usually occurs in lacrimal and nasal secretions, saliva, duodenal juice, bronchial secretion, cerebrospinal fluid and breast milk. The concentration of a1-antitrypsin in amniotic fluid commonly corresponds to approximately 10% of its normal serum level. Inflammation, infections, malignant diseases, pregnancy or estrogen treatment may lead to a two- to threefold increase in serum concentration. Patients with a1-antitrypsin deficiency, however, do not show a noteworthy induction by these stimuli. The antiproteolytic activity of a1-antitrypsin (half life 4–5 days) is not only directed against trypsin, but also against many serine proteases (for example chymotrypsin, pancreatic elastase, collagenase, renin, urokinase, clotting factor XII) and neutral proteases of polymorphonuclear leukocytes. Therefore, the old term a1-antitrypsin is often replaced by the more inclusive term a1-protease inhibitor. The antiproteolytically active center of a1-antitrypsin is located near the carboxyterminus of the polypeptide. Here the peptide chain forms a loop whose amino acid sequence keeps the molecule in a metastabile form (Fig. 83.1). This loop with methionine in position 358 forms the structural basis for the inhibition of serine proteases. Oxidation of methionine abolishes the antiproteolytic effect. The most important substrate for a1-antitrypsin is neutrophil elastase. Protease inhibition occurs by forming a 1:1 complex of a1-antitrypsin and its target protease.
H. Dancygier, Clinical Hepatology, DOI: 10.1007/978-3-642-04519-6_83, © Springer-Verlag Berlin Heidelberg 2010
1071
83 α1 - Antitrypsin Deficiency
1072 H2O2 Met 358
Leukocyte collagenase Leukocyte elastase Monocyte elastase
394 C Other serine proteases
N Z342
Fig. 83.1 Structure of the active center of a1-antitrypsin. The molecule forms a loop as a prerequisite for its antiproteolytic effect. The amino acid at position 358 determines the substrate specificity. For example, methionine: inhibition of leukocyte elastase; arginine: inhibition of thrombin. Oxidation of methionine leads to the loss of enzymatic activity. Z mutation results in an exchange of amino acids at position 342
Definition The classical form of a1-antitrypsin deficiency is an autosomal-codominant disorder that was described for the first time in 1963. Reduced serum levels of a1-antitrypsin or its complete absence may lead to liver disease and to the development of pulmonary emphysema. The changes in the liver are characterized by a secretory defect of mutant a1-antitrypsin which accumulates in the endoplasmic reticulum of hepatocytes forming globular inclusions. In the pediatric patient, liver disease may manifest as neonatal cholestasis or juvenile cirrhosis, in the adult as chronic liver disease leading to cirrhosis and hepatocellular carcinoma. Most patients die of respiratory failure (50–70%; not discussed in this chapter), 10–15% of decompensated liver cirrhosis [8].
Epidemiology a1-antitrypsin deficiency is a relatively frequent autosomal-codominant disorder caused by the mutation of two alleles. It occurs in approximately 1:1,800 live births and is the most common genetic cause of liver disease in children.
Etiology and Pathogenesis The gene coding for a1-antitrypsin is located on chromosome 14 close to the genes for the immunoglobulin heavy chains. It consists of five exons. While exon I
regulates gene expression by binding nuclear proteins, exon V is coding for the active center of a1-antitrypsin. Several point mutations of a1-antitrypsin cause a perturbation in protein structure (a1-antitrypsin Z or a1-ATZ) with consequent polymerization and intracellular accumulation. The retention of polymers of a1-antitrypsin within hepatocytes results in protein overload [8]. The reduction of serum levels of a1-antitrypsin is not caused by an impairment of protein synthesis at the translational or transcriptional level, but is due to a transport defect of the mutant protein across the endoplasmic reticulum to the Golgi apparatus. The translated protein contains a sequence of 24 amino acids at its N-terminus, signaling its location in the endoplasmic reticulum where carbohydrate side chains are attached to three asparagine residues. Usually a modification of these carbohydrate chains takes place in the Golgi apparatus with transformation of the molecule from the “high mannose” to the “complex type” (processing). This transformation is the prerequisite for the secretion of the protein from the liver into the extracellular space. The mutant Z-gene leads to an amino acid substitution (lysine for glutamic acid at position 342) resulting in an unstable molecule. The ensuing “aggregate” of a1-antitrypsin molecules, due to its new physical properties cannot be transported through the tubular system of the endoplasmic reticulum. Structural processing in the Golgi apparatus cannot occur, thus preventing exocytosis of a1-ATZ proteins into the blood. However, single proteins may separate from the aggregates, cross the Golgi apparatus and appear in the circulation. These a1-ATZ monomers exhibit partial protease inhibitor activity (see below) and explain residual a1-antitrypsin levels in serum. The complete causal chain that leads to liver damage remains elusive. The retention of a1-ATZ in the endoplasmic reticulum, hepatocyte damage induced by uninhibited leukocyte proteases, and stimulation of cellular autoimmune reactions are currently discussed. A correlation between a1-antitrypsin deficiency in serum, its retention in the endoplasmic reticulum and the development of liver damage could be experimentally demonstrated in phenotype PiZZ animals. The a1-antitrypsin phenotype is extremely variable. Currently, more than 100 allelic variants of the a1antitrypsin gene are known. Two alleles determine an individual’s phenotype. They may be differentiated by their electrophoretic mobility on isoelectric focussing
Clinical Manifestations
1073
and are designated with capital letters. Fast moving proteins receive the first letters of the alphabet, while the most slowly moving protein is denominated with letter Z. The most common phenotype is PiMM (Pi = protease inhibitor) is associated with normal serum levels of a1-antitrypsin. In Europe, in addition to the most prevalent M allele, S and Z alleles occur at significantly lower frequencies. Cryptic genetic variants within the a1-antitrypsin gene may contribute to susceptibility to liver disease. Single nucleotide polymorphisms that confer a significant risk for liver disease have been identified [2]. In Table 83.1 the most important a1-antitrypsin phenotypes, their prevalence, their impact on a1-antitrypsin serum levels and the development of liver disease is reported.
(Fig. 83.2). The diagnosis can be confirmed by specific immunohistochemical staining (Fig. 83.3). An antibody that specifically recognizes a conformationdependent neoepitope on polymerized a1-antitrypsin has also been described [7]. In the heterozygous state inclusions are present without associated liver disease. In the adult with homozygous a1-antitrypsin deficiency, the disease may progress to micronodular or mixed macro- and micronodular type cirrhosis with little inflammatory changes in the fibrous septa and parenchyma. In neonates and infants biliary lesions predominate. Neonatal cholestasis, ductular reaction and fibrosis occur. Occasionally liver disease progresses to biliary type cirrhosis.
Clinical Manifestations Pathology The microscopical changes are characterized by numerous distinct globular eosinophilic intracytoplasmic inclusions. They occur predominantly in periportal or periseptal hepatocytes, but may occasionally be seen in the cytoplasm of bile duct epithelial cells. Concomitant steatosis is often present. On PAS staining after diastase digestion the diastase resistant inclusions are bright red to purple Table 83.1 a1-antitrypsin phenotypes Allelic Amino Amino acid pattern acid position PiMM
The clinical manifestations of patients with homozygous PiZZ a1-antitrypsin deficiency are highly variable. They depend on the age at first manifestation, on the organs involved and the rate of progression. The major organs involved are lungs and liver. Pulmonary disease is characterized by early developing pulmonary emphysema. Extrahepatic manifestations may rarely occur and encompass pancreatic fibrosis, membranoproliferative glomerulonephritis, panniculitis,
Homo-/heterozygous
a1-antitrypsin concentration in serum (N = 100–300 mg/dL)
Significance
Glutamate Glutamate Lysine
Homozygous
100%
Normal phenotype
PiZZ
264 342 342
Homozygous
10–15% of N
PiMZ
342
Lysine
Heterozygous
60% of N
PiSS
264
Valine
Homozygous
60% of N
PiMS
264
Valine
Heterozygous
60% of N
PiSZ
264 342
Valine Lysine
Heterozygous
40% of N
Marked configurational change with secretory defect. Hepatic and pulmonary changes. 3% of population. No liver damage. Configurational change. Rapid protein metabolism by accelerated mRNA-degradation (no secretory dysfunction). 7% of population. No liver damage. Liver damage less severe than in PiZZ.
N normal
1074
83 α1 - Antitrypsin Deficiency
Fig. 83.2 a1-antitrypsin deficiency. PAS positive, diastase resistant intracellular globules are present in periportal repatocytes. (PAS staining after diastase digestion; x 400)
Fig. 83.3 a1-antitrypsin immunoreactive hepatocytes. Note the accentuation in staining of the outer border of the globules. Avidin-Biotin Peroxidase
systemic vasculitis, and vascular aneurysms [4, 11]. The following discussion is confined to liver disease. In the newborn, neonatal cholestasis with persistent jaundice is often noticed in the first or second month. The liver may be enlarged and palpable. Pruritus,
hypercholesterolemia, dark urine, steatorrhea with acholic stools and deficiency of fat soluble vitamins may occur. The clinical picture resembles extrahepatic biliary atresia (see Chapters 56 and 109). Some children show growth retardation. Occasionally the
Therapy
disease may manifest with gastrointestinal bleeding, bleeding from the umbilical cord stump or by an increased propensity to develop hematomas. Only approximately 10% of children with a1-antitrypsin deficiency exhibit a hepatosplenomegaly with ascites and impaired synthetic liver function in early childhood. The prevalence of acute liver failure in childhood is even less. The disease may also first manifest in juveniles or in early adulthood with an increase in abdominal girth due to hepatosplenomegaly or ascites or by bleeding esophageal varices. In some of these patients an accurate history may reveal a prolonged neonatal jaundice of unknown cause. a1-antitrypsin deficiency is also a rare cause of hepatic disease in adults presenting with signs of chronic liver disease, portal hypertension or with a hepatocellular carcinoma.
Laboratory Findings In addition to an elaborate family history (diseases of liver and lungs?) and a history of the perinatal period the diagnosis of a1-antitrypsin deficiency is based on common laboratory findings (serum electrophoresis [a1-antitrypsin is an a1-globulin], aminotransferases, parameters of cholestasis and bilirubin, synthetic liver function). Serum electrophoresis should be used as the initial screening test. An a1-antitrypsin deficiency often may already be recognized by a reduced or absent a1-globulin fraction on serum electrophoresis. Additionally, a1antitrypsin concentration should be measured directly. Serum levels of a1-antitrypsin less than 20% of normal hint towards a homozygous type PiZZ, while a decrease to 40–70% of normal is caused by the heterozygous types PiSZ or PiMZ. a1-ATZ is demonstrated by isoelectric focussing, where it causes an atypical band, due to its altered mobility in the electrical field. a1-antitrypsin phenotype should be determined in all cases of neonatal hepatitis or chronic liver disease of unknown origin in child- and early adulthood. A monoclonal antibody is available for identification and quantitative measurement of type PiZZ that may also be used in prenatal diagnosis of a1-antitrypsin deficiency. Since the gene has been cloned and sequenced, diagnosis at the genetic level is also possible [12]. The histological findings (see above) complement the diagnosis.
1075
Differential Diagnosis The differential diagnosis has to include cholestatic syndromes in childhood, especially extrahepatic biliary atresia and viral infections. For further discussion see Chapters 56, 85 and 109.
Course and Prognosis A national screening study in Sweden showed that of 200,000 newborns screened 120 had PiZ [9]. Fourteen of them had prolonged obstructive jaundice, nine with severe clinical and laboratory evidence of liver disease. Five had only laboratory evidence of liver disease. Eight other PiZ infants had minimal abnormalities in serum bilirubin and hepatic enzyme activity and variable hepatosplenomegaly. All PiZ infants with hepatic abnormalities appeared healthy at 6 months of age. During further follow-up liver cirrhosis may develop in early childhood. It is unknown whether genetic or exogenous factors abet progression. Possibly patients in whom a1-ATZ cannot be adequately degraded within the endoplasmic reticulum are at particular risk of disease progression. Ultimately only about 10–15% of patients with a1-antitrypsin deficiency develop a clinically significant disease within the first 20 years of life. It may be assumed that in a significant portion of the remaining patients histological changes are present that, however, will lead to overt liver disease later in life [10, 13]. Fifteen percent of male adults 50–60 years old with a1-antitrypsin deficiency of the PiZZ type have cirrhosis. It is currently unknown why only a small proportion of PiZZ individuals progress to clinically significant disease. Men with a1-antitrypsin deficiency and cirrhosis are also at a significantly higher risk for primary liver cancer [5]. Currently there is no evidence that the heterozygous phenotype (PiMZ or PiSZ) predisposes children or adults for clinically relevant liver disease.
Therapy A causal treatment of liver disease induced by a1antitrypsin deficiency is not available.
1076
The administration of chemical chaperones that mediate increased secretion of mutant a1-ATZ as a potential pharmacological strategy for prevention of liver injury and emphysema has generated encouraging results in animal experiments but did not live up to its expectations in humans [1]. Gene therapy influencing synthesis and secretion of a1-ATZ by introducing viral vectors is in its initial experimental stages and not ready for clinical use [3]. Orthotopic liver transplantation is the treatment of choice in advanced liver cirrhosis [6].
References 1. Burrows JA, Willis LK, Perlmutter DH (2000) Chemical chaperones mediate increased secretion of mutant alpha 1-antitrypsin (alpha 1-AT) Z: A potential pharmacological strategy for prevention of liver injury and emphysema in alpha 1-AT deficiency. Proc Natl Acad Sci U S A 97: 1796–801 2. Chappell S, Hadzic N, Stockley R, et al (2008) A polymorphism of the alpha1-antitrypsin gene represents a risk factor for liver disease. Hepatology 47: 127–32 3. Duan YY, Wu J, Zhu JL, et al (2004) Gene therapy for human alpha1-antitrypsin deficiency in an animal model using SV40derived vectors. Gastroenterology 127: 1222–32
83 α1 - Antitrypsin Deficiency 4. Elzouki AN, Eriksson S (1994) Abdominal aortic aneurysms and alpha 1-antitrypsin deficiency. J Intern Med 236: 587–91 5. Eriksson S, Carlson J, Velez R (1986) Risk of cirrhosis and primary liver cancer in alpha1-antitrypsin deficiency. N Engl J Med 314: 736–9 6. Filippino F, Soubrane O, Devictor D et al (1994) Liver transplantation for end-stage liver disease associated with alpha1antitrypsin deficiency in children: pretransplant natural history timing and results of transplantation. J Hepatol 20: 72–8 7. Janciauskiene S, Eriksson S, Callea F, et al (2004) Differential detection of PAS-positive inclusions formed by the Z, Siiyama, and Mmalton variants of alpha1-antitrypsin. Hepatology 40: 1203–10 8. Perlmutter DH, Brodsky JL, Balistreri WF, et al (2007) Molecular pathogenesis of alpha-1-antitrypsin deficiencyassociated liver disease: A meeting review. Hepatology 45: 1313–23 9. Sveger T (1976) Liver disease in a1-antitrypsin deficiency detected by screening of 200,000 infants. N Engl J Med 294: 1216–21 10. Sveger T, Eriksson S. (1995) The liver in adolescents with alpha 1-antitrypsin deficiency. Hepatology 22: 514–7 11. Takii Y, Inoue H, Karashima E, et al (2003) Systemic vasculitis associated with alphal-antitrypsin deficiency. Intern Med 42: 619–23 12. Teckman JH (2007) a1-antitrypsin deficiency in children. Semin Liver Dis 27: 274–81 13. Volpert D, Molleston JP, Perlmutter DH (2000) Alpha1antitrypsin deficiency-associated liver disease progresses slowly in some children. J Pediatr Gastroenterol Nutr 31: 258–63
84
Porphyrias Ulrich Stölzel and Manfred O. Doss
Chapter Outline Abbreviations ............................................................... 1077 Definition....................................................................... 1077
Abbreviations AIP ALA ALAD
Epidemiology ................................................................ 1078 Etiology and Pathogenesis ........................................... 1079 Acute Porphyrias ............................................................ 1079 Non-acute Porphyrias..................................................... 1081
ALADP ALAS CEP
Pathology ...................................................................... 1082 Porphyria Cutanea Tarda ................................................ 1083 Erythropoietic Protoporphyria ....................................... 1084 Clinical Manifestations ................................................ 1084 Acute Porphyrias ............................................................ 1084 Non-acute Porphyrias..................................................... 1086 Diagnosis ....................................................................... 1087 Acute Porphyrias ............................................................ 1087 Non-acute Porphyrias..................................................... 1088 Differential Diagnosis .................................................. 1088 Acute Hepatic Porphyrias .............................................. 1088 Chronic Hepatic Porphyria and Porphyria Cutanea Tarda ......................................... 1088 Therapy and Prognosis ................................................ 1089 Acute Porphyrias ............................................................ 1089 Non-acute Porphyrias..................................................... 1090
CHP COPRO CPO EPP FECH HCC HCP HEP HEPTA PBG PBGD PPO PROTO URO UROD UROS VP XLPP
Acute intermittent porphyria d-Aminolevulinic acid d-Aminolevulinic acid dehydratase porphyria dehydratase d-Aminolevulinic acid dehydratase porphyria (Doss porphyria) d-Aminolevulinic acid synthase Congenital erythropoietic porphyria (Morbus Günther) Chronic hepatic porphyria Coproporphyrin Coproporphyrinogen oxidase Erythropoietic protoporphyria Ferrochelatase Hepatocellular carcinoma Hereditary coproporphyria Hepatoerythropoietic porphyria Heptaporphyrin Porphobilinogen Porphobilinogen deaminase Protoporphyrinogen oxydase Protoporphyrin Uroporphyrin Uroporphyrinogen decarboxylase Uroporphyrinogen III synthase Variegate porphyria X-linked Protoporphyria
References ..................................................................... 1091
Definition Porphyrias are a heterogeneous group of metabolic disorders, which are based on a genetic deficiency along the heme synthesis (Table 84.1) [2]. Only the H. Dancygier, Clinical Hepatology, DOI: 10.1007/978-3-642-04519-6_84, © Springer-Verlag Berlin Heidelberg 2010
1077
1078
84 Porphyrias
Table 84.1 Enzyme defects along the heme synthesis in porphyrias, regulated induction of ALAS1, and major clinical manifestations Porphyria Enzyme Induction of ALAS1 Major clinical manifestation Neurovisceral Cutaneous Anemia Liver ALADP (Doss) Lead intoxication AIP CEP (Günther) PCT/HEP HCP VP EPP
ALAD ALAD PBGD UROS UROD CPO PPO FECH
+ + + − − + + −
++ + ++ − − + + −
− – − ++ + −/+ −/+ −/+
−/+ +a − ++ − − − −/+
− +b − −/+ + − −
a
Lead also inhibits the enzymes CPO and FECH “Lead hepatitis”
b
biochemical results of the metabolic disorders and not mutations or enzyme deficiencies per se lead to clinical manifestations, in which interoperating endogenous and exogenous factors are triggered off. Clinically they can be divided into acute and nonacute porphyrias, as well as pathogenetically into hepatic and erythropoietic porphyrias [20]. Apart from the recessive congenital erythropoietic porphyria (Günther’s disease) and the exclusively cutaneous type of protoporphyria, all other porphyrias are classified as hepatic. The clinical presentation of acute hepatic porphyrias includes an abdominal–neuropsychiatric–cardiovascular syndrome, whereas chronic hepatic, erythropoietic porphyrias present with dermatological symptoms due to photodermatosis. The symptomatic phase of acute hepatic porphyria is characterized by excessive accumulation and excretion of the porphyrin precursors daminolevulinic acid (ALA), porphobilinogen (PBG) and porphyrins. This includes the intermittent acute variations, which are distinguished via the localisation of the genetically disturbed enzyme sequence. Among acute porphyrias, the acute intermittent porphyria (AIP) is most common, followed by the variegate porphyria (VP), the hereditary coproporphyria (HCP) and a rare recessive acute hepatic porphyria with d-aminolevulinic acid-dehydratase deficiency (ALADP, synonym: porphobilinogen-synthase-defect porphyria, Doss-porphyria), which is biochemically similar to lead poisoning. Therefore lead poisoning as toxic and toxo-genetic acute porphyria can be integrated into the acute types. The opposite of acute porphyrias are the porphyria cutanea tarda (PCT) as a chronic hepatic porphyria (CHP) and the erythropoietic porphyria (EPP) with likewise chronic course.
The diagnosis of clinical symptomatic porphyrias is based on the biochemical analysis of the metabolic excesses, in which each porphyria expresses its own specific diagnostic (excretory) constellation. Porphyrias are characterised by a huge molecular heterogeneity. They can be caused by a multitude of different mutations. Genetic defects of homozygous porphyrias show that there is quite often a compound heterozygosity. This means that both alleles are differently mutated. Rare homozygous forms can also be found among dominant autosomal hereditary porphyrias. Molecular testing is helpful to screen asymptomatic carriers. However, since asymptomatic gene carriers of porphyric disorders are common in the normal population, genetic testing is not recommended for clinically diagnosing porphyrias. Although there is a considerable interplay between gene defect and environmental factors, only a minority of cases may occur as predominantly acquired disease. Dual porphyrias have been diagnosed in rare cases with clinical and biochemical findings of two porphyrias. For example, a double heterozygous condition of coexistent AIP and PCT genes in the same individual was described. Apart from the genetically predisposed erythropoietic and hepatic porphyrias, clinically asymptomatic secondary porphyrinurias and porphyrinemias can be detected. The latter appear reactive among a number of different diseases and dysfunctions.
Epidemiology The three most important porphyrias are the acute intermittent porphyria (AIP), the Porphyria cutanea tarda (PCT) and the erythropoietic protoporphyria (EPP).
Etiology and Pathogenesis
1079
The observed frequencies among different porphyrias diagnosed in the German Competence Center for Porphyria Diagnosis and Consultation (www.por phyria.com) between 1965 and 2006 are shown in Table 84.2. The proportion among acute porphyrias in that period was AIP:VP:HCP:ALADP = 71:11:6:0.3. Hepatic types occur much more often compared to erythropoietic porphyrias. Data recorded from surveys of porphyria centres in Europe listed in Table 84.3 show the prevalence of the genetic defects. The secondary (asymptomatic) dysfunctions of porphyrin metabolism caused by other different diseases outweigh by far the “primary” porphyrias. The asymptomatic secondary coproporphyrinuria is in the first place of all hepatic porphyrin metabolic disorders, before the primary porphyrias. Recently in Germany some patients were diagnosed with lead induced acute porphyria due to lead contaminated marijuana.
Etiology and Pathogenesis Acute Porphyrias The pathogenesis of acute hepatic porphyrias (AIP, VP, HCP, ALADP, lead poisoning) is multifactorial. The hereditary enzyme defect destabilizes the normally impeccably regulated hepatic porphyrin biosynthesis. This defect can persist without any clinical effects for a lifetime. The majority of the gene carriers (circa 80%) never develop a clinical porphyria manifestation with increased urinary excretion of porphyrin precursors and porphyrins. Moreover, in some individuals typical biochemical signs of a latent state can be seen in the absence of complaints and clinical symptoms. The final product heme itself regulates, via repression of the key enzyme ALAS 1, the production of porphyrin precursors and porphyrins in the liver [6].
Table 84.2 Number and sex ratio (f/m) of different porphyrias diagnosed in the German Competence Center for Porphyria Diagnosis and Consultation (www.porphyria.com) (1965–2006) Porphyrias/acute hepatic porphyrias Porphyrias Number of cases (f/m) Porphyria cutanea tarda (chronic hepatic porphyria) Protoporphyria (erythropoietic and erythrohepatic) Congenital erythropoietic porphyria (Günther’s disease) Acute intermittent porphyria Variegate porphyria Hereditary coproporphyria Doss-porphyria Total
Table 84.3 Gene mutations and prevalence of various porphyrias Porphyria Chromosome location ALADP (Doss) AIP CEP (Günther) PCT/HEP**** HCP VP EPP *
9q34 11q23.3 10q25.2–q26.3 1p34 3q12 1q22 18q21
Prevalence (cases/100,000) reported from various centers in Europe So far six cases described *** High prevalence in South Africa (founder effect) **** Only 20 cases of HEP so far described **
~2,000 198 32 706 105 61 3 3,105
~1/2 ~1/1 ~1/2 ~2/1 ~1/1 ~2/1 −/3 ~1/1.3
Number of mutations
Prevalence*
8 >200 >20 >50 >30 >100 >100
Rare** 5–10 0.1 20–50 0.5 1 0.5***
1080
Exogenous and endogenous influences such as drugs, fasting, stress, alcohol or hormones may cause consumption of regulatory heme (e.g. for cytochromes) in the liver con-sequenced by de-repressing ALAS 1. This induction is the starting phase of the hepatic porphyria process leading to excessively stimulated porphyrin synthesis and expansion of porphyrin precursors and porphyrin metabolites in tissue and in blood. Both porphyrin precursors ALA and PBG are considered to exhibit neuropharmacological effects. The metabolic explosive character of the increase in porphyrin precursors masks the underlying hereditary enzyme deficiency and leads, in terms of overcompensation, to an excessive porphyrin synthesis. The increase of metabolites correlates with symptoms of the acute clinical porphyria crisis. The pathophysiological links between metabolic derangement and expression of clinical symptoms have yet to be elucidated. A clinical manifestation without an increase of ALA and PBG does not exist. The deficiency of the enzyme activity remains constant for life and is not an indicator of the pathogenetic, metabolic and clinical process of the disease. The disease is triggered by the induction of hepatic ALAS and corresponding metabolic reactions. The molecular genetics of acute porphyrias is shown in Table 84.3.
Acute Intermittent Porphyria Mutations in the porphobilinogen deaminase (PBGD) gene are without any doubt associated with the manifestation of AIP. It is transmitted as an autosomal dominant trait. The activity of the enzyme can be reduced with diminished (cross-reactive immunological material (CRIM) negative) (Type I) or normal protein content of the PBGD (CRIM-positive) (Type III). The human gene is located on the large arm of chromosome 11 splitting into 15 exons including 10 kb of DNA. Two different promoters produce either an erythroid or a non-tissue-specific isoenzyme. Rare mutations in areas, which are reserved exclusively for the non-specific enzyme, do not lead to alterations of the erythroid form of the isoenzyme. As a result, a subtype of the acute intermittent porphyria exists with normal PBGD activity in the erythrocytes (Type II). The rate of such patients in Germany is 5%. Whereas more than 200 different mutations were found for the classical
84 Porphyrias
type of the acute intermittent porphyria, only a few mutations are known for the non-erythroid subtype of acute intermittent porphyria. Variegate Porphyria Mutations in the protoporphyrinogen oxidase (PPOX) gene are associated with the manifestation of the variegate porphyria (VP). The complete genomic sequence of the gene is clarified [38]. In the meantime various mutations in the PPOX gene were found worldwide. The gene for human PPOX is located on the long arm of the chromosome 1. Rare homozygous carriers for VP have been described. The founder gene mutation R59W was first described by Meissner et al. and corresponds to the high incidence of VP in South Africa [37]. Approximately 20,000 individuals in South Africa carry the R59W mutation derived from a family that emigrated from The Netherlands in the seventeenth century. Hereditary Coproporphyria The gene of the human coproporphyrinogen oxidase (CPO) is localized on the long arm of chromosome 3 locus 12 with seven exons and six introns containing 14 kb DNA. Different mutations have been described in heterozygous patients. Furthermore, homozygous and compound-heterozygous gene carriers show the molecular heterogeneity of porphyrias. Almost each family seems to have its own mutation. Doss-Porphyria (ALADP) (Delta-Aminolevulinic Acid-Dehydratase-Defect) ALADP is a result of an inherited autosomal recessive disorder. The first two patients were described by Doss et al. in Germany displaying two separate point mutations of the ALAD gene, one in each allele [15, 41]. The expression of one mutation results in an almost inactive enzyme. The other mutation leads to an unstable protein with a shorter half-life period, indicating that a compound heterozygote constellation accounts for the near-total deficiency in patients and the halfnormal activity in their parents and other family members. Heterozygotes with 50% ALAD activity or individuals who carry a gene with one aberrant allele
Etiology and Pathogenesis
1081
are more sensitive to lead and can develop symptoms under low lead exposure [13, 14]. The prevalence of heterozygotes is 2% in the asymptomatic population. Therefore, most instances of compound heterozygosity in ALAD result in spontaneous abortion. ALADP is the first example of a morphine-based conformational disease [26].
Non-acute Porphyrias Porphyria Cutanea Tarda Porphyria cutanea tarda (PCT) is associated with impaired function of the enzyme uroporphyrinogen decarboxylase (UROD) in the liver, leading to characteristic alterations of urinary heme precursors and to typical lesions of sun-exposed skin (Table 84.4). [9, 34]. The UROD gene is composed by ten exons with 3 kb DNA in length and is located on the short arm chromosome 1 locus 34. According to Elder et al. three types of PCT are distinguished [8, 16]. Type I (Sporadic Type). The UROD activity is diminished in overt disease and returns to normal in clinical remission. This type is not related to mutations within the URO-D Locus. Manifestation seems to be modulated by other mutated genes, e.g. HFE gene, by viral infections or environmentally triggered. Type II (Familial, Hereditary Type). Approximately half of all cases with PCT Type II are genetically predisposed by about 50% reduced UROD activity in all tissues. So far more than 50 different mutations of UROD have been described (Table 84.3). Type III. This type is characterized by normal activity and concentration of the erythroid UROD. The
reduced UROD-activity was found to be limited to the liver. Many asymptomatic gene carriers indicate a less distinctive phenotypic penetrance of the defect and the role of further exo- and endogenous conditions is emphasized. Thus, further genetic modifications responsible for the development of a clinical manifestation have to be taken in account. More detailed information concerning the molecular background has been stepwise elucidated within the last years. Manifestation of PCT in women aged between 20 and 40 related to oral contraceptives is not rare. The estrogen induced PCT is genetically predisposed in about 80% (diminished UROD). Hepatoerythropoietic porphyria (HEP) is a rare porphyria with clinical manifestation mostly in childhood. The HEP is characterized by homozygous or compound heterozygous mutations of UROD (activity below 10%) and accumulation of porphyrins in liver and blood associated with high urinary excretion. Porphyria Cutanea Tarda and Iron. Iron overload is common in PCT and much evidence exists that iron is an inhibitory cofactor of UROD activity in hepatocytes. Elevated serum iron markers point towards an association with hemochromatosis, which has been found in 2–27% of patients with PCT. Compared to healthy controls, a high frequency of the C282Y mutation (ranging from 11% to 47%) in the HFE gene, the major genetic alteration in genetic hemochromatosis, has been found in patients with PCT from the UK, Germany, The Netherlands, Southern Italy, Spain, Australia and the USA. In a study from Northern Italy, however, C282Y occurred as frequently in PCT patients as in controls, while another much lesser predictive HFE mutation (H63D) was significantly increased in PCT patients.
Table 84.4 Pathobiochemical progression and clinical expression of chronic hepatic porphyria to PCT Liver porphyrin Liver injury Condition Urinary porphyrins accumulation Pattern Total (mmol/24 h) Normal Secondary coproporphyrinuria CHP A CHP B CHP C CHP D (PCT)
Cutaneous symptoms
URO >> HEPTA COPRO >> URO > HEPTA
− −
− +
− −
HEPTA URO > COPRO > HEPTA URO > HEPTA > COPRO URO > HEPTA >> COPRO
(+) + ++ +++
+ + + +
− − −/+ +/++
1082
Sixty-one percent of the PCT patients in Saxony (eastern part of Germany) carry HFE mutations [48]. The patients with homozygous mutations C282Y (5%) show serological and histological significant signs of increased iron storage. The HFE gene codes for a HLA antigen (MHC class I) a very similar molecule (HFE-protein) that is expressed on the external membrane of hepatocytes and a multitude of cell types. The HFE gene mutations C282Y and much less H63D affect iron uptake via transferring receptor into the cell and lead to an unnecessarily high iron absorption in the small intestine. Patients with hereditary hemochromatosis and excessive iron storage are mostly homozygous for the mutations C282Y. In contrast, the heterozygous or compound heterozygous occurrence of the mutations C282Y or H63D lead at the most to a clinically insignificant increased iron accumulation. Accordingly, based on clinical studies, iron removal is an efficient treatment of patients with PCT, resulting in improvement of hepatic UROD activities in Type I. Patients with PCT and homozygous mutation C282Y should be treated with phlebotomy similar to patients with hemochromatosis. For patients with PCT and heterozygous mutations of the HFE-gene a treatment with chloroquine seems sufficient, as they do not develop a heavy iron overload [48]. The data about a direct influence of iron on UROD activity are contradictory and findings of direct inhibition of the enzyme via iron, could not be reproduced by others. Uroporphyinogen could be converted into porphomethene by oxidation of a single bridge carbon between adjacent pyrrole rings, which inhibit the UROD. Recently discovered mutations of the hemochromatosis-HFE-gene (C282Y, H63D) were significantly more often found homozygous and heterozygous in patients with PCT [39]. The HFE-protein modulates the intake of transferrin bound iron into cells such as hepato- and enterocyte, and HFE Mutations can amplify intestinal iron uptake. A worldwide number of studies strongly suggest heterozygous, compound heterozygous and homozygous HFE genotypes as an essential predisposition for a siderosis preceding the clinical manifestation of PCT. Ethanol-treated HFE (−/−) mice seem to be an excellent model for studies of alcohol-mediated PCT [46].
84
Porphyrias
Erythropoietic and X-linked Protoporphyria A partial deficiency of the ferrochelatase (FECH) activity forms the basis of the erythropoietic protoporphyria (EPP). The genetic modus seems to follow in most cases an autosomal dominant (d-EPP) trait with a different degree of penetrance. However, gene polymorphisms located on the non mutated chromosome in trans position (so called hypomorphic FECH allele IVS3-48C) contribute to clinical expression [19]. The FECH gene is located on chromosome 18 and consists of 45 kb including 11 exons. The first de novo mutation, two deletions and two-point mutations were found in Finnish families with erythropoietic protoporphyria. Sarkany et al. described a double heterozygous, recessive autosomal form (r-EPP) with heavy liver involvement [40]. In approximately 7% of families FECH mutations are not detected by current methods. These findings indicate that EPP may rarely be caused by mutations at a locus other than FECH. Recently S. Whatley described eight families with ALAS-2 gene mutations (51). These gain of function mutations casuse a previously unrecognized X-linked protoporphyria (XLPP) characterized by high protoporphyrin concentrations in erythrocytes.
Congenital Erythropoietic Porphyria (Guenther’s Disease) The congenital erythropoietic porphyria (CEP) is a rare autosomal recessive disease of the heme biosynthesis characterised by considerably reduced activity of the enzyme uroporphyrinogen III synthase (UROS) [21]. Hitherto discovered mutations in the UROS gene show a great heterogeneity and the majority of patients with CEP display compound heterozygosity. An exception represents a single “missense-mutation” C37R, which can be found in up to one third of all UROS alleles. The disease is characterised by accumulation of isomer Type I porphyrins in the bone marrow, spleen and other organs.
Pathology Despite slightly elevated liver enzymes and reports of increased risk of hepatocellular carcinoma in acute porphyrias, progressive liver disease is not characteristic.
Pathology
1083
In contrast, significant pathology of the liver occurs in PCT and EPP.
Porphyria Cutanea Tarda The liver biopsy cylinder emits typical red fluorescence due to porphyrin accumulation when exposed to long wave UV light (Woods light, 366 nm) that can precede the skin manifestation of the disease (Fig. 84.1). With a urinary excretion of approximately 2 mmol/24 h, the liver is already full of accumulated porphyrins. The red fluorescence is caused by uro- and heptaporphyrins. Computed tomography and ultrasound sometimes detect round lesions in the liver, which have been shown to corresponded histologically to focal steatosis. These lesions disappear after therapy of PCT with phlebotomy or chloroquine [36]. Focal nodular hyperplasia (FNH) has also been described and partly traced back to an intake of estrogens. In a large cohort including more than 200 patients with PCT, Köstler et al. found histological proven liver cirrhosis in 13% [28, 29]. Geographically, different prevalences of liver cirrhosis could correlate with a regionally varying occurrence of cofactors such as chronic hepatitis C or certain hemochromatosis HFE mutations [17, 39]. In general, each underlying liver disease characterizes the histological picture of the liver. While some authors describe the histological picture of the liver in PCT with periportal-accentuated siderosis, portal inflammation and steatosis, others point out characteristic needle-shaped intracytoplasmic crystals (Fig. 84.2) [28, 35]. These water-soluble crystal structures showing double refraction in polarized light were considered to be deposited accumulated porphyrins. The proof of such crystals located very close to the intracellular ferritin-containing iron points towards interactions between iron and porphyrin synthesis [44]. Since elevated aminotransferase (ALT and AST) levels occur in more than half of the patients without markers of HCV and/or HBV infection, liver damage in PCT may occur in the absence of these viruses [47]. This is supported by the finding that in patients without HCV and/or HBV infection, higher serum ALT and AST activities were found in patients with overt disease or relapse, whereas patients in remission displayed significantly lower serum enzyme activities.
Fig. 84.1 The liver biopsy cylinder emits a typical red fluorescence in PCT when exposed to long wave UV light (Woods light, 366 nm)
Fig. 84.2 Accumulated porphyrins form characteristic needle shaped intra-cytoplasmic crystals (arrows) in hepatocytes (Kindly provided by Professor Dr. med. E. Köstler, Department of Dermatology, Klinikum Dresden Friedrichstadt, Germany)
Depending on the associated liver damage, patients with PCT display elevated enzyme activities of ALT, AST and g-GT in serum. Since most patients show higher activities of ALT compared to AST in serum, this pattern corresponds more to viral hepatitis and to non-alcoholic rather than to alcoholic liver disease. A differentiation and revision of liver changes in PCT have become possible because of the serological capability to prove the HCV infection since 1989. Molecular genetic procedures have been available to recognize mutations of the HFE gene responsible for hemochromatosis since 1996 [18, 33]. Therefore, older reports on coincidence between PCT and hepatocellular carcinoma (HCC) should be clarified since the role of HCV in PCT is established and the incidence of
1084
HCC in HCV liver cirrhosis is high with an incidence of 3–10% per year [45]. Additionally, neoplasia is common in hemochromatosis and risks can be additive if both diseases are associated with each other. The predominating injuries can induce chronic hepatitis, steatosis, a more or less intensified siderosis, liver fibrosis or, in case of an advanced or combined damage, liver cirrhosis. The hepatocellular accumulation of porphyrin and the dimension of the porphyrinuria correlate with the activity and amplify liver damage.
Erythropoietic Protoporphyria The hepatocellular uptake and excretion of the lipophile protoporphyrin into the bile is the most important pathophysiological aspect for liver pathology. One quarter of all patients with EPP have an associated liver damage that can progress to cirrhosis. 10% of all patients develop gallstones; these gallstones consist mainly of protoporphyrin. The capacity of the liver for the clearance of the protoporphyrin is limited. In case of an uncomplicated course with only cutaneous symptoms, the deposition of protoporphyrin in the liver is insignificant. In contrast, overtaxing the liver excretory capacity leads to a crystalline storage of protoporphyrin
Fig. 84.3 Hepatic “Maltese Cross” structures (arrow) in EPP that show a clear birefringence in polarized light (Kindly provided by PD Dr. med. J.O. Habeck, Department of Pathology, Klinikum Chemnitz, Germany)
84 Porphyrias
in “Maltese Cross” structures that show a clear birefringence in polarized light (Fig. 84.3). Protoporphyrin crystallizes in a high concentration and is probably hepatotoxic in concentrations greater than 500 mg/g (normal approximately 1 mg/g). The protoporphyrin induced liver damage can progress into fibrosis and cholestatic cirrhosis. Irreversible liver damage is characterized by decreasing fecal protoporphyrin excretion as a “signum malum ominis”. Enterohepatic reuptake and circulation of protoporphyrin further contributes to retention.
Clinical Manifestations Acute Porphyrias The description “acute hepatic porphyrias” points towards the potentially acute character of the clinical manifestation. The age of onset is mostly after puberty up to the third decade of life. Females are affected more than males. Initial manifestation in children and teenagers as well as in elderly people is very rare. The acute porphyria syndrome develops similarly in all four types of the acute hepatic porphyria and cannot be differentiated clinically. This applies also to the VP and the HCP in which skin symptoms
Clinical Manifestations
(photodermatosis on face and hands) are mostly missing in central Europe. Abdominal pain, intermittent and colicky, is the initial and most frequent symptom [23]. At the same time or later, back pain and extremity pain as well as paresthesias can occur. Nausea and vomiting, constipation and ileus symptoms can follow. Tachycardia and dark-reddish urine are important diagnostic clues. The characteristic color of the urine increases overnight (Fig. 84.4a and b). If a porphyria is not diagnosed and the porphyria progresses uncontrolled, peripheral motor and sensory neuropathy are the most frequent complications. First the extensor muscles of hands and arms are affected. Some patients go on to develop reduced tendon reflexes, sensory abnormalities, ocular symptoms and cranial nerve dysfunction. Nerve conduction studies and needle EMG demonstrate a mixed axonal-demyelization polyneuropathy in AIP patients. Thirty percent of all patients display hyponatremia and hypokalemia as well as an increase of creatinine and urea in serum. Twenty percent show hyperbilirubinemia, hypercholesterolemia, proteinuria, leukocytosis, anemia and an increase of thyroid hormone concentrations in serum. Liver changes are usually mild in acute hepatic porphyrias. Mild elevated liver enzymes in serum (ALT, AST) can be observed, histologically accompanied with slightly elevated liver fat and iron content. Stein and Tschudy demonstrated hypercholesterolemia as well as an increase of aminotransferases in serum in all patients [49]. Observations from Scandinavia in a larger cohort of patients showed that patients with acute hepatic porphyrias have a significantly higher risk of developing liver cirrhosis and hepatocellular carcinoma (HCC). Kauppinen and Mustajoki analyzed 82 deceased Finnish porphyria patients (63 patients with acute intermittent porphyria and 19 patients with variegate porphyria, 42 men and 40 women with an average age of 57 years) [27]. HCC was found as the cause of death in seven patients (six patients with acute intermittent porphyria and one patient with variegate porphyria). Bjersing et al. reported on HCC in 17 Swedish patients with acute intermittent porphyria. At the Marburg Porphyria Center (Germany) one case of pancreatic cancer and three cases of hepatocellular cancer in patients with acute intermittent porphyria were observed. Usually the development of an acute porphyria crisis is closely related to the intake of porphyrinogenic medication, poor dietary intake or fasting, physical stress, alcohol and
1085
a
b
Fig. 84.4 The characteristic color of the urine (a) in AIP increases overnight (b)
infections. Moreover, premenstrual manifestations are not rare in female patients and difficult to distinguish from non-porphyria induced complaints [5]. In male patients smoking was found to be associated with the number of clinical manifestations. In lead intoxication microcytic anemia, basophilic stippling on blood smear, and a “lead line” (bluish pigmentation on the gum-tooth line) can additionally be found. The course of an acute hepatic porphyria follows a certain sequence: latent stage, manifestation as clinical
1086
exacerbation, remission, latency in sense of a clinical cure, and potentially renewed clinical manifestation.
Non-acute Porphyrias
84 Porphyrias
Hepatoerythropoietic Porphyria HEP presents in childhood with severe skin sensitivity, hypertrichosis and scarring often associated with hemolytic anemia and splenomegaly. Manifestations may also be observed in adults.
Porphyria Cutanea Tarda Erythropoietic Protoporphyria The porphyria cutanea tarda (PCT) derives its name from the cutaneous lesions that develop on sun light exposed areas. The clinical onset of the disease is usually in adult life (Fig. 84.5). Blisters and scars develop predominantly on the hands and face, often associated with easy vulnerability of the skin and a characteristic hypertrichosis periorbitally close to the temples and to the cheekbones occurring periorbitally. The fluid-filled vesicles can rupture easily. Additionally, some patients display hyperpigmentation of the skin. Darkly colored urine only occurs in cases of excessively high porphyrin concentrations (above 10 mmol/24 h, normally less than 0.2). The development of chronic hepatic porphyria is almost identical to the sequence of the subclinical stage: porphyrin storage in the liver and urinary excretion, acceleration of porphyrin accumulation with help of manifestation factors, clinical stage of the cutaneous symptoms, remission with decline of metabolites and stabilization in the latent subclinical stage.
Cutaneous photosensitivity occurs already in early childhood and leads to burning, itching, pain, edema and erythema on sunlight-exposed areas (Fig. 84.6). One quarter of all patients display mild anemia with hypochromia and microcytosis. It is not rare that protoporphyria is manifested in adulthood as hepatobiliary cholestatic disease since photosensitivity can be absent or hidden because of subjective habituation to avoid sunlight. 10% of all patients develop gallstones, which consist mainly of protoporphyrin. The liver complication is the most important clinical aspect of the protoporphyria in adulthood. From a clinical point of view, in patients with unexplained jaundice, hepatomegaly and abdominal pain this disease should be taken into account and light sensitivity should be asked for. Patients mostly consult a physician because of skin symptoms but the liver complication is the most
Fig. 84.5 Cutaneous lesions in PCT on sunlight-exposed areas
Fig. 84.6 Cutaneous photosensitivity in EPP can occur already in early childhood and leads to burning, itching, pain, oedema and erythema on sunlight-exposed areas
Diagnosis
1087
important and limiting clinical aspect of advanced EPP. Motor neuropathy was reported in end-stage protoporphyric liver disease.
Congenital Erythropoietic Porphyria (Günther’s Disease) Besides serious photosensitivity with blisters, erosions, ulcerations, hirsutism and mutilations, a characteristic reddish-brown discoloration of the teeth containing high concentrations of porphyrin (erythrodontia) may appear. They fluoresce brightly red under long-wave UV-light. The disease becomes mainly apparent in childhood but can also occur in adulthood. Important findings are anemia, haemolysis and a hepatosplenomegaly. The urine is often reddish-brown coloured because of an excessively high excretion of porphyrins of the isomer I series, mainly uro- and coproporphyrin I.
Diagnosis Acute Porphyrias It should be emphasized that it is clinically more important to differentiate between an acute hepatic porphyria and a chronic hepatic porphyria than it is to differentiate between the four acute hepatic porphyrias (AIP, HCP, VP, ALADP). The diagnosis of each type of clinical symptomatic acute hepatic porphyria is based on an increased excretion of both porphyrin precursors ALA, PBG and porphyrins in the urine. Simultaneously, depending on each underlying hereditary enzyme deficiency, a typical constellation of elevated porphyrins in
urine and stool allows distinguishing among the acute porphyrias (Table 84.5). Suspecting acute hepatic porphyria, 20 mL of urine should be analyzed for elevated excretion of ALA and PBG and total porphyrins. This turns out to be almost always positive in cases of an acute hepatic porphyria and therefore an immediate diagnostic and therapeutic orientation is possible. The diagnosis of an acute hepatic porphyria, including considerable therapeutic and long term prophylactic consequences, should not be based on screening procedures as these can turn out to be incorrect (falsepositives or false-negatives). Further special diagnostic tools help to sub-classify acute hepatic porphyrias using criteria listed in the Table 84.5, including measuring the activity of porphobilinogen-deaminase in erythrocytes. In the absence of an increase of both porphyrin precursors (ALS and PBG), an acute porphyria syndrome cannot be diagnosed even in the presence of abdominal, neurological and cardiovascular symptoms that point towards an acute hepatic porphyria. A normal or only limited excretion of ALA and PBG excludes de facto the diagnosis of acute hepatic porphyria. Measuring enzyme activities confirms the genetic disorders. However, the enzyme defect itself does not necessarily lead to clinical symptoms and can remain a sub-clinical variant lifelong. Thus, enzyme examinations as well as molecular genetic analysis for the diagnosis of a clinical acute hepatic porphyria are not relevant. Polysymptomatic patients suspected of having acute porphyria but displaying normal urinary excretion of porphyrin precursors and porphyrins do not suffer from a porphyria even in case of a lowered porphobilinogen-deaminase in the erythrocytes. Enzyme activities at the edge of the statistically normal distribution are not criteria for a porphyia tendency, when the urinary metabolic excretion in a clinical porphyria-like syndrome is normal.
Table 84.5 Differential diagnosis of acute porphyrias and lead intoxication Porphyria Urine ALA PBG URO COPRO ALADP (Doss) AIP HCP VP Lead intoxication
↑↑ ↑↑ ↑↑ ↑↑ ↑↑
↑ = elevated, n = normal, v = variable
(↑) ↑↑ ↑↑ ↑↑ (↑)
↑ ↑↑ ↑ ↑ ↑
↑↑ ↑↑ ↑↑ ↑↑ ↑↑
COPRO n v ↑↑ ↑ n
Stool PROTO n v ↑ ↑↑ n
Erythrocytes PROTO ↑ v v v ↑
1088
84 Porphyrias
Non-acute Potphyrias
Differential Diagnosis
Chronic Hepatic Porphyria and Porphyria Cutanea Tarda
Acute Hepatic Porphyrias
The diagnosis of a PCT or a chronic hepatic porphyria is based on an excessive increase of uro- and heptacarboxyporphyrin up to a proportion of 80% of total urinary porphyrin excretion [10]. The urinary excretion of the remaining porphyrins can also rise. The excretion of PBG remains normal while urinary ALS can be slightly elevated especially under the influence of alcohol. The corresponding concentration of plasma uro- and heptacarboxyporphyrin and of stool isocoproporphyrin is increased. Characteristic red porphyrin fluorescence of the liver biopsy, if processed to long wave UV light (Woods light, 366 nm), points towards the diagnosis of PCT. Reduced activity of the UROD in the liver, either because of exogenous-toxic (PCT Type I) or genetic (PCT Types II and III) reasons, is obligate for the development of CHP or PCT. Lower activity of the UROD in the erythrocytes is characteristic for a hereditary disposition (PCT Type II). UROD activity should not be measured routinely since hereditary UROD deficiency does not play a role in modulating demographic or clinical features of PCT. Table 84.4 shows that the pattern of urinary porphyrin excretion as well as porphyrin storage in the liver is crucial for the differentiation of the subclinical stage. The process from latency up to the manifestation corresponds with a progressive increase of uro- and heptacarboxyporphyrin in liver, urine, plasma and stool. In overt PCT the urinary copro-/ uroporphyrin quotient drop to 0.1 (normally approximately 8). The inversion of the physiological copro-/uroporphyrin relation starts off the chronic hepatic porphyria phase that does not show any cutaneous symptoms (Table 84.4) [13].
Diagnostically acute porphyrias should be differentiated from a multitude of diseases including abdominalneurological, cardiovascular and physical symptoms. The differential diagnosis is ultimately linked to pathobiochemical examination and established criteria. An important differential diagnosis is acute and chronic lead poisoning, which occurs as toxic or toxo-genetically determined porphyria. The metabolic abnormalities in lead poisoning are very similar with the ALADP (Doss porphyria) (Table 84.5). The pathobiochemical demarcation includes different enzyme reactivations in lead poisoning but not in Doss porphyria. Clinically lead intoxication is characterized by very comparable symptoms. In addition it can be associated with microcytic anemia, basophilic stippling on blood smear and a “lead line” (bluish pigmentation on the gum-tooth line). Since lead affects heme synthase enzymes (ALAD, CPO and FECH), a significantly elevated urinary ALA concentration (more than fivefold the upper limit of normal) combined with normal or only slightly elevated urinary PBG as well as increased urinary COPRO and zinc complexed red cell protoporphyrin allow the differentiation of acute hepatic porphyrias from secondary coproporphyrinurias. Alcoholic liver disease can be accompanied by abdominal and neurological symptoms as well as an isolated (unspecific pattern) coproporphyrinuria, and consequently misinterpreted clinically as an acute hepatic porphyria [12]. Fecal porphyrin examination is very important in the differential diagnosis of porphyrias. HCP is characterized by a marked elevation of the coproporphyrin isomer III in stool and urine (isomer inversion), while VP and EPP are associated with increased fecal protoporphyrin concentration (Table 84.5).
Erythropoietic Protoporphyria
Chronic Hepatic Porphyria Whenever an increased concentration of free protopor- and Porphyria Cutanea Tarda phyrin is found in heparinized blood (erythrocytes and plasma) EPP should be suspected. The urinary porphyrin precursors ALA and PBG are not elevated. The simultaneous examination of heparinized blood, stool and urine is mandatory to question liver involvement.
The differential diagnosis includes other skin diseases that are caused by exposure to sunlight and other porphyrias. Photocutaneous symptoms can occur in EPP, CEP, HEP, HCP and VP, but not in AIP and Doss
Therapy and Prognosis
porphyria. All these diseases can be distinguished with the meticulous analysis of the urinary porphyrins and porphyrin precursors (ALA, PBG) in stool and blood. The very rare homozygous type of the PCT, the hepatoerythropoetic porphyria (HEP) as well as Günther’s disease (CEP) occur already in infancy or early adolescence. CEP can be distinguished from hepatoerythropoietic porphyria (HEP) by dominance of isomer I porphyrins in urine and the absence of high levels of isocoproporphyrin in feces. Furthermore, in HEP the erythrocyte protoporphyrin is elevated and consists mainly of zinc protoporphyrin, whereas an increase of the erythrocyte protoporphyrin cannot be observed in the heterozygous form of the PCT. An extremely low activity of the UROD (95%. However, in up to 80% of patients, especially those with FNH smaller than 3 cm in diameter, a central scar may not be detectable. Liver-specific
101.3
Focal Nodular Hyperplasia
MR-contrast agents enable the diagnosis in the majority of cases with atypical FNH. The central artery, the tortuous intratumoral vessels, hypervascularization and delayed venous filling can also be visualized by angiography. Hepatobiliary scanning with trimethylbromoiminodiacetic acid (TBIDA) typically reveals a “hot spot” of radioactivity in the clearing phase usually persisting 60 min after application of the substance [2]. Because of the presence of Kupffer cells, the lesion takes up 99mTechnetium (99mTc) sulfur colloid, though this is a nonspecific finding. Neither angiography nor scintigraphic imaging are nowadays required in the diagnosis of FNH. If ultrasonographic, CT or MR imaging yield typical findings of FNH, a histological confirmation is not necessary and the lesion may be followed clinically and by sequential ultrasound examinations. The vast majority of FNH do not enlarge. If, however, US, CT or MRI fail to establish the diagnosis, which may easily occur if the typical central hypervascular scar is lacking, histological examination of the lesion is mandatory. The histological diagnosis depends largely on the size of the tissue sample obtained. Even if this is too small to allow for a definite diagnosis of FNH, histology will permit the exclusion of malignancy. Lesions deeply embedded in the hepatic parenchyma should be biopsied percutaneously. More superficially localized lesions should undergo open biopsy or tissue resection during laparoscopy. This procedure will yield enough material for a definite diagnosis and will reduce the associated bleeding risk.
Differential Diagnosis FNH must be distinguished from other hepatic mass lesions, especially metastases, HCA and hepatocellular carcinoma. The diagnosis is not difficult if a typical configuration with a central scar, fibrous septa and a spoke-wheel vascular pattern is seen. However, even a typical angiographic pattern does not allow for a definitive differentiation of a well-vascularized and hyperperfused FNH from hepatocellular carcinoma. Calcifications within an FNH occur rarely. They are encountered more often in fibrolamellar carcinoma. When interpreting liver biopsies one should be aware that FNH-like changes may be observed in liver tissue adjoining a fibrolamellar carcinoma.
References
In small biopsy samples differentiation from liver cirrhosis might be difficult. A periseptal ductular proliferation, the complete lack of the normal acinar architecture, absence of lipofuscin, the presence of cholate stasis and multiple thick-walled vascular profiles support the diagnosis of a FNH [5].
Natural History and Prognosis FNH is not a premalignant condition and malignant transformation has not been reported. The idea that FNH might be a precursor of fibrolamellar carcinoma has not been substantiated. On long-term follow up changes in FNH size are rarely observed, with fewer than 5% of cases enlarging or decreasing in size [20]. Isolated cases with increasing FNH-size during pregnancy or in women taking oral contraceptives have been described, although this is not the rule. The risk of bleeding and rupture is much less than in HCA with the exception of the telangiectatic variant of FNH (see above) that appears to have a risk of bleeding similar to that observed in patients with an HCA [1].
Therapy Small lesions or asymptomatic FNH deeply embedded in hepatic parenchyma need no treatment [4, 13, 20]. The patient should be reassured and the lesion followed clinically and by sequential imaging, mostly ultrasound. The discontinuation of oral contraceptives is not necessary. Large, symptomatic FNH or asymptomatic but rapidly growing tumors should be resected surgically. This is indicated in only a small minority of patients. Arterial embolization or ligation are alternative treatment options in selected patients.
References 1. Bioulac-Sage P, Rebouissou S, Sa Cunha A, et al (2005) Clinical, morphologic, and molecular features defining so-called telangiectatic focal nodular hyperplasias of the liver. Gastroenterology 128: 1211–8 2. Boulahdour H, Cherqui D, Charlotte F, et al (1993) The hot spot hepatobiliary scan in focal nodular hyperplasia. J Nucl Med 34: 2105–10
1287 3. Butron Vila MM, Haot J, Desmet VJ (1984) Cholestatic features in focal nodular hyperplasia of the liver. Liver 4: 387–95 4. Cherqui D, Rahmouni A, Charlotte F, et al (1995) Management of focal nodular hyperplasia and hepatocellular adenoma in young women: a series of 41 patients with clinical, radiological, and pathological correlations. Hepatology 22: 1674–81 5. Fabre A, Audet P, Vilgrain V, et al (2002) Histologic scoring of liver biopsy in focal nodular hyperplasia with atypical presentation. Hepatology 35: 414–20 6. Fukukura Y, Nakashima O, Kusaba A, et al (1998) Angioarchitecture and blood circulation in focal nodular hyperplasia of the liver. J Hepatol 29: 470–5 7. Gaffey MJ, Iezzoni JC, Weiss LM (1996) Clonal analysis of focal nodular hyperplasia of the liver. Am J Pathol 148: 1089–96 8. Goldin RD, Rose DS (1990) Focal nodular hyperplasia of the liver associated with intracranial vascular malformation. Gut 31: 554–5 9. Luciani A, Kobeiter H, Maison P, et al (2002) Focal nodular hyperplasia of the liver in men: is presentation the same in men and women? Gut 50: 877–80 10. Mathieu D, Zafrani ES, Anglade MC, et al (1989) Association of focal nodular hyperplasia and hepatic hemangioma. Gastroenterology 97: 154–7 11. Mathieu D, Kobeiter H, Maison P, et al (2000) Oral contraceptive use and focal nodular hyperplasia of the liver. Gastroenterology 118: 560–4 12. Nguyen BN, Flejou JF, Terris B, et al (1999) Focal nodular hyperplasia of the liver: a comprehensive pathological study of 305 lesions and recognition of new histologic forms. Am J Surg Pathol 23: 1441–54 13. Pain JA, Gimson AE, Williams R, et al (1991) Focal nodular hyperplasia of the liver: results of treatment and options on management. Gut 32: 524–7 14. Paradis V, Laurent A, Flejou JF, et al (1997) Evidence for the polyclonal nature of focal nodular hyperplasia of the liver by the study of X-chromosome inactivation. Hepatology 26: 891–5 15. Paradis V, Bièche I, Dargére D, et al (2003) A quantitative gene expression study suggests a role for angiopoietins in focal nodular hyperplasia. Gastroenterology 124: 651–9 16. Rebouissou S, Bioulac-Sage P, Zucman-Rossi J (2008) Molecular pathogenesis of focal nodular hyperplasia and hepatocellular adenoma. J Hepatol 48: 163–70 17. Reymond D, Plaschkes R, Lathy A, et al (1995) Focal nodular hyperplasia of the liver in children: review of follow-up and outcome. J Pediatr Surg 30: 1590–3 18. Scalori A, Tavani A, Gallus S, et al (2002) Risk factors for focal nodular hyperplasia of the liver: an Italian case-control study. Am J Gastroenterol 97: 2371–3 19. Wanless IR, Albrecht S, Bilbao J, et al (1989) Multiple focal hyperplasia of the liver associated with vascular malformations of various organs and neoplasia of the brain: a new syndrome. Mod Pathol 2: 456–62 20. Weimann A, Ringe B, Klempnauer J, et al (1997) Benign liver tumors: differential diagnosis and indications for surgery. World J Surg 21: 983–90 21. Weimann A, Mossinger M, Fronhoff K, et al (1998) Pregnancy in women with observed focal nodular hyperplasia of the liver. Lancet 351: 1251–2 22. Whelan TJ, Baugh JH, Chandor S (1973) Focal nodular hyperplasia of the liver. Ann Surg 177: 150–8
1288
101.4
Bile Duct Adenoma
101.4 Bile Duct Adenoma
Clinical Manifestations
Definition
Biliary adenomas are asymptomatic. Because of their small size they are missed on non-invasive imaging and are usually detected incidentally at laparoscopy or laparotomy performed for other reasons where they can be mistaken for metastatic carcinoma.
Bile duct adenomas usually are solitary, small (mean size 1.3 mm), unencapsulated, firm, grey-white, subcapsular nodules consisting of proliferating bile ducts [2, 5].
Differential Diagnosis Histology Microscopically they consist of a cluster of small, uniform, non-dilated biliary acini and tubules lined by a columnar epithelium, and embedded in a loose fibrohyaline stroma (Fig. 101.3). Mononuclear inflammatory cells are regularly found in the fibrous matrix, whereas lymphoid follicles are only occasionally encountered. The adenomatous biliary cells express antigens that can also be demonstrated in the peribiliary glands of the normal liver. This led some authors to assume that biliary adenomas arise from peribiliary glandular elements and that they in fact represent peribiliary gland hamartomas instead of true neoplasms [3].
Fig. 101.3 Biliary adenoma. Trichrome stain (×200)
The differential diagnosis includes biliary microhamartomas (von Meyenburg complexes). These acquired hamartomatous malformations of the finest branches of the biliary tree are found in the periportal region and are composed of ectatic bile ducts lined by low cuboidal epithelial cells. Their lumina communicate with bile ducts and often contain bile. Obliteration occurs frequently and causes cystic dilatation. When they are large and/or multiple they are often associated with polycystic kidney or liver disease (see Chapter 57). Occasionally differentiation of a bile duct adenoma from a well-differentiated cholangiocarcinoma or from metastatic adenocarcinoma may be difficult. The absence of atypia, dysplasia and glandular variation helps to make the correct diagnosis.
Diagnosis
A variant of bile duct adenoma with clear-cell morphology mimics renal cell carcinoma [1]. Diffuse macroscopically recognizable hyperplasia of the peribiliary glands of intrahepatic and extrahepatic bile ducts is an extremely rare condition of unknown pathogenesis. This condition has been described in a patient with hepatic necrosis [4].
Therapy Since bile duct adenomas do not cause adverse clinical effects no treatment is required. Adenomas of the common bile duct and of the ampulla/papilla of Vater are discussed in Chapter 115.
References 1. Albores-Saavedra J, Hoang MP, Murakata LA, et al (2001) Atypical bile duct adenoma, clear cell type: a previously undescribed tumor of the liver. Am J Surg Pathol 25: 956–60 2. Allaire GS, Rabin L, Ishak KG, et al (1988) Bile duct adenoma. A study of 152 cases. Am J Surg Pathol 12: 708–15 3. Bhathal PS, Hughes NR, Goodman ZD (1996) The so-called bile duct adenoma is a peribiliary gland hamartoma. Am J Surg Pathol 20: 858–64 4. Dumas A, Thung SN, Lin CS (1998) Diffuse hyperplasia of the peribiliary glands. Arch Pathol Lab Med 122: 87–9 5. Wanless IR (2002) Benign liver tumors. Clin Liver Dis 6: 513–26
1289
101.5 Biliary Cystadenoma Definition and Epidemiology Biliary cystadenoma, also called hepatobiliary cystadenoma with mesenchymal stroma, is a very rare benign tumor that probably arises from ectopic embryonic tissue. It occurs almost exclusively (95%) in women of all age groups. Patients between 30 and 50 years are most commonly affected.
Pathology The lesion has a slight predilection for the right liver lobe, is usually solitary and surrounded by a fibrous capsule. At the time of diagnosis most tumors are very large with a diameter between 25 and 30 cm. The tumor is always multilocular containing a mucinousgelatinous or serous and clear fluid. Histologically two variants are distinguished, a serous type that is exceedingly rare and a more common mucinous type. The epithelium is tall and columnar, may display papillary foldings and cystic invaginations, but may also be atrophic and flattened with focal ulcerations. Due to the presence of spindle-shaped stromal cells the matrix may resemble ovarian stroma [1–3]. Inflammatory changes, scar formation and calcification may occur in the septa running between the cysts.
Diagnosis Clinical Manifestations The clinical picture is not characteristic. Small tumors are asymptomatic, large lesions may cause right upper quadrant abdominal pain. Depending on the size and location of the mass it also may be palpable. Rupture, hemorrhage and obstruction of the biliary tree by the tumor rarely occur [5].
1290
101.5
Biliary Cystadenoma
Laboratory Findings
Therapy
Specific laboratory changes do not exist. Serum a1fetoprotein and CEA are not elevated. Elevated Ca 19–9 levels have been described, but this finding is nonspecific [6].
Complete operative resection is the treatment of choice. Because the mucinous type may undergo malignant transformation, complete surgical resection is mandatory and curative. Incomplete resection may lead to recurrence.
References Imaging Techniques A biliary cystadenoma appears as a solitary, well encapsulated, multilocular cystic mass on sonography, CT and MRI. Because laboratory examinations and imaging techniques yield nonspecific results, the definitive diagnosis of a biliary cystadenoma is usually made by the histologic examination of the resected specimen. A preoperative biopsy is not advisable.
Differential Diagnosis The differential diagnosis includes first and foremost a cystadenocarcinoma [7]. Alveolar echinococcosis, the rare mesenchymal hamartoma and unilobar Caroli’s disease are further conditions to be considered [4].
1. Devaney K, Goodman ZD, Ishak KG (1994) Hepatobiliary cystadenoma and cystadenocarcinoma. A light microscopic and immunohistochemical study of 70 patients. Am J Surg Pathol 18: 1078–91 2. Ishak KG, Willis GW, Cummis SD, et al (1977) Biliary cystadenoma and cystadenocarcinoma: report of 14 cases and review of the literature. Cancer 29: 322–38 3. Regev A, Reddy KR, Berho M, et al (2001) Large cystic lesions of the liver in adults: a 15 year experience in a tertiary center. J Am Coll Surg 193: 36–45 4. Siebenkotten V, Wennig M, Malms J, et al (1999) Ein zystischer echinokokkenähnlicher Lebertumor. Z Gastroenterol 37: 379–83 5. Sutton CD, White SA, Berry DP, et al (2000) Intrahepatic biliary cystadenoma causing luminal common bile duct obstruction. Dig Surg 17: 297–9 6. Thomas JA, Scriven MW, Puntis MC, et al (1992) Elevated serum Ca 19–9 levels in hepatobiliary cystadenoma with mesenchymal stroma. Two case reports with immunohistochemical confirmation. Cancer 70: 1841–46 7. Woods GL (1981) Biliary cystadenocarcinoma. Case report of hepatic malignancy originating in benign cystadenoma. Cancer 47: 2936–40
Therapy
101.6 Biliary Papillomatosis Definition Biliary papillomatosis is a rare disease characterized by multiple papillary adenomas with thin fibrovascular stalks involving both the intrahepatic and extrahepatic biliary tree.
Epidemiology, Etiology and Pathogenesis There are no systematic epidemiological data on biliary papillomatosis. Women are slightly more often affected than men. The etiology and pathogenesis of the disease are unknown.
1291
polyps, mucin plugs, sloughed tumor debris and blood clots resulting in multiple contrast medium filling defects. Whenever possible several intraductal forceps biopsies should be obtained. Thickening and irregularities of the bile duct wall may be visualized by intraductal endoscopic ultrasound. However, the findings are nonspecific and do not allow for the exclusion of malignancy.
Differential Diagnosis Cystically or aneurysmatically dilated bile ducts in mucin-hypersecreting variants (intraductal papillary mucinous tumors) should be differentiated from cystadenoma, cystadenocarcinoma and liver abscess.
Prognosis Diagnosis Clinical Manifestations The clinical manifestations are characterized by repeated episodes of abdominal pain, recurrent suppurative cholangitis with jaundice, septicemia and hemobilia. Blood clots in the common bile duct and hemobilia may cause acute pancreatitis [4–7, 9].
Laboratory Findings The laboratory findings are nonspecific. Cholestatic parameters (AP and gGT) and aminotransferase levels may be increased. If cholangitis is present inflammatory markers, such as the concentration of C-reactive protein and the erythrocyte sedimentation rate, rise. There are no specific tumor markers for biliary papillomatosis.
Imaging Techniques The diagnosis is made by ERCP, MRCP and cholangioscopy. The intra- and extrahepatic bile ducts show multiple saccular and segmental dilatations with
Biliary papillomatosis has a strong malignant potential. The majority of patients experience transformation to papillary cholangiocarcinoma. Gastroenteric metaplasia with aberrant expression of cytokeratin 20, mucin core proteins and mucin carbohydrate antigens is frequent in the neoplastic areas, and increasing grades of biliary epithelial dysplasia give rise to in situ and then invasive carcinoma [1, 8]. Histologically, phenotypically and clinically the biliary papillary neoplasms resemble intraductal papillary mucinous neoplasms of the pancreas. Thus, the prognosis of biliary papillomatosis is grave and the disease runs a relentless course with most patients dying from septicemia, acute liver failure or cholangiocarcinoma. Survival rates between 20% and 50% at 3 years have been reported [6].
Therapy Management is difficult. Antibiotic treatment of recurrent cholangitis cannot prevent progression of the disease. The rare segmental forms of biliary papillomatosis may be amenable to surgical resection. Intraluminal radiation with 192iridium and orthotopic liver transplantation yield encouraging results [2, 3].
1292
References 1. Amaya S, Sasaki M, Watanabe Y, et al (2001) Expression of MUC1 and MUC2 and carbohydrate antigen Tn change during malignant transformation of biliary papillomatosis. Histopathology 38: 550–60 2. Beavers KL, Fried MW, Johnson MW, et al (2001) Orthotopic liver transplantation for biliary papillomatosis. Liver Transpl 7: 264–5 3. Gunven P, Gorsetman J, Ohlsen H, et al (2000) Six-year recurrence free survival after intraluminal iridium-192 therapy for human bilobar biliary papillomatosis. Cancer 89: 69–73 4. Kim YS, Myung SI, Kim SY, et al (1998) Biliary papillomatosis: clinical, cholangiographic and cholangioscopic findings. Endoscopy 30: 763–67 5. Kim JD, Lee KM, Chung WC, et al (2007) Acute pancreatitis and cholangitis caused by hemobilia from biliary papillomatosis. Gastrointest Endosc 65: 177–80 6. Lee SS, Kim MH, Lee SK, et al (2004) Clinicopathologic review of 58 patients with biliary papillomatosis. Cancer 100: 783–93 7. Mercadier M, Bodard M, Fingerhut A, et al (1984) Papillomatosis of the intrahepatic bile ducts. World J Surg 8: 30–5 8. Vassiliou I, Kairi-Vassilatou E, Marinis A, et al (2006) Malignant potential of intrahepatic biliary papillomatosis: a case report and review of the literature. World J Surg Oncol. 4: 71 9. Wang YJ, Lee SD, Lai KH, et al (1993) Primary biliary cystic tumors of the liver. Am J Gastroenterol 88: 599–603
101.7
Hemangioma
101.7 Hemangioma Definition Hemangioma is a benign tumor originating from hepatic blood vessels. Diffuse systemic hemangiomatosis denotes the occurrence of hemangiomas in multiple organs, including the liver [2, 10, 11].
Epidemiology Cavernous hemangioma is the most common benign liver tumor. It occurs in any age group and is more common in women than in men, with a ratio of 3–5:1 [4]. The incidence in autopsy studies varies between 0.4% and 20% depending on the accuracy of liver dissection. On ultrasound examination the prevalence is approximately 1%.
Pathology Most hemangiomas are well-defined solitary lesions. However, especially large hepatic hemangiomas may have irregular edges and a less well-defined interface with the surrounding liver parenchyma [8]. Their gross appearance is spongy-reddish or bluish and they vary in size from a few millimeters to >20 cm in diameter, with most measuring 10 cm are defined as giant hemangiomas [1]. Microscopically dilated, endothelium lined, blood filled, anastomosing cavities are seen (Fig. 101.4). Depending on its developmental stage the hemangioma may be purely cavernous, partially or totally thrombosed. It may heal by increasing sclerosis leaving behind a scarred nodule.
Diagnosis Clinical Manifestations Most hemangiomas are asymptomatic and are found incidentally during a sonographic examination of the abdomen. Depending on their size and subcapsular
Diagnosis
1293
Fig. 101.4 Hemangioma with large blood filled vascular cavities separated by delicate fibrous strands. Trichrome stain (×200)
location they may cause a vague discomfort in the right upper abdomen. Occasionally a large hemangioma may cause abdominal symptoms because of a mass effect leading to compression of bile ducts with consequent cholestasis. Giant hemangiomas may lead to disseminated intravascular coagulation (Kasabach-Merrit syndrome).
Laboratory Findings Small hemangiomas do not cause any laboratory abnormalities. Large hemangiomas may lead to slight elevations of g-GT and alkaline phosphatase serum levels, and cause a thrombocytopenia. Giant hemangiomas have been associated with elevations of indirect reacting serum bilirubin, due to intravascular hemolysis of trapped red cells.
Imaging Techniques The diagnostic work-up primarily relies on imaging procedures, such as ultrasound, computed tomography and magnetic resonance imaging. Angiography and scintigraphic techniques have been largely replaced by these modalities in the diagnosis of hepatic hemangiomas. See also Chapters 37, 38 and 39.
Sonography is widely available and should be the imaging technique applied first. Even small hemangiomas (20 cm in diameter. Two microscopic types have been described [3]. In type 1 the vascular spaces resemble capillary channels lined by a simple endothelial layer with a scant collagenous matrix. The stroma of larger tumors contains proliferated bile ducts, areas of hemorrhagic necrosis, fibrosis, dystrophic calcifications and regularly foci of extramedullary hemopoiesis. Type 2 tumors exhibit poorly formed vascular spaces with papillary proliferations of a multilayered endothelium. This type has to be distinguished from angiosarcoma. Transitional forms between infantile hemangioendothelioma type 2 and angiosarcoma have been described [3].
Diagnosis Clinical Manifestations Approximately half of the patients present with an abdominal mass, anorexia, vomiting, failure to thrive and lethargy. Rarely, a systolic bruit may be auscultated over large tumors due to intratumoral arteriovenous shunts. These patients may develop congestive heart failure.
1296
Spontaneous rupture with subsequent hemoperitoneum is a rare complication. Malignant transformation is a very rare event [3, 11, 12].
Laboratory Findings Mild nonspecific elevations of liver enzymes (aminotransferases, AP, gGT) are observed. Anemia, thrombocytopenia due to platelet sequestration, disseminated intravascular coagulation (Kasabach-Merrit syndrome) and liver failure have also been described. Infantile hemangioendotheliomas may express type 3 iodothyronine deiodinase and cause severe hypothyroidism in some patients [5, 8]. Alpha-fetoprotein is only seldom elevated [10].
Imaging Techniques On US, CT and MRI the tumor appears as a complex, inhomogeneous mass lesion with areas of cystic degeneration, hemorrhages and large draining veins. ColorDoppler sonography and angio-MRI have widely replaced conventional hepatic angiography and may establish the vascular nature of the tumor and document its multiple arteriovenous shunts [9]. Imaging studies, however, cannot differentiate between hemangioendothelioma and angiosarcoma. Percutaneous liver biopsy is contraindicated because of the associated bleeding risk.
Therapy Uncomplicated infantile hemangioendothelioma does not require treatment since spontaneous involution of tumors over a time period of 5–8 years may occur [4]. In symptomatic patients treatment is mandatory. Therapeutic options, however, are limited and due to the rarity of the tumor studies with a large number of patients are not available. Medical treatment options include corticosteroids, interferon alpha, and, in life-threatening cases, cyclophosphamide [4, 6]. In infants with hypothyroidism supranormal doses of L-thyroxine may be required for
101.8
Infantile Hemangioendothelioma
normalization of thyroid function until the tumor involutes or is resected [5, 8]. Radiation therapy, hepatic artery embolisation or ligation are alternative treatment options [7]. Surgical resection has the highest rate of success but is technically demanding and sometimes not feasible in patients with a giant hemangioendothelioma or with multiple lesions. Orthotopic liver transplantation should be considered if all other therapies fail or are not eligible [2, 14].
References 1. Biecker E, Fischer HP, Strunk H, et al (2003) Benign hepatic tumors. Z Gastroenterol 41: 191–200 2. Daller JA, Bueno J, Gutierrez J, et al (1999) Hepatic hemangioendothelioma: clinical experience and management strategy. J Pediatr Surg 34: 98–105 3. Dehner LP, Ishak KG (1971) Vascular tumors of the liver in infants and children: a study of 30 cases and review of the literature. Arch Pathol 92: 101–11 4. Ezekowitz RA, Mulliken JB, Folkman J (1992) Interferon alfa-2a therapy for life threatening hemangiomas of infancy. N Engl J Med 326: 1456–63 5. Guven A, Aygun C, Ince H, et al (2005) Severe hypothyroidism caused by hepatic hemangioendothelioma in an infant of a diabetic mother. Horm Res 63: 86–9 6. Hurvitz SA, Hurvitz CH, Sloninsky L, et al (2000) Successful treatment with cyclophosphamide of life-threatening diffuse hemangiomatosis involving the liver. J Pediatr Hematol Oncol 22: 527–32 7. Laird WP, Friedman S, Koop CE, et al (1976) Hepatic haemangiomatosis. Successful management by hepatic artery ligation. Am J Dis Child 130: 657–9 8. Lee TC, Barshes NR, Agee EE, et al (2006) Resolution of medically resistant hypothyroidism after liver transplantation for hepatic hemangioendothelioma. J Pediatr Surg 41: 1783–5 9. Mortele KJ, Ros PR (2002) Benign liver neoplasmas. Clin Liver Dis 6: 119–45 10. Sari N, Yalcin B, Akyuz C, et al (2006) Infantile hepatic hemangioendothelioma with elevated serum alpha-fetoprotein. Pediatr Hematol Oncol 23: 639–47 11. Selby DM, Stocker JT, Ishak KG (1992) Angiosarcoma of the liver in childhood. A clinicopathologic and follow-up study of 10 cases. Pediatr Pathol 12: 485–9 12. Selby DM, Stocker JT, Waclawiw MA, et al (1994) Infantile hemangioendothelioma of the liver. Hepatology 20: 39–45 13. Stanley P, Geer GD, Miller JH, et al (1989) Infantile hepatic haemangiomas. Cancer 64: 936–49 14. Walsh R, Harrington J, Beneck D, et al (2004) Congenital infantile hepatic hemangioendothelioma type II treated with orthotopic liver transplantation. J Pediatr Hematol Oncol 26: 121–3
References
101.9 Lymphangioma and Hepatic Lymphangiomatosis The existence of a solitary lymphangioma of the liver is controversial, since the few published cases may well represent misdiagnosed mesenchymal hamartomas (K.G. Ishak, personal communication, 2000). However, the occurrence of multiple small (1–5 cm in diameter) hepatic lymphangiomas, denominated lymphangiomatosis, is well documented. They consist of anastomosing, cystically dilated, endothelium-lined lymph vessels containing lymph-like chylous fluid. In most patients hepatic lymphangiomatosis is associated with lymphangiomas in other organs, including the spleen, skeleton, kidneys, gastrointestinal tract, soft tissues, brain, lungs and mediastinum [1, 5]. Symptoms depend on the size and location of tumors. Small solitary lymphangiomas are asymptomatic, whereas lymphangiomatosis may lead to liver failure. On ultrasound and computed tomography lymphangiomas appear as cystic lesions, and hepatic lymphangiomatosis has been reported to mimic polycystic liver disease [4]. Fine needle biopsy may lead to peritoneal lymphorrhea [2]. Small, solitary lesions need no treatment. Large, symptomatic lesions and lymphangiomatosis may require surgical resection or orthotopic liver transplantation [3].
1297
101.10 Mesenchymal Hamartoma Mesenchymal hamartoma of the liver is a rare developmental cystic tumor that occurs most commonly in the first 2 years of life with a male-to-female ratio of 2:1. Grossly the tumor is unencapsulated and consists of solid and cystic components. Microscopically the lesion is composed of immature mesenchymal cells, bile ducts, and hepatocytes. Due to accumulation of fluid in the cysts, it usually progresses in size. Rapid enlargement may occasionally cause respiratory distress and edema of the lower extremities, and mimic malignancy. Intratumoral arteriovenous shunts may cause heart failure, and even death as a result of respiratory complications [1]. On US and CT imaging studies the tumor appears as a cystic mass composed of multiple cystic areas separated by septa. In younger patients, mesenchymal hamartoma may appear more solid because the cysts are smaller [2]. The MR imaging features usually reflect the predominantly cystic nature of this tumor. Signal intensities can differ because of varying concentrations of protein in the cysts [3]. Surgical resection or orthotopic liver transplantation of symptomatic progressive tumors is the sole therapeutic option.
References References 1. Chan SC, Huang SF, Lee WC, et al (2005) Solitary hepatic lymphangioma–a case report. Int J Clin Pract Suppl 147: 100–2 2. Damascelli B, Spagnoli I, Garbagnati F, et al (1984) Massive lymphorrhoea after fine needle biopsy of the cystic haemolymphangioma of the liver. Eur J Radiol 4: 107–9 3. Datz C, Graziadei IW, Dietze O, et al (2001) Massive progression of diffuse hepatic lymphangiomatosis after liver resection and rapid deterioration after liver transplantation. Am J Gastroenterol 96: 1278–81 4. O’Sullivan DA, Torres VE, de Groen PC, et al (1998) Hepatic lymphangiomatosis mimicking polycystic liver disease. Mayo Clin Proc 73: 1188–92 5. Van Steenbergen W, Joosten E, Marchal G, et al (1985) Hepatic lymphangiomatosis. Report of a case and review of the literature. Gastroenterology 88: 1968–72
1. Arfa MN, Gharbi L, Zaafrani MR, et al (2003) Cystic mesenchymal hamartoma of the liver report of a case and review of the literature. Hepatogastroenterology 50(Suppl 2): ccxlix–ccli 2. Horton KM, Bluemke DA, Hruban RH, et al (1999) CT and MR imaging of benign hepatic and biliary tumors. Radiographics 19: 431–51 3. Ros PR, Goodman ZD, Ishak KG, et al (1986) Mesenchymal hamartoma of the liver: radiologic-pathologic correlation. Radiology 158: 619–24
1298
101.11 Lipomatous Tumors Lipoma True hepatic lipomas are exceedingly rare tumors. They consist of mature adipocytes with interspersed isolated blood vessels. One case of tuberous sclerosis associated with hepatic lipoma has been reported [10]. The tumors usually remain asymptomatic and are detected incidentally on imaging studies. On ultrasound examination they are hyperechogenic with a dorsal acoustic shadow of varying intensity. On CT scanning the welldelineated mass has a density comparable to subcutaneous fat and, on MR imaging hepatic lipomas have a high signal intensity on T1-weighted images with only a minimal signal decrease on T2-weighted sequences [2, 11 21]. Treatment is not required.
Pseudolipoma This pseudotumor is mostly found incidentally at autopsy or during an abdominal operation. It manifests as a small, yellowish lesion surrounded by a fibrous capsule immersed in a superficial depression of the liver surface at the level of Glisson’s capsule. Pseudolipomas result from the detachment of epiploic appendixes from neighbouring colon or omentum and subsequent adhesion to the liver surface. Histologically, a localized accumulation of fat cells is seen with a varying admixture of connective tissue, calcifications and even ossifications. These pseudotumors have no clinical significance [13].
Focal Steatosis See also Chapter 37. Circumscribed steatotic areas in the liver are a frequent finding. They do not represent tumors, and their only clinical significance lies in the fact that they must not be confused with a neoplastic liver lesion and cause a cascade of complex and costly diagnostic investigations. The cause of focal steatosis is unknown. These focal changes in fat distribution are possibly caused by regional circulatory disturbances [7].
101.11
Lipomatous Tumors
On ultrasound examination, focal steatosis usually occurs anterior to the central portal vein branches as a more or less well-delineated hypoechoic area compared to the remainder of the liver (see Fig. 37.4). Even if large, these “mass lesions” do not encroach upon the vascular architecture of the liver, which differentiates them from true tumors. The experienced sonographer has no difficulty in diagnosing focal fatty liver. CT and MRI studies are not required.
Angiomyolipoma Definition and Epidemiology Angiomyolipomas are rare, benign mesenchymal tumors. Most angiomyolipomas affect the kidneys. The isolated occurrence in the liver is rare. Females are affected more often than males, and the mean age at the time of diagnosis is approximately 50 years. An association of angiomyolipoma with tuberous sclerosis has been described [6, 10]. The concomitant occurrence of angiomyolipoma with focal nodular hyperplasia, bile duct adenoma, hemangioma and hepatocellular carcinoma has been reported in single cases [3, 8, 15].
Pathology On gross examination the tumors are red to yellow, reflecting their heterogeneous composition of fat, vessels and muscle cells. They are well demarcated from the surrounding liver parenchyma and vary in size from a few millimeters to >30 cm in diameter. Angiomyolipomas derive from perivascular epithelioid cells and share a similar gene expression profile with hepatic stellate cells [12, 16, 18, 19]. Histologically the tumors are heterogeneous with varying proportions of adipocytes, blood vessels and smooth muscles. In two thirds of cases bone marrow elements are found (angiomyomyelolipoma). If only adipocytes and vascular structures are present the lesion is described as an angiolipoma. Myelolipomas contain adipocytes and hemopoietic cells. In rare cases only trace amounts of fat are found [24]. If the smooth muscle component (spindle shaped, epithelioid)
Angiomyolipoma
predominates, the differentiation from mesenchymal tumors may be difficult. Some angiomyolipomas resemble epithelial tumors and may mimic hepatocellular carcinoma or metastases from clear cell renal carcinoma [23]. Despite the benign nature of the tumor on histological examination, angiomyolipomas frequently display a growth pattern mimicking invasiveness, which might lead to an erroneous diagnosis of malignancy.
Fig. 101.6 Angiomyolipoma. Hematoxylin & Eosin (×200). Sonographically the tumor appeared as a homogeneous hyperechoic lesion indistinguishable from a hemangioma
Fig. 101.7 Angiomyolipoma (same case as in Figure 101.6). Immunocytochemical staining of the melanocytic marker HMB-45
1299
Therefore, pathologists should not overdiagnose malignancy based solely on the histological growth pattern of angiomyolipomas [20]. Immunohistochemical studies have shown angiomyolipomas to express the melanocytic markers HMB45, MART-1 (Melan A), microophthalmia transcription factor, tyrosinase, smooth muscle actin, vimentin, desmin and KIT (CD 117) (Figs. 101.6 and 101.7) [5, 16].
1300
101.11
Lipomatous Tumors
Diagnosis
Therapy
Clinical Manifestations
Most patients with angiomyolipoma are asymptomatic and do not need treatment. They may be managed expectantly and monitored on a regular basis [26]. Spontaneous rupture and malignant transformation are exceedingly rare [4, 9]. Symptomatic and large tumors should be resected. The prognosis after surgical resection is excellent and recurrence is rare [17, 22].
Clinically, most angiomyolipomas are asymptomatic and are found incidentally. However, the tumors may attain a large size, cause hepatomegaly, abdominal discomfort, nausea and in rare cases a Budd–Chiari syndrome [14].
Laboratory Findings There are no specific serologic diagnostic markers for angiomyolipoma.
Imaging Methods Imaging tools visualize the hypervascular nature and the fatty component of the lesion. However, because of the variability of the different tissue components the appearance on US, CT and MR imaging is heterogeneous. On ultrasound examination the tumors are well-delineated, hyperechoic with an irregular echopattern. They cannot be distinguished from a hemangioma. On CT scanning they are predominantly hypodense with an irregular contrast enhancement. On MRI tumors show hypointensity or hyperintensity on T1-weighted images and heterogeneous hyperintensity on T2-weighted images [22]. The combined application of dynamic spiral CT, MRI and contrast-enhanced ultrasound allow for the detection of a vascular pattern with a prominent efferent tumor vein [1, 27]. The specificity of this vascular pattern, however, has not been documented yet. The main clinical challenge is the exclusion of primary hepatic or metastatic malignancy. If imaging procedures do not allow for the establishment of a definitive diagnosis and do not permit the exclusion of a malignancy, then a needle biopsy with special immunostains should be performed. HMB-45 is the best marker available for diagnosis [25].
References 1. Ahmadi T, Itai Y, Takahashi M, et al (1998) Angiomyolipoma of the liver: significance of CT and MR dynamic study. Abdom Imaging 23: 520–6 2. Basaran C, Karcaaltincaba M, Akata D, et al (2005) Fatcontaining lesions of the liver: cross-sectional imaging findings with emphasis on MRI. AJR Am J Roentgenol 184: 1103–10 3. Chang YC, Tsai HM, Chow NH (2001) Hepatic angiomyolipoma with concomitant hepatocellular carcinomas. Hepatogastroenterology 48: 253–5 4. Dalle I, Sciot R, de Vos R, et al (2000) Malignant angiomyolipoma of the liver: a hitherto unreported variant. Histopathology 36: 443–50 5. Fetsch PA, Fetsch JF, Marincola FM, et al (1998) Comparison of melanoma antigen recognized by T cells (MART-1) to HMB-45: additional evidence to support a common lineage for angiomyolipoma, lymphangiomyomatosis, and clear cell sugar tumor. Mod Pathol 11: 699–703 6. Fricke BL, Donnelly LF, Casper KA, et al (2004) Frequency and imaging appearance of hepatic angiomyolipomas in pediatric and adult patients with tuberous sclerosis. AJR Am J Roentgenol 182: 1027–30 7. Fukukura Y, Fujuyoshi F, Inoue H, et al (2000) Focal fatty infiltration in the posterior aspect of hepatic segment IV: relationship to pancreaticoduodenal venous drainage. Am J Gastroenterol 95: 3590–5 8. Goodman ZD, Ishak KG (1994) Angiomyolipomas of the liver. Am J Surg Pathol 8: 745–50 9. Guidi G, Catalano O, Rotondo A (1997) Spontaneous rupture of a hepatic angiomyolipoma: CT findings and literature review. Eur Radiol 7: 335–7 10. Hirasaki S, Koide N, Ogawa H, et al (1999) Tuberous sclerosis associated with multiple hepatic lipomatous tumors and hemorrhagic renal angiomyolipoma. Intern Med 38: 345–8 11. Horton KM, Bluemke DA, Hruban RH, et al (1999) CT and MR imaging of benign hepatic and biliary tumors. Radiographics 19: 431–51
Inflammatory Pseudotumor 12. Kannangai R, Diehl AM, Sicklick J, et al (2005) Hepatic angiomyolipoma and hepatic stellate cells share a similar gene expression profile. Hum Pathol 36: 341–7 13. Karhunen PJ (1985) Hepatic pseudolipoma. J Clin Pathol. 38: 877–9 14. Kelleher T, Staunton M, Malone D, et al (2004) Budd Chiari syndrome associated with angiomyolipoma of the liver. J Hepatol 40: 1048–9 15. Langner C, Homayounfar K, B. Ruten, et al (2001) Gleichzeitiges Auftreten von Angiomyolipom, fokaler nodulärer Hyperplasie, cholangiozellulärem Adenom und Hämangiom in der Leber. Pathologe 22: 417–23 16. Makhlouf HR, Remotti HE, Ishak KG (2002) Expression of KIT (CD117) in angiomyolipoma. Am J Surg Pathol 26: 493–7 17. McKinney CA, Geiger JD, Castle VP, et al (2005) Aggressive hepatic angiomyolipoma in a child. Pediatr Hematol Oncol 22: 17–24 18. Nonomura A, Mizukami Y, Kadoya M (1994) Angiomyolipoma of the liver. A collective review. J Gastroenterol 29: 95–105 19. Nonomura A, Minato H, Kurumaya H (1998) Angiomyolipoma predominantly composed of smooth muscle cells: problems in histological diagnosis. Histopathology 33: 20–7 20. Nonomura A, Enomoto Y, Takeda M, et al (2006) Invasive growth of hepatic angiomyolipoma; a hitherto unreported ominous histological feature. Histopathology 48: 831–5 21. Prasad SR, Wang H, Rosas H, et al (2005) Fat-containing lesions of the liver: radiologic-pathologic correlation. Radiographics 25: 321–31 22. Ren N, Qin LX, Tang ZY, et al (2003) Diagnosis and treatment of hepatic angiomyolipoma in 26 cases. World J Gastroenterol 9: 1856–8 23. Szekely E, Schaff Z, Madaras L, et al (2000) Trabecular angiomyolipoma mimicking hepatic cell carcinoma. Pathol Oncol Res 6: 224–6 24. Wang SN, Tsai KB, Lee KT (2006) Hepatic angiomyolipoma with trace amounts of fat: a case report and literature review. J Clin Pathol 59: 1196–9 25. Xu AM, Zhang SH, Zheng JM, et al (2006) Pathological and molecular analysis of sporadic hepatic angiomyolipoma. Hum Pathol 37: 735–41 26. Yeh CN, Chen MF, Hung CF, et al (2001) Angiomyolipoma of the liver. J Surg Oncol 77: 195–200 27. Zheng RQ, Kudo M (2005) Hepatic angiomyolipoma: identification of an efferent vessel to be hepatic vein by contrastenhanced harmonic ultrasound. Br J Radiol 78: 956–60
1301
101.12 Fibrous Tumors Solitary Fibrous Tumor This very rare tumor is also called localized fibrous mesothelioma or submesothelial fibroma. It can reach a size of up to 20 cm in diameter and may be pedunculated. Microscopically it is composed of parallel bundles of collagen and reticulin fibers. The cellular component is variable. Diagnosis is by liver biopsy. Symptomatic tumors are treated by surgical resection.
Inflammatory Pseudotumor Definition and Epidemiology An inflammatory pseudotumor is a rare tumor with fewer than 200 cases reported in the literature. It has also been called inflammatory myofibroblastic tumor and plasma cell granuloma of the liver. It is found primarily in men, with a male to female ratio of 3.5:1. The mean age at diagnosis is approximately 33 years [8, 15, 16, 18, 23]. Inflammatory pseudotumors may occur alone or be associated with various conditions, such as autoimmune pancreatitis, IgG4 associated primary sclerosing cholangitis, primary biliary cirrhosis, and malignancy (mainly gastrointestinal and biliary tract cancers) [5, 7, 9, 14, 19, 25]. An association of an inflammatory pseudotumor with rare hereditary diseases, such as the Papillon-Lefevre syndrome (palmar-plantar hyperkeratosis and severe periodontal destruction) has also been described [3].
Etiology and Pathogenesis The etiopathogenesis is poorly understood. Viral (HIV, EBV), fungal and bacterial infectious have been hypothesized to play a role. Recently Actinomyces and Bacteroides caccae were demonstrated within an inflammatory pseudotumor of a patient and in hepatic
1302
tissue of another patient with an inflammatory pseudotumor, respectively [1, 21]. The concomitant occurrence of inflammatory pseudotumor with IgG4 associated diseases, such as primary sclerosing cholangitis and autoimmune pancreatitis suggest an immune background in its pathogenesis [25].
Pathology The majority of inflammatory pseudotumors are solitary lesions, with 90% occurring within the liver and 10% located at the hepatic hilum. The size of the tumor varies from 1 to 25 cm in diameter. The lesion is usually vaguely demarcated from the surrounding liver parenchyma and might infiltrate portal and hepatic vein branches as well as bile ducts. Microscopically, inflammatory pseudotumor consists of proliferating fibrovascular tissue and infiltrating chronic inflammatory cells (Fig. 101.8). There is a polyclonal proliferation of plasma cells, lymphocytes, foamy histiocytes, fibroblasts and myofibroblasts. The cells may be arranged in whirls alongside collagen bundles and proliferated blood vessels. The latter occasionally display obliterative endophlebitic lesions [17]. Granulomas may be present.
Fig. 101.8 Inflammatory hepatic pseudotumor. Sonographically the tumor appeared as a hypoechoic mass. Trichrome stain (×400)
101.12 Fibrous Tumors
Diagnosis Clinical Manifestations Depending on its size and location the tumor may cause symptoms due to mass effect on neighbouring structures. Clinical manifestations include fever, malaise, weight loss, and right upper quadrant pain. Cholestatic jaundice due to recurrent pyogenic cholangitis and portal hypertension may occur [22]. Laboratory Findings Laboratory data often reveal evidence of an inflammatory process indicated by leukocytosis, an elevated erythrocyte sedimentation rate, and a positive C reactive protein. Rarely serum CA19–9 levels may be elevated [10]. Imaging Techniques Imaging studies yield nonspecific results. On ultrasound most lesions appear hypoechoic. The most common CT findings are a single hypodense lesion with either no significant change or a delayed persistent enhancement after administration of contrast medium.
References
MRI findings also are nonspecific. Signal intensity characteristics on both unenhanced T1- and T2-weighted images vary from hypointense to hyperintense. Mostly, however, on unenhanced MR imaging there is hyperintensity on T2-weighted images. Recently a case of hepatic inflammatory pseudotumor identified by FDG-PET has been reported [6]. Microscopic examination of tumor tissue is the only reliable method of establishing the diagnosis and liver biopsy therefore should be performed early in the work-up of a hepatic mass lesion of unknown cause [13].
Differential Diagnosis The differential diagnosis includes all solid tumors, primarily hepatocellular carcinoma. The ultrasound, CT and MRI appearance of a hepatic hilar pseudotumor is indistinguishable from that of cholangiocarcinoma [20]. The histological differential diagnosis includes an organized chronic hepatic abscess, a rhabdomyosarcoma, a malignant fibrosing histiocytoma and a sclerosing hepatocellular carcinoma.
Therapy and Prognosis Inflammatory pseudotumors have a small but definite malignant potential and treatment is therefore advised. Regression, either spontaneous or following therapy with steroids, antibiotics or nonsteroidal anti-inflammatory drugs, as well as malignant transformation are rare, but documented [2, 4, 7,12, 24] The prognosis after complete surgical resection is excellent.
References 1. Bernard M, Marie I, Riachi G, et al (2005) Inflammatory pseudotumor of the liver revealing gynecological Corynebacterium infection. Scand J Gastroenterol 40: 875–7 2. Biecker E, Zimmermann A, Dufour JF (2003) Spontaneous regression of an inflammatory pseudotumor of the liver. Z Gastroenterol 41: 991–4
1303 3. Czauderna P, Sznurkowska K, Korzon M, et al (1999) Association of inflammatory pseudotumor of the liver and Papillon-Lefevre syndrome – case report. Eur J Pediatr Surg 9: 343–6 4. Colakoglu O, Unsal B, Haciyanli M, et al (2005) A successfully managed inflammatory pseudotumour of liver without surgery: report of a case. Acta Gastroenterol Belg 68: 382–4 5. Kanno A, Satoh K, Kimura K, et al (2005) Autoimmune pancreatitis with hepatic inflammatory pseudotumor. Pancreas 31: 420–3 6. Kawamura E, Habu D, Tsushima H, et al (2006) A case of hepatic inflammatory pseudotumor identified by FDG-PET. Ann Nucl Med 20: 321–3 7. Koide H, Sato K, Fukusato T, et al (2006) Spontaneous regression of hepatic inflammatory pseudotumor with primary biliary cirrhosis: case report and literature review. World J Gastroenterol 14: 1645–8 8. Moran CA, Ishak KG, Goodman ZD (1998) Solitary fibrous tumor of the liver: a clinicopathologic and immunohistochemical study of nine cases. Ann Diagn Pathol 2: 1–7 9. Nishimura R, Teramoto N, Tanada M, et al (2005) Inflammatory pseudotumor of the liver associated with malignant disease: report of two cases and a review of the literature. Virchows Arch 447: 660–4 10. Ogawa T, Yokoi H, Kawarada Y (1998) A case of inflammatory pseudotumor of the liver causing elevated serum CA19–9 levels. Am J Gastroenterol 93: 2551–5 11. Pack GT, Baker HW (1953) Total right hepatic lobectomy. Report of a case. Ann Surg 138: 253–8 12. Pecorella I, Ciardi A, Memeo L, et al (1999) Inflammatory pseudotumor of the liver–evidence for malignant transformation. Pathol Res Pract 195: 115–20 13. Sakai T, Shiraki K, Yamamoto N, et al (2002) Diagnosis of inflammatory pseudotumor of the liver. Int J Mol Med 10: 281–5 14. Sasahira N, Kawabe T, Nakamura A, et al (2005) Inflammatory pseudotumor of the liver and peripheral eosinophilia in autoimmune pancreatitis. World J Gastroenterol 11: 922–5 15. Schmid A, Janig D, Bohuszlavizki A, et al (1996) Inflammatory pseudotumor of the liver presenting as incidentaloma: report of a case and review of the literature. Hepatogastroenterology 43: 1009–14 16. Shek TWH, Ng IOL, Chan KW (1993) Inflammatory pseudotumor of the liver. Report of four cases and review of the literature. Am J Surg Pathol 17: 231–8 17. Someren A (1978) “Inflammatory pseudotumor” of the liver with occlusive phlebitis. Am J Clin Pathol 69: 176–81 18. Strohm WD, Stähle KS, Schlumm G (1996) Inflammatorischer Pseudotumor der Leber. Fallbericht über die seltene Differenzialdiagnose des hepatozellulären Karzinoms. Z Gastoenterol 34: 132–7 19. Toda K, Yasuda I, Nishigaki Y, et al (2003) Inflammatory pseudotumor of the liver with primary sclerosing cholangitis. J Gastroenterol35: 304–9 20. Tublin ME, Moser AJ, Marsh JW, et al (2007) Biliary inflammatory pseudotumor: imaging features in seven patients. AJR Am J Roentgenol 188: W44–8 21. White JE, Chase CW, Kelley JE, et al (1997) Inflammatory pseudotumor of the liver associated with extrahepatic infection. South Med J 90: 23–9
1304 22. Yoon KH, Ha HK, Lee JS, et al (1999) Inflammatory pseudotumor of the liver in patients with recurrent pyogenic cholangitis: CT-histopathologic correlation. Radiology 211: 373–9 23. Zamir D, Jarchowsky J, Singer C, et al (1998) Inflammatory pseudotumor of the liver – a rare entity and a diagnostic challenge. Am J Gastroenterol 93: 1538–40 24. Zavaglia C, Barberis M, Gelosa F, et al (1996) Inflammatory pseudotumor of the liver with malignant transformation. Report of two cases. Ital J Gastroenterol 28: 152–9 25. Zen Y, Harada K, Sasaki M, et al (2004) IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitis-associated sclerosing cholangitis: do they belong to a spectrum of sclerosing pancreatitis? Am J Surg Pathol 28: 1193–203
101.13
Various Rare Tumors
101.13 Various Rare Tumors In addition to the tumors described in the preceding sections, some uncommon benign tumors of the liver are mentioned here for completeness. They are, however, of limited clinical importance, and have been described primarily as case reports or in small series. These tumors or tumor-like lesions comprise leiomyomas, benign schwannomas, chondromas, benign teratomas, granular cell tumors, adrenal-remnant tumors, pancreatic and splenic heterotopias, endometrial cysts, focal extramedullary hematopoietic tumors, tumor-like reactive lymphoid hyperplasias, ectopic hepatic pregnancy and epidermoid cysts. Leiomyomas are well-circumscribed smooth muscle tumors that occur extremely rarely in the liver. They have been described in renal transplant recipients, in patients infected with HIV and EBV, and in an asymptomatic hepatitis B carrier [3–5]. They have no specific radiologic or ultrasound characteristics. A case with a myxoid matrix appearing on CT scan as a cystic lesion has also been reported [6]. Spongiotic pericytoma (Ito cell tumor) appears to originate from hepatic stellate cells. So far, only one case has been reported [1]. The polycyclic tumor contained multiple nodular cell aggregates, and tumor cells expressed vimentin, CD34, CD105, CD99, CD56, and smooth muscle actin. It remains unclear whether this tumor is benign or malignant [2].
References 1. Bioulac-Sage P, Laumonier H, Laurent C, et al (2008) Benign an malignant vascular tumors of the liver in adults. Semin Liver Dis 28: 302–14 2. Kaiserling E, Müller H (2005) Neoplasm of hepatic stellate cells (spongiotic pericytoma): a new tumor entity in human liver. Pathol Res Pract 201: 733–43 3. Mesenas SJ, Ng KY, Raj P, et al (2000) Primary leiomyoma of the liver. Singapore Med J 41: 129–31 4. Sclabas GM, Maurer CA, Wente MN, et al (2002) Case report: hepatic leiomyoma in a renal transplant recipient. Transplant Proc 34: 3200–2 5. Wang MH, Wu CT, Hung CC, et al (2000) Hepatic leiomyomatous neoplasm associated with Epstein Barr virus infection in an adult with acquired immunodeficiency syndrome. J Formos Med Assoc 99: 873–5 6. Yoon GS, Kang GH, Kim OJ (1998) Primary myxoid leiomyoma of the liver. Arch Pathol Lab Med 122: 1112–5
Malignant Tumors
102
Henryk Dancygier
Chapter Outline 102.1 Hepatocellular Carcinoma ............................... 1307 Definition....................................................................... 1307 Epidemiology ................................................................ 1307 Etiology ......................................................................... 1308 Pathogenesis.................................................................. 1310 Chronic Hepatitis B Virus Infection .............................. 1311 Chronic Hepatitis C Virus Infection .............................. 1312 Liver Cirrhosis ............................................................... 1312 Alcoholic Liver Disease ................................................. 1312 Nonalcoholic Fatty Liver Disease .................................. 1312 Aflatoxin B1 and Other Toxins ....................................... 1312
Other Scoring Systems................................................... 1325 Comparison of Different Staging Systems..................... 1325 Prevention and Screening ............................................ 1326 Therapy ......................................................................... 1326 Surgical Resection.......................................................... 1326 Liver Transplantation ..................................................... 1327 Locally Ablative Techniques.......................................... 1327 Medical Therapy ............................................................ 1329 References ..................................................................... 1329
102.2 Fibrolamellar Carcinoma ................................. 1337 Definition....................................................................... 1337
Pathology ...................................................................... 1313
Epidemiology ................................................................ 1337
Macroregenerative Nodules ........................................... 1313 Liver Cell Dysplasia....................................................... 1313 Dysplastic Foci............................................................... 1314 Dysplastic Nodules ........................................................ 1314 Progression from Dysplasia to Hepatocellular Carcinoma ...................................................................... 1314 Hepatocellular Carcinoma ............................................. 1315
Etiology and Pathogenesis ........................................... 1337
Diagnosis ....................................................................... 1317 Clinical Manifestations .................................................. 1317 Laboratory Findings ....................................................... 1317 Imaging Techniques ....................................................... 1319 Approach to a Hepatic Mass in a Cirrhotic Liver ......................................................... 1319 Differential Diagnosis .................................................. 1321 Prognosis and Staging.................................................. 1321 TNM System .................................................................. 1323 Okuda Staging System ................................................... 1323 Cancer of the Liver Italian Program .............................. 1324 Barcelona Clinic Liver Cancer Staging Classification .................................................................. 1325
Pathology ...................................................................... 1337 Diagnosis ....................................................................... 1337 Differential Diagnosis .................................................. 1337 Prognosis and Treatment............................................. 1338 References ..................................................................... 1338
102.3 Hepatoblastoma................................................. 1338 Definition....................................................................... 1338 Epidemiology ................................................................ 1338 Etiology and Pathogenesis ........................................... 1338 Pathology ...................................................................... 1338 Diagnosis ....................................................................... 1339 Clinical Manifestations .................................................. 1339 Technical Investigations ................................................. 1339
H. Dancygier, Clinical Hepatology, DOI: 10.1007/978-3-642-04519-6_102, © Springer-Verlag Berlin Heidelberg 2010
1305
1306
102
Malignant Tumors
Course and Prognosis .................................................. 1339
102.6 Embryonal Sarcoma ......................................... 1345
Therapy ......................................................................... 1339
Definition....................................................................... 1345
References ..................................................................... 1339
Epidemiology ................................................................ 1345 Etiology and Pathogenesis ........................................... 1345
102.4 Angiosarcoma .................................................... 1340
Pathology ...................................................................... 1345
Definition....................................................................... 1340
Diagnosis ....................................................................... 1346
Epidemiology ................................................................ 1340
Clinical Manifestations .................................................. 1346 Laboratory Findings ....................................................... 1346 Imaging Techniques ....................................................... 1346
Etiology and Pathogenesis ........................................... 1340 Pathology ...................................................................... 1340 Diagnosis ....................................................................... 1341 Clinical Manifestations .................................................. 1341 Laboratory Findings ....................................................... 1341 Imaging Techniques ....................................................... 1341
Differential Diagnosis .................................................. 1346 Course and Prognosis .................................................. 1346 Therapy ......................................................................... 1346 References ..................................................................... 1346
Differential Diagnosis .................................................. 1341 Course and Prognosis .................................................. 1341
102.7 Primary Hepatic Malignant Lymphoma ........ 1347
Therapy ......................................................................... 1342
Epidemiology ................................................................ 1347
References ..................................................................... 1342
Pathogenesis.................................................................. 1347 Pathology ...................................................................... 1347
102.5 Epithelioid Hemangioendothelioma ................ 1343
Diagnosis ....................................................................... 1347
Definition....................................................................... 1343
Clinical Manifestations .................................................. 1347 Laboratory Findings ....................................................... 1347 Imaging Techniques ....................................................... 1348
Epidemiology ................................................................ 1343 Etiology and Pathogenesis ........................................... 1343 Pathology ...................................................................... 1343 Diagnosis ....................................................................... 1344 Clinical Manifestations .................................................. 1344 Laboratory Findings ....................................................... 1344 Imaging Techniques ....................................................... 1344
Differential Diagnosis .................................................. 1348 Course and Prognosis .................................................. 1348 Therapy ......................................................................... 1348 References ..................................................................... 1348
Differential Diagnosis .................................................. 1344
102.8 Various Rare Tumors ........................................ 1349
Course and Prognosis .................................................. 1344
Malignant Fibrous Histiocytoma ................................ 1349
Therapy ......................................................................... 1344
Kaposi’s Sarcoma ......................................................... 1349
References ..................................................................... 1345
Other Rare Tumors ...................................................... 1350 References ..................................................................... 1350
Epidemiology
The most common malignant liver tumors are hepatic metastases. The approach to liver metastases has changed in the last years. Liver metastases from colorectal cancer in particular are approached nowadays more aggressively. Depending on the clinical situation they may be resected or treated with locally ablative methods, such as ethanol injection, cryotherapy, laser or radiofrequency ablation or by transarterial chemoembolization. In the following sections only primary malignant liver tumors are discussed. Cholangiocarcinoma is discussed in Chapter 116.
1307
102.1 Hepatocellular Carcinoma Definition Hepatocellular carcinoma (HCC) is a malignant epithelial tumor originating from hepatocytes and consisting of liver cell-like but abnormal cells. The basic histologic structure with a trabecular-like arrangement of tumor cells surrounding sinusoidal lumina may nearly always be detected in histologically different HCCs [107, 200].
Epidemiology HCC belongs to the most common malignant tumors worldwide with nearly 1 million new cases occurring yearly. In high incidence areas (>20 new cases/105 inhabitants/year) approximately 20–40% of all malignant tumors are HCCs. Men are affected more often than women (8:1 in high incidence areas, 2–3:1 in low incidence areas). The mean age at manifestation in Western Europe and in the US is between 50 and 60 years. The incidence of HCC exhibits marked geographical variations (Fig 102.1). High incidence areas with 100–150 new cases per 105 inhabitants per year are East, West and Central Africa, China, Korea, Thailand and Vietnam. Moderate incidence rates of 5–20 new cases per 105 inhabitants per year are observed in Japan, the Middle East, in South and in Central America. Low incidence rates of up to five new cases per 105 inhabitants per year occur in North, West and Central Europe, North and South America, Australia, Central Asia and in the white population of North and South Africa. The incidence in central Europe is 3–7/105 inhabitants, in the Mediterranean area 5–20/105 [61]. The geographical variation in the incidence of HCC probably is related to the different geographical distribution of risk factors (see below) [30, 193]. In high incidence areas younger, previously healthy people are affected more often, and HCC relatively frequently develops in a noncirrhotic liver and progresses rapidly. a1-Fetoprotein levels in serum nearly always are elevated. HCC patients in the USA and in Europe tend to be older, HCC develops on the background of cirrhosis in approximately 90% of cases,
1308
102
Malignant Tumors
< 3.3 < 5.6 < 9.0 < 15.0 < 98.9
Fig. 102.1 Worldwide incidence of hepatocellular carcinoma (Adapted from [17]. With permission)
a1-fetoprotein levels in serum are elevated more rarely, and the course is slower and less aggressive than in high incidence areas. Overall HCC incidence, especially in younger people, is rising in Western countries, possibly reflecting the increased incidence in chronic hepatitis C infection [17, 60, 186]. Ethnic factors affect the development of HCC, and among patients with chronic hepatitis C and cirrhosis, liver cancer risk was reported to be increased fourfold in Asians and doubled in African-American men, compared with Whites [169].
Etiology The risk factors for HCC are listed in Table 102.1. Liver cirrhosis is a precancerous condition and each patient with liver cirrhosis, irrespective of its etiology carries an increased HCC risk. The risk of HCC correlates with the duration and etiology of liver cirrhosis (Fig. 102.2). Patients with chronic hepatitis B and C, with hereditary hemochromatosis and with alcoholic liver disease have the highest relative risk of HCC [12, 54, 216]. Increased age, anti-HCV-positivity,
prolongation of partial thromboplastin time and low platelet counts define a subgroup of patients with liver cirrhosis at a particularly high risk for HCC [238]. HCV genotype 1b is associated with a statistically significant higher risk of developing HCC than other HCV genotypes [23]. Although interferon therapy reduces the risk of HCC, 3.5% of patients with chronic hepatitis C still develop HCC after interferon-induced sustained viral response. Elderly, male patients, with an advanced histologic stage seem to be at a high risk for the development of HCC even after achieving a sustained viral response [113]. On a worldwide scale, chronic HBV infection is the most important cause of HCC. More than 60% of HCC cases in hyperendemic areas are HBsAg positive. The lifetime risk of a HBsAg-positive person developing a HCC is approximately 40%. The presence of HBeAg and HBV-DNA further increases this risk [37, 249]. Alcoholic liver disease is the most common risk factor for HCC in Western countries. Liver iron overload and C282Y mutation are associated with a higher risk of HCC in patients with alcoholic cirrhosis 1[65]. Insulin resistance states, such as type 2 diabetes mellitus, obesity in men, and nonalcoholic fatty liver disease are becoming increasingly significant as risk factors
Etiology
1309
Table 102.1 Risk factors for hepatocellular carcinomaa Chronic hepatitis B (± D), C Liver cirrhosis (especially of viral, hemochromatotic and alcoholic origin) Insulin resistance states Diabetes mellitus Obesity (in men) Nonalcoholic fatty liver disease Toxins Ethanol Nictotin Aflatoxin Oral contraceptives [152] Anabolic androgenic steroids Membranous obstruction of inferior vena cavab [212] a1-antitrypsin deficiencyb [68] Glycogen storage disease type I and III [46, 51] Galactosemia Progressive familial intrahepatic cholestasis (PFIC)b [112] Ataxia telangiectasiab Porphyria cutanea tarda [73] Tyrosinemiac [153, 243] a
The first three categories are by far the most important Single cases are documented. Evidence is inconclusive to establish a causal relation with HCC c HCC occurs in approximately one third of patients who survive the first 2 years of life. HCC may also develop in a transplanted liver b
80 70
HCC risk (%)
60
HBV HDV
60
HCV
Hemochro -matosis
40 Alcohol
30 20 10 M. Wilson 0
PBC
Liver disease
Fig. 102.2 HCC-risk in patients with liver cirrhosis of different etiologies (From [12])
for HCC (particularly in affluent Western countries), and are responsible for the majority of HCC cases that hitherto could not be attributed to a “traditional” risk factor [26, 63, 64, 66, 123, 154]. Type 2 diabetes mellitus is associated with a two to three fold increase in the risk of HCC, regardless of the presence of other major HCC risk factors [48]. Recent evidence also suggests
that individual risk factors, such as alcohol, chronic virus hepatitis B and C, type 2 diabetes mellitus, obesity and tobacco interact and are synergistic risk factors for HCC [36, 37, 39, 84, 94, 157, 171, 239, 254]. Up to 45% of patients with hereditary hemochromatosis die of HCC if treated inadequately (see Chapter 82). The risk of HCC in a cirrhotic hemochromatotic liver is increased up to 200-fold [53, 69, 170]. Rarely HCC may also occur in a non-cirrhotic hemochromatotic liver or in liver cirrhosis after successful iron depletion by phlebotomy. For practical purposes it may be assumed that HCC in hereditary hemochromatosis develops in a cirrhotic liver. Oral contraceptives increase the risk of HCC approximately fourfold after an intake for 5 years. This association is proven in areas with low incidence rates of HCC. After discontinuing therapy, an increased HCC risk persists for approximately 10 years. Anabolic androgenic steroids promote tumor formation. It is not entirely clear, however, whether the described tumors are highly differentiated HCCs or whether they instead represent hepatocellular adenomas. Peliotic areas frequently occur within these tumors. They are not associated with increased a1-fetoprotein serum levels and rarely metastasize. Inborn or acquired membranous obstruction of the inferior vena cava above the junction with the liver veins may be associated with the development of HCC [212]. The cause is unknown. Relapsing parenchymal losses alternating with regenerative phases leading to a chronic increase in hepatocyte turnover are being incriminated. Glycogen storage disease (type I and III) usually is associated with hepatocellular adenomas, but occasional HCCs also have been described [46, 51]. The inborn error of metabolism associated with the highest risk of HCC is hereditary tyrosinemia type I. In one study 16 out of 43 children developed a HCC [243]. All of the children had liver cirrhosis prior to the formation of HCC. The risk of HCC is increased approximately 60-fold in patients with hepatic porphyrias [105]. HCC has been reported in patients with familial adenomatous polyposis, Alagille’s syndrome, ataxia telangiectasia, Weber-Rendu-Osler’s disease, biliary atresia and congenital hepatic fibrosis. But the evidence for a causal relationship is weak, and the concomitant occurrence of HCC and these disorders probably is incidental in most cases.
1310
102
There is epidemiological evidence that increased consumption of coffee reduces the risk of liver cancer, though inference on causality remains open [19, 76, 88, 124].
Pathogenesis The exact pathogenesis of HCC is unknown. It is clear, however, that hepatocarcinogenesis is a multistage process involving an interplay of exogenous and endogenous factors, of direct carcinogens (for example, chemical and viral [HBV] carcinogenesis) and indirect carcinogenic mechanisms (for example, chronic necroinflammation) (Fig. 102.3). The chronic necroinflammatory process is characterized by recurrent destruction of hepatic parenchyma associated with continuous stimulation of regeneration and hepatic remodeling. Cytokines and immunomodulatory substances, such as interleukins, interferon and tumor necrosis factor-a, proteases and growth factors are released and may result in the emergence of premalignant foci of dysplastic hepatocytes which ultimately may undergo malignant transformation [1, 93]. The molecular pathogenesis of HCC is not uniform. HCCs are genetically highly heterogenous tumors, with multiple chromosomal abnormalities having been described, but not all of them are operative in each HCC [190]. A high rate of premalignant changes in
Chronic necroinflammation Destruction of hepatic parenchyma Hepatic regeneration and remodeling Fibrosis and cirrhosis Low grade dysplasia High grade dysplasia Hepatocellular carcinoma
Fig. 102.3 The pathogenesis of hepatocellular carcinoma is a multistage process
Malignant Tumors
noncancerous tissue before the formation of a solitary tumor has been revealed by complementary DNA microarray analysis [111]. Mutations have been detected in genes involved in DNA-repair (p53, HBV x gene), cell cycle control (retinoblastoma gene 1, cyclin D, p16), in apoptosis and growth inhibition, in cell–cell interactions and in signal transduction (b-catenin, E-cadherin). Epigenetic modifications of tumor suppressor genes, such as gene-silencing by DNA-methylation have also been demonstrated [194]. Recently, etiology-dependent and etiology-independent oncogenes have been identified [201]. As in other malignant tumors, overexpression of protooncogenes and silencing of tumor suppressor genes ultimately results in the formation of HCC [33, 244]. In addition to mutations and epigenetic alterations, genetic susceptibility plays a role in HCC development. Genetic polymorphisms in drug metabolizing enzymes, such as UDP-glucuronosyltransferases, N-acetyl transferases, glutathione-S-transferases and cytochrome P450 enzymes are associated with HCC risk and age of onset [236]. Several growth factors, such as insulin-like growth factors, epidermal growth factor (EGF), transforming growth factor-b (TGF- b) are involved in hepatocarcinogenesis, although their precise role still must be defined [5, 28, 189, 222]. Thus, EGF gene polymorphism has been shown to be associated with risk for development of HCC in liver cirrhosis through modulation of EGF levels [222]. Evidence from animal experiments suggests that embryonic liver fodrin (ELF), a TGF-b adaptor and signaling molecule, functions as a critical adaptor protein in TGF-b modulation of angiogenesis as well as cell cycle progression. Loss of ELF in the liver leads to cancer formation by deregulated hepatocyte proliferation and stimulation of angiogenesis in early cancers [5, 205]. Angiopoietin-1 and angiopoietin-2 have been shown to be involved in tumor angiogenesis, and increased expression of angiopoietin-1 and angiopoietin-2 has been show to occur in the development in HCC [230]. The telomere hypothesis of cancer initiation applies also to human HCC. Telomere shortening may initiate cancer by induction of chromosomal instability. Telomere shortening correlates with increasing aneuploidy of chromosome 8 in human HCC. The inactivation of cell cycle checkpoints coincides with further telomere shortening and an accumulation of DNA damage in HCC [93, 183–185, 198].
Pathogenesis
While definitive proof of a stem cell origin of HCC is still lacking, there is data suggesting that human liver tumors can be derived from hepatic progenitor cells rather than from mature cell types. Recent evidence suggests that most combined hepatocellularcholangiocarcinomas arise from hepatic progenitor cells that retained their potential to differentiate into the hepatocytic and biliary lineages [135, 204]. Chemical carcinogenesis models in the liver demonstrate varying degrees of oval cell proliferation. There is also preliminary evidence that HCC may maintain a bipotential phenotype consistent with an oval cell origin [211].
Chronic Hepatitis B Virus Infection (See also Section 63.3). Chronic HBV infection is of major significance in the development of HCC in the Far East and in the Sub-Sahara regions. In Asia HBV genotype C is associated with an increased risk of HCC [32]. The geographical distribution pattern of the HBV carrier state coincides with the incidence of HCC in these regions. Serologic markers of a past or present HBV infection occur in approximately 80% of HCC patients. The relative risk of HCC in HBsAg-carriers is approximately 220-fold compared with HBsAg-negative persons in these geographical zones. Approximately 25% of European HCC patients have evidence of a HBV infection. Considering the lower prevalence rates of HBV infection in Europe, the association of HBV with HCC is as strong as in high incidence areas [6]. Active HBV replication plays a pivotal role in HBVinduced carcinogenesis, and the incidence of HCC depends on the viral load and on the duration of HBV infection. The cumulative incidence of HCC is 1.3% in persons with serum HBV-DNA levels of less than 300 copies/mL and increases to an incidence of 14.9% in those with HBV-DNA levels of 106 copies/mL or more. Elevated serum HBV-DNA level (≥10,000 copies/mL) is a strong risk predictor of HCC independent of HBeAg, serum alanine aminotransferase level, and liver cirrhosis [38]. However, once HBV-induced cirrhosis is established the risk of HCC further increases significantly. The risk of HCC is particularly high in perinatally acquired HBV infection. Perinatal transmission and
1311
maternal viral load are important risk factors in hepatocarcinogenesis. In the Far East (except for Japan) HBV is transmitted predominantly perinatally (i.e. “vertically”), and HBV infection is active and replicative during pregnancy and delivery in most women. In Africa, spread of HBV is primarily horizontal. Following perinatal transmission, the probability of becoming a chronic HBV carrier is 95%. The risk of HCC is approximately 40% in horizontal transmission during childhood, and 10% in horizontally acquired adulthood HBV infection [35]. The latency period between HBV infection and the development of HCC is approximately 30 years and may reach even 60 years in individual cases. HBV induces HCC formation in several ways. HBV replication promotes and maintains chronic necroinflammation, thus promoting hepatic carcinogenesis indirectly [81]. In addition, HBV integrates into the host’s genome and may act as a direct carcinogen. In nearly 90% of HBV-associated HCCs, HBV-DNA was found to be integrated into cellular genes [161]. Integration of viral DNA into protooncogenes and tumor suppressor genes (p53) may initiate malignant transformation. HBV-DNA integration may induce the production of the transactivator protein hepatitis Bx antigen (HBx) that may stimulate tumor promoter signaling pathways [37, 106]. HBx deregulates DNA methyltransferase promoter activity, and promotes both specific regional hypermethylation and global hypomethylation [180]. Its integration into the host’s genome results in alterations of tumor suppressor gene p53 which leads to inhibition of apoptotis and cell cycle arrest. In addition, it up-regulates vascular endothelial growth factor and stimulates angiogenesis [133, 205]. These epigenetic modulations by HBx suggest a mechanism for HBV-mediated hepatocarcinogenesis even in the absence of cirrhosis [233]. HBV maintains its pro-oncogenic properties also in the case of occult HBV infection and there is clear evidence that occult HBV is a risk factor for development of HCC. Occult HBV infection is characterized by the persistence of HBV-DNA within the liver tissue of HBsAg-negative individuals. Both integrated viral DNA and covalently closed circular HBV genomes may be detected in patients with occult HBV infection. Moreover, the presence of free HBV genomes is associated with persistence of viral transcription and replication [187, 188, 245].
1312
Chronic Hepatitis C Virus Infection HCV is carcinogenic and chronic HCV infection is closely related to the development of HCC. In Japan and Southern Europe HCV may be demonstrated in up to 80% of patients with HCC. HCV genotype 1b is associated with a higher HCC risk. The latency period between HCV infection and the development of HCC is 20–30 years. The precise mechanism of hepatocarcinogenesis in humans by HCV is currently unclear. The virus replicates within the tumor tissue, but (in contrast to HBV) HCV-RNA is not integrated into the host’s genome. Presumably chronic necroinflammation with the continuous stimulation of proliferation and regeneration, and the development of cirrhosis are the background for malignant transformation. In addition, HCV core protein promotes proliferation of human hepatoma cells by activation of the MAPK/ERK pathway through upregulation of transforming growth factor-a transcription via activation of nuclear factor-kB [199]. In contrast to HBV-induced HCC, HCV-associated HCC almost exclusively develops in a cirrhotic liver by a multistep and multicentric process [174]. Recent studies have found trace HCV viral material both among sustained responders and in patients with chronic liver disease who are HCV-RNA negative, suggesting the entity of occult hepatitis C. Little is known of the potential importance of occult type C hepatitis for the development of HCC. The finding of occult hepatitis B in noncirrhotic HCCs among patients with hepatitis C who achieved sustained virologic response after treatment raises interesting questions regarding coinfections and the natural history of both of these viral hepatitis agents [77].
Liver Cirrhosis Liver cirrhosis is the most important precancerous condition. Irrespective of its etiology, it is an independent risk factor for HCC, especially in countries with low to moderate HCC incidence rates. In Europe liver cirrhosis is usually due to chronic ethanol consumption and/or to chronic HBV or/and HCV infection. The yearly incidence of HCC in patients with virus-induced liver cirrhosis is approximately 1.5–3%. The risk of HCC is higher in HBV-HCV coinfection compared to
102
Malignant Tumors
each viral disease alone. Alcoholic liver cirrhosis is associated with malignant transformation in 3–10% of cases after a follow-up of 10–20 years. Alcohol is believed to act as a cocarcinogen. The exact pathogenetic mechanisms of malignant transformation in a cirrhotic liver are unknown. Presumably the continuous necroinflammatory process associated with loss of liver parenchyma not only leads to the formation of regenerative nodules, but also to genomic injury. Subsequent impairment of cellular proliferation and differentiation results in the occurrence of liver cell dysplasia and finally in the emergence of malignant foci (see below “Pathology”) [15].
Alcoholic Liver Disease See Chapter 88.
Nonalcoholic Fatty Liver Disease See Chapter 89.
Aflatoxin B1 and Other Toxins Aflatoxin is a genotoxic and mutagenic mycotoxin produced by the ubiquitary fungus Aspergillus flavus. It is the most potent experimental liver carcinogen. Aspergillus flavus contaminates food that has been stored improperly. Epidemiologic studies in Africa have shown a clear correlation between aflatoxin contaminated food and risk of HCC. Aflatoxin B1 is transformed by cytochrome P450 enzymes (CYP1A2 and CYP3A4) to its active moiety aflatoxin B1–8, 9–epoxide, which is a potent carcinogen that can form DNA adducts. In hyperendemic areas with aflatoxin exposure and chronic HBV infection a particularly high prevalence of mutation in codon 249 of the p53 gene is found with an exchange of arginine for serine (Arg249Ser-p53) [87, 160]. The algal toxin microcystine may contaminate well water and is held responsible for the development of HCC in certain regions in China. Chewing betel nut that is prevalent in Asia is also believed to be associated with an increased incidence of HCC.
Pathology
Other chemical carcinogens, such as vinyl chloride, thorotrast or arsenic induce the development of hepatic angiosarcomas.
Pathology HCCs develop in a multistage process presumably from multicentric, clonally proliferating cells. Most small (1.5 cm, reduction or loss of reticulin fibers, high grade nuclear atypia, increased mitotic activity, multinucleated hepatocytes, pseudoglandular arrangement of hepatocytes, increased capillarization of sinusoids are all features that favor the diagnosis of HCC. The transition from a premalignant lesion to a small HCC is associated with a sharp increase in glypican 3 expression. Thus, immunohistochemical glypican 3 expression may help to distinguish a small HCC from a dysplastic nodule [136]. Despite all diagnostic efforts, however, assigning a lesion as high grade dysplastic or already as definitely malignant is often impossible, especially in small liver biopsy samples. This notwithstanding, the clinician should expect the
Pathology
pathologist in addition to grading and staging hepatic lesions also to comment on the presence or absence of liver cell dysplasia, particularly when dealing with biopsies from nodular lesions.
Hepatocellular Carcinoma Excellent descriptions of the macroscopic and microscopic pathology of HCC dating back to the early years of the last century are available [58, 59, 176]. Relatively little has been added to these seminal works during the last decades. However, aside from a few exceptions the descriptive morphology of a HCC is clinically not very relevant, neither from the epidemiological nor from the biological point of view.
1315
different way than the usual HCC. Small HCC is defined as a tumor less than 2 cm in diameter that is usually well-differentiated, contains portal tracts, is surrounded by a fibrous capsule, and almost always develops in a cirrhotic liver. Uninodular small HCCs have an excellent postoperative prognosis with 5 year survival rates of >90% [100, 115, 218]. However, it is still a matter of debate if small HCC is indeed a separate clinical entity or just the T1 stage of a regular HCC. Pedunculated HCC is rare, with fewer than 50 cases described. It probably originates from accessory lobes of the liver and usually arises from the lower surface of the right liver lobe. Pedunculated HCC is not substantially different from HCC in general. Despite an average weight of >1 kg the slow growth and good prognosis relate to its extrahepatic location. Due to its peduncle it may be resected quite easily [3].
Gross Anatomy Microscopic Anatomy Eggel’s macroscopic classification of 1901 has essentially maintained its value until today [59]. Accordingly, three macroscopic types of HCC may be distinguished: • Multinodular type • Massive, and • Diffuse type The multinodular type is characterized by many, quite well-delineated tumor nodes scattered throughout the liver. The massive or expanding type exhibits a main tumor mass, sometimes with a few satellite nodules, which may be separated from the surrounding liver tissue by a fibrous capsule. In the diffuse or spreading type many tumor masses with ill-defined borders coalesce and intermingle with surrounding liver tissue. Combinations between these main types are common. Often tumor nodes show regressive changes, such as hemorrhages, necrosis or biliary extravasates. HCC tends to invade vessels and to spread hematogenously. Japanese authors have classified HCC into an infiltrative, expanding, mixed (infiltrative and expanding) and a diffuse type. This classification, however, does not yield important additional insights, and essentially corresponds to Eggel’s work. Japanese investigators again have drawn attention to the existence of a small HCC as a discrete clinical entity. It is said to behave a priori in a biologically
Histologically most HCCs display cellular and architectural similarities with the normal liver. Tumor cells are typically arranged in trabeculae separated by vascular sinusoidal spaces (Fig. 102.4). Even in less welldifferentiated HCCs these features may be found every now and then. The histological spectrum of HCCs ranges from well-differentiated tumors that may be difficult to distinguish from the normal liver, to anaplastic, highly undifferentiated carcinomas [96]. Microscopically, different growth patterns may be distinguished: Trabecular (platelike). The trabecular variant is the basic pattern from which all other forms may be derived. Tumor cells grow in cords of variable thickness. The trabeculae are separated by sinusoid-like, occasionally cavernous, endothelium-lined spaces. Kupffer cells are diminished or completely absent. The connective tissue stroma is only scant or lacking. Reticulin fibers are usually absent. Pseudoglandular (acinar). The pseudoglandular variant may derive from the trabecular form by central degeneration of solid trabeculae or by dilatation of bile canaliculi into gland-like spaces. The tumor appears acinar, glandlike. The pseudoglandular spaces may be filled with bile, cellular debris, fibrinous exudate, or a homogenous, colloid-like material reminiscent of thyroid follicles.
1316
102
Malignant Tumors
Fig. 102.4 Differentiated hepatocellular carcinoma. Trabecular arrangement of tumor cells separated by vascular sinusoidal spaces. Hematoxylin and Eosin stain (×400)
Solid (compact). The solid variant is basically a trabecular HCC in which the sinusoids are compressed by growing cancer cells imparting the tumor a solid appearance. Scirrhous. Scirhhous HCC (SHCC) accounts for approximately 5% of all HCCs. The majority of SHCC (88%) are located close to the liver capsule [121]. Cords of tumor cells are embedded in an abundant fibrous stroma, and the diagnosis of SHCC is made on the basis of a scirrhous histological pattern exceeding 50% of the tumor area. Common stromal components of SHCC are collagen types I and III, and almost all stromal cells are a-smooth muscle actin-positive [175]. This variant is most often seen following radiation, chemotherapy or infarction. Cholangiocarcinomas and metastases may have a similar appearance, and indeed some pathologists believe that scirrhous HCC actually is a cholangiocarcinoma in many cases. The so-called sclerosing hepatic carcinoma belongs to this group. It usually arises in a noncirrhotic liver and is characterized clinically by (paraneoplastic) hypercalcemia. Sclerosing carcinomas do not constitute a separate histopathological entity. Fibrolamellar. See Section 102.2 The cytological features of HCCs may vary: Liver cell-like. Most often tumor cells resemble normal hepatocytes. The extent of nuclear hyperchromasia and nuclear polymorphism as well as the nuclear to cytoplasmic ratio depend on the degree of tumor
differentiation. The cytoplasm is finely granular and often more basophilic than that of normal hepatocytes. Canaliculi are often demonstrable between tumor cells. Pleomorphic. Pleomorphic variants are characterized by a loss of the trabecular pattern with marked variation in cellular and nuclear size and shape with the occasional occurrence of bizarre giant cells. Clear cell. The clear cytoplasm of tumor cells in this variant is primarily due to the presence of glycogen, but also of water and fat. These tumors must be distinguished from metastatic renal carcinoma or from adrenal tumors infiltrating the liver. Groups of clear cells also may occur in well-differentiated HCCs. Oncocytic. Oncocyte-like cells with an eosinophilic, granular cytoplasm are typical of fibrolamellar carcinoma. Their granularity is due to a large number of mitochondria. Spindle cell (pseudosarcomatous or sarcomatoid). Spindle cell tumors have a sarcomatoid appearance and should be characterized further immunohistochemically for the expression of desmin, actin, myosin and myoglobin. If epithelial and spidle cell components occur concomitantly the term carcinosarcoma is applied by some pathologists. Lymphocytic infiltration. This is a rare subtype of HCC with a lymphoid stroma. It has a better prognosis than regular HCC [67, 241]. Intracellular inclusions. Intracellular inclusions occur in many HCCs. Globular hyaline inclusion bodies are found in up to 15% of cases. They commonly consist
Diagnosis
of a1-antitrypsin, fibrinogen or other export proteins. Albumin and fibrinogen may also appear as pale bodies. Mallory-Denk bodies are the expression of impaired metabolism of intermediary filaments. They are readily immunostained by anti-ubiquitin antibodies. Ground glass inclusions may be due to HBsAg expression or to fibrin accumulation. Some HCCs may contain bile droplets. They testify to the hepatocellular nature of the tumor. Cytoplasmic material may herniate into the nucleus and appear as nuclear inclusions in histological sections. Grading of HCC. The degree of differentiation does not always correlate with the biological behavior of HCC. In addition, various grades of differentiation may occur in different areas in one and the same tumor. Therefore grading does not assume a major clinical significance in the management of patients with HCC although vascular invasion is seen more often in moderately or poorly differentiated HCCs than in well-differentiated tumors. Occasionally it may be difficult to recognize the hepatocellular origin of tumor cells. Immunocytochemical staining with liver specific antibodies, for example Hep Par 1 and visualization of bile canaliculi with polyclonal anti-CEA or CD10 is often helpful in these cases (see Fig. 3.5) [129]. Most HCCs express cytokeratins 8 and 18 (hepatocytic markers). However, 50% also express cytokeratins 7 and 19 (cholangiocytic markers). Simultaneous expression of hepatocytic and cholangiocytic markers was demonstrated in 61.5% of cases in a recent study [110]. Thus cytokeratin immunostaining only contributes little to the differential diagnosis between HCC and cholangiocarcinoma [52]. Immunostaining for glypican 3 and survivin is more specific and may confirm the diagnosis of HCC [34, 149]. Clathrin heavy chain and formiminotransferase cyclodeaminase have recently been described as novel immunohistochemical tumor markers for HCC [203]. Expression of a1-fetoprotein is observed in only approximately 25% of HCCs. Moreover, it often is weak and patchy in distribution. The specificity of a1-fetoprotein expression is relatively high, while its sensitivity is low. On the other hand most hepatoblastomas (see Section 102.3) show a strong a1-fetoprotein expression.
Diagnosis The diagnosis of HCC rests on laboratory findings, sonographic and radiologic techniques and on histopathology [221].
1317
Clinical Manifestations HCC remains asymptomatic for long periods of time. If diagnosis would rely merely on clinical manifestations it would inevitably be made in an advanced stage of the disease. Symptoms are nonspecific and are those of the underlying chronic liver disease if HCC develops in the context of chronic liver disease. Patients with liver cirrhosis who, without an obvious reason develop ascites, hepatic encephalopathy, variceal bleeding or fever of unknown origin should be investigated for the presence of an HCC. In advanced stages patients complain about a sense of pressure and fullness in the upper abdomen and report weight loss. Jaundice may be caused by bile duct compression or may be due to diffuse parenchymal tumor infiltration. Rarely a tumor may rupture into the peritoneal cavity causing an acute intraperitoneal hemorrhage and peritonitis. Over large, well-vascularized tumors a blood flow murmur may be heard in up to 25% of cases. Rarely, a Budd–Chiari syndrome or obstruction of the inferior vena cava may be the initial manifestation of an HCC. Occasionally patients with HCC develop paraneoplastic syndromes, such as hypoglycemia (consumption of glucose by the tumor; secretion of insulin-like growth factor II by the HCC in less than 5% of cases), erythrocytosis (production of erythropoietin by the HCC), hypercalcemia (secretion of parathyroid hormonerelated protein; predominantly in the sclerosing variant of HCC), watery diarrhea (secretion of vasoactive intestinal peptide and other gastrointestinal peptides) or arterial hypertension (production of angiotensinogen by the HCC) [20]. The incidence of extrahepatic metastasis is approximately 13% [101].
Laboratory Findings The laboratory findings are nonspecific and usually the expression of the underlying liver cirrhosis (see Chapter 79). In addition to the routine parameters of liver function, the measurement of tumor markers assumes an important role in patients with hepatic mass lesions.
1318
a1-Fetoprotein a1-Fetoprotein (AFP) is the most common serum tumor marker used. In countries with a high incidence of HCC serum concentrations of AFP are elevated in up to 90% of patients, occasionally >50,000 ng/mL. In countries with low or intermediate HCC incidence rates AFP levels are increased less often and serum concentrations are usually lower. AFP production by the tumor is age dependent, with younger patients showing higher AFP levels. Patients with an HCC that develops in the context of alcoholic cirrhosis usually have lower serum AFP levels than those in whom HCC is caused by viral liver cirrhosis. Up to 40% of patients with a small HCC have normal AFP levels. Patients with fibrolamellar HCC also usually have normal AFP levels (see Section 102.2). The majority of patients with liver cirrhosis and slightly elevated serum AFP levels do not have a HCC. However, AFP levels >500 ng/mL in a cirrhotic patient are virtually diagnostic of HCC, and AFP levels of approximately 100 ng/ mL and lower, but steadily rising should arouse the suspicion of an underlying HCC. AFP concentrations do not correlate with the severity of clinical manifestations or with the size of the tumor. Possibly, however, AFP levels ≥1,000 ng/mL indicate a poor long-term prognosis after tumor resection (see below) [83]. The sensitivity of AFP is 39–64% and the specificity 76–91%. The specificity depends on the etiology of HCC and is higher in HBsAg-positive patients (78%) than in HBsAg-negative patients (50%) [12, 70, 75]. Even if the “best-case” estimates of AFP sensitivity and specificity are accurate, AFP has limited utility for detecting HCC. AFP levels should be measured after a nodular liver lesion has already been detected with imaging techniques [82]. The molecular structure of AFP is not uniform. Attempts at increasing the specificity of AFP in the diagnosis of HCC have been based on the different reactivities of its oligosaccharide side chains with lectins. The incidence of HCC in HCV-related cirrhosis was reported to be significantly higher in patients with elevated Lens culinaris agglutininreactive fraction of AFP (AFP-L3%) than in those with elevated “regular” AFP. The high sensitivity of approximately 91% for AFP-L3% persisted among patients with elevated AFP (20–200 ng/mL) suggesting that AFP-L3% may have clinical utility in patients with AFP concentrations of 20–200 ng/mL.
102
Malignant Tumors
Measurements of different AFP fractions, however, are still experimental and have not yet been adopted into clinical practice. Increased AFP levels occur during pregnancy, in gonadal tumors and as an expression of liver regeneration following hepatic parenchymal necrosis. Hereditary persistence of AFP may be due hepatocyte nuclear factor-1 mutations that result in AFP gene expression. Unexplained persistent elevated AFP levels should lead to family study and/or AFP gene promoter sequencing to avoid inappropriate explorations and treatment decisions [2].
Des-g-Carboxy-Prothrombin Des-g-carboxy-prothrombin (DCP) has been assumed to be more sensitive than AFP especially in small HCC. However, in approximately 20% of HCCs with a diameter of 2 cm detected in a cirrhotic liver, current management guidelines for HCC do not require biopsy in every patient to prove the diagnosis [22, 65]. The diagnosis of HCC can be established without a positive biopsy if a conclusive vascular pattern (see above) is present on contrast enhanced imaging (US, MRI or CT) in combination with AFP serum levels. However, the sensitivity of these noninvasive criteria is 33% and absence of a conclusive pattern does not rule out malignancy [72]. Noninvasive morphologic criteria for the diagnosis of HCC, such as arterial hypervascularity
Malignant Tumors
combined with washout in the portal-venous phase, have been reported to be satisfied in only 61% of small nodules in cirrhosis. Relying on imaging techniques alone, diagnosis of HCC would be missed in up to 38% of cases in nodules < 2 cm in diameter [14]. Therefore, the AASLD guidelines suggest a greater role for image-guided biopsy of lesions greater than 1 cm clinically suspicious for HCC [9]. However, even liver biopsy findings may be inconclusive and it may be difficult to distinguish dysplastic lesions from highly differentiated HCCs. The suggested sequence of tests used to diagnose HCC in a cirrhotic liver primarily depends on the size of the lesion. An algorithm for the evaluation of a liver mass in a cirrhotic liver according to the AASLD practice guidelines is reported in Fig. 102.6 [22].
Mass on surveillance ultasound in a cirrhotic liver < 1 cm
1Ð2 cm
> 2 cm
Repeat US at 3Ð4 month intervals
Two dynamic imaging studies
One dynamic imaging technique
Stable over 18Ð24 months
Enlarging
Coincidental typical vascular pattern on dynamic imaging
Typical vascular pattern with one technique
Atypical vascular pattern with both techniques
Atypical vascular pattern
Typical vascular pattern on dynamic imaging or AFP >200 ng/mL
Biopsy
Diagnostic of HCC
Return to standard surveillance protocol (6Ð12 monthly)
Non diagnostic
Other diagnosis
Repeat biopsy or imaging follow-up
Proceed according to lesion size
Change in size/profile Repeat imaging and/or biopsy Positive
Negative
Treat as hepatocellular carcinoma
Fig. 102.6 Algorithm for the evaluation a mass lesion in a cirrhotic liver (According to the AASLD Practice Guidelines [22]. With kind permission)
Prognosis and Staging
Lesions Less Than 1 cm in Diameter These lesions should be followed with US at intervals from 3 to 6 months. If there has been no growth over a period of up to 2 years, one can return to routine surveillance.
Lesions 1–2 cm in Diameter These lesions should be investigated further with two dynamic studies, either CT scan, contrast US or MRI with contrast. If the appearances are typical of HCC (arterial hypervascularity with washout in the portalvenous phase) in two techniques, then the lesion should be regarded as HCC and treated accordingly without the need of biopsy. If the vascular pattern is typical with only one or atypical with both techniques, the lesion should be biopsied with a fine needle. According to the European Association for the Study of Liver Diseases (EASL) recommendations these lesions should be biopsied irrespective of their vascular profile [21]. Patients with lesions 1–2 cm in diameter with a nonconclusive vascular profile and a negative biopsy should continue to undergo enhanced follow-up by repeat imaging and/or biopsy. The characterization of a hepatic nodule < 2 cm by imaging techniques is more difficult and less reliable than of larger lesions. Up to 25% of these small nodules with arterial enhancement, but without venous washout, in a cirrhotic liver will remain stable or regress over time and thus are not HCC [22]. Biopsy is therefore important in these patients. However, fine needle biopsies of hepatic nodules < 2 cm also carry inherent problems. The false negative rate is 30–40%. This is due to sampling error, i.e. the lesion is so small that one cannot be certain that the sample does indeed derive from the lesion. Moreover, there is disagreement between pathologists as to the dividing line between dysplasia and well-differentiated HCC. Eighty percent of patients with high-grade dysplastic nodules, however, develop an HCC within 3 years. It may even be difficult to distinguish a well-differentiated HCC from normal liver on biopsy. An additional concern about needle biopsy is tumor cell seeding. Needle track seeding has been estimated to have a prevalence of up to 5% with systemic seeding potentially occurring even more often [217]. However, a recent systematic review and meta-analysis concluded
1321
that the incidence of needle tract tumour seeding following biopsy of an HCC is 2.7% overall, or 0.9% per year [211a].
Lesions Larger Than 2 cm in Diameter A nodule in a cirrhotic liver larger than 2 cm in diameter with the typical features of HCC on one dynamic imaging technique should be regarded as HCC. The positive predictive value of the clinical and radiological findings exceeds 95% and therefore this lesion does not require biopsy [21, 22]. Alternatively, if the AFP is >200 ng/mL liver biopsy is also not necessary. However, if the vascular pattern on imaging is atypical and the AFP is less than 200 ng/mL or if the nodule is detected in a non-cirrhotic liver, biopsy should be performed.
Differential Diagnosis The differential diagnosis of HCC includes all focal liver lesions, i.e. all benign and malignant tumors including metastases (see Chapter 101). The imaging characteristics of focal liver lesions are discussed in Chapters 37 and 38. For the approach to the patient with a focal liver lesion see Chapter 51. In the setting of chronic HBV infection (without cirrhosis) or cirrhosis of any etiology a focal lesion found incidentally or on screening has a high likelihood of being a regenerative or a dysplastic nodule or HCC.
Prognosis and Staging Spontaneous regression of HCC may occur, but is extremely rare and up to the year 2000 only 24 cases were reported in the English literature [220]. Overall HCC is usually detected late in its natural history and its prognosis is severe. The mean survival time after diagnosis is approximately 6–20 months. In the United States the overall 1-year relative survival rate increased from 14% during 1977–1981 to 23% during 1992–1996. Between the same two time periods, less improvement was seen in the 5-year survival rates, which increased
1322
Malignant Tumors
factors, such as cancer-related symptoms and signs (ascites, bilirubin, portal vein thrombosis) or an invasive tumoral pattern [158]. Thus, the 3-year survival rate is 50% in asymptomatic patients with multinodular HCC, in contrast to only 8% in patients with either cancer-related symptoms or with portal vein thrombosis or extrahepatic spread (Fig. 102.7). In addition, there is increasing data to suggest that effective screening and surveillance, and the development of therapeutic interventions for HCC (see below), have led to improvements in the prognosis for HCC patients [158, 226]. Molecular prognostication by analysis of gene expression profiling emerges as a new technique to predict outcome of HCC, and will probably be adopted into clinical practice in coming years. HCC is a genetically heterogeneous tumor composed of several genetically homogeneous subclasses, each of which harbors characteristic genetic alterations [104]. Based on their genetic makeup HCCs differ in their biological aggressiveness. By analyzing the “genetic signature” survival and early recurrence after HCC resection can be predicted [103, 111, 122, 125, 229]. The prognostic value of pretreatment tumor marker elevation may differ according to the type of curative treatment [234]. AFP-L3 and DCP (see above) may have prognostic value only in patients treated with locoregional ablation. Elevated DCP and AFP-L3 levels pre- and post-ablation were reported to be significant predictors for HCC recurrence after curative ablation [225, 233]. These data, however, need further confirmation.
100 80 Probability (%)
from 2% to only 5%. The median survival increased slightly from 0.57 years during 1977 to 1981 to 0.64 years during 1992 to 1996 [62]. Significant racial variation in survival was reported which may be partly explained by a lower likelihood of receipt of therapy and more advanced HCC at diagnosis among blacks and Hispanics [49]. Survival times after diagnosis of HCC are shorter in high incidence areas than in low incidence areas. This, however, may be due to lead time bias, with HCC being detected earlier in its natural history (i.e. at an earlier stage) than, for example, in a high incidence area such as Africa. The majority of Asian HCC patients are not suitable for curative surgical treatment. The overall median survival has been reported to be 3 months, and the 1-year survival only 7.8%. The median survival times of patients with Okuda stages I, II, and III (see below) were 5.1 months, 2.7 months, and 1.0 month, respectively. Independent prognostic variables were serum bilirubin, blood urea, serum alpha-fetoprotein, and Okuda stage [253]. The shorter survival of Asian patients may be due to the different etiology of HCC in Asia, where chronic HBV infection accounts for 70–80% of cases. HBVrelated HCCs have a greater aggressiveness than HCVrelated tumors; a high viral load prior to treatment is an adverse factor for survival [29, 131]. HCC mortality trends remain variable across Europe. In the early 2000s the highest HCC mortality rates in men were in France (6.8/100,000), Italy (6.7), and Switzerland (5.9), whereas the lowest ones were in Norway (1.0), Ireland (0.8), and Sweden (0.7). In women, a slight increase in overall HCC mortality was observed in Spain and Switzerland, while mortality decreased in several other European countries, particularly since the mid-1990s. In the early 2000s, female HCC mortality rates were highest in Italy (1.9/100,000), Switzerland (1.8), and Spain (1.5) and lowest in Greece, Ireland, and Sweden (0.3) [18]. Five-year relative survival in Europe was < 10%, ranging from 8% (southern Europe) to 5% (eastern Europe). The improved survival may be due to greater surveillance of cirrhotic patients. The survival gap between clinical and population-based series suggests patients with cirrhosis and HCC should be managed in centers of excellence [30]. Survival of untreated HCC patients strongly depends on baseline liver function (Child-Pugh class and MELD score) and on the presence or absence of prognostic
102
p2 cm, vascular invasion
Cancer of the Liver Italian Program
or Multiple tumors in one liver lobe, each 50% a1-Fetoprotein
0 1 2
15 cm in size. More rarely HAS presents as a solitary tumor [7]. Macroscopically, HAS appears as a greyish-white tumor with hemorrhagic and necrotic areas, blood-filled cavernous spaces of varying size and net-like fibrous strands. Thorotrast-induced HAS presents as a spongy, hemorrhagic lesion in which the thorotrast appears as a yellowish, calcareous material. A capsule is absent. Microscopically, HAS consists of spindle-shaped or round, poorly differentiated malignant endothelial cells that exhibit severe nuclear atypia and frequent mitoses. The tumor infiltrates the surrounding liver parenchyma
Course and Prognosis
and grows along preformed vascular structures, such as dilated sinusoids, terminal hepatic venules and portal vein branches. It leads to pressure atrophy of normal hepatocytes, separates liver cell plates and distorts the acinar structure of the liver. Tumor cells form irregularly anastomosing, blood-filled vascular channels. In contrast to hepatic epithelioid hemangioendothelioma (see Section 102.5), there is little stromal tissue. Occasionally epithelioid or spindle cells form solid tumor masses that may resemble fibrosarcomas. Foci of extramedullary hematopoiesis occur in the majority of cases. Factor VIII-associated and CD34-antigen may be demonstrated by immunohistochemistry, and positivity of endothelial markers is a clue for diagnosis, but may be variable within the tumor [6]. Thorotrast appears as a yellowish-brown to grey cristalline material that is predominantly deposited at the periphery of the tumor (“Thorotrast capsule”).
Diagnosis Clinical Manifestations Symptoms of HAS are nonspecific. Patients complain of abdominal pain, fatigue, increasing weakness and weight loss. A rapid increase in abdominal girth may be the leading sign in children [2]. Hepatomegaly occurs in 50%, with jaundice and ascites seen in 25% of cases. A vascular murmur may be audible above the liver. Clinical presentation may also be acute with rupture and peritoneal bleeding in 15–27% of cases [12].
Laboratory Findings The laboratory findings are nonspecific and do not help in establishing the diagnosis. Thrombocytopenia is present in half of patients at the time of diagnosis. Tumor markers, such as AFP and CEA, are normal.
Imaging Techniques Thorotrast-induced HAS may already be discernible on plain abdominal radiography by visible deposits of the contrast agent. On ultrasound, CT and MRI HASs
1341
appear as multiple masses or as a heterogeneous dominant mass. The sonographic echopattern is irregular. On contrast-enhanced US, irregularly distributed vascular channels and blood deposits may be seen. On CT-scan the tumors are hypodense with irregular enhancement due to necroses and hemorrhages after administration of contrast [4]. MRI images essentially correspond to the CT findings with heterogeneous enhancement on the arterial and portal venous phase. MRI is useful to demonstrate the hemorrhagic and hypervascular nature of the tumor. In the final analysis, all imaging methods, including angiography (nowadays very rarely employed), yield nonspecific findings that do not allow for the reliable distinction of HAS from large hemangiomas, hemangioendotheliomas and other vascular tumors. A definite diagnosis can only be established by histological examination. The diagnostic puncture of angiomatous tumor masses, however, even with a fine needle is dangerous and may lead to massive, lifethreatening bleeding in up to 16% of cases. Moreover, a false-negative result occurs in up to 50% of cases of fine needle biopsies, showing nonspecific, reactive inflammatory or fibrotic lesions. Therefore, it is suggested that liver tissue be obtained under laparoscopic guidance.
Differential Diagnosis The differential diagnosis includes all hypervascular hepatic tumors. Multicentric involvement of the entire liver with vascular masses, and the concomitant presence of splenic tumors and a hemoperitoneum argue for an angiosarcoma.
Course and Prognosis The prognosis of HAS is dismal. Most patients die within 6 months of diagnosis. Only 3% of patients survive longer than 2 years after diagnosis. Approximately 50% of patients die from hepatic failure. On autopsy, splenic and pulmonary metastases are found in two thirds of the deceased. The question of whether the tumor originated from the liver or whether it represents a primary, multicentric angiosarcoma often cannot be answered.
1342
Therapy Since HAS progresses rapidly, and most angiosarcomas are multifocal, most cases are discovered at an advanced stage, and fewer than 20% of the patients receive surgery [3]. If possible, localized tumors should be resected. In single cases a liver transplantation has been performed. Angiosarcomas have the poorest prognosis of all malignant liver tumors after hepatic transplantation. Recurrences occur in two thirds of patients, and all patients die within 2–3 years after transplantation. Thus, liver transplantation is not a valid therapeutic option in patients with HAS, and has consequently been abandoned [14]. Systemic chemotherapy is not effective in HAS.
References 1. Alrenga DP (1975) Primary angiosarcoma of the liver. Int Surg 60: 198–203 2. Awan S, Davenport M, Portmann B, et al (1996) Angiosarcoma of the liver in children. Pediatr Surg 31: 1729–32 3. Bioulac-Sage P, Laumonier H, Laurent C, et al (2008) Benign an malignant vascular tumors of the liver in adults. Semin Liver Dis 28: 302–14 4. Buetow PC, Buck JL, Ros PR, et al (1994) Malignant vascular tumors of the liver. Radiologic-pathologic correlation. From the archives of the AFIP. Radiographics 14: 153–66 5. Creech JL Jr, Johnson MN (1974) Angiosarcoma of the liver in the manufacture of polyvinyl chloride. J Occup Mad 16: 150–1
102
Malignant Tumors
6. Guarda LA, Ordonez NG, Smith LG Jr, et al (1982) Immunoperoxidase localization of factor VIII in angiosarcomas. Arch Pathol Lab Med 106: 515–6 7. Ishak KG (1976) Malignant mesenchymal tumors of the liver. In: Okuda K, Peters RL (eds) Hepatocellular carcinoma. Wiley, New York, pp 247–307 8. Ito Y, Kojiro M, Nakashima T, et al (1988) Pathomorphologic characteristics of 102 cases of Thorotrast-related hepatocellular carcinoma, cholangiocarcinoma, and hepatic angiosarcoma. Cancer 62: 1153–62 9. Kasper ML, Schonfield L, Strom RL, et al (1984) Hepatic angiosarcoma and bronchioloalveolar carcinoma induced by Fowler’s solution. JAMA 252: 3407–8 10. Levy DW, Rindsberg S, Friedman AC, et al (1986) Thorotrastinduced hepatosplenic neoplasia: CT identification. Am J Roentgenol 146: 997–04 11. Lincoln DT, Singal PK, Al-Banaw A (2007) Growth hormone in vascular pathology: neovascularization and expression of receptors is associated with cellular proliferation. Anticancer Res 27: 4201–18 12. Locker GY, Doroshow JH, Zwelling LA, et al (1979) The clinical features of hepatic angiosarcoma: a report of four cases and a review of the English literature. Medicine (Baltimore) 58: 48–64 13. MacMohan HE, Murphy AS, Bates MI (1947) Endothelial cell sarcoma of liver following thorotrast injections. Am J Pathol 23: 585–611 14. Maluf D, Cotterell A, Clark B (2005) Hepatic angiosarcoma and liver transplantation: case report and literature review. Transpl Proc 237: 2195–9 15. Mani H, van Thiel DH (2001) Mesenchymal tumors of the liver. Clin Liv Dis 5: 219–57 16. Regelson W, Kim U, Ospina J, et al (1968) Hemangioendothelial sarcoma of liver from chronic arsenic intoxication by Fowler’s solution. Cancer 21: 514–22 17. Soini Y, Welsh JA, Ishak KG, et al (1995) p53 mutations in primary hepatic angiosarcomas not associated with vinyl chloride exposure. Carcinogenesis 16: 2879–81 18. van Kampen RJ, Erdkamp FL, Peters FP (2007) Thorium dioxide-related haemangiosarcoma of the liver. Neth J Med 65: 279–82
Pathology
102.5 Epithelioid Hemangioendothelioma
1343
hypothesis, HEH originates from a primitive reticuloendothelial stem cell that is capable of differentiating into endothelial and dendritic cells.
Definition Hepatic epithelioid hemangioendothelioma (HEH) is a rare, usually multifocal neoplasm of vascular origin with a clinical course intermediate between benign hemangioma and malignant angiosarcoma.
Epidemiology Since its first description by Weiss and Enzinger in 1982, approximately 450 cases have been published until 2008 [6, 9]. The incidence is 10 cm. The nodular tumor masses tend to coalesce, ultimately affecting the entire liver. The tumor cells grow along preformed vascular structures. Despite extensive infiltration of the liver, however, the portal tracts and terminal hepatic venules usually remain discernible, allowing for the delineation of acinar structures. Intraacinar tumor growth leads to atrophy of hepatocytes and finally to the loss of trabecular structure (Fig. 102.10). Papillary tumor proliferations may invade venous vessels. The neoplastic cells have a dendritic, spindle-shaped, irregular appearance with numerous interdigitating extensions, or they are epithelioid, rounded with abundant cytoplasm. Intracytoplasmic vacuoles that may contain red blood cells occur commonly. Immunohistochemical demonstration of endothelial markers, such as factor VIII-associated and CD34 antigen is positive. The fibrous stroma is rich in sulfated mucopolysaccharides which, in places, impart a myxoid, hyalinized appearance. With progression
1344
of the lesions fibrosis increases and calcifications appear, so that it may be difficult to identify the tumor cells in the sclerosed areas [3, 5].
102
Malignant Tumors
on small needle biopsy specimens, and HEH may be misinterpreted for scar tissue, cirrhosis, veno-occlusive disease, metastatic signet ring cell carcinoma, sclerosing hepatocellular carcinoma, cholangiocarcinoma, chondrosarcoma, leiomyosarcoma or angiosarcoma.
Diagnosis Clinical Manifestations
Differential Diagnosis
Approximately 20% of patients are asymptomatic at the time of diagnosis and the tumor is discovered incidentally. The remainder present with right upper quadrant pain (50%), hepatomegaly (20%) and weight loss (16%) [6]. Jaundice, fever and signs and symptoms of portal hypertension occur more rarely. A Budd-Chiari like syndrome may occur in isolated cases, possibly due to tumor invasion or fibrous obliteration of terminal hepatic venules and sublobular veins [8].
The differential diagnosis includes all, especially hypervascular, liver tumors. Metastatic adenocarcinoma and various tumors with a fibrous stroma, such as cholangiocarcinoma, scirrhous HCC, or sclerosed hemangioma, should also be considered.
Laboratory Findings 16% of patients do not show any laboratory abnormality, and in the remainder findings are nonspecific. Increased alkaline phosphatase (70%), g-glutamyl transpeptidase (45%), aminotransferases (23–29%), and bilirubin (20%) are the most prominent changes. Most tumor markers (e.g., a1-fetoprotein, carcinoembryonic antigen, and CA 19-9) are in the normal range.
Imaging Techniques US, CT and MRI are helpful in delineating discrete tumor nodules, and in visualizing confluent tumor masses, thus allowing for the appreciation of the intrahepatic growth pattern of HEH. Imaging studies (with and without contrast enhancement), however, cannot provide a specific diagnosis. Positron-emission tomography scan currently plays no role in the diagnosis of HEH. The contrast between numerous intrahepatic tumors and a good clinical condition, the slow course of the disease, and the presence of intratumoral calcifications, are suggestive of HEH [1]. The definitive diagnosis requires a histopathological analysis. A large tumor sample should be obtained since the rate of missed diagnoses may amount to 75%
Course and Prognosis HEH has a highly variable behavior and there are no clinical parameters that allow for the estimation of its prognosis in the individual patient. The tumor has a relatively low malignant potential and many patients have a slowly progressive course, surviving for decades. However, a rapidly fatal evolution is also possible. Histopathological criteria, such as nuclear polymorphism and mitotic activity, also do not yield useful prognostic information [3, 5]. Irrespective of the type of treatment (or no treatment), approximately 40% of patients survive for more than 5 years after diagnosis. Single cases with survival times of >20 years have been documented. Approximately every fourth patient develops metastases, predominantly in the lungs, abdominal, mediastinal and portal lymph nodes, as well as in the mesentery, peritoneum, spleen and bones.
Therapy Due to its multicentric nature, surgical resection usually is only possible in approximately 10% of patients. If only isolated tumor nodules are present, liver resection is the treatment of choice, with 1-year and 5-year survival rates of 100% and 75%, respectively. The most common management is liver transplantation (45% of patients), with 1-year and 5-year patient survival rates of 96% and 55%, respectively.
Pathology
Systemic chemotherapy or radiotherapy are only moderately effective, with 1-year and 5-year survival rates of 73% and 30%, respectively [2, 6].
References 1. Bioulac-Sage P, Laumonier H, Laurent C, et al (2008) Benign and malignant vascular tumors of the liver in adults. Semin Liver Dis 28: 302–14 2. Demetris AJ, Minervini M, Raikow RB, et al (1997) Hepatic epithelioid hemangioendothelioma. Am J Surg Pathol 21: 263–70 3. Ishak KG, Sesterhenn IA, Goodman ZD, et al (1984) Epithelioid hemangioendothelioma of the liver: a clinicopathologic and follow-up study of 32 cases. Hum Pathol 15: 839–52 4. Läuffer JM, Zimmermann A, Krähenbühl L, et al (1996) Epithelioid hemagioendothelioma of the liver. A rare hepatic tumor. Cancer 78: 2318–27 5. Makhlouf HR, Ishak KG, Goodman ZD (1999) Epithelioid hemangioendothelioma of the liver. A clinicopathologic study of 137 cases. Cancer 85: 562–82 6. Mehrabi A, Kashfi A, Fonouni H, et al (2006) Primary malignant hepatic epithelioid hemangioendothelioma: a comprehensive review of the literature with emphasis on the surgical therapy. Cancer 107: 2108–21 7. Taege C, Holzhausen HJ, Günter G, et al (1999) Das maligne epitheloide Hämangioendotheliom der Leber. Ein sehr seltener Tumor im Kindesalter. Pathologe 20: 345–50 8. Walsh MW, Hytiroglou P, Thung SN, et al (1998) Epithelioid hemangioendothelioma of the liver mimicking Budd-Chiari syndrome. Arch Pathol Lab Med 122: 846–8 9. Weiss SW, Enzinger FM (1982) Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma. Cancer 50: 970–81
1345
102.6 Embryonal Sarcoma Definition Embryonal sarcoma (ES) of the liver is a rare primitive neoplasm, unique to the liver.
Epidemiology Twenty-five percent of all childhood liver tumors are ESs. Eighty-eight percent of the tumors occur before the age of 15 years [3, 4].
Etiology and Pathogenesis Both are unknown. Aberrations of chromosome 19q have been described both in mesenchymal hamartomas and in ES, which gave reason to the hypothesis that ES may originate from malignant transformation of mesenchymal hamartomas [1].
Pathology Macroscopically, ES usually are single, large, globular masses with solid and cystic gelatinous areas, measuring up to >20 cm in size. Seventy-five percent of the tumors are localized in the right liver lobe. Microscopic features included spindle, oval, stellate, epithelioid or multinucleated cells loosely or densely arranged in a myxomatous matrix. Entrapped bile ducts and hepatic cords are often present at the periphery of the tumours. Microvesicular fat vacuoles, intracellular and extracellular eosinophil, periodic acid-Schiff-positive, diastase-resistant hyaline globules are commonly present. Atypical mitoses are frequent [2–5, 7]. ES may invade adjacent organs and metastasize to the lungs and to the abdomen.
1346
102
Malignant Tumors
Diagnosis
Course and Prognosis
Clinical Manifestations
ESs grow fast. Pulmonary metastases and recurrences after resection occur frequently. Only approximately one-third of patients survive 3 years after diagnosis [5].
An abdominal mass and right upper quadrant pain are the most frequent findings at diagnosis. Further symptoms, such as fatigue, nausea, vomiting, fever and jaundice may supervene.
Laboratory Findings Liver enzymes are usually normal. AFP is not elevated.
Imaging Techniques US, CT and MRI disclose a hepatic mass with solid and cystic areas. On CT-scan approximately 90% of the tumor has the density of water. ES of the liver may undergo pluripotential differentiation. Diagnosis is based on histological features of large tumor samples. Immunohistochemistry has no specific or diagnostic relevance [7].
Differential Diagnosis The differential diagnosis encompasses all solid hepatic masses. Tumors with cystic components, such as cystadenomas and cystadenocarcinomas, parasitic cysts, and posttraumatic hematomas should all be included in the differential diagnosis.
Therapy Whenever possible, complete surgical resection with or without adjuvant chemotherapy should be attempted. A response to chemotherapy has been observed in isolated patients in whom tumor resection was not possible. Doxorubicin, platinum, cyclophosphamide, dacarbazine, 5-fluorouracil and vincristine have been used [5, 6].
References 1. Lauwers GY, Grant LD, Donnelly WH, et al (1997) Hepatic undifferentiated (embryonal) sarcoma arising in a mesenchymal hamartoma. Am J Surg Pathol 21: 1248–54 2. Leuschner I, Schmidt D, Harms D (1990) Undifferentiated sarcoma of the liver in childhood: morphology, flow cytometry and literature review. Hum Pathol 21: 68–76 3. Perilongo G, Carli M, Sainati L, et al (1987) Undifferentiated (embryonal) sarcoma of the liver in childhood: results of a retrospective Italian study. Tumori 73: 213–7 4. Stocker JT, Ishak KG (1978) Undifferentiated (embryonal) sarcoma of the liver. Report of 31 cases. Cancer 42: 336–48 5. Walker NI, Horn MJ, Storn RW, et al (1992) Undifferentiated (embryonal) sarcoma of the liver. Pathologic findings and long-term survival after complete surgical resection. Cancer 69: 52–9 6. Webber EM, Morrison KB, Pritchard SL, et al (1999) Undifferentiated embryonal sarcoma of the liver: results of clinical management in one center. J Pediatr Surg 34: 1641–4 7. Zheng JM, Tao X, Xu AM, et al (2007) Primary and recurrent embryonal sarcoma of the liver: clinicopathological and immunohistochemical analysis. Histopathology 51: 195–203
Diagnosis
102.7 Primary Hepatic Malignant Lymphoma The liver is one of the organs most commonly involved in malignant lymphomas. In patients with Hodgkin’s lymphoma the liver is involved in 5–10%, in NonHodgkin’s lymphoma in 15–40% of cases. On the other hand, primary hepatic malignant lymphomas (PHML) are very rare and account for 0.4–1% of all extranodal lymphomas at most. Currently, fewer than 200 cases of PHML have been reported in the literature [3, 8, 10, 18, 20]. A primary hepatic presentation of Hodgkin’s lymphoma is extremely rare [19].
Epidemiology PHML occurs in all age groups, but predominantly in men older than 50 years. Immunocompromised patients, such as those with HIV-infection, are predominantly affected [6, 17].
1347
Microscopically the lymphomatous infiltrates typically occur in the portal tracts. They may, however, involve the adjacent acinar parenchyma. A lymphomatous infiltration of the sinusoids favors hepatic involvement in extrahepatic lymphoma rather than PHML [1, 4, 20]. Approximately two thirds of PHML are B-cell, and 25% are T-cell lymphomas. Primary low-grade B-cell lymphomas of MALT-type occurring in the liver have also been described [11, 12]. They are characterized by a dense lymphomatous infiltrate of the portal tracts with lymphoepithelial lesions of the bile ducts and may mimic a chronic hepatitis or an inflammatory cholangiopathy. Hepato-splenic g/d T-cell lymphomas represent a subgroup of peripheral T-cell lymphomas that in addition to the liver also affect the spleen and bone marrow. They are aggressive tumors, occurring usually in young adults and commonly develop in the context of chronic immunosuppression or long-standing antigenic stimulation, especially after organ transplantation. In contrast to most B-cell lymphomas, g/d T-cell lymphomas diffusely infiltrate the sinusoids.
Pathogenesis Diagnosis PHML probably originates from portal lymphocytes or from Kupffer cells. They usually do not develop in the background of an underlying chronic liver disease. However, there are single case reports of the development of PHML in patients with primary biliary cirrhosis [15, 16]. Viruses (for example, EBV) could play a pathogenetic role especially in immunocompromised patients. Hepatitis C virus is known to be a lymphotropic virus that can sustain clonal B-cell expansion, and increasing evidence points toward a role of HCV infection in the etiology of malignant lymphomas [7, 14]. A causal relationship between chronic HCV infection and PHML is not established. However, a small series of PHML has been reported, suggesting a nonfortuitous association with HCV infection [9].
Clinical Manifestations Symptoms are nonspecific with right upper quadrant pain, hepatomegaly, and jaundice. Fever, night sweats and weight loss (B symptoms) occur in 50% of patients. g/d T-cell lymphomas usually present with signs of systemic disease. Rarely, occlusion of the portal vein with signs of portal hypertension or a cholestasis due to lymphomatous infiltration of the bile ducts may be the leading clinical signs. Very rarely PHML may present as acute liver failure. Histologically these patients usually show a massive infiltration of sinusoids, portal tracts and vessel walls with lymphoma cells.
Pathology PHML may occur as a solitary lesion, as a multicentric tumor or as a diffuse infiltration of the liver (in 16% of cases). Patients with AIDS usually present with multicentric PHML.
Laboratory Findings There are no specific laboratory findings. Aminotransferases and alkaline phosphatase may be elevated.
1348
102
Malignant Tumors
Imaging Techniques
References
Depending on the growth pattern US, CT and MRI show a tumor mass, a multifocal or a diffuse process. Contrast enhancement does not increase the diagnostic specificity. Due to their high glycolytic activity PHML take up fluorodeoxyglucose on PET scan [5]. The diagnosis is established by image-guided needle biopsy with no need to proceed to surgical biopsy [2]. Immunocytochemical examinations are mandatory in order to not misinterpret the lesions as poorly differentiated carcinoma.
1. Anthony PP, Sarsfield P, Clarke T (1990) Primary lymphoma of the liver: clinical ad pathological features of 10 patients. J Clin Pathol 43: 1007–13 2. Appelbaum L, Lederman R, Agid R, et al (2005) Hepatic lymphoma: an imaging approach with emphasis on imageguided needle biopsy. Isr Med Assoc J 7: 19–22 3. Ata AA, Kamal IA (1965) Primary reticulum cell sarcoma of the liver: a case report. J Egypt Med Assoc 48: 514–21 4. Avlonitis VS, Linos D (1999) Primary hepatic lymphoma: a review. Eur J Surg 165: 725–9 5. Bangerter M, Moog F, Griesshammer M, et al (1997) Usefulness of FDG-PET in diagnosing primary lymphoma of the liver. Int J Hematol 66: 517–20 6. Baschinsky DY, Weidner N, Baker PB, et al (2001) Primary hepatic anaplastic large-cell lymphoma of T-cell phenotype in acquired immunodeficiency syndrome: a report of an autopsy case and review of the literature. Am J Gastroenterol 96: 227–32 7. Chowla A, Malhi-Chowla N, Chidambaram A, et al (1999) Primary hepatic lymphoma in hepatitis C: case report and review of the literature. Ann Surg 65: 881–3 8. De Ment SH, Mann RB, Staal SP, et al (1987) Primary lymphomas of the liver. Report of six cases and review of the literature. Am J Clin Pathol 88: 255–63 9. De Renzo A, Perna F, Persico M, et al (2008) Excellent prognosis and prevalence of HCV infection of primary hepatic and splenic non-Hodgkin’s lymphoma. Eur J Haematol 81: 51–7 10. Gaulard P, Zafrani ES, Mavier P, et al (1986) Peripheral T-cell lymphoma presenting as predominant liver disease: a report of three cases. Hepatology 6: 864–8 11. Koubaa Mahjoub W, Chaumette-Planckaert MT, Penas EM, et al (2008) Primary hepatic lymphoma of mucosa-associated lymphoid tissue type: a case report with cytogenetic study. Int J Pathol 16: 301–7 12. Maes M, Depardieu C, Dargent JL, et al (1997) Primary lowgrade B-cell lymphoma of MALT-type occurring in the liver: a study of two cases. J Hepatol 27: 922–7 13. Nagano K, Fukuda Y, Nakano I, et al (1999) Case report: reactive lymphoid hyperplasia of liver coexisting with chronic thyroiditis: radiographical characteristics of the disorder. J Gastroenterol Hepatol 14: 163–7 14. Nieters A, Kallinowski B, Brennan P, et al (2006) Hepatitis C and risk of lymphoma: results of the European Multicenter Case-Control Study EPILYMPH. Gastroenterology 131: 1879–86 15. Prabhu BM, Medeiros J, Kumar D, et al (1998) Primary hepatic low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) associated with primary biliary cirrhosis. Mod Pathol 11: 404–10 16. Sato S, Masuda T, Oikawa H, et al (1999) Primary hepatic lymphoma associated with primary biliary cirrhosis. Am J Gastroenterol 94: 1669–73 17. Scerpella EG, Villareal AA, Casanova PF, et al (1996) Primary lymphoma of the liver in AIDS: report of a new case and review of the literature. J Clin Gastroenterol 22: 51–3
Differential Diagnosis PHML is a very rare tumor, not very significant in the differential diagnosis of hepatic mass lesions. If, however, solitary or multiple liver lesions develop in immunocompromised patients PHML should be considered. A rare differential diagnosis is reactive lymphatic hyperplasia (pseudolymphoma) which may appear as a space occupying lesion. It is seen occasionally in patients with underlying immunologic disorders, such as chronic thyroiditis [13].
Course and Prognosis The median survival time of patients with PHML is approximately 1.5 years. Patients without an underlying disease have a slower progression and longer survival times. Prognosis is especially severe in immunocompromised patients.
Therapy Solitary nodules have a relatively favorable prognosis after surgical resection. Further treatment options are systemic chemotherapy and radiotherapy. Controlled trials as to the best treatment regimen are not available.
Kaposi’s Sarcoma 18. Wohlfarth A, Wohlfarth M, Rieß R, et al (1999) Das primäre extranodale Non-Hodgkin-Lymphom der Leber. Leber Magen Darm 29: 42–4 19. Yokomori H, Kaneko F, Sato A, et al (2008) Primary hepatic presentation of Hodgkin’s lymphoma: a case report. Hepatol Res 38: 1054–7 20. Zafrani ES, Gaulard P (1993) Primary lymphoma of the liver. Liver 13: 57–61
1349
102.8 Various Rare Tumors Malignant Fibrous Histiocytoma Primary hepatic malignant fibrous histiocytoma (MFH) is a rare entity with ill-defined clinicopathologic characteristics. MFH usually occur in muscle and in the retroperitonal soft tissue. At present, only approximately 35 cases of primary hepatic MFH have been reported in the literature [2, 5, 6]. The precise nature of MFH has been debated for years. Currently, a histiocytic lineage of the tumor cells is no longer favored [1]. The average age at diagnosis is between 50 and 60 years. There is no gender predilection. Symptoms are nonspecific with abdominal pain, fever, malaise, anorexia, and weight loss. Macroscopically, hepatic MFH usually appears as a solitary mass measuring 5.5–20 cm. Histologically, a storiform-pleomorphic pattern with variable degrees of necrosis predominates. A myxoid pattern is seen in only 10–15% of cases [3–5]. Laboratory findings and imaging techniques (US, CT, MRI) yield nonspecific findings. The diagnosis is made by histology. The prognosis of hepatic MFH depends primarily on tumor size and stage at the time of diagnosis. No effective therapy for hepatic MFH is available and the mean survival time is only approximately 3 months. Systemic chemotherapy and transarterial chemoembolization are not effective. Whenever possible surgical resection should be performed. Possibly ezrin expression in tumor cells can provide additional prognostic information. Isolated patients with a low ezrin immunoreactivity score (4 years after surgery [5].
Kaposi’s Sarcoma Kaposi sarcoma (KS) is induced by human herpes virus 8. Hepatic KS occurs only in AIDS patients and is usually associated with KS lesions in other organs. Hepatic KS lesions are seen in 12–25% of fatal cases in this population, but do not appear to contribute to morbidity and mortality of the disease [7].
1350
Involvement of the liver with KS is typically multicentric. The tumor nodes vary in size from a few mm to approximately 7 cm. Macroscopically, the nodes appear red-brown, spongiform, and hemorrhagic. Histologically, spindle-shaped tumor cells containing hyaline globules with large, irregular nuclei occur in the portal tracts, but occasionally may infiltrate the adjacent parenchyma. Spindle cells express endothelial cell markers CD31, CD34, and also VEGF receptor 3 and podoplanin [9]. Slit-like vascular spaces and hemosiderin accumulation are typical, and peliotic foci are often seen at the periphery of the tumors [8]. The latter must be differentiated from bacillary peliosis hepatis, occurring also more often in AIDS patients.
Other Rare Tumors In addition to the hitherto described tumors hepatic leio- and rhabdomyosarcomas, squamous cell carcinomas, malignant teratomas, carcinoids, fibro- and liposarcomas may originate primarily in the liver [10].
102
Malignant Tumors
References 1. Al-Agha OM, Igbowke AA (2008) Malignant fibrous histiocytoma: between past and present. Arch Pathol Lab Med 132: 1030–5 2. Alberti-Flor JJ, O’Hara MF, Weaver F, et al (1985) Malignant fibrous histiocytoma of the liver. Gastroenterology 89: 890–3 3. Fujita S, Lauwers GY (1998) Primary hepatic malignant fibrous histiocytoma: report of a case and review of the literature. Pathol Int 225–9 4. Fukuyama M, Koike M (1986) Malignant fibrous histiocytoma arising in the liver. Arch Pathol Lab Med 110: 203–6 5. Li YR, Akbari E, Tretiakova MS, et al (2008) Primary hepatic malignant fibrous histiocytoma: clinicopathologic characteristics and prognostic value of ezrin expression. Am J Surg Pathol 32: 1144–58 6. Schweyer S, Meyer-Venter R, Lorf T, et al (2000) Malignes fibröses Histiozytom der Leber. Z Gastroenterol 38: 243–8 7. Bioulac-Sage P, Laumonier H, Laurent C, et al (2008) Benign an malignant vascular tumors of the liver in adults. Semin Liver Dis 28: 302–14 8. Ioachim HL, Adsay V, Giancotti FR, et al (1995) Kaposi’s sarcoma of internal organs. Cancer 75: 1376–85 9. Weninger W, Partanen TA, Breiteneder-Geleff S (1999) Expression of vascular endothelial growth factor and podoplanin suggests a lymphatic endothelial cell origin of Kaposi’s sarcoma tumor cells. Lab Invest 79: 243–51 10. Mani H, van Thiel DH (2001) Mesenchymal tumours of the liver. Clin Liv Dis 5: 219–57
Liver Transplantation: Indications, Preoperative Evaluation and Posttransplantation Management
103
Scott A. Fink and Robert S. Brown, Jr.
Chapter Outline
Evaluation and Listing ................................................ 1366 Contraindications to Liver Transplant ...................... 1368
History........................................................................... 1354 Philosophy ..................................................................... 1354 The Evaluation Process ............................................... 1355
Age ................................................................................. 1368 Psychosocial Contraindications ..................................... 1369 Cardiopulmonary Contraindications .............................. 1369 Infectious Contraindications .......................................... 1369
Listing for Transplantation ......................................... 1355 Scoring Systems and Prioritization on the Waiting List ....................................................... 1356 Impact of MELD on Outcomes and Transplant Benefit ................................................ 1356 Indications for Transplantation .................................. 1357 Minimal Listing Criteria ................................................ 1357 Alcoholic Liver Disease ................................................. 1358 Viral Hepatitis ................................................................ 1359 Cholestatic Liver Disease............................................... 1360 Malignant Diseases of the Liver .................................... 1360 Metabolic Liver Disease ................................................ 1364 Vascular Disease of the Liver......................................... 1364 Fulminant Hepatic Failure ............................................. 1364 Indications for Liver Transplant in the Child ........... 1365 Pediatric Cholestatic Diseases ....................................... 1365 Pediatric Metabolic Liver Diseases................................ 1366 Viral and Non-viral Hepatitis in Children ...................... 1366 Hepatic Malignancy in Children .................................... 1366 Retransplantation in Children ........................................ 1366
The Waiting List ........................................................... 1370 Management on the Waiting List ................................... 1370 Timing of Transplantation.............................................. 1370 Delisting Criteria............................................................ 1371 Living Donor Liver Transplantation .......................... 1371 The Posttransplant Period........................................... 1372 The Perioperative Period ................................................ 1372 Immunosuppression ....................................................... 1373 Rejection ........................................................................ 1375 New Onset Diabetes Mellitus Following Transplant ..... 1375 Arterial Hypertension..................................................... 1375 Hyperlipidemia .............................................................. 1376 Biliary Complications .................................................... 1376 Vascular Complications ................................................. 1376 Recurrent Disease .......................................................... 1376 Infection ......................................................................... 1377 Conclusion .................................................................... 1378 References ..................................................................... 1379
H. Dancygier, Clinical Hepatology, DOI: 10.1007/978-3-642-04519-6_103, © Springer-Verlag Berlin Heidelberg 2010
1353
1354
103
Liver Transplantation: Indications, Preoperative Evaluation and Posttransplantation Management
Perhaps more than any other field in medicine, transplantation relies on a utilitarian ethic. Far fewer organs are available than there are patients who need them. Liver transplant physicians and surgeons must decide whom the optimal candidates for transplant are and when they should be transplanted. Resources in medical care are generally plentiful and physicians make most decisions about modalities of care without concern about the relative or absolute availability of the modality. The transplant physician must choose those patients who are most like to benefit from receiving a new liver and who will thrive after transplant. The choice of which patient to transplant is difficult and requires rigorous evaluation of the patient, the patient’s support system, progression of both liver disease and comorbidities, and prospects for recovery. Mathematical models that assess risk by combining medical facts with disease epidemiology such as the Model for Endstage Liver Disease (MELD) score in use in the United States have assisted with these decisions. In the end, the transplant enterprise rations organs and care to those who are perceived to benefit most. This chapter focuses on indications for transplantation, the evaluation and management of the patient prior to transplant, and the common challenges of managing the patients in the posttransplant period.
History Although transplantation as a safe, effective therapeutic modality has come into its own only in the past 50 years, the concept of the successful replacement of human organs has captivated scientific discourse for millennia. One need only to look at the mythologic chimera to appreciate a subtext of appreciation of the hypothesis of grafting non-self parts onto a patient to achieve both function and tolerance of the organ. Starzl et al. performed the first human liver transplant on March 1, 1963 in a child with biliary atresia [90]. The child died intraoperatively. The second and third patients, both adults, died 22 and 7.5 days postoperatively respectively of complications from extensive pre-transplant malignancy. By the end of 1963, a total of seven patients had received liver transplants [20, 63, 91, 93]. Due to the poor results being achieved a voluntary worldwide moratorium on transplantation was imposed until 1967 so that the issues involved with transplantation could be studied further.
Later series of patients proved more successful. During the interval period, it was learned that patients awaiting transplant who were severely ill and could not wait for a matched organ would not suffer tremendously by receiving an unmatched one [39, 91]. The next advance was the appreciation that a “triple drug cocktail” of antithymocyte globulin introduced in combination with azathioprine and prednisone could achieve better results [39, 92]. The next major advance was the discovery of cyclosporine in 1973 and its implementation into clinical practice in 1983. By the 1990s, liver transplantation had become an accepted treatment for cirrhosis with morbidity and mortality in carefully selected patients, which were similar to those for other complex, tertiary procedures.
Philosophy By necessity, transplantation decisions are guided by a utilitarian philosophy. In the best of all possible worlds, a treatment modality would be without risk and available to all those who would benefit from it. The treatment of hepatic encephalopathy with lactulose, for example, is essentially without risk, inexpensive, and widely available to those who need it. On the other hand, some therapies are so difficult to tolerate, so dangerous to the patient, and so cost ineffective that they are rarely dispensed. Until the advent of antibiotic therapy, pneumonectomy was the mainstay of therapy for tuberculosis. The procedure, of course, was poorly effective and had high morbidity and mortality. Antituberculous medical therapy is for more efficacious with significantly less morbidity and mortality. Most treatment decisions are in the middle where physicians balance the risks and benefits of several management strategies. A liver transplant is a far more nuanced decision for both the physician and the patient. It is the only effective therapy for end stage liver disease yet it is not available to all due to organ shortage. And the operation carries both significant risk and substantial benefit. End stage liver disease is cured but replaced by a new and different chronic condition by way of a major surgical procedure. The patient must be ill enough to derive a benefit from transplant. The patient must not be too ill in order to have a reasonable chance to
Listing for Transplantation
survive through and thrive after the transplant. Moreover, one patient’s transplant affects all the other patients awaiting transplant. While the patient receiving a new liver benefits from the transplant, patients on the remainder of the waiting list who did not receive the graft are still at risk for adverse pre-transplant outcomes until such time as they themselves receive a liver transplant. Utilitarian philosophy dictates that resources should be focused on where they would do the most good. Maximal good at minimal cost is a common mantra of utilitarian thinkers. Rationing a limited supply of organs to a large pool of eligible recipients becomes a utilitarian enterprise.
The Evaluation Process Once the patient’s primary medical care team suspects that a patient would potentially benefit from liver transplantation, the patient is usually referred to a specialist who is trained in recognizing patients who meet criteria for possible transplant listing. Frequently, it is a gastroenterologist or a hepatologist in the community who refers the patient to a liver transplant center. Primary care physicians or other specialists may also pursue the referral directly. Physicians who are not specialists in transplantation need to be educated in deciding when a patient with liver disease is a candidate for transplant evaluation. After a referral is made, the patient is seen and evaluated by the liver transplant center. What is the patient’s risk for surgery? Does the patient have preexisting medical conditions unrelated to their liver disease that would make transplantation unnecessarily risky? Does the patient have psychosocial barriers to transplant? Does the patient have the social support structure in place to adequately ensure that they will be compliant with the rigorous medical regimen required of a liver transplant recipient? These questions all need to be answered. Another crucial issue is whether the patient’s liver disease is at a sufficiently early stage that they would derive no survival benefit from and thus should not be listed for transplantation. Conversely, the patient’s liver disease should not have progressed to such an advanced state that surgery would be overwhelmingly risky. The patient has to be evaluated for coexisting medical
1355
conditions that would make transplantation surgery or the post-operative course too risky. Once the psychosocial and medical evaluations have been completed, the transplant center must take this information and make a decision whether the patient should be placed on the transplant list. This usually involves an objective evaluation and discussion by a committee composed of transplant surgeons, hepatologists, psychiatrists, social workers, transplant coordinators, nurses, and others who decide whether patients would benefit from listing for transplant.
Listing for Transplantation The subsequent discussion focuses on the process of listing for transplantation in the United States. European and other systems function differently but the themes of the American model are illustrative of systems in place in other countries to list patients for transplant. Once a transplant center decides to place a patient on the waiting list for transplant, the patient is registered with the United Network for Organ Sharing (UNOS) Organ Center. UNOS runs a centralized computer network that includes every transplant hospitals’ waiting list and links all organ procurement organizations (OPOs). The system currently in place is called UNet (see “http://www.unos.org”) and involves a passwordprotected data entry system where each candidate needs to be verified by at least one other person with UNet access. Once entered onto a transplant center’s waiting list, the patient is made part of the national organ allocation infrastructure from which decisions about organ allocation are made. Organs are allocated locally within the local organ distribution unit (usually 1–3 OPO’s coverage area) first. If no appropriate recipient is found locally it then proceeds to the level of local OPO’s UNOS region, and then nationally to the other ten UNOS regions for all patients with chronic liver disease. Broader regional sharing arrangements are available patients with acute liver failure in most regions and now to allow regional sharing before local allocation to patients with MELD scores 500 IU/mL are associated with very low rates of recurrence when used with or without oral antiviral agents. Our center uses combination therapy indefinitely at the current time as long-term data on emergence of resistant HBV on antiviral therapy without HBIg is lacking.
Cholestatic Liver Disease (See also Chapters 73–77). Patients transplanted for cirrhosis due to primary biliary cirrhosis and primary sclerosing cholangitis, the benign cholestatic liver diseases have some of the best long-term outcomes in liver transplantation. To assess severity, the Mayo models for primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) are frequently used. Patients with a Child-Pugh score greater than or equal to 7 or the advent of portal hypertensive bleeding are eligible by current criteria for listing for transplant. Alternatively, patients with a Mayo model risk score predicting greater than 10% mortality at 1 year should be listed for transplant [53]. The patient with PSC and recurrent episodes of cholangitis presents special challenges to the liver transplant team. These patients may have MELD scores that inadequately reflect mortality since morbidity and
mortality are more commonly due the development of resistant bacterial or fungal infections. These patients may be underserved by their MELD scores. They also suffer from greatly impaired quality of life due to the need for frequent endoscopic or percutaneous procedures and frequently require external drainage. Added priority for OLT for these patients may be obtained in some cases by petitioning the regional review board (RRB) for additional MELD points. A similar approach can be taken for other types of patients in whom their degree of quality of life impairment is not reflected by MELD. Patients with PBC and intractable pruritus or severe metabolic bone disease in patients may petition for additional MELD points. This is controversial as it diverts livers away from patients with higher mortality risks and these exceptions are decreasing in frequency. An alternate solution is to view these complications as indication for proceeding to living donor liver transplantation if an adequate donor volunteers.
Malignant Diseases of the Liver Because extrahepatic spread of hepatobiliary tumors brings with them a poor prognosis, selection of patients with malignant disease for liver transplant is complicated. Theoretically, the primary malignant diseases of the hepatobiliary tract, hepatocellular carcinoma (HCC) and cholangiocarcinoma, when confined to the liver, could be cured with surgical resection. Surgical resection, however, often would result in insufficient hepatic reserve remaining for the patient. As a result, patients will often need a transplanted organ to replace the resected organ, due to either to bilobar disease or severe liver disease in the remnant that would lead to liver insufficiency post-resection. Additionally even with adequate reserve and a curative resection, the liver remnant retains malignant potential and thus is at high risk for de novo and recurrent cancer. Thus transplant has evolved into a crucial therapy for these diseases. Due to the difficulty in predicting whether the malignancy has spread to extrahepatic sites and rendered transplantation futile, criteria have been developed to stratify the risks of recurrence of tumor. These criteria are based on size and other tumor characteristics. These criteria are then used to decide whether to list patients with a malignancy for transplantation.
Indications for Transplantation
Cholangiocarcinoma (See also Chapter 116). Cholangiocarcinoma is a highly malignant neoplasm arising from the bile duct epithelia. Sixty percent occur in the perihilar region at the confluence of the right and left hepatic ducts (Klatskin tumor). Primary sclerosing cholangitis is the most common known risk factor for the development of cholangiocarcinoma. Currently, there are no effective medical therapies for cholangiocarcinoma. After diagnosis, the median survival is 9–12 months, with long-term survival being infrequent. Even with resection, local recurrence is common. Patients in whom the cholangiocarcinoma arises in the context of PSC present special issues. Patients with PSC and cholangiocarcinoma have disease that is more frequently multifocal and are more likely to have fibrotic/ cirrhotic liver disease that makes the risk of liver failure and death following resection prohibitive [33]. Historically, cholangiocarcinoma recurred in most patients and was viewed as a contraindication to transplantation. Reported long-term survival rates following transplantation ranging from 20% to 30%, significantly lower than those for patient transplanted for cirrhosis [87]. The treatment for cholangiocarcinoma, however, has changed dramatically over the past decade and with it the survival prospects following transplantation. While prior studies showed poor outcomes and high recurrence rates in patients with cholangiocarcinoma who had been transplanted, some caveats should be kept in mind regarding this data. First, this older data originated from patients in varying stages of disease. Next, selection criteria of candidates for transplantation were poorly defined. Finally, in no cases were adjuvant and neoadjuvant chemotherapy was given. In 1994, a new management protocol involving preoperative chemoradiotherapy followed by liver transplantation for patients with localized perihilar cholangiocarcinoma and regional lymph node negative disease was introduced at the Mayo Clinic. With this new protocol, 92% of patients were alive at 1 year following transplant and 82% were alive at 5 years [74]. These data suggested that the use of neoadjuvant therapy in these patients selects a group of patients with cholangiocarcinoma who will likely achieve a clear survival benefit from transplantation. We and others have modified the protocol using different chemotherapeutic agents with more activity in pancreatic and biliary tract
1361
tumors in combination with brachytherapy and/or external beam radiation. Better treatment strategies and improved detection with MRCP, ERC, intraductal ultrasound and biopsy, and FISH of biliary aspirates can further improve outcomes. However, this indication remains controversial. Transplantation should only be performed in the context of well-defined clinical studies at centers with experience in this type of protocol.
Hepatocellular Carcinoma (See also Chapter 102.1). Primary cancer of the liver, hepatocellular carcinoma presents similar, but less vexing, difficulties. Like cholangiocarcinoma, HCC is frequently tied to primary liver disease in this case coexisting cirrhosis or viral hepatitis. Unlike cholangiocarcinoma, a large body of data has shown that small HCC can be treated with liver transplant with a low recurrence rate. Controversy in this area exists is as to the size limit of the tumor(s) for transplantation and acceptable recurrence rates. Current recommendations are that liver transplantation is indicated in patients with small HCC (Stage I–II, i.e., T1-2, N0, M0 disease) with no evidence of invasion of large vascular structures or extrahepatic disease [26]. The prognostic value of high alpha-fetoprotein (AFP) levels is controversial. Recurrence is higher for patients with elevated AFP values, especially those >1,000–2,000. These patients are more likely to have either more extensive disease in the liver than noted on pre-operative imaging or occult extrahepatic disease. Though no cutoff of AFP is recommended to exclude patients from OLT, caution and planned exploration with an identified back-up candidate prior to OLT may be prudent for patients with AFP > 1,000, especially if the number has risen despite locoregional therapy. If patients clearly have no evidence of extrahepatic spread and the tumor appears small enough that metastasis would seem unlikely, then transplantation can offer high long-term cure rates with low recurrence rates post-OLT. The optimal diagnostic criteria for hepatocellular carcinoma as well as the role of pre-transplant therapy remain controversial. While lesions above a certain size can be diagnosed as hepatocellular carcinoma based on imaging only, smaller lesions present diagnostic challenges. At one extreme are some experts
1362
103
Liver Transplantation: Indications, Preoperative Evaluation and Posttransplantation Management
who have called for biopsy with histologic confirmation of all lesions being evaluated for transplantation. Some advocate biopsy only for nodules less than 2 cm in size, the protocol supported by the guidelines put forth by the European Association for the Study of Liver Disease (EASL) [82]. Others do not feel that biopsy is needed when characteristic imaging is obtained, largely due to concerns about false-negative results with biopsy. Given rates of “incidental” HCC on explants in HCV patients of up to 20%, it is prudent to go with the assumption that lesions that appear as HCC on imaging performed with liver specific protocols should be assumed to be HCC even without a biopsy. We advocate biopsy of all lesions in patients who have no other independent indication for OLT, e.g. a patient with Child A cirrhosis, a small lesion (2 cm that is characteristic of HCC, however, the risk of core biopsy as well as the risk of needle-track spreading and false-negative results make a presumptive diagnosis of HCC an appropriate choice. It is important to note that fine needle aspiration does not provide the architectural detail required for diagnosis of a welldifferentiated HCC and core needle biopsy is required. Tumor size, AFP level, presence of vascular or capsular invasion, bilobular location, and number of nodules are poor prognostic factors and independently predict mortality from and recurrence of HCC. AFP is a strong predictor of recurrence and AFP greater than 300 ng/dL indicates a high chance of recurrence [26]. Since it is based on a postoperative scoring system rather than pre-OLT imaging, the TNM system of staging cannot be used with 100% accuracy to evaluate for transplant. Utilizing an international registry of hepatic tumors in liver transplantation, Klintmalm et al. showed that tumor size greater than 5 cm, presence of vascular invasion and a poorly-differentiated histologic grade of the tumor are strong negative predictors of patient survival after transplantation for HCC [44]. If selection of candidates is limited to patients with solitary tumors less than 5 cm or to subjects with up to three nodules, each under 3 cm in size, then the 5-year survival rate may exceed 70% and the recurrence rate is usually less than 15% following transplantation [10, 41, 50, 58, 83]. These criteria, known as the Mazzaferro or “Milan” criteria remain the standard criteria used to
select patients with HCC for OLT and are used to adjust priority for OLT at UNOS. Other more liberal size criteria (e.g. UCSF criteria) have also been proposed based on retrospective studies showing good results. The UCSF criteria show similar survival rates for patients with single tumors less than 6.5 cm or two lesions less than 4.5 cm to those within the Milan criteria [101]. Priority on the waiting list for OLT for HCC. Because many patients with HCC have relatively wellcompensated cirrhosis and are therefore underserved by scoring systems which emphasize both clinical and biochemical markers of end stage liver disease, corrective measures have been developed to ensure that HCC patients are not disadvantaged in organ allocation. The current MELD-based scoring system used by UNOS, for example, allows for an exception to be made for patients with hepatocellular carcinoma. These patients receive special “exception points” if they meet certain diagnostic parameters for their HCC. The rationale behind this rule is that patients with HCC may not have cirrhosis or intrinsic liver disease. They would have lower MELD scores based on laboratory scores that do not accurately predict their risk of mortality on the waiting list due to tumor growth. They would consequently have less chance of transplantation and more progression of their tumors on the waiting list. Allowing for a correction to the MELD score for patients with HCC has compensated for these patients being underserved by their “physiologic” MELD score. The low priority for HCC in the prior allocation scheme had led to a high dropout rate secondary to tumor progression. Since patients with HCC would derive a very large benefit from early transplantation prior to metastasis or growth of the lesion, the allocation system was altered to take this into account. Initially, T1 lesions were given a MELD score of 24 and T2 lesions a score of 29. The priority was increased every 3 months. No priority was given to tumors that exceeded these guidelines. The result was a marked increase in the number of HCC patients being transplanted along with very short waiting times and a decrease in the dropout rate to close to zero. Surprisingly, up to 25% of patients transplanted in the United States with HCC after the initial implementation of MELD exception points did not have evidence of HCC in the explanted liver, suggesting incorrect interpretation of the findings or imaging results which led to the diagnosis of HCC. This finding has led some
Indications for Transplantation
to postulate that encouragement of early transplant in the MELD era might provide incentive for limited workups in these patients [30, 83]. Most of these were T1 lesions, less than 2 cm. Additional modification has led to a reduced MELD priority for T2 lesions (24 points and now 22 points) with no additional priority for T1 lesions. This has reduced the total proportion of HCC patients among transplant recipients and should reduce the rate of HCC cases without histologic confirmation in the explant. Living donor liver transplantation offers distinct benefits for the patient with HCC. With LDLT, the transplant can be performed earlier, before the HCC has metastasized. Those patients with single tumors less than 5–7 cm in size, or with three or fewer nodules, and no evidence of extrahepatic disease or vascular invasion can be considered for LDLT. In fact, this may be the best option for the growing number of patients with cirrhosis and small tumors [95, 96]. LDLT results in a better outcome for patients with HCC, with a lower risk of death (RR = 0.35). LDLT patients are younger and tend to have lower MELD scores. Furthermore, by limiting use of the donor pool, LDLT allows more patients to undergo transplantation [51]. However, enthusiasm for LDLT as an ideal option for HCC patients has been tempered by recent data showing increased recurrence when compared with DDLT recipients [27]. Since many patients with HCC have HCV and owing to the slow growth of the HCC, it had been thought that these patients may be the ideal candidates for efforts to eradicate HCV prior to transplant. Since patients with decompensated cirrhosis oftentimes cannot tolerate ribavirin and pegylated interferon, therapy had previously not been an option in many cases. Everson et al. recently reported the use of a Low Accelerating Dosage Regimen of interferon and ribavirin (LADR) whereby patients are begun on low doses of the medication with doses being escalated as tolerated [25]. They showed that viral eradication on therapy can be achieved in up to 40% of patients. Patients transplanted on therapy for as little as 12 weeks with negative HCV RNA in the serum have only an approximate 20% risk of viral recurrence post-transplant. This will likely provide a substantial survival benefit by decreasing post-OLT morbidity from HCV recurrence. Since patients with HCC often have no decompensation and oftentimes do not have urgent needs to be transplanted owing to the relatively slow-growing nature of HCC and success of locoregional therapy, they may be ideal
1363
candidates for this regimen. It is likely that only LDLT candidates and those with HCC MELD upgrades would be able to tolerate LADR and undergo transplantation while still on antiviral therapy. Therapy for HCC pre-OLT. The role of pre-transplant locoregional or systemic therapy is unclear. The goal of pre-transplant therapy is to reduce tumor burden in order to prevent recurrence and to prevent progression on the waiting list. Theoretically, necrotic tumor would be less likely to be spread during mobilization and removal of the liver during the transplant. Various forms of locoregional therapy, as detailed in other chapters, exist. In the past, approaches have included chemotherapy directed at lesions via an intraarterial pump, transcatheter embolization of the arterial supply of a lesion, and radiofrequency ablation. All these modalities have been used with varying degrees of success. Transarterial chemoembolization (TACE) has been used routinely to prevent progression of HCC during the waiting period. Prior to the 1990s, therapy toward unresectable HCC was seen as palliative, not curative. In 1995, Venook et al. showed that patients who receive preoperative chemoembolization followed by OLT can achieve long-term survival. Ten of 11 patients with unresectable, histologically-confirmed HCC who received preoperative chemoembolization and later underwent OLT remained tumor-free at a median time of 40 months [99]. More recently, chemoembolization or TACE, whereby a chemotherapeutic agent is injected along with a compound that limits circulation to the tumor, has shown some effectiveness even without transplantation. Randomized data on the efficacy of pre-transplant TACE is limited, both in the transplant and non-transplant populations. However, lower posttransplant recurrence rates have been seen in chemoembolized patients compared with patients with incidental tumors, despite larger tumor size in the chemoembolization group. This may represent an effect of TACE at lowering recurrence rates although it may also reflect differences in tumor biology in the two groups. Since TACE treats entire lobes of the liver, it also treats tumors that might be too small to be seen on imaging. Percutaneous ethanol or acetic acid injection and radiofrequency ablation (RFA) are being used increasingly for a wide variety of malignant diseases of the liver. RFA and acetic acid can be used in lesions up to 5 cm; RFA can also be performed in the operating
1364
103
Liver Transplantation: Indications, Preoperative Evaluation and Posttransplantation Management
room with laparoscopy or laparotomy, usually with ultrasound guidance. For larger lesions, directed ablation usually achieves a higher degree of necrosis than TACE. Needle track spread can occur and is a concern. Recurrence risk after percutaneous catheter ablative therapy is less well studied and cannot be predicted [26, 82]. Often a combination of approaches is used particularly if the lesion is larger (e.g. beyond the UNOS criteria for additional priority) or waiting time is predicted to be long. Data suggest that neoadjuvant therapy for HCC improves posttransplant survival. A study looking at pretransplant ablative therapy (ethanol injection, embolization, TACE, and RFA) among patients registered in the International Registry of Hepatic Tumors in Liver Transplantation showed a dramatic increase in recurrence-free survival after OLT among patients with HCC who had undergone ablative therapy. 69% of patients were alive free of tumor in the ablation group as compared with 31% of patients in the group that did not receive ablation therapy (P < 0.0001) [44]. Interestingly, the positive impact of therapy increased as tumor characteristics worsened with the survival benefit increasing as the number of nodules in the tumor grew.
Metabolic Liver Disease The metabolic liver diseases, including Wilson’s disease, hereditary hemochromatosis, and a1-antitrypsin disease, all are indications for transplantation since they all can lead to irreversible damage in the liver. Since these diseases are all characterized by having systemic effects outside of the liver, the pretransplant workup must include a coordinated workup to allow for identification of systemic disease that would preclude transplantation. Hemochromatosis can lead to iron deposition in the myocardium resulting in an irreversible cardiomyopathy or conduction system damage with arrhythmia. Cardiac dysfunction is a primary reason for higher mortality after transplant in patients with hemochromatosis than those with other indications. a1-antitrypsin deficiency can lead to pulmonary emphysema, requiring careful cardiopulmonary evaluation to exclude pulmonary insufficiency or pulmonary hypertension. Occasionally, combined liver–lung transplant is required but end-stage liver and lung disease rarely coexist.
Vascular Disease of the Liver Vascular abnormalities such as Budd–Chiari syndrome or veno-occlusive disease frequently result in acute hepatic failure because of the abrupt nature of the disease development. Portal vein thrombosis is much better tolerated and rarely causes liver failure. Portal vein thrombosis is usually the result of chronic liver disease and presents with sudden worsening of portal hypertension. Because of its frequent association with HCC, careful screening for HCC should occur with all new cases of portal vein thrombosis. Thrombosis may in fact be a harbinger of other vascular or hematologic disease. As vascular thrombosis is generally associated with some underlying coagulation disturbances, the workup for all patients with vascular thrombosis must include evaluation for a hypercoagulable state or underlying malignancy that could have lead to the disease. Many of these patients have underlying hematologic disorders, e.g., polycythemia vera, and, in addition to blood testing, bone marrow biopsy is frequently needed. Any hypercoagulable state that is found must be corrected. This aspect is crucial to the success of the transplant. Patients transplanted for Budd–Chiari need to be treated with anti-coagulation medication postOLT for life due to the high rate of recurrent clotting in this cohort.
Fulminant Hepatic Failure Fulminant hepatic failure, the rapid development of encephalopathy, coagulopathy and jaundice in those without a history of chronic liver disease, is an indication for liver transplantation. While patients may progress rapidly to a state of critical illness and die prior to transplant, those who do undergo transplantation have excellent outcomes. Transplantation should be considered in any patient who presents with acute liver failure but must be actively pursued upon the onset of stage II encephalopathy [53]. The criteria for the definition of fulminant hepatic failure include the development of hepatic encephalopathy within 8 weeks of the onset of symptoms in a patient without a history of liver disease. Subacute hepatic failure is defined as the development of hepatic encephalopathy within 6 months but after 8 weeks of the onset of symptoms in a
Indications for Liver Transplant in the Child
patient not previously know to have liver disease. Patients with subacute failure have a virtually universal mortality without organ replacement and all should be considered for transplant [53]. Acetaminophen toxicity is the most common cause of fulminant liver failure. Viral etiologies follow in frequency. Drug toxicity is the most common form of subfulminant liver failure when the etiology is known. Patients with fulminant hepatic failure need to be cared for in a monitored setting with close observation. A number of patients who meet criteria for the diagnosis will recover full liver function without therapy [66]. It is therefore critical to understand the chances of recovery in patients with fulminant hepatic failure prior to a decision to accept an organ for transplantation. If the patient has a clear opportunity for full recovery, transplant may become unnecessary. On the other hand, waiting too long may lead to irreversible cerebral edema and death. The use of the King’s College criteria and other prognostic scoring systems, as well as transjugular liver biopsy to look for massive or submassive necrosis, may assist clinicians in differentiating patients with a low chance of spontaneous recovery from those who should undergo expedited transplant. A quandary arises when one is presented with acute liver failure secondary to acute alcoholic hepatitis. As discussed above, alcoholism presents significant psychosocial barriers to transplantation, particularly if the transplant is performed in a patient without a history of abstinence from alcohol. If a patient has a known drinking history and the liver failure is clearly secondary to alcoholic hepatitis after a binge drinking episode, the transplant team is faced with a dilemma as to whether to transplant a liver into an individual with a known predilection for alcohol abuse without knowing the patient’s chances for recovery from addiction. In most centers alcoholic hepatitis is viewed as a contraindication to OLT. Exceptions are occasionally made on a case-by-case basis in acute settings particularly in young patients or unclear etiology (e.g. alcohol plus acetaminophen toxicity).
Indications for Liver Transplant in the Child Special consideration must be paid to the pediatric patient with liver failure. Their disease patterns can be unique. The stakes are very high, particularly in infants.
1365
Living donor liver transplantation is more common as parents will often volunteer to donate for their children. These issues make pediatric liver transplantation distinct from adult liver transplantation. The indications for pediatric liver transplantation are similar to those for adult liver transplant but vary in prevalence; the most common indication is cholestatic diseases (predominantly biliary atresia), metabolic diseases, fulminant hepatic failure, chronic active hepatitis, malignancy, Budd–Chiari syndrome, parenteral nutrition induced cirrhosis, trauma, and Caroli’s disease (UNOS Policy 3, Appendix 3B) [97]. Like adults, children should be listed for transplantation if decompensation has already occurred. Unlike most adult cases, transplantation in children may be also pursued if liver failure is considered inevitable even in the absence of any signs of disease as most disease are cured with transplant, will not recur and earlier transplant may allow for more normal growth and development. Decompensation includes intractable cholestasis, portal hypertension with or without variceal bleeding, multiple episodes ascending cholangitis, failure of synthetic function including coagulopathy or low serum albumin or low cholesterol, failure to thrive, growth failure or malnutrition, intractable ascites, encephalopathy, unacceptable quality of life including school failure or intractable pruritus, metabolic defects for which liver transplantation will reverse life-threatening complications, prevent irreversible central nervous system damage, or life threatening complications of stable liver disease such as hepatopulmonary syndrome. The failure of growth or normal development is an indication for transplantation. Liver transplant will usually reverse growth failure with significant catch-up growth if performed early in the course of disease.
Pediatric Cholestatic Diseases Cholestatic disease is the most common indications for liver transplant in children. Obstructive cholestasis includes biliary atresia and sclerosing cholangitis. Biliary atresia alone accounts for 60–70% of childhood liver transplants. Though potentially curative when performed in the first 45 days of life, the Kasai procedure (hepaticoenterostomy) to treat congenital biliary atresia does not completely obviate the need for transplantation in most cases. Even with timely performance of the procedure, around 75% of patients will
1366
103
Liver Transplantation: Indications, Preoperative Evaluation and Posttransplantation Management
develop cirrhosis with portal hypertension and require a transplant. Children who have undergone the Kasai procedure should be listed for transplant when any indication for transplant occurs or if the surgeon deems the operation to have a high probability of failure. Without the Kasai procedure, death is inevitable before age two and children not undergoing the procedure or who have significant portal hypertension precluding Kasai should be listed as soon as the diagnosis is made (UNOS Policy 3 Appendix 3B) [97]. Mild and severe forms of intrahepatic cholestasis may require transplant. Even in mild cases, pruritus may be so severe as to require transplantation. Severe forms of intrahepatic cholestasis, such as Byler’s disease and Alagille syndrome can lead to cirrhosis requiring transplant. With Alagille syndrome, cardiomyopathy is a frequent association and may make transplantation impossible. Careful cardiac evaluation is therefore warranted (UNOS Policy 3 Appendix 3B) [97].
of the general indications for liver transplant are met. Autoimmune hepatitis, often with overlap with sclerosing cholangitis (overlap syndrome or autoimmune cholangiopathy) may require transplantation, especially in adolescence, if immunosuppressive therapy is unsuccessful at controlling the inflammation.
Hepatic Malignancy in Children Hepatoblastoma (see Section 102.3) is the most frequent primary liver malignancy in children. Unlike HCC, hepatoblastoma is locally invasive with late distant metastases and a better long-term prognosis and children should be immediately listed if the disease is confined to the liver but unresectable or if recurrent tumor is found after resection (UNOS Policy 3 Appendix 3B) [97]. Neoadjuvant chemotherapy is frequently used pre-transplant for patients with extensive disease. HCC is a rare indication for transplant in children except as a complication of metabolic liver disease (e.g., tyrosinemia).
Pediatric Metabolic Liver Diseases Metabolic diseases of childhood which are indications for transplant include urea cycle defects, Crigler–Najjar syndrome, tyrosinemia, Wilson Disease, and cystic fibrosis. The presence of any metabolic defect in the pediatric patient with liver disease needs to be investigated prior to transplant as some metabolic defects have extrahepatic manifestations that may not be reversible with liver transplant. Therefore, liver transplant should be considered only if the defect is localized to the liver or, if it occurs in extrahepatic tissue, does not involve the central nervous system. The defect needs to be corrected by a normally functioning liver. Finally, the extrahepatic manifestations of the metabolic defect should not be so severe so as to preclude liver transplant. Tyrosinemia is associated with a high rate of HCC and this needs to be investigated carefully.
Viral and Non-viral Hepatitis in Children Owing to the amount of time needed to go from inflammation to cirrhosis, viral hepatitis is a relatively infrequent indication for transplant in children. Nevertheless, children should be listed for transplant if one or more
Retransplantation in Children Hepatic artery thrombosis post-OLT is the most common indication for retransplantation in children and occurs at a higher frequency, particularly with reduced size grafts than in adult OLT. It may present very acutely and require urgent retransplantation [19]. Other indications for retransplantation include acute rejection (rare), primary non-function, chronic rejection, and recurrent disease. Chronic rejection is frequently due to medication noncompliance during adolescence and requires careful psychosocial evaluation to ensure compliance post-retransplantation.
Evaluation and Listing Once the decision to evaluate a patient for transplant is made and the patient has been referred to a transplant center for evaluation, the pretransplant workup is begun (Table 103.1). Although the protocol and requirements vary from hospital to hospital, most programs require a basic battery of laboratory work examining the patient’s general chemistry and hematologic
Evaluation and Listing
1367
Table 103.1 Pretransplant workup Triage Pathology Consults
Radiology
Cardiology
Pulmonary
Neurology Patients over 60 or with history of coronary artery disease Any patient with history of seizures, CVA, or neurological disorders Gastrointestinal
Gynecology Consults (optional)
Laboratory studies Chemistries
Hematology Serologies
Other
Review records and medical history Review biopsy if available Transplant coordinator Transplant hepatologist Transplant surgeon Social worker Psychiatrist Doppler ultrasound to assess portal vein patency MRI/MRV/MRCP EKG Bone density scan Chest x-ray (PA and lateral) Bone scan (if patient with hepatocellular carcinoma) Chest CT (if patient with hepatocellular carcinoma) 2D Bubble echocardiogram Adenosine stress test (patient > 45 years old or with risk factors for coronary artery disease Coronary angiography (if positive stress test or high risk for coronary artery disease) Room air arterial blood gas Pulmonary function testing with DLCO Arterial blood gas on 100% oxygen (if bubble echocardiogram is positive) Carotid Doppler ultrasound MRI brain
Neurology consult Colonoscopy (if over 50 or with elevated CEA) Upper endoscopy (screen for varices) ERCP (if history of PSC) PAP Mammogram Anesthesia Dental Nutrition Infectious disease Ophthalmology Physical rehabilitation Interventional radiology Oncology Electrolytes (N, K, Cl, CO2, Mg, PO4), BUN, creatinine, glucose, albumin, total protein, AST, ALT, total bilirubin, alkaline phosphatase, LDH, GGTP, ferritin, Iron (transferrin saturation), AFP, cholesterol, TSH, uric acid CBC with differential and platelet count, PT, PTT Hepatitis B (SAg, DNA, CAb, EAg, EAb) Hepatitis C (anti-HCV, RNA quantitative, genotype) RPR, varicella titers EBV (IgG and IgM) CMV antibody HIV antibody ABO with antibody screen (x2) PPD with anergy panel
1368
103
Liver Transplantation: Indications, Preoperative Evaluation and Posttransplantation Management
counts. In addition, laboratory examinations frequently include elements of the liver disease workup that have not been previously performed. The workup also includes a search for occult infection, which could be reactivated with immunosuppression. Chest x-ray and PPD are performed to ensure that the patient does not have latent tuberculosis. RPR testing for evidence of latent syphilis and HIV testing is performed. Any infections, chronic or otherwise, should be treated or under control to prior to transplant. A thorough workup includes an evaluation of the patient’s general medical condition and fitness for major surgery. EKG, chest radiography, echocardiogram (frequently a saline contrast or “bubble” echocardiogram to exclude intrapulmonary shunting due to hepatopulmonary syndrome), cardiac stress testing, and pulmonary function testing with DLCO and arterial blood gas are common elements of the workup. Close coordination with a referring physicians and specialists is required to best understand the patient’s preoperative risk. Imaging of the abdomen and hepatic parenchyma and vasculature is routinely performed on all pre-transplant patients. Ultrasound can be used to assess the patency of the portal and hepatic vasculature and to determine liver size. CT or MRI are frequently used to exclude HCC or for abnormalities on ultrasound. Additional tests, e.g. right heart catheterization to exclude pulmonary hypertension, should be used selectively based on the results of the aforementioned workup. As mortality and morbidity following transplant may be related to compliance with medication, a thorough psychiatric evaluation of the patient and his or her capabilities is paramount [102]. Resumption of addictive behavior following transplantation could adversely affect survival and must be treated beforehand. Since the patient’s psychosocial status and social support may impact on compliance and outcome, a thorough exclusion or correction of any psychiatric or socioeconomic barriers is crucial and should include evaluation by a psychiatrist and/or social worker. Forty-three percent of candidates for liver transplantation have at least one psychiatric disorder, so an understanding of the patient’s psychiatric state is crucial to assessing suitability for transplant [76]. As a result, dedicated social workers and psychiatrists are integral members of the transplant team and their evaluation is critical in transplant selection and management. Socioeconomic barriers to compliance can negatively impact graft survival. If immunosuppressive
medications cannot be obtained due to insurance, work or cultural issues, failure of the graft is likely. Socioeconomic barriers can make follow-up difficult or lead to recidivism to addictive behavior. A thorough evaluation can detect future challenges that could be avoided. Financial coordinators assess adequacy of transplant insurance coverage. Social workers assist the patients in obtaining additional financial support for transplantation and appropriate follow-up. The goal should be to provide care to all that require it. If these resources are not readily available, then the social work team should attempt to identify adequate resources for patients to undergo transplant successfully.
Contraindications to Liver Transplant A basic tenet of dealing with a scarce resource like a donated organ is that one should only transplant those candidates in whom a reasonable chance of graft and patient survival is predicted. There are individuals in whom, for one reason or another, transplantation is contraindicated. Some contraindications are relative. If ameliorated before transplant, then the transplant can proceed. Others are absolute. In these cases, there is no reasonable expectation that either the patient or the graft will survive with an acceptable quality of life for an acceptable period of time post-transplant, or justice prevents allocation to an individual who is unlikely to ever meet the criteria for OLT. It is important to note that relative contraindications, particularly for living donor liver transplants, vary from center to center. Most contraindications to liver transplant relate to comorbid conditions [95, 96]. Relative contraindications to transplant include alcohol or illicit drug use within 6 months in a patient with a history of alcohol or substance abuse, extrahepatic malignancy in the past (not including non-melanoma skin cancer or those that meet oncologic definition of cure), and systemic sepsis [53].
Age Advancing age is an important relative contraindication to liver transplantation. Data suggest that in order to have good outcomes, patients above the age of 70
Contraindications to Liver Transplant
need to undergo liver transplant in a relatively wellcompensated state. If these patients are allowed to wait until their MELD score is high, their chances of debility or of developing comorbid medical conditions that would preclude transplant rise significantly [81].
Psychosocial Contraindications As discussed, alcohol abuse is a relative contraindication to liver transplantation. Although some patients do maintain good graft function if they continue to drink following transplant, recurrence of disease with resumption of alcohol use remains a concern. Unfortunately, there are few reliable predictors of relapse in alcohol patients making the identification before the transplant of those patients at greatest risk for relapse following transplantation difficult [8, 48].
Cardiopulmonary Contraindications The presence of pulmonary disease, particularly pulmonary hypertension, can be an absolute contraindication to liver transplantation as severe pulmonary hypertension or severe hypoxemia from hepatopulmonary syndrome makes the patient an unacceptable operative risk. During the transplant procedure, hemodynamic challenges are manifest, particularly during the time of vena caval clamping and reperfusion of the newly implanted graft following restoration of caval flow. These changes may overwhelm the patient whose right ventricular function is impaired. A mean pulmonary artery pressure of greater than 35 mmHg is considered by many to be a contraindication if it is impossible to lower with medications pre-transplant. Right heart catheterization should follow a suggestion of pulmonary hypertension on echocardiography [18]. The presence of hepatopulmonary syndrome predicts morbidity and mortality in patients with end stage liver disease. Patients with the hepatopulmonary syndrome have nearly twice the 1-year mortality of other transplant recipients. However, early hepatopulmonary syndrome is reversible with OLT and can be viewed as an indication to expedite transplantation. Diagnosis is difficult as there are no strict definitions for the diagnostic criteria [4]. Criteria currently accepted by most
1369
centers include the presence of liver disease combined with a pO2 of 70 mmHg or less while breathing room air, and evidence of intrapulmonary vascular dilatation or shunting. Response to breathing 100% oxygen and calculation of shunt ratios does not adequately predict outcomes for patients with hepatopulmonary syndrome [56]. Because Doppler echocardiography has a poor predictive value in estimating pulmonary artery pressures, right heart catheterization is recommended to assess for the presence of portopulmonary hypertension in patients at risk [4].
Infectious Contraindications HIV Infection It was previously thought that infection with the human immunodeficiency virus (HIV) was an absolute contraindication to liver transplantation. Though it remains controversial, with many centers still regarding transplantation of HIV infected individuals as experimental, other centers have transplanted HIV positive patients with acceptable results. Thus, HIV is now at most relative contraindication to OLT. Concerns have included the cumulative impact of virologic and pharmacologic immunosuppression, inability to control HIV viremia, and decreased life expectancy after transplantation. In the era of highly active anti-retroviral therapy (HAART), however, these ideas have been reassessed. Transplantation of selected HIV positive patients with suppressed HIV viral load is now being performed in selected patients and is the subject of a NIH-sponsored multi-center study. It has been shown, for example, that HIV patients with hepatitis B virus who receive prophylaxis against recurrence of HBV following transplantation have excellent short and long-term survival rates [104]. Various centers have published results that show 1-year survival rates that are no different for HIV positive and negative patients [31, 73]. Caution needs to be taken during the transplant evaluation to ensure the absence of occult infection or other HIV-associated comorbidities that would contraindicate transplantation. The current absolute contraindications to liver transplant in patients with HIV disease include uncontrollable HIV due to multidrug
1370
103
Liver Transplantation: Indications, Preoperative Evaluation and Posttransplantation Management
resistance, chronic renal failure, leukoencephalopathy, advanced malnutrition, requirement for life support, and the presence of opportunistic infections. Requirements for life support pre transplant and advanced malnutrition correlate with poor survival following transplantation. Patients should not have had a recent opportunistic infection within 6–12 months, previous Kaposi’s sarcoma, and infection with JC polyoma virus. Of note, history of pneumocystic carinii pneumonia is not a contraindication to transplant [31]. Since the cirrhotic patient usually has hypersplenism, their CD4 counts may appear to be low due to their liver disease and not secondary to infection with HIV. Lower CD4 counts can be accepted if based on comparison with the absolute neutrophil count [31]. Another relative contraindication for patients with HIV disease is a noncompliance with HIV medications. Patients who are ineligible for HAART owing to intolerance of the medication because of severe liver dysfunction should be considered for transplant if they have shown prior responsiveness to HAART [31]. Also unclear are the contraindications for patients with HIV disease who are characterized as long-term nonprogressors and have low, stable viral counts in the absence of therapy with HAART. If they meet certain criteria, therefore, HIV patients should be considered for transplant. Patients with HIV disease should only be transplanted at centers with particular expertise in peri-transplant HIV management and where a transplant pharmacologist is involved who has particular expertise in drug-drug interactions given the complexity of managing immunosuppressive drugs and concomitant HAART. A transplant infectious disease specialist who has worked with issues involving HIV and transplant is also highly recommended [31].
Other Infectious Contraindications Patients with active, uncontrolled infection cannot be transplanted. Infection presents a significant risk to the transplanted patient given the high dose immunosuppression required of patients acutely following transplantation. Most immunosuppressive protocols involve high dose steroid pulses immediately following transplantation. Patients who have spontaneous bacterial peritonitis need to be treated adequately prior to transplantation. Infection with drug resistant bacteria or fungi may require delisting or deactivation until these
pathogens are eradicated as the outcome of transplantation can be poor in this setting (see delisting criteria below). Though rigorous data are lacking, recommendations for treatment of resistant bacteria (methicillin resistant Staphylococcus aureus and vancomycin resistant enterococci being the most common) or fungi are 4–6 weeks of appropriate antibiotics/antifungals with surveillance cultures and documentation of eradication.
The Waiting List Management on the Waiting List While on the waiting list, it is crucial that the transplant team remain invested in the care for the patient’s end-stage liver disease. Deficiencies in attending to the pre-transplant medical needs of patients are common. Screening rates for HCC are poor. Standard preventive procedures for patients with end-stage liver disease, including endoscopic screening for esophageal varices and primary or secondary prophylaxis against variceal bleeding may not be followed [55]. MELD scores need to be updated regularly, every 3 months on average or when there is any change in the patient’s clinical condition. Adjusting the patient’s MELD score regularly ensures that the patient will be at a place on the waiting list appropriate to their condition.
Timing of Transplantation Transplantation should be timed so that the patient derives the maximum benefit from receiving a new liver. If the transplant is performed too early, before the patient develops liver failure, for example, then the morbidity and mortality from transplant will outweigh the benefits. On the other hand, if the transplant team waits too long to list a patient for transplant, then the risks of the procedure can overshadow the benefits of the transplant. It is important to remember that MELD foretells pre, not posttransplant survival. It is a powerful tool for determining who those patients are who would most benefit from transplant. Data suggest that patients with
Living Donor Liver Transplantation
MELD scores less than 15 do not derive a survival benefit in the first year, particularly those with scores less than 12. For MELD scores above 15, the survival benefit increases with each increase in MELD [60]. In a separate study by Desai and colleagues, MELD score was found to be a relatively poor predictor of posttransplant outcomes in all but patients with the highest 20% of MELD scores [21]. If a patient is moribund due to end-stage liver disease, comatose, in renal failure, and/or on a ventilator, then the risks of dying regardless whether he or she is transplanted or not outweigh the now-diminished benefit of the transplant. Analysis of UNOS data showed that hospitalization in the intensive care unit prior to transplant, retransplantation, female donor to male recipient, age greater than 44 years, and recipient race increased the rate of allograft failure, specifically the need for retransplantation, among patients receiving adult-to-adult living donor liver transplant predicted poor outcome [1]. There is no absolute MELD cut-off for transplant futility. Though the post-transplant risk of dying increases by 50% at high MELD scores (>30) and there is a higher rate of waiting list removal for the reason of “death/too sick,” outcomes in a selected group sickest patients are still reasonable, especially given the over 300-fold increase in mortality pre-transplant in high MELD candidates. Ideally, the optimal timing for transplant is when patients begin to show evidence of decompensation or achieve a MELD score of 15 or greater. Synthetic dysfunction, malnutrition, or experiencing the first complication of cirrhosis indicates the onset of decompensation. It is expected that patients will survive the waiting time required to procure an organ based on their MELD score. Patients with HCC should be referred for transplant evaluation as soon as the tumor is discovered. Children should be referred for transplant evaluation at the point that they fall off their growth curve [14]. Though there is no longer an advantage to early referral in terms of waiting time, early referral allows the team to address pre-transplant problems and optimize management and timing of transplantation.
Delisting Criteria If the patient’s condition has worsened to the point that the procedure’s risks would now outweigh benefits or
1371
the patient’s condition has improved significantly, transplant may no longer be the best option for the patient. Delisting or temporarily deactivating patients from the transplant list involves a calculation that the patient would not derive a survival benefit from the transplant. There have been calls for the development of absolute minimum cutoff survival rates for acceptable predicted post-transplant survival. These rates would likely range from 40% to 60% [67]. In response to calls for the development of an intermediate status such as a temporary deactivation status or a modification of the patient’s MELD score with a decrease in points for critical complications, patients can be temporarily suspended on the waiting list as a Status 7 without losing priority on reactivation [67]. Mechanical ventilation, requirement for hemodialysis, fungal or resistant bacterial infections, and a prior transplant all adversely impact likelihood of post-transplant survival. If several of these factors are present, the post-transplant risk becomes prohibitive and transplant should be deferred. Current research is directed at developing evidence-based recommendations for delisting. Patients should be removed from the transplant list if their condition deteriorates to the extent that it is unlikely that they would survive the procedure. All previously discussed absolute contraindications to listing are reasons for delisting if they transpire after listing while a patient is awaiting transplant. This includes resumption of alcohol use while awaiting transplantation [65].
Living Donor Liver Transplantation First performed by Yamaoka et al. in Japan in 1994, centers in the United States have performed over 1,700 living donor liver transplants (LDLT) since 1989 in children and 1998 in adults (Source: UNOS). Because living donation permits the timing of transplantation independent of waiting time and severity of liver disease, criteria for transplantation in these patients are somewhat different than for patients waiting for deceased donor organs. Timing of LDLT is a great deal more flexible. The transplant team can select a transplant time that is individualized for the particular patient. The living donor organ has significantly less cold ischemia time than the deceased donor organ as a consequence of moving immediately from the donor to the recipient. Owing to
1372
103
Liver Transplantation: Indications, Preoperative Evaluation and Posttransplantation Management
rigorous screening of the living donor, the organ should be coming from a healthy individual. For these reasons, living donor livers hypothetically of better quality than deceased donor livers. On the flip side, the living donor allograft has significantly less hepatic mass than a full-sized deceased donor organ. To date outcomes of living donation and deceased donor transplantation have been similar. There is a potential benefit from LDLT to the patients awaiting deceased donor liver transplant as well. Every transplant with a liver obtained from a living donor potentially frees up a deceased donor organ for transplant into another recipient as living donor recipients are not part of the deceased donor recipient pool [96]. Thus living donation potentially benefits everybody on the transplant waiting list. Patients receiving a living donor organ have a reduced waiting period. This decreases the risks of decompensation or death prior to transplantation thus improving the chances for success. As a result, patients receiving living donor grafts have improved survival on the waiting list and overall survival from the time of listing [9]. Mortality on the waiting list for living donor recipients is half that of those listed for DDLT only [49, 80]. Since the transplant is performed on an elective basis, the operation can proceed immediately after the workup is performed and the donor is deemed a good candidate. Secondary to the flexibility of the waiting period prior to transplant in living donor recipients, the team has time to stabilize the patient’s comorbid conditions, further improving the chances for success [95, 96]. LDLT grafts have tremendous growth potential; the graft doubles in size within 4 weeks of transplantation, generating over 150,000 hepatocytes every second for the first week following transplant [6, 57]. Questions have risen as to whether there are any negative implications of the accelerated growth rate found in the liver segment transplanted in living donor liver transplants. It has been postulated, for example, that this growth potential may predispose to more aggressive recurrence of HCV in patients transplanted for HCV cirrhosis. Several recent large studies have shown that the incidence and severity of HCV recurrence were not different between DDLT and LDLT recipients [79]. Patients with decompensated cirrhosis with ChildPugh scores greater than or equal to 10 are the most appropriate patients for LDLT. Acute hepatic failure is also an acceptable indication but concerns regarding
coercion and adequacy of the donor workup given the time constraints on donor workup have made this indication somewhat controversial. Recipients should meet standard indications for OLT and not have any contraindications. Using the current donor and recipient criteria, on a national level only 5% of patients listed for deceased donor liver transplants currently undergo living donor transplants mainly related to lack of appropriate donors [95]. As with deceased donor transplantation, the ideal candidate for living donor liver transplant is one who is sick enough to derive a benefit from transplantation but not so sick as to incur potentially high post-transplant mortality risk. A simple rule of thumb is that an appropriate LDLT candidate is a patient you would transplant today if organs were unlimited. The MELD score can help identify candidates for living donor liver transplantation who are not likely to benefit because they are either too sick or too well to undergo transplant [29]. In a study by Trotter et al., between 1997 and 1999, 51% of 100 potential LDLT recipients evaluated at one center were rejected [96]. The most frequent reasons for donor rejection included medical comorbidity, high-risk psychosocial issues, obesity, financial issues, and procurement of a deceased donor organ during the evaluation. Overall in experienced LDLT programs, it appears about one-third of adult patients on the waiting list may have a potential donor and half of these will undergo the procedure, indicating that LDLT may be applicable in up to 15% of patients on the waiting list [96].
The Posttransplant Period The Perioperative Period The transplant recipient is usually very ill at the beginning of the procedure. He/she may be profoundly coagulopathic, anemic, encephalopathic, and vasodilated owing to the hyperdynamic circulatory status of the cirrhotic patient. These factors, in addition to the technical challenges of the procedure itself, make perioperative setting very challenging. Patients usually remain intubated immediately following the procedure. Most often, they are brought directly to a surgical intensive care unit where recovery
The Posttransplant Period
from anesthesia is supervised by a team of anesthesiologists, surgical intensivists, transplant surgeons, and transplant hepatologists. Hypovolemia, owing to both intraoperative bleeding and fluid losses, is common and oftentimes requires assessment with a pulmonary artery catheter. Particular attention needs to be paid to the pulmonary artery pressures. Owing to vena caval and aortic manipulation during the operation, pulmonary pressures may vary widely during the surgery. Patients are oftentimes loaded with fluid in the intravascular space. Poor renal function before the transplant may preclude the patient from properly mobilizing this fluid. The team managing the patient postoperatively must be attentive to pulmonary arterial pressures, wedge pressures, and cardiac output to properly manage the patient’s fluid status. Patients should be extubated as soon as feasible. Lines should be discontinued as soon as possible as they remain niduses of infection in immunocompromised host. Patients should have their diets advanced as soon as bowel function returns. At our center, patients are transferred to the transplant ward once they are extubated and hemodynamically stable. Once on the floor, the focus of care shifts to more routine postoperative management. Patients’ diets are advanced. They are encouraged to ambulate. Wounds are given the proper care. In addition, immunosuppressive regimens must be properly established and patients should be educated about their medical regimens prior to being discharged from the hospital. A team often comprised of a pharmacist, nurse or nurse practitioner, and physician assistant provides medication teaching. They are taught about the side effects and doses. We use a book with pictures of individual pills and a brief quiz to assess their knowledge. Successful completion of the teaching is a prerequisite for discharge home.
Immunosuppression Together with advances in surgical technique, advances in immunosuppression have permitted rapid advances in liver transplantation over the past two decades. Modern immunosuppression ideally precludes the patient from recognizing the allograft as nonself while at the same time minimally affecting the body’s ability to respond to other nonself antigens, primary infective
1373
pathogens. Immunosuppression can broadly be divided into four categories; steroids, calcineurin inhibitors, cell cycle inhibitors, and monoclonal antibodies. Discovered by Jean-François Borel in 1973 in the soil fungus Tolypocladium inflatum, the FDA approved cyclosporine in 1983, which revolutionized transplantation. By inhibiting T-cell activation, cyclosporine selectively suppresses cell-mediated immunity. Cyclosporine binds to cytoplasmic receptor protein known as cyclophilin. It then inhibits the calcium and calmodulindependent phosphatase calcineurin. Calcineurin is integrally involved in the transcription process that activates IL-2 and other cytokines. Produced by T-helper cells, these cytokines play key role in the cellular recruitment that alters the cellular milieu of the graft and precipitates acute cellular rejection. As with all calcineurin inhibitors, cyclosporine has numerous side effects including nephrotoxicity and neurotoxicity. Between 10% and 27% of patients may experience neurotoxicity from cyclosporine. Effects may range from mild tremors to seizures and frank neuropsychiatric disturbances. The effects of calcineurin inhibitors on the development of hyperlipidemia, hypertension, and diabetes mellitus will be discussed later on this chapter. The pharmacokinetics of calcineurin inhibitors is affected by other medications that induce or inhibit cytochrome P450 activity, some of which may be commonly used in the transplant setting. Azole antifungals, for example, will raise the levels of calcineurin inhibitors. Earlier formulations of cyclosporine required emulsion in a fatty-substance such as whole milk. Owing to both the difficulty of taking this liquid form and to the unreliable absorption associated with this, a newer microemulsion form of cyclosporine was developed. This form of cyclosporine is the predominant form in use today. The newer calcineurin inhibitor, tacrolimus (also commonly referred to by its clinical trial number FK506), is a 100-fold more potent than cyclosporine. Similar to cyclosporine it inhibits transcription of cytokines and chemotactic factors critical to the immune response. However, tacrolimus binds to different cellular receptor, FK binding protein (FKBP12), to exert its effects. The complex then enters the cytoplasm to inhibit calcineurin and the production of IL-2, 3, 4, 8 and other chemotactic factors. Since it is more potent than cyclosporine, therapeutic tacrolimus levels are roughly one tenth those of cyclosporine. It has a similar side effect profile and
1374
103
Liver Transplantation: Indications, Preoperative Evaluation and Posttransplantation Management
pharmacokinetics to cyclosporine. Tacrolimus has supplanted cyclosporine as the predominant first-line immunosuppressive agent in most programs in the US, though there is debate as to which has superior outcomes in patients with hepatitis C and HCC. Corticosteroids have broad effects on the immune system and were the original immunosuppressants used in transplantation. They block T cell and antigen presenting cell- induced cytokine expression. They predominantly block production of IL 1, 2, 3, and 6. Unlike calcineurin inhibitors, which are used primarily as maintenance immunosuppressants, steroids can be used as both maintenance agents and for the treatment of acute cellular rejection. Steroids are typically given in high doses (up to 1 g) intraoperatively and then tapered. They are used as induction therapy perioperatively and are eventually tapered in most patients. Similar doses are used in the treatment of acute cellular rejection. Because high dose steroids accelerates the progression of recurrent hepatitis C post transplant, their use for the rejection in patients transplanted for hepatitis C virus is approached with caution and avoided whenever possible in some programs. Azathioprine, an imidazole derivative of mercaptopurine antagonizes purine metabolism. This inhibits the synthesis of the DNA, RNA, and proteins central to the maturation of immune cells. A corollary to this property is the fact that a central side effect of their use is myelosuppression. In rare cases, azathioprine can cause significant hepatotoxicity. Mycophenolate mofetil (MMF) is a more potent alternative cell cycle inhibitor. MMF is metabolized to mycophenolic acid, which inhibits de novo purine nucleotide synthesis via disruption of production of inosine monophosphate dehydrogenase and guanosine nucleotides. These actions prevent the DNA replication required in both B and T lymphocytes which are unable to use alternative salvage pathways to produce purines. The most common side effect of MMF is GI upset and diarrhea, which may improve in some cases with decreased dose or change to an enterically coated formulation of mycophenolic acid. A proton pump inhibitor is frequently used to prevent GI ulceration from MMF. Cellular immune machinery can also be targeted directly through the use of monoclonal and polyclonal antibodies. The polyclonal antibodies include antithymocyte globulin (Thymoglobulin, ATG) which is directed against multiple T-cell epitopes. These include CD 2, 3, 4, 8, 16, 28, and the T cell receptor. They exert their effects on natural killer cells and macrophages.
The oldest polyclonal antibody, ATG’s use has been augmented by the use of more specific monoclonal antibodies which may not lead to as many wide-reaching and long-lasting effects on the immune system. The monoclonal antibodies include the anti-T cell antibody OKT3 (muronomab), and anti IL-2 receptor antibodies daclizumab (Zenapax), and basiliximab (Simulect). OKT3 binds to the CD3 receptor thus inactivating the T cell receptor. Basiliximab and daclizumab bind to and block binding of IL-2 to the IL-2 receptors to inhibit antagonize T cell proliferation. Antibody preparations are used either to treat steroidrefractory rejection or to spare the use of steroids or calcineurin inhibitors. Induction with delayed calcineurin inhibitors are frequently used in patients with renal failure or coma peri-transplant. OKT3 and thymoglobulin are used primarily to treat acute cellular rejection, but are also used for induction. Daclizumab and basiliximab are usually used for induction in steroid-free or calcineurin-sparing protocols. Rapamycin is similar to tacrolimus in that it binds to FKBP12 and the response of T and B cell activation by cytokines. It also prevents cell-cycle progression and proliferation. Interestingly, rapamycin has a second binding site known as the TOR receptor (target of rapamycin). By blocking this receptor, rapamycin blocks progression of the cell cycle. Owing to the association of its use with hepatic artery thrombosis in two clinical studies, the US FDA has issued a black box warning against its use in liver transplant recipients. Other unique side effects of rapamycin include hyperlipidemia and impaired wound healing. Immunosuppression regimens can broadly be categorized as induction, maintenance, or anti-rejection regimens. Perioperatively, recipients usually receive bolus doses of steroids and begin calcineurin inhibitors once they are able to take oral medications. Oftentimes, monoclonal antibodies such as basiliximab or daclizumab are used in lieu of calcineurin inhibitors if the patient has shown signs of renal insufficiency prior to transplant in order to offset the nephrotoxic effects of these drugs. Since monoclonal antibodies may exert their effects for weeks, calcineurin inhibition can be delayed. Cell cycle inhibitors are also given during induction. By the time the patient is ready for discharge from an uncomplicated liver transplant (usually on the order of 1–2 weeks postoperatively), the patient is usually discharged on a maintenance regimen of a calcineurin inhibitor kept at relatively higher therapeutic levels, a steroid taper, with or without a cell cycle inhibitor. One
The Posttransplant Period
1375
Table 103.2 Effects of important drugs on cyclosporine and tacrolimus levels Increase Decrease Azole antifungals Macrolides Calcium channel blockers Amiodarone Protease inhibitors
Rifampin Carbamazepine Phenytoin Fosphenytoin Phenobarbital Rifabutin St. John’s Wort
must remain cognizant of the numerous interactions other medications may have with calcineurin inhibitors which may raise or lower calcineurin levels (Table 103.2). The treatment of acute cellular rejection is dependent on the patient’s reason for transplant. Usually a biopsy is undertaken if rejection is suspected to evaluate for other sources of abnormal liver chemistries such as recurrent viral hepatitis, ductular obstruction, or new viral infection from pathogens such as cytomegalovirus. Once rejection is established, the first line therapy is usually a steroid bolus and maximization of existing immunosuppression. If this regimen fails and a second biopsy still shows rejection, then one often moves on to the use of monoclonal antibody preparation such as Thymoglobulin or OKT3.
Rejection Graft loss due to acute cellular rejection is a rare occurrence due to the ability of aggressive treatment to treat rejection. While aggressive maintenance immunosuppressive regimens clearly have prevented acute cellular rejection and are responsible for long-term graft survival, their adverse effects can be difficult to manage. Acute cellular rejection biopsies are given a score (“Banff” score) indicating a combination of venous and bile duct damage and portal inflammation. This score determines the severity of the rejection episode (Table 29.10) [38].
incidence of 13.4% [34]. This number is significantly higher in patients receiving tacrolimus which has been reported to have an incidence of new onset diabetes mellitus associated with it use from 10.4% to 22.7% and is higher in HCV positive recipients than in patients without HCV [34, 84]. Cyclosporine therapy may increase insulin secretion in patients with a high pretransplant risk of new onset diabetes mellitus. Impaired pretransplant glucose tolerance and a body mass index greater than 25 were important risk factors for new onset diabetes mellitus [85]. Recipient age greater than 45 and high rates of steatosis in the allograft have also been correlated with the incidence of post transplant new onset diabetes mellitus [62]. The use of methylprednisolone boluses is clearly associated with impaired glucose tolerance and diabetes. One report estimated that each steroid bolus increases the risk for the development of diabetes mellitus by 9% [5]. Conversion to cyclosporine from tacrolimus improves glycemic control and reduces insulin requirement [23]. Among oral hypoglycemic agents, pioglitazone, rosiglitazone, and sulfonylureas have all been tried with success [54, 85]. Most patients are tapered to lower doses of steroids fairly quickly following transplant. Those patients who do develop diabetes mellitus are at increased risk for poor posttransplant outcomes. It is associated with a threefold increase in 10-year mortality, much of which is due to its association with infections [5]. Recipients with diabetes mellitus have increased rates of cardiovascular events, infections, and ophthalmologic complications [40]. A review of the United Network for Organ Sharing database revealed impaired 5-year patient and graft survival compared with controls. Type I diabetic patients had the most impaired survival post transplant [103]. Patients with the metabolic syndrome have evidence of increased insulin resistance, obesity, hypertension, and hyperlipidemia. More than half of patients post liver transplant have been reported to develop the metabolic syndrome. These patients have a more than threefold increased risk for vascular events and are 50% more likely to develop frank diabetes mellitus [47].
New Onset Diabetes Mellitus Following Transplant
Arterial Hypertension
New onset diabetes mellitus is common following transplant. It has been reported to occur with an
Occurring in more than half of patients following liver transplant, arterial hypertension is the most common
1376
103
Liver Transplantation: Indications, Preoperative Evaluation and Posttransplantation Management
cardiovascular complication following liver transplant [13, 32, 86]. Elevations in plasma endothelin-1 and increased arterial stiffness from various causes are thought to be important in the pathogenesis of posttransplant hypertension [64]. Hypertension is usually treated with calcium channel and beta- blockers posttransplant owing to concerns about enhancement of calcineurininduced nephrotoxicity with ACE inhibition.
obstruction. ERCP is only successful in 25% of patients in treatment of biliary casts [71]. Many patients will require retransplant. MRI has emerged as an important modality in diagnosing biliary obstruction and leaks following transplant. Using ERCP as a reference standard, one study showed that MRCP had a sensitivity and negative predictive value of 100% and a positive predictive value of 92.9% in detecting strictures [43].
Hyperlipidemia Vascular Complications Hyperlipidemia is also common following liver transplant. As many as 45% of patients will develop elevated serum lipid levels post-OLT [45, 69, 94]. Cyclosporine seems to preferentially dispose to hyperlipidemia and conversion to tacrolimus from cyclosporine has been shown to reduce hyperlipidemia [77].
Biliary Complications Biliary complications are identified in up to one quarter of patients, 45% of whom had strictures and 18% of whom had bile leaks in one series. Endoscopic therapy via endoscopic retrograde cholangiopancreatography (ERCP) was successful in most patients with strictures and virtually all patients with bile leaks [75]. Patients with anastomoses of the bile duct directly to a roux-limb of small bowel usually require percutaneous transhepatic cholangiography due to the difficulty of inserting an endoscope so deep into the bowel to find the anastomotic site for endoscopic retrograde cholangiography. However, a recent series showed that ERCP can be performed in selected patients with a roux limb by experienced endoscopists, though it depends on the length of the roux limb [15]. Bile leaks are easily identified on ERCP as 87% of patients have their leak site identified via this modality. Furthermore, these leaks can be treated in over 80% of patients. Bile duct obstruction relief via ERCP is slightly less successful with only 71% of patients achieved relief [71]. Bile duct cast syndrome is an uncommon entity whereby the small ducts of the transplanted liver fill with secretions and residue. This admixture hardens and forms cast-like structures, which can lead to
The most common vascular complication is hepatic artery thrombosis, which can be catastrophic in the early post-transplant period. Bile ducts are exquisitely sensitive to ischemia and derive all their blood supply from the arterial circulation immediately post-OLT. Hepatic artery thrombosis may lead to severe diffuse ischemia that can result in acute liver failure or biliary complications including leaks, biloma collections, subsequent infections, sepsis, or diffuse structuring and eventual graft failure. Hepatic artery thrombosis is usually diagnosed on Doppler ultrasound, which is frequently performed during the first few days following transplant. When identified, hepatic artery thrombosis can be repaired surgically or via vascular interventional radiology procedures with good results. It is key to identify this complication early. It occurs in 3–9% of transplants and acute graft loss is possible. One 10-year series showed that it occurred in 4.9% of patients. It was associated with Roux-en-y anastomosis, prolonged cold ischemia, operative time, use of blood products, retransplant, reoperation, and the use of aortic conduits [88].
Recurrent Disease The Achilles heel, so to speak, of the liver transplant enterprise has been recurrent disease, particularly recurrent hepatitis. Thanks to more aggressive prophylactic intervention and effective oral therapy, hepatitis B virus recurrence is prevented in the majority of patients. Recurrence of hepatitis C, however, continues to be a problem for the transplant hepatologist and is the leading cause of long-term graft loss.
The Posttransplant Period
1377
Recurrence of hepatitis C virus vexes the transplant physician. While recurrence of viremia is near universal, recurrence of clinically significant viral hepatitis is fortunately an occurrence in a minority of patients. Yet it is well established that the use of steroid boluses is associated with recurrence. For this reason, the immunosuppressive protocols of many institutions usually reserve steroid boluses as a second-line regimen after all other therapeutic changes such as maximizing current calcineurin levels or conversion to the other calcineurin (e.g. changing cyclosporine to tacrolimus) have been exhausted. Patients who develop recurrent HCV are particularly challenging to manage. Thus far, no effect prophylactic regimen is available to prevent recurrence of HCV. For those who do progress to clinically significant chronic hepatitis, treatment can be extremely difficult. Retransplantation is an option but patients retransplanted for recurrent HCV have high mortality postoperatively [2]. Some transplant programs will not retransplant patients for recurrence of HCV. A number of case series have shown some encouraging results with treatment of patients with pegylated interferon and ribavirin regimens following transplant (see Section 63.3 “Hepatitis C”). Concerns about precipitation of
Nosocomial infections
Viral HSV
acute cellular rejection, patient tolerance, and effectiveness in bringing about sustained virologic responses have hampered their widespread use.
Infection Posttransplantation infections can generally be broken down into three different periods, the immediate postoperative period (from hospital discharge through the first month), from the first through 6 months, and from 6 months onward (Fig. 103.2). Infections perioperatively generally are aggressive forms of the nosocomial and surgical infections common in patients who have had major procedures or who have been hospitalized for long periods of time. Infections over the next 5 months are generally opportunistic infections such as EBV, Cryptococcus, aspergillus, and CMV. Infections after 6 months are mostly community acquired or persistent infections such as urinary tract infections, human herpesvirus, influenza, and community acquired pneumonias [78]. Bacterial infection generally occurs in the immediate posttransplant period and is associated with nosocomial
Unconventional or opportunistic infections
Community-acquired or persistent infections
Onset of CMV EBV, HHV3, influenza, RSV, adenovirus
CMV-retinitis or colitis Papilleomavirus, PTLD
Onset of hepatitis B or hepatitis C Bacterial
Wound infections, catheter related infections, pneumonia Nocardia Listeriosis, tuberculosis
Fungal
Pneumocystis Aspergillus
Candida
Protozoal
Fig. 103.2 Posttransplantation infections according to time after transplantation (Source [81]; reproduced with permission)
0
Cryptococcus Geographically restricted, endemic fungi
Strongyloides Toxoplasma Leishmania Trypanosoma cruzi 1
2
3
4
5
6
Time after transplantation, months
1378
103
Liver Transplantation: Indications, Preoperative Evaluation and Posttransplantation Management
infections. A recent series showed that 62.7% of infections in the period from 1998 to 2003 were bacteremia. This represented a rapid increase from prior intervals. Interestingly, the proportion of bacteremias that were due to infections with gram positive organisms fell from 75% to 48.3% and the proportion due to infection with gram negative organisms rose from 25% to 51.8%. The most common pathogens in bacteremic patients were methicillin-resistant Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa [11, 89]. Cytomegalovirus (CMV) infection is a common cause of late posttransplant complications with a peak incidence at 6–7 weeks post-OLT. CMV is unique in that it can precipitate episodes of acute cellular rejection. It is thought to directly affect antigen and cytokine expression and its effects are protean including a flulike illness, vasculitis-like syndromes including pneumonitis, nephritis, colitis, and hepatitis, and predisposition to other opportunistic infections as well as rejection and graft dysfunction [28]. Fortunately, CMV does not affect overall patient survival. It occurred in one series in 65.8% of patients [36]. Interestingly, a decline in CMV infection was noted between 1998 and 2003 [89]. Since CMV usually is due to reactivation from the donor graft or the recipient, those at highest risk for CMV infection posttransplant are those patients who were CMV negative prior to transplant and received a CMV positive graft (“D + R-”). Those CMV negative recipients receiving CMV negative grafts (“D-R-”) are at lowest risk. Decisions about whether to perform surveillance for CMV with PCR and use preemptive treatment or to use selected or universal prophylaxis vary widely and are often based on the donor and recipient CMV status. As with other viral infections, risk factors for CMV infection include aggressive immunosuppression. In one study, patients on cyclosporine-based regimens and on three-drug (calcineurin, steroids, mycophenolate mofetil) were at increased risk for CMV [35]. Other risk factors for CMV infection within 3 months posttransplant include recipient CMV status, donor age, and recipient lymphocyte count [7]. Epstein–Barr virus is significant in that it is associated with an uncommon entity found in the posttransplant population known as posttransplant lymphoproliferative disorder (PTLD). This is a polyclonal or monoclonal lymphoid proliferation of rapid onset. It is more common in children who have received extensive rejection treatment, and is usually extranodal. One series found
its incidence in 22 of 621 transplant recipients [46]. The treatment is to minimize immunosuppression and use antiviral therapy to allow the immune system to clear EBV. Fungal infections can be catastrophic in liver transplant patients [70]. Fungal peritonitis is extremely difficult to sterilize and fungal pneumonia is associated with very poor outcomes. Systemic fungal infection, in particular aspergillosis is also difficult to clear. For these reasons, the question of antifungal prophylaxis had been considered. Some patients can be identified as low-risk for invasive fungal infections and routine posttransplantation antifungal prophylaxis is unnecessary. Candidiasis is a frequent cause of posttransplant fungal infection. Use of antibiotic prophylaxis against spontaneous bacterial peritonitis prior to transplant, posttransplant hemodialysis, and retransplantation all are predictive of invasive candidiasis. Candida albicans is the most frequent species followed by candida glabrata. Invasive candidiasis carries with it a mortality of greater than 30%. Non-albicans candida species and prior antifungal prophylaxis are associated with poorer outcomes [37]. Invasive aspergillus infections are usually fatal. Once aspergillus is established in the body enough to manifest itself clinically, it is usually impossible to eradicate. The aspergillus galactomannan test oftentimes is effective in detecting aspergillus infection prior to any clinical manifestations. One series of living donor liver transplant recipients identified risk factors for invasive aspergillosis including preoperative intensive care unit stays and preoperative steroid use [68].
Conclusion With adequate post-transplant care, 1-year survival postOLT can approach 90%. Impressive gains in surgical technique, immunosuppression, management of complications, and aggressive pretransplant care are first and foremost responsible for good outcomes following a liver transplant. Appreciation of the full spectrum of patient care includes attention to the patient’s psychosocial needs and general health. Rigorous screening of patients pretransplant allows for the selection of those patients who will benefit most from a liver transplant. Finally, new mathematical models for patient survival
References
pretransplant are altering organ allocation systems worldwide and allow for organs to be transplanted into those patients who will derive the greatest survival benefit from receiving a liver transplant.
References 1. Abt PL, Mange KC, Olthoff KM, et al (2004) Allograft survival following adult-to-adult living donor liver transplantation. Am J Transplant 4: 1302–7 2. Alamo JM, Gomez MA, Preja F, et al (2006) Morbidity and mortality in liver retransplantation. Transplant Proc 38: 2475–7 3. Anderson RD, Chimakotia S, Guo K, et al (2007) Intramuscular hepatitis B immunoglobulin (HBIG) and nucleosides for prevention of recurrent hepatitis B following liver transplantation. Clin Transplant 21: 510–7 4. Arguedas MR, Abrams GA, Krowka MJ, et al (2003) Prospective evaluation of outcomes and predictors of mortality in patients with hepatopulmonary syndrome undergoing liver transplantation. Hepatology 37: 192–7 5. Baid S, Cosimi AB, Farrell MC, et al (2001) Posttransplant diabetes mellitus in liver transplant recipients. Transplantation 72: 1066–72 6. Baltz AC, Trotter JF (2003) Living donor liver transplantation and hepatitis C. Clin Liver Dis 7: 651–5 7. Basse G, Esposito L, Mengelle C, et al (2006) Predictive factors for cytomegalovirus infection after OLT using an ultrasensitive polymerase chain reaction. Transpl Proc 38: 2839–41 8. Bellamy CO, DiMartini AM, Ruppert K, et al (2001) Liver transplantation for alcoholic cirrhosis. Transplantation 72: 619–26 9. Berg CL, Gillespie BW, Merion RM, et al (2007) Improvement in survival associated with adult-to-adult living donor liver transplantation. Gastroenterology 133: 1806–13 10. Bismuth H, Majno PE, Adam R (1999) Liver transplantation for hepatocellular carcinoma. Semin Liver Dis 19: 311–22 11. Blair JE, Kusne S (2005) Bacterial, mycobacterial, and protozoal infections after liver transplantation-part I. Liver Transpl 11: 1452–9 12. Brown RS, Lake JR (2005) The survival impact of liver transplantation in the MELD era, and the future for organ allocation and distribution. Am J Transpl 5: 203–4 13. Canzanello VI, Textor SC Taler SJ, et al (1998). Late hypertension after liver transplantation. Liver Transpl Surg 4: 328–34 14. Carithers RL Jr (2000) Liver transplantation. Liver Transpl 6: 122–35 15. Chahal P, Baron TH, Poterucha JJ, et al (2007) Endoscopic retrograde cholangiography in post-orthotopic liver transplant population with roux-en-y biliary reconstruction. Liver Transpl 13: 1168–73 16. Charlton M, Seaberg E, Wiesner R, et al (1998) Predictors of patient and graft survival following liver transplantation for hepatitis C. Hepatology 28: 823–30
1379 17. Charlton M, Ruppert K, Belle SH, et al (2004) Long-term results and modeling to predict outcomes in recipients with HCV infection. Liver Transpl 10: 1120–30 18. Colle IO, Moreau R, Godinho E, et al (2003) Diagnosis of portopulmonary hypertension in candidates for liver transplantation. Hepatology 37: 401–9 19. D’Alessandro AM, Ploeg RJ, Knechtle SJ, et al (1993) Retransplantation of the liver – a seven-year experience. Transplantation 55: 1083–7 20. Deminclean, Noureddine, Vigos, et al (1964) Tentative d’homogreffe hepatique. Mem Acad Chir 90: 177 21. Desai NM, Mange KC, Crawford MD, et al (2004) Predicting outcome after liver transplantation. Transplantation 77: 99–106 22. Dickson RG, Terrault NA, Ishitani M, et al (2006) Protective antibody levels and dose requirements for IV5% Nabi hepatitis immune globulin combined with lamivudine in liver transplantation for hepatitis B induced end stage liver disease. Liver Transpl 12: 124–33 23. Dumortier J, Bernard S, Bouffard Y, et al (2006) Conversion from tacrolimus to cyclosporine in liver transplanted patients with diabetes mellitus. Liver Transpl 12: 659–64 24. Everhart JE, Beresford TP (1997) Liver transplantation for alcoholic liver disease. Liver Transpl Surg 3: 220–6 25. Everson GT, Trotter J, Forman L, et al (2005) Treatment of advanced hepatitis C with a low accelerating dosage regimen of antiviral therapy. Hepatology 42: 255–62 26. Figueras J, Ibanez L, Ramos E, et al (2001) Selection criteria for liver transplantation in early-stage hepatocellular carcinoma with cirrhosis. Liver Transpl 7: 877–83 27. Fisher RA, Kulik LM, Freise CE, et al (2007) Hepatocellular carcinoma recurrence and death following living and deceased donor liver transplantation. Am J Transpl 7: 1601–8 28. Fishman JA, Emery V, Freeman R, et al (2007). Cytomegalovirus in transplantation -challenging the status quo. Clin Transpl 21: 149–58 29. Freeman RB (2003) The impact of the model for end-stage liver disease on recipient selection for adult living donor liver donation. Liver Transpl 9: S54–S59 30. Freeman RB, Wiesner RH, Edwards E, et al (2004) Results of the first year of the new liver allocation plan. Liver Transpl 10: 7–15 31. Fung J, Eghtesad B, Patel-Tom K, et al (2004) Liver transplantation in patients with HIV infection. Liver Transpl 10: S39–53 32. Guchelberger O, Bechstein WO, Neuhaus R, et al (1997) Cardiovascular risk factors in long-term follow-up after orthotopic liver transplantation. Clin Transpl 11: 60–5 33. Heimbach JK, Haddock MG, Alberts SR, et al (2004) Transplantation for hilar cholangiocarcinoma. Liver Transpl 10: S65–8 34. Heisel O, Heisel R, Balshaw R, et al (2004) New onset diabetes mellitus in patients receiving calcineurin inhibitors. Am J Transpl 4: 583–95 35. Hoppe L, Marroni CA, Bressane R, et al (2006) Risk factors associated with cytomegalovirus infection in orthotopic liver transplant patients. Transpl Proc 38: 1922–3 36. Hopper C, Marroni CA, Bressare R, et al (2006) Impact of cytomegalovirus infection on long-term survival after orthotopic liver transplantation. Transpl Proc 38: 1924–5
1380
103
Liver Transplantation: Indications, Preoperative Evaluation and Posttransplantation Management
37. Husain S, Tollemar J, Dominguez EA, et al (2003) Changes in the spectrum and risk factors for invasive candidiasis in liver transplant recipients. Transplantation 75: 2023–9 38. International Panel (1997) Banff schema for grading liver allograft rejection. Hepatology 25: 658–63 39. Iwesaki Y, Porter KA, Arend JR, et al (1967) The preparation and testing of horse antidog and antihuman antilymphoid plasma on serum and its protein factors. Surg Gynecol Obstet 124: 1–24 40. John PR, Thuluvath PJ (2001) Outcome of liver transplantation in patients with diabetes mellitus. Hepatology 34: 889–95 41. Jonas S, Bechstein WO, Steinmuller T, et al (2001) Vascular invasion and histopathologic grading to determine outcome after liver transplantation for hepatocellular carcinoma in cirrhosis. Hepatology 33: 1080–6 42. Kamath PS, Wiesner RH, Malinchoc M, et al (2001) A model to predict survival in patients with end-stage liver disease. Hepatology 33: 464–70 43. Kitazano MT, Qayyum A, Yeh BM, et al (2007) Magnetic resonance cholangiography of biliary structures after liver transplantation. J Magn Reson Imaging 25: 1168–73 44. Klintmalm GB (1998) Liver transplantation for hepatocellular carcinoma. Ann Surg 228: 479–90 45. Kobashigawa JA, Khasiske BL (1997) Hyperlipidemia in solid organ transplantation. Transplantation 66: 331–8 46. Koch DG, Christiansen L, Lazarchick J, et al (2007) Posttransplantation lymphoproliferative disorder – the great mimic in liver transplantation. Liver Transpl 13: 904–12 47. Laryea M, Watt KD, Molinari M, et al (2007) Metabolic syndrome and liver transplant recipients. Liver Transpl 13: 1104–14 48. Lim JK, Keefe EB (2004) Liver transplantation for alcoholic liver disease. Liver Transpl 10: S31–8 49. Liu CL, Lam B, Lo CM (2003) Impact of right-lobe live donor liver transplantation on patients waiting for liver transplantation. Liver Transpl 9: 863–9 50. Llovet JM, Fuster J, Bruix J, et al (1999) Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma. Hepatology 30: 1434–40 51. Lo CM, Fan S, Liu C, et al (2004) The role and limitation of living donor liver transplantation for hepatocellular carcinoma. Liver Transpl 10: 440–7 52. Longheval G, Vereerstraeten P, Thiry P (2003) Predictive models of short- and long-term survival in patients with survival in patients with nonbiliary cirrhosis. Liver Transpl 9: 260–7 53. Lucey MR, Brown KA, Everson GT, et al (1997) Minimal criteria for placement of adults on the liver transplant waiting list. Liver Transpl Surg 3: 628–37 54. Luther P, Baldwin Jr. P (2004) Pioglitazone in the management of diabetes mellitus after transplantation. Am J Transpl 4: 2135–8 55. Macedo G, Lopes S, Barroso S, et al (2003) Implementation of screening and preventive strategies in liver transplant candidates [Abstract]. Transpl Proc 35: 115 56. Mandell MS (2004) Hepatopulmonary syndrome and portopulmonary hypertension in the model for end-stage liver disease (MELD) era. Liver Transpl 10: S54–8 57. Marcos A, Fisher RA, Ham JM, et al (2000) Liver regeneration and function in donor and recipient right lobe adult living donor liver transplantation. Transplantation 69: 1375–9
58. Mazzaferro V, Regalia E, Doci R, et al (1996) Liver transplantation for hepatocellular carcinoma in patients with cirrhosis. N Engl J Med 334: 693–9 59. McDiarmid SV, Anand R, Lindblad AS, et al (2002) Development of a pediatric end-stage liver disease score to predict poor outcome in children awaiting liver transplantation. Transplantation 74: 173–81 60. Merion RM, Schaubel DE, Dykstra DM, et al (2005) The survival benefit of liver transplantation. Am J Transpl 5: 307–13 61. Merion RM, Wolfe RA, Dykstra DM, et al (2003) Longitudinal assessment of mortality risk among candidates for liver transplantation. Liver Transpl 9: 12–8 62. Mirabella S, Brunati A, Ricchiuti A, et al (2005) New-onset diabetes after liver transplantation. Transpl Proc 37: 2636–7 63. Moore FD, Birtch AG, Dagher F, et al (1964) Immunosuppression and liver transplantation. Ann NY Acad Sci 120: 729–38 64. Neal DA, Brown MJ, Wilkinson IB, et al (2005) Mechanisms of hypertension after liver transplantation. Transplantation 79: 935–40 65. Neuberger J, Schulz KH, Day C, et al (2002) Treatment for alcoholic liver disease. J Hepatol 36: 130–7 66. O’Grady J, Alexander GJ, Hayllar KM, et al (1989) Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 97: 439–45 67. Olthoff KM, Brown RS, Delmonico FL, et al (2004) Summary report of a national conference: evolving concepts in liver allocation in the MELD and PELD era. Liver Transpl 10: A6–22 68. Osawa M, Ito Y, Hirai T, et al (2007) Risk factors for invasive aspergillosis in living donor liver transplant recipients. Liver Transpl 13: 566–70 69. Palumbo JD, Lopes SM, Zeisel SH, et al (1987) Effectiveness of orthotopic liver transplantation on the restoration of cholesterol metabolism in patients with end-stage liver disease. Gastroenterology 93: 1170–7 70. Pappas PG, Andes D, Schuster M, et al (2006) Invasive fungal infections in low-risk liver transplant recipients. Am J Transpl 6: 386–91 71. Pfau PR, Kochman ML, Lewis JD, et al (2000) Endoscopic management of postoperative liver transplantation. Gastrointest Endosc 52: 55–63 72. Pugh RNH, Murray-Lion IM, Dawson JC, et al (1979) Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 60: 640–6 73. Ragni M, Belle SH, Im KA, et al (2003) Survival of human immunodeficiency virus-infected liver transplant recipients. J Infect Dis 188: 1412–20 74. Rea DJ, Heimbach JK, Rosen CB, et al (2005) Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg 242: 451–8 75. Rerknimitr R, Sherman S, Fogel EL, et al (2002) Biliary tract complications after orthotopic liver transplantation with choledochocholedochostomy anastomosis. Gastrointest Endosc 55: 224–31 76. Rocca P, Cocuzza E, Rasetti R, et al (2003) Predictors of psychiatric disorders in liver transplantation candidates. Liver Transpl 9: 721–6
References 77. Roy A, Kneteman N, Lilly L, et al (2006) Tacrolimus as intervention in the treatment of hyperlipidemia after liver transplant. Transplantation 82: 494–500 78. Rubin RH, Wolfson JS, Cosimi AB, et al (1981) Infection in the renal transplant recipient. Am J Med 70: 405–11 79. Russo MW, Galanko J, Beavers K, et al (2004) Patient and graft survival in hepatitis C recipients after adult living donor liver transplantation in the United States. Liver Transpl 10: 340–6 80. Russo MW, LaPointe-Rudow D, Kinkhabwala M, et al (2004) Impact of adult living donor liver transplantation on waiting time survival in candidates listed for liver transplantation. Am J Transpl 4: 427–31 81. Safdar K, Neff GW, Montalbano M, et al (2004) Liver transplant for the septuagenarians. Transpl Proc 36: 1445–8 82. Sala M, Fuster J, Llovet JM, et al (2004) High pathological risk of recurrence after surgical resection for hepatocellular carcinoma. Liver Transpl 10:1294–300 83. Sala M, Varela M, Bruix J (2004) Selection of candidates with hepatocellular carcinoma in the MELD era. Liver Transpl 10: S4–9 84. Saliba F, Lakehalm M, Pageaux GP, et al (2007) Risk factors for new-onset diabetes mellitus following liver transplantation and impact of hepatitis c virus infection. Liver Transpl 13: 136–44 85. Sato T, Inagaki A, Uchida K, et al (2003) Diabetes mellitus after transplant. Transplantation 76: 1320–6 86. Sheiner PA, Magliocca JF, Bodian CA, et al (2000) Longterm medical complications in patients surviving ≥ five years after liver transplant. Transplantation 69: 781–9 87. Shimoda M, Farmer DG, Colquhoun SD, et al (2001) Liver transplantation for cholangiocellular carcinoma. Liver Transpl 7: 1023–33 88. Silva MA, Jambulingam PS, Gunson BK, et al (2006) Hepatic artery thrombosis following orthotopic liver transplant. Liver Transpl 12: 146–151 89. Singh N, Wagener MM, Obman A, et al (2004) Bacteremias in liver transplant recipients. Liver Transpl 10: 844–9 90. Starzl TE, Marchioro TL, Vonkaulla KN, et al (1963) Homotransplantation of the liver in humans. Surg Gynecol Obstet 117: 659–76 91. Starzl TE, Marchioro TL, Rowldand DT, et al (1964) Immunosuppression after experimental and clinical homotransplantation of the liver. Ann Surg 160: 411–39
1381 92. Starzl TE, Machioro TL, Porter KA, et al (1967) The use of heterologous antilymphoid agents in canine and in human renal homotransplantations. Surg Gynecol Obstet 124: 301–8 93. Starzl TE, Murase M, Marcos M, et al (2005) History of liver and multivisceral transplantation. In: Bussuttil RW, Klintmalm GK (eds) Transplantation of the Liver. Elsevier Sanders, Philadelphia, PA 94. Steagall MD, Everson G, Schroter G, et al (1995) Metabolic complications after liver transplantation. Transplantation 60: 1057–60 95. Trotter JF (2000) Selection of donors and recipients for living donor liver transplantation. Liver Transpl 6: S52–8 96. Trotter JF, Wachs M, Trouillot T, et al (2000) Evaluation of 100 patients for living donor liver transplantation. Liver Transpl 6: 290–5 97. UNOS Policy 3 Appendix 3B http://www.unos.org/ PoliciesandBylaws/policies/docs/policy_15.doc 98. Veldt BJ, Lainé F, Guillygomarc’h A, et al (2002) Indications of liver transplantation in severe alcoholic liver cirrhosis. J Hepatol 36: 93–8 99. Venook AP, Ferrell LD, Roberts JP (1995) Liver transplantation for hepatocellular carcinoma. Liver Transpl Surg 4: 242–8 100. Wiesner RM, McDiarmid SV, Kamath PS, et al (2001) Application of MELD and PELD to liver allocation. Liver Transpl 7: 567–80 101. Yao FY, Ferrell L, Bass NM, et al (2001) Liver transplantation for hepatocellular carcinoma. Hepatology 33: 1394–403 102. Yoo HY, Galabova V, Edwin D, et al (2002) Socioeconomic status does not affect the outcome of liver transplantation. Liver Transpl 8: 1133–7 103. Yoo HY, Thuluvath PJ (2002) The effect of insulin-dependent diabetes mellitus on outcome of liver transplantation. Transplantation 74: 1007–12 104. Yoshida EM, Erb SR, Partovi N, et al (1999) Liver transplantation for chronic hepatitis B infection with the use of combination lamivuudine and low-dose hepatitis B immune globulin. Liver Transpl Surg 5: 520–5 105. Zheng S, Chen Y, Liang T, et al (2006) Prevention of hepatitis B recurrence after liver transplantation using lamivudine or lamivudine combined with hepatitis B immunoglobulin prophylaxis. Liver Transpl 12: 253–8
Risk of Surgery in Patients with Liver Disease
104
Patrick S. Yachimski and Lawrence S. Friedman
Chapter Outline Effects of Surgery on the Liver ................................... 1383 Liver Biochemical Tests................................................. 1383 Hepatic Blood Flow and Hemodynamic Effects............ 1384 Hypoxemia ..................................................................... 1384 Hepatic Metabolism of Anesthetic Agents .................... 1385 Operative Risk in Patients with Liver Disease .......... 1385 Challenges in Estimating Operative Risk ...................... 1385 Preoperative Screening .................................................. 1386 Conditions for Which Elective Surgery is Contraindicated .......................................................... 1387 Surgery in Patients with Chronic Liver Disease ............ 1388 Perioperative Care ....................................................... 1394 Coagulopathy ................................................................. 1394 Ascites ............................................................................ 1395 Renal Dysfunction ......................................................... 1395 Encephalopathy .............................................................. 1395 Nutrition ......................................................................... 1396 Postoperative Monitoring ............................................ 1396 References ..................................................................... 1396
Patients with liver disease may face increased risk when undergoing surgical procedures. Appropriate care of these patients includes preoperative assessment and identification of those at increased risk, optimization of medical therapy for liver disease before surgery, and postoperative management of manifestations of decompensated liver disease. The magnitude of risk for an individual patient is a function of both the severity of the underlying liver disease and the nature of the surgical procedure. In addition, perioperative factors, including hemodynamic perturbations during surgery and use of systemic anesthetic or sedative medications, can have pronounced physiologic effects in patients with compromised hepatic function. This chapter outlines an approach to the assessment and management of patients with liver disease preparing for surgery and reviews methods of risk stratification. Liver transplantation is not a subject of this chapter and is addressed elsewhere in the textbook (see Chapter 103).
Effects of Surgery on the Liver Liver Biochemical Tests Minor elevations in serum aminotransferase, bilirubin, and/or alkaline phosphatase levels occur commonly following surgical procedures [25, 30]. For instance, in a series of patients undergoing laparoscopic cholecystectomy and in whom preoperative liver biochemical test results were normal, elevation of aminotransferase levels to approximately two times normal was detected in more than 70% of patients postoperatively [35].
H. Dancygier, Clinical Hepatology, DOI: 10.1007/978-3-642-04519-6_104, © Springer-Verlag Berlin Heidelberg 2010
1383
1384
Such elevations are typically transient, are not indicative of hepatic dysfunction, and therefore are of negligible significance. Higher aminotransferase elevations (aspartate aminotransferase [AST] and alanine aminotransferase [ALT] levels ≥3 times normal) in the postoperative setting are suggestive of hepatic injury, in many cases resulting from ischemia. In patients with known underlying liver disease, postoperative liver biochemical test elevations may be clinically significant and merit careful attention. For example, marked hyperbilirubinemia may be indicative of hepatic decompensation and should prompt evaluation for encephalopathy, coagulopathy, and other manifestations of decompensated disease.
Hepatic Blood Flow and Hemodynamic Effects The liver has a dual afferent blood supply consisting of portal venous and hepatic arterial blood flow. Perfusion from either of these sources may be compromised in patients with cirrhosis and portal hypertension, because of portal venous hypertension and impaired arterial autoregulation. Moreover, patients with cirrhosis may have alterations in the systemic circulation, due to arteriovenous shunting, and reduced splanchnic inflow. As a consequence of these circulatory derangements, the liver is particularly susceptible to ischemia in patients with cirrhosis and portal hypertension (see Chapter 62). Ischemic insults may be the result of frank episodes of hypoperfusion, such as systemic hypotension in the setting of hemorrhage or sepsis. Other insults may be more subtle. For example, positive pressure mechanical ventilation and surgical techniques such as pneumoperitoneum during laparoscopic surgery [72] or traction on abdominal viscera may cause alterations in hepatic perfusion. In addition, administration of most volatile anesthetic agents results in decreased hepatic blood flow [29]. This is particularly the case with halothane and enflurane, which exert a negative inotropic effect and reduce systemic vascular resistance [7, 63]. Animal data suggest that isoflurane causes relatively less perturbation in hepatic arterial blood flow [29], and this agent is often preferred for patients with liver disease. Desflurane and sevoflurane are similarly thought to have little effect on hepatic arterial blood flow.
104
Risk of Surgery in Patients with Liver Disease
Hypoxemia Pulse oximetry may demonstrate low oxygen saturation in approximately 20% of patients awaiting liver transplantation [58]. The overall prevalence of hypoxemia in patients with liver disease cannot be estimated precisely, however, because pulse oximetry may overestimate arterial oxygen tension in patients with cirrhosis [1]. Nonetheless, among the population of patients with liver disease awaiting general surgical procedures, the potential for significant intraoperative hypoxemia may be anticipated in those with specific manifestations of decompensated disease (Table 104.1). For instance, pulmonary mechanics may be compromised by the presence of either ascites or hepatic hydrothorax, which may impede mechanical ventilation. Ascites, encephalopathy, and the use of sedative anesthetics all may contribute to an increased risk of perioperative aspiration. Hepatopulmonary syndrome is characterized by liver disease and an increased alveolar-arterial gradient in the presence of an intrapulmonary shunt caused by dilated ateriovenous communications (see Chapter 80). Clinical clues to hepatopulmonary syndrome include platypnea (increased dyspnea in the upright posture) and orthodeoxia (oxygen desaturation in the upright posture). A substantial rate of early postoperative mortality due to cardiopulmonary complications has been reported in patients with hepatopulmonary syndrome undergoing liver transplantation [5]. Elective surgery should be avoided in patients with hepatopulmonary syndrome. Portopulmonary hypertension describes pulmonary hypertension in the presence of advanced liver disease (see Chapter 80) and may be suspected on the basis of echocardiographic findings, although right heart catheterization may be required for precise estimates of pulmonary arterial pressures [17, 45]. Severe pulmonary hypertension refractory to medical therapy is associated with a high operative mortality rate in patients
Table 104.1 Causes of hypoxemia in patients with liver disease Hepatopulmonary syndrome Portopulmonary hypertension Moderate or severe ascites Hepatic hydrothorax Aspiration Comorbid illness (e.g., chronic obstructive pulmonary disease)
Operative Risk in Patients with Liver Disease
undergoing liver transplantation [47] and is therefore a contraindication to transplant listing. Although published data regarding surgery in patients with portopulmonary hypertension are limited, pulmonary hypertension of any etiology has been shown to correlate with postoperative mortality among patients undergoing noncardiac surgical procedures [49], and patients with portopulmonary hypertension should be considered to be at high (if not prohibitive) surgical risk.
Hepatic Metabolism of Anesthetic Agents Genetic polymorphisms of cytochrome P450 2E1 have been implicated in occasional episodes of fulminant hepatitis following halothane exposure [44], and halothane is now used rarely in adults (see Chapter 93). Beyond this notable exception, however, there are few data to suggest that either the choice of anesthetic agent or mode of administration (inhaled or spinal) influences outcome in patients with liver disease [64, 91]. One study of patients undergoing coronary artery bypass surgery reported a higher frequency of postoperative serum aminotransferase elevations among patients receiving propofol compared with sevoflurane anesthesia, but the difference was likely of no clinical or physiologic significance [53]. In fact, although propofol is metabolized by hepatic glucuronidation, its serum half-life remains relatively short even in patients with cirrhosis and it is an effective and appropriate anesthetic agent in patients with liver disease [77]. Alterations in the action of neuromuscular blocking agents used in induction of anesthesia may be more pronounced among patients with liver disease. Particularly for agents with an expanded volume of distribution, such as vecuronium and rocuronium, the onset of and recovery from anesthesia may be prolonged [43,50]. Atracurium and cisatracurium are considered the preferred muscle relaxants in patients with liver disease because neither the liver nor the kidney is required for their elimination. Further, the duration of neuromuscular blockade produced by atracurium is not affected by decreased levels of plasma cholinesterase, which is synthesized by the liver. Doxacurium, which is eliminated primarily by the kidney, is preferred for prolonged procedures such as liver transplantation.
1385
Operative Risk in Patients with Liver Disease Challenges in Estimating Operative Risk In a retrospective study of 733 cirrhotic patients undergoing surgery at the Mayo Clinic between 1980 and 1991, the 30-day operative mortality rate was 11.6%, and the overall complication rate was 30% [92]. These figures encompass patients undergoing a broad range of surgical procedures, from excision of skin lesions to laparotomy, surgery on the thoracic cavity, or intracranial surgery. In addition to the severity of liver disease (see later), morbidity and mortality in this cohort was associated with indicators of comorbid illness, including chronic obstructive pulmonary disease, perioperative infection, and American Society of Anesthesiologists (ASA) class (Table 104.2) [92]. Such variables may be predictive of risk in patients without liver disease and may be applicable in any global assessment of fitness for surgery. The particular challenge in assessing operative risk among patients with liver disease is to identify patients at risk and characterize the risk with use of a prediction algorithm. This process begins with recognition of the presence of liver disease, followed by grading of the severity of liver disease with attention to specific manifestations of decompensated disease. Both the Child-Turcotte-Pugh (CTP) score (Child class) and Model-for-Endstage-Liver-Disease (MELD) score have been applied as a means of discriminating low-risk from high-risk patients (see Chapters 79 and 103). The majority of published studies describing operative risk in patients with liver disease derive from Table 104.2 American Society of Anesthesiologists (ASA) classification Class I II III IV V E
Healthy patient Patient with mild systemic disease without functional limitation Patient with severe systemic disease with functional limitation Patient with severe systemic disease that is a constant threat to life Moribund patient not expected to survive >24 h with or without surgery Emergent nature of surgery (added to classification I–V as above)
1386
104
Table 104.3 Operative mortality in patients with cirrhosis Author, year N Type of surgery (Reference)
Overall mortality ratea
Mortality rate stratified by Child class or MELD score
30%
Child A: 10% Child B: 31% Child C: 76% Child A: 10% Child B: 30% Child C: 82% Child A: 3% Child B: 41% Child C: 100% MELD 1.5 times the upper limit of normal on at least two occasions), elective surgery may need to be delayed so that further investigation can be undertaken, including biochemical and serologic testing for viral hepatitis, autoimmune liver disease, and metabolic disorders. Abdominal ultrasonography or magnetic resonance cholangiopancreatography may be considered when there is suspicion of cholestasis or biliary obstruction (Table 104.4). Abdominal computed tomography or magnetic resonance imaging may reveal a liver size and contour suggestive of cirrhosis or may detect intraabdominal varices and splenomegaly compatible with portal hypertension. However, abdominal imaging cannot reliably identify hepatic fibrosis or cirrhosis. If establishing the presence or absence of cirrhosis is essential for operative planning or predicting surgical risk, or in
Table 104.4 Evaluation of liver biochemical abnormalities based on predominant pattern: noninvasive testing options Hepatocellular pattern (elevated serum aminotransferase levels) Hepatitis B surface antigen and antibody Hepatitis C antibody Serum iron studies (iron, ferritin, total iron binding capacity) Celiac sprue serology (tissue transglutaminase antibody) Antinuclear antibody Serum ceruloplasmin level Serum alpha-1 antitrypsin level Abdominal ultrasound Cholestatic pattern (elevated serum alkaline phosphatase and/or bilirubin levels) Antimitochondrial antibody Abdominal ultrasound Magnetic resonance cholangiopancreatography
1387
instances when noninvasive evaluation fails to reveal the specific cause of abnormal liver biochemical test results, a liver biopsy may be necessary.
Conditions for Which Elective Surgery is Contraindicated Acute Hepatitis Acute hepatitis may be caused by viral infection, autoimmune or genetic disorders, or toxin-mediated injury (including prescription medications, over-the-counter medications such as acetaminophen, herbal supplements, and alcohol [see next section]) (see Chapter 49). The diagnosis of acute hepatitis can be made and the etiology determined in almost all instances through noninvasive means such as a history, physical examination, and serologic testing. Patients with acute hepatitis are thought to have an increased operative risk, particularly for abdominal surgical procedures [30]. This conclusion comes from studies reported in 1958 and 1963, describing operative mortality rates of 9.5–13% in patients with acute hepatitis [39,80]. In the former series, 42 patients with viral hepatitis and 16 patients with drug-induced hepatitis were identified retrospectively over a 12-year period. In the majority of instances, exploratory laparotomy had been performed for suspected extrahepatic biliary obstruction, and the operative mortality rate among those discovered to have viral hepatitis was 9.5% [80]. Although the diagnosis of acute viral hepatitis as well as surgical techniques have evolved since these studies were published, the standard recommendation remains that elective surgery should be deferred in patients with acute hepatitis. This recommendation is particularly appropriate when considering that most cases of acute hepatitis are self-limited and improve clinically and biochemically with supportive care.
Acute Alcoholic Hepatitis Acute alcoholic hepatitis occurs when excessive alcohol consumption leads to necroinflammatory changes in the liver, including hepatocyte swelling, an inflammatory infiltrate, and hepatocyte necrosis (see
1388
Chapter 88). Presenting symptoms may include jaundice, fever, and hepatomegaly. Some patients present with manifestations of decompensated hepatic disease, including ascites, encephalopathy, and gastrointestinal bleeding. The 30-day mortality rate may exceed 50% for patients with severe acute alcoholic hepatitis. Acute alcoholic hepatitis must be distinguished from acute cholecystitis. Fever, right upper quadrant tenderness, and leukocytosis can be present in both diseases, but the pronounced jaundice and hyperbilirubinemia seen in alcoholic hepatitis are uncommon in cases of cholecystitis. Laparotomy performed in a patient with unsuspected or undiagnosed acute alcoholic hepatitis may have serious consequences, as is underscored by data from a retrospective series of patients with alcoholic hepatitis who underwent either open or percutaneous liver biopsy [32]. The mortality rate was 58% among the 12 patients who underwent open biopsy, compared with 10% among the 39 patients who underwent percutaneous biopsy. Because liver biopsy was performed in addition to a second surgical procedure during exploratory laparotomy in 9 of the 12 patients, and only one death in this group was clearly related to intraabdominal hemorrhage, laparotomy itself, rather than liver biopsy, appears to have been responsible for the high mortality rate in this group [32]. Acute alcoholic hepatitis is a contraindication to elective surgery. Abstinence from alcohol for 6–12 weeks generally results in resolution of hepatic inflammation and hyperbilirubinemia. Occasionally, however, alcoholic hepatitis may persist for months despite prolonged abstinence from alcohol. We recommend a 12-week delay, as well as a thorough reassessment of hepatic function, before elective surgery following a diagnosis of acute alcoholic hepatitis.
Acute Liver Failure Acute liver failure describes acute liver injury with the development of coagulopathy and hepatic encephalopathy within 26 weeks of the onset of illness in a patient without known preexisting liver disease (see Chapter 78). Patients are severely ill and have a grave prognosis without liver transplantation. They are therefore unlikely to survive any surgical procedure other than liver transplantation.
104
Risk of Surgery in Patients with Liver Disease
Surgery in Patients with Chronic Liver Disease Chronic Viral Hepatitis Chronic hepatitis is characterized by liver inflammation of greater than 6 months’ duration. The differential diagnosis includes viral, autoimmune, and genetic disorders. The most common cause is viral hepatitis caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) infection (see Chapter 63). Chronic hepatitis may be asymptomatic without obvious physical findings and may persist for decades. Diagnosis is often based on the detection of persistently elevated aminotransferase levels. Liver biopsy is often indicated to identify the presence and extent of hepatic fibrosis. Literature before the identification of HCV suggested that the risk of surgery is increased in patients with chronic hepatitis. A report from 1970 described two patients (both female and in their teens with hepatomegaly and jaundice of 3–4 months’ duration who might be considered cases of acute hepatitis or acute liver failure by current criteria) who underwent exploratory laparotomy and died postoperatively, at 18 and 27 days respectively, of hepatic coma [38]. However, in the absence of hepatic fibrosis or cirrhosis, there are no compelling data to suggest that surgical risk is increased in patients with chronic viral hepatitis. A study of nearly 2,500 patients in a Veterans Affairs cohort who underwent surgery over a 5-year period reported a mortality rate of 0.7% in HCV-seropositive patients, as compared with a mortality rate of 2.5% in HCVseronegative patients [15]. Patients in the HCV seropositive group were younger, had a lower mean ASA class, and had a shorter mean duration of surgery than patients in the HCV-seronegative group. Each factor predicted mortality in a multivariate analysis, and HCV serostatus was not significantly associated with mortality. Similarly, there was no observed difference in complication rates between the two groups [15]. Postoperative liver biochemical test abnormalities can be expected in patients with chronic viral hepatitis. In a series of patients undergoing laparotomy, HCVseropositive patients had higher mean postoperative serum AST and alkaline phosphatase elevations than matched HCV-uninfected controls [61]. However, resolution of these changes and correlation with any adverse outcome were not described in this study, and it is
Operative Risk in Patients with Liver Disease
uncertain whether these liver biochemical abnormalities were of any clinical significance [61]. Similarly, patients with chronic HBV infection but without significant hepatic necroinflammatory activity or fibrosis should face no increase in operative risk. Patients with chronic viral hepatitis may require long-term antiviral therapy. Nucleoside/nucleotide analog therapy for chronic HBV should not be interrupted in the perioperative period; hepatitis flares may follow cessation of therapy, and interruption of treatment may raise concerns about viral resistance when therapy is resumed. Patients receiving therapy for HCV may experience myelosuppression due to peginterferon and hemolytic anemia due to ribavirin. Leukopenia, when present, may contribute to functional immunosuppression. Treatment-induced thrombocytopenia, if severe, may contribute to operative bleeding. In general, however, peginterferon and ribavirin therapy should not be discontinued without consulting the patient’s treating gastroenterologist or hepatologist.
1389
Some investigators have suggested modification of the length of the Roux limb, from a distal to a more proximal Roux-en-Y gastric bypass, when cirrhosis is found on an intraoperative frozen section of the liver [78]. Patients with NASH who achieve weight loss following successful bariatric surgery may experience histologic improvement in steatohepatitis and perhaps even fibrosis [8, 26, 51]. Excessively rapid weight loss, however, may paradoxically worsen steatohepatitis and even precipitate hepatic failure, as has been observed following biliopancreatic diversion and jejunoileal bypass [4, 14, 33, 89]. Individual patients with NAFLD may have other comorbidities of the metabolic syndrome such as insulin resistance, hypertriglyceridemia, and hypertension, and are thus at significant risk for cardiovascular morbidity [36, 82]. Overall survival is lower among patients with NAFLD compared with matched controls, with cardiovascular disease as the leading cause of mortality [20]. The increase in mortality underscores the need for thorough and attentive preoperative cardiac risk stratification in patients with NAFLD who undergo elective surgery.
Nonalcoholic Fatty Liver Disease (NAFLD) Nonalcoholic fatty liver disease is associated with overweight and obesity and is the hepatic manifestation of the metabolic syndrome (see Chapter 89). NAFLD describes a range of hepatic disease activity, ranging from bland steatosis, to nonalcoholic steatohepatitis (NASH), to steatohepatitis with fibrosis and, ultimately, cirrhosis. Ultrasound imaging may detect increased echogenicity indicative of fatty liver, but a liver biopsy is necessary to distinguish steatohepatitis with or without fibrosis from bland steatosis. Abdominal surgery in patients with NAFLD has come under increased attention due to the prevalence of this condition in the bariatric surgery population. Up to 6% of patients who undergo gastric bypass surgery will be found intraoperatively to have cirrhosis, and more than 90% of morbidly obese patients who undergo bariatric surgery will have histologic evidence of hepatic steatosis [11, 54]. Patients with NAFLD in the absence of advanced hepatic fibrosis do not appear to be at increased operative risk for elective surgical procedures, but the presence of NAFLD may influence operative management. Hepatomegaly due to NAFLD in some instances may require conversion from a laparoscopic to an open approach to Roux-en-Y gastric bypass [75].
Other Causes of Chronic Liver Disease Patients with hemochromatosis may have myocardial iron deposition and are at risk for cardiomyopathy and cardiac conduction abnormalities, which may manifest in the perioperative period. In the past, outcomes were poorer following liver transplantation in patients with hemochromatosis, but with improved preoperative management, outcomes are now similar to those for patients with liver disease of other causes. Manifestations of Wilson’s disease may include neuropsychiatric disturbances. When present, the patient’s ability to participate in informed procedural consent and clinical decision-making may be impaired. In addition, surgical procedures may precipitate neuropsychiatric symptoms. D-penicillamine, used as chelation therapy for Wilson’s dose, impairs collagen cross-linking and may subsequently impair wound healing, and the dose should therefore be reduced in the preoperative and early postoperative periods. Parenchymal damage may accumulate in the lungs as well as liver in patients with alpha-1 antitrypsin deficiency. Thorough history taking and physical examination with attention to respiratory function should be
1390
conducted in such patients; pulmonary function testing should be performed before elective surgery when emphysema is suspected. Autoimmune hepatitis in remission is not a contraindication to elective surgery in a patient with compensated hepatic function. However, patients receiving chronic glucocorticoid therapy for either autoimmune hepatitis or an autoimmune hepatitis-overlap syndrome may have adrenal suppression and should receive appropriate perioperative “stress” doses of glucocorticoids to avert adrenal crisis.
Cirrhosis Operative Risk Stratification by Child Class Cirrhosis is characterized by hepatic parencyhmal necrosis with fibrosis and nodular regeneration (see Chapter 79). As a result of fibrosis and disorganized hepatic architecture, sinusoidal pressure increases and may lead to portal hypertension. Major clinical sequelae of cirrhosis are generally the result of impaired hepatic synthetic function (such as hypoalbuminemia or prolongation of the prothrombin time) or the effects of portosystemic shunting (gastroesophageal varices, splenomegaly with hypersplenism), or a combination of the two (encephalopathy). Surgical risk is increased in patients with cirrhosis, and the magnitude of perioperative risk correlates with the degree of hepatic decompensation. Clinical factors that are not specific to hepatic disease, such as ASA class, presence of chronic obstructive pulmonary disease, and elevated serum creatinine level, increase the risk of perioperative complications in patients with cirrhosis [92]. In addition, liver-specific indices, specifically the CTP score (Child class) and MELD score correlate with mortality. General consensus has held that elective surgical procedures are well tolerated by patients with Child class A cirrhosis, permissible with thorough preoperative evaluation and medical optimization for patients with Child class B cirrhosis (with the exception of extensive hepatic resection or cardiac surgery [see later]), and contraindicated in patients with Child class C cirrhosis. Operative risk increases further in cases of emergent surgery. Data in support of the correlation
104
Risk of Surgery in Patients with Liver Disease
between the Child class and operative risk derive from retrospective series since the 1970s. In a study published in 1984, Garrison and colleagues reported a retrospective series of 100 cirrhotic patients who underwent abdominal surgery. The 30-day operative mortality rate was 30%, with a stratified mortality rate of 10% for patients with Child class A cirrhosis, 31% for those with Child class B cirrhosis, and 76% for those with Child class C cirrhosis [27]. Mortality rates stratified by type of surgical procedure were 21% for biliary tract surgery, 35% for peptic ulcer surgery, and 53% for colonic resections. The vast majority of deaths (87%) were attributed to sepsis or multiorgan failure, or both. In multivariable analysis (excluding the Child class), the presence of ascites, infection, and coagulopathy each independently predicted operative mortality [27]. Mansour and colleagues reported nearly identical results in 1997 [56]. Among 92 patients undergoing abdominal surgery including cholecystectomy and hernia repair, the 30-day mortality rate was 26%: 10% (5/48) for patients with Child class A cirrhosis, 30% (10/33) for those with Child class B cirrhosis, and 82% (9/11) for those with Child class C cirrhosis. Emergency surgery was associated with a higher mortality rate than nonemergent surgery: 22% versus 10% for patients in Child class A; 38% versus 30% for those in Child class B; and 100% versus 82% for those in Child class C [56]. For some cirrhotic patients, the degree of portal hypertension may be disproportionate to the severity of hepatic parenchymal dysfunction. Therefore, even among patients with Child class A cirrhosis, the presence of portal hypertension may be associated with operative morbidity, particularly postoperative ascites. Transjugular intrahepatic portosystemic shunt (TIPS) therapy for portal decompression has been reported as a bridge to abdominal surgery in small series of selected Child class A patients with portal hypertension [6, 31]. No study has prospectively validated the predictive value of the CTP score or Child class in assessing operative risk. Moreover, the above data must be interpreted in light of the evolution of surgical indications and techniques since the original studies were conducted. For example, with the advent of effective gastric acid suppression and therapy to eradicate Helicobacter pylori, as well as endoscopic hemostatic therapy, surgery for peptic ulcer disease has become much less common.
Operative Risk in Patients with Liver Disease
Operative Risk Stratification by MELD Score The MELD score is based on the patient’s serum bilirubin level, creatinine level, and International Normalized Ratio (INR). The score was initially developed as a means of predicting survival in patients undergoing TIPS [55] and was subsequently validated as a predictor of mortality in patients awaiting liver transplantation. The MELD score has supplanted the CTP score as the principal criterion for donor liver allocation in the United States and elsewhere (see Chapter 103). In predicting operative risk among cirrhotic patients undergoing non-transplant surgery, the MELD score appears to be at least as accurate as the Child class and may allow more precise numerical estimates of operative mortality for individual patients [66]. Among a retrospective cohort of 140 surgical patients with cirrhosis undergoing gastrointestinal, genitourinary, cardiovascular, thoracic, and musculoskeletal procedures, increasing MELD score correlated with an increasing mortality rate in a linear fashion. The mortality rate increased approximately 1% with each increase in MELD score of one point within the range of 5 to 20 and 2% with each increase in MELD score of one point for MELD scores above 20 [65]. The overall perioperative mortality rate was 16.4%, with all deaths occurring in patients who underwent gastrointestinal, cardiovascular, or thoracic procedures and no deaths in those who underwent genitourinary or musculoskeletal procedures [65]. The MELD score may also be used in a dichotomous fashion to predict operative outcomes. In a case-control study of patients who underwent cholecystectomy, two deaths occurred in patients with a MELD score ≥8, as compared with no deaths in patients with a MELD score below 8 [53]. A MELD score ≥8 demonstrated a sensitivity of 91% and specificity of 77% in predicting 90-day postoperative morbidity. A relatively high complication rate (17%) was observed in the control group in this study [70]. The usefulness of the Child class and MELD score for stratifying operative risk has been compared in a number of studies [9, 22]. In a series of 40 patients who underwent abdominal, genitourinary, or head and neck surgery and had an overall 30-day operative mortality rate of 17%, the correlation between the Child class and MELD score in predicting mortality was 0.76 [22]. Specific mortality rates were 15% (2/13) for patients in Child class A, 9% (2/22) for those in Child
1391
class B, and 60% (3/5) for those in Child class C, compared with 8% (1/12) for those with a MELD score ≤8, 10% (2/21) for those with a MELD of score 9–16, and 57% (4/7) for those with a MELD score ≥17 [22]. Higher 30-day and 90-day mortality rates were evident in patients who underwent emergent (n=16) as compared with elective (n=24) surgery [22]. The most compelling data in support of the MELD score for operative risk stratification come from a large retrospective study of operative outcomes in cirrhotic patients published in 2007 by Teh and colleagues at the Mayo Clinic [84]. A total of 772 subjects underwent surgery during two time periods, 1980–1990 and 1994– 2004. Five hundred eighty-six subjects underwent digestive surgery, 107 underwent orthopedic surgery, and 79 underwent cardiovascular surgery. For patients with a MELD score >8, each one-point increase in the MELD score resulted in a 14% increase in both 30-day and 90-day mortality rates and a 15% increase in the 12-month mortality rate (Fig. 104.1). In multivariate analysis, MELD score, age, and ASA class were significant predictors of risk. ASA class appeared to be the strongest predictor of 7-day mortality, whereas the MELD score appeared to be the strongest predictor of mortality beyond 7 days [84]. A clinical prediction rule derived from this cohort is available at the website http://www.mayoclinic.org/ meld/mayomodel9.html. On providing a patient’s age, ASA class, INR, serum bilirubin level, and serum creatinine level, numeric estimates of the patient’s 7-day, 30-day, 90-day, 1-year, and 5-year mortality rates are generated (Table 104.5). This prediction rule has not yet been validated prospectively, and its performance, therefore, may be somewhat less robust than its performance in the derivation cohort. At present the MELD score appears to be the best tool for estimating perioperative risk in patients with cirrhosis. Use of the MELD score and Child class for this purpose need not be mutually exclusive. The Child class remains a useful strategy for rapid bedside assessment of disease severity and risk stratification.
Operative Risk Associated with Specific Types of Surgery Except where specifically mentioned earlier, much of the available data focuses on patients who underwent general abdominal surgery. Factors to be considered in
1392
104
100
Mortality (%)
80 60 40 20 0 a
0
5
10
16
20
25
30
MELD score
100
Mortalility (%)
80 60 40 20 0 b
0
5
10
16
20
25
30
MELD score
Fig. 104.1 Relationship between operative mortality and MELD score in 772 subjects with cirrhosis who underwent surgery in 1980–1990 or 1994–2004. Panel A shows 30-day mortality; Panel B shows 90-day mortality. For patients with a MELD score > 8, each one-point increase in the MELD score resulted in a 14% increase in both 30-day and 90-day mortality rates. (From [84. With permission.) MELD Model for Endstage Liver Disease
Table 104.5 Risk factors for postoperative mortality in patients with cirrhosis according to the Mayo Clinic Model Input variables Age ASA Class (see Table 104.2) Serum bilirubin level (mg/dL) Serum creatinine level (mg/dL) International normalized ratio Etiology of cirrhosis (alcoholic or cholestatic versus viral/other) From http://www.mayoclinic.org/meld/mayomodel9.html. ASA, American Anesthesiologists Association
cirrhotic patients undergoing abdominal surgery include decreased hepatic blood flow due to traction on abdominal viscera, delayed wound healing, and the development of incisional hernias, particularly in patients with ascites. Further modifications in risk assessment, and
Risk of Surgery in Patients with Liver Disease
attention to specific elements of operative morbidity, may be appropriate in cirrhotic patients undergoing nonabdominal surgery or specific abdominal operations. Biliary tract surgery and obstructive jaundice. Biliary tract surgery, including cholecystectomy, can present unique challenges in patients with cirrhosis. Increased vascularity of the gallbladder bed in the context of portal hypertension can result in bleeding during dissection of the gallbladder. An increased risk of bleeding should be anticipated in patients with advanced cirrhosis as demonstrated by a prolonged prothrombin time or thrombocytopenia, although the actual risk of bleeding does not correlate with coagulopathy [73, 85]. In general, laparoscopic cholecystectomy is permissible for patients with Child class A cirrhosis and selected patients with Child class B cirrhosis [18, 71, 90]; however, an open approach is recommended if cholecystectomy is necessary in patients with Child class C cirrhosis or a MELD score >8 and portal hypertension. In a patient with decompensated cirrhosis who presents with cholecystitis and requires an acute biliary intervention, percutaneous cholecystostomy may be preferable to cholecystectomy. Cirrhotic patients may present with jaundice caused by extrahepatic biliary obstruction rather than parenchymal liver disease. In a series of 373 patients presenting with acute biliary obstruction between 1976 and 1981, Dixon and colleagues reported a 30-day mortality rate of 9.1% [19]. In this cohort, 92 (25%) underwent a Whipple resection, hepaticojejunostomy, or creation of another type of biliary-enteric anastomosis; the remainder underwent cholecystectomy, with or without intraoperative bile duct exploration. Not surprisingly, the mortality rate was significantly higher among patients presenting with malignant versus benign biliary obstruction (26.1% versus 3.7%, p < 0.0005). Additional factors predictive of mortality included age greater than 60 years, anemia (hematocrit value 11 mg/dL) [19]. Perioperative morbidity in patients with acute biliary obstruction may be due to hemodynamic and circulatory insults as well as renal dysfunction, particularly in patients with sepsis due to suppurative cholangitis. A possible mechanism for these systemic complications includes translocation of gut micoflora into the systemic circulation and resulting endotoxemia. Intestinal barrier integrity may be compromised in patients with obstructive jaundice and in those with cirrhosis, leading to increased permeability to microorganisms [42, 69].
Operative Risk in Patients with Liver Disease
Limited animal and human data suggest that gut decontamination by oral administration of lactulose may attenuate the risk of endotoxemia, but it is not clear that any clinical benefit is directly attributable to lactulose administration, as opposed to administration of antibiotics and careful attention to the patient’s hemodynamic and volume status [46, 67 87]. Therefore, although lactulose therapy is appropriate for the perioperative management of cirrhotic patients with encephalopathy, administration of lactulose to cirrhotic patients prior to biliary surgery is not standard practice. Hemodynamic and volume support with crystalloid or colloid, with monitoring of urine output, as well as avoidance of nephrotoxic drugs such as aminoglycoside antibiotics, constitute appropriate management in such cases. There are no data to suggest that preoperative biliary decompression in patients with obstructive jaundice leads to a decrease in operative morbidity or mortality. However, endoscopic (or percutaneous) biliary therapy is preferable to surgery in patients with specific causes of biliary obstruction, such as choledocholithiasis and biliary stricture. In a small retrospective series of cirrhotic patients with acute cholangitis due to choledocholithiasis, mortality rates were 100% (2/2) in those undergoing emergent surgery but only 7% (1/15) in those undergoing emergent endoscopic therapy [16]. On the other hand, a larger retrospective study identified cirrhosis as an independent risk factor for complications among patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) (multivariate adjusted odds ratio 2.93, 95% confidence interval 1.48–9.50); the increased risk was attributable principally to hemorrhage following sphincterotomy [23]. Endoscopic papillary balloon dilation has been recommended as an alternative to sphincterotomy, with a lower risk of hemorrhage (but possibly a higher risk of pancreatitis), in cirrhotic patients with coagulopathy [68]. Cardiac surgery. Cardiac surgery and procedures requiring use of cardiopulmonary bypass carry higher risks than intraabdominal or other general surgical procedures in patients with cirrhosis. Factors contributing to an increased risk of hepatic decompensation include total time on bypass, use of pulsatile rather than nonpulsatile bypass flow, and administration of vasopressor agents for hemodynamic support. Cardiopulmonary bypass may adversely affect platelet function and fibrinolysis, further exacerbating coagulopathy. In two retrospective series of patients who underwent surgery requiring cardiopulmonary bypass, relatively
1393
low mortality rates were observed in those with Child class A cirrhosis: 0% (0/10) and 3% (1/31), respectively, but rates were markedly increased in those with Child class B (44–50%) and C (100%, n=2) cirrhosis. More than 75% of Child class B and C patients experienced hepatic decompensation perioperatively [40, 81]. The Child class and MELD score appear to be comparable in predicting operative risk in cirrhotic patients undergoing cardiac surgery [81]. In the above cohort described by Suman and colleagues, a CTP score of >7 demonstrated 86% sensitivity and 92% specificity for predicting mortality and 66% sensitivity and 97% specificity for predicting hepatic decompensation. Similarly, a MELD score of >13 demonstrated 71% sensitivity and 89% specificity for predicting mortality and 67% sensitivity and 97% specificity for predicting hepatic decompensation [81]. These limited data suggest that cardiac surgery may be accomplished safely in patients with a low CTP score (Child class A and carefully selected class B patients) or low MELD score. Cardiac surgery should otherwise be avoided, and less invasive options considered, in patients with advanced cirrhosis. Portal decompression with TIPS placement as a bridge to cardiac surgery in patients with portal hypertension has been described in individual case reports [76]; however, because a TIPS may increase right ventricular preload, it may be contraindicated in patients with impaired cardiac function. Hepatic resection. Not uncommonly, resection of a hepatic lesion may be considered, among other options, in a patient with underlying liver disease (particularly a patient with cirrhosis in whom a focal hepatocellular carcinoma [HCC] develops). Increasingly, liver transplantation has been preferred over resection in patients with either one lesion 90% of hepatocytes and the restoration of a normal liver function [33, 83]. In patients, examples for gene substitution are the partial correction of severe hemophilia A by the ex vivo transduction of autologous skin fibroblasts with the normal/wild-type factor VIII gene, followed by laparoscopic implantation of the genetically modified fibroblasts into the omentum majus or of hemophilia B by adenovirus-associated vector (AAV)-based gene transfer [55, 90]. In rare situations in which a hepatocelluar carcinoma (HCC) is caused by the mutation of a tumor suppressor gene, e.g., the p53 gene, the substitution of the mutated by the normal/ wild-type gene in vitro can reduce the number of tumor cell colonies and restore cisplatin sensitivity [116, 119].
Gene Therapy of Liver Diseases
1405
Hepatocyte Transplantation
introduced into or synthesized in the cells (decoy strategy), by binding of single-stranded nucleic acids to double-stranded DNA, forming a triple helix structure, hybridization of RNA molecules possessing endonuclease activity (ribozymes) to RNA, resulting in its sequence-specific cleavage, RNA interference (RNAi) by small inhibiting RNA (siRNA) or microRNA (miRNA), block of translation by antisense oligonucleotides and the intracellular synthesis of peptides or proteins, interfering with their normal counterpart, termed dominant negative (DN) mutant strategy (Fig. 105.1) [14, 23, 40, 42–44, 56, 100–102, 112]. These different strategies have been applied to a number of malignant and infectious diseases. In particular ribozymes, siRNAs, antisense oligonucleotides and DN mutants have been experimentally explored to treat hepatitis B virus (HBV) and hepatitis C virus (HCV) infections.
Allogeneic or ex vivo genetically modified autologous hepatocyte transplantation is a promising strategy to treat hereditary monogenic liver diseases. In patients with familial hypercholesterolemia (FH) that is caused by various mutations in the low density lipoprotein (LDL) receptor gene, apart from orthotopic liver transplantation, liver-directed gene therapy has been performed in a pilot study in five patients [6, 10, 34, 35, 45]. Autologous liver cells, prepared from a surgical biopsy, were transduced ex vivo with a recombinant retrovirus expressing the normal LDL receptor. These ex vivo genetically modified hepatocytes were transplanted by portal infusion and resulted in significant and prolonged reductions in LDL cholesterol in 3/5 patients for at least 4 months, demonstrating the feasibility of engrafting a limited number of ex vivo transduced hepatocytes. Also, allogeneic hepatocyte transplantation has been successfully used in patients to partially correct Crigler-Najjar syndrome type I and glycogen storage disease type I [26, 80].
Ribozymes Ribozymes (‘ribonucleic acid enzymes’) were originally discovered as naturally occurring RNA molecules that catalyze the sequence-specific cleavage of RNA and RNA splicing reactions [40, 101]. This catalytic activity is the major attraction of the ribozyme concept since one ribozyme can cleave many target RNAs. Ribozymes that cleave RNA are being developed as inhibitors of gene expression and viral replication. Several studies have clearly demonstrated that hammerhead ribozymes can specifically cleave HBV RNA or HCV RNA in vitro [5, 66, 91, 107]. In vivo, however,
Block of Gene Expression or Function For diseases caused by the expression of an acquired gene or the overexpression of an endogenous gene, blocking gene expression can be an effective therapeutic approach. Several strategies can be employed (Fig. 105.1): interference with the transcription of genes by binding of transcription factors to nucleic acids
Block of gene expression 5Õ
A
A
G
C
C
G
C
T
A
T
G
T
G
A
C
3Õ DNA
1 3Õ
T
T
C
G
G
C
5Õ
A
A
G
C
C
5
T
A
C
A
C
T
G
G
C
U
A
U
G
U
G
A
C
3Õ mRNA
Translation
4
Fig. 105.1 Strategies aimed at blocking gene expression
A
Transcription
2 3
G
5Õ
AAG Lys
CCG Pro
CUA Leu
UGU Cys
GAC Asp
Protein
1406
105 A Look to the Future: Gene Therapy in Liver Diseases
an efficient ribozyme-mediated cleavage of HBV RNA could not be demonstrated to date. For HCV infection, the elimination of HCV RNA in infected hepatocytes by ribozymes has also been reported [66, 111].
Small Interfering RNA siRNA interference is a recently discovered basic intracellular mechanism that has been explored also for the inhibition of HBV and HCV infection (Fig. 105.2) [23, 56, 100, 112]. For HBV, inhibition of viral gene expression and replication has been shown in vitro and in different mouse models in vivo [29, 32, 57, 58, 71, 99, 104, 118]. For HCV, inhibition of viral gene expression and replication has been shown in vitro in the replicon system [54, 88, 114]. While effective in blocking viral gene expression and replication, in vivo oversaturation of celluar miRNA/ short hairpin RNA (shRNA) pathways can result in lethal hepatotoxicity. For future siRNA-based strategies in animals or humans, these findings indicate that the control of intracellular shRNA expression levels through optimizing shRNA dose and sequence will be key to reduce the risk of oversaturating endogenous small siRNA pathways.
Antisense Oligonucleotides Antisense nucleic acids are designed to specifically bind to RNA or mRNA, resulting in the formation of RNA– DNA (antisense oligodeoxynucleotides) or RNA–RNA hybrids (antisense oligoribonucleotides) with an arrest of RNA replication, reverse transcription or mRNA translation [14, 42, 43, 102, 109]. Antisense effects can
be potentiated by degradation of RNA in RNA-DNA hybrids by cellular RNases H. While conceptually simple, it is clear now that not all desired as well as undesired effects are caused by the target sequence specific antisense action of the oligonucleotides or the cellular enzymes mentioned above [9, 22]. The antisense strategy has been successfully applied in vitro to HBV infection [8, 30, 81, 115] and to HCV infection [1, 39, 75, 98, 105, 110]. In addition, studies in nude mice, in the duck hepatitis B virus (DHBV) and the woodchuck hepatitis virus (WHV) model of HBV infection demonstrated the in vivo applicability of this approach [4, 82, 117]. While no toxic effects have been observed in these experiments, the contribution of non-antisense effects to the inhibition of viral replication or gene expression has not been systematically assessed in most studies. Independent of the antisense or non-antisense mechanism of the biological effects, an in vitro screening procedure for the identification of functionally active oligonucleotides should greatly facilitate the design of oligonucleotide based antiviral therapies [9, 103].
Interfering Peptides or Proteins The intracellular synthesis of interfering peptides or proteins, including single chain or whole non-secreted antibodies, is aimed at the specific interference with the assembly or function of viral structural or non-structural proteins and represents a type of intracellular immunization. This approach has been shown for block mammalian and avian hepadnavirus gene expression and replication in vitro. For example, the fusion of different polypeptides of various lengths to the carboxy-terminus ATP
siRNA
ADP
Helicase
2
1
RISC (RNA Induced Silencing Complex)
Target mRNA
AAAA
Nuclease
Cellular nucleases
Fig. 105.2 Principle of RNA interference [56]
4 Degradation by cellular RNases
AAAA
3
Gene Therapy of Liver Diseases
1407
of the viral core protein yields DN mutants [21, 94, 95, 108]. These DN mutants are species-specific and suppress viral replication by at least 90% at an effector to target ratio of 1:10. Moreover, the non-secretory form of the hepatitis B e antigen (HBeAg) was shown to effectively inhibit viral replication and may indeed act as a natural regulator of HBV propagation [11, 36, 96]. The potential advantage of DN mutants over ribozymes or antisense oligonucleotides is their relative independence from viral sequence variations, minimizing the risk of selecting or accumulating ‘therapy escape’ mutants.
DNA Vaccination A novel approach is DNA vaccination resulting in the manipulation of the immune system by introduction of expression vectors into muscle cells or dendritic cells and long lasting cellular and humoral immune responses. The direct gene transfer into muscle [7] represents an exciting new development and elegant application of gene therapy [7, 72, 84]. The therapeutic DNA vaccine acts by the intracellular plasmid-derived synthesis of a viral protein which enters the cell’s MHC class I pathway [72]. Only proteins that originate within the cell can be processed by MHC class I molecules that carry fragments of the protein to the cell surface. There they stimulate CD8+ cytotoxic T cells, resulting in cell-mediated immunity. In principle, this strategy is applicable to the treatment of acquired genetic diseases, associated with the expression of disease-specific antigens serving as targets for CD8+ cytotoxic T cells. Therapeutic DNA vaccination has been experimentally explored for HBV as well as HCV infection and
"Targeted therapies" small molecule inhibitors (mibs) of kinases and monoclonal antibodies (mabs) against growth factors et al.
holds great promise as an effective molecular therapy for these viral diseases [20, 62, 64, 69, 70, 97, 106]. In this context, the coexpression of HBsAg and interleukin-2 was shown to greatly increase humoral as well as cellular immune response [16].
Gene Augmentation Complex genetic diseases are among the most prevalent clinical problems. In this situation, gene augmentation is aimed at the local expression of a therapeutic gene product that is physiologically not expressed or expressed at therapeutically insufficient levels. This strategy is explored among others for the treatment of hepatocellular carcinoma (HCC) (Fig. 105.3).
Suicide Gene Therapy An interesting strategy to treat HCCs is genetic prodrug activation therapy via the introduction of a ‘suicide gene’ into malignant cells followed by the administration of the prodrug. This concept has been experimentally explored in HCC cells in vitro and in vivo, e.g., for the HSV-tk gene [47, 52, 53, 87, 113], the gene encoding cytosine deaminase (CD) that converts the prodrug 5-fluorocytosine to 5-fluorouracil which inhibits RNA and DNA synthesis during the S-phase of the cell cycle [51], the gene encoding purine nucleoside phosphorylase that converts purine analogs into freely diffusible toxic metabolites [61, 77] as well as the gene encoding cytochrome P450 4B1 [76, 77]. A significant bystander effect of cell killing caused by suicide gene
Tumor supressor gene substitution Suicide gene therapy
Telomerase apoptosis modulation
Immune therapy Tumor antigens Cytokines
Fig. 105.3 HCC treatment: experimental strategies, including gene therapy
Oncolytic viruses
Antiangiogenic gene therapy
1408
expression could be demonstrated in vitro and in vivo, based on cell-cell contact rather than release of cytotoxic substances from the transduced cells [63]. At the same time, the bystander effect may also affect nonmalignant dividing cells in the target tissue, potentially limiting the application of this strategy.
105 A Look to the Future: Gene Therapy in Liver Diseases
could be detected [12, 13]. Since AFP is not only expressed by tumor cells but also by regenerating liver cells and in liver cirrhosis immunization against AFP carries the risk of autoimmune hepatitis, as has been experimentally shown in mice [28].
Immune Therapy with Antigen Presenting Cells Antiangiogenic Gene Therapy This concept has been experimentally explored in a HCC mouse model using the angiostatin gene. Angiostatin gene transfer resulted in reduced tumor volume and vascular density [48].
The use of antigen presenting cells (APC) is another strategy that has been explored employing dendritic cells (DC) exposed to tumor lysates, peptides or ex vivo tranduced with tumor antigen expressing DNA constructs. While this strategy is conceptually very interesting, to date there are no data available that demonstrate its clinical efficacy [49].
Oncolytic Viruses This new and elegant approach uses p53 mutations for selective, adenovirus-mediated lysis of tumor cells. Thus, an adenovirus mutant was engineered that replicates selectively in p53-deficient human tumor cells [41, 68]. Other examples are the adenoviral introduction of Smac antagonizes the inhibitor of apoptosis proteins in HCC tumor cells and enhances tumor cell death and tumor-specific replication-restricted adenoviral vectors [38, 86]. Further, the intravascular administration of a replication-competent genetically engineered herpes simplex virus (HSV)-1 resulted in oncolysis of a diffuse HCC [85]. More efficient HSV-1-based vectors have been developed [67].
Immune Therapy In the process of malignant transformation new antigenic surface proteins can be expressed (tumor antigens), oncofetal proteins can be re-expressed, for example alpha fetoprotein (AFP) and cytokine genes can induce cytolytisis of tumor cells.
AFP-Specific Immune Therapy This strategy has been explored in mice and humans. Vaccination with an AFP-expressing DNA construct resulted in tumor rejection and prolonged survival in a mouse model [31]. Also in patients AFP-specific T cells
Cytokine Gene Therapy Cytokine genes, such as tumor necrosis factor (TNF)alpha, granulocyte macrophage colony stimulating factor (GM-CSF), interferon (IFN)-alpha or IFN-gamma, interleukin (IL)-2, -4, -6, -7, -12 and -18, B7–1, CD40 ligand and others have been explored in preclinical HCC animal models and in some patients with gastrointestinal tumors. Complete regression of a HCC was demonstrated in vivo by TNF-alpha, IL-2, IL-12 and an activatable interferon regulatory factor-1 in mice [3, 15, 46, 60]. Gene transfer was achieved in vivo by delivering retroviral or adenoviral vectors systemically, directly into the tumor or into the peritoneal cavity [15, 46]. A pilot study in patients with gastrointestinal tumors exploring the intratumoral injection of an adenoviral IL-12 expression construct showed only marginal efficacy, however [92].
Molecular Prevention of Liver Diseases DNA-based prophylactic vaccination against HBV infection, for example, is possible by intramuscular injection of a plasmid expressing hepatitis B surface antigen (HBsAg). HBsAg is taken up by cells via phagocytosis or endocytosis, processed through the major histocompatibility complex (MHC) class II system and primarily stimulates an antibody response through CD4+ helper T cells with the production of anti-HBs [17–19, 72, 73, 84]. While the DNA-based
References
vaccination against HBV infection induces anti-HBs antibodies and prevents HBV infection, DNA-based vaccination against HCV infection of chimpanzees has been shown not to prevent infection but to result in the resolution of acute HCV infection through an effective vaccine-induced cellular immune response [24, 25].
Summary and Perspectives Molecular analyses have become an integral part of biomedical research as well as clinical medicine. The definition of the genetic basis of many human diseases has led to a better understanding of their pathogenesis and has in addition offered new perspectives for their diagnosis, therapy and prevention. Genetically, human diseases can be classified as hereditary monogenic, acquired monogenic and complex genetic diseases. Based on this classification, gene therapy is based on six concepts: gene repair, gene substitution, cell or organ transplantation, block of gene expression or function, gene augmentation and DNA vaccination. While the recent developments in gene therapy for liver diseases are promising, various delivery, targeting and safety issues need to be addressed before these strategies will enter clinical practice. Nevertheless, gene therapy will become part of the management of patients with liver diseases, complementing existing therapeutic and preventive strategies.
References 1. Alt M, Renz R (1995) Specific inhibition of hepatitis C viral gene expression by antisense phosphorothioate oligodeoxynucleotides. Hepatology 22: 707–17 2. Anderson WF (1992) Human gene therapy. Science 256:808–13 3. Barajas M, Mazzolini G (2001) Gene therapy of orthotopic hepatocellular carcinoma in rats using adenovirus coding for interleukin 12. Hepatology 33: 52–61 4. Bartholomew RM, Carmichael EP (1995) Targeted delivery of antisense DNA in woodchuck hepatitis virus-infected woodchucks. J Viral Hepatitis 2: 273–8 5. Beck J, Nassal M (1995) Efficient hammerhead ribozymemediated cleavage of the structured hepatitis B virus encapsidation signal in vitro and in cell extracts, but not in intact cells. Nucl Acids Res 23: 4954–62 6. Bilheimer DW, Goldstein JL (1984) Liver transplantation to provide low density lipoprotein receptors and lower plasma
1409 cholesterol in a child with homozygous familial hypercholesterolemia. N Engl J Med 311: 1658–64 7. Blau HM, Springer ML (1995) Muscle mediated gene therapy. N Engl J Med 333: 1554–6 8. Blum HE, Galun E (1991) Inhibition of hepatitis B virus by antisense oligodeoxynucleotides. Lancet 337: 1230 9. Branch AD (1996) A hitchhiker’s guide to antisense and nonantisense biochemical pathways. Hepatology 24: 1517–29 10. Brown MS, Goldstein JL (1986) A receptor-mediated pathway for cholesterol homeostasis. Science 232: 34–7 11. Buckwold VE, Xu Z (1996) Effects of a naturally occurring mutation in the hepatitis B virus basal core promoter on precore gene expression and viral replication. J Virol 70: 5845–51 12. Butterfield LH (2004) Immunotherapeutic strategies for hepatocellular carcinoma. Gastroenterology 127: S232–41 13. Butterfield LH, Meng WS (2001) T cell responses to HLAA*0201-restricted peptides derived from human alpha fetoprotein. J Immunol 166: 5300–8 14. Calabretta B (1991) Inhibition of protooncogene expression by antisense oligodeoxynucleotides: biological and therapeutic implications. Cancer Res 51: 4505–10 15. Cao G, Kuriyama S (1997) Complete regression of established murine hepatocellular carcinoma by in vivo tumor necrosis factor alpha gene transfer. Gastroenterology 112: 501–10 16. Chow YH, Huang WL (1997) Improvement of hepatitis B virus DNA vaccines by plasmids coexpressing hepatitis B surface antigen and interleukin-2. J Virol 71: 169–78 17. Davis HL, Mancini M (1996) DNA-mediated immunization to hepatitis B surface antigen–longevity of primary response and effect of boost. Vaccine 14: 910–5 18. Davis HL, McCluskie MJ (1996) DNA vaccine for hepatitis B: Evidence for immunogenicity in chimpanzees and comparison with other vaccines. Proc Natl Acad Sci USA 93: 7213–8 19. Davis HL, Michel ML (1993) DNA-based immunization induces continuous secretion of hepatitis B surface antigen and high levels of circulating antibody. Hum Mol Genet 2: 1847–51 20. Davis HL, Schirmbeck R (1995) DNA-mediated immunization in mice induces a potent MHC class I-restricted cytotoxic T lymphocyte response to the hepatitis B envelope protein. Human Gene Ther 6: 1447–56 21. Delaney MA, Goyal S (1991) Design of modified core genes that inhibit replication of woodchuck hepatitis virus. In: Hollinger FB, Lemon SM, Margolis H (eds) Viral hepatitis and liver disease. Williams & Wilkins, Baltimore, MD, pp 667–8 22. Dougherty WG, Parks TD (1995) Transgenes and gene suppression: telling us something new? Curr Opin Cell Biol 7: 399–405 23. Dykxhoorn DM, Lieberman J (2005) The silent revolution: RNA interference as basic biology, research tool, and therapeutic. Annu Rev Med 56: 401–23 24. Folgori A, Capone S (2006) A T-cell HCV vaccine eliciting effective immunity against heterologous virus challenge in chimpanzees. Nat Med 12: 190–7 25. Forns X, Payette PJ (2000) Vaccination of chimpanzees with plasmid DNA encoding the hepatitis C virus (HCV) envelope E2 protein modified the infection after challenge with homologous monoclonal HCV. Hepatology 32: 618–25 26. Fox IJ, Chowdhury JR (1998) Treatment of the CriglerNajjar syndrome type I with hepatocyte transplantation. N Engl J Med 338: 1422–6
1410 27. Friedmann T (1989) Progress toward human gene therapy. Science 244: 1275–81 28. Geissler M, Mohr L (2001) Immunotherapy directed against alpha-fetoprotein results in autoimmune liver disease during liver regeneration in mice. Gastroenterology 121: 931–9 29. Giladi H, Ketzinel-Gilad M (2003) Small interfering RNA inhibits hepatitis B virus replication in mice. Mol Ther 8: 769–76 30. Goodarzi G, Gross SC (1990) Antisense oligodeoxyribonucleotides inhibit the expression of the gene for hepatitis B virus surface antigen. J Gen Virol 71: 3021–25 31. Grimm CF, Ortmann D (2000) Mouse alpha-fetoproteinspecific DNA-based immunotherapy of hepatocellular carcinoma leads to tumor regression in mice. Gastroenterology 119: 1104–12 32. Grimm D, Streetz KL (2006) Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature 441: 537–41 33. Grompe M (2001) The pathophysiology and treatment of hereditary tyrosinemia type 1. Semin Liver Dis 21: 563–71 34. Grossman M, Rader DJ (1995) A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia. Nat Med 1: 1148–54 35. Grossman M, Raper SE (1994) Successful ex vivo gene therapy directed to liver in a patient with familial hypercholesterolaemia. Nat Genet 6: 335–41 36. Guidotti LG, Matzke B (1996) The hepatitis B virus (HBV) precore protein inhibits HBV replication in transgenic mice. J Virol 70: 7056–61 37. Gutierrez AA, Lemoine NR (1992) Gene therapy for cancer. Lancet 339: 715–721 38. Hallenbeck PL, Chang YN (1999) A novel tumor-specific replication-restricted adenoviral vector for gene therapy of hepatocellular carcinoma. Hum Gene Ther 10: 1721–33 39. Hanecak R, Brown-Driver V (1996) Antisense oligonucleotide inhibition of hepatitis C virus gene expression in transformed hepatocytes. J Virol 70: 5203–12 40. Haseloff J, Gerlach WL (1988) Simple RNA enzymes with new and highly specific endoribonuclease activities. Nature 334: 585–91 41. Heise C, Sampson-Johannes A (1997) ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents. Nat Med 3: 639–45 42. Helene C (1991) Rational design of sequence-specific oncogene inhibitors based on antisense and antigene oligonucleotides. Eur J Cancer 27: 1466–71 43. Helene C, Toulme JJ (1990) Specific regulation of gene expression by antisense, sense and antigene nucleic acids. Biochim Biophys Acta 1049: 99–125 44. Herschkowitz I (1987) Functional inactivation of genes by dominant negative mutations. Nature 329: 219–22 45. Hoeg JM, Starzl TE (1987) Liver transplantation for treatment of cardiovascular disease: comparison with medication and plasma exchange in homozygous familial hypercholesterolemia. Am J Card 59: 705–7 46. Huang H, Chen SH (1996) Gene therapy for hepatocellular carcinoma: long-term remission of primary and metastatic tumors in mice by interleukin-2 gene therapy in vivo. Gene Ther 3: 980–7 47. Ido A, Nakata K (1995) Gene therapy for hepatoma cells using a retrovirus vector carrying herpes simplex virus
105
A Look to the Future: Gene Therapy in Liver Diseases
thymidine kinase gene under the control of human alphafetoprotein gene promoter. Cancer Res 55: 3105–9 48. Ishikawa H, Nakao K (2003) Antiangiogenic gene therapy for hepatocellular carcinoma using angiostatin gene. Hepatology 37: 696–704 49. Iwashita Y, Tahara K (2003) A phase I study of autologous dendritic cell-based immunotherapy for patients with unresectable primary liver cancer. Cancer Immunol Immunother 52: 155–61 50. Jones JT, Lee SW (1996) Tagging ribozyme reaction sites to follow trans-splicing in mammalian cells. Nat Med 2: 643–8 51. Kanai F, Lan KH (1997) In vivo gene therapy for alpha-fetoprotein-producing hepatocellular carcinoma by adenovirus-mediated transfer of cytosine deaminase gene. Cancer Res 57: 461–5 52. Kanai F, Shiratori Y (1996) Gene therapy for alpha-fetoprotein-producing human hepatoma cells by adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene. Hepatology 23: 1359–68 53. Kaneko S, Hallenbeck P (1995) Adenovirus-mediated gene therapy of hepatocellular carcinoma using cancer-specific gene expression. Cancer Res 55: 5283–7 54. Kapadia SB, Brideau-Andersen A (2003) Interference of hepatitis C virus RNA replication by short interfering RNAs. Proc Natl Acad Sci USA 100: 2014–8 55. Kay MA, Manno CS (2000) Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector. Nat Genet 24: 257–61 56. Kitabwalla M, Ruprecht RM (2002) RNA interference – a new weapon against HIV and beyond. N Engl J Med 347: 1364–7 57. Klein C, Bock CT (2003) Inhibition of hepatitis B virus replication in vivo by nucleoside analogues and siRNA. Gastroenterology 125: 9–18 58. Konishi M, Wu CH (2003) Inhibition of HBV replication by siRNA in a stable HBV-producing cell line. Hepatology 38: 842–50 59. Kren BT, Parashar B (1999) Correction of the UDPglucuronosyltransferase gene defect in the gunn rat model of crigler-najjar syndrome type I with a chimeric oligonucleotide. Proc Natl Acad Sci USA 96: 10349–54 60. Kroger A, Ortmann D (2001) Growth suppression of the hepatocellular carcinoma cell line Hepa1–6 by an activatable interferon regulatory factor-1 in mice. Cancer Res 61: 2609–17 61. Krohne TU, Shankara S (2001) Mechanisms of cell death induced by suicide genes encoding purine nucleoside phosphorylase and thymidine kinase in human hepatocellular carcinoma cells in vitro. Hepatology 34: 511–8 62. Kuhöber A, Pudollek HP (1996) DNA immunization induces antibody and cytotoxic T cell responses to hepatitis B core antigen in H-2b mice. J Immunol 156: 3687–95 63. Kuriyama S, Nakatani T (1995) Bystander effect caused by suicide gene expression indicates the feasibility of gene therapy for hepatocellular carcinoma. Hepatology 22: 1838–46 64. Lagging LM, Meyer K (1995) Immune responses to plasmid DNA encoding the hepatitis C virus core protein. J Virol 69: 5859–63 65. Lan N, Howrey RP (1998) Ribozyme-mediated repair of sickle ß-globin mRNAs in erythrocyte precursors. Science 280: 1593–6
References 66. Lieber A, He C-Y (1996) Elimination of hepatitis C virus RNA in infected human hepatocytes by adenovirus-mediated expression of ribozymes. J Virol 70: 8782–91 67. Liu BL, Robinson M (2003) ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties. Gene Ther 10: 292–303 68. Lowe SW (1997) Progress of the smart bomb cancer virus. Nat Med 3: 606–8 69. Major ME, Vitvitski L (1995) DNA based immunization with chimeric vectors for the induction of immune responses against the hepatitis C virus nucleocapsid. J Virol 69: 5798–805 70. Mancini M, Hadchouel M (1996) DNA-mediated immunization in a transgenic mouse model of the hepatitis B surface antigen chronic carrier state. Proc Natl Acad Sci USA 93: 12496–501 71. McCaffrey AP, Nakai H (2003) Inhibition of hepatitis B virus in mice by RNA interference. Nat Biotechnol 21: 639–44 72. McDonnell WM, Askari FK (1996) DNA vaccines. N Engl J Med 334: 42–5 73. Michel ML, Davis HL (1995) DNA-mediated immunization to the hepatitis B surface antigen in mice: aspects of the humoral response mimic hepatitis B viral infection in humans. Proc Natl Acad Sci USA 92: 5307–11 74. Miller AD (1992) Human gene therapy comes of age. Nature 357: 455–60 75. Mizutani T, Kato N (1995) Inhibition of hepatitis C virus replication by antisense oligonucleotide in culture cells. Biochem Biophys Res Commun 212: 906–11 76. Mohr L, Rainov NG (2000) Rabbit cytochrome P450 4B1: a novel prodrug activating gene for pharmacogene therapy of hepatocellular carcinoma. Cancer Gene Ther 7: 1008–14 77. Mohr L, Shankara S (2000) Gene therapy of hepatocellular carcinoma in vitro and in vivo in nude mice by adenoviral transfer of the Escherichia coli purine nucleoside phosphorylase gene. Hepatology 31: 606–14 78. Morgan RA, Anderson WF (1993) Human gene therapy. Annu Rev Biochem 62: 191–217 79. Mulligan RC (1993) The basic science of gene therapy. Science 260: 926–32 80. Muraca M, Gerunda G (2002) Hepatocyte transplantation as a treatment for glycogen storage disease type 1a. Lancet 359: 317–8 81. Nakazono K, Ito Y (1996) Inhibition of hepatitis B virus replication by targeted pretreatment of complexed antisense DNA in vitro. Hepatology 23: 1297–303 82. Offensperger WB, Offensperger S (1993) In vivo inhibition of duck hepatitis B virus replication and gene expression by phosphorothioate modified antisense oligodeoxynucleotides. EMBO J 12: 1257–62 83. Overturf K, Al-Dhalimy M (1996) Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type I. Nat Genet 12: 266–73 84. Pardoll DM, Beckerleg AM (1995) Exposing the immunology of naked DNA vaccines. Immunity 3: 165–9 85. Pawlik TM, Nakamura H (2000) Oncolysis of diffuse hepatocellular carcinoma by intravascular administration of a replication-competent, genetically engineered herpesvirus. Cancer Res 60: 2790–5 86. Pei Z, Chu L (2004) An oncolytic adenoviral vector of Smac increases antitumor activity of TRAIL against HCC in human cells and in mice. Hepatology 39: 1371–81
1411 87. Qian C, Bilbao R (1995) Induction of sensitivity to ganciclovir in human hepatocellular carcinoma cells by adenovirus mediated gene transfer of herpes simplex virus thymidine kinase. Hepatology 22: 118–23 88. Randall G, Grakoui A (2003) Clearance of replicating hepatitis C virus replicon RNAs in cell culture by small interfering RNAs. Proc Natl Acad Sci USA 100: 235–40 89. Rosenberg SA (1992) Gene therapy for cancer. JAMA 268: 2416–9 90. Roth DA, Tawa NE, Jr. (2001) Nonviral transfer of the gene encoding coagulation factor VIII in patients with severe hemophilia A. N Engl J Med 344: 1735–42 91. Sakamoto N, Wu CH (1996) Intracellular cleavage of hepatitis C virus RNA and inhibition of viral protein translation by hammerhead ribozymes. J Clin Invest 98: 2720–8 92. Sangro B, Mazzolini G (2004) Phase I trial of intratumoral injection of an adenovirus encoding interleukin-12 for advanced digestive tumors. J Clin Oncol 22: 1389–97 93. Sarver N, Cairns S (1996) Ribozyme trans-splicing and RNA tagging: Following the messenger. Nature Med 2: 641–2 94. Scaglioni P, Melegari M (1996) Use of dominant negative mutants of the hepadnaviral core protein as antiviral agents. Hepatology 24: 1010–7 95. Scaglioni PP, Melegari M (1994) Characterization of hepatitis B virus core mutants that inhibit viral replication. Virology 205: 112–20 96. Scaglioni PP, Melegari M (1997) Posttranscriptional regulation of hepatitis B virus replication by the precore protein. J Virol 71: 345–53 97. Schirmbeck R, Bohm W (1995) Nucleic acid vaccination primes hepatitis B virus surface antigen specific cytotoxic T lymphocytes in nonresponder mice. J Virol 69: 5929–34 98. Seki M, Honda Y (1995) Phosphorothioate antisense oligodeoxynucleotides capable of inhibiting hepatitis C virus gene expression: in vitro translation assay. J Biochem 118: 1199–204 99. Shlomai A, Shaul Y (2003) Inhibition of hepatitis B virus expression and replication by RNA interference. Hepatology 37: 764–70 100. Taylor JA, Naoumov NV (2005) The potential of RNA interference as a tool in the management of viral hepatitis. J Hepatol 42: 139–44 101. Thompson JD, Macejak D (1995) Ribozymes in gene therapy. Nat Med 1: 277–8 102. Tseng BY, Brown, K.D. (1994) Antisense oligonucleotide technology in the development of cancer therapeutics. Cancer Gene Ther 1: 65–71 103. Tuerk C, Gold L (1990) Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science 249: 505–10 104. Uprichard SL, Boyd B (2005) Clearance of hepatitis B virus from the liver of transgenic mice by short hairpin RNAs. Proc Natl Acad Sci USA 102: 773–8 105. Vidalin O, Major ME (1996) In vitro inhibition of hepatitis C virus gene expression by chemically modified antisense oligodeoxynucleotides. Antimicrob Agents Chemother 40: 2337–44 106. Vitiello A, Ishioka G (1995) Development of a lipopeptide based therapeutic vaccine to treat chronic HBV infection. I. Induction of a primary cytotoxic T lymphocyte response in humans. J Clin Invest 95: 341–9
1412 107. von Weizsäcker F, Blum HE (1992) Cleavage of hepatitis B virus RNA by three ribozymes transcribed from a single DNA template. Biochem Biophys Res Commun 189 :743–8 108. von Weizsäcker F, Wieland S (1996) Inhibition of viral replication by genetically engineered mutants of the duck hepatitis B virus core protein. Hepatology 24: 294–9 109. Wagner RW (1994) Gene inhibition using antisense oligodeoxynucleotides. Nature 372: 333–5 110. Wakita T, Wands JR (1994) Specific inhibition of hepatitis C virus expression by antisense oligodeoxynucleotides. In vitro model for selection of target sequence. J Biol Chem 269: 14205–10 111. Welch PJ, Tritz R (1996) A potential therapeutic application of hairpin ribozymes – in vitro and in vivo studies of gene therapy for hepatitis C virus infection. Gene Ther 3: 994–1001 112. Williams BR (2005) Targeting specific cell types with silencing RNA. N Engl J Med 353: 1410–1 113. Wills KN, Huang WM (1995) Gene therapy for hepatocellular carcinoma: chemosensitivity conferred by adenovirus-mediated transfer of the HSV-1 thymidine kinase gene. Cancer Gene Ther 2: 191–7
105 A Look to the Future: Gene Therapy in Liver Diseases 114. Wilson JA, Jayasena S (2003) RNA interference blocks gene expression and RNA synthesis from hepatitis C replicons propagated in human liver cells. Proc Natl Acad Sci USA 100: 2783–8 115. Wu GY, Wu CH (1992) Specific inhibition of hepatitis B viral gene expression in vitro by targeted antisense oligonucleotides. J Biol Chem 267: 12436–9 116. Xu GW, Sun ZT (1996) Tissue-specific growth suppression and chemosensitivity promotion in human hepatocellular carcinoma cells by retroviral-mediated transfer of the wildtype p53 gene. Hepatology 24: 1264–8 117. Yao Z, Zhou Y (1996) In vivo inhibition of hepatitis B viral gene expression by antisense phosphorothioate oligodeoxynucleotides in athymic nude mice. J Viral Hepat 3: 19–22 118. Ying C, De Clercq E (2003) Selective inhibition of hepatitis B virus replication by RNA interference. Biochem Biophys Res Commun 309: 482–4 119. Zender L, Kock R (2002) Gene therapy by intrahepatic and intratumoral trafficking of p53-VP22 induces regression of liver tumors. Gastroenterology 123: 608–18
Gross and Microscopic Anatomy
106
Ulrich Beuers and Henryk Dancygier
Chapter Outline Embryonic Development ............................................. 1417 Gallbladder ................................................................... 1417 Extrahepatic Bile Ducts ............................................... 1418 References ..................................................................... 1421
Embryonic Development The gallbladder and bile ducts are of endoblastic origin and develop, like liver parenchyma, from the hepatic diverticulum (see also section I) [4]. This liver bud derives from a thickening of the endoblastic epithelium in the anterior (ventral) foregut wall between days 18 and 22 of embryogenesis [7]. The human gallbladder anlage can be identified as early as day 29 of embryogenesis as a dilatation along the distal half of the hepatic diverticulum. The extrahepatic bile ducts are formed during withdrawal of the duodenum from the septum transversum and, thereby, drawing out of the stalk of the hepatic diverticulum. Two nearby buds form the pancreas [4].
Gallbladder The gallbladder is a distensible muscular pear-shaped sac closely attached to the undersurface of the right liver lobe. Its size varies from 6 to 12 cm in length and 2.5–5 cm in width and it may contain 20 up to 50 mL of bile. The gallbladder consists of a fundus, a corpus, an infundibulum and a neck which opens up to the cystic duct (Fig. 106.1). After emptying, the gallbladder wall forms multiple villous formations separated by crypts which may extend through the muscularis and form a network of “Rokitansky-Aschoff sinuses”. These sinuses may be a source of inflammation in case of bacterial stasis, for example in cholecystitis due to gallstone disease. The gallbladder wall is composed of a mucosa, a lamina propria, a muscularis, and a serosa (Fig. 106.2). The mucosa contains a surface epithelium with a single H. Dancygier, Clinical Hepatology, DOI: 10.1007/978-3-642-04519-6_106, © Springer-Verlag Berlin Heidelberg 2010
1417
1418
106
Gross and Microscopic Anatomy
Fundus
Mucosal folds
Corpus
Smooth muscle Connective tissue Serosa
Collum
Fig. 106.2 Cross section through the gallbladder wall with the typical mucosal foldings (According to [6])
Cystic duct with spiral plica Common hepatic duct
Common bile duct
Fig. 106.1 Gallbladder opened through a longitudinal section (According to [6])
layer of tall columnar cells. The nuclei are ovoid and situated at the basal pole. The apical membrane forms multiple microvilli. Tubuloalveolar mucus-forming glands are localized in the wall of the gallbladder neck where the mucous membrane forms a spiral valve (of Heister) which contributes to regulation of bile flow in and out of the gallbladder. The surface epithelium is attached to a lamina propria which contains blood and lymph vessels. A muscularis mucosae and a submucosa are lacking. The muscularis propria is composed of smooth muscle bundles which are oriented in longitudinal, circular and oblique directions. The adventitia is a layer of connective tissue containing blood and lymphatic vessels, nerve fibers, and diverse cell types including ganglion cells, lymphocytes, and lipocytes. In the wall attached to the liver, small bile duct structures, possibly of embryonic origin, and directly connected to intrahepatic bile ducts can sometimes be identified (“Luschka’s bile ducts”). These may become a cause of biliary leakage after cholecystectomy. The gallbladder is supplied by the cystic artery, an end artery, which commonly originates from the right
hepatic artery. The cystic vein drains blood from gallbladder and cystic duct usually to the portal vein. Lymphatic vessels of the gallbladder drain into a lymph node at the neck of the gallbladder. Sympathetic (s) and parasympathetic (ps) nerve fibers accompanying the hepatic artery and the portal vein form a network in the gallbladder wall and are relevant for transmission of pain (s) and gallbladder contraction (ps) and relaxation (s).
Extrahepatic Bile Ducts The extrahepatic bile ducts consist of the right and left hepatic ducts which may show wide variations in form and number, and converge at the hilum 1–2 cm outside the liver surface to form the common hepatic bile duct. The cystic duct connects the S-shaped gallbladder neck over a length of about 4 cm with the common hepatic duct. Together, they form the common bile duct which passes dorsal to the upper duodenum to the pancreatic head, and enters the duodenal wall after fusion with the pancreatic duct (90% of cases; separate openings of bile duct and pancreatic duct in 10%) to form a common channel (Y-pattern) or just a common opening (V-pattern) [1]. The duodenal opening of the common bile duct and the pancreatic duct at the papilla of Vater is tightly controlled by a circular muscle, the sphincter of Oddi (Fig. 111.1) [5]. The wall of the extrahepatic ducts consists of a columnar epithelium of cholangiocytes, a fibromuscular layer, and a serosa. The muscularis of the human extrahepatic bile ducts contains thin, mainly longitudinally oriented layers of smooth muscle which may contract sporadically, but in contrast to some
Extrahepatic Bile Ducts
animal species, appear unable to exhibit effective peristaltic activity [8]. A dense network of sympathetic, parasympathetic and peptidergic nerve fibers surrounds the bile ducts in submucosal and subserosal layers. The sphincter of Oddi in particular is innervated by a dense network of cholinergic and peptidergic neurons. The common bile duct and the hepatic ducts are lined by simple columnar epithelium. Tubulo-alveolar intramural glands are a regular finding. In the terminal common bile duct the epithelial cells sit on a loose layer of connective tissue, the tunica fibromuscularis that becomes more and more dense as it approaches the hilum of the liver (Fig. 106.3). The ampullary epithelium forms cryptlike folds (Fig. 106.4). The various cell types of the
1419 Table 106.1 Cell types in the epithelium of human extrahepatic bile ducts • • • • •
Main epithelial cells Goblet cells Tuft cells Endocrine/paracrine cells Lymphocytes
human extrahepatic bile ducts have been studied on transpapillary biopsies obtained during endoscopic retrograde cholangiography [2, 3]. The superficial epithelium of the extrahepatic bile ducts contains five different cell types (Table 106.1). The most frequent cell type occurring in extrahepatic human bile ducts is the main epithelial cell. This cell has a regular polygonal or cylindrical form. Beneath the microvillous brush border there is a terminal web. In the supranuclear region many mitochondria are present. Lysosomes and peroxisomes are found less frequently. Many cells have a prominent Golgi apparatus. Secretory vacuoles, as a further sign of their metabolic activity, are frequently found in the cytoplasm. The vesicles of the smooth endoplasmic reticulum are often grouped together in separate cell compartments. The rough endoplasmic reticulum is only poorly developed. The epithelial cells are in close contact with one another. This is accomplished by indentations of neighboring cell membranes as well as by desmosomes (Fig. 106.5).
Fig. 106.3 Endoscopic transpapillary biopsy of the common bile duct. The tall columnar epithelial cells of the common bile duct rest on a dense fibromuscular layer. Scanning electron microscopy (From [3])
Fig. 106.4 Ampullary biopsy. The epithelium forms crypt-like invaginations. Scanning electron microscopy (From [3])
Fig. 106.5 Cross-section of surface epithelial cell of common bile duct displaying a well-developed Golgi apparatus and indentations of cell membranes of neighboring cells. Transmission electron microscopy (From [3])
1420
106
Gross and Microscopic Anatomy
a
b
Fig. 106.7 Tuft cell (From [3])
Fig. 106.6 (a) Goblet cell in common bile duct. Transmission electron microscopy. (b) Endoscopic transpapillary biopsy of common hepatic duct. A single goblet cell discharging its mucous content is seen at the center of the micrograph. The epithelial cells of the hepatic duct present a well-developed brush border. Scanning electron microscopy (From [3])
Scattered goblet cells are found only rarely in normal bile ducts (Fig. 106.6). In chronic cholangitis their number may increase markedly. The so called tuft cell is a very rare intraepithelial cell type that occurs in the ampullary epithelium (Fig 106.7). This cell is round to oval, its cytoplasm is less osmophilic than that of neighboring epithelial cells, and it contains some lysosomes and few mitochondria. As compared with the main epithelial cell, fewer organelles are present. The nucleus is situated basally and is oval in shape. Typical for this cell type
Fig. 106.8 Two endocrine/paracrine cells with characteristic infranuclear granules. The cell on the left is a somatostatin-storing D-cell (From [3])
is the microvillous tuft that protrudes beyond the level of the brush border of neighboring cells into the duct lumen. The microvilli possess thick central microfilaments that reach deep down into the
References
cytoplasm where they are anchored in the microfilamentous cytoskeleton. Endocrine/paracrine cells are a rare but regular constituent of the extrahepatic bile ducts (Fig. 106.8). They are most prevalent in the epithelium of the ampulla and cystic duct, but are scattered throughout the entire extrahepatic bile duct system. These cells contain various amines and peptides, such as serotonin and somatostatin [2]. Vasoactive intestinal peptide (VIP) immunoreactivity is found throughout the entire extrahepatic bile duct system and is confined to nerve fibers running beneath the epithelium and within the muscle layer. The corresponding nerve cell bodies are located mainly in the wall of the cystic duct. Lymphocytes belonging to the mucosa associated lymphatic tissue are found throughout the entire extrahepatic bile duct system. Intraepithelial lymphocytes are predominantly T helper cells, while intramural lymphocytes mostly belong to the suppressor/cytoxic subtype. Approximately 1–2% of intraepithelial lymphocytes are large granulated lymphocytes, i.e. cells exhibiting natural killer activity
1421
References 1. Bhandari M, Toouli J (2007) Motility of the biliary tree. In: Rodès J et al (eds) Oxford textbook of clinical hepatology. Oxford University Press, Oxford, pp 304–11 2. Dancygier H, Klein U, Leuschner U, et al (1984) Somatostatin-containing cells in the extrahepatic biliary tract of humans. Gastroenterology 86: 892–6 3. Dancygier H (1989) Endoscopic transpapillary biopsy (ETPB) of human extrahepatic bile ducts–light and electron microscopic findings, clinical significance. Endoscopy 21: 312–20 4. Desmet VJ, Van Eycken P, Roskams T (1999) Embryology of the liver and intrahepatic biliary tract. In: Rodès J et al (eds) Oxford textbook of clinical hepatology. Oxford University press, Oxford, pp 51–61 5. Hand BH (1963) An anatomical study of the choledochoduodenal area. Br J Surg 50: 486–94 6. Schiebler TH, Schmidt W, Zilles K (eds) (1999) Anatomie, 8th edn. Springer, Berlin/Heidelberg/New York, pp 588–9 7. Tan CE, Moscoso GJ (1994) The developing human biliary system at the porta hepatis level between 29 days and 8 weeks of gestation: a way to understanding biliary atresia. Part 1. Pathol Int 44: 587–99 8. Toouli J, Watts JM (1971) In-vitro motility studies on the canine and human extrahepatic biliary tracts. Aust N Z J Surg 40: 380–7
Physiology of the Gallbladder and the Extrahepatic Bile Ducts
107
Ulrich Beuers
Chapter Outline Physiology of the Gallbladder ..................................... 1423 Bile Storage and Excretion ............................................ 1423 Gallbladder Motility....................................................... 1424 Physiology of the Extrahepatic Bile Ducts ................. 1424 Physiology of the Sphincter of Oddi ........................... 1425 References ..................................................................... 1426
Physiology of the Gallbladder Bile Storage and Excretion In humans, the gallbladder serves as a storage reservoir for bile secreted by liver cells and for bile modified by cholangiocytes. Approximately 50% of hepatic bile is taken up by the gallbladder, with the remainder directly released into the duodenum. During interdigestive storage, bile is effectively concentrated to 10–20% of the original volume entering the gallbladder. Removal of electrolytes and water from gallbladder bile is mediated by active and passive mechanisms, among which coordinated Na+/H+ and Cl−/HCO3− exchange via a highly expressed type 3 Na+/H+ exchanger (NHE-3) and the Cl−/HCO3− exchanger 2 (AE2) may play a pivotal role for transepithelial transport of NaCl to the serosal side. Water absorption is assumed to occur secondary to NaCl transport across the mucosa mainly via aquaporins. Solute transporters like the apical bile salt transporter, ASBT, and the organic anion transporting protein, OATP-A, may mediate uptake of conjugated bile acids and other organic anions, and conjugate export pumps may mediate apical transport of various organic anions into the gallbladder lumen (MRP2) and basolateral transport into the blood (MRP3). However, their exact contribution to solute exchange across human gallbladder mucosa is yet unclear. Bile acids as the major organic solutes of bile (by weight, 68% bile acids; 22% phospholipids, 4% cholesterol, 4.5% proteins, 0.5% bilirubin) reach concentrations up to more than 100 mmol/L in the gallbladder and can, thereby, be secreted into the intestinal lumen in a highly concentrated form [5]. Bile acids have a critical function in digestion and mucosal defense. They are mediators of intestinal lipid absorption by forming mixed
H. Dancygier, Clinical Hepatology, DOI: 10.1007/978-3-642-04519-6_107, © Springer-Verlag Berlin Heidelberg 2010
1423
1424
107
micelles with dietary lipids in the intestinal lumen. Bile acids exert signaling properties at physiological concentrations in all cell types equipped with bile acid transporters such as hepatocytes, cholangiocytes and intestinal mucosal cells. Thereby, they may modulate expression and function of proteins involved in biotransformation and transport of exogenous and endogenous substrates on a transcriptional level via interaction with nuclear receptors, e.g. the farnesoid X receptor, FXR. In parallel, bile acids interact with a wide range of cellular signaling cascades including cytosolic free Ca++, protein kinase C (PKC) isoforms, mitogen-activated kinases (MAPK) Erk1/2, p38MAPK, and JNK, phosphoinositol-3-kinases (PI3K), protein kinase B (PKB), protein kinase A (PKA) and numerous others involved in short-term posttranscriptional regulation of biotransformation and secretion [2, 3]. Bile acids act also as modulators of intestinal peptide hormone secretion such as fibroblast growth factor 19 (FGF19). FGF19 is involved in the regulation of bile acid metabolism and gallbladder filling.
Gallbladder Motility Contraction and relaxation of the gallbladder are under complex neurohumoral control and are intimately related to the tone of the sphincter of Oddi. Cholecystokinin (CCK) is a potent stimulus for a contractile response of the gallbladder. CCK is released upon ingestion of a fator protein-rich meal from the proximal small intestine. Serum levels correlate with the contractile response of the gallbladder. CCK induces a slow contraction of the gallbladder with markedly enhanced gallbladder bile secretion into the duodenal lumen over a period of 20 min. In addition, gastrin releasing peptide (GRP), histamine (via H1 receptors), motilin, neuropeptide Y, secretin (together with CCK), and substance P stimulate gallbladder contraction. In contrast, FGF19, histamine (via H2 receptors), neurotensin, pancreatic polypeptide, peptide YY, and somatostatin are among the signaling agents which counteract contraction and induce gallbladder relaxation (Table 107.1). Vagal stimulation may lead to gallbladder contraction whereas stimulation of sympathetic nerves may lead to gallbladder distension. Postprandial gallbladder contraction is controlled by central nervous, gastric and duodenal stimuli and may result in >75% bile expulsion. Central nervous effects may be responsible for up to 40% of gallbladder emptying as has been
Physiology of the Gallbladder and the Extrahepatic Bile Ducts Table 107.1 Agents affecting gallbladder motility Stimulus
Gallbladder contraction
Acetylcholine Cholecystokinin (CCK) Fibroblast growth factor (FGF19) Gastrin releasing peptide (GRP) Histamine (via H1) (via H2) Motilin Neuropeptide Y Neurotensin Pancreatic polypeptide Peptide YY Secretin (with CCK) Somatostatin Substance P
+ +
Gallbladder relaxation
+ +
+ + + + + + + + + +
shown in subjects after a virtual dinner. Gastric distension and duodenal stimulation of CCK release after meal ingestion then increases gallbladder contraction to more than 75%. In the interdigestive phase, the gallbladder partially contracts at regular intervals to release up to 40% of its contents [4].
Physiology of the Extrahepatic Bile Ducts Human bile duct epithelia contribute a volume of 25% (−40%) of an alkaline, bicarbonate-rich fluid to daily bile secretion. It is assumed from animal studies that mainly cholangiocytes of “large” ductules and ducts with a diameter > 15 μm are responsible for bicarbonate-rich fluid secretion. Cholangiocytes are equipped with a wide variety of apical and basolateral transport proteins which allow for transport of solutes from bile to blood (“cholehepatic shunt” of solutes like bile acids secreted into bile and returning to the liver via cholangiocytes and the peribiliary plexus) and secretion of electrolytes, e.g. Cl− and HCO3− into bile (see also Chapter 52). The apical cAMP-sensitive Cl− channel CFTR and the apical Cl−/ HCO3− exchanger 2 (AE2) play a pivotal role for alkalinization of bile. In addition, apical Ca++-sensitive Cl− channels may contribute to HCO3-rich choleresis. Biliary Cl− secretion may cause paracellular Na+ movement
Physiology of the Sphincter of Oddi
TUDCA
TUDCA
ATP
ATP P2Y receptor
Hepatocyte
ClÐ Ca2+-dependent ClÐ-channel HCO3Ð
ClÐ cPKCα
AE
2
[Ca2+]i
➡
into the bile duct lumen followed by transcellular water movement along an osmotic gradient via water channels (aquaporins), further enhancing cholangiocellular fluid secretion. Basolateral Na+ uptake is mediated by Na+/H+ exchange via NHE1 and the Na+/K+/2Cl− cotransporter NKCC1, whereas apical Na+ uptake is mediated by the Na+/H+ exchanger NHE2. The apical sodium bile acid transporter, ASBT, together with the basolateral bile acid transporters, OSTα/OSTβ and MRP3, may mediate “cholehepatic shunting” of conjugated bile acids from bile to the peribiliary plexus. Unconjugated bile acids (e.g., C24 dihydroxy and C23 nor-dihydroxy bile acids) may enter cholangiocytes via the apical membrane in exchange for HCO3−.The role of a basolateral truncated ASBT in basolateral bile acid secretion is less clear. It is also unclear whether relevant amounts of bile acids are shunted under physiological conditions across cholangiocytes from bile to the peribiliary plexus via the above-mentioned mechanisms or whether these mechanisms only provide an “escape strategy” under conditions of biliary obstruction. Interestingly, receptor-mediated regulation of cholangiocyte secretion occurs both via the basolateral and apical membrane indicating that blood- as well as bile-derived signaling agents may affect cholangiocyte function. Stimuli of cholangiocyte HCO3− secretion include secretin together with CCK, acetylcholine, ATP, or VIP. Inhibitors of cholangiocyte HCO3− secretion include endothelin, insulin, or somatostatin. Purinergic (P2γ) receptors, insulin receptors and insulin-like growth factor-1 (IGF-1) receptors have been identified on apical cholangiocyte membranes. They support the concept of hepatocyte-cholangiocyte crosstalk via e.g. ATP, insulin or IGF-1 in bile. Cholangiocytehepatocyte crosstalk via cholangiocyte-derived IGF-1, nerve growth factor (NGF) or vascular endothelial growth factor (VEGF) secreted into the peribiliary plexus back to the liver has also been described [1]. Bile acids – like various hormones and cytokines – may exert regulation of cholangiocyte secretion in a way similar to their modulation of hepatocellular secretion [3]. The therapeutic bile acid ursodeoxycholic acid (UDCA) is known to stimulate HCO3− secretion into bile both in man and in experimental animals. It has been speculated that UDCA might stimulate cholangiocyte HCO3− secretion through Ca++-dependent mechanisms via activation of a Ca++dependent Cl− channel different from CFTR and concomitant stimulation of Cl−/HCO3− exchange via AE2
1425
cPKCα
ClÐ Cholangiocyte
Fig. 107.1 Model of a crosstalk between hepatocytes and cholangiocytes: modulation of cholangiocyte secretion by taurineconjugated ursodeoxycholic acid (TUDCA) [3]. For details, see text
(Fig. 107.1). UDCA conjugates increase the concentration of cytosolic free Ca++ in cholangiocytes and increase membrane binding of Ca++-sensitive cPKCα, mechanisms similar to those observed in hepatocytes [3]. In addition, UDCA conjugates might also increase the concentration of cytosolic free Ca++ in cholangiocytes indirectly by stimulating hepatocellular ATP secretion into bile which then might induce Ca++-dependent Cl− secretion via apical P2γ ATP receptors (Fig. 107.1).
Physiology of the Sphincter of Oddi The sphincter of Oddi controls release of bile (and pancreatic juice) into the duodenum [4]. A remarkable species variability exists in motility and function of the sphincter of Oddi. The human sphincter of Oddi exerts a basal pressure 3 mmHg above the low pressure in the bile ducts and the pancreatic ducts. Superimposed on the basal pressure, phasal contractions are observed at a rate of about 4/min (see also Chapters 47 and 111). Bile flow after a meal is promoted by both a reduction of the phasic contractions and a fall in the sphincter of Oddi basal pressure. Various hormones and a dense network of nerves tightly control the function of the sphincter of Oddi. Among these, met-enkephalin, morphine, neuropeptide Y, nitric oxide, and substance P have been shown to stimulate sphincter of Oddi contraction whereas CCK, calcitonin gene-related peptide (CGRP), glucagon, peptide YY, somatostatin, and tramadol inhibit sphincter of Oddi activity [4].
1426
107
References 1. Alvaro D, Mancino MG, Glaser S, et al (2007) Proliferating cholangiocytes: a neuroendocrine compartment in the diseased liver. Gastroenterology 132: 415–31 2. Anwer MS (2004) Cellular regulation of hepatic bile acid transport in health and cholestasis. Hepatology 39: 581–90
Physiology of the Gallbladder and the Extrahepatic Bile Ducts 3. Beuers U (2006) Drug insight: Mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat Clin Pract 3: 318–28 4. Bhandari M, Toouli J (2007) Motility of the biliary tree. In: Rodès J et al (eds) Oxford textbook of clinical hepatology. Oxford University Press, Oxford, pp 304–11 5. Wagner M, Trauner M (2007) Physiology of bile formation. In: Rodès J et al (eds) Textbook of clinical hepatology, 3rd edn. Oxford University Press, Oxford, pp 290–304
Anomalies of the Gallbladder and the Cystic Duct
108
Michael A. Kern and Peter Schirmacher
Chapter Outline Numerical Anomalies of the Gallbladder .................. 1429 Positional Anomalies of the Gallbladder ................... 1430 Internal and External Morphological Anomalies of the Gallbladder ........................................................ 1431 Anomalies of the Cystic Duct ...................................... 1431
Anomalies of the gallbladder and extrahepatic bile ducts can occur in relation to number, position or shape. Several of these anomalies have clinical significance. The knowledge of such anomalies is essential not only for the diagnosis of biliary disease but also with respect to the growing abundance of minimally invasive therapeutical strategies in the treatment of gallbladder and extrahepatic bile duct diseases.
References ..................................................................... 1432
Numerical Anomalies of the Gallbladder Agenesis of the gallbladder occurs in up to 0.13% of the population and it is the result of a failure of the cystic bud to develop. Patients with this anomaly fall into one of three broad categories: children with multiple congenital anomalies, asymptomatic adults in whom the abnormality is first discovered at autopsy, and symptomatic adults who have cholelithiasis. In the case of gallbladder agenesis, the cystic duct is also almost invariably absent and the surface of the liver may not contain the usual corresponding depression [3, 16, 25]. Other congenital anomalies that have been associated with agenesis include polycystic kidney disease, tracheoesophageal fistulae, cardiac anomalities, annular pancreas, Kippel–Feil syndrome, and gastrointestinal anomalies, including imperforate anus, duodenal atresia, and shortening of the ascending colon [13, 17, 29]. This anomaly may also accompany congenital hypoplasia of the right lobe of the liver. A hypoplastic gallbladder may occur when the caudal bud undergoes incomplete development or when the solid stage of the bud is not recanalized. This anomaly may be found in association with congenital
H. Dancygier, Clinical Hepatology, DOI: 10.1007/978-3-642-04519-6_108, © Springer-Verlag Berlin Heidelberg 2010
1429
1430
108
biliary atresia and in cystic fibrosis. This condition should be differentiated from an acquired postinflammatory, fibrotic shrinkage of the gallbladder. Although an absent gallbladder usually remains asymptomatic, the risk of developing cholelithiasis is increased. Through the preoperative determination of an absent gallbladder, extirpation of a presumably symptomatic gallbladder can be avoided [9]. Duplication of the gallbladder is uncommon (4 out of 1,000 cases) (Fig. 108.1). Both gallbladders may drain into their own separate cystic ducts or via one bifid duct. There are rare examples of cases in which one of the cystic ducts drains directly into either the left or right hepatic duct or even into the duodenum. Duplication of the gallbladder may also be associated
Normal
Hypoplastic
Agenesis
Phrygian cap
Diverticulum
Hourglass
Bilobed
Double
Numerical
Fig. 108.1 Variations of the gallbladder
Anomalies of the Gallbladder and the Cystic Duct
with abnormalities of vascular supply, including an anomalous anterior displacement of the right hepatic artery [9]. An incomplete duplication of the gallbladder (vesica fellea divisa), may be differentiated form a complete duplication (vesica fellea duplex). A vesica fellea divisa is characterized by a dividing wall containing all wall components (in contrast to a septated gallbladder, vesica septa, see below), which separates the fundus and, in some cases, the corpus of both gallbladders as well. The neck portion of the gallbladder is not duplicated and only one cystic duct is present. The external shape of the gallbladder may be completely normal. In the case of a vesica fellea duplex, which is approximately five times more frequent, two main forms are differentiated: the Y-type and the H-type (the most frequent variation). The Y-type is characterized by the confluence of both cystic ducts to a common end portion whereas the H-type denominates two complete gallbladders and two separate cystic ducts, which either enter the common hepatic duct separately or they enter the common hepatic duct as well as the right or left hepatic duct. The location and size of these gallbladders can vary. A triplicate of the gallbladder is an extreme rarity [9, 10 15, 19, 22, 30].
Positional Anomalies of the Gallbladder Minor malpositionings of the gallbladder, which are usually of little clinical significance, include an intrahepatic gallbladder and a floating gallbladder (i.e. one that is distracted from the surface of the liver by its own mesentery). Intrahepatic gallbladders rarely cause specific clinical problems, although basically they are subject to diseases commonly encountered in normally positioned organs. These diseases include inter alia cholecystitis, cholelithiasis, and abscess formation. Problems may, however, be encountered at cholecystectomy, when liver tissue may need to be excised to allow for adequate exposure of the gallbladder. In most instances, however, the gallbladder is not deeply buried in the liver. Intrahepatic gallbladders may also cause diagnostic problems on imaging studies if the possibility of a malpositioned organ is not considered. In the case of the floating gallbladder, the gallbladder may be completely covered by peritoneum, and the fixation of the organ is achieved through the
Anomalies of the Cystic Duct
supplying vessels as well as a string-like fold of the peritoneum ending at the ventral edge of the liver. This anomaly is pathologic, as a rotation of the vessels can cause ischemia and subsequent gangrene of the gallbladder. The presence of a floating gallbladder has also been associated with hypoplasia of the left lobe of the liver. Rarely, one will find a left-sided gallbladder, in which the cystic duct joins either the common hepatic duct or the right or left hepatic ducts. Equally seldom is a retro-duodenal position of the gallbladder [9, 12].
Internal and External Morphological Anomalies of the Gallbladder A multiseptate gallbladder is a congenital anomaly that is readily diagnosed by ultrasound examination. The lumen is partitioned by thin septa covered by normal mucosa and consisting of a muscle layer and a lamina propria in continuity with the bladder wall. The septa may be fenestrated or noncommunicating (Figs. 108.1 and 108.2). Both the body and the fundus of the gallbladder can display a congenital kink. In its complete form the kinking includes the serosa, and in its incomplete form it is sub-serous in nature and the surface of the gallbladder appears normal. If the fundus of the gallbladder shows kinking the condition is called a “phrygian
1431
cap.” This anomaly accounts for approximately 5% of cases and there are no associated pathophysiological processes [9, 32]. A congenital stricture of the gallbladder has also been described. This anomaly can be present in various parts of the gallbladder. When the gallbladder is constricted around the middle of the organ as the result of an anomaly in the gallbladder bed it is referred to as an “hourglass” gallbladder. Rarely, a true congenital gallbladder diverticulum can be found, in which the complete organ wall exists within the diverticulum. The usual location for such diverticula are the fundus and the neck (Fig. 108.1).
Anomalies of the Cystic Duct Knowledge of the variations of the cystic duct is important, especially to avoid injury when performing laparoscopic and open cholecystectomy. Approximately 13% of individuals show some variations of the bile ducts, including abnormalities of the cystic or common bile ducts and the presence of accessory hepatic ducts (Table 108.1). Usually the cystic duct, 4 cm long on average, joins the common hepatic duct at an acute angle from the right side approximately 3 cm distal to the confluence of the right and left hepatic ducts. There are many variations, for which the frequencies have been reported in wide ranges. The union with the common bile duct may occur abnormally high or low. The union may occur from the left instead of from the right side, after crossing the front or from behind. It is also possible for the cystic duct to join into the right or, very rarely, the left hepatic duct. Even if only one gallbladder is present, two cystic ducts may connect the gallbladder with the common hepatic duct. A few cases of cystic dilation of the cystic duct, with or without the presence of stones, have been reported. An isolated duplication of the cystic duct is extremely rare and, when present, it can be associated with a highly variable union of both ducts (Fig. 108.3) [1, 6, 7]. Table 108.1 Anomalies of the extrahepatic biliary tract
Fig. 108.2 Multiseptate gallbladder
Stenosis and atresia Cystic disease of the common bile duct Accessory hepatic duct Malpositioning and reduplication of the common bile duct
1432
108
a
b
d
c
e
Fig. 108.3 Examples of anomalies of the cystic duct. (a) Absent cystic duct. (b) Cystic duct joining common bile duct at lower level. (c) Long cystic duct fused to the common bile duct. (d) Cystic duct joining the right hepatic duct. (e) Cystic duct joining at the junction of both hepatic ducts
References for Chapter 108 are listed at the end of Chapters 110 (page 1437)
Anomalies of the Gallbladder and the Cystic Duct
Anomalies of the Extrahepatic Bile Ducts
109
Michael A. Kern and Peter Schirmacher
Chapter Outline Anomalies in the Number and/or Course of the Extrahepatic Bile Ducts .................................... 1433 Form Anomalies of the Extrahepatic Bile Ducts ....... 1434
Variations in the course, form and number of extrahepatic bile ducts are frequent. Thus, the differentiation between a variation of a normal and pathological state is not always easy. The knowledge of such variations is especially important with regard to operative and nonoperative bile duct interventions.
Congenital Bile Duct Cysts............................................ 1434 Congenital Biliary Atresia and Stenosis ........................ 1435 References ..................................................................... 1436
Anomalies in the Number and/or Course of the Extrahepatic Bile Ducts The right hepatic duct can join the cystic duct, which is a clinically important anomaly. If, intraoperatively, this duct is ligated distal to the union, the bile flow from the right liver lobe will be blocked. The right hepatic duct can also drain directly into the gallbladder. Both hepatic ducts can join the duodenum directly without first uniting, whereby in these cases, the right hepatic duct usually incorporates the cystic duct [8, 18]. Duplication of the common bile duct, i.e. splitting after the union of both hepatic ducts, is very rare. Both ducts may then join the gastrointestinal tract in a highly variable pattern along different portions of the GI-tract (see below). Course anomalies of the bile duct are merely variations in location of the junction with the gastro-intestinal tract. This usually occurs in the middle third of the descending part of the duodenum, but it can vary both in an oral and aboral direction. Rare cases may include a proximal shift as far as the stomach or a distal shift as far as the ileum or even the colon [20]. True accessory (i.e. additional) or aberrant bile ducts with connection to the gallbladder or the cystic duct are generally rare but usually have normal bile drainage capacity; however, when present, they have important surgical considerations because, if overlooked,
H. Dancygier, Clinical Hepatology, DOI: 10.1007/978-3-642-04519-6_109, © Springer-Verlag Berlin Heidelberg 2010
1433
1434
they can cause bile leakage as well as bile drainage disturbances. A true rarity is the congenital bronchobiliary fistula, i.e. an inborn connection between the respiratory tract and the biliary system. While the Sphincter of Oddi usually includes both the distal bile duct as well as the segment of the pancreatic duct that is in close proximity to the duodenum, the union of the bile and pancreatic ducts may occur above the sphincter and lead to the formation of a “common channel”. This anomaly, which has also been discussed as a possible cause of a bile duct cyst, has been shown to increase the risk of malignancy. When a bile duct cyst is present, the malignancy usually occurs in this duct or in the gallbladder; however, when a bile duct cyst is not present, a carcinoma can only be found in the gallbladder.
Form Anomalies of the Extrahepatic Bile Ducts Congenital Bile Duct Cysts Idiopathic (congenital) bile duct cysts refer to dilatations of the extrahepatic biliary tract and are therefore not cysts in an anatomical sense. They vary in size and location and can be present singularly or in multiplicity (Fig. 109.1) [2, 4, 6]. The separation of the common hepatic duct or the cystic duct can also be affected by this dilation; the transition to the rest of the biliary tract is always prominent. Because this dilation can occur proximal to the junction of the cystic duct with the common hepatic duct, the term “biliary cyst” should be used strictly for this case, contrary to common clinical terminology. This term also includes intrahepatic biliary cystic lesions. According to the Todani classification, 5 types of cystic biliary lesions can be differentiated [33]: • Type Ia: solitary, fusiform (spindle-shaped), extrahepatic cystic transformation of the bile duct with cystic duct involvement (about 80% of cases) • Type Ib: segmental, extrahepatic dilation • Type Ic: diffuse or columnal extrahepatic dilation • Type II: saccular-like, extrahepatic supraduodenal cysts • Type III: intraduodenal diverticulum (choledochocele)
109
Anomalies of the Extrahepatic Bile Ducts
• Type IVa: intra- and extrahepatic fusiform cysts • Type IVb: multiple extrahepatic cysts • Type V: solitary or multiple intrahepatic cysts (Caroli syndrome) (see Chapter 56) Depending on the size of the cysts, compression of neighboring structures is often the consequence and a chronic bile stasis is often found proximally to the cysts. All cysts (with the exception of choledochoceles) histologically demonstrate scattered islets of columnar epithelium; typical biliary epithelium is not present. The relatively thick wall contains predominantly connective tissue with a small amount of smooth muscle. Depending on the age of the patient, inflammatory changes of the wall can be seen with increasing frequency. Choledochoceles are usually lined by duodenal mucosa or, more rarely, by biliary or mixed mucosa. The clinical presentation is typically characterized by one or more of the following symptoms: jaundice, swelling, and/or pain in the right upper quadrant. If the disease manifests itself in the first few weeks of life, jaundice is often the only symptom. If the biliary cyst first becomes symptomatic after the first decade of life, it may cause abdominal pain occasionally accompanied by intermittent jaundice. Whether the development of biliary cysts can pathogenetically lead to a related wall weakness, inflammatory processes, or a distal drainage blockade, has not yet been decided. The
Fig. 109.1 Different types of congenital cystic dilatations of the common bile duct
Form Anomalies of the Extrahepatic Bile Ducts
anomalous junction of the bile duct with the pancreatic duct distally to the duodenum with a long “common channel” is most frequently associated with the common form of biliary cysts (Type I), as it is most often seen in association with these cysts. Because the union lies above the Sphincter of Oddi, pancreatic secretions can flow into the bile duct without hindrance, which can promote inflammatory destructive biliary tract alterations even in utero. The clinical importance of biliary cysts lies in their association with increased stone formation and cholangitis. This may lead to secondary biliary cirrhosis and an increased frequency of carcinoma within the area of the dilatation in approximately 20% of cases. Histologically, these are adeno-, squamous cell- and undifferentiated carcinomas. Therapeutically, operative draining methods (i.e. choledochocystojejunostomy) have been replaced by methods involving the removal of the dilated biliary segment and bilioenteric anastomoses (usually a hepaticojejunostomy). The advantage of resection lies in the low rate of stone formation and subsequent recurrent cholangitis, as well as the decreased risk for carcinoma. Choledochoceles can be differentiated from the other choledochal cysts histologically (see above). To achieve free drainage, an opening to the duodenum or an endoscopic sphincterotomy is performed [27, 34, 35].
1435
further diagnostic evaluation. These diagnostics include, in addition to radiologic imaging, liver biopsy. Characteristically, portal edema, ductular reaction, ductular bile thrombi and swelling of hepatocytes with the formation of giant multinucleated hepatocytes and detection of neutrophil granulocytes is observed. The respective malformation is characterized by the location of the atretic lesion; that is, whether the common bile duct, hepatic duct, cystic duct and gallbladder as well as the intrahepatic biliary tract are involved. Clinically, the Kasai classification is used for extrahepatic biliary atresia (Fig. 109.2) [21]. Without therapy, there is a risk of hemorrhage as the result of vitamin K deficiency (from a resorption deficiency), infection, and liver failure. In the case of solitary extrahepatic atresia, proper intrahepatic biliary structures can be demonstrated histologically. In the more unfavorable forms of the disease, the intrahepatic biliary tract is involved in the destructive process, which can advance to progressive liver failure even after a successful Kasai’s portoenterostomy. While an operative correction is not possible in the case of complete atresia, extrahepatic atresia can be successfully treated before irreversible liver damage results if diagnosed early
Congenital Biliary Atresia and Stenosis Congenital biliary atresia describes a wide spectrum of inborn obliterative cholangiopathies and ranges from complete absence of the entire intra- and extrahepatic biliary system to a singular, localized stenosis of the bile duct (see also Chapter 56) [5]. Altogether, its incidence is approximately 1/10,000 live births. The cause of the differing forms of biliary atresia is not clear. Several acquired etiologies have been discussed, especially exposure to viruses in the later stages of pregnancy. Metabolic causes or genetic defects may also be involved. Histologically, fibrosis-inducing, inflammatory and angioproliferative changes are found in areas of structural bile duct remnants. In approximately 25% of cases this condition is associated with extrabiliary malformations. The diagnosis is usually made within the first weeks of life after clinical symptoms including persistent jaundice, acholic stools and hepatomegaly prompt
I
IIb
IIa
III
Fig. 109.2 Classification of biliary atresia according to Kasai. Type 1: closure of the common bile duct; Type 2a: closure of the common hepatic duct; Type 2b: closure of the common hepatic duct, the common bile duct and the cystic duct as well as cystically dilated biliary ducts in the region of the portal vein; Type 3: like Type 2b plus the absence of anastomosis-capable biliary tracts in the portal vein
1436
enough (preferably before the 8th week of life). Depending on whether an anastomosis-compatible biliary tract is present (rare), either a biliodigestive anastamosis (Roux-en-Y) or a Kasai’s portoenterostomy is performed. In this operation, atretic tract remnants are removed and a jejunal loop disconnected via Roux-en-Y is anastomosed with the cut surface of the liver hilus, so that the small, connected biliary ducts can drain. In the case of an inoperable atresia or after an unsuccessful operation, the last therapeutic option is a liver transplantation, which has become increasingly more successful in recent years. Biliary atresia is presently the most frequent cause for transplantation in childhood [11, 14, 24, 31].
References for Chapter 109 are listed at the end of Chapters 110 (page 1437)
109
Anomalies of the Extrahepatic Bile Ducts
Benign Strictures of the Extrahepatic Bile Ducts
110
Michael A. Kern and Peter Schirmacher
Strictures, or scarred narrowing, of the extrahepatic biliary tract can have several etiologies. One must distinguish this condition from extraluminal stenosis resulting from, for example, compression of the distal biliary tract in chronic pancreatitis. Additionally, the possibility of a malignant stricture must always be considered and investigated. Benign strictures in the biliary tract most frequently occur postoperatively, especially after laparascopic cholecystectomy. Direct intraoperative biliary tract injuries or clips placed too close to the bile duct can form a stricture via ischemia and/or scarring. Biliary tract strictures occur with significant frequency after liver transplantation and are mostly of ischemic nature, while those due to primary sclerosing cholangitis are mostly inflammatory (see Chapters 52, 75 and 103). A suspicion of the diagnosis is possible through an indicative clinical history combined with the clinical and laboratory evidence of cholestasis (with or without jaundice). Sonographically, the biliary tract proximal to the stricture is dilated. Diagnosis is confirmed by endoscopic retrograde cholangiography, during which therapy can be performed [28]. Through the combination of dilatation of the stricture and stenting, the mechanical obstruction can be permanently eliminated in many cases. This procedure is especially successful in early postoperative stenoses located below the bifurcation. Anatomically difficult cases (e.g. after Billroth II procedure) may be approached with percutaneous transhepatic cholangiographic methods in the hands of skilled interventional gastroenterologists or radiologists. If dilatation and stenting are unsuccessful, the possibility of a neoplastic process must be evaluated and an operative revision is usually necessary [23, 26].
References for Chapters 108, 109, 110 1. Adkins RB Jr, Chapman WC, Reddy VS (2000) Embryology, anatomy, and surgical applications of the extrahepatic biliary system. Surg Clin North Am 80: 363–79 2. Alonzo-Lej F, Revor WB, Pessagno DJ (1959) Congenital choledochal cyst, with a report of 2, and analysis of 94 cases. Surg Gynecol Obstet Int Abstr Surg 108: 1–30 3. Azmat N, Francis KR, Mandava N, et al (1993) Agenesis of the gallbladder revisited laparoscopically. Am J Gastroenterol 88: 1269–70 4. Babbitt DP (1969) Congenital choledochal cysts: new etiological concept based an anomalous relationships of common bile duct and pancreatic duct. Ann Radiol 12: 231–40 5. Bates MD, Bucuvalas JC, Alonso MH, et al (1998) Biliary atresia: pathogenesis and treatment. Semin Liver Dis 18: 281–93 6. Benhidjeb T, Ridwelski K, Wolff H, et al (1991) Anomalie der pankreatiko-biliären Verbindung und Ätiologie der Choledochuszysten. Zentralbl Chir 116: 1195–203 7. Berci G (1992) Biliary ductal anatomy and anomalies. Surg Clin North Am 72: 1069–75 8. Blecha MJ, Frank AR, Worley TA, et al (2006) Aberrant right hepatic artery in laparoscopic cholecystectomy. JSLS 10: 511–13 9. Bolck F, Machnik G (1978) Fehlbildungen der Gallenblase und der extrahepatischen Gallengänge. In: Doerr W, Seifert G, Uehlinger E (Hrsg) Spezielle pathologische Anatomie, Bd 10: Leber und Gallenwege. Springer, Berlin/Heidelberg/ New York, pp. 757–79 10. Boyden EA (1926) The accessory gallbladder; an embryological and comparative study of aberrant biliary vesicles occurring in man and the domestic mammals. Am J Anat 38: 177 11. Carmi R, Magee CA, Neill CA, et al (1993) Extrahepatic biliary atresia and associated anomalies: etiologic heterogeneity suggested by distinctive patterns of associations. Am J Med Genet 45: 683–93 12. Chung CC, Leung KL, Lau WY, et al (1997) Ectopic gallbladder revisited, laparoscopically: a case report. JCC 40: 464–6
H. Dancygier, Clinical Hepatology, DOI: 10.1007/978-3-642-04519-6_110, © Springer-Verlag Berlin Heidelberg 2010
1437
1438 13. Coughlin JP, Rector FE, Klein MD (1992) Agenesis of the gallbladder in duodenal atresia: two case reports. J Pediatr Surg 27: 1304 14. Davids PHP, Tanka AKF, et al (1992) Benign biliary strictures. Surgery or endoscopy. Ann Surg 3: 237–43 15. Elsayes KM, Oliveira EP, Narra VR, et al (2007) Magnetic resonance imaging of the gallbladder: spectrum of abnormalities. Acta Radiol 48: 476–82 16. Frey C, Bizer L, Ernst C (1967) Agenesis of the gallbladder. Am J Surg 114: 917–26 17. Gotohda N, Itano S, Horiki S, et al (2000) Gallbladder agenesis with no other biliary tract abnormality: report of a case and review of the literature. J Hepatobil Pancreat Surg 7: 327–30 18. Grosfeld JL, Rescorla FJ, Skinner MA, et al (1994) The spectrum of biliary tract disorders in infants and children. Arch Surg 129: 513–8 19. Harlaftis N, Gray SW, Skandalakis JE (1977) Multiple gallbladders. Surg Gynecol Obstet 145: 928–34 20. Horsmans Y, De Grez T, Lefebvre V, et al (1996) Double common bile duct with ectopic drainage of the left lobe into the stomach. Case report and review of the literature. Acta Gastroenterol Belg 40: 256–57 21. Kasai M (1974) Treatment of biliary atresia with special reference to hepatic portoenterostomy and its modifications. Prog Pediatr Surg 6: 5–52 22. Knight M (1981) Anomalies of the gallbladder bile ducts and arteries. In: Lord Smith of Marlow, Sherlock S (eds) Surgery of the gallbladder and bile ducts, 2nd edn. ButterworthHeinemann, Oxford, pp 97–116 23. Kuga H, Yamaguchi K, Shimizu S, et al (1998) Carcinoma of the pancreas associated with anomalous junction of pancreaticobiliary tracts: report of two cases and review of the literature. J Hep Bil Pancr Surg 5: 113–6
110
Benign Strictures of the Extrahepatic Bile Ducts
24. Lefkowitch JH (1998) Biliary atresia. Mayo Clin Proc 73: 90–95 25. Nardello O, Muggianu M, Cagetti M (2007) Agenesis of the gallbladder. Ann Ital Chir 78: 45–7 26. Okamura K, Hayakawa H, Kuze M, et al (2000) Triple carcinomas of the biliary tract associated with congenital choledochal dilatation and pancreaticobiliary maljunction. J Gastroenterol 35: 465–71 27. O’Neill JA (1992) Choledochal cyst. Curr Probl Surg 29: 365–410 28. Ponsky JL (1996) Endoscopic approaches to common bile duct injuries. Surg Clin North Am 76: 505–13 29. Praseedom RK, Mohammed R (1998) Two cases of gall bladderagenesisandreviewoftheliterature.Hepatogastroenterology 45: 954–5 30. Skandalakis JE, Gray SW, Ricketts R, et al (1994) The extrahepatic biliary ducts and the gallbladder. In: Skandalakis JE, Gray SW (eds) Embryology for surgeons, 2nd edn. Williams & Wilkins, Baltimore, MD, pp 296–333 31. Smith MT, Sherman S, Lehman GA (1995) Endoscopic management of benign strictures of the biliary tree. Endoscopy 27: 253–66 32. Stolte M (1980) Morphologie der Gallenwege. In: Bartelheimer H, Ossenberg FW, Schreiber HW (Hrsg) Die kranken Gallenwege. Witzstrock, Baden-Baden Köln New York 33. Todani T, Watanabe J, Narusue M, et al (1977) Congenital bile duct cysts. Am J Surg 134: 263–9 34. Todani T, Watanabe Y, Fuji T, et al (1984) Anomalous arrangement of the pancreatobiliary ductal system in patients with a choledochal cyst. Am J Surg 147: 672–6 35. Traverso LW (1986) Management of biliary cysts. Probl Gen Surg 3: 147–56
Motility Disorders of the Bile Ducts and Postcholecystectomy Syndrome
111
Hans-Dieter Allescher
Chapter Online Postcholecystectomy Syndrome .................................. 1441 Definition and Epidemiology ......................................... 1441 Etiology and Pathogenesis ............................................. 1441 Clinical Presentation and Diagnosis .............................. 1442 Differential Diagnosis .................................................... 1442 Sphincter of Oddi Dysfunction ................................... 1445 Diagnostic Procedures ................................................... 1445 Sphincter of Oddi Dyskinesia ..................................... 1451 SOD Type I .................................................................... 1451 SOD Type II ................................................................... 1452 SOD Type III.................................................................. 1452 Clinical Course and Prognosis ....................................... 1453 Therapy .......................................................................... 1453 References ..................................................................... 1454
Postcholecystectomy Syndrome Definition and Epidemiology Cholecystectomy is an efficient and effective way to treat symptomatic gallbladder stones or cholecystitis with an excellent postoperative outcome. However, in a small subgroup of patients biliary type symptoms persist even after removal of the gallbladder, and in some patients new, colicky symptoms in the right upper quadrant develop. For the subgroup of patients with persistent or new complaints after cholecystectomy the term “postcholecystectomy syndrome” has be coined. Postoperative complaints can occur in 2–15% of patients, though only a very small portion of these patients suffer from a functional disorder of the papillary region (sphincter of Oddi dysfunction), which can be related either to an organic stenosis of the papillary region or to a motility disorder of the sphincter of Oddi (sphincter of Oddi dyskinesia) (see below).
Etiology and Pathogenesis In patients with suspected postcholecystectomy syndrome, it is mandatory to evaluate and distinguish different possible origins of their symptoms. Besides a biliary etiology, the symptoms can be related to organic disorders of the upper GI-tract or to functional bowel disorders such as functional dyspepsia or irritable bowel syndrome. Patients with functional bowel disease should ideally be identified prior to cholecystectomy because even though they may have cholecystolithiasis, the likelihood of cholecystectomy resulting in a durable improvement in their symptoms is low. H. Dancygier, Clinical Hepatology, DOI: 10.1007/978-3-642-04519-6_111, © Springer-Verlag Berlin Heidelberg 2010
1441
1442
111
Motility Disorders of the Bile Ducts and Postcholecystectomy Syndrome
Sometimes these patients with false indications for surgery are also categorized as postcholecystectomy syndrome. In a relatively small subgroup of patients (5–15%), symptoms originate in the biliary system and the biliary or pancreatic sphincter. These patients show certain abnormalities of the biliary or pancreatic system, which can be identified by means of different diagnostic tests (e.g. ultrasound, laboratory tests, ERCP, hepatobiliary scintigraphy, sphincter of Oddi manometry). The etiology of sphincter of Oddi dyskinesia (SOD) is not completely understood. Some data suggest that it is caused by disturbances of the autonomic neural innervation of the sphincter region (Fig. 111.1). Cholecystokinin octapeptide (CCK) induces the release of other inhibitory mediators (VIP, NO) in the sphincter muscle, which usually inhibits SO motility. In patients with SOD, CCK induces a characteristic paradoxical excitatory contractile response of the sphincter segment. This could indicate that in SOD patients a similar disorder of the inhibitory nerves is present as it is in achalasia. In addition, there is experimental evidence that a reflex pathway exists between the gallbladder, duodenum and sphincter of Oddi, which could be severed during cholecystectomy. In this case SOD would be a consequence of the operative procedure. There are some patients, however, who have SOD even with their gallbladder in situ. As with other functional disorders,
Ductus choledochus Duodenal wall
Pancreas (Acini)
Ductus pancreaticus
Duodenal wall
Ampulla hepatopancreatica
Sphincter of Oddi Sphincter ampullae
Fig. 111.1 Anatomy of the sphincter of Oddi region
the symptoms could be a reason for the operative removal of the gallbladder. In this case SOD would be the cause and not the consequence of the operation.
Clinical Presentation and Diagnosis Patients with a biliary origin of postcholecystectomy complaints suffer from typical colicky, postprandial right upper quadrant pain. The pain often radiates to the back and to the right shoulder, and can last for several hours. These symptoms can be associated with elevations of cholestatic liver enzymes. In contrast, intermittent cholestasis, slight jaundice or fever as well as acholic stool is atypical for functional disorders of the sphincter of Oddi and is more likely due to a mechanical obstruction or stenosis [7]. When the functional disorder involves the pancreatic segment, either isolated or in combination with the biliary sphincter, recurrent attacks of mild pancreatitis or elevation of pancreatic enzymes can be observed. As a first step it is important to rule out pathologic structural or anatomical causes of the symptoms (e.g., stones, tumors of the papilla). This includes laboratory tests (liver enzymes, alkaline phosphatase, γGT, bilirubin, lipase, amylase) and upper GI endoscopy as well as an abdominal ultrasound. To rule out retained bile duct stones transcutaneous abdominal ultrasound, MRCP or endoscopic ultrasound can be used [1]. When MRCP is unavailable or a distal CBD stone is suspected, endoscopic ultrasound is preferred as it has been shown to have the best negative predictive value with lowest complication rate. Using MRCP or ERCP additional etiologies of postoperative biliary complaints such as benign bile duct strictures, a long cystic duct with retained stones, or bile duct or papillary tumors can be identified (Fig. 111.2). If these causes of the biliary symptoms can be ruled out, dysfunction of the papilla has to be considered.
Differential Diagnosis In the following overview different etiologies of upper abdominal complaints following cholecystectomy are summarized.
Postcholecystectomy Syndrome
1443
a
b
c
(continued)
1444
111
Motility Disorders of the Bile Ducts and Postcholecystectomy Syndrome
d
e
Fig. 111.2 Different pathologic findings in patients with postcholecystectomy syndrome. (a) Retained stone in the common bile duct, (b) dilated segmental right intrahepatic bile duct; visualized only on postoperative MRCP (lower panel),
Reasons for typical right upper quadrant biliarytype pain after cholecystectomy are Bile duct stones Bile duct injuries (Postoperative) scarring of the bile duct Structural abnormalities of the bile (choledochocele) • Long cystic duct with retained stone(s) • Mirizzi syndrome • • • •
duct
(c) adenoma of the papilla of Vater, (d) postoperative common bile duct stricture, (e) stenosing papillitis. Endoscopic sphincterotomy via a guidewire
• Tumors of the bile duct or the papilla • Sphincter of Oddi dysfunction – Stenosis of the papilla – Sphincter of Oddi dyskinesia • Other organic reasons in the upper abdomen (e.g. peptic ulcer) • Functional bowel disorders – Functional dyspepsia (FD) – Irritable bowel syndrome (IBS)
Sphincter of Oddi Dysfunction
Bile Duct Stones A retained and overlooked stone in the bile duct following cholecystectomy has to be considered as cause of a post-cholecystectomy syndrome (1–6%) and should be ruled out with percutaneous ultrasound, endoscopic ultrasound, MRCP or ERCP. Even intraoperative cholangiography via the cystic duct does not completely rule out a retained stone, as stones can still be found in up to 4% of patients. Most of the patients with a retained stone develop symptoms shortly after the operation. However, in some patients a symptom-free postoperative interval of several weeks or longer can be present. Similar to the acute situation, endoscopic ultrasound and MRCP are the diagnostic methods of choice to rule out a retained stone. These methods have widely replaced ERCP as they bear no risk of postinterventional pancreatitis in the diagnostic setting. If a stone is identified, ERCP and endoscopic sphincterotomy followed by stone extraction is the therapy of choice. Long Cystic Duct with Retained Stone A long cystic duct has been discussed for a long time as a possible cause of postoperative complaints. A remaining dilated proximal cystic duct remnant with Heister’s spiral valve or a retained stone can cause symptoms [21, 30]. If the stone is retained in the more distal part of the cystic duct, a compression of the closely related bile duct system can occur (Mirizzi-Syndrome). The results of interventional studies are contradictory. Whereas some series report an improvement of symptoms after removal of the long cystic duct, others failed. Another possible cause for symptoms in patients with a long cystic duct remnant is the formation of neuromas and granulomas due to suturing material following conventional cholecystectomy. Bile Duct Strictures In cases of complicated intraoperative situations with severe inflammation, bleeding or injuries of the duct system, postoperative scarring of the tissue can lead to a stricture or even obstruction of the bile duct system. The incidence of such scarring is reported in the literature to be in the range of 5–10%, mostly involving the middle part of the bile duct [9].
1445
The clinical presentation is characterized by progressive jaundice and cholangitis, and can thus be distinguished from SO dysfunction. This situation can be suspected by abdominal ultrasound showing a typical dilatation of the biliary system proximal to the stenosis, and can be verified by either MRCP or ERCP. The treatment is based on endoscopic dilatation of the stricture and long term stenting with large diameter stents and/or multiple stents for several months. In cases that are refractory to endoscopic therapy, surgical intervention with a biliary bypass procedure should be considered. Stenosis and Tumors of the Papilla Scaring of the papilla, adenomas and malignant tumors of the papilla can lead to papillary obstruction with subsequent biliary symptoms. These conditions can be present prior to cholecystectomy, and symptoms persist or even worsen after removal of the gallbladder. Papillary adenomas and tumors can usually be identified by endoscopic inspection or biopsy of the papilla with a side-viewing instrument. Sometimes an endoscopic sphincterotomy is necessary for correct identification and diagnosis. Scarring of the papilla with a papillary stenosis (e.g. postinflammatory, papillitis stenosans) shows a considerable similarity and overlap with sphincter of Oddi dyskinesia (see below).
Sphincter of Oddi Dysfunction Sphincter of Oddi dysfunction is responsible for “postcholecystectomy syndrome” in only a minority of cases (5–15%) Altogether this abnormality is observed in fewer than 1% of all patients who have undergone cholecystectomy. The symptoms are characterized by typical colicky right upper quadrant pain or by recurrent attacks of pancreatitis [11, 24, 29]. In the latter situation, intermittent obstruction of the pancreatic outflow tract leads to recurrent attacks of pancreatitis.
Diagnostic Procedures The diagnosis of sphincter of Oddi dyskinesia is primarily based on the exclusion of other organic disorders of the bile duct system (see above) and the surrounding
1446
111
Motility Disorders of the Bile Ducts and Postcholecystectomy Syndrome
Table 111.1 Classification of sphincter of Oddi dyskinesia (SOD) based on clinical criteria (Milwaukee criteria) [7, 11] Typical right upper quadrant pain SOD type I + SOD type IIa + SOD type III + a At least one of three criteria positive
Elevation of AP, γGT Dilatation of the bile duct AST or ALT 2–3 times ULN (ERCP) > 12 mm
Drainage of contrast medium from bile duct > 45 min
+ +/−a −
+ +/−a −
+ +/−a −
Table 111.2 Classification of sphincter of Oddi dyskinesia (SOD) of the pancreatic sphincter based on clinical criteria Typical right upper quadrant pain SOD type I + SOD type IIa + SOD type III + a At least one of three criteria positive ULN Upper limit of normal
Elevation of amylase or lipase > 1.5–2 times ULN
Dilatation of the pancreatic duct (ERCP) > 6 mm
Drainage of contrast medium from pancreatic duct > 9 min
+ +/−a −
+ +/−a −
+ +/−a −
organs. Laboratory tests show recurrent abnormalities of cholestatic enzymes (alkaline phosphatase, gammaglutamyltransferase) or of aminotransferases. Usually an increase of two to three times the upper limit of normal can be observed (see Tables 111.1 and 111.2, and introduction to SOD). These laboratory findings can be used to differentiate organic disorders as they usually present with higher and more persistent elevation of laboratory values. Abdominal ultrasound or MRCP can be used to evaluate the bile duct system, including the measurement of extrahepatic bile duct diameter (normal: 45 min) (Table 111.3). In some patients a characteristic pain response upon intubation or manipulation of the papilla can be observed, which is regarded by some groups as a separate clinical entity of a “hypersensitive bile duct system”. The presence of biliary pain, pathologic laboratory and ERCP
findings (or, subsequently, noninvasive imaging) has been used to subdivide patients with SOD in different groups according to the Milwaukee classification (see below) [7, 11].
Table 111.3 Tests for the diagnosis of sphincter of Oddi dyskinesia Pharmacological provocation tests
ERCP MRCP Ultrasound with provocation tests
Hepatobiliary scintigraphy with or without provocation tests Probatory stent placement Botulinum toxin injection Sphincter of Oddi manometry
Codeine test (50 mg) Morphine (0.12 mg/kg)-neostigmine (0.012 mg/kg) test (Nardi-Test) Fentanyl test CCK-test (20 ng/kg i.v.) Ceruletide 5 μg i.v. Secretin test (1 U/kg)
Bile ducts: fat rich meal (American breakfast, Lipomul 1.5 mg/kg); CCK-OP 10–20 ng/kg/3 min i.v.); ceruletide (50 ng/kg i.v.) Pancreas: secretin (1 U/kg i.v.) Morphine (0.04 mg/kg i.v.) CCK-OP (10–20 ng/kg/3 min i.v.) Oral nitrates See text See text See text
Sphincter of Oddi Dysfunction
Sphincter of Oddi Manometry See Chapter 47. Introduction of a manometric catheter device during ERCP allows a functional evaluation and manometric characterization of the sphincter of Oddi. After having established normal manometric findings and normal pressure values in the sphincter of Oddi, several manometric abnormalities have been described in patients with sphincter of Oddi dyskinesia, which could be diagnostic for this disorder [7, 17, 26]. These findings include: 1. Increased contraction frequency (tachyoddi) > 10/min 2. Increased proportion of retrograde contractions >20% 3. Increased contraction amplitudes (>180 mmHg) with prolonged duration (>7 s) 4. Increased basal sphincter pressure (>40 mmHg) 5. Paradoxical contractile response upon pharmacological stimulation with cholecystokinin octapeptide (CCK-OP) Based on these motility phenomena the presence of sphincter of Oddi dyskinesia has been postulated. In the clinical setting sphincter of Oddi manometry is the gold standard for the diagnosis of SOD. Based on a prospective therapeutic study, the finding of increased basal sphincter pressure has gained acceptance for the diagnosis of SOD and a sphincter Oddi pressure of >40 mmHg is used for discrimination [7]. The clinical relevance of other findings is still a matter of debate. An increased basal sphincter pressure is not only used for diagnosis of SOD, but can also be used to predict the response rate of endoscopic sphincterotomy in these patients (see below). Sphincter of Oddi manometry, however, is technically difficult and demanding, as an atraumatic intubation of the papilla should be performed to avoid artifacts and complications. Also, spasmolytics such as butylscopolamine or glucagon, cannot be used as they can suppress the phasic activity of the sphincter. Additionally, the analysis and evaluation of the manometry tracings requires manometric knowledge and experience with this method and interpretation is complicated by possible artifact due to movement of the catheter and kinking of the probe. As SO manometry is also associated with considerable complications, its clinical role is not without controversy and the procedure should only be performed in specialized centers by experienced specialists. Even in these specialized centers SO manometry is not feasible in 10–15% of patients due to failed
1447
intubation of the papilla, and is associated with considerable side effects (acute pancreatitis) in 5–15%. Besides sphincter Oddi manometry, a series of pharmacological provocative tests have been suggested and introduced for diagnosis of SOD (see “overview on provocative tests”). Even though some of these tests can suggest the presence of SOD without manometry by inducing typical clinical symptoms, the sensitivity and specificity of these tests is too low to be useful in clinical practice. Another diagnostic approach to SOD uses either hepatobiliary scintigraphy (e.g. HIDAscintigraphy) with or without pharmacological provocation or use of spasmolytics. Similarly, abdominal ultrasound evaluation of the bile and pancreatic duct with provocative stimulation of biliary flow by a fatrich meal or CCK-OP has been suggested. These methods can be used to identify a possible functional obstruction in the papillary region, however they also need profound experience and have a low positive predictive value. In a recent study, symptomatic improvement following a probatory intrasphincteric injection of botulinum toxin was evaluated as a discriminative diagnostic test for patients with SOD [32].
Pharmacologic Provocation Tests For a positive diagnosis of SOD, a series of pharmacological stimulation tests have been suggested, which should induce and reproduce the typical clinical symptoms [5, 14, 23]. However none of these tests has been shown to have sufficient clinical sensitivity and specificity for routine clinical use. Some of these tests are used in combination with imaging methods such as hepatobiliary scintigraphy, abdominal ultrasound or endoscopic ultrasound (see below).
ERCP, MRCP ERCP is the fundamental diagnostic procedure in a patient with suspected SOD, especially to rule out structural abnormalities and other disorders or diseases (Figs. 111.3 and 111.4). The increasing use of MRCP, however, qualifies this non-invasive imaging method as a possible first choice prior to ERCP. However, no prospective or interventional studies on patients with SOD are available so far. MRCP can identify and rule out significant structural abnormalities. However, whether
1448
111
Fig. 111.3 ERCP in type I SOD. Markedly dilated common bile duct
Fig. 111.4 Normal papillary function during ERCP
Motility Disorders of the Bile Ducts and Postcholecystectomy Syndrome
Sphincter of Oddi Dysfunction
MRCP adds significant additional information in patients with normal laboratory findings and sonographically non dilated bile ducts remains to be shown. As MRCP cannot add additional information on bile duct emptying or papillary movements, the role of MRCP in SOD (type II and III) remains experimental.
Abdominal Ultrasound with Provocation Tests Evaluation of the bile duct and pancreatic duct diameter before and after a provocative stimulus (fat-rich meal, CCK-OP, ceruletide, secretin) was evaluated and used for differentiation of sphincter of Oddi dysfunction. Abdominal ultrasound before and after a provocative meal (fat-rich American breakfast, Lipomul) or CCK-OP or its agonist ceruletide allows the functional evaluation of the biliary system and the biliary sphincter [3]. A provocative meal releases endogenous CCK which causes a contraction of the gallbladder and a relaxation of the papillary sphincter leading to increased bile flow in healthy people. Thus, despite the contractile effect on the gallbladder CCK normally causes a reduction or at least only a small increase (40 mmHg). If further management and treatment is based on these results, then patients with increased basal sphincter pressure show a significantly higher symptomatic response (80–99%) to endoscopic sphincterotomy than patients without an increase of basal sphincter pressure (30–35%). In sham controlled studies patients with or without increased basal sphincter pressure were randomized to endoscopic sphincterotomy or sham treatment. Only the sphincterotomy group showed an increased symptomatic response in patients with increased sphincter of Oddi pressure, whereas the sham procedures showed no effect irrespective of whether the pressure was increased or not. Interestingly, only the increased basal pressure could be used to predict the treatment response to endoscopic sphincterotomy, whereas other manometric abnormalities showed no predictive value and no correlation with the treatment response [7, 8].
It has to be mentioned that in subsequent studies which confirmed this finding, a clear distinction between organic and functional stenosis was not always made. As mentioned, an organic stenosis can be differentiated from a functional sphincter of Oddi dyskinesia by pharmacologic interventions (spasmolytics, nitrates, CCK) during sphincter of Oddi manometry or hepatobiliary scintigraphy [12]. On the other hand, especially those studies which investigated spasmolytics during manometry or showed a symptomatic improvement of patients with SOD type II to intrasphincter botulinum toxin support and demonstrate that the symptomatic patients have a functional disorder of the sphincter of Oddi. However, due to the complication rate of the procedure, there is still some controversy whether sphincter of Oddi manometry must or should be performed prior to endoscopic sphincterotomy. New technical advances (aspirating catheter, prophylactic stenting, electronic manometric system) have significantly reduced the complication rate and might increase the clinical use of sphincter of Oddi manometry. Eventually the probatory injection of botulinum toxin could be useful in the clinical setting in order to indicate which patients will benefit the most from endoscopic sphincterotomy. In borderline cases additional use of ultrasound or scintigraphy with provocative testing may help to determine when to proceed with sphincter of Oddi manometry and/or endoscopic sphincterotomy.
SOD Type III The most difficult group of patients presents only with typical biliary right upper quadrant pain without laboratory or morphological abnormalities. Patients in this group outnumber those in the other subtypes and there is a considerable overlap with other functional disorders of the abdominal region (e.g. functional dyspepsia). Sphincter of Oddi manometry should therefore not be applied in general to all these patients. Thus, the difficulty is to select patients which will benefit from further diagnostic interventions. The question is whether the different provocative tests can be used to differentiate these patients. As a first step ultrasound or scintigraphy with a provocative meal or stimulation could be used as they are not associated with major side effects or complications. If one
Sphincter of Oddi Dyskinesia
1453
Table 111.4 Prevalence of increased sphincter of Oddi basal pressure (>40 mmHg) in cholecystectomized patients with typical biliary symptoms SOD type I
SOD type II
SOD type III
Toouli (1985) [27]
−
−
Geenen (1989) [7]
−
Lans (1991) [13]
65% n = 17 −
20% n = 26 55% n = 42 50% n = 47 16% n = 19 18% n = 22 –
10% n = 240 0% n = 15 7% n = 27 −
60% n = 35 61% n = 38
55% n = 38 50% n = 30
Raddawi (1991) [16] Meshkinpur (1992) [15] Rolny (1993) [19] Botoman (1994) [4] Wehrmann (1996) [33]
60% n = 15 65% n = 17 − 100% n = 17
−
Source: Modified after [34]
Table 111.5 Results of sphincter of Oddi manometry and of endoscopic sphincterotomy in patients with SOD type I, II and III Increased SO basal pressure (>40 mmHg)
Clinical response to endoscopic sphincterotomy
SOD type I SOD type II
60–100% 40–86%
SOD type III
20–55%
55–91% 80–90% (>40 mmHg) 20–35% (40 mmHg)
of these tests shows a positive result, further imaging with MRCP or ERCP could be indicated. In patients with SOD type III the percentage with a pathological manometric finding is significantly lower when compared to type I or II (see Table 111.4). Additionally, these patients also show a decreased symptomatic response rate to endoscopic sphincterotomy even if an increase in sphincter of Oddi pressure (>40 mmHg) is present (Table 111.5). Thus the use of sphincter of Oddi manometry is disputed in this patient group. In general, ERCP and endoscopic manometry are reserved for selected cases and should be performed in a specialized center. Thus in these patients a trial of medical therapy should be used as a first step. Another possibility could be the probatory intrasphincteric injection of botulinum toxin as discussed above.
Clinical Course and Prognosis Only few data and studies are available on the long term outcome of patients with SOD. In a long term prospective study which followed patients for 4 years after endoscopic sphincterotomy, Geenen et al. showed that patients with elevated sphincter of Oddi pressure had a good and stable long term symptomatic response [8]. After endoscopic sphincterotomy there is the possibility of scarring and development of a stenosis of the orifice especially in the first month following sphincterotomy. If the sphincter muscle is completely cut through this usually attains no clinical relevance. However, in cases where symptoms reoccur after a symptom free interval this possibility has to be taken into account and diagnostic imaging and eventually even repeated manometry should be performed. As an alternative, repeat sphincterotomy can be performed, though it has an increased risk of bleeding and perforation. Alternatively, balloon dilatation of the papilla (6–8 mm balloon) or stenting of the papilla can be performed. In some patients with elevated sphincter pressure there is no symptomatic relief following sphincterotomy. Several reasons have to be considered. • Incomplete sphincterotomy with some fibers of the biliary or the pancreatic sphincter still intact • Simultaneous dysfunction of the pancreatic sphincter (35–65%) which would require a simultaneous sphincterotomy of the pancreatic sphincter segment • Other reasons for the pain attacks (chronic pancreatitis, retained stones, strictures, motility disorders of the upper GI tract, irritable bowel syndrome, functional dyspepsia) In order to rule out a papillary origin in these nonresponders, the completeness of the sphincterotomy has to be evaluated and pancreatic involvement has to be ruled out by manometry of the pancreatic sphincter segment if this was not carried out during the initial diagnostic manometry, as recommended.
Therapy The therapeutic alternatives in patients with sphincter of Oddi dyskinesia comprise medical therapy and endoscopic interventions.
1454
111
Motility Disorders of the Bile Ducts and Postcholecystectomy Syndrome
Medical Therapy Biliary pain in SOD is thought to originate from spastic contractions of the sphincter of Oddi region. As for other spastic disorders, different spasmolytics and choleretics have been suggested and tested in patients with SOD. Besides glucagon and nitrates, which are mostly used for diagnostic purposes, anticholinergics (e.g., butylscopolamine) and Ca2+ channel antagonists have been used for therapy [2, 10, 20, 22]. Two prospective placebo controlled studies evaluated the influence of nifedipine on the level and frequency of biliary pain in patients with SOD. Nifedipine reduced pain frequency in 75% of the patients. Even though these studies were performed with relatively few patients, empiric treatment with nifedipine is warranted in patients with SOD type III and in less severe cases of patients with SOD type II [20]. In another study, a progesterone containing preparation was used with clinical success. Other treatment options such as bile acids, pancreatic enzymes or choleretics have not been tested in prospective controlled studies. Botulinum toxin injection can be used in a subgroup of patients as a diagnostic and therapeutic tool.
Endoscopic Interventional Therapy In all patients with severe symptoms or overt obstruction of bile flow (SOD type I) and in all patients with proven sphincter of Oddi dyskinesia with increased basal sphincter pressure endoscopic sphincterotomy is the therapy of choice. Under these circumstances manometry can also be used to verify the completeness of the sphincterotomy. The effectiveness of endoscopic sphincterotomy has been shown in a prospective trial in 47 patients with SO-dysfunction (SOD type II) and has meanwhile been shown in several other studies for all types of SOD. However, the success rates of endoscopic sphincterotomy in patients with elevated sphincter pressure decrease progressively from SOD type I to type II and III (Table 111.3). Similar to sphincter of Oddi manometry, there is an increase in the complications rate with endoscopic sphincterotomy. Patients with SOD type II and III show a significantly higher rate of post sphincterotomy pancreatitis (12.5%) than patients with cholelithiasis (3.7%). Moreover, there seems to be an inverse relationship
with bile duct diameter. While patients with markedly dilated bile duct showed a low rate of pancreatitis (>15 mm, 2.4%), there was a progressive increase in the pancreatitis rate with decreasing bile duct width (10–15 mm, 3.2%; 5–10 mm, 13.8%). Especially in patients with normal bile duct diameter ( 1.5 cm, gallbladder 60–90% < 50% filled with stones, bile ducts occluded, acute cholecystitis,-angitis, susp. for bile duct carcinoma As above. solitary stones > 2 cm, 3 stones 1 cm, anatomic >80% conditions As above, no limitation by stone number and size 95%
18–24 months
30–60%
12–24 months
15–20%
9h
30–60%
Therapy
As in oral litholysis, recurrence of stones after ESWL therapy is a major problem, although the rate is 10–15% lower than with oral treatment alone. Therefore, annual ultrasound examinations after ESWL therapy should be performed to monitor for stone recurrence. Bile acid therapy is recommended as follow-up treatment.
Contact Litholysis During this procedure a liquid solvent is injected into the gallbladder or the biliary tree [18, 37]. The gallbladder is punctured percutaneously through the gallbladder bed. After insertion of a thin catheter into the gallbladder, methyl-tertiary-butyl ether (MTBE) is instilled in small doses and immediately aspirated. Contact litholysis of bile duct stones can be performed after cholecystectomy through a T-tube, via a nasobiliary tube or after percutaneous transhepatic puncture of the bile ducts (PTC). A European survey of more than 800 patients has shown that percutaneous gallbladder puncture is successful in 95% and that stones are completely dissolved in 96% of cases at a median time of 9 h (Table 112.11). For solitary stones the mean treatment time is 4 h, for multiple concrements 12 h [14, 21]. The most important complication is bile leakage after catheter removal, which occurs in 4% of the patients. As already mentioned, due to technical difficulties this procedure is no longer performed.
Cholecystectomy Cholecystectomy is the treatment of choice in patients with symptomatic cholecystolithiasis. In contrast to conservative treatment methods, the obvious benefit of cholecystectomy is that in addition to the removal of the offending stones, the gallbladder is also removed. Contraindications for surgery today are rare and include significant comorbidities and untreated coagulopathies. Contraindications for laparoscopic cholecystectomy are severe cardiorespiratory diseases, portal hypertension, clotting disorders, ileus, diffuse peritonitis, infections of the abdominal wall, acute biliary pancreatitis, the Mirizzi syndrome and patients
1477
with suspected malignancy of the biliary system. Acute cholecystitis, bile duct stones, morbid obesity, gallbladder shrinkage and porcelain gallbladder, empyema of the gallbladder, and diaphragmatic hernia are all relative contraindications, mainly for less experienced surgeons. Approximately 90% of all cholecystectomies are nowadays performed laparoscopically. Open cholecystectomy is only performed in 4–6% of cases due to the above mentioned complications. The results of the laparoscopic procedure are similar to that of the conventional method [3, 7, 29, 34]. Complications occur in 4.42% versus 5.57% during conventional operation. Disadvantages of laparoscopic operation are the time of the procedure, the more frequent occurrence of bile duct (0.6%) or vascular lesions (0.3%), and intestinal injuries (0.1%). In patients with acute cholecystitis the complication rate of laparoscopic operation is lower than that of the conventional procedure. The overall mortality rate is 0.08–0.4% (Table 112.12). Advantages of laparoscopic cholecystectomy are the lower doses Table 112.12 Results of conventional and laparoscopic cholecystectomy Conventional cholecystectomy Mortality 90%, this method is still underused in the diagnosis of choledocholithiasis. The most important disadvantage of endosonography is that it is a time-consuming procedure and requires gastroenterologists with specialized training. In the hand of a well-trained physician, however, endosonography is as valuable in stone diagnostics as endoscopic retrograde cholangiography and even superior to ERC with regard to the prepapillary and periductular region of the bile duct.
Radiologic Techniques Oral and intravenous cholangiography are only of historical interest. Scintigraphy also has no place in the diagnosis of bile duct stones. Computed tomography (CT) is less important for diagnosis of bile duct stones and shows concrements only incidentally. Magnetic resonance cholangio-pancreatography (MRCP) is a non-invasive method which in optimal cases visualizes the biliary tree with the same quality as ERC. The specificity of bile duct alterations in some centers is 80–100%, and sensitivity 96%. Endoscopic retrograde cholangio-pancreaticography (ERCP) is superior to all other techniques in demonstrating intra- and extrahepatic bile duct stones. Today, it is a routine procedure of which the risks are well-known. The importance of diagnostic ERCP has
Complications
been dramatically reduced over the last few years due primarily to MRCP and endoscopic ultrasound, and it has therefore become mainly a therapeutic procedure. ERCP is indicated if choledocholithasis is suspected, in biliary pancreatitis, acute cholangitis, in cases of stenosis of the papilla of Vater caused by gallstones and in cases after bilio-enteric anastamosis with a so-called sump-syndrome. Contraindications for ERCP are few and the reader is referred to Chapter 40 for further details. Worth mentioning here in particular are the presence of large communicating pancreatic pseudocysts and of large post-cholecystectomy bilomas resulting from bile leaks (risk of contamination and superinfection). In patients with Billroth II gastric resection or Rouxen-Y gastric bypass, unassisted ERCP is only successful in about 50%. The proximal section of the bowel can be too long, so that it is impossible to advance the tip of the duodenoscope to the region of the papilla. A similar problem exists when the angle of the anastomosis of the gut is too acute. Additionally, the orientation of the bile duct in the afferent limb is rotated 180 degrees, making cannulation and therapy difficult for unexperienced operators. Recently, techniques such as double-balloon enteroscopy and transgastric laparascopic assisted approaches have made ERCP more successful in such patients with altered anatomy. Large juxtapapillary diverticula of the duodenum can be found in about 20% of the patients. If the papilla is sunken in the middle of the diverticulum or when it is located more to the right or the left side it may be nearly impossible to cannulate the bile duct and/or to perform an adequate sphincterotomy safely. In these patients it can be helpful for cannulation to support the papilla by injecting fluids in its surrounding (thus lifting the orifice) or to evert the diverticulum using endoclips. Additionally, papillary balloon dilation following a small sphincterotomy may provide a safer and more effective path for extracting stones. The overall complication rate of ERCP is 2.5%, and the mortality rate of diagnostic ERCP is 0.07% (Table 113.1). Long time manipulations at the papilla of Vater increase the risk, as do repeated injections of contrast medium. The largest risk of ERCP is the uneducated and untrained endoscopist. In skilled hands, the success rate of ERCP is 90–95%. If an endoscopic approach is not successful or possible, percutaneous transhepatic cholangiography (PTC) offers an alternative diagnostic and therapeutic route to the bile ducts. PTC helps to differentiate
1483 Table 113.1 Results of diagnostic ERC and PTC in patients with choledocholithiasis Procedure Complication rate Mortality rate successful ERC > 95%
PTC 94–98%
0.1–2.8% Drugs: 0.2–0.6% Extravasation: 0.1–0.5% Pancreatitis: 1.0–1.6% 1.0–2.0% Sepsis: 1.4–3.1% Leakage: 1.5–1.9% Bleeding: 0.4%
< 0.1%
0.2–0.9%
extra- and intrahepatic cholestasis, and is especially suited for investigations in the distal part of the common bile duct. An experienced interventional gastroenterologist or radiologist has a success rate of 95–98%. Puncture of the bile ducts is easier the more the ducts are dilated. The complication rate lies between 1–2%. The mean mortality rate is 0.5% and thus higher than for ERC (Table 113.1).
Complications Localisation and quality of pain in patients with uncomplicated choledocholithiasis is not different from that of cholecystolithiasis. But about 50% of patients develop colics, which is more than double of that of cholecystolithiasis. Five percent complain of a continuing pain in the right upper abdomen, radiating into the back or shoulder, 10% suffer from uncharacteristic complaints and only 25% are completely free of symptoms. The simultaneous occurrence of colics or pain, of fever, chills and of jaundice is a classical triad of symptoms caused by bile duct stones and is called Charcot-triad. In about 30% of the patients during physical examination the gallbladder is enlarged and sensible for pressure. Usually liver and spleen are not palpable. Because bile duct stones can induce severe lifethreatening complications when untreated, also asymptomatic concrements have to be removed. The most frequent complications are cholangitis and acute pancreatitis. The degree to which (if any) bile duct stones are responsible for the development of cancer of the biliary tree is unclear. The late complication of biliary cirrhosis has become a rarity in the time of ultrasonography and ERCP.
1484
Cholangitis Cholangitis and sepsis are dangerous complications (see Chapter 114). The most frequent cause of cholangitis is bile duct stones, followed by iatrogenic causes, such as operations or endoscopic manipulations within the bile ducts, and then infestation with parasites. Bacterial infection of the bile ducts happens only when the pressure in the biliary tree increases, i.e. when the bile flow into the intestine is reduced or interrupted. Predisposing situations for a bacterial invasion are long-term obstruction by stones, foreign bodies and large peripapillary diverticula. Especially at risk are older patients, because in this group bacteria can be found in healthy bile ducts in 70% even in the absence of stones. Additionally, the absence of secretory IgA seems to favor infections. Bile cultures present with the same bacterial spectra as in acute cholecystitis: Escherichia coli, Klebsiella, Pseudomonas aeruginosa and enterobacteria. In suppurative cholangitis multiple organisms may be found. Blood cultures are positive in 40–90%. Besides the above-mentioned bacteria, salmonellas, yersinia and M.tuberculosis have been demonstrated. Cryptosporidia and cytomegaloviruses make the picture even more complicated in cases of AIDS. Due to the occlusion of the bile ducts, jaundice develops, the stool becomes white and the urine dark. If the disease worsens sepsis, kidney insufficiency and septic shock may supervene. The fever increases to 40°C, bilirubin to 10 mg% (170 mmol) or even higher, and leukocytosis amounts to 20,000/mL or more. The risk of bleeding can be estimated by measuring platelet count and prothrombin time. The combination of Charcot’s triad (fever, right upper quadrant pain, and jaundice) with mental status changes and hypotension (implying sepsis) is referred to as Reynold’s syndrome or pentad. The differential diagnosis of bacterial cholangitis includes acute alcoholic hepatitis, liver abscesses, perforation of an abscess into the abdominal cavity, and in rare cases the crises of sickle cell anemia. In patients with alcoholic hepatitis and sickle cell anemia the bile ducts are not dilated on ultrasonography. Liver abscesses can be diagnosed by ultrasound or by CT. Perforation of a visceral organ into the abdominal cavity is associated with signs and symptoms of acute peritonitis. Especially endangered by suppurative cholangitis are patients older than 55 years of age, women, patients with other severe concomitant diseases (e.g. liver cirrhosis,
113
Bile Duct Stones
liver abscess, renal insufficiency), and patients with cholangitis following PTC.
Liver Abscess A severe complication is liver abscess (see Chapter 65 and 66). If abscesses develop from diffuse cholangitis, the liver surface is speckled with multiple yellow dots. If these lesions coalesce, larger abscesses are formed. Large solitary abscesses can infiltrate the surrounding liver tissue, or when encapsulated can compress it. A liver abscess has to be expected if sufficient drainage of the biliary system in combination with medicamentous therapy is unsuccessful, if the liver size increases, and if during palpation the patient has pain. Intrahepatic abscesses with kidney insufficiency are the most frequent complications of cholangitis.
Biliary Pancreatitis 15% of all gallstone patients suffer from gallstone pancreatitis. Biliary pancreatitis is more frequently seen in patients with bile duct stones than with acute cholecystitis. The existence of a so-called common channel which drains both the pancreatic and the bile duct is seen in more than 90% of all patients. Surprisingly, bile duct stones are found in only 2–5% of patients with suspected biliary pancreatitis, however 80–90% of these patients have stones in the gallbladder. Therefore it is suspected that biliary pancreatitis is induced during stone passage. This is supported by the observation that more than 80% of the patients with pancreatits have gallstones in the stool, while in only 10% of patients without pancreatitis stones can be detected in the stool. The so-called microliths, which are very small concrements of less than 3 mm in diameter, induce pancreatitis four times more often than larger stones. The role of gallbladder sludge in the development of biliary pancreatitis is still unclear. But since 70% of all patients with a so-called idiopathic pancreatitis have gallbladder sludge, this finding could play a role similar to that of microliths and smaller concrements. The clinical course of biliary pancreatitis is characterised by the combination of symptoms caused by
Treatment of Choledocholithiasis and Cholangitis
bile duct occlusion and those of acute pancreatitis. The patient complains of colicky pain due to the gallstones and of pain radiating into the back as seen in acute pancreatitis. In addition to the cholestatic enzymes alpha-amylase and lipase are increased in the serum. Cholestatic enzymes and bilirubin further increase when edema of the pancreatic head due to inflammation compresses and narrows the common bile duct. A correct diagnosis is possible in 90%. Differential diagnosis is papillary tumour, a tumour located in the pancreatic head, and parasite infestation. Treatment includes the administration of analgesics, intravenous fluids, and antibiotics. Close observation for early signs of complications such as cardiac, renal or pulmonary insufficiency is absolutely necessary. In cases of sepsis, urgent ERCP within 24 h to decompress the bile duct significantly reduces mortality from 20% to 2%.
Bile Duct Carcinoma It is rather improbable that there is a connection between the rare bile duct carcinoma and the frequently observed bile duct stones. Only in 20% of patients with bile duct carcinoma are bile duct stones demonstrated. As with gallbladder carcinoma, bile duct carcinoma is a tumor of older age with the exception of patients with primary sclerosing cholangitis. Histologically in 95% it is adenocarcinoma. Gallbladder carcinoma is seen 2–3 times more often than bile duct carcinoma.
Treatment of Choledocholithiasis and Cholangitis Endoscopic Stone Extraction The treatment of choice for bile duct stones is endoscopic sphincterotomy (EST) followed by stone extraction [35]. The aim of this procedure is an efficient reduction of pressure in the biliary tree and subsequent drainage. In patients with severe symptoms and cholangitis, endoscopy is combined with antibiotics, and in cases with complicated concrements adjuvant procedures may be necessary. In patients with an in situ
1485
gallbladder, cholecystectomy should eventually be performed. ERC with endoscopic sphincterotomy is an extremely successful approach to common bile duct stones and has reduced the need for surgical operations to 0.2%. Long-term post EST complications due to the severed papilla of Vater are exceedingly rare. Even when remnants of food or air can be demonstrated in the common bile duct and ascension of bacteria is theoretically possible, there is no convincing data to suggest an increased risk of future cholangitis or biliary obstruction. As long as bile flow is possible and the pressure in the common bile duct is low, these findings are harmless. If sphincterotomy is considered to be high-risk (e.g., coagulopathic patients, ampulla located within a diverticulum), dilation of the papilla with or without a small sphincterotomy can be considered. Typically, dilation with balloon catheters with a diameter of 8–10 mm are used; it has been shown that these small balloons do not cause lacerations of muscle fibres and are safe [36]. In the case of large bile duct stones (>2 cm), dilation with larger balloons has been reported but may carry greater risks such as perforation and post-ERCP pancreatitis. Medicinal dilation of the papilla can be induced by sublingual application of glycerol-trinitrate tablets. Approximately 1–2 min after application of the drug the muscles of the sphincter dilate. With this procedure only very small concrements have been shown to pass through the papilla and in a few cases even after preceding lithotripsy. Since the efficacy of this procedure is uncertain it is only indicated in special situations and is not routinely practiced. In patients with simultaneous bile duct and gallbladder stones, ERCP is typically performed first, followed by elective cholecystectomy within the next 6 weeks. This has been clearly shown in two studies in which after EST “wait and see” was compared to EST followed by cholecystectomy within the above mentioned interval. In the “wait and see” procedure colic occurred in 20% vs. 5% of the surgical group, cholecystitis in 6%, cholangitis in 15% vs. 6%, emergency operations in 37% vs. 0%, and emergency ERC in 10% instead of 0%. Whether EST and stone extraction should precede or follow operation or should be performed during cholecystectomy is still under discussion. In cases of acute cholecystitis, however, there is no good data on whether it is advantageous to perform ERCP or cholecystectomy first.
1486 Table 113.2 Surgical and endoscopic therapy of choledocholithiasis plus cholecystitis (“therapeutic splitting”) Bile duct stones alone: Endoscopic sphincterotomy, endoscopic stone extraction, no surgery Bile duct stones plus gallbladder stones: “therapeutic splitting”: First: endoscopic sphincterotomy and stone extraction, especially in patients with cholangitis, biliary pancreatitis Second: cholecystectomy later With “therapeutic splitting” surgery should follow endoscopic procedures within 6 weeks, because: In “wait and see” procedure colic develops in 20% instead of 5% after surgery cholecystitis develops in 6% instead of 0% cholangitis develops in 15% instead of 6% emergency operation necessary in 37% instead of 0% emergency ERCP necessary in 10% instead of 0%
The mortality rate in patients with choledocholithiasis and cholangitis is 2–3%, though after emergency operation it increases to nearly 10–20% (Table 113.2). The results of endoscopic sphincterotomy are excellent. EST is successful in 85% without any early or late complications. But in 3–5% restenosis can develop. After EST 85–95% are stone-free, but in 5–20% stone recurrence can occur, especially if the length of the incision of the sphincterotomy was too short [4]. The complication rate of ERC with sphincterotomy is low. The most important measure to prevent complications is drainage of the bile duct if stone extraction was not successful during the first session. The most frequent complication during EST is bleeding caused by injury to the arteria retroduodenalis or one of its branches, followed by cholangitis and pancreatitis (Tables 113.3 and 113.4). The most important early complication is retro-duodenal perforation. Frequency of bleeding is correlated with the length of the incision. Using a needle knife instead of the classic pull-type (e.g. Erlanger) sphincterotome seems to lower the complication rate. Drainage of the pancreatic duct diminishes the risk of pancreatitis in the case that the mouth of the duct is swollen due to manipulations at the biliary tree. Bleeding is treated endoscopically by balloon tamponade, thermocoagulation, or by injections of fluids such as dilute epinephrine. The indication for operation in cases of perforation depends on the amount of bile that leaks into the retroperitoneum and the degree of peritoneal infection. The mortality rate of EST amounts to 0.4–0.8%.
113
Bile Duct Stones
Table 113.3 Complications of endoscopic sphincterotomy and stone extraction Gallbladder Gallbladder in situ removed or in situ Cholangitis Bleeding
(%) 1.6 1.0–2.3
Perforation
0.3–0.8
Pancreatitis Total
1.4–5.0 6.9–10.0
Mortality due to ERCP: Mortality (total):
0.4–0.8 2.3
(%) Cholecystitis 5–20 Surgery necessary: 10–15 Mortality after operation: 0–26
Source: Adapted from Freeman ML [9a], Endoscopy 1997 Table 113.4 Results and early complications of endoscopic sphincterotomy in patients with bile duct stones Stone Complications Finding Mortality free rate 84–97%
5–7%
Bleeding 2.3% 0.5–1.0% Cholangitis 1.6% Pancreatitis 1.4%, Perforation 0.8%
Unsatisfactory results or complications which develop weeks or even months after sphincterotomy are called late complications. Late complications include stone recurrence, seen in 15–20%, stenosis of the papilla, and the recurrence or worsening of symptoms from which the patient suffered before surgery (Table 113.5).
Adjuvant Treatment Procedures If there is a prepapillary impacted stone, a pre-cut or a circumcision of the papilla with a needle knife can Table 113.5 Late results of endoscopic sphincterotomy in patients with bile duct stones and stenosis of the papilla Stone free Recurrent stones Stenosis after sphincterotomy Restenosis
73–94% 3–21% 2.3–6.1% 8–33%
Symptom-free, improved Stones: symptoms as before Stones: symptoms deteriorated Stenosis: symptoms unchanged Stenosis: symptoms deteriorated
87–91% 4–13% 1–4% 9–19% 1–8%
Treatment of Choledocholithiasis and Cholangitis Table 113.6 Therapeutic results of endoscopically unextractable bile duct stones Method Stone position Stone free, comments Mechanical lithotripsy Litholysis Electrohydraulic lithotripsy Laser-lithotripsy Ultrasoundlithotripsy Surgery
Common bile duct Extra-, mainly intrahepatic Extra- and intrahepatic Extra- and intrahepatic ?
80–90%; stones ≥ 2.5 cm: 25% 50%, time consuming procedure 85%, expensive, costly
Extra- and intrahepatic
95–98%, increased morbidity and mortality
75–95%, expensive, costly, Under investigation
be helpful. If the stone is too large to be extracted through the distal common bile duct or through the papilla, the intraduodenal segment of the bile duct can be dilated and/or the stone can be crushed using a mechanical lithotripter. Mechanical lithotripsy with a strengthened Dormia-type basket has a success rate of 80–95% for stones that could not be extracted with ordinary means (Table 113.6). The result depends on stone size and the degree of hardness [26]. The success rate with concrements of 2.5 cm in diameter, for example, is only 25%. Calcified or very old and hard stones can result in rupture of the lithotripter. The complication rate of mechanic lithotripsy is 1% and is mainly due to sphincterotomy. Stone gravel, small concretions or fragments which cannot be extracted with a Dormia basket can be removed by an extraction balloon. Other procedures which have been developed to support endoscopic treatment are electrohydraulic lithotripsy (EHL), laser lithotripsy, ultrasound lithotripsy and extracorporeal shock wave lithotripsy (ESWL) [5]. EHL and laser lithotripsy are cumbersome procedures which typically require two skilled operators controlling a “mother” duodenoscope and “baby” cholangioscope which is inserted into the bile duct (cholangioscopy; see Chapter 41). The lithotripsy probe is passed through the accessory channel of the cholangioscope and applied to the stone under direct vision. Due to the expense of the equipment and the technical challenges of the procedure, it is only performed in specialized centers. In the hands of an expert, 80–90% of stones that have failed extraction with ordinary means and mechanical lithotripters can be removed.
1487
Laser lithotripters come in a variety of types. With a pulsed Neodyn-YAG-laser, for example, energy is carried forward through a 0.2 mm glass fibre to the stone surface. With the flash light pulsed colored laser (Rhodanium-6G-laser) the instrument differentiates between tissue and the concrement which diminishes the risk of tissue injury. Ultrasound lithotripsy is performed via a rigid nephroscope which leads the ultrasound probe percutaneously transhepatically through a 1.7 cm sinus-tract into the bile ducts. With this procedure intra- and extrahepatic concretions can be treated successfully. Extracorporeal shock wave lithotripsy (ESWL) is approved in Europe for extra- and intrahepatic bile duct stones after endoscopic sphincterotomy and insertion of a nasobiliary drain. After fragmentation the stone remnants can be extracted. In patients with large stones complete removal is possible in 86%. The 30-day mortality rate amounts to 0.9%. ESWL-treatment is especially suitable for stones proximal to bile duct stenosis, after bends of the common bile duct and for concrements in the cystic duct after previous cholecystectomy and postcholecystectomy syndrome.
Treatment of Cholangitis Treatment of cholangitis includes stone extraction, drainage and the administration of antibiotics [16, 32]. All three measures have to be performed simultaneously. If immediate removal of the concrement is impossible a nasobiliary tube has to be placed into the bile duct allowing for sufficient drainage and decrease of pressure. From aspirated bile, cultures are performed. As in acute cholecystitis, Escherichia coli, Klebsiella and enterococcus predominate. After endoscopic or surgical manipulations Pseudomonas aeruginosa and other anaerobic bacteria are also found. Medical treatment of cholangitis consists of infusion of intravenous fluid, administration of analgesics, and antibiotics (e.g. piperacillin and third generation cephalosporins with or without aminoglycosides or metronidazole). When the combination of endoscopic and drug therapy is successful, complaints and fever disappear within 24–48 h. Because endoscopic therapy of cholangitis has a mortality rate of only 5–8% it is superior to surgery with a mortality rate of 10–20%.
1488
Surgery for Bile Duct Stones Surgical treatment of bile duct stones nowadays is only necessary in 0.2% of all patients, such as those with Billroth-II-resection of the stomach or Roux-en-Y gastric bypass in which the papilla cannot be approached by the tip of the endoscope [23]. In patients with stenosis of the papilla or incarceration of gallstones, transduodenal papillotomy is performed. In cases with a long stenosis of the common bile duct and with proximally located concretions latero-lateral choledochoduodenostomy or jejunostomy is performed. In the case of choledochojejunostomy a sufficiently long Roux-en-Y anastomosis prevents the disadvantage of previous procedures in which the development of a so-called sumpsyndrome can occur. A sump-syndrome is defined as gallstones, sludge and bacteria in the eliminated portion of the common bile duct between papilla of Vater and the anastomosis. Here, new choledochal concrements can develop and lead to cholangitis and occlusion of the anastomosis. The risk of developing the so-called syndrome of Roux-en-Y anastomosis caused by an overgrowth of bacteria is a minor one. Which procedure is chosen by the surgeon depends on the general condition of the patient, on risk factors and on the patient’s age. The mortality rate of surgical revision of the common bile duct lies between 0–4%. Stone clearance is achieved in 95–98% of patients; in 1–5%, residual stones remain. In 15% of patients, recurrent stones will develop.
Therapy of Hepatolithiasis The treatment of intrahepatic concrements is difficult and requires complex procedures. If the stone number is small one can try to extract the stones endoscopically after sphincterotomy, hoping that the more proximal concretions will follow spontaneously into the gut. Since extrahepatic and gallbladder stones often exist together with intrahepatic concrements, the usual procedure is cholecystectomy, revision of the common bile duct with or without bilio-enteric anastomosis and resection of a liver segment. Resection is always necessary when intrahepatic stenosis or prestenotic abscesses exist. The results of surgical treatment are good. The outcome depends on the age of the patient, the total risk, the mode of the procedure and especially the experience of the surgeon. Success rate amounts to
113
Bile Duct Stones
90%. While the recurrence for extrahepatic stones is rather low, intrahepatic stones recur in approximately 25% of patients.
Cholelitholysis Chemical dissolution of bile duct stones is only indicated when endoscopic procedures are unsuccessful and surgery is contraindicated. Whether the 10% of remaining stones after endoscopic procedures in an operable patient without contraindications should be treated surgically or chemically depends on the experience of the physicians involved. But the decision also depends on the wishes of the patient, the anatomical situation, on the stone type, the general condition of the patient, and whether the method of litholysis is available or not. Chemical dissolution is always performed in the hospital because the litholytic solvents have to be instilled into the bile ducts via a catheter. This can be done transpapillary, via a nasobiliary tube, percutaneously transhepatically after puncture of the gallbladder, or through a T-tube after cholecystectomy. Only cholesterol concrements and brown calcium bilirubinate stones can be dissolved; calcified cholesterol stones, calcified brown pigment stones and black pigment stones of the gallbladder are insoluble. The advantages of litholysis are the low rate of complications and low costs. But the most important advantage of litholysis is the possibility also to dissolve intrahepatic stones, especially when they are located in the periphery. Disadvantages of litholysis are the long treatment time (up to 3 months and more) and the staffing situation. Since dissolution rate of bile duct stones does not exceed 50%, in some patients it makes sense only to reduce stone size and not completely to dissolve the concrements and then to extract the smaller stones endoscopically as early as possible. As mentioned previously, chemical dissolution of bile duct stones is rarely performed any longer. For the treatment of cholesterol concrements methyl-tertiary-butyl-ether (MTBE) can be used. But MTBE should not enter the intestine and should not be injected into the biliary system with increased pressure. Treatment should start with small amounts of MTBE which have to be aspirated immediately after instillation. Dissolution of pure cholesterol stones is 100%, and treatment time is a couple of hours only. MTBE can induce mucosal damage in the bile duct,
References
and because it is an ether, somnolence after reabsorption in the intestine can occur. Primary calcium bilirubinate concrements, the brown stones of the bile ducts usually seen after endoscopic or surgical manipulations, only dissolve in an EDTAsolvent at pH 9.4. The solvent is injected by means of a perfusor in a dosage of 15–20 mL/h. EDTA (ethylenediamine-tetra-acetic acid) is a chelating solvent which chelates calcium bilirubinate in an alkaline milieu. The results are not convincing, but in some patients dissolution therapy may be the only option one has. The treatment of intrahepatic bile duct stones, especially when in a peripheral position of the biliary tree, is a great and life-long challenge, and dissolution therapy may be the only, although unsatisfactory, option one has. In very few patients with complicated bile duct stones, only the combination of endoscopic procedures, extracorporeal shock wave lithotripsy and contact dissolution will be successful. Unfortunately, stone recurrence is frequent.
References 1. Behar J, Lee KY, Thompson WR, Biancani P (1989) Gallbladder contraction in patients with pigment and cholesterol stones. Gastroenterology 97: 1479–84 2. Carey MC, LaMont JT (1992) Cholesterol gallstone formation. 1. Physical chemistry of bile and biliary lipid secretion. Progr Liver Dis 10: 139–63 3. Collet D (1997) Laparoscopic cholecystectomy in 1994. Results of a prospective survey conducted by SFCERO on 4624 cases. Surg Endosc 11: 56–63 4. Cotton BP (1986) Two to nine year follow up after sphincterotomy for stones in patients with gallbladders. Gastrointest Endosc 32: 157–8 5. Cotton BP, Kozarek RA, Schapiro RH, et al (1990) Endoscopic laser lithotripsy of large bile duct stones. Gastroenterology 99: 1128–33 6. Crowther RS, Soloway RD (1990) Pigment gallstone pathogenesis: from man to molecules. Semin Liver Dis 3: 171–80 7. Deziel DJ (1994) Complications of cholecystectomy. Incidence, clinical manifestations, and diagnosis. Surg Clin North Am 74: 809–23 8. Dyk PA, Hoda F, Osmer ES, et al (2003) Microarry analysis of hepatic gene expression in gallstone-susceptible and gallstone-resistant mice. Mammalian Genome 14: 601–10 9. Ell C, Schneider HT, Benninger J, et al (1992) Significance of computed tomography for shock-wave therapy of radiolucent gallbladder stones. Gastroenterology 101: 1409–16 9a. Freeman ML (1997) Complications of endoscopic biliary sphincterotomy: a review. Endoscopy 29:288–97 10. Giovannucci E, Colditz GA, Stampfer MJ (1993) A metaanalysis of cholecystectomy and risk of colorectal cancer. Gastroenterology 105: 130–41
1489 11. Goldbohm RA, van den Brandt PA, Van’ T, Veer P, et al (1993) Cholecystectomy and colorectal cancer: evidence from a cohort study on diet and cancer. Int J Cancer 53: 735–8 12. Gracie W, Ransohoff D (1982) The natural history of silent gallstones. The innocent gallstone is not a myth. N Engl J Med 307: 798–800 13. Griffith DP, Gleeson MJ (1990) Gallstones: advantages and disadvantages in five treatment alternatives. J Lithotripsy Stone Dis 2: 184–98 14. Hellstern A, Leuschner U, Benjaminov A, et al (1998) Dissolution of gallbladder stones with methyl tert-butyl ether and stone recurrence: a European survey. Dig Dis Sci 43: 911–20 15. Kaminski DL, Feinstein WK, Desphande YG (1994) The production of experimental cholecystitis by endotoxin. Prostaglandins 47: 233–5 16. Lai ECS, Mok EPT, Tan ESY, et al (1992) Endoscopic biliary drainage for severe acute cholangitis. N Engl J Med 326: 1582–6 17. Lammert F, Wang DQ-H, Wittenburg H, et al (2003) Lith genes control mucin accumulation, cholesterol crystallization, and gallstone formation in A/J and AKR/J inbred mice. Hepatology 36: 1145–54 18. Leuschner U (1994) Contact dissolution. Eur J Gastroenterol Hepatol 6: 873–9 19. Leuschner M, Leuschner U, Strohm WD, et al (1984) Radiological and ultrasonographic investigations with respect to patient selection and monitoring for chemical gallstone dissolution. Hepatogastroenterology 31: 140–3 20. Leuschner U, Güldütuna S, Hellstern A (1991) Etiology, pathogenesis and therapy of pigment gallstones. Dig Dis 9: 282–93 21. Leuschner U, Hellstern A, Güldütuna S, et al (1991) Direct contact dissolution of gallbladder stones with methyl tert-butyl ether: experience in 209 patients. Ergebn Gastroenterol Verh 26: 199–201 22. Lowenfels AB, Walter AM, Althans DP, et al (1989) Gallstone growth, size and risk of gallbladder cancer: an interracial study. Int J Epidem 18: 50–7 23. Neoptolemos JP, Shaw DE, Carr-Locke DL (1989) A multivariate analysis of preoperative risk factors in patients with common bile duct stones–implications for treatment. Ann Surg 209: 157–61 24. Pereira SP, Veysey MJ, Kennedy C, et al (1997) Gallstone dissolution with oral bile acid therapy. Importance of pretreatment CT scanning and reasons for nonresponse. Dig Dis Sci 42: 1775–82 25. Petroni ML, Jazrawi RP, Lanzini A, et al (1996) Repeated bile acid therapy for the long-term management of cholesterol gallstones. J Hepatol 25: 719–24 26. Riemann JF, Demling L (1983) Lithotripsy of bile duct stones. Endoscopy 15: 191–6 27. Ros E, Valderrama R, Bru C, et al (1994) Symptomatic versus silent gallstones. Radiographic features and eligibility for nonsurgical treatment. Dig Dis Sci 39: 1697–703 28. Ros E, Zambón D (1987) Postcholecystectomy symptoms. A prospective study of gallstone patients before and two years after surgery. Gut 28: 1500–4 29. Roslyn JJ, Binns GS, Huges EFX, et al (1993) Open cholecystectomy: a contemporary analysis of 42472 patients. Ann Surg 218: 129–37 30. Sackmann M, Pauletzki J, Sauerbruch T (1991) The Munich gallbladder lithotripsy study. Results of the first 5 years with 711 patients. Ann Intern Med 114: 290–6
1490 31. Sama C, Labate AMM, Taroni F, et al (1990) Epidemiology and natural history of gallstone disease. Semin Liver Dis 3: 149–58 32. Sauter G, Ruckdeschel G, Sauerbruch T (1992) Antibiotische Prophylaxe und Therapie infektiöser Komplikationen. Z Gastroenterol 30: 705–8 33. Schafmyer C, Tepel J, Franke A, et al (2006) Investigation of the Lith1 candidate genes ABCB11 and LXRA in human gallstone disease. Hepatology 44: 650–7 34. Schwesinger WH, Diehl AK (1996) Changing indications for laparoscopic cholecystectomy. Surg Clin North Am 76: 493–504 35. Seifert E, Schulte F, Chalybäus C (1989) Quo vadis endoskopische Sphinkterotomie? Z Gastroenterol 27: 77–82 36. Staritz M, Poralla T, Dormeyer H-H, et al (1985) Endoscopic removal of common duct stones through the intact papilla after medical sphincter dilatation. Gastroenterology 88: 1807–1811
113
Bile Duct Stones
37. Thistle JL, May GR, Bender CE, et al (1989) Dissolution of cholesterol gallbladder stones by methyl tert-butyl ether administered by percutaneous transhepatic catheter. N Engl J Med 320: 633–9 38. Villanova N, Bazzoli F, Taroni F, et al (1989) Gallstone recurrence after successful oral bile acid treatment. A 12-year follow-up study and evaluation of long-term postdissolution treatment. Gastroenterology 97: 726–31 39. Warren BL (1992) Small vessel occlusion in acute acalculous cholecystitis. Surgery 111: 163–5 40. Wolpers C, Hofmann AF (1993) Solitary versus multiple cholesterol gallstones. Mechanisms of formation and growth. J Clin Invest 71: 423–34 41. Zuin M, Petroni ML, Grandinetti G, et al (1991) Comparison of effects of chenodeoxycholic and ursodeoxycholic acid and their combination on biliary lipids in obese patients with gallstones. Scand J Gastroenterol 26: 257–62
Biliary Infections
114
Ulrich Beuers
Chapter Outline Bacterial Cholangitis ................................................... 1493 Pathogenesis ................................................................... 1493 Diagnosis........................................................................ 1494 Treatment ....................................................................... 1495 Prophylaxis .................................................................... 1497 Fungal Cholangitis ....................................................... 1498 Diagnosis........................................................................ 1498 Treatment ....................................................................... 1498 Parasitic Cholangitis .................................................... 1498
Bacterial Cholangitis Acute bacterial cholangitis is a severe, potentially lifethreatening disease which followed an always lethal course still a hundred years ago [46]. Bacterial cholangitis is characterized by the clinical signs and symptoms of jaundice, spiking fever (with chills), and right upper quadrant (RUQ) abdominal pain, also referred to as “Charcot’s triad” [6, 20]. Introduction of medical and interventional treatment options has led to a reduction of mortality of acute bacterial cholangitis to < 10% at the end of the last century [36].
Pathogenesis ................................................................... 1498 Diagnosis and Treatment................................................ 1498
Pathogenesis HIV Cholangiopathy .................................................... 1499 Pathogenesis ................................................................... 1500 Diagnosis........................................................................ 1500 Treatment ....................................................................... 1500 References ..................................................................... 1501
Acute bacterial cholangitis develops in immunocompetent individuals when two pathological conditions are fulfilled: (1) Bacteria in bile (“bacterobilia”) and (2) bile duct obstruction leading to an increased intraductal pressure.
Bacteria in Bile Bile is sterile in healthy individuals [15, 25, 44]. Anatomical barriers protect bile from being invaded by bacteria both via the hematogenous route by hepatocellular and cholangiocellular gap junctions and via the enteric route by constant bile flow, the bacteriostatic action of bile acids and immunoglobulins, particularly IgA in bile, and a well functioning sphincter of Oddi [52]. Risk factors for invasion of bacteria into the biliary tree include common bile duct (CBD) stones, benign, and to a markedly lesser degree, malignant biliary H. Dancygier, Clinical Hepatology, DOI: 10.1007/978-3-642-04519-6_114, © Springer-Verlag Berlin Heidelberg 2010
1493
1494
114
strictures, endoscopic sphincterotomy, and biliary endoprosthesis. Obstructive jaundice, recent clinical infections, age > 70 years, diabetes mellitus, and previous biliary interventions may further enhance the risk for bacterobilia [52]. In the early phase of acute cholangitis, bacteria are detected in at least 75% of bile cultures and often in blood cultures taken during episodes of fever. Mixed infections of bile are found in 30–80% of bacterial cholangitis and in > 80% of cases with severe acute suppurative cholangitis [49, 57]. The most commonly detected bacteria are Gram-negative E. coli and Klebsiella spp. as well as Gram-positive Enterococcus faecalis (Table 114.1) [37, 52, 57]. Enterobacter spp., Citrobacter spp., Proteus spp. and anaerobes like Bacteroides spp. or Clostridium spp. may be found in a minority of cases. After biliary endoscopic or surgical interventions, a mixed flora of the above mentioned Gram-negative bacteria together with Gram-positive bacteria, anaerobes or with Pseudomonas spp. can be expected [45]. Insertion of biliary stents is universally associated with bacterobilia, and stent occlusion frequently leads to bacterial cholangitis. It is generally assumed, but not proven, that bacteria invade the biliary tree under pathological conditions via the duodenum. The pattern of germs found in bile mirrors the predominant bacteria isolated from the upper GI tract [2]. Bacteria in a normal bile duct with low pressure (8–12 cm H2O) do not cause clinical cholangitis, as can be observed after routine endoscopic retrograde cholangiography when cholangitis is only observed in a very low percentage of patients, although bacterial contamination of the biliary tree can barely be avoided [7]. Experimental studies indicate that transfer of bacteria from bile to blood mainly via a transcellular route requires an elevation of biliary pressure to at least 15–20 cm H2O [26]. Table 114.1 Bacteria cultured in bile during bacterial cholangitis [37, 52, 57] E. coli Klebsiella spp. Streptococcus faecalis (Enterococcus) Enterobacter spp. Citrobacter spp. Proteus spp. Bacteroides spp. Clostridium spp.
Bile Duct Obstruction The most frequent cause of bacterial cholangitis is choledocholithiasis. In approximately 10–15% of patients with cholecystolithiasis, gallbladder stones pass into the common bile duct (CBD), and this rate may rise to 25% in the elderly. Thus, all patients with symptomatic cholecystolithiasis should be screened for the presence of bile duct stones [21]. CBD stones remain undetected in 1–5% of patients after cholecystectomy for symptomatic cholelithiasis. Bile duct stones deriving from the gallbladder are most commonly cholesterol stones. In contrast, those developing in the biliary tree after cholecystectomy, during chronic recurrent cholangitis, during parasitic infections of the biliary tree, due to congenital anatomical anomalies such as Caroli’s disease or due to secondary stricturing, sclerosis, and dilation of the bile ducts, are mainly pigment stones. Choledocholithiasis leads to bacterial cholangitis in about 10% whereas malignant strictures of the biliary tree only rarely induce bacterial cholangitis as long as interventions have not been performed.
Diagnosis The diagnosis of bacterial cholangitis is based on clinical findings as well as laboratory tests and imaging studies (Table 114.2) [6]. Typical clinical signs and symptoms such as the “Charcot’s triad” (fever, jaundice, right upper quadrant pain) are observed today less frequently than 25 years ago: fever is observed in 90% of patients with bacterial cholangitis, but jaundice is only observed in two of three patients, and right upper quadrant abdominal pain in less than half of patients [8, 32]. However, severe cases with sepsis and Table 114.2 Diagnostic workup of patients with suspected bacterial cholangitis Signs and symptoms
44–58% 14–34% 0–53%. Biochemical tests 5–13% 0–6% 3–10% 1–18% 4–16%
Biliary Infections
Microbiological tests Imaging Imaging and treatment
Fever, jaundice, RUQ pain, confusion, hypotension (Charcot’s trias, Reynold’s pentad) Leukocytes, CRP, bilirubin, alkaline phosphatase, lipase Blood culture Abdominal ultrasound EUS or MRC ERCP
Bacterial Cholangitis
shock who fulfill “Reynold’s pentad” (fever, jaundice, right upper quadrant pain, confusion, hypotension) are still found in 5% of the mostly elderly patients with acute bacterial cholangitis. Laboratory tests may help to confirm the diagnosis of bacterial cholangitis: Leukocytosis (> 10 G/L) is common (70%), but leukopenia may be found in severe cases [32]. CRP is frequently elevated at least 10- to 20-fold. Hyperbilirubinemia is greater than 2 mg/dL (>34 μmol/L) in 80% of cases, and there is a two- to fivefold increase of alkaline phosphatase in up to 75% of patients. Serum transaminases are markedly elevated only in a minority of patients [32]. Blood cultures are positive in 60% of cases. Bile cultures are not routinely recommended before beginning antibiotic treatment, but may be positive in 75–100%. A meta-analysis of 22 studies, including more than 9,000 patients with symptomatic cholecystolithiasis, analyzed ten clinical, biochemical and ultrasound findings for the prediction of choledocholithiasis as the most frequent cause of bacterial cholangitis [1]. The positive likelihood ratio (LR + : sensitivity/1-specificity) indicating choledocholithiasis was highest for Charcot’s triad (18.3), suspicion of bile duct stones on ultrasound (13.6), jaundice (10.1) and a dilated common bile duct > 6–7 mm (LR + 6.9). Hyperbilirubinemia (4.8), elevated alkaline phosphatase (2.6), pancreatitis (2.1), cholecystitis (1.6), and elevated amylase (1.5) had a limited predictive value for choledocholithiasis. None of the criteria alone reached a sufficient sensitivity for the detection of bile duct stones although seven of ten criteria reached a specificity above 90% [1]. Abdominal ultrasound has a sensitivity of up to 50% to detect bile duct stones. A common bile duct > 6–7 mm enhances its sensitivity to 75% in non-cholecystectomized patients [40]. Conventional abdominal computed tomography (CT) has a sensitivity similar to ultrasound, but is associated with considerable exposure to irradiation and requires more sophisticated technical equipment. Conventional CT has, therefore, no place in routine diagnostic workup when choledocholithiasis is suspected. In contrast, endoscopic ultrasound (EUS) has a high sensitivity (95–100%) and specificity (97–98%) for detection of extrahepatic bile duct stones, but also can detect other causes of biliary obstruction and has therefore become the diagnostic procedure of choice in centers with highly skilled endoscopists [55]. Magnetic resonance cholangiography (MRC) has recently developed into a highly sensitive and specific (> 85–100%)
1495
technique equivalent to EUS for the detection of causes of biliary obstruction [16, 22, 23, 33, 54, 55]. MRC is not invasive and not accompanied by exposure to irradiation. Thus, MRC may be helpful in the diagnostic work-up of a patient with bacterial cholangitis in centers equipped with up-to-date technology. Accuracy of helical computed-tomographic cholangiography (HCT-C) for detection of choledocholithiasis appears comparable to MRC, but HCT-C is associated with exposure to irradiation and a risk of adverse reactions to the contrast agent administered intravenously [33]. Endoscopic retrograde cholangiography (ERC) remains the gold standard for concomitant detection and treatment of choledocholithiasis and other causes of bile duct obstruction. In experienced hands, a sensitivity of 90–100% and a specificity > 90% for the detection of bile duct stones are reached. Although accompanied by complications such as pancreatitis, cholangitis, or bleeding after endoscopic sphincterotomy (EST), this procedure combines high diagnostic accuracy with therapeutic options for efficient biliary drainage such as basket or balloon extraction of stones, dilatation of strictures, and biliary decompression via stenting or temporary nasobiliary drainage.
Treatment Therapeutic measures are directed against the two key pathogenetic factors of cholangitis: bacteria in bile and obstruction of bile flow. Thus, adequate antibiotic treatment and decompression and drainage of the biliary tree are equally warranted [6].
Antibiotic Treatment The antibiotic is chosen empirically according to (i) the most common pathogens expected to cause cholangitis (see above), (ii) biliary penetration and activity of the antibiotic, and (iii) the likelihood of resistance of pathogens in the clinical environment [56, 57]. Acylaminopenicillins like mezlocillin and piperacillin cover Gram-negative bacteria as well as enterococcus spp. more efficiently than aminopenicillins, are effectively secreted into bile not only in healthy persons, but also in patients with cholangitis, and may reach biliary levels 200- to 300-fold higher than the mean inhibitory
1496
114
concentration of common biliary pathogens [19, 20]. In addition, effective biliary bactericidia in vivo has been shown [47]. Addition of a beta lactamase inhibitor broadens the spectrum of amino- and acylaminopenicillins and diminishes bacterial resistance. Cephalosporins (group 2 and 3) also cover Gram-negative bacteria and are adequately excreted into bile, but are less effective against Enterococcus spp. and Pseudomonas aeruginosa. Ciprofloxacin is excreted into bile effectively, can be administered orally, and covers Gram-negative bacteria and Pseudomonas aeruginosa [57]. The new generation fluoroquinolone (group 4), moxifloxacin, is also effectively secreted into bile not only in health, but also in obstructive cholangitis, reaching biliary concentrations sufficiently above the minimal inhibitory concentrations for most of the expected bacteria including Enterococcus spp. and anaerobes [47]. Aminoglycosides (e.g., gentamicin, tobramycin), active against Gram-negative bacteria and Pseudomonas spp., and vancomycin, active against Enterococcus spp., are inadequately excreted into bile. Nevertheless, aminoglycosides in combination with amoxicillin are used for the initial systemic treatment of severe bacterial cholangitis in some centers in order to counteract the consequences of systemic bacteremia. It
Biliary Infections
needs to be kept in mind, however, that the risk of otoand nephrotoxicity of aminoglycosides is aggravated in cholestasis. Imipenem/meropenem represent potent parenteral antibiotics which cover the whole spectrum of bacteria causing ascending cholangitis including Gramnegative strains, Pseudomonas aeruginosa, Enterococcus spp., and anaerobes [57]. They should, however, be reserved for most severe, life-threatening infections when other regimens have failed (Table 114.3).
Decompression of Bile Ducts Severe bacterial cholangitis requires immediate mechanical decompression of the biliary tree to prevent sepsis and septic shock. ERC is the therapeutic procedure of choice which allows, after endoscopic sphincterotomy (EST) (or endoscopic balloon dilation [EBD] of the papilla in patients with coagulopathy and small calculi), extraction of calculi, stenting of stenoses or biliary drainage via a nasobiliary tube [3, 5, 14, 31, 35, 51]. Stenting has been shown to be equivalent to nasobiliary drainage in the acute management of severe obstructive cholangitis [48]. Pregnancy or advanced
Table 114.3 Antibiotics recommended for treatment of acute bacterial cholangitis Gram-negative enterobacteriaceae (E. coli, Klebsiella spp., Enterobacter spp., Citrobacter spp., and Proteus spp.) and Enterococcus spp., (as well as Pseudomonas spp. when endoscopic or surgical interventions at the biliary tree have previously been performed) should be adequately covered when empirical antibiotic treatment of bacterial cholangitis is considered [57]. Thus, aminopenicillins + beta lactamase inhibitors, ureidopenicillins (+ beta lactamase inhibitors), group 2 or 3 cephalosporins (+ metronidazol), or group 2 fluorchinolones (+ metronidazol) appear useful as first-line treatment considering the spectrum of bacteria covered, potential side effects, and costs. Aminoglycosides (e.g., gentamycin, tobramycin, gernebcin; cave: oto-, nephrotoxicity, aggravated in cholestasis), active against Gram-negative bacteria and Pseudomonas spp., and vancomycin, active against Enterococcus spp., are inadequately excreted into bile. Aminoglycosides in combination with amoxicillin are used for the initial systemic treatment of severe bacterial cholangitis in some centers in order to counteract the consequences of systemic bacteremia. Group 4 fluorchinolones and carbapenemes should be reserved for severe cases unresponsive to other treatment options. Antibiotic Gram-neg. Enterococcus Pseudomonas Anaerobes High daily i.v. dose for spp. spp. adults with normal kidney and liver function Amoxicillin + Clavulanic acid * Ampicillin + Sulbactam * Mezlocillin Mezlocillin + Combactam Piperacillin Piperacillin + Tazobactam Ceftazidime (group 3b ceph.) Cefotaxime (group 3a ceph.) Cefuroxime (group 2 ceph.) Ciprofloxacin (group 2 fluo.) * Moxifloxacin (group 4 fluo.) * Imipenem/Meropenem Metronidazole * *
Oral administration possible
+ + + + + + + + + + + +
± ± + + + +
± + +
+ + +
+ + +
± ± ± + ± +
+ + +
3 × 2.2 g 3 × 3g 3 × 5g M:3 × 5 g C:3 × 1 g 3 × 4g 3 × 4.5 g 3 × 2g 3 × 2g 4 × 1.5 g 3 × 0.4 g 1 × 0.4 g 3 × 1g 3 × 0.5 g
Bacterial Cholangitis
1497
age are not contraindications for ERC [27, 30]. Only when ERC cannot be performed for technical reasons (e.g., after Billroth II and other gastrointestinal surgery, or tumor growth impairing endoscopic access to the biliary tree), the percutaneous transhepatic route should be chosen to achieve biliary decompression.
Prophylaxis After biliary tract surgery, the rate of wound infections was reported to be 15% (3–47%) as documented in a meta-analysis encompassing 42 randomized controlled trials with 4,125 patients [42]. Risk factors included age > 60 years, common bile duct stones, previous biliary tract interventions, jaundice, morbid obesity and diabetes mellitus. Antibiotic prophylaxis with β-lactam antibacterials (e.g., ceftriaxone, cefuroxime, cefotaxime, piperacillin) effectively diminished the rate of wound infections in these cohorts by 9%. A single dose before surgery was as effective as multiple doses. Fluoroquinolones have recently been shown to be as effective as common β-lactam antibacterials [57]. After percutaneous transhepatic cholangiography (PTC), the effect of antibiotic prophylaxis has not been studied in trials comparable to those after surgery or ERCP. However, the frequency of infectious complications which reaches up to 20% without prophylaxis, may justify regular use of antibiotic prophylaxis until appropriate clinical trials are available. A protocol like the one mentioned below for patients at risk for post-ERCP cholangitis may be considered. After endoscopic retrograde cholangiopancreaticography (ERCP), cholangitic sepsis was observed in
1.4% of 10,881 patients studied for post-ERCP complications in 10 large cohorts and in 2% of a large unselected population of 10,000 patients assembled by postal questionnaires [7, 52]. Mortality of post-ERC cholangitis reached 10 to 16% in severe cases, but was only 2.9% in a series of prospective, placebo-controlled trials on use of antibiotic prophylaxis in which 6.5% of 539 placebo-treated patients developed cholangitis [4, 7, 52]. A meta-analysis revealed that antibiotic prophylaxis diminished rates of bacteremia, but not cholangitis and sepsis after ERCP and could, therefore, not be recommended for routine use during ERCP [24]. The most important risk factor for septicemia following endoscopic biliary stenting was incomplete biliary drainage (91%!) in a prospective study of 347 patients with obstructive cholestasis [43]. Additional risk factors were prior cholangitis, elevated white blood cell count, bile duct strictures, and number of ERCPs. These data suggest that antibiotic prophylaxis before/after ERCP should be restricted to (i) Patients with unrelieved biliary obstructions–antibiotic treatment should be continued in these patients until complete biliary drainage is achieved (ii) Patients with primary sclerosing cholangitis, as they are at particular risk for at least focal incomplete biliary drainage and chronic bacterobilia after ERCP and (iii) Immunocompromised individuals at high risk for infectious complications (e.g., post liver transplant; HIV) (Table 114.4) A regimen of ciprofloxacin, 750 mg p.o. 2 h before ERCP and 6 h after ERCP has been proposed as first line antibiotic prophylaxis in these patients, as it appropriately
Table 114.4 Antibiotic prophylaxis prior to surgical or endoscopic (ERC) interventions of the bile ducts [6]. No adequate data are available for prophylactic antibiotic treatment prior to percutaneous transhepatic cholangiography (PTC) Intervention Rate of infectious Recommended antibiotic regimen Ref. complications Biliary tract surgery
Wound infection 15% (3–47%)
ERC (a) No biliary obstruction (b) Biliary obstruction expected or unrelieved
Cholangitis 1–2%
(c) Sclerosing cholangitis (d) Immunodeficiency (e.g., HIV, immunosuppressive treatment after liver transplantation)
β-lactam antibiotic (e.g., cefuroxime, ceftriaxone, cefotaxime, piperacillin) or fluoroquinolone 1 h before surgery
9, 39
9, 14, 42 (a) None (b) β-lactam antibacterial (cephalosporin or ureidopenicillin ± beta lactamase inhibitor) or fluoroquinolone, until obstruction relieved (see Table 114.3) (c + d) ciprofloxacin 750 mg p.o.2 hrs before and 6 hrs after ERC or β-lactam antibacterial i.v. (optimal dose and duration of treatment unknown)
1498
considers activity against the bacterial spectrum expected, adequate biliary drug enrichment even in cholestasis, drug tolerability, and costs [52]. As an alternative, amoxicillin plus beta-lactamase inhibitors have been considered as suitable for prophylactic treatment in patients undergoing endoscopic interventions in the biliary tree [38]. Optimal duration of prophylactic treatment after endoscopic interventions remains to be determined. After surgical construction of a bilio-enteric anastomosis, some patients may develop recurrent ascending cholangitis and may need long-term antibiotic prophylaxis to avoid development of biliary fibrosis/ cirrhosis. As an alternative to oral fluoroquinolones, cotrimoxazole (trimethoprim/ sulfamethoxazole) has been proposed for long-term use in these patients at risk (Table 114.4, see also above) [57].
Fungal Cholangitis Fungal cholangitis remains anecdotal in otherwise healthy individuals. “Fungobilia” has only recently attracted more clinical attention when biliary Candida infections were reported in cohorts of patients with primary sclerosing cholangitis (PSC) and dominant biliary strictures or immunocompromised patients, e.g. after liver transplantation [18, 34]. In these patients, repeated endoscopic interventions, frequent antibiotic treatment in the recent past, and immunosuppressive therapy may have contributed synergistically to fungal infection of the biliary tree (see Chapter 68).
Diagnosis In the case series reported, clinical signs and symptoms of cholangitis were only described in a portion of the patients affected. Hyperbilirubinemia and CRP elevation were more pronounced in PSC patients with Candida infection than in those without Candida infection [34]. Different Candida species (C. albicans, C. glabrata, C. tropicalis) were identified in bile of these patients.
114
Biliary Infections
adequate levels to eradicate Candida from bile [10]. Nevertheless, antifungal treatment of biliary candidiasis did not always lead to fungal clearance, and spontaneous clearance without antifungal treatment was also reported in single cases [34]. Thus, the effectiveness of antifungal treatment for biliary candidiasis remains to be proven.
Parasitic Cholangitis Biliary parasites are responsible for cholangitic features at considerable rates mainly in tropical and subtropical areas of the world [6]. The nematode Ascaris lumbricoides and the trematodes (“liver flukes”) Clonorchis sinensis, Opisthorchis viverrini, Opisthorchis felineus, Dicrocoelium dendriticum, Fasciola hepatica and Fasciola gigantica are the most common biliary parasites. The cestodes Echinococcus granulosus and Echinococcus multilocularis usually are diagnosed as focal lesions of the liver or other organs and are, therefore, not discussed here although they may invade the biliary tree in rare cases and, thereby, cause biliary complications (see Chapters 66 and 67).
Pathogenesis Parasite-induced bile duct damage and inflammation with bile duct strictures, focal bile duct dilatations, and biliary fibrosis may be induced by chemical irritation of biliary endothelia by parasitic secretion and parasite eggs, mechanical bile duct obstruction, and initiation of pigment stone formation [11]. In addition, parasiteinduced bacterial superinfection together with mechanical obstruction, may be responsible for episodes of acute cholangitis.
Diagnosis and Treatment Nematode Cholangitis
Treatment The antifungal drugs fluconazole and caspofungin are secreted into bile and may be expected to reach
Ascaris lumbricoides is found worldwide, but is reported as a major cause of biliary pain and cholangitis often in young patients from tropic and subtropic areas, e.g. India or South America. Nematode eggs are mostly
HIV Cholangiopathy
ingested with contaminated vegetables via the oral route. Cholangitis is usually induced by migration of larvae or young adult worms into the biliary tree where they may cause – together with comigrating intestinal bacteria – suppurative cholangitis, biliary obstruction, abscesses, cholangiectases, sometimes papillary hyperplasia, gallstone formation, biliary fibrosis and even cirrhosis. The diagnosis of ascaris lumbricoides cholangitis is made by blood eosinophilia and stool examination, ultrasound, CT, and ERCP. The treatment includes antibiotics for bacterial superinfection, spasmolytic agents for pain relief, and anthelmintic drugs (mebendazole 100 mg p.o. bid for 3 days; albendazole 400 mg p.o. daily for 3 days; pyrantel 10 mg/kg b.w. p.o. once). Worms can then be removed via the endoscopic route.
Trematode Cholangitis The “liver flukes” Clonorchis sinensis, Opisthorchis felineus, Opisthorchis viverri and Dicrocoelium dendriticum are found mainly in Asia and Eastern Europe. They undergo a biphasic life cycle in an intermediate host (a freshwater snail and subsequently freshwater fish) and a definitive host, a mammal. Trematode eggs are passed in the feces of the definitive host, and develop to ciliated microcidia in freshwater which are ingested by or penetrate into snails and multiply into tailed cercariae. Cercariae are taken up by or penetrate freshwater fish. Humans and other mammals develop liver fluke cholangitis after ingestion of raw infected fish. After infection, patients are often asymptomatic, but may develop recurrent cholangitis, secondary gallstone disease, and fibrosing bile duct alterations. Longterm biliary infection is a serious risk factor for development of cholangiocarcinoma. The diagnosis is made by detection of ova in the stool or in bile. The treatment of choice is praziquantel; alternatively, albendazole can be administered (Table 114.5). “Liver flukes” like Clonorchis sinensis have been held responsible for the development of recurrent pyogenic cholangitis (RPC; synonymous: oriental cholangiohepatitis, hepatolithiasis) [29, 39]. RPC is mostly restricted to Southeast Asian countries and emigrants from this part of the world, and is mainly found in rural areas with a low socioeconomic status. Patients mostly present with initial symptoms before the age of 40. Clinical symptoms include Charcot’s triad with jaundice, spiking fever, and right upper quadrant pain. Hepatomegaly is a frequent
1499
finding. Endoscopic retrograde cholangiography (ERC) reveals dilation of extra- and large intrahepatic bile ducts, biliary strictures at the papilla and at intrahepatic sites and typical involvement specifically of the lateral part of the left hepatic duct. Bile ducts are filled with debris and small stones in almost all patients. Complications of RPC include Gram-negative septicemia and septic shock, empyema of the gallbladder, rupture or fistulization of an obstructed intrahepatic bile duct into neighbouring structures, hemobilia, portal vein thrombosis, abscesses in liver, lungs, and brain, biliary cirrhosis, and acute pancreatitis. Cholangiocarcinoma mainly in the left atrophic hepatic lobe was observed in 3%, and overall mortality was 10% in 427 patients undergoing surgical or nonsurgical transcutaneous treatment during follow-up for 4–10 years [28]. Fasciola hepatica occurs worldwide [17]. Hosts are cattle and sheep, but humans may also be infected after ingestion of contaminated watercress or other waterplants. Signs and symptoms of cholangitis and blood eosinophilia develop in the early migratory phase of infection. Eosinophilic infiltrates, liver abscesses, and fibrosing cholangitis are observed later in the course. The diagnosis is made by detection of ova in stool or bile, fasciola antigen in stool, and a serologic test. Treatment of choice is triclabendazole, 10 mg/kg b.w. p.o. on one or two subsequent days after a meal.
HIV Cholangiopathy Cholestasis and liver injury are common in HIV-infected patients [6]. HIV cholangiopathy represents only one of numerous causes (see also Chapters 52 and 69). Elevation of serum biochemical markers of cholestasis such as alkaline phosphatase and γ-glutamyl transpeptidase levels have been reported in up to 55% of patients [53]. These alterations can in part be explained by concomitant infections with hepatitis B or C or alcohol abuse. Drugs represent a major culprit of liver damage in HIV-infected patients and may cause relevant liver injury in up to 10% of patients under highly active antiretroviral therapy (HAART) with nucleoside and non-nucleoside reverse transcriptase inhibitors or protease inhibitors [50]. Antimicrobial agents for the prophylaxis of respiratory infections and Mycobacterium avium complex disease (e.g., clarithromycin, azithromycin), for the prophylaxis and treatment of pneumocystis jiroveci pneumonia
1500
114
(e.g., trimethoprim-sulfamethoxazole), antifungal agents for the treatment of esophageal candidiasis and systemic mycoses (e.g., ketoconazole, itraconazole, to a lesser extent fluconazole), and antituberculosis agents (e.g., isoniazid, rifampin, pyrazinamide) are associated with considerable rates of hepatotoxicity. Systemic infections with involvement of the hepatobiliary system accompanying HIV disease include bacillary angiomatosis caused by Rochalimaea henselae and R. quintana, mycobacterial infections including M. avium complex (MAC) and M. tuberculosis, as well as fungal infections with Cryptococcus neoformans, Coccidioides imitis, Sporothrix schenckii, or histoplasmosis. Beside these numerous causes of hepatobiliary injury in HIV disease, a specific type of cholangitis first reported in 1986 has been described mainly in advanced stages of HIV infection which resembles primary sclerosing cholangitis and has been named HIV cholangiopathy [41].
Biliary Infections
Diagnosis Clinical symptoms include epigastric or right upper quadrant pain (73–90%) and fever (50–65%), whereas jaundice and pruritus are uncommon. Alkaline phosphatase is markedly (mean five- to sevenfold the upper limit of normal) elevated in almost all patients whereas serum transaminases are only mildly elevated. Abdominal ultrasound and CT scan are of limited diagnostic help. Endoscopic retrograde cholangiography (ERC) or magnetic resonance cholangiography (MRC) disclose the typical features of bile duct damage. Four patterns of HIV cholangiopathy have been described: (i) Sclerosing cholangitis and papillary stenosis (50%) (ii) Papillary stenosis alone (15%) (iii) Intrahepatic sclerosing cholangitis (20%) and (iv) Extrahepatic bile duct strictures with or without intrahepatic sclerosing cholangitis (15%) [12] Liver histology reveals features of cholangitis with portal edema, neutrophilic infiltrations, bile ductular proliferation, and cholestasis.
Pathogenesis The cause of HIV cholangiopathy most likely is infectious. No single causative agent has been identified so far. In biopsy specimens, cytomegalovirus, cryptosporidium, microsporidia, and mycobacterium avium complex have all been isolated, albeit at variable rates up to 75% [53].
Table 114.5 Parasitic cholangitis Parasite
Treatment of HIV cholangiopathy includes endoscopic sphincterotomy in symptomatic patients with papillary stenosis which may relieve RUQ pain, but does not regularly affect biochemical abnormalities [9, 13, 53, 58].
Source of infection (distribution)
Anthelminthic medical treatment optionsa
Nematodes
Ascaris lumbricoides
Vegetables (worldwide, but mainly Asia and South America)
Mebendazole (100 mg bid, 3 days) Albendazole (400 mg daily, 3 days) Pyrantel (10 mg/kg b.w. once)
Trematodes
(a) Clonorchis sinensis Opisthorchis felineus Opisthorchis viverrini (b) Fasciola hepatica
(a) Raw freshwater fish (Asia and Eastern Europe)
(a) Praziquantel (25 mg/kg b.w. tid, 1 day) Albendazole (400 mg bid, 7 days)
(b) Watercress and other waterplants
(b) Triclabendazole (10 mg/kg b.w. once, 1 or 2 days)
Echinococcus granulosus Echinococcus multilocularis
Vegetables or wild fruits contaminated with fox (or dog) feces (worldwide)
Albendazole (12–15 mg/kg b.w. daily in 2 doses, for adults 400 mg bid, 3 months) Mebendazole (50–60 mg/kg b.w. daily in 3 doses during meals, 3–12 months)
Cestodes
a
Treatment
All drugs are given p.o.
References
Medical treatment with ursodoexycholic acid improves cholestasis, but long-term effects are unknown. In contrast, treatment of opportunistic pathogens does not seem to have an effect on HIV cholangiopathy. In studies in the 1990s, survival of patients suffering from HIV cholangiopathy was poor (14–41% after 1 year), mainly due to the progression of the underlying HIV disease [9, 13]. This indicates that HIV cholangiopathy is a late manifestation of HIV infection.
References 1. Abboud PA, Malet PF, Berlin JA, et al (1996) Predictors of common bile duct stones prior to cholecystectomy: a metaanalysis. Gastrointest Endosc 44: 450–5 2. Bapat RD, Supe AN, Patwardhan A, et al (1976) Biliary sepsis: an ascending infection. Indian J Gastroenterol 15: 126–8 3. Baron TH, Harewood GC (2004) Endoscopic balloon dilation of the biliary sphincter compared to endoscopic biliary sphincterotomy for removal of common bile duct stones during ERCP: a metaanalysis of randomized, controlled trials. Am J Gastroenterol 99: 1455–60 4. Benchimol D, Bernard JL, Mouroux J, et al (1992) Infectious complications of endoscopic retrograde cholangio-pancreatography managed in a surgical unit. Int Surg 77: 270–3 5. Bergman JJ, Rauws EA, Fockens P, et al (1997) Randomised trial of endoscopic balloon dilation versus endoscopic sphincterotomy for removal of bileduct stones. Lancet 349: 1124–9 6. Beuers U (2007) Cholangitis and biliary tract infections. In: Rodès J et al (eds) Oxford textbook of clinical hepatology, 3rd edn. Oxford University Press 7. Bilbao MK, Dotter CT, Lee TG, et al (1976) Complications of endoscopic retrograde cholangiopancreatography (ERCP). A study of 10,000 cases. Gastroenterology 70: 314–20 8. Boey JH, Way LW (1980) Acute cholangitis. Ann Surg 191: 264–70 9. Bouche H, Housset C, Dumont JL, et al (1993) AIDS-related cholangitis: diagnostic features and course in 15 patients. J Hepatol 17: 34–9 10. Bozzette SA, Gordon RL, Yen A, et al (1992) Biliary concentrations of fluconazole in a patient with candidal cholecystitis: case report. Clin Infect Dis 15: 701–3 11. Carpenter HA (1998) Bacterial and parasitic cholangitis. Mayo Clin Proc 73: 473–8 12. Cello JP (1992) Human immunodeficiency virus-associated biliary tract disease. Semin Liver Dis 12: 213–8 13. Cello JP, Chan MF (1995) Long-term follow-up of endoscopic retrograde cholangiopancreatography sphincterotomy for patients with acquired immune deficiency syndrome papillary stenosis. Am J Med 99: 600–3 14. Classen M, Demling L (1974) Endoscopic sphincterotomy of the papilla of vater and extraction of stones from the choledochal duct (author’s transl). Dtsch Med Wochenschr 99: 496–7
1501 15. Csendes A, Fernandez M, Uribe P (1975) Bacteriology of the gallbladder bile in normal subjects. Am J Surg 129: 629–31 16. de Ledinghen V, Lecesne R, Raymond JM, et al (1999) Diagnosis of choledocholithiasis: EUS or magnetic resonance cholangiography? A prospective controlled study. Gastrointest Endosc 49: 26–31 17. Dobrucali A, Yigitbasi R, Erzin Y, et al (2004) Fasciola hepatica infestation as a very rare cause of extrahepatic cholestasis. World J Gastroenterol 10: 3076–7 18. Domagk D, Fegeler W, Conrad B, et al (1992) Biliary tract candidiasis: diagnostic and therapeutic approaches in a case series. Am J Gastroenterol 101: 2530–6 19. Dooley JS, Hamilton-Miller JM, Brumfitt W, et al (1984) Antibiotics in the treatment of biliary infection. Gut 25: 988–98 20. Dooley JS (1999) Cholangitis and biliary tract infections. In: Bircher H, Benhamou JP, McIntyre N, Rizzetto M, Rodès J (eds) Oxford textbook of clinical hepatology. Oxford University Press, Oxford, pp 1649–56 21. EAES C (1998) Diagnosis and treatment of common bile duct stones (CBDS). Results of a consensus development conference. Scientific Committee of the European Association for Endoscopic Surgery (E.A.E.S.). Surg Endosc 12: 856–64 22. Fernandez-Esparrach G, Gines A, Sanchez M, et al (2007) Comparison of endoscopic ultrasonography and magnetic resonance cholangiopancreatography in the diagnosis of pancreatobiliary diseases: a prospective study. Am J Gastroenterol 102: 1632–9 23. Fulcher AS, Turner MA, Capps GW, et al (1998) RARE MR cholangiopancreatography: experience in 300 subjects. Radiology 207: 21–32 24. Harris A, Chan AC, Torres-Viera C, et al (1999) Metaanalysis of antibiotic prophylaxis in endoscopic retrograde cholangiopancreatography (ERCP). Endoscopy 31: 718–24 25. Hatfield AR, Leung T, Ahmet Z, et al (1982) The microbiology of direct bile sampling at the time of endoscopic retrograde cholangiopancreatography. J Infect 4: 119–25 26. Huang T, Bass JA, Williams RD (1969) The significance of biliary pressure in cholangitis. Arch Surg 98: 629–32 27. Hui CK, Liu CL, Lai KC, et al (2004) Outcome of emergency ERCP for acute cholangitis in patients 90 years of age and older. Aliment Pharmacol Ther 19: 1153–8 28. Jan YY, Chen MF, Wang CS, et al (1996) Surgical treatment of hepatolithiasis: long-term results. Surgery 120: 509–14 29. Jeyarajah DR (2004) Recurrent Pyogenic Cholangitis. Curr Treat Options Gastroenterol 7: 91–8 30. Kahaleh M, Hartwell GD, Arseneau KO, et al (2004) Safety and efficacy of ERCP in pregnancy. Gastrointest Endosc 60: 287–92 31. Kawai K, Akasaka Y, Murakami K, et al (1974) Endoscopic sphincterotomy of the ampulla of Vater. Gastrointest Endosc 20: 148–51 32. Keaveny AP (2000) Infections of the bile ducts. In: Afdhal NH (ed) Gallbladder and biliary tract diseases. Marcel Dekker, New York, pp 823–42 33. Kondo S, Isayama H, Akahane M, et al (2005) Detection of common bile duct stones: comparison between endoscopic ultrasonography, magnetic resonance cholangiography, and helical-computed-tomographic cholangiography. Eur J Radiol 54: 271–5
1502 34. Kulaksiz H, Rudolph G, Kloeters-Plachky P, et al (2006) Biliary candida infections in primary sclerosing cholangitis. J Hepatol 45: 711–6 35. Lai EC, Mok FP, Tan ES, et al (1992) Endoscopic biliary drainage for severe acute cholangitis. N Engl J Med 326: 1582–6 36. Lee JG (1998) Role of endoscopic therapy in cholangitis. Am J Gastroenterol 93: 2016–8 37. Leung JW, Ling TK, Chan RC, et al (1994) Antibiotics, biliary sepsis, and bile duct stones. Gastrointest Endosc 40:716–21 38. Lorenz R, Herrmann M, Kassem AM, et al (1998) Microbiological examinations and in-vitro testing of different antibiotics in therapeutic endoscopy of the biliary system. Endoscopy 30:708–12 39. Mahadevan U, Bass NM (2002) Sclerosing cholangitis and recurrent pyogenic cholangitis. In: Feldman M, Friedman LS, Sleisenger MH (eds) Sleisenger & Fordtran’s gastrointestinal and liver disease. WB Saunders, Philadelphia, pp 1131–52 40. Majeed AW, Ross B, Johnson AG, et al (1999) Common duct diameter as an independent predictor of choledocholithiasis: is it useful? Clin Radiol 54: 170–2 41. Margulis SJ, Honig CL, Soave R, et al (1986) Biliary tract obstruction in the acquired immunodeficiency syndrome. Ann Intern Med 105: 207–10 42. Meijer WS, Schmitz PI, Jeekel J (1990) Meta-analysis of randomized, controlled clinical trials of antibiotic prophylaxis in biliary tract surgery. Br J Surg 77: 283–90 43. Motte S, Deviere J, Dumonceau JM, et al (1991) Risk factors for septicemia following endoscopic biliary stenting. Gastroenterology 101: 1374–81 44. Nielsen ML, Justesen T (1976) Anaerobic and aerobic bacteriological studies in biliary tract disease. Scand J Gastroenterol 11: 437–46 45. Pitt HA, Postier RG, Cameron JL (1982) Biliary bacteria: significance and alterations after antibiotic therapy. Arch Surg 117: 445–9
114
Biliary Infections
46. Rogers L (1903) Biliary abscesses of the liver: with operation. Br Med J 2: 706–7 47. Schwab D, Grauer M, Hahn EG, et al (1974) Biliary secretion of moxifloxacin in obstructive cholangitis and the nonobstructed biliary tract. Aliment Pharmacol Ther 22: 417–22 48. Sharma BC, Kumar R, Agarwal N, et al (2005) Endoscopic biliary drainage by nasobiliary drain or by stent placement in patients with acute cholangitis. Endoscopy 37: 439–43 49. Shimada K, Noro T, Inamatsu T, et al (1981) Bacteriology of acute obstructive suppurative cholangitis of the aged. J Clin Microbiol 14: 522–6 50. Spengler U, Lichterfeld M, Rockstroh JK (2002) Antiretroviral drug toxicity–a challenge for the hepatologist? J Hepatol 36: 283–94 51. Staritz M, Poralla T, Dormeyer HH, et al (1985) Endoscopic removal of common bile duct stones through the intact papilla after medical sphincter dilation. Gastroenterology 88: 1807–11 52. Subhani JM, Kibbler C, Dooley JS (1999) Review article: antibiotic prophylaxis for endoscopic retrograde cholangiopancreatography (ERCP). Aliment Pharmacol Ther 13: 103–16 53. Te HS (2004) Cholestasis in HIV-infected patients. Clin Liver Dis 8: 213–28 54. Varghese JC, Liddell RP, Farrell MA, et al (2000) Diagnostic accuracy of magnetic resonance cholangiopancreatography and ultrasound compared with direct cholangiography in the detection of choledocholithiasis. Clin Radiol 55: 25–35 55. Verma D, Kapadia A, Eisen GM, et al (2006) EUS vs MRCP for detection of choledocholithiasis. Gastrointest Endosc 64: 248–54 56. Wacha H, Helm EB (1982) Efficacy of antibiotics in bacteriobilia. J Antimicrob Chemother 9(Suppl A): 131–7 57. Westphal JF, Brogard JM (1999) Biliary tract infections: a guide to drug treatment. Drugs 57: 81–91 58. Yusuf TE, Baron TH (2004). AIDS Cholangiopathy. Curr Treat Options Gastroenterol 7: 111–7
115
Benign Tumors Marcus Wiedmann, Christian Wittekind, Michael Tröltzsch, and Joachim Mössner
Chapter Outline Benign Tumors of the Gallbladder ............................. 1505 Definition ....................................................................... 1505 Epidemiology ................................................................. 1505 Etiology and Pathogenesis ............................................. 1506 Pathology ....................................................................... 1506 Clinical Manifestations .................................................. 1507 Diagnosis........................................................................ 1507 Differential Diagnosis .................................................... 1508 Therapy and Prognosis ................................................... 1508 Benign Tumors of the Extrahepatic Bile Ducts ......... 1509 Definition ....................................................................... 1509 Epidemiology ................................................................. 1509 Etiology and Pathogenesis ............................................. 1509 Pathology ....................................................................... 1510 Clinical Manifestations .................................................. 1510 Diagnosis........................................................................ 1510 Differential Diagnosis .................................................... 1511 Therapy and Prognosis ................................................... 1511
Benign Tumors of the Gallbladder Definition Benign tumors of the gallbladder consist of neoplasms that are derived from the gallbladder’s wall. A classification of benign gallbladder tumors was first proposed in 1970: they are primarily divided into neoplastic and non-neoplastic lesions [16]. Currently the WHO classification of tumors is most commonly used [32]. The most common neoplastic lesion is an adenoma. Benign mesodermal tumors such as leiomyomas and lipomas are rare. The most common non-neoplasic lesions (pseudotumors) are cholesterol polyps (the presence of which is referred to as “cholesterolosis”), followed by adenomyomas (the presence of which is referred to as “adenomyomatosis”), and inflammatory polyps.
Benign Tumors of the Ampulla of Vater .................... 1512 Definition ....................................................................... 1512 Epidemiology ................................................................. 1512 Etiology and Pathogenesis ............................................. 1512 Pathology ....................................................................... 1512 Clinical Manifestations .................................................. 1513 Diagnosis........................................................................ 1513 Differential Diagnosis .................................................... 1513 Therapy and Prognosis ................................................... 1514 References ..................................................................... 1515
Epidemiology Benign gallbladder tumors (polyps) can be found in 0.004% to 14% of resected gallbladders and between 1% to 7% of gallbladders assessed by ultrasonography [15, 35, 37, 51, 57, 81]. A solitary polyp is found in approximately half of the cases, two polyps in about 18%, and three or more polyps in approximately 31%. Most of the polyps (about 71%) are located in the corpus of the gallbladder, about one quarter in the infundibulum, and the remaining in the fundus. Average size of the polyps is between 3 and 5 mm. No clear association has been observed between the presence of polyps and the patient’s age (although they have only
H. Dancygier, Clinical Hepatology, DOI: 10.1007/978-3-642-04519-6_115, © Springer-Verlag Berlin Heidelberg 2010
1505
1506
rarely been described in children), sex, weight, number of pregnancies, use of estrogens/gestagens in women, or any other risk factors [37]. The prevalence of adenomas of the gallbladder is below 5% [57, 59]. They are rarely associated with Peutz-Jeghers-syndrome and sometimes with Gardner’s syndrome [25, 74]. Granular cell tumors of the gallbladder represent only 4% of all granular cell tumors that occur in the biliary tract [80]. Tumor-like lesions are more common within the gallbladder than within the extrahepatic bile ducts. Adenomyomatosis of the gallbladder can be found in up to 5% of cholecystectomy specimens. It occurs more commonly in females and in patients with a mean age of 53 years.
Etiology and Pathogenesis The majority of gallbladder tumors (polyps) are not neoplastic but hyperplastic (adenomyomatosis) or represent lipid deposits (cholesterolosis). Both entities are mucosal abnormalities of the gallbladder wall. Cholesterolosis in association with gallstones is by far the most common pathologic finding in the gallbladder [37]. Its etiology is unknown and unrelated to atherosclerosis. Abnormal deposits of triglycerides, cholesterol precursers, and cholesterol esters can be found in the gallbladder wall. Adenomyomatosis is a benign condition of the gallbladder characterized by overgrowth of the mucosa, thickening of the muscular wall, and formation of intramural diverticuli or sinus tracts termed RokitanskyAschoff sinuses, likely caused by incorporation of cholesterol. According to localisation one can distinguish the focal form (“polypoid”) from the segmental form (mostly in the fundus) and from the diffuse adenomyomatosis. Heterotopia (aberrant tissue) is defined as ectopic, non-neoplastic, regularly composed tissue found in the gallbladder. It is derived from dysontogenetic dislocation of cells from the former foregut, mostly stomach or pancreatic tissue [16, 78]. Potential complications include mucosal ulceration, obstruction, hemorrhage, and pancreatitis. Very rarely, liver, thyroid gland, or adrenal gland tissue can be found [9, 12, 20, 34]. Malacoplakia is a rare entity, usually found in the urinary tract but described in a wide range of tissues. It
115
Benign Tumors
is a rare and special form of inflammation and usually incidentally discovered in cholecystectomy specimens. The pathogenesis of malacoplakia is not proven, but it is thought to arise from chronic infection and a deficient lytic response by macrophages. The preponderance of malacoplakia in the urinary tract and the colon, and its rarity in the gallbladder, may be explained by the fact that exposure to coliform organisms in the former sites is much more frequent. Immunosuppression is thought to be another important pathogenetic factor in the development of malacoplakia.
Pathology The histologic types of benign gallbladder tumors include the following: • Epithelial Tumors – Adenoma (tubulary, papillary, tubulo-papillary) – Cystadenoma – Papillomatosis (Adenomatosis) • Non-epithelial Tumors – Granular cell tumor – Ganglioneurofibromatosis – Leiomyoma – Lipoma – Hemangioma – Lymphangioma – Neurofibroma • Tumor-like Lesions – Cholesterol polyps – Adenomyomas – Inflammatory polyps – Regenerative epithelial atypia – Papillary hyperplasia – Intestinal metaplasia – Pylorus-gland-metaplasia – Squamous metaplasia – Heterotopia – Xanthogranulomatous cholecystitis – Cholecystitis with lymphoid hyperplasia – Malacoplakia – Stump neuroma after amputation Adenomas are benign neoplasias of the gland epithelium, which are typically polypoid and distinct. They are divided according to their growth pattern into tubulary, papillary, and tubulo-papillary adenomas.
Benign Tumors of the Gallbladder
Cholesterol polyps are tumor-like lesions that are less than 1 mm in diameter in about two third of cases, which gives the mucosa a coarse and granular appearance that is characteristic of the diffuse or planar type of cholesterolosis. The remaining one third of cases are referred to as the polypoid form in which nodules are larger and polypoid in appearance. In the polypoid form the deposits give rise to solitary or multiple cholesterol polyps that are attached to the underlying mucosa with a fragile epithelial pedicle, the core of which is composed of lipid filled macrophages (Fig. 115.1). The macroscopic aspect of cholesterol polyps are yellow deposits, which on the background of hyperemic mucosa led to the description of this finding as “strawberry gallbladder”. Pathologically, the gross appearance of malacoplakia is of a soft yellowish mass. Microscopically, malacoplakia is characterized by a mononuclear cell infiltration. The so-called Michaelis Gutman inclusion bodies seen in some of these cells are pathogonomonic. Michaelis Gutman bodies are discrete, lamellated structures 5–10 μm in diameter, which are thought to represent remnants of phagosomes mineralized by calcium and iron deposits. A case of malacoplakia of the gallbladder is described by Charpentier et al. [14]. The cytoplasm of histiocytes in the gallbladder wall was filled with granules positive for periodic acid-Schiff, von Kossa’s, and Perls’ stains, which is highly suggestive of malacoplakia. Both local inflammation and
Fig. 115.1 Histological image of cholesterolosis resulting from abnormal deposits of triglycerides, cholesterol precursers, and cholesterol esters
1507
recent neoplasia could have played a role in the histogenesis of the malacoplakia.
Clinical Manifestations Clinical symptoms of patients are not characteristic. Abdominal discomfort or upper abdominal pain is commonly reported, similar to complaints for cholelithiasis [52, 63]. Since sometimes both entities occur together, a precise allocation of symptoms is difficult.
Diagnosis Tumors (polyps) are usually found incidentally on ultrasonography (US) or after cholecystectomy. They appear as little echogenic immobile or pedunculated tumors (the patient needs to change position during the US examination for the differentiation from gallstones!) of the gallbladder’s wall without dorsal echo extinction (Fig. 115.2a). However, ultrasound characteristics alone are insufficient to exclude the possibility of gallbladder carcinoma or premalignant adenomas (Fig. 115.2b). When detected on ultrasonography, their clinical significance relates largely to their malignant potential. Gallbladder polyps are well-visualized, the detection of a vessel at the polyps’ base by color duplex ultrasound is helpful for the assumption of adenoma (Fig. 115.2c). Intramural cystic formation (anechoic diverticula) with echogenic foci and/or reverberation artifacts (so-called comet’s tail artifacts) together with full or partial thickening of the gallbladder wall are considered to be the diagnostic findings for adenomyomatosis on US examination (Fig. 115.2d). If intramural diverticula are not identified, differentiating adenomyomatosis from other causes of gallbladder wall thickening, such as inflammation or carcinoma, is difficult. However, in comparison to malignancies of the gallbladder vascular architecture remains intact. Endoscopic ultrasound (EUS) may be helpful for distinguishing benign polyps and adenomyomatosis from adenomas and adenocarcinomas [27, 65]. Precision of endoscopic US is higher than that of transabdominal US (87–97% vs. 52–76%) [2, 72]. Computed tomography (CT) is less helpful in distinguishing benign from malignant polyps [28]. In contrast, dynamic magnetic
1508
115
a
c
Benign Tumors
b
d1
d2
Fig. 115.2 (a–d) Ultrasound imaging of (a) a small polyp, appearing as little echogenic immobile tumor of the gallbladder’s wall without dorsal echo extinction, (b) adenoma of the gallbladder (size above 6 mm with a broad basis, more roundish than a cholesterol polyp), (c) adenoma of the gallbladder with a
vessel at the polyps’ base, and (d) adenomyomatosis of the gallbladder (intramural cystic formation with echogenic foci and reverberation artefacts together with full or partial thickening of the gallbladder wall)
resonance imaging (MRI) and MR cholangiography (MRC) can help differentiate benign from malignant lesions in equivocal cases, and provide information as to disease extent [67]. Small polypoid lesions of strawberry gallbladder can be differentiated successfully from gallbladder carcinoma using positron emission tomography (PET) scanning with 18-fluorodeoxyglucose (FDG). PET reveals a focus of FDG uptake at the site of gallbladder carcinoma. No focal uptake is noted in cholesterol polyps.
(see Chapter 116), hepatocellular carcinoma, metastatic disease to the gallbladder fossa, empyema, hematoma, sludge, acute/chronic cholecystitis, carcinoid tumor, metastatic melanoma, gallbladder wall thickening caused by acute hepatitis, ascites, hypoalbuminemia, liver cirrhosis, congestive heart failure, pancreatitis, and gallbladder wall-varices.
Differential Diagnosis The most important differential diagnoses for benign tumors of the gallbladder are: gallbladder carcinoma
Therapy and Prognosis Gallbladder polyps are mostly benign, representing cholesterol or inflammatory polyps most of the time. Whereas malignant polyps usually occur as single polyps within the gallbladder, cholesterol or inflammatory polyps are usually multiple. According to an analysis
Benign Tumors of the Extrahepatic Bile Ducts
by Shinkai et al., 37% of the patients develop gallbladder neoplasia if there are less than three polyps within the gallbladder with a size of 5–10 mm [69]. In contrast, only 6% of patients develop neoplasia if the size of the polyps is below 5 mm. Cholecystectomy is recommended if polyp size exceeds 10 mm. In several large studies, polyps with a size > 10 mm were likely to show neoplastic transformation (adenoma) and the risk for carcinoma was almost 50% [44, 47, 48, 51, 57, 76, 81]. For a polyp size of 5–10 mm cancer risk is lower, but cholecystectomy should be considered if there are further risk factors, such as patient’s age > 50 years, detection of a solitary polyp, and/or concurrent gallstones [19, 40, 50, 57, 76]. For polyps > 18–20 mm, open cholecystectomy is the method of choice because of a high risk of malignancy [40, 41, 44, 59]. If cholecystectomy is not performed, a close monitoring of the polyp size is recommended (first every 6 months, then, if polyp size is stable, every year) [44, 51]. Polyps < 5 mm do not require surgery, but rather a frequent follow-up period. Surgical excision and antibiotic therapy form the mainstay of therapy against malacoplakia, although a variety of other treatments have been tried. Cholecystectomy, with or without peri-operative antibiotics, is likely to be adequate treatment for malakoplakia of the gallbladder, although the small number of cases do not allow for a detailed assessment of therapeutic efficacy at this stage.
Benign Tumors of the Extrahepatic Bile Ducts Definition Benign tumors of the extrahepatic bile ducts consist of neoplasms that are derived from the bile ducts’s wall. Currently WHO classification of tumors is most commonly used [32].
Epidemiology The most common neoplastic lesions are epithelial tumors, which are mostly adenomas.
1509
Cystadenomas are more common in the extrahepatic bile ducts than in the gallbladder. After incomplete resection recurrence rate is high. Papillomatosis (adenomatosis) is a rare disease characterized by multiple papillary and recurrent adenomas, which cover extended sections of the extrahepatic bile ducts and even can reach into the gallbladder and intrahepatic bile ducts [18]. It is a tumor of middleage to elderly people, with a male: female ratio of 2:1. Associated conditions are Clonorchis sinensis infection, primary sclerosing cholangitis (PSC), choledochal cyst, Caroli’s syndrome eventually confined to one liver lobe, and dysplasia of the gallbladder. Non-epithelial benign tumors, such as leiomyomas and lipomas are very rare. Less than 1% of granular cell tumors are located in the extrahepatic bile ducts, although this is the most common non-epithelial benign tumor of the extraheptic bile ducts [80]. The majority of the patients are black and female [23]. The common bile duct (50%) and cystic duct (37%) are most commonly involved. Additional biliary pathologic disorders are present in more than half of the patients, e.g. papillary “pseudocarcinomatous” hyperplasia of epithelium [79].
Etiology and Pathogenesis Adenomas of the extrahepatic bile ducts are sometimes associated with familial adenomatosis. The risk of malignancy of extrahepatic cystadenoma is unknown, but some cases are reported. Adenomas of papillomatosis often contain areas with high-grade dysplasia, which are sometimes difficult to distinguish from cholangiocarcinoma. Risk of malignancy is much higher for papillomatosis than for single adenomas. Granular cell tumor is a benign mesenchymal tumor, which can occur in the whole body, but is mostly located in the mouth-jaw-area. According to current opinion, the tumor is derived from Schwann-cells (localization of the nervous-system-specific protein (S-100 protein) in the granular component cells) and therefore classified as a neurogenic tumor. Ganglioneurofibromatosis is very rare and can be part of multiple endocrine neoplasia (MEN) type 2b. It occurs predominantly in children and young adults. Papillary hyperplasia is usually associated with chronic cholecystitis, ulcerative colitis and primary sclerosing cholangitis. In these cases it occurs
1510
focally or segmentally, and intestinal metaplasia is common. Primary papillary hyperplasia is not associated with inflammation and is much rarer.
Pathology The histologic types of benign bile duct tumors include the following: • Epithelial Tumors – Adenoma (tubulary, papillary, tubulo-papillary) – Cystadenoma – Papillomatosis (Adenomatosis) • Non-epithelial Tumors – Granular cell tumor – Ganglioneurofibromatosis – Leiomyoma – Lipoma – Hemangioma – Lymphangioma – Neurofibroma • Tumor-like Lesions – Regenerative epithelial atypia – Papillary hyperplasia – Intestinal metaplasia – Pylorus-gland-metaplasia – Squamous metaplasia – Malacoplakia – Congenital cysts – Primary sclerosing cholangitis (PSC) Papillary adenomas consist of tissue papillae, which are covered by cubic and cylindrical mucinous epithelium. Metaplasia and enterochromaffin cells were described in this adenoma type. Kushima et al. reported this phenomenon as “pyloric gland type adenoma with squamoid spindle cell metaplasia” [42]. According to the literature, epithelial dysplasia is more commonly found in papillary than in tubulary adenomas [25, 39, 52, 55, 66]. Tubulo-papillary adenomas are diagnosed if at least 20% of the lesions consist of tubular, papillary structures. Grossly, papillomatosis presents as friable, papillary masses. At microscopy it appears as multiple papillary adenomata with complex gland formation and variable degrees of atypia (Fig. 115.3b and c). Laminin staining reveals frequent invasion which cannot be appreciated on hematoxylin and eosin staining. Aspiration cytology shows distinctive features permitting
115
Benign Tumors
differentiation from cholangiocarcinoma, namely (1) hypercellular smear, (2) very broad and often doublecell layered sheets of ductal columnar epithelium, (3) papillary configuration, (4) preserved honeycomb pattern with even nuclear spacing, and (5) dysplastic but not frankly malignant nuclear features. Atypia and dysplastic changes are frequently found and transition to adenocarcinoma frequently reported. Ganglioneurofibromatosis consists of Schwanncells, proliferation of ganglia cells in the lamina propria, and enlarged nerve bundles in the lamina muscularis and lamina subserosa. Regenerative epithelial atypia as a tumor-like lesion represents non-dysplastic atypia, which occurs in regenerative or defective epithelium. It consists of a mixture of cylindric epithelial cells with or without mucus, atrophic cubic epithelium, and thin rod-like cells. Primary papillary hyperplasia involves the total mucosa and shows no metaplasia.
Clinical Manifestations Clinical symptoms of patients are not characteristic; very often, abdominal discomfort or upper abdominal pain is reported. Sometimes patients present with jaundice or biliary colic due to bile duct obstruction by the tumor.
Diagnosis Tumors are usually found incidentally on ultrasonography. Ultrasound characteristics alone are insufficient to exclude the possibility of cholangiocarcinoma or premalignant adenomas. When detected on ultrasonography, their clinical significance relates largely to their malignant potential. In papillomatosis, non-shadowing biliary masses are found on ultrasound. In addition to the usual features of obstruction, there is frequently sludge and even choledocholithiasis. On CT, intrahepatic masses and duct dilatations can be seen, but the findings are nonspecific and variable. Extent of the lesions can be better outlined by MRI than by CT. On endoscopic retrograde cholangiopancreaticography (ERCP), mucinous discharge from a dilated ampulla is the typical finding; in addition there are multiple filling defects
Benign Tumors of the Extrahepatic Bile Ducts
a
1511
b
c
Fig. 115.3 (a–c) Papillomatosis (adenomatosis) of the common bile and right hepatic duct in a 76-year-old female patient. (a) Tumor lesions are shown by ERC (white arrows). (b, c) bile duct histology after right-sided hemihepatectomy confirmed diagnosis
and supple stenoses (Fig. 115.3a). ERCP is not sufficient to delineate extent; one author with experience of nine cases found additional tumor in 4 patients with transhepatic cholangiography/cholangioscopy where ERCP suggested only extrahepatic involvement [38].
Differential Diagnosis Cholangiocarcinoma of the extrahepatic bile ducts (see Chapter 116) is the most important differential diagnosis. Benign, segmental, non-traumatic inflammatory strictures of the biliary tract were infrequently reported with the exception of primary sclerosing cholangitis [30, 31, 53, 70]. Many benign nontraumatic inflammatory strictures of the common bile duct have been generally considered to be a variant of primary
sclerosing cholangitis. However, Standfield et al. described 12 cases of benign strictures of unknown etiology, and differentiated them from the localized form of sclerosing cholangitis [71]. Inflammatory conditions of the common bile duct, which are potential etiological factors, included bacteria or virus infection, parasite infestation, abdominal trauma, congenital abnormality, inflammatory pseudotumors, and complication of chemotherapy.
Therapy and Prognosis There are no reliable diagnostic methods to distinguish benign lesions from cholangiocarcinoma in patients without histologically confirmed adenocarcinoma.
1512
Therefore, in the presence of bile duct obstruction of unknown cause, potentially resectable lesions should always be explored and resected to offer patients with a malignancy the chance for cure. Treatment of papillomatosis with hepatectomy can be curative; however, recurrence after ‘curative’ hemihepatectomy has been described. Stenting and brachytherapy with 192 Iridium after electrocoagulation have been used for palliation. Liver transplantation has been advocated.
Benign Tumors of the Ampulla of Vater
115
Benign Tumors
Etiology and Pathogenesis Ampullary adenomas can occur sporadically, or in the setting of familial polyposis syndromes such as FAP [46]. For these patients, there is a 100- to 200-fold increased risk of adenocarcinoma [58]. The pathogenesis of BGH remains poorly understood. Gland stimulation by gastric hyperacidity was originally thought to induce hyperplasia; however, only 45% of patients demonstrate hyperacidity and 20% have low gastric acidity. Other suggested mechanisms include proliferation in response to local irritation or excessive parasympathetic activity.
Definition Pathology Benign tumors of the Ampulla of Vater are most commonly villous and tubulovillous adenomas; although classified as benign, ampullary adenomas have the potential to undergo malignant transformation to ampullary carcinomas, similar to the adenoma-carcinoma sequence of other gastrointestinal tumors [79]. Currently WHO classification of tumors is most commonly used [32].
Epidemiology Benign neoplasms of the ampulla of Vater are rare, representing less than 10% of periampullary neoplasms. Adenomas are considered precancerous and usually occur within the fifth or sixth decade (tumors may occur much earlier in patients with familial polyposis syndromes). The prevalence of ampullary adenoma has been estimated to be 0.04–0.12% in autopsy series. However, they are being increasingly recognized with widespread screening programs for highrisk patients such as those with familial adenomatous polyposis (FAP). Brunner’s gland hyperplasia (BGH) usually presents in middle age with no sex predominance; however, cases have been described from early infancy to 80 years of age. Hyperplasia of these glands is a rare condition, with only 144 cases being described in the literature. BGH around the ampulla of Vater is particularly rare, having been described only twice in the literature [36, 49].
The histologic types of benign tumors of the Ampulla of Vater include the following: • • • • • • • • • • • •
Villous adenoma Tubulovillous adenoma Fibroadenoma Hemangioma Leiomyoma Leiofibroma Lipoma Lymphangioma Hamartoma Gangliocytic paraganglioma Neuroendocrine tumors Brunner’s gland hyperplasia (BGH)
Gangliocytic paraganglioma (GP) is a rare, typically benign tumor that shows neuroectodermal (neurosustentacular or Schwannian and neuronal) and neuroendocrine differentiation. Once thought to arise exclusively from the periampullary region as a solitary lesion, recent reports have documented both origins of GP in a variety of extra-duodenal sites as well as synchronous multifocal presentation of the tumor. The epithelioid tumor cells show diffuse immunohistochemical expression of keratin (CAM 5.2), chromogranin, and synaptophysin, supporting true neuroendocrine differentiation; ganglion cells express S-100 protein and neurofilament protein; and the spindled elements express S-100 protein, neurofilament protein, and glial fibrillary acidic protein indicating Schwannian differentiation. The finding of another GP
Benign Tumors of the Ampulla of Vater
occurring outside the periampullary region bolsters the argument for a stem cell origin of this unusual tumor. Brunner’s glands are mucus-secreting acinar glands located in the deep mucosa and submucosa of the duodenum, emptying into the crypts of Lieberkuehn. The glands secrete mucus, pepsinogen, and urogastrone in response to acid stimulation. In 1934, Feyrter classified the abnormal glandular proliferation into three types– type 1, type 2, and type 3 [24]. Type 1 has diffuse nodular hyperplasia, in which multiple sessile projections are found throughout the duodenum. Type 2 has circumscribed nodular hyperplasia limited to the duodenal bulb. Type 3 has glandular adenoma with polypoid lesions. It is unclear whether these three histological types are different manifestations of a single disease. The histological similarity between diffuse hyperplasia, hamartoma, and adenoma may indicate a common pathological origin. However, Feyrter’s classification is controversial, and some authors suggest that all forms should be considered [45]. Furthermore, the nomenclature used in the literature is inconsistent. The terms adenoma, brunneroma, and hamartoma have been used interchangeably with BGH. Consequently, there is no consensus regarding the classification of benign pathology of Brunner’s glands. Histological features favoring hamartoma include lack of encapsulation; admixture of muscular, glandular, and adipose tissues; presence of continuous sheets of Brunner’s glands from the submucosa through the body of the tumor; and lack of any cellular atypia [24]. The presence of both ductal and glandular components is a further evidence of a hamartomatous origin, features which are unusual in hyperplasia or neoplasia. Dysplasia is not seen in Brunner’s gland tumors, suggesting that the term adenoma is a misnomer [45]. A case, presented by Janes et al., does not support these concepts as there was no evidence of hamartoma [36]. It rather suggested that hyperplasia can occur independently from hamartomatous change in Brunner’s glands.
Clinical Manifestations The occurrence of biliary obstruction presenting as jaundice in 50–75% of patients with benign ampullary tumors is the most common clinical finding [75]. Nonspecific symptoms, such as weight loss, vague abdominal pain (rarely biliary colic), nausea, vomiting, fever, and anorexia have all been described. Benign
1513
ampullary tumors can cause heme-positive stools and may lead in some patients to iron-deficiency anemia. Up to 25% of patients have associated common bile duct stones secondary to cholestasis. Some patients infrequently develop cholangitis or acute pancreatitis [56]. More than half of the patients with BGH present with abdominal pain, 43% have melena, and 12% experience hematemesis.
Diagnosis Initial evaluation of patients with clinical features suggesting an ampullary neoplasm should include radiologic imaging, typically beginning with a transabdominal ultrasound. A CT scan or MRI is frequently obtained to exclude pancreatic mass in patients with evidence of bile duct obstruction on ultrasound. Patients with biliary obstruction should undergo cholangiography, which is typically accomplished by MRCP and/or ERCP. Whereas MRCP is less invasive, ERCP with the use of a side-viewing endoscope allows direct visualization of the tumor and the acquisition of biopsies, preferably after sphincterotomy. However, biopsies cannot reliably exclude the presence of malignant foci within an ampullary adenoma which are reported in 30–60% [17, 62, 73, 77, 79]. Where local expertise is available, EUS and intraductal ultrasound (IDUS) can provide valuable tumor staging information. Small-bowel radiological studies have a sensitivity of 92% for detecting BGH. A smooth-walled filling defect in the duodenum is the commonest finding. Localized tumors can present as pedunculated or sessile filling defects with a sharp border, typical of submucosal lesions. However, adenocarcinoma arising from Brunner’s gland can also appear as a sessile polypoid lesion; so further investigation is indicated when these features are present. CT scanning may demonstrate fat within the lesion or enhancement after intravenous contrast. Only two reports describe EUS features of BGH, showing a submucosal mass in the fourth echolayer [8, 36].
Differential Diagnosis Differential diagnoses include ampullary carcinoma (see Chapter 116), duodenal adenocarcinoma, leiomyosarcoma, gastrointestinal stromal tumor, lymphoma,
1514
115
pancreatic carcinoma and distal bile duct carcinoma invading the ampulla of Vater, intraductal papillary mucinous neoplasm (IPMN), and ectopic pancreatic tissue.
Therapy and Prognosis Whereas it is generally agreed upon that all ampullary tumors should be removed or resected, patient selection for the various treatments, including pancreaticoduodenectomy, local resection and endoscopic treatment, remains controversial. Stage of disease, patient characteristics (i.e. age and comorbid conditions), and local availability of expertise determine treatment options. The observation that histologic progression of papillary adenomas to carcinomas is very low in FAP patients (11% in one study of Burke and colleagues) prompted some experts to advocate surveillance endoscopy with biopsies, rather than excision, for ampullary adenomas with normal endoscopic appearance and without dysplasia on biopsy [11]. However, large prospective studies on this issue have not been performed. Pancreaticoduodenectomy (Whipple procedure) is still considered to be the definitive approach for achieving curative resection of ampullary adenomas as this therapy has been shown to have a low tumor recurrence rate. However, although mortality rates have fallen to remarkably low levels for such an extensive operation (0–10%), morbidity (25–65%), length of hospital stay, and possibly quality-of life issues continue to fuel interest in less invasive alternatives.
a
Fig. 115.4 (a, b) Ampullary adenoma. (a) Endoscopic snare excision (papillectomy) and (b) plastic stent insertion into the pancreatic duct after papillectomy to protect against post-ERCP pancreatitis (white arrows)
Benign Tumors
Surgical ampullectomy, first reported in 1899, has experienced resurgent interest as a possible less morbid option [4]. A number of technical variations of the procedure have evolved. Most entail mobilization of the duodenum and longitudinal duodenotomy, followed either by simple excision of the ampullary neoplasm or an extended excision, involving the ampulla and adjacent duodenal and ductal tissue [10, 22]. Hospital mortality after ampullectomy is less than 0.4%, and surgical morbidity, e.g. cholangitis, below 10% [3]. However, tumor recurrence rate ranges from 0% to approximately 50% in several reports [1, 10, 13, 17, 22, 29, 62, 64, 77]. Therefore, patients treated with local resection should undergo surveillance endoscopy. Endoscopic snare excision (papillectomy) for ampullary adenomas (Fig. 115.4a) was first described in the late 1980s, followed by further reports in the 1990s, and early 2000s [5, 6, 54, 68]. Its role remains controversial and it is currently performed in only a small number of referral centers with expertise in interventional endoscopy. Of critical importance is retrieval of the entire resected specimen to ensure the absence of a focus of adenocarcinoma. Temporary drainage of biliary and pancreatic ducts (Fig. 115.4b) is advisable to prevent severe obstruction and pancreatitis. A systematic review estimated that success rates range from 46% to 92%, while recurrence rates range from 0% to 33% [33]. Complication rates are approximately 10–15%, consisting mainly of acute pancreatitis, bleeding, and late papillary stenosis. Endoscopic ablation with the Nd: YAK laser, mono-/bipolar thermal ablation, photodynamic therapy
b
References
(PDT), and argon plasma coagulation (APC) have been described, too [7, 21, 26, 43, 61, 68]. Finally, in patients who refuse surgical or endoscopical tumor resection, or are not candidates due to comorbidities, but who have symptoms attributable to biliary or pancreatic duct obstruction, endoscopic drainage alone may provide effective symptomatic relief. The efficacy of COX-2 inhibitors (which reduce colonic polyps inpatients with FAP) in reducing ampullary adenomas in FAP patients has not been well studied, although at least one study suggested a possible benefit [60]. In this randomized, double blind, placebo controlled study of celecoxib (100 mg twice daily (n = 34) or 400 mg twice daily (n = 32) ) versus placebo (n = 17), given orally twice daily for six months to patients with FAP, efficacy was assessed qualitatively by blinded review of shuffled endoscopy videotapes comparing the extent of duodenal polyposis at entry and at six months, and quantitatively by measurement of the percentage change in duodenal area covered by discrete and plaque-like adenomas from photographs of high and low density polyposis. As a result, shuffled and blinded video review showed a statistically significant effect of 400 mg twice daily celecoxib compared with placebo treatment (p = 0.033) with all five independent observers scoring a beneficial effect. Overall, patients taking celecoxib 400 mg twice daily showed a 14.5% reduction in involved areas compared with a 1.4% for placebo (p = 0.436). However, patients with clinically significant disease at baseline (greater than 5% covered by polyps) showed a 31% reduction in involved areas with celecoxib 400 mg twice daily compared with 8% on placebo (p = 0.049). Whether managed surgically or endoscopically, the outcome of BGH is uniformly good. Endoscopic removal offers a safe and cost-effective alternative to open surgery.
References 1. Asbun HJ, Rossi RL, Munson JL (1993) Local resection for ampullary tumors. Is there a place for it? Arch Surg 128: 515–20 2. Azuma T, Yoshikawa T, Araida T, et al (2001) Differential diagnosis of polypoid lesions of the gallbladder by endoscopic ultrasonography. Am J Surg 181: 65–70 3. Beger HG, Staib L, Schoenberg MH (1998) Ampullectomy for adenoma of the papilla and ampulla of Vater. Langenbecks Arch Surg 383: 190–3
1515 4. Beger HG, Treitschke F, Gansauge F, et al (1999) Tumor of the ampulla of Vater: experience with local or radical resection in 171 consecutively treated patients. Arch Surg 134: 526–32 5. Bertoni G, Sassatelli R, Nigrisoli E, et al (1997) Endoscopic snare papillectomy in patients with familial adenomatous polyposis and ampullary adenoma. Endoscopy 29: 685–8 6. Binmoeller KF, Boaventura S, Ramsperger K, et al (1993) Endoscopic snare excision of benign adenomas of the papilla of Vater. Gastrointest Endosc 39: 127–31 7. Bleau BL, Gostout CJ (1996) Endoscopic treatment of ampullary adenomas in familial adenomatous polyposis. J Clin Gastroenterol 22: 237–41 8. Block KP, Frick TJ, Warner TF (2000) Gastrointestinal bleeding from a Brunner’s gland hamartoma: characterization by endoscopy, computed tomography, and endoscopic ultrasound. Am J Gastroenterol 95: 1581–3 9. Boyle L, Gallivan MV, Chun B, et al (1992) Heterotopia of gastric mucosa and liver involving the gallbladder. Report of two cases with literature review. Arch Pathol Lab Med 116: 138–42 10. Branum GD, Pappas TN, Meyers WC (1996) The management of tumors of the ampulla of Vater by local resection. Ann Surg 224: 621–7 11. Burke CA, Beck GJ, Church JM, et al (1999) The natural history of untreated duodenal and ampullary adenomas in patients with familial adenomatous polyposis followed in an endoscopic surveillance program. Gastrointest Endosc 49: 358–64 12. Busuttil A (1974) Ectopic adrenal within the gall-bladder wall. J Pathol 113: 231–3 13. Cahen DL, Fockens P, de Wit LT, et al (1997) Local resection or pancreaticoduodenectomy for villous adenoma of the ampulla of Vater diagnosed before operation. Br J Surg 84: 948–51 14. Charpentier P, Prade M, Bognel C, et al (1983) Malacoplakia of the gallbladder. Hum Pathol 14: 827–8 15. Chen CY, Lu CL, Chang FY, et al (1997) Risk factors for gallbladder polyps in the Chinese population. Am J Gastroenterol 92: 2066–8 16. Christensen AH, Ishak KG (1970) Benign tumors and pseudotumors of the gallbladder. Report of 180 cases. Arch Pathol 90: 423–32 17. Clary BM, Tyler DS, Dematos P, et al (2000) Local ampullary resection with careful intraoperative frozen section evaluation for presumed benign ampullary neoplasms. Surgery 127: 628–33 18. Colombari R, Tsui WM (1995) Biliary tumors of the liver. Semin Liver Dis 15: 402–13 19. Csendes A, Burgos AM, Csendes P, et al (2001) Late followup of polypoid lesions of the gallbladder smaller than 10 mm. Ann Surg 234: 657–60 20. Curtis LE, Sheahan DG (1969) Heterotopic tissues in the gallbladder. Arch Pathol 88: 677–83 21. Desilets DJ, Dy RM, Ku PM, et al (2001) Endoscopic management of tumors of the major duodenal papilla: Refined techniques to improve outcome and avoid complications. Gastrointest Endosc 54: 202–8 22. Farouk M, Niotis M, Branum GD, et al (1991) Indications for and the technique of local resection of tumors of the papilla of Vater. Arch Surg 126: 650–2
1516 23. Farris KB, Faust BF (1979) Granular cell tumors of biliary ducts. Report of two cases and review of the literature. Arch Pathol Lab Med 103: 510–2 24. Feyrter F (1938) Ueberwucherungen der Brunnerschen Druesen. Virchows Arch 293: 509–26 25. Foster DR, Foster DB (1980) Gall-bladder polyps in PeutzJeghers syndrome. Postgrad Med J 56: 373–6 26. Fowler AL, Barham CP, Britton BJ, et al (1999) Laser ablation of ampullary carcinoma. Endoscopy 31: 745–7 27. Fujita N, Noda Y, Kobayashi G, et al (1999) Diagnosis of the depth of invasion of gallbladder carcinoma by EUS. Gastrointest Endosc 50: 659–63 28. Furukawa H, Kosuge T, Shimada K, et al (1998) Small polypoid lesions of the gallbladder: differential diagnosis and surgical indications by helical computed tomography. Arch Surg 133: 735–9 29. Galandiuk S, Hermann RE, Jagelman DG, et al (1988) Villous tumors of the duodenum. Ann Surg 207: 234–9 30. Gerhards MF, Vos P, van Gulik TM, et al (2001) Incidence of benign lesions in patients resected for suspicious hilar obstruction. Br J Surg 88: 48–51 31. Golematis B, Giannopoulos A, Papchristou DN, et al (1981) Sclerosing cholangitis of the bifurcation of the common hepatic duct. Am J Gastroenterol 75: 370–2 32. Hamilton SR (2000) Pathology and genetics of tumours of the digestive system. WHO Classification of Toumors, IARC, Lyon, 2000 33. Han J, Kim MH (2006) Endoscopic papillectomy for adenomas of the major duodenal papilla (with video). Gastrointest Endosc 63: 292–301 34. Harach HR (1998) Ectopic thyroid tissue adjacent to the gallbladder. Histopathology 32: 90–1 35. Heyder N, Gunter E, Giedl J, et al (1990) Polypoid lesions of the gallbladder. Dtsch Med Wochenschr 115: 243–7 36. Janes SE, Zaitoun AM, Catton JA, et al (2006) Brunner’s gland hyperplasia at the ampulla of Vater. J Postgrad Med 52: 38–40 37. Jorgensen T, Jensen KH (1990) Polyps in the gallbladder. A prevalence study. Scand J Gastroenterol 25: 281–6 38. Kim YS, Myung SJ, Kim SY, et al (1998) Biliary papillomatosis: clinical, cholangiographic and cholangioscopic findings. Endoscopy 30: 763–7 39. Kimura W, Muto T, Esaki Y (1994) Incidence and pathogenesis of villous tumors of the gallbladder, and their relation to cancer. J Gastroenterol 29: 61–5 40. Koga A, Watanabe K, Fukuyama T, et al (1988) Diagnosis and operative indications for polypoid lesions of the gallbladder. Arch Surg 123: 26–9 41. Kubota K, Bandai Y, Noie T, et al (1995) How should polypoid lesions of the gallbladder be treated in the era of laparoscopic cholecystectomy? Surgery 117: 481–7 42. Kushima R, Remmele W, Stolte M, et al (1996) Pyloric gland type adenoma of the gallbladder with squamoid spindle cell metaplasia. Pathol Res Pract 192: 963–9; discussion 970–1 43. Lambert R, Ponchon T, Chavaillon A, et al (1988) Laser treatment of tumors of the papilla of Vater. Endoscopy 20(Suppl 1): 227–31 44. Lee KF, Wong J, Li JC, et al (2004) Polypoid lesions of the gallbladder. Am J Surg 188: 186–90 45. Levine JA, Burgart LJ, Batts KP, et al (1995) Brunner’s gland hamartomas: clinical presentation and pathological features of 27 cases. Am J Gastroenterol 90: 290–4
115
Benign Tumors
46. Lindor NM, Greene MH (1998) The concise handbook of family cancer syndromes. Mayo Familial Cancer Program. J Natl Cancer Inst 90: 1039–71 47. Mainprize KS, Gould SW, Gilbert JM (2000) Surgical management of polypoid lesions of the gallbladder. Br J Surg 87: 414–7 48. Mangel AW (1997) Management of gallbladder polyps. South Med J 90: 481–3 49. Mayoral W, Salcedo JA, Montgomery E, et al (2000) Biliary obstruction and pancreatitis caused by Brunner’s gland hyperplasia of the ampulla of Vater: a case report and review of the literature. Endoscopy 32: 998–1001 50. Moriguchi H, Tazawa J, Hayashi Y, et al (1996) Natural history of polypoid lesions in the gall bladder. Gut 39: 860–2 51. Myers RP, Shaffer EA, Beck PL (2002) Gallbladder polyps: epidemiology, natural history and management. Can J Gastroenterol 16: 187–94 52. Nagahama M, Muto Y, Yamada M, et al (1997) Villous adenoma of the gallbladder: a case report. Hepatogastroenterology 44: 681–4 53. Neuhaus P, Jonas S, Bechstein WO, et al (1999) Extended resections for hilar cholangiocarcinoma. Ann Surg 230: 808–18; discussion 819 54. Norton ID, Gostout CJ, Baron TH, et al (2002) Safety and outcome of endoscopic snare excision of the major duodenal papilla. Gastrointest Endosc 56: 239–43 55. Nugent KP, Spigelman AD, Talbot IC, et al (1994) Gallbladder dysplasia in patients with familial adenomatous polyposis. Br J Surg 81: 291–2 56. Ohmori K, Kinoshita H, Shiraha Y, et al (1976) Pancreatic duct obstruction by a benign polypoid adenoma of the ampulla of Vater. Am J Surg 132: 662–3 57. Okamoto M, Okamoto H, Kitahara F, et al (1999) Ultrasonographic evidence of association of polyps and stones with gallbladder cancer. Am J Gastroenterol 94: 446–50 58. Pauli RM, Pauli ME, Hall JG (1980) Gardner syndrome and periampullary malignancy. Am J Med Genet 6: 205–19 59. Persley KM (2005) Gallbladder Polyps. Curr Treat Options Gastroenterol 8: 105–108 60. Phillips RK, Wallace MH, Lynch PM, et al (2002) A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis. Gut 50: 857–60 61. Ponchon T, Berger F, Chavaillon A, et al (1989) Contribution of endoscopy to diagnosis and treatment of tumors of the ampulla of Vater. Cancer 64: 161–7 62. Posner S, Colletti L, Knol J, et al (2000) Safety and longterm efficacy of transduodenal excision for tumors of the ampulla of Vater. Surgery 128: 694–701 63. Rabast U, Padel T, Rammert H, et al (1989) Adenomatosis of the bile ducts as a rare cause of cholestasis. Dtsch Med Wochenschr 114: 866–70 64. Ryan DP, Schapiro RH, Warshaw AL (1986) Villous tumors of the duodenum. Ann Surg 203: 301–6 65. Sadamoto Y, Kubo H, Harada N, et al (2003) Preoperative diagnosis and staging of gallbladder carcinoma by EUS. Gastrointest Endosc 58: 536–41 66. Sagar PM, Omar M, Macrie J (1993) Extrahepatic biliary papillomatosis occurring after removal of a dysplastic gall bladder. HPB Surg 6: 219–21
References 67. Schwartz LH, Black J, Fong Y, et al (2002) Gallbladder carcinoma: findings at MR imaging with MR cholangiopancreatography. J Comput Assist Tomogr 26: 405–10 68. Shemesh E, Nass S, Czerniak A (1989) Endoscopic sphincterotomy and endoscopic fulguration in the management of adenoma of the papilla of Vater. Surg Gynecol Obstet 169: 445–8 69. Shinkai H, Kimura W, Muto T (1998) Surgical indications for small polypoid lesions of the gallbladder. Am J Surg 175: 114–7 70. Smadja C, Bowley NB, Benjamin IS, et al (1983) Idiopathic localized bile duct strictures: relationship to primary sclerosing cholangitis. Am J Surg 146: 404–8 71. Standfield NJ, Salisbury JR, Howard ER (1989) Benign nontraumatic inflammatory strictures of the extrahepatic biliary system. Br J Surg 76: 849–52 72. Sugiyama M, Atomi Y, Yamato T (2000) Endoscopic ultrasonography for differential diagnosis of polypoid gall bladder lesions: analysis in surgical and follow up series. Gut 46: 250–4 73. Takashima M, Ueki T, Nagai E, et al (2000) Carcinoma of the ampulla of Vater associated with or without adenoma: a clinicopathologic analysis of 198 cases with reference to
1517 p53 and Ki-67 immunohistochemical expressions. Mod Pathol 13: 1300–7 74. Tantachamrum T, Borvonsombat S (1979) Gardner’s syndrome asscociated with adenomatouis polyp of gallbladder: a report of case. J Med Assoc Thai 62: 441–447 75. Taxier M, Sivak MV, Jr, Cooperman A (1979) Villous adenoma of the ampulla of Vater. Gastrointest Endosc 25: 155–6 76. Terzi C, Sokmen S, Seckin S, et al (2000) Polypoid lesions of the gallbladder: report of 100 cases with special reference to operative indications. Surgery 127: 622–7 77. Treitschke F, Beger HG (1999) Local resection of benign periampullary tumors. Ann Oncol 10(Suppl 4): 212–4 78. Uchiyama S, Imai S, Suzuki T, et al (1995) Heterotopic gastric mucosa of the gallbladder. J Gastroenterol 30: 543–6 79. Yamaguchi K, Enjoji M (1991) Adenoma of the ampulla of Vater: putative precancerous lesion. Gut 32: 1558–61 80. Yamaguchi K, Kuroki S, Daimaru Y, et al (1985) Granular cell tumor of the gallbladder. Report of a case. Acta Pathol Jpn 35: 687–91 81. Yang HL, Sun YG, Wang Z (1992) Polypoid lesions of the gallbladder: diagnosis and indications for surgery. Br J Surg 79: 227–9
Malignant Tumors
116
Marcus Wiedmann, Helmut Witzigmann, and Joachim Mössner
Chapter Outline Gallbladder Cancer ..................................................... 1519 Definition ....................................................................... 1519 Epidemiology ................................................................. 1519 Etiology and Pathogenesis ............................................. 1520 Pathology ....................................................................... 1521 Clinical Manifestations .................................................. 1521 Diagnosis........................................................................ 1521 Differential Diagnosis .................................................... 1522 Therapy and Prognosis ................................................... 1522 Recurrent Gallbladder Cancer........................................ 1524 Extrahepatic Cholangiocarcinoma ............................. 1524 Definition ....................................................................... 1524 Epidemiology ................................................................. 1524 Etiology and Pathogenesis ............................................. 1526 Pathology ....................................................................... 1527 Clinical Manifestations .................................................. 1527 Diagnosis........................................................................ 1527 Differential Diagnosis .................................................... 1529 Therapy and Prognosis ................................................... 1530 Malignant Tumors of the Ampulla of Vater .............. 1552 Definition ....................................................................... 1552 Epidemiology ................................................................. 1552 Etiology and Pathogenesis ............................................. 1552 Pathology ....................................................................... 1552 Clinical Manifestations .................................................. 1552 Diagnosis........................................................................ 1552 Differential Diagnosis .................................................... 1553 Therapy and Prognosis ................................................... 1554 References ..................................................................... 1554
Gallbladder Cancer Definition Gallbladder carcinoma is a malignant tumor originating from the epithelium of the gallbladder. According to de Groen, approximately 67% of the biliary tract tumors are gallbladder carcinomas (Fig. 116.1a) [69]. The American Joint Committee on Cancer (AJCC) and UICC (Union Internationale Contre le Cancer) have designated staging by the TNM classification of 2002 (Table 116.1) [354].
Epidemiology Gallbladder cancer affects women two to six times more often then men and its incidence steadily increases with age (the peak incidence is 70–75 years). In 2007, 9,250 new cases and 3,250 deaths from gallbladder (and other biliary) cancer were estimated in the United States. The highest frequency of gallbladder cancer is reported for Japan, Korea, Poland, Israel, Northern India, Pakistan, and South American countries like Chile, Ecuador, Mexico, and Bolivia [319, 361]. Low incidence is seen in Singapore, Nigeria, and USA. Incidence also varies within a country and shows large racial and ethnic variations (thus, in the USA, there is a 50% greater incidence in white people of both sexes than in black populations; Native, Japanese, and Hispanic Americans also show a high incidence).
H. Dancygier, Clinical Hepatology, DOI: 10.1007/978-3-642-04519-6_116, © Springer-Verlag Berlin Heidelberg 2010
1519
1520
a
116
Table 116.1 TNM- and UICC-Classification of gallbladder cancer TX T0 Tis T1 T1a T1b T2
T3
b
T4
NX N0 N1 MX
Fig. 116.1 Resection specimens of (a) gallbladder cancer and (b) hilar cholangiocarcinoma
Etiology and Pathogenesis Cholelithiasis (65–90%) is an associated finding in the majority of gallbladder cancer cases, but less fewer than 1% of patients with cholelithiasis develop this cancer. Additional cholecystitis was found in approximately 10% of the patients [303]. Cancer risk is higher in patients with symptomatic cholelithiasis than in patients with asymtomatic cholelithiasis [428]. Asymtomatic gallstones > 3 cm or “porcellain gallbladder” (wall thickening) significantly increases the cancer risk. Additional risk factors are gallbladder polyps (see Chapter 115), Mirizzi’s syndrome, anomalous pancreaticobiliary duct junction (APBDJ), carcinogens (methylcholanthrene, o-aminoazotoluene, nitrosamines, oral contraceptives, methyldopa, and isoniazide), segmental adenomyomatosis of the gallbladder (see Chapter 115), chronic inflammatory bowel disease (IBD), polyposis coli, obesity, multiparity and chronic infections like Salmonella
Malignant Tumors
M0 M1 Stage 0 Stage IA Stage IB Stage IIA Stage IIB Stage III Stage IV
Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ Tumor invades lamina propria or muscle layer Tumor invades lamina propria Tumor invades the muscle layer Tumor invades the perimuscular connective tissue; no extension beyond the serosa or into the liver Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent organ or structure, such as the stomach, duodenum, colon, or pancreas, omentum or extrahepatic bile ducts Tumor invades main portal vein or hepatic artery or invades multiple extrahepatic organs or structures Regional lymph nodes cannot be assessed No regional lymph node metastasis Regional lymph node metastasis Distant metastasis cannot be assessed No distant metastasis Distant metastasis Tis N0 M0 T1 N0 M0 T2 N0 M0 T3 N0 M0 T1-3 N1 M0 T4 any N M0 any T any N M1
Regional lymph nodes are: cystic duct node and the pericholedochal, hilar, peripancreatic (head only), periduodenal, periportal, celiac, and superior mesenteric nodes
typhi, Salmonella paratyphi, Helicobacter bilis, and Helicobacter pylori [12, 38, 67, 88, 203, 233, 259, 274, 319, 322]. Studies investigating genetic abnormalities during carcinogenesis of gallbladder cancer are still limited. It is hypothesized that chronic irritation of the gallbladder mucosa over a period of years, by pancreaticobiliary reflux in patients with APBDJ or cholecystitis in patients with cholelithiasis, may predispose to malignant transformation, or act as promoter for carcinogenic exposure or genetic predisposition. K-RAS mutations were discovered in 39–59% and abnormalities of tumor suppressor gene P53 (mutations especially in exons 5 and 8, loss of heterozygosity (LOH) in chromosome
Gallbladder Cancer
area 17p13.1, and P53-overexpression) in 35–92% [218, 250]. Whereas K-RAS mutations are more common in APBDJ patients, abnormalities of tumor suppressor gene P53 are more common in patients with cholelithiasis and chronic cholecystitis. In addition, LOH in the APC (3%)-, DCC (45%)-, RB (13%)- and NM23-H1 (7%)- genes were reported besides microsatellite instability (17%) [426]. TNF (tumor necrosis factor) mRNA and TNF protein expression is increased during the development of gallbladder mucosa from hyperplasia, dysplasia to carcinoma, and is increased with tumor stage. This finding suggests that TNF is involved in the pathogenesis of gallbladder carcinoma induced by gallstones and the TNF expression in cancer cells may serve as a marker for tumor stage [341]. The occasional presence of hTERT protein in normal and regenerative gallbladder mucosa reflects their regenerative capacity. Nevertheless, significantly higher hTERT indices in low and high grade dysplastic epithelia and in gallbladder adenocarcinomas are probably a consequence of hTERT re-expression, an early event in the multistep process of gallbladder carcinogenesis [236].
1521
gallbladder cancer can appear as infiltrative, nodular, papillary, or as a combination of these morphologies. The lack of a well-defined muscularis layer permits early vascular, lymphatic, and neural invasion. Tumors frequently extend outside of the gallbladder, invading adjacent organs, particularly the liver, as they grow.
Clinical Manifestations The most common symptoms caused by gallbladder cancer are right-sided upper abdominal pain (75%), nausea and vomiting (30%), anorexia, and jaundice in an advanced stage with liver infiltration. However, patients with early invasive gallbladder cancer are most often asymtomatic, or they have nonspecific symptoms. In patients who present with symptoms, the tumor is rarely diagnosed preoperatively. Very often, patients report a long history of cholelithiasis and chronic cholecystitis.
Diagnosis Pathology The histologic types of gallbladder cancer include the following: • • • • • • • • • • • • •
Carcinoma in situ Adenocarcinoma, not otherwise specified (NOS) Papillary carcinoma Adenocarcinoma, intestinal type Mucinous carcinoma Clear cell adenocarcinoma Signet-ring cell carcinoma Adenosquamous carcinoma Squamous cell carcinoma Small cell (oat cell) carcinoma* Undifferentiated carcinoma* Carcinoma, NOS Carcinosarcoma
The most common type (80–90%) is adenocarcinoma. Some histologic types have a better prognosis than others; papillary carcinomas have the best prognosis. Grossly, *
Grade 4 by definition.
Laboratory studies are generally nondiagnostic; an elevated alkaline phosphatase or serum bilirubin may be related to bile duct obstruction. Serum tumor markers such as carcinoembryonic antigen (CEA) or CA 19-9 are often elevated but not diagnostically useful because they lack specificity. Ultrasound is often the first test performed in the evaluation of gallbladder cancer. On ultrasound, gallbladder cancer appears as thickening of the gallbladder wall or as a mass lesion compressing or growing into the bile duct. Inflammatory changes can be difficult to distinguish from gallbladder cancer, however ultrasound contrast agents have proven to be useful for clarification of biliary tumors. Endoscopic ultrasound may be helpful in staging tumor extent (also for defining lymph node involvement in the porta hepatis or peripancreatic regions) and to distinguish benign polyps and adenomyomatosis from adenomas and adenocarcinomas [106, 329]. Computed tomography (CT) is less helpful in distinguishing benign from malignant polyps [110]. In contrast, dynamic magnetic resonance imaging (MRI) and MR cholangiography (MRC) can help differentiate benign from malignant lesions in equivocal cases, and provide information as to disease extent [339].
1522
116
Malignant Tumors
ducts or bile duct cytology studies have a low diagnostic yield. However, laparoscopy and biopsy are extremely useful for assessment of peritoneal metastasis, extent of disease, and suitability of surgery in patients with locally advanced disease.
Differential Diagnosis Most important differential diagnoses for gallbladder carcinoma are: empyema, hematoma, sludge, acute/ chronic cholecystitis, gallbladder wall thickening caused by acute hepatitis, ascites, hypoalbuminemia, liver cirrhosis, congestive heart failure, pancreatitis, gallbladder wall-varices, benign tumors (such as polyps, hemangioma, fibroma, myoma, adenoma), and adenomyomatosis.
Therapy and Prognosis Curative Treatment
Fig. 116.2 ERC from a patient with gallbladder cancer. Stenosis in the middle of the common hepatic bile duct (white arrows)
MRI is particularly useful for visualizing invasion into hepatoduodenal ligament, portal vein encasement, and lymph node involvement [427]. Endoscopic retrograde cholangiography (ERC) and percutaneous transhepatic cholangiography (PTC) are of little use for patients suspected of having gallbladder cancer since the gallbladder is not displayed in most cases (Fig. 116.2). These procedures may be helpful in planning the surgical procedure (as they may indicate tumor growth into intrahepatic bile ducts or into the common bile duct) and in decompressing the common bile duct in case of cholestasis with or without cholangitis. Fine-needle aspiration cytology (FNAC), guided by (endoscopic) ultrasound or CT, is becoming more frequently used for preoperative cytodiagnosis; the reported sensitivity is 88% [8]. This technique has particular relevance for confirming diagnosis in advanced stages in which non-surgical treatment is being pursued. Brushings of obstructed bile
When gallbladder cancer is previously unsuspected and is discovered in the mucosa of the gallbladder at pathologic examination, it is curable in more than 80% of cases. Gallbladder cancer suspected before surgery because of symptoms, however, usually penetrates the muscularis and serosa and is curable in fewer than 5% of patients. In patients with superficial cancer (T1 or confined to the mucosa) the disease is often cured after cholecystectomy without further therapy with a 5-year survival rate of nearly 100%, according to a study by Shirai et al [347]. Therefore, follow-up without a second operation is very often recommended for pT1 cancer without a positive margin. However, many surgeons favor simple cholecystectomy for patients with T1a cancers only, while more radical resections are considered for patients with T1b tumors – derived from the fact that T1b tumors are associated with a higher incidence of lymph node metastases than are T1a tumors (15% vs. 2.5%) – although there is no general consensus about this issue [187, 252, 279, 363, 401, 420]. In a Japanese study, 5-year survival for patients with pT2 and pT3 tumors was 40% and 0% after cholecystectomy alone [347]. Results of a radical second
Gallbladder Cancer
operation showed that patients with pT2 cancer had a 5-year survival of 90%, which was significantly better than cholecystectomy alone (p < 0.05). In addition, there was a prolongation of survival in patients with pT3 or pT4 [347]. These results were confirmed by other studies [252, 347, 364, 400, 419]. Another study reported on patterns of lymph node spread from gallbladder cancer and outcomes of patients with metastases to lymph nodes in 111 consecutive surgical patients in a single institution from 1981 to 1995 [389]. There was no neurovascular invasion or lymph node involvement in 15 patients with pT1 tumors, however 60 of 96 patients with pT2-4 tumors had lymph node metastases. The pericholedochal lymph node was the most common metastatic lymph node, followed by the cystic lymph node. The frequency of metastases in retroportal, posterosuperior pancreaticoduodenal, and interaorticocaval lymph nodes was > 15% in all cases. pT3-4 tumors had significantly more lymph node involvement (79%) and significantly higher N2:N1 ratios (2.5) than pT2 tumors (46% and 0.6, respectively). There was no difference in 5-year survival between N0 and N1 groups in pT2-4 tumors (66% in N0 and 53% in N1). Patients with N2 disease had a significantly worse prognosis, but four patients survived > 5 years. Therefore, the pericholedochal and cystic lymph nodes are the initial site of spread from gallbladder cancer and the frequency of lymph node involvement is strongly influenced by the depth of invasion of the primary tumor. It is therefore concluded that a radical (second) operation, including extended tumor resection ± partial hepatectomy (commonly segments IVb and V) and removal of regional lymphatics and lymph nodes (including the porta hepatis and superior pancreatic nodes), should be carried out for pT2 or more advanced carcinoma [206, 210, 400]. The role of extended lymphadenectomy, including the retropancreatic and aortocaval basins, is unclear and should be attempted only in selected cases [348]. Implantation of the carcinoma at all port sites (including the camera site) after laparoscopic removal of an unsuspected cancer is a problem. Even for stage I cancers, the port sites must be excised completely [235, 282, 349, 408]. In jaundiced patients, there should be consideration of preoperative percutaneous transhepatic biliary drainage for relief of biliary obstruction. Among the absolute contraindications to surgery are liver or peritoneal metastases, ascites, extensive involvement of hepatoduodenal ligament, and encasement or occlusion
1523
of major vessels. Morbidity and mortality rates from resection for gallbladder cancer vary widely, with major morbidity rates ranging from 5% to 54%, and perioperative mortality rates from 0% to 21%. Beneficial adjuvant chemotherapy has been demonstrated in only a single multicenter prospective randomized study, especially for patients after incomplete (R1-) resection [366]. The five-year survival rate in patients treated with mitomycin C and 5-Fluorouracil was 26% in comparison to 14% for the untreated group (p < 0.05). Adjuvant external radiotherapy or chemoradiation have shown some benefit in small studies only [147, 211, 381]. Therefore, adjuvant treatment for gallbladder cancer is currently not standard procedure and patients should be included in clinical studies.
Palliative Treatment With the exception of some patients with focal UICC stage IIA disease, stage IIB-IV cancer cannot be completely resected, although it represents the majority of cases of gallbladder cancer. Often the cancer invades directly into adjacent liver or biliary lymph nodes or has disseminated throughout the peritoneal cavity. Spread to distant parts of the body is not uncommon. At this stage, standard therapy is directed at palliation. The goal of palliation is relief of pain, jaundice, and bowel obstruction, along with prolongation of life. The preferred approach to biliary obstruction is percutaneous transhepatic radiologic catheter bypass or endoscopically placed stents [19]. Palliative surgery, such as segment-III-choledochojejunostomy, may relieve bile duct obstruction and is warranted when symptoms produced by biliary obstruction (pruritus, hepatic dysfunction, and cholangitis) outweigh other symptoms from the cancer. A few patients have very slow-growing tumors and may live several years [56, 180]. However, nowadays this procedure has only a small relevance, because of the high technical success rate of endoscopic and percutaneous transhepatic stenting. The use of external-beam radiation therapy (EBRT) with or without chemotherapy as a primary treatment has been reported in small groups of patients to produce short-term control. Similar benefits have been reported for radiation therapy with or without chemotherapy administered following resection [138, 353].
1524
To date, external-beam radiation therapy is not standard procedure, however, it can, on occasion, alleviate biliary obstruction in some patients and may supplement bypass procedures. Standard chemotherapy has not been established for gallbladder cancer, though occasional patients may be palliated [138]. Most clinical studies have been small and uncontrolled; a combination of 5-FU/doxorubicine/ mitomycine (FAM), gemcitabine-monotherapy, and 5-FU in combination with interferon alpha-2b yielded response rates up to 30% [50, 136, 295]. Adding cisplatin and doxorubicin to the last protocol (PIAF) did not significantly increase response rate (35%), but did worsen toxicity [294]. Combining infusional 5-FU with cisplatin alone or with cisplatin and epirubicine (ECF) resulted in an overall response rate of 24% and 19–40% in studies that included also bile duct cancer patients [81, 89, 320]. Capecitabine, an orally active fluoropyrimidine derivative, appears to be an active agent for gallbladder cancer, both as a single agent, and in combination with cisplatin and oxaliplatin [189, 266, 293]. Whether 5-FU and leucovorin adds benefit to gemcitabine alone remains an open question. On the other hand, the combination of gemcitabine and the oral 5-FU prodrug capecitabine seems to be active for gallbladder cancer. In a phase II study, one third of 24 gallbladder cancer patients had a partial response, and the median survival was 16 months [64]. Also promising seems to be a combination of gemcitabine und cisplatin, which yielded a response rate of 64% and a median survival of 42 weeks in a small phase II study (8 patients with advanced gallbladder cancer) [240]. A second study, including a higher number of gallbladder cancer patients (n = 30), showed a response rate of only 37% and a median survival of 20 weeks [77]. Others have reported good benefit and good tolerability for GemOx (gemcitabine plus oxaliplatin) [14, 133]. Early results of a multicenter phase II trial of 35 patients with chemotherapy-naïve advanced or metastatic gallbladder carcinoma using gemcitabine plus oxaliplatin and 5-FU are promising [398]. Median survival was 10 months, with an 1-year survival rate of 30%. Finally, patients treated with docetaxel ± gemcitabine showed only a minor response between 0% and 20% [213, 283, 297]. Generally, clinical trials should be considered as a first option for most patients. At present, they are exploring ways of improving local control with
116
Malignant Tumors
radiation therapy combined with radiosensitizer drugs and new chemotherapy regimens.
Recurrent Gallbladder Cancer The prognosis for any treated cancer patient with progressing or recurrent gallbladder cancer is poor. The question and selection of further treatment depends on many factors: tumor burden, prior treatment, site of recurrence, and individual patient considerations. Patients may have portal hypertension caused by portal vein compression by the tumor. Transperitoneal and intrahepatic metastases are not uncommon. For recurrent gallbladder cancer, clinical trials are appropriate and should be considered when possible.
Extrahepatic Cholangiocarcinoma Definition According to de Groen approximately 22% of biliary tract tumors are hilar carcinomas (Klatskin tumors) (Fig. 116.1b). Eight percent occur in the distal bile duct [69]. The American Joint Committee on Cancer (AJCC) and UICC (Union Internationale Contre le Cancer) have designated staging by the TNM classification of 2002 (Tables 116.2 and 116.4) [354]. Hilar cholangiocarcinomas are further sorted according to the BismuthCorlette classification (Table 116.3, Fig. 116.3) [35].
Epidemiology Overall, cholangiocarcinoma is a rare neoplasm. Worldwide, it accounts for approximately 3% of all gastrointestinal cancers. The incidence rates of cholangiocarcinoma vary greatly among different areas of the world, and this variation is related to distribution of risk factors. Intrahepatic and extrahepatic cholangiocarcinoma have different epidemiologic features. Whereas the incidence of intrahepatic carcinoma is increasing in North America and Western Europe since 1970, as has been reported by Wetzel et al and West et al, the
Extrahepatic Cholangiocarcinoma
1525
Fig. 116.3 BismuthCorlette-classification of hilar cholangiocarcinoma (From [30]. With permission)
Table 116.2 TNM- and UICC-Classification of extrahepatic cholangiocarcinoma TX T0 Tis T1 T2 T3
T4
NX N0 N1 MX M0 M1 Stage 0 Stage IA Stage IB Stage IIA Stage IIB Stage III Stage IV
Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ Tumor confined to bile duct Tumor invades perifibromuscular connective tissue Tumor invades liver, gallbladder, pancreas, and/ or unilateral branches of portal vein (right or left) or of hepatic artery (right or left) Tumor invades adjacent structures: main trunk of portal vein or its bilateral branches, hepatic artery, and or neighbor organs/structures like colon, stomach, duodenum, abdominal wall Regional lymph nodes cannot be assessed No regional lymph node metastasis Regional lymph node metastasis Presence of distant metastasis cannot be assessed No distant metastasis Distant metastasis Tis T1 T2 T3 T1-3 T4 any T
N0 N0 N0 N0 N1 any N any N
M0 M0 M0 M0 M0 M0 M1
incidence of extrahepatic cholangiocarcinoma is decreasing [406, 407]. The cause of this rise is not exactly known–some authors postulate the rising
Table 116.3 Bismuth-Corlette-classification of hilar cholangiocarcinoma I II IIIA IIIB IV
Tumor below the confluence Tumor confined to confluence Tumor extention into right hepatic duct Tumor extention into left hepatic duct Tumor extention into right and left hepatic ducts
incidence due to the increasing prevalence of chronic infection with hepatitis B and C–and does not appear to be explained simply by improvements in diagnosis or changes in coding practice. In the United States, the reported age-adjusted incidence of extrahepatic cholangiocarcinoma is 1.2 in 100,000 for men and 0.8 in 100,000 for women [49]. As a general rule, the incidence increases with age, with the typical patient between 50 and 70 years old. However, patients with primary sclerosing cholangitis (PSC) and those with choledochal cysts present nearly two decades earlier [39]. Moreover, the age-adjusted mortality rate of extrahepatic cholangiocarcinoma is also decreasing in Western countries, with the exception of Italy and Japan [186]. In the United states, the age-adjusted mortality rates declined from 0.6 in 100,000 in 1979 to 0.3 in 100,000 in 1998 [292]. To this end, current evidence indicates minor improvements in 5-year survival rates of extrahepatic cholangiocarcinoma from 11.7% in 1973–1977 to 15.1% in 1983–1987 [49].
1526
116
Table 116.4 TNM- and UICC-classification of ampullary carcinoma TX T0 Tis T1 T2 T3 T4 NX N0 N1 MX M0 M1 Stage 0 Stage IA Stage IB Stage IIA Stage IIB Stage III Stage IV
Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ Tumor confined to Ampulla of Vater or sphincter of Oddi Tumor invades duodenal wall Tumor invades pancreas Tumor invades peripancreatic soft tissue and/or other neighboring organs/structures Regional lymph nodes cannot be assessed No regional lymph node metastasis Regional lymph node metastasis Presence of distant metastasis cannot be assessed No distant metastasis Distant metastasis Tis N0 M0 T1 N0 M0 T2 N0 M0 T3 N0 M0 T1-3 N1 M0 T4 any N M0 any T any N M1
Etiology and Pathogenesis Approximately 10% of patients with cholangiocarcinoma are found to have an established risk factor [26]. Risk factors for cholangiocarcinoma are PSC (perhaps smoking as additional enhancing risk factor) and/or ulcerative colitis, chronic empyematous cholangitis, chronic intrahepatic lithiasis (Oriental cholangiohepatitis), chronic salmonella infection, choledochal cysts, Caroli’s disease, liver cirrhosis, and biliodigestive anastomosis. The annual incidence of cholangiocarcinoma in patients with PSC has been estimated to be between 0.6% and 1.5% per year, with a life time risk of 8–20% [27, 39, 208]. Rare factors in the Western world are carcinogens (thorium dioxide (in the past), asbestos, radon, nitrosamines, methyldopa, isoniazide, dioxin, polychlorinated biphenyls, and cigarette smoke), chronic hepatitis B or C, and biliary parasites (Opistorchis viverrini and less common Clonorchis sinensis) [27, 31, 53, 62, 75, 201, 228, 289, 344, 357, 373, 380, 384, 402]. Solitary adenoma, Lynch syndrome II, and biliary papillomatosis are regarded as precancerous conditions (see Chapter 115). An association between diabetes mellitus, obesity (BMI > 30), thyrotoxicosis, alcoholic liver disease, chronic
Malignant Tumors
pancreatitis and cholangiocarcinoma has been suggested [7, 405, 409]. During the last years, molecular biology enabled fundamental insight into tumor pathogenesis. Thus, transformation from normal into malignant bile duct tissue requires a sequence of different gene mutations, similar to the adenoma-dysplasia-carcinoma-sequence in colon carcinoma, although our knowledge is limited in comparison to this much more frequent tumor type [126]. These mutations can be grouped into several gene classes: proto-oncogenes, tumor suppressor genes, and mismatch-repair genes. In general, all tumors develop genetic and functional mechanisms to induce self-sufficiency in growth signals, insensitivity to antigrowth signals, tissue invasion and metastasis, limitless replicative potential, sustained angiogenesis, and evading apoptosis [125, 130]. Mutated oncogenes, such as K-RAS, C-MYC, C-ERB-B1 (epidermal derived growth factor-1, EGF-1), C-ERB-B2 (epidermal derived growth factor-2, EGF-2), and C-MET stimulate tumor cell proliferation, in addition to COX-2 (cyclooxygenase-2)-overexpression, which induces C-ERB-B1- and AKT-gene-activation (anti-apoptotic protein) [6, 54, 66, 109, 129, 314, 350, 362]. Proinflammatory cytokines, such as interleukin-6 (IL-6), induce cell proliferation via MAPK (mitogen activated protein kinase)- and JAK/STAT (Janus kinase/signal transducer and activator of transcription)-signallingtransduction-pathways and upregulation of inducible nitric oxide synthase (iNOS), which induces increased production of nitric oxide (NO) [137]. NO itself or peroxynitrite, generated by the reaction of NO with superoxide anions, may modify or alter DNA bases, resulting in direct DNA damage, inhibit apoptosis by caspase 9-nitrosylation and MCl-1-induction (anti-apoptotic protein), or inactivate DNA-repair-proteins and regulate the activity of DNA methyltransferases [157, 158, 164, 165, 202, 385, 404]. TNF (tumor necrosis factor)-alpha substantially activates NFkappaB, MAPK and Akt signalling which in turn activates matrix metalloproteinase-9 (MMP-9) secretion and tumor cell invasiveness [371]. Therefore, inflammation processes and bile salts generate growth- and anti-apoptotic signals and promote carcinogenesis. Detectable tumor suppressor gene mutations involve P53 and P16 [28, 45, 71, 97, 135, 372, 390]. These mutations result in impaired cell aging, supported by telomerase-overexpression (> 70% of tumors) [161, 334]. In addition, there are modifications in cell cycle- and apoptosis-regulation [5, 146, 160, 313, 343,
Extrahepatic Cholangiocarcinoma
372, 423]. These modifications cause a reduced rate of apoptosis and increase cell cycle progression. Invasiveness and ability to induce metastases is influenced by VEGF (vascular endothelial growth factor)-, MMP (matrix-metallo-proteinase)- and HAAH (humane aspartyl-asparaginyl-beta-hydroxylase)-overexpression [24, 153, 181, 217, 237, 238, 271, 374]. This phenomenon is accompanied by increased rate of angiogenesis and inhibition of cell adhesion by deactivation of E-CADHERIN [90, 181]. WISP1v (Wnt-inducible secreted protein 1)-overexpression in 49% of tumors induces lymphatic and perineural invasion [370]. In addition, human cholangiocarcinoma cells escape immune surveillance either by disabling FasR signalling and/or increasing FasL expression to induce apoptosis of invading T cells [313]. Recent experimental results reported activities of the Fas and FasL promoters being regulated by NF-kappaB [280]. The exact meaning of further phenomenons, such as CCK-BR (CCK-B/gastrin receptor)-, ETS-1-, REG-1 alpha (regenerating gene-1)-, PKR (RNA activated protein kinase)- expression, APC-gene mutations, and aberrant methylation of death-associated protein kinase (DAPK) still has to be explored [47, 132, 159, 179, 231, 375].
Pathology Adenocarcinomas are the most common type of extrahepatic bile duct cancers. The histologic types are listed below: • • • • • • • • • • • •
Carcinoma in situ Adenocarcinoma Papillary adenocarcinoma Adenocarcinoma, intestinal type Mucinous adenocarcinoma Clear cell adenocarcinoma Signet-ring cell carcinoma Adenosquamous carcinoma Squamous cell carcinoma Small cell (oat cell) carcinoma Undifferentiated carcinoma Carcinoma, not otherwise specified (NOS)
Malignant mesenchymal tumors, although rare, include the following: • Embryonal rhabdomyosarcoma • Leiomyosarcoma • Malignant fibrous histiocytoma
1527
Lesions can be described as mass-forming, periductal or intraductal, or as mixed mass-forming and periductal [291].
Clinical Manifestations Cholangiocarcinoma usually becomes symptomatic when the tumor obstructs the biliary drainage system, causing painless jaundice. Common symptoms include pruritus (66%), abdominal pain (30–50%), weight loss (30–50%), and fever (up to 20%). The pain is generally described as a constant dull ache in the right upper quadrant. Physical signs include jaundice (90%), hepatomegaly (25–40%), or right upper quadrant mass (10%). A palpable gallbladder, caused by obstruction distal to the takeoff of the cystic duct (Courvoisier’s sign), occurs rarely.
Diagnosis The first suspicion of extrahepatic cholangiocarcinoma generally relies on clinical examination and increased cholestasis parameters (γ-GT, alkaline phosphatase, and bilirubin), whereas transaminases are either normal or only slightly elevated. Since sensitivity and specificity of tumor makers are low, they should be used only as adjunct after diagnosis has been made. Tumor diagnosis should never rely on tumor markers only. CA 19-9, CEA, and CA-125 are currently the most commonly used markers. They are elevated in approximately 85%, 30%, and 40–50%, respectively, of patients with cholangiocarcinoma [69, 150, 290, 317]. It is important to know that cholestasis causes false increase of tumor markers. For CA 19-9, a borderline value of > 100 U/mL has been proposed for diagnosis of cholangiocarcinoma, if there is no cholestasis [51, 269, 290]. In a study, accuracy for the diagnosis of cholangiocarcinoma in patients with PSC was 86% for a combination of tumor markers using the formula CA 19-9 + (CEA × 40) [317]. Recent studies indicate that detection of circulating hTERT (human telomerase reverse transcriptase) and serum trypsinogen-2 may be used as novel tumor markers [223, 224]. It is the aim of imaging methods to evaluate bile duct irregularities in terms of their dignity, to determine local tumor extent and resectability, and to diagnose/exclude
1528
116
Fig. 116.4 Diagnostic flowsheet for extrahepatic cholangiocarcinoma and gallbladder cancer. MRC, magnetic resonance cholangiography; MRI, magnetic resonance imaging; MRA, magnetic resonance angiography; CT, computed tomography
* *
Fig. 116.5 ERC from a patient with hilar cholangiocarcinoma Bismuth type IV: high-grade irregular bile duct stenosis which extends 11 mm subhilar, 9 mm into the right and 11 mm into the left hepatic duct (white arrows). Bile ducts are dilated intrahepatically (white asterices)
distant metastases in case of malignant tumors, in order to enable stage related therapy [351]. Usually, transabdominal ultrasound with color duplex is performed first, because it is cheap and widely available (Fig. 116.4). During recent years, new technological developments, such as THI (tissue harmonic imaging), and use of
Malignant Tumors
contrast-enhanced ultrasound, such as Sonovue™, allow improved imaging of hilar cholangiocarcinoma [21]. If bile ducts are sonographically dilated, non-invasive combined dynamic magnetic resonance imaging (MRI) and MR cholangiography (MRC) should follow [131]. Several studies affirm a sensitivity between 70% and 100% for this combination [3, 15, 108, 232, 241, 421, 432]. Magnetic resonance angiography (MRA) can be added to this procedure, if blood vessel invasion is suspected. Cholangiocarcinoma appears as a hypointense lesion on T1-weighted images, that is hyperintense on T2-weighted images (Fig. 116.6a). Two recently introduced technical improvements have contributed to further increasing the diagnostic value of MRI, including MRCP. The first is parallel imaging (iPAT), and the second is respiratory independent sequences navigator triggering, which have substantially increased the spatial resolution as a critical parameter in biliary imaging [429]. If MRC and MRI are not available, contrast enhanced spiral computed tomography (CT) should be performed, which is less sensitive according to a study by Nebit et al [267]. However, there is a lack of larger studies comparing sensitivity of MRI and CT for the diagnosis of cholangiocarcinoma. In addition, recently multidetector row CT (MDCT) has been developed with a tumor detection rate of up to 90%, thus leading to an important improvement in CT technology. Following initial imaging, surgical consultation is recommended at an experienced hepatobiliary center to decide about tumor resectability [187]. Endoscopic retrograde cholangiography (ERC) and, to a lesser degree, percutaneous transhepatic cholangiography (PTC), are important for tissue sampling and therapy planning despite of the high sensitivity of MRI/MRC (Fig. 116.5) [40]. In addition, endoscopy should be reserved for treatment of cholangitis and preoperative and palliative stenting. Combined brush cytology and forceps biopsy should be performed, because this combination yields a positive histology for extrahepatic cholangiocarcinoma in 40–70% [185]. Transpapillary cholangioscopy significantly increases the ability to distinguish between malignant and benign dominant bile duct stenoses in patients with PSC [379]. Procedures, such as digital imaging analysis for evaluation of cell aneuploidia and fluorescence in situ hybridization (FISH) for chromosomal analysis, may increase sensitivity of histology [327]. Sensitivity may be even further increased by methylation analysis of tumor suppressor genes p16INK4a and p14ARF and real-
Extrahepatic Cholangiocarcinoma
1529
c a
b
3.5 3.5 mm mm
Fig. 116.6 Hilar cholangiocarcinoma. (a) MRI with magnetic contrast medium of Bismuth-Corlette type IV tumor (encircled), (b) tumor imaging with intraductal ultrasound (IDUS; 15 MHz,
6 French probe), and (c) imaging of the 2.4 × 1.2 ×2.7 cm sized tumor with F-18-deoxy-glucose-positron emission tomography (FDG-PET)
time reverse transcription polymerase chain reaction (RT-PCR) assays for the detection of human aspartyl (asparaginyl) beta-hydroxylase (HAAH) and homeobox B7 (HoxB7) mRNA from intraductal bile and brush cytology specimens [96, 195]. Whether endoscopic ultrasound (EUS)-guided fine-needle aspiration of suspected hilar cholangiocarcinoma in potentially operable patients with negative brush cytology will become a standard procedure is unknown, although an initial study showed a sensitivity of 89% and specificity of 100% [104]. Recently introduced imaging techniques, such as intraductal endoscopic ultrasound (IDUS), positron emission tomography (PET), and PET/CT, are not yet routine procedures (Fig. 116.6b and c) [13, 104, 107, 183, 194, 300, 311, 324].
Laparoscopy before laparotomy to exclude peritoneal metastases is recommended in some cases [168].
Differential Diagnosis It is important for the clinician to realize that there is a remarkably high number of patients with presumed Klatskin tumors, which turn out to be benign fibrosing cholangitis after resection (Fig. 116.7). It has been agreed, however, that any localized extrahepatic bile duct obstruction coexisting with intrahepatic bile duct dilatation should be considered to be malignant until proven otherwise [118, 143, 196, 312]. This agreement arose because of the difficulty in obtaining a
1530
Fig. 116.7 ERC from a patient with fibrosing cholangitis. Hilar stenosis mimics hilar cholangiocarcinoma (white arrows)
histopathologic diagnosis in patients with obstructive jaundice caused by a bile duct stricture. The lack of histopathological evidence might result in some patients being inappropriately treated for malignant disease when a benign stricture was present and vice versa. In the study of Gerhards et al, a false-positive preoperative diagnosis of malignancy resulted in a 15% resection rate of benign lesions in patients with suspicious hilar strictures [118]. The lack of clinical constitutional symptoms such as body weight loss and elevated tumor markers may implicate the possible benign entity of the disorder. Benign, segmental, non-traumatic inflammatory strictures of the biliary tract were infrequently reported with the exception of primary sclerosing cholangitis [118, 123, 168, 352]. Many benign nontraumatic inflammatory strictures of the common bile duct have been generally considered to be a variant of primary sclerosing cholangitis. However, Standfield et al described 12 cases of benign strictures of unknown etiology, and differentiated them from the localized form of sclerosing cholangitis [360]. Inflammatory conditions of the common bile duct, which are potential etiological factors, included bacteria or virus infection, parasite infestation, abdominal trauma, congenital abnormality, inflammatory pseudotumors, and complication of chemotherapy. The current state of diagnostic imaging fails to deliver a reliable discrimination between benign and
116
Malignant Tumors
malignant hilar lesions. All clinical and imaging features are quite compatible with a malignant tumor in the liver hilum. Application of improved diagnostic methods, such as thin-section spiral CT, MRI/MRC and PET, can potentially increase the diagnostic accuracy, but neither could reliably differentiate malignant from benign lesions [288]. A recent study using FDG-PET for diagnosing hilar cholangiocarcinoma could not demonstrate any significant benefit in the differentiation between cholangiocarcinoma and Klatskin mimicking tumors [104]. However, only two patients with Klatskin-mimicking lesions were included into this study. The decision to undertake resection of the strictures in these patients should not be considered as an error of judgment. In analogy to lesions of the pancreatic head, resection of the lesion is still the most reliable way to rule out malignancy. Therefore, resection of a benign stricture mimicking a malignant lesion in the extrahepatic bile duct cannot be avoided completely. Most benign segmental strictures of the extrahepatic bile duct reported in the literature are located at the hilum or the distal common bile duct. In conclusion, there are no reliable diagnostic methods to distinguish Klatskin tumors from benign lesions in patients without histologically confirmed adenocarcinoma. Therefore, in the presence of hilar obstruction, potentially resectable lesions should always be explored and resected to offer patients with a potential Klatskin tumor the chance for cure.
Therapy and Prognosis Curative Treatment for Hilar Cholangiocarcinoma It has been recognized that only curative resection, which requires hepatic resection, offers patients with hilar cholangiocarcinoma a chance of cure and long-term survival [127, 166, 168, 182, 205, 268, 302, 340]. Recent results from the American SEER (Surveillance, Epidemiology, and End Results) database suggest a cumulative 53.7% improvement in survival for extrahepatic cholangiocarcinoma after surgical resection from 1973 through 2002. This trend may largely be caused by developments in imaging technology, improvements in patient selection and advances in surgical techniques [264].
Extrahepatic Cholangiocarcinoma
The clear superiority of curative (R0) resection over palliative endoprosthesis placement is confirmed in several studies [168, 192, 193, 302, 417]. Even resection with a histologically positive margin offers a survival benefit as compared to palliative treatment in most reports except for the study by Jarnagin et al [139, 168, 182, 209, 302, 417]. In older studies, fewer than 30% of patients are suitable for formally curative resection (R0 resection) [168]. However, in the last 5–10 years, resectability rates could be improved to 50–60% by increased surgical radicality [139, 182, 268, 340]. Clarification of operability (pre- and intraoperatively) as well as the surgical procedure itself requires a high level of experience [32, 33]. Typical criteria for non-resectability are: (1) patients unfit or otherwise unable to tolerate a major operation, (2) hepatic cirrhosis, (3) hepatic duct involvement up to secondary biliary radicals bilaterally, (4) encasement or occlusion of the main portal vein proximal to its bifurcation (relative criterion; portal vein resection and reconstruction may be possible), (5) atrophy of one hepatic lobe with encasement of contralateral portal vein branch, (6) atrophy of one hepatic lobe with contralateral involvement of secondary biliary radicals,(7) unilateral tumor extension to secondary biliary radicals with contralateral portal vein branch encasement or occlusion, and (8) distant metastases (peritoneum, liver, lung, N2 lymph nodes) (Jarnagin and Shoup 2004) [169]. The close contiguity of the tumor to important structures in the hepatic hilum such as the hepatic artery and portal vein and the longitudinal spread mostly along and within the intrahepatic bile ducts are the most limiting factors to yield tumor-free margins. Despite extended resection, only short longitudinal and lateral tumor-free margins can be obtained.
Preoperative Biliary Drainage Liver dysfunction caused by obstructive jaundice is a relevant risk factor in major hepatic resections. There are no prospective randomized trials investigating the effect of preoperative biliary drainage on morbidity and mortality in jaundized patients before liver resection. In non-randomized studies, no difference in mortality was observed between patients with and without biliary drainage [61, 116, 144, 268, 302]. No difference with respect to morbidity was seen in four studies [116, 268,
1531
302, 417]. On the other hand, higher complication rates after biliary stenting were reported by other authors [61, 144, 168]. Despite these non-conclusive data, the authors of the majority of recent studies dealing with hilar cholangiocarcinoma recommend biliary drainage in order to decrease the serum bilirubin level below 2–5 mg/dL before resection [85, 139, 182, 205, 209, 254, 340, 382]. Recovery of hepatic function after biliary decompression takes about 4 weeks, so that surgery should be done not too early [340].
Resection of Hilar Cholangiocarcinoma Basic principles of oncological surgery are R0 resection with wide longitudinal and lateral safety margins, monobloc-resection of the tumor and no touch technique, i.e. no manipulation at the tumor side. Obedience to these rules is limited by the anatomical setting. Hilar resection alone may result in formal R0 resection in patients with Bismuth-Corlette type I/II tumors, however safety margins are only several millimeters. Therefore, limited resection should only be performed in patients with poor general and functional operability. Hilar resection with left-sided liver resection requires dissection in close vicinity of the tumor for preparation of the right liver artery and right main trunk of the portal vein, therefore it can not be completely complied with no touch technique. Moreover, risk of complication is increased for extended left-sided resection by the high number of right-sided bile duct anastomoses to be sewn together. With right trisegmentectomy (Brisbane classification 2000), i.e. resection of liver segments 4–8 including segment 1 and portal vein segment resection de-principe, highest radicality can be achieved [23]. Therefore this technique is the procedure of first choice, if permitted by tumor extent, technical conditions of operation and functional conditions [268]. By cutting the left hepatic bile duct at segmental bifurcation 2/3, i.e. 3–5 cm distant to the hilar region, and principal portal vein segment resection between portal vein main stem and left main trunk with end-toend anastomosis, preparations levels are not in close vicinity to the tumor (no touch technique) and extended safety margins can be achieved (Fig. 116.8). The rates of hilar resection in series of resected hilar cholangiocarcinomas range between 0% and 24% [48, 139, 151, 167, 168, 182, 190, 192, 205, 209, 254, 268, 302, 340, 417]. Except for two reports in which 42%
1532
Fig. 116.8 Right-sided trisegmentectomy. I: right hepatic artery and liver segment IV artery are cut through. II: choledochal duct is resected suprapancreatically and left hepatic duct is resected at the umbilical fissure at the area of segment 2/3 bifurcation. By resecting the portal vein, tumor free margin can be extended
and 71% of patients respectively underwent hilar resection alone [116, 382]. Concomitant liver resection revealed higher rates of R0 resection as compared to hilar resection alone in all studies but one [167, 168, 192, 254, 268]. Surprisingly, survival time did not differ between patients with and without additional liver resection in four reports [193, 254, 382, 417]. In three studies, hepatic resection proved to be a significant prognostic factor [167, 168, 205]. These controversial data with respect to survival may be caused by the small number of patients with hilar resection alone in these studies. In two series in which 75% of Bismuth-Corlette type I/II tumors were treated with hilar resection alone, survival of these patients was worse than for those with type III/IV tumors with liver resection [205, 268]. Capusotti et al reported longer survival of patients with Bismuth-Corlette type I/II tumors treated with liver resection as compared to hilar resection alone [48]. On the basis of these results, concomitant hepatic resection should be routinely performed even in patients with Bismuth-Corlette type I/II tumors. Concomitant vascular resection had no impact on survival, using multivariate analysis, in six studies [139, 167, 192, 205, 340, 417]. Whenever curative resection of tumor-infiltrated vascular segments is possible, the patients have a similar long-term prognosis to those without vascular tumor involvement. Neuhaus et al reccommend right trisegmentectomy with portal vein resection as procedure of choice, combining “no touch technique” and increased lateral radicality [268].
116
Malignant Tumors
There is no relevant evidence that portal vein embolization, which is recommended before extended hepatic resections by some groups, is important to reduce operative mortality [139, 182, 205, 340]. Caudate lobectomy is recommended as an obligatory procedure for curative resection by the majority of authors, although the data did not show any impact on outcome [48, 167, 192, 302]. High complication rates ranging from 14% to 85% were observed in the literature and were dominated by infective complications and bile leaks [48, 116, 190]. In-hospital mortality rates range from 7.5% to 18% in studies which included at least 40 patients and used an aggressive resectional approach. However, there are two recent series with 0% and one report with 1.3% in-hospital mortality [34, 182, 205]. In our own study, neither the UICC 2002 system nor the Bismuth-Corlette classification system providing information only about longitudinal tumor extent, correlated preoperatively with the likelihood of R0 resection [34, 354, 417]. This finding was confirmed by Hemming et al for the Bismuth-Corlette classification and by Jarnagin et al for the AJCC system, which is comparable to the UICC system from 1997 [98, 139, 168, 355]. Understaging was the main problem in our series, as was also seen by Gerhards et al [116]. This can be partly explained by the periductal and intraductal type of tumor growth with minimal mass lesion and the difficulty to assess lymph node involvement. Therefore, because of limitations of current diagnostic tools laparotomy is indicated in any patients except for those with distant metastases, poor general condition or obviously locally advanced tumor. In patients with locally advanced tumors preliminary laparoscopy should be performed to preclude peritoneal and liver metastases in order to avoid unnecessary laparotomy. New preoperative staging systems, such as the proposed T–staging of Jarnagin et al, for prediction of resectability based on new imaging techniques should be considered [168]. Five-year survival rates vary in 11 relevant publications, with a minimal study length of 10 years between 12.5% and 32.8% (Table 116.5). These publications include many patients that were not operated according to the current radicality principles. In contrast, recent publications including only radically and/or R0-resected patients report 5-year survival rates of 35–44%, respectively 72% (Table 116.6). Despite variability in patient populations and adjuvant chemoradiation in some patients, these new data display an
Extrahepatic Cholangiocarcinoma
1533
Table 116.5 Hilar cholangiocarcinoma: 5-year overall survival after resection in studies with at least 10 years durationa Author and year
(n)
(%)
(Pichlmayr et al. 1996) [302] (Miyazaki et al. 1998) [254] (Neuhaus et al. 1999) [268] (Kosuge et al. 1999) [209] (Launois et al. 1999) [216] (Todoroki et al. 2000) [382] (Jarnagin et al. 2001) [168] (IJitsma et al. 2004) [151] (Rea et al. 2005) [321] (Witzigmann et al. 2006) [417] (Baton et al. 2007) [20]
125 76 95 65 40 101 80 42 46 60 59
27.1 26 22b 32.8 12.5c 28d 27 22 26 22e 20f
a
Including perioperative mortality and R0-, R1-, and R2-resections n = 15 liver transplantations with Kausch-Whipple-operation c n = 4 liver transplantations d Postoperative radiation in 28 patients e n = 1 liver transplantation f n = 25 adjuvant therapy b
so-called “cluster-transplantations” and the combination of pancreaticoduodenectomy (Whipple procedure) with liver transplantation did not improve survival rate [162, 268]. Evaluation of relevance of liver transplantation as an oncological concept was neglected in the past decade due to the inadequate supply of donor organs. Perhaps adult-to-adult living donor liver transplantation and excellent results of neoadjuvant chemoradiation at Mayo Clinic in Rochester/USA may revitalize the indication of liver transplantation for cholangiocarcinoma [172, 321]. Nowadays, a general exclusion of patients with Klatskin-tumors from liver transplantation is no longer justified.
Resection of Distal Cholangiocarcinoma
Patients with cancer of the distal end of the bile duct Table 116.6 Hilar cholangiocarcinoma: 5-year overall survival and no distant metastases require pancreaticoduodenectomy (Whipple procedure), which is the only after liver resection and/or R0-resection curative treatment. Author and year (n) (%) a Pancreaticoduodenectomy is usually performed in (Neuhaus et al. 1999) [268] 34 72 (Kawasaki et al. 2003) [182] 79 40b locally resectable cases including biliodigestive anato(Seyama et al. 2003) [340] 58 40c mosis with a Roux-en-loop. A pylorus-preserving oper(Hemming et al. 2005) [139] 53 35d ation is preferable, and is feasible in most patients. Of all (Sano et al. 2006) [331] 102 44e patients with distal cholangiocarcinoma, approximately (Liu et al. 2006) [229] 27 41 50% present with resectable tumors at time of diagnosis. a Right trisegmentectomy with portal vein and R0-resection in all + However, resectability rate varies between 22% and patients, no perioperative mortality b 91% in published studies [100, 261, 262, 397]. Only patients with R0-resection c Extended right or left hemihepatectomy in all patients; only one Perioperative mortality after radical resection of surgeon distal cholangiocarcinoma varies between 1.4% und e Postoperative chemoradiation after R1-, R2-resection and for 11%, with the rate of clinically relevant and severe positive lymph nodes f morbidity between 22% and 41% [100, 397, 422, 425]. n=39 intrahepatic cholangiocarcinoma with hilar infiltration Whereas 5-year survival rates were below 20% at the beginning of the 1990s, 5-year survival rates in later improvement of long-term survival after resection of reports are between 16% and 44% (Table 116.7). LongKlatskin-tumors. term survival depends on R0 status in most of the studies. Lymph node status and tumor differentiation are Liver Transplantation for Hilar Cholangiocarcinoma Oncological goals are best met by liver transplantation, including complete removal of the bile duct system, no touch technique, and wide tumor-free margins. However, 5-year survival rates in small studies are only between 17% and 36% and therefore not better than after tumor resection [162, 302, 326]. Even extended
Table 116.7 Distal cholangiocarcinoma: 5-year overall and median survival after resection Author and year (n) (months) (%) (Nagorney et al. 1993) [260] (Fong et al. 1996) [100] (Yeo et al. 1997) [422] (Yoshida et al. 2002) [425] (Jang et al. 2005) [166]
50 45 65 26 151
24 33 20 20.5 25
44 27 16 37 32.5
1534
116
independent prognostic factors in some, but not all of the studies [100, 166, 422, 425].
Neoadjuvant and Adjuvant Therapy Neoadjuvant chemoradiation prior to resection has been investigated so far only in small case series [245]. Chemoradiation is followed by inflammation and necrosis at the liver hilum, increasing complication risk of subsequent resection [178, 321]. Therefore, neoadjuvant chemoradiation in combination with liver resection is not established. The approach of chemoradiation and subsequent liver transplantation has recently been investigated in a small study with highly selected patients [321]. In this study, patients with hilar cholangiocarcinoma at UICC stages I and II and PSC as mainly underlying disease were treated. The neoadjuvant concept
comprised chemoradiation (total dose of 45 Gy) with 5-Fluorouracil (5-FU) as bolus during the first 3 days of radiation, followed by intraluminal brachytherapy with 20–30 Gy and staging-laparotomy. Patients without distant and lymph node metastases were treated with 5-FU or capecitabine until transplantation. Those patients that were transplanted after this selective neoadjuvant treatment reached 5-year survival rates of 82%. However, there was no histological or cytological proof of malignancy in 8 of 38 finally transplanted patients (21%), neither at time of diagnosis nor at time of operation. Adjuvant strategies for hilar cholangiocarcinoma were tested in only two prospective comparative studies, so far (Table 116.8). In the first study, including patients with hilar cholangiocarcinoma, postoperative external radiation neither prolonged survival nor improved quality of life in comparison to patients who
Table 116.8 Hilar cholangiocarcinoma: Adjuvant therapy Author and year Therapy Mode dose (Gy)
(Reding et al. 1991) [323] (Pitt et al. 1995) [304] (prosp)
RT no RT RT no RT RT
(Gonzalez Gonzalez et al. 1999) [124] (Todoroki et al. 2000) [382]
RT
(Gerhards et al. 2003) [117]
no RT RT
(Kelley et al. 2004) [184] (Sagawa et al. 2005) [330]
RT no RT CRT no RT RT
Radiation NA EBRT 46 Gy + BT 13 Gy EBRT 40–45 Gy (+BT 10 Gy) IORT 21 Gy (+ EBRT 44 Gy) EBRT 42 Gy + BT 10 Gy EBRT 46 Gy EBRT 39–54 Gy (5FU) EBRT 37 Gy (+ BT 37 Gy)
no RT
Malignant Tumors
(n)
Median survival (months)
5-YSR (%)
27 98 23
13 8 14
NA NA NA
27 52
15 24
NA 24
28
32*
33.9*
19 41
10 21
13.5 17
30 20 41 53 39
30* 8 40.5* 24 23
24 11 NA NA 24
30
20
30
Chemotherapy (Takada et al. 2002) [366] (prosp) (Takeda et al. 2004) [369]
CT
MMC + 5-FU
58
NA
26.7
no CT CT (i.a.) no CT
60 18 19
NA
5-FU c.i.
24.1 47.6*[1] 39.5a
Prosp: prospective study; RT: radiation therapy; CRT: chemoradiation; CT: chemotherapy; i.a.: intraarterial; c.i.: continuous infusion (24 h); EBRT: external radiation therapy; IORT: intraoperative radiation therapy; BT: brachytherapy; MMC: mitomycin C; NA: nonapplicable * p < 0,05 a 3-year survival rate
Extrahepatic Cholangiocarcinoma
had only operation alone [304]. In a second published study, adjuvant chemotherapy, consisting of single dose mitomycin C at the day of operation and two 5-day cycles of 5-FU, followed by orally administered 5-FU until tumor progression, was compared to postoperative surveillance of patients, only. The 5-year survival rate was 26.7% in the adjuvant arm compared to 24.1% in the control arm (p > 0.05) [366]. In both studies, however, inhomogeneous populations with both curatively and palliatively resected tumors were included. Formal randomization was not part of the Pitt-study. Also, the types of therapy, radiation without chemotherapy and orally administered 5-FU can not be regarded as standard therapy. In contrast, some retrospective surgical studies reported about long time survival and improved tumor control after adjuvant radiation therapy. In a study by Todoroki et al. patients with locally advanced tumors received intra- and/or postoperative radiation after R1 resection or no further treatment. The five-year survival rate was 34% in the adjuvant therapy group in comparison to 13.5% in the untreated group [382]. Data was confirmed by another study, where some of the patients received postoperative adjuvant external radiation and/or intraluminal brachytherapy. The five-year survival rate was 19% in the adjuvant therapy group in comparison to 11% in the untreated group, and median survival was 24 months in comparison to 8 months [117]. Adjuvant chemoradiation reduced recurrence rate of biliary carcinoma in non-randomized studies, yielding a median survival time of up to 41 months and a 5-year survival rate of up to 53.5%. In these studies, 5-FU was used as radiosensitizer [184, 392]. In our own pilot-study, it was the aim to determine the toxicity and efficacy of a postoperative regimen combining radiotherapy and chemotherapy with gemcitabine and capecitabine in extrahepatic bile duct cancer. Patients were eligible after surgery for extrahepatic bile duct adenocarcinoma. Surgery included resection of lymph node positive cancer, incomplete resections and diagnostic laparotomy in unresectable tumors. Patients received a fractionated radiotherapy of 49.6 Gy accompanied by gemcitabine once a week. After a 2-week rest, patients were treated with gemcitabine and capecitabine on a 3-week cycle. The treatment continued for six cycles in nonmeasurable disease or until disease progression or intolerable toxicity. There were 18 patients (resection/laparotomy 7/11) enrolled between
1535
August 2003 and April 2005. Radiotherapy was completed in all patients and a total of 66 cycles of chemotherapy was administered. Fatigue and nausea were the most common mild adverse events. Grade 3 and 4 toxicity was rare after resection but frequent in unresectable disease and consisted of fatigue, nausea, duodenal ulcer, cachexia, and cholangitis in 1, 2, 2, 4, and 4 patients, respectively. We observed a 50% disease stabilization rate in patients with measurable disease. Median overall survival was 7.9 months in patients with unresectable tumors. Median overall survival in patients after resection has not been reached at a median followup of 19.5 months. Thus, radiochemotherapy using gemcitabine followed by gemcitabine and capecitabine is an active regimen with manageable toxicity after resection of extrahepatic bile duct cancer but has significant toxicity in unresectable disease [337]. In summary, neoadjuvant and adjuvant chemotherapy/chemoradiation have shown some benefit for patients with hilar cholangiocarcinoma, but they do not represent an established therapy. Further prospective, randomized studies are required. A new approach might be the use of photodynamic therapy (PDT) for the treatment of hilar cholangiocarcinoma in a neoadjuvant setting, because of the high tumor recurrence rate of up to 76% after curative (R0) resection. Having accomplished a successful treatment in a single case, we investigated the use of PDT prior to tumor resection in six patients and in one patient prior to liver transplantation in a small pilot study [29, 30, 411]. In all patients, R0 resection was achieved. Four patients developed minor surgical complications, even though the bilioenteric anastomoses were sewn to PDT-treated bile ducts. No viable tumor cells were found in the inner 4 mm layer of the surgical specimens. The PDT-pretreated epithelium of the tumor-free proximal resection margins exhibited only minimal inflammatory infiltration. The 1-year recurrence-free survival rate was 83% and 5-year overall survival 42%. Similar results have also been reported by Nanashima et al. who treated eight patients with porfimer sodium PDT in an adjuvant setting [263]. Five patients had extrahepatic bile duct cancer, two had intrahepatic cholangiocarcinoma, and one had ampullary carcinoma. Cancer cells were microscopically detected in the stump of the hepatic duct in six patients, and biliary stenosis caused by remnant tumor was observed in one patient. One patient had tumor recurrence with occlusion of the bile duct. At 48 h prior to PDT, porfimer
1536
sodium was injected intravenously. A pulse laser by an eximer dye laser (50–100 J/cm2) with a wavelength of 630 nm was applied through an endoscope to the hepatic stump or tumor lesion. Marked destruction of the tumor and ductal epithelium was observed on day 1 after PDT. After PDT, four patients developed mild dermatitis, but no severe morbidity or mortality was noted. In patients who underwent PDT for the stump, one patient showed distant metastasis at 31 months, and four patients did not show tumor recurrence at 17, 12, 12, and 6 months, respectively. However, one of the eight patients died at 2 months of an unrelated cause. In two patients with occlusion caused by tumor growth, resolution of bile duct stenosis was noted on day 7. These patients showed re-occlusion by tumor at 20 and 8 months. In summary, neoadjuvant and adjuvant PDT in these two small studies was a safe and a useful option for a better survival benefit in patients with bile duct cancer undergoing surgical resection, however further studies are required.
Palliative Management The goal of palliative treatment is to achieve stable long-term biliary drainage in order to improve quality of life and prolong survival. Refractory obstructive cholestasis leads to death owing to severe bacterial cholangitis or liver failure [94].
Stenting for Extrahepatic Cholangiocarcinoma The median survival time of patients with nonresectable hilar cholangiocarcinoma is approximately 3 months without intervention and 4–10 months with biliary drainage [73, 94, 230, 305]. Successful endoscopic drainage rates with plastic stents have been reported to range from approximately 40–80% [80, 230, 305, 306]. In contrast, a randomized study by Ortner et al, which contained 79% Bismuth type IV tumors, showed a decrease of cholestasis by at least 50% within the first week in only 21% with stenting alone [278]. An endoscopic approach for biliary stent insertion is preferred over an ultrasoundguided percutaneous approach. Cholestasis was more efficiently reduced and 30-day and overall mortality rates were lower in a randomized study [359]. Percutaneous transhepatic cholangiodrainage (PTCD)
116
Malignant Tumors
should be used after failure of endoscopy and for anatomically difficult situations, i.e. after partial gastrectomies, especially with Roux-en-y anastomosis [74]. In these cases the papilla Vater can often not be reached endoscopically. In selected cases both methods can be combined as“rendezvous-approach”. Recently, a new technique of endoscopic biliary-enteric bypass was introduced which comprises endosonographically guided bile duct puncture followed by biliary drainage into the duodenum [43]. The major complication of endoprosthesis implantation is stent occlusion with consecutive cholangitis [258]. Light and electron microscopy studies of blocked stents revealed that the material blocking the lumina was composed of a matrix of bacterial cells and their fibrillar anionic extracellular products. Crystals of calcium bilirubinate, calcium palmitate, and cholesterol were embedded within this matrix. Bacterial cells were attached to the stent surface by a fibrillar matrix, suggesting that the initial event in stent clogging is the development of an adherent bacterial biofilm. Bacterial enzyme activity (beta-glucuronidase and phospholipase) leads to the deposition of crystals. Therefore, it was assumed that the use of antibiotics and/or ursodeoxycholic acid may reduce bacterial adhesion and stent clogging. However, prophylactic long-term antibiosis and/or ursodeoxycholic acid have not turned out to be useful in several studies [128]. Therefore, a close monitoring of patients for early detection of latent biliary sepsis is important for longterm success of stent therapy. As part of this monitoring, plastic endoprostheses should be routinely exchanged every 3 months [310]. Technical questions regarding stent material, number and location of stents have not been completely answered. Polyurethane and polyethylene seemed to be slightly better in comparison to Teflon according to a preclinical study [215]. However in a prospective randomized trial of Teflon versus polyethylene stents for distal malignant biliary obstruction Teflon material did not improve patency in biliary stents with an Amsterdamtype design [395]. Early complication rates were similar in both groups (10%). The median follow-up was 142 days. Stent dysfunction occurred in 28 Teflon and 29 polyethylene stents. The thirty-day mortality was 14% in both groups. Patient survival did not differ significantly between the groups (median survival: Teflon 165 days, polyethylene 140 days). The median stent patency was 83 days for Teflon and 80 days for polyethylene stents, and was not significantly different either. To
Extrahepatic Cholangiocarcinoma
assess whether the use of large stents is justified, Speer et al. retrospectively reviewed the results of 8 F stents with pigtails and 10 F straight stents in the palliation of biliary obstruction due to malignancy [358]. The incidence of cholangitis following stent insertion was significantly lower with 10 F stents compared with 8 F stents (5% vs. 34%, p < 0.001). Stent survival until blockage was significantly longer for 10 F compared with 8 F (median 32 weeks vs. median 12 weeks, p < 0.001). In addition, Kadakia and Starnes retrospectively compared the efficacy and complications of 10 F biliary stents with 11.5 F stents in the management of malignant and benign biliary tract diseases [175]. They concluded that 10 F stents have the same success rate and complication rate as 11.5 F stents in the management of biliary tract diseases, thus a stent size bigger than 10 F offers no significant advantage. A new approach may be the use of an Olympus DoubleLayer stent (DLS; perfluoro alkoxy, without sideholes). In a prospective randomized comparison of this stent with the standard polyethylene stent (with sideholes), including a total of 120 patients with jaundice due to malignant strictures of the middle to distal third of the common bile duct, 28 DLS patients (47%) and 17 polyethylene stent patients (29%) died without clinical evidence of stent occlusion after a mean of 114 and 105 days, respectively (p < 0.05). Twenty-six DLS patients (43%) and 38 polyethylene stent patients (63%) had symptoms of stent clogging after a mean of 144 and 99 days, respectively (p < 0.05). Stent dysfunction (stent orifice impacted on the bile duct or duodenal wall, stent migration) was recorded in 6 DLS patients (10%) and 5 polyethylene patients (8%) (n.s.). Kaplan-Meier analysis of DLS and PE stent clogging-free survival showed a significantly longer patency period with the DLS stents (p = 0.0005). Tringali et al. concluded that these results showed that DoubleLayer stents have a longer patency period than polyethylene stents [386]. Another new development, as described by Raju et al., is a 10 F “winged” stent without a lumen to prevent stent occlusion [316]. A prospective, randomized study revealed a lower cholangitis rate after unilateral stent insertion in comparison to bilateral stent insertion [70]. However, so far general consensus regarding unilateral versus bilateral bile duct drainage has not been obtained. In general, at least 25% of liver tissue should be drained and contrast medium should be injected only in those bile duct segments that will be finally drained.
1537
There is no need to drain a certain liver lobe, it is better to drain the easiest accessible one. In case of concurrent single-sided liver atrophy as a result of tumor induced blood vessel occlusion the primarily intact liver lobe has to be drained. Recent studies showed that MRCP-guided drainage of the widest dilated bile ducts can improve results of stent therapy [102, 142]. Cost analyses in patients with middle and distal bile duct or ampullary cancer showed that metallic stents were advantageous in patients surviving more than 6 months, whereas a plastic stent was advantageous in patients surviving 6 months or less according to several studies [174, 199, 310, 399]. Self-expanding metal stents (SEMS), which can be inserted endoscopically and percutaneously, have the advantage of a higher patency rate with consecutive lower rates of reinterventions and rehospitalizations in comparison to less costly plastic stents [73, 399]. The higher patency rate of metallic stents is related to the wider lumen and better drainage of segmental bile duct branches. These data were confirmed by a recent singlecenter prospective randomized controlled trial comparing the patency of 10 F polyethylene stents and covered 30 F (10 mm)steel Wallstents™ in patients with nonresectable malignant common bile duct strictures [356]. As a result, median patency times were 1.8 and 3.6 months in the polyethylene stents and Wallstents™ groups, respectively (p = 0.002). Interestingly, if overall costs of therapy, determined by adding the cost of hospitalization to the costs of the stent, were compared, there was no difference between both groups. The authors recommended the more-effective SEMS in unresectable patients with malignant common bile duct strictures, who survive a median of 4.5 months and less costly plastic stents for patients who have distant metastases. A newly designed Y stent for advanced hilar cholangiocarcinoma may improve technical and clinical efficacy of endoscopic stent placement [222]. Despite the higher patency rate of SEMS, stent dysfunction can be induced by tumor ingrowth, overgrowth, clogging with sludge or stones, or stent dislocation. Stent dysfunction can be managed by insertion of additional plastic or metal stents, laser treatment or balloon dilatation [376]. Whether stent occlusion may be prevented by covered SEMS or brachytherapy is currently unknown. A prospective randomized study evaluating patients with distal malignant biliary duct obstruction showed that a polyurethane covered Diamond™-stent is superior to a non-covered metallic stent in
1538
terms of patency rate [155]. However, cholecystitis and pancreatitis rates were higher in the covered metallic stent group. Overall survival was equivalent in both groups. In contrast, a recent study comparing polyurethane-covered Wallstents™ that were used in 36 patients with uncovered Wallstents™ that were used in 41 patients found no significant difference between stent patencies [424]. Cholecystitis occurred in one patient of the covered Wallstent™ group but in none of the uncovered Wallstent™ group. Stent occlusion occurred after a mean of 398 days in the covered group and after 319 days in the uncovered Wallstent group (p > 0.05). Stent patency rates were 83%, 78%, 67%, and 54% at 100, 200, 300, and 400 days, respectively, in the covered group and 83%, 66%, 54%, and 36% in the uncovered group, which was not significantly different. However it has to be mentioned that this study was not a prospective, randomized study and sample size was not large. However, another non-randomized study by Park et al. supported these results [285].
Photodynamic Therapy (PDT) for Hilar Cholangiocarcinoma PDT is based on the administration of a photosensitizer which localizes selectively within the target, mostly tumor tissue. The mechanisms by which this localization occurs are complex and not fully understood. High vascular permeability of the agents, as well as their affinity for proliferating endothelium and the lack of lymphatic drainage in tumors may contribute to an accumulation in tumors [76]. Moreover, tumors might have increased lipid content, elevated numbers of lowdensity lipoprotein receptors, abnormal vasculature, and decreased pH. In a second step, non-thermal laser light of a specific wavelength is applied, adapted to the absorption spectrum of the sensitizer to be excited. Following the absorption of light the compound is transformed into a relatively long-lived electronically excited state via a short-lived excited singlet state [140]. This so-called triplet state can undergo two kinds of reactions. In a type I reaction, it can react directly with a substrate, such as the cell membrane or a molecule, and transfer a hydrogen atom or electron to form radicals. The radicals interact with oxygen to produce oxygenated products. Alternatively, in a type II reaction, which is more common, the triplet can transfer its energy directly to oxygen to generate singlet
116
Malignant Tumors
oxygen. Therefore, the effects of both PDT reaction types are oxygen dependent. Tumor destruction, mediated by oxygenated products and singlet oxygen, can be explained by several mechanisms causing necrosis and apoptosis. First, PDT kills tumor cells directly, secondly it damages the tumor-associated vasculature, leading to tumor infarction, and finally can activate an immune response against tumor cells. In detail, PDT has been demonstrated to induce (1) direct cytotoxicity by degeneration of lipids in cell membranes, (2) microvascular damage from platelet activation and thromboxane-induced vessel constriction and thrombus formation, probably mediated by nitric oxide, (3) cytosolic and mitochondrial membrane damage with cytochrome C release, bcl-2 depletion and induction of apoptosis, and (4) release of inflammatory mediators that induce T-lymphocyte mediated cellular immune response. The extent of photodamage and cytotoxicity is multifactorial and depends on the type of photosensitizer used, its localization and administered dose, the light source used, generating the light exposure dose and light fluence rate, the oxygen availability in the target, and finally the time interval between the administration of the photosensitizer and the light treatment. Because PDT is a cold photochemical process, there is no tissue heating, and connective tissues such as collagen and elastin are largely unaffected. PDT should not be performed in patients with acute porphyria, poor kidney or liver function (creatinine > 3 mg/dL, international normalized ratio of prothrombin time [INR] > 2.2), encasement or thrombosis of the main blood vessels, leukopenia (leukocytes < 2,000/cmm), thrombocytopenia (< 50,000/ mm3), and terminal tumor stage. Interest in using PDT for palliative treatment of advanced non-resectable CC has been given rise to by a case report, documenting the success of PDT performed via percutaneous cholangioscopy in a single patient with incompletely resected bile duct carcinoma (Table 116.9) [244]. This type of treatment caused a prolonged survival time of more than 4 years in a tumor entity with a median survival of only 4–6 months. Ortner et al performed the first prospective, non-randomized single-arm study including nine patients with advanced Bismuth type III and IV hilar CC, who showed no sufficient drainage after endoscopic stent insertion [277]. Two days after intravenous administration of porfimer sodium (Photofrin™) at 2 mg/kg body weight, intraluminal photoactivation at 630 nm was performed
Extrahepatic Cholangiocarcinoma
1539
Table 116.9 Palliative photodynamic therapy in hilar cholangiocarcinoma Protocol n Photosensitizer Drainage Survival# Phase I
1
Phase II Phase II Phase II
9 21 23
Phase II Phase II Phase II Phase II Phase III
8 4 6 24 20 19 8 36 24
Phase II Phase II Phase II Phase II Phase III Phase II
25 16 16 68 56
Reference
Dihematoporphyrin 2 Photofrin II Photofrin II Photofrin II
T-Drain
48
(McCaughan et al. 1991) [244]
Plastic stent Plastic stent Plastic stent
14.6 (3–19.2) 15 12.0 (10.4–13.6)
Photosan-3 5-ALA Photofrin II Photofrin II Photofrin II
Plastic stent and PTCD Plastic stent Plastic stent Metallic stent Plastic stent Plastic stent Plastic stent Plastic stent PTCD
4.0 (1.7–14.8) NA NA 9.9 (6.4–13.4)+ 16.4** 3.3 9.2+ 11.2 (2.5–17.3) 18.6 (2.1–27)
(Ortner et al. 1998) [277] (Ortner 2000) [276] (Berr et al. 2000b; Wiedmann et al. 2004) [30, 410] (Zoepf et al. 2001a) [434] (Zoepf et al. 2001b) [435] (Rumalla et al. 2001b) [328] (Dumoulin et al. 2003) [83] (Ortner et al. 2003) [278]
Plastic stent Plastic stent Plastic stent Plastic stent Plastic stent
8.1 21* (3–30) 7 (1–24) 12** (8.8–15.3) 6.4 (4.2–8.5)
Photofrin II Photofrin II Hematoporphy-rine derivative Photofrin II Photosan-3 Photofrin II
(Harewood et al. 2005) [134] (Pereira et al. 2005) [299] (Shim et al. 2005) [342] (Prasad et al. 2005) [308] (Zoepf et al. 2005) [433] (Witzigmann et al. 2006) [417]
NA: non-applicable; #median (range) in months from diagnosis * p < 0.05; **p < 0.01; +median (range) in months from therapy
cholangioscopically with laser diffusing fibers. After PDT, bilirubin serum levels declined significantly (p = 0.004) with no increase during the two monthly followups. Quality of life indices improved dramatically and remained stable. Thirty-day mortality was 0%, and median survival 439 days. Side effects were limited to skin hyperpigmentation, but no acute phototoxicity, in all patients. One patient also reported fever and pain, self-limited, for 2 weeks after PDT. Ortner’s work was subsequently expanded to a larger study of 21 patients [276]. We performed our own study, including 23 patients with hilar CC (Bismuth type III, n = 2; type IV; n = 21) who were treated with a combination of bile duct stenting and endocopically performed Photofrin™PDT [30]. In detail, we intubated the tumor stenosis with a translucent ERC-cannula and inserted a 400 μm thin quartz fiber with either a 2, 3, or 4 cm long cylindrical light diffuser and radioopaque markers (Lambda Plaus PDL-2, Coherent, Dieburg, Germany). The power emmitted by the diffuser tip through the ERC cannula had been calibrated to 0.400 W/cm before PDT and checked thereafter using an integrating sphere power meter. The tumor stenoses were exposed to laser light for 10 min with a light dose of 242 J/cm2. The patients showed a 6 months survival rate of 91% after diagnosis
and 74% after start of PDT with a median local tumor response of 74%, 54%, 29%, and 67% after the first, second, third, and fourth PDT session. Cholestasis, performance, and quality of life of the patients improved clearly. Cholangitis rate with PDT was not higher than in historical control patients with Bismuth type III tumors and bile duct drainage, only. After a five year follow-up, median survival time after diagnosis was 18 months for patients without peritoneal carcinosis (n = 19) and 12 months for all patients (n = 23) [415]. Survival was 63%, 26%, 16%, and 5% after 1, 2, 3, and 4 years, respectively. Of the patients who died, 73.9% (n = 17) were because of tumor progression; 26.1% died as a result of cholangitis (n = 4), septic shock (n = 1), or appendicitis/peritonitis (n = 1). For all patients, except one with diffuse liver metastases, there was improvement in cholestasis, performance, and quality of life, which was maintained for an extended period of time. These data were confirmed by a similar recent phase II study including 36 patients [299]. In 2001, Zopf et al. described the use of a novel laser diode PDT system in the treatment of eight patients with Bismuth II-IV non-resectable CC using Photosan-3 (2 mg/kg; dihematoporphin ether) and a light dose of 200 J/cm2 at a wavelength of 633 nm [434]. Four weeks after initial
1540
PDT, which was performed transpapillary (n = 4) or percutaneously (n = 4), all patients showed a marked reduction of bile duct stenosis. The median serum bilirubin value declined from 5.8 to 1.0 mg/dL. The median survival time was 119 days (52–443 days). The therapeutic value of percutaneous transhepatic PDT in patients with advanced bile duct cancer was subject of another prospective trial [342]. The utility of intraductal ultrasonography (IDUS) for the assessment of responses and for regular follow-up after PDT was also examined. PTCD was initiated before PDT. Following dilation and maturation of the PTCD tract, percutaneous PDT was performed. Intraluminal photoactivation was carried out using percutaneous cholangioscopy 2 days after intravenous application of a hematoporphyrin derivative. All patients were additionally provided with percutaneous bile duct drainage catheters after PDT. IDUS was conducted monthly to measure the thickness of the tumor mass before and after PDT. Twenty-four patients with advanced cholangiocarcinomas (Bismuth IIIa, n = 4; IIIb, n = 10; IV, n = 10) were treated with PDT. At 3 months after PDT, the mean thickness of the tumor mass had decreased from 8.7 ± 3.7 mm to 5.8 ± 2.0 mm (p < 0.01). At 4 months after PDT, the thickness of the mass had increased to 7.0 ± 3.7 mm. Quality of life indices improved dramatically and remained stable 1 month after PDT; the Karnofsky index increased from 39 to 58 points (p = 0.003). The 30-day mortality rate was 0%, and the median survival time was 558 days (range 62–810 days). Another single-arm study described a new method of applying photodynamic therapy in the biliary tract by using accessories available in the United States [328]. Patients were injected with 2 mg/kg of sodium porfimer and 48 h later a commercially available cylindrical diffusing laser fiber was inserted into an 8 F biliary catheter equipped with a 0.038 inch side-hole at its distal tip. After positioning of a 0.035 inch guidewire proximal to the biliary stricture, the preloaded catheter was advanced over the guidewire by using the monorail technique. Laser light was applied at a power of 4 mW/ cm fiber for a total energy of 180 J/cm2. By using the preloaded biliary catheter, adequate positioning of the laser fiber was achieved in all patients. A fracture of the diffuser tip occurred during one of the treatments. Two patients developed acute cholangitis and two patients experienced skin phototoxicity. The applicability of this technique was confirmed in a recent study by Harewood et al. [134] It was concluded that (1) PDT
116
Malignant Tumors
treatment every 3 months is applicable, (2) patient selection for PDT need not to be based on response to primary biliary stenting, and (3) the average cost of treatment per patient would be US $ 10,337, which is based on direct medical costs estimated from USA Medicare ambulatory patient classification (ABC 2003) plus professional fees for hospital-based outpatient procedures and can be compared with the costs of management with biliary stenting alone. Another study examined factors associated with increased survival after PDT [309]. Twenty-five patients with cholangiocarcinoma who were treated with PDT at the Mayo Clinic in Rochester/USA from 1991 to 2004 were studied. Patients received PDT treatments every 3 months. Plastic biliary stents (10– 11.5 F) were inserted to decompress the biliary system after PDT. Survival analysis was performed using Kaplan-Meier curves and Cox proportional hazards models. The median overall survival period was 344 days. The median survival period after PDT was 214 days. The 1-year survival rate was 30%. On multivariate analysis, the presence of a visible mass on imaging studies (hazard ratio, 3.55; 95% confidence interval, 1.21–10.38), and increasing time between diagnosis and PDT (hazard ratio, 1.13; 95% confidence interval, 1.02–1.25) predicted a poorer survival rate after PDT. A higher serum albumin level (hazard ratio, 0.16; 95% confidence interval, 0.04–0.59) predicted a lower mortality rate after PDT. The conclusion from this study was that patients with unresectable cholangiocarcinoma without a visible mass may benefit from earlier treatment with PDT. Another prospective phase II study investigated PDT and consecutive metal stent insertion for palliation of hilar CC [83]. It was feasible but there was only a modest benefit in overall survival in comparison to a historical control group. In addition, a small study investigated the use of 5-aminolevulinic acid (5-ALA) for the palliative treatment of hilar CC [434]. Light activation was performed 5–7 h after oral administration of 5-ALA. All patients had an endoprosthesis placed in the bile duct after PDT. However, 4 weeks after PDT, 5-ALA had failed to significantly reduce malignant bile duct obstruction and thus can not be recommended for the palliative treatment of bile duct cancer. Finally, we reported the first prospective, uncontrolled trial in patients with hilar cholangiocarcinoma which compared outcome after palliative PDT and resectional therapy [417].
Extrahepatic Cholangiocarcinoma
As expected, survival after palliative PDT was inferior to R0 resection. However, patients treated with PDT showed a similar survival time to that of patients with incomplete R1/R2 resection, although the former were more ill. Despite these improvements in palliative treatment by PDT, an aggressive resectional approach is justified in view of the facts that even during surgery completeness of tumor resection can hardly be defined and longterm survival is observed after complete resection of advanced tumor stages and even after R1 resection. The first prospective, randomized multicenter trial, including our hospital, confirmed preliminary data from the above mentioned non-randomized studies [278]. Patients with hilar CC fulfilling inclusion criteria (nonresectable tumor, tumor diameter > 3 cm, tumor clearly visible on CT and ERCP, unequivocal positive histology, no evidence of cancer of another organ) were randomized to group A (stenting and subsequent PDT) and group B (stenting alone). For PDT, Photofrin™ at 2 mg/ kg body weight was injected intravenously 2 days before intraluminal photoactivation (wavelength, 630 nm; light dose, 180 J/cm2). Further treatments were performed in cases of residual tumor in the bile duct. Oral ciprofloxacin therapy 250 mg twice daily was started before ERCP and continued for 14 days. The primary outcome parameter was survival time. Secondary outcome parameters were cholestasis and quality of life. PDT resulted in prolongation of survival (group A: n = 20, median 493 days; group B: n = 19, median 98 days; p < 0.0001). It also improved biliary drainage and quality of life. The study was terminated prematurely because PDT proved to be so superior to simple stenting treatment that further randomization was deemed unethical. It was remarkable that an additional group of 31 patients who were excluded from randomization because of a statistically significant lower Karnovsky performance status, but received PDT treatment voluntarily, performed as well as the randomized PDT group. The second prospective randomized trial investigated the effect of Photosan-3 based PDT plus stenting on survival time in 32 patients with advanced hilar CC [433]. In the control group, patients were treated with endoprostheses but no PDT. PDT group and the control group were comparable due to age, gender, performance status, bilirubin level, and Bismuth stage. The median survival time after randomization was 7 months for the control group and 21 months for the PDT group (p = 0.01). In half of the initially percutaneously treated
1541
patients, a change from percutaneous to transpapillary drainage after PDT was possible. Four patients showed infectious complications after PDT versus one patient in the control group. In summary, in 2 prospective randomized studies palliative PDT for non-resectable hilar CC was effective in restoring biliary drainage and improving quality of life and prolonging survival; thus, PDT should become a standard treatment. Finally, Cheon et al. suggest that serum Il-6 concentration may serve as a marker for monitoring the response to treatment of cholangiocarcinoma with PDT [60].
Surgical Palliation Because surgical drainage procedures do not offer any advantage to nonsurgical palliation, biliary stenting is regarded as the palliative method of choice.
Palliative Chemotherapy In general, cytostatic therapy has to be evaluated critically according to the goal of palliative treatment to improve quality of life and prolong survival. Time for treatment and hospitalization for complications of chemotherapy have to be substrated from the limited total survival time. In addition, toxicity of therapy may negatively influence quality of life. Reserve of liver function is normally limited for these tumors, which may result in an increased rate of complications of cytostatics as a consequence of decreased drug metabolization. There is an additional risk of latent cholangitis and sepsis for patients with extrahepatic cholangiocarcinoma with the typical feature of bile duct obstruction. This risk is increased with cytostatic therapy. In the nineties, in a randomized phase III study including biliary tract and pancreatic cancer patients, 5-FU-based chemotherapy was shown to be better than best supportive care (Table 116.10) [121]. While the prolongation of overall survival failed to reach significance for biliary tract cancer patients (2.5 versus 6.5 months, p = 0.1) – possibly due to the low number of patients (n = 37) – quality of life was improved and the average quality-adjusted survival was prolonged in the group of patients randomized to the chemotherapy. However, the FELV-protocol (5-FU, etoposid and
1542
116
Table 116.10 Randomized studies of palliative chemotherapy for biliary cancer Author and year (n) Drugs Dose (mg/m2), Protocol
Malignant Tumors
Response rate (%)
Median Survival (months)
1-YSR (%)
Phase III (Glimelius et al. 1996) [121]**
90
F(E)LV
d 1–3 / 3 week
(8)
6*
NA
(Rao et al. 2005) [320]
54
BSC FELV
d 1–3 / 3 week
(2) 15
2.5 12
50
ECF
d 1(EC), d 1–21 (F) / 3 week
19
9
21
5-FU
600 p.o. d 1–5 / 6 week
10
5.3 / 6.5
NA
5-FU/Strepto
600 (F)+500 (S) d 1–5 / 6 (F)/12 8 (S) week 500 d 1–5/6 week (F) + 150 d 1 (C) 10 310 (F) d 1–5 / 6 week 0
3.5 / 3
NA
2.5 / 2 6.0
NA 25
Phase II (Falkson et al. 1984) [93]***
(Takada et al. 1994) [367]a
87
81
5-FU/ mCCNU 5-FU FAM
(Kornek et al. 2004) [207]
51
MMC/Gem
310 (F), d 1–5, 12 (A) d 8, 6 (M) d 1 / 6 week d 1 (M), d 1,15 (G) / 4 week
(Ducreux et al. 2005) [82]
58
MMC/Cap HD 5-FU
d 1 (M), d 1–14 (C) / 4 week d 1,8,15,22,29,36 / 8 week
31 7
9.3 5
41 29
5-FU /LV/ CDDP
d 1,(8),15,(22),29,(36) / 8 week
19
8
30
4
6.2
14
20
6.7
23
*
p < 0.05 (pancreatic and biliary cancer; p = 0.1 for biliary cancer only [n = 37]) Response rate was not formally investigated *** Survival was separately investigated for gallbladder cancer and bile duct cancer a Study included pancreatic cancer patients FELV: 5-Fluorouracil + Etoposide + Leucovorin; BSC: best supportive care; ECF: Epirubicine + Cisplatin + 5-Fluorouracil; Strepto: Streptozotocin; mCCNU: methyl-CCNU; FAM: 5-FU + Adriamycin + Mitomycin C; MMC: Mitomycin C; Gem: Gemcitabine; Cap: Capecitabine; HD: high dose; LV: Leucovorin; CDDP: Cisplatin; NA: non-applicable **
leucovorin) that was followed in the study is used only seldomly because of its toxicity, although epirubicin, cisplatin and 5-FU (ECF) combination was not more effective in a second phase III study [320]. Ten years ago a randomized trial demonstrated the superiority of gemcitabine over 5-FU in pancreatic cancer considering clinical benefit response, progression-free and overall survival [44]. Based on the analogy of carcinogenesis of biliary tract cancer and pancreatic cancer, gemcitabine was adopted for palliative chemotherapy for biliary tract cancer. Nevertheless, a randomized controlled trial of gemcitabine compared to 5-FU has not been performed up to date and there is no evidence based on non-randomized trials supporting superiority of gemcitabine alone compared to 5-FU alone in biliary tract cancer [86]. Favourable results have been published from a GERCOR (Groupe Coopérateur Multidisciplinaire en Oncologie) trial evaluating the GemOx regimen in biliary tract cancer [14]. GemOx comprises gemcitabine
at a dose of 1,000 mg/m2 infused over 100 min (fixed dose rate of 10 mg/m2/min) on day 1, followed by oxaliplatin 100 mg/m2 on day 2, repeated every 14 days. Remarkably, untreated patients with good performance status (WHO 0–2) and adequate renal and liver functions (serum creatinine < 1.5 × upper limit of normal [ULN] and bilirubin < 2.5 × ULN) were enrolled (group A) as well as patients with performance status > 2 or bilirubin > 2.5 × ULN, or prior chemotherapy for advanced disease (group B). Such an enrollment policy is unusual for trials but represents well the reality of the patients with advanced biliary tract cancer. Noteworthy, patients with performance status of > 2 are capable of only limited selfcare, confined to bed or chair more than 50% of waking hours. According to the NCCN guidelines these patients would have received best supportive care only. Of course, results of group A (n = 33) were better than of group B (objective response 36% vs 22%, stable disease 26% vs 30%, median progression-free survival
Extrahepatic Cholangiocarcinoma
5.7 vs 3.9 months and overall survival 15.4 vs 7.6 months, respectively). However, results from group B indicate that GemOx has some activity even in patients with a poor prognosis who have received previous chemotherapy. Tolerability of GemOx in group B did not differ significantly from that in group A patients, indicating that this combination is safe in patients with a poor prognosis or pretreated by chemotherapy [14]. A meta-analysis by Eckel et al. failed to demonstrate an increase of the activity of gemcitabine combined with fluoropyrimidenes compared with gemcitabine alone [86]. Nevertheless, results of some trials were remarkable. The combination of gemcitabine with capecitabine (response rate (RR) 31%, tumor control rate (TCR) 73%, progression free survival (PFS) 7 months, overall survival (OS) 14 months) did better than the active combination with continuous infusional 5-FU (RR 33%, TCR 63%, PFS 3,7 months, OS 5,3 months) [197, 198]. Even if the differences in survival times may be partly due to selection bias, the combination of gemcitabine and capecitabine is an interesting one, as this combination demonstrated significant prolongation of survival in patients with pancreatic cancer in a large randomised controlled trial compared to gemcitabine alone [68]. Guidelines for the treatment of cholangiocarcinoma have been published 2002 by the BASL (British Association for the Study of the Liver) [185]. Consensus conclusion from predominately phase II trials suggest: (1) RRs of 5-FU-based and (older) single agents are 10–20%, (2) RRs of newer single agents, such as gemcitabine, vary from 20% to 30%, (3) RRs of recent phase II combinations vary from 20% to 40%, and (4) gemcitabine in combination with cisplatin shows 30–50% RRs. The results of the above mentioned recent pooled analysis of clinical trials are somewhat different but agree in principle concerning the combination of gemcitabine with cisplatin: (1) more than half of fluoropyrimidine based trials reported RRs of more than 20%, (2) more than a half of single agent gemcitabine trials and nearly all trials of newer single agents reported RRs of less than 20%, (3) about 40% of combination trials reported RRs of 20% or less, and (4) the middle half of gemcitabine plus platinum combinations results in RRs between 26% and 50%, i.e. one quarter of this combination trials reported RRs of 50% or greater [86]. Furthermore, significant correlations of RRs and tumor control rates with progressionfree and overall survival times were found in this analysis. Nevertheless, there is no evidence based on large randomized controlled trials supporting the
1543
combination of gemcitabine and platinum compounds as accepted standard treatment. Large, randomized controlled trials, such as the UK National Cancer Research Institute ABC-02 trial, evaluating the definite role of platinum compounds in combination with gemcitabine compared to gemcitabine alone are needed for a higher level of evidence. The guidelines of the US National Comprehensive Cancer Network (NCCN v.1.2007) recommend, depending on the patient’s general condition, best supportive care, a clinical trial, 5-fluorouracil (5-FU), or gemcitabine. In summary, owing to the lack of randomized phase III studies (Tables 116.11–116.17), there is no standard regimen for palliative chemotherapy of cholangiocarcinoma.
Palliative Radiotherapy Regarding palliative radiation therapy, there are even fewer studies and there is no proof that external or intraluminal radiation improves survival or quality of life (Tables 116.18 and 116.19) [186, 252]. Single case reports demonstrate improvement of cholestasis and pain [204, 256, 273]. Median survival of patients varies widely in different studies between 4 and 23 months [105, 176, 346, 368, 388]. Low patient numbers, an uncontrolled and mostly retrospective study design, as well as a high variation in radiation dose and method (external, intraluminal, percutaneously or endoscopically, intraoperatively or combined) permit no final conclusion. Attention may be paid to complications after radiation therapy. In studies of intraluminal brachytherapy the cholangitis rate was as high as 44% and the rates of gastroduodenal ulcer and stenoses were as high as 25% after combined treatment [41, 105, 124, 176, 204, 368].
Palliative Chemoradiation The status of combined chemoradiation in comparison to chemotherapy, radiation or stenting is unclear (Table 116.20) [191]. In summary, it has to be concluded that currently there is no standard protocol for palliative radiation therapy or chemoradiation of cholangiocarcinoma. Therefore, patients should be included in randomized phase III studies.
1544
116
Table 116.11 Monotherapy with fluoropyrimidines Author, Year Entity (n) Drugs
(Chen et al. 1998) [57]
BC
19
5-FU/LV
(Choi et al. 2000) [65]
BC
28
5-FU/LV
(Malik and Aziz 2003) [239] (Patt et al. 2004) [293]
GBC
30
5-FU/LV
18 8 13
Cap
(Mani et al. 1999) [242]
BC GBC BC
UFT/LV
(Chen et al. 2003) [58]
BC
16
UFT/LV
(Ikeda et al. 2005) [152]
BC
19
UFT
Malignant Tumors
Dose (mg/m2), Protocol
Response rate (%)
Median survival (mo)
1-YSR (%)
2600 c.i./ 150 d 1,8,15,22,29,36 / 8 week 375b/25 d 1–5 / 4 week 425b/20 d 1–5 / 4 week 2000 d 1–14 / 3 week
33
7
NA
32
6
39
7
14.8
NA
6 50 0
8.1 9.9 7
44 38 NA
0
5
19
5
8.8
21
300/90 d1–28 / 5 week 300/60 d1–28 / 5 week 360 daily
BC: biliary carcinoma; GBC: gallbladder cancer; b: bolus; c.i.: continuous infusion (24 h); LV: folic acid (Leukovorin); UFT: Uracil/ Tegafur; Cap: Capecitabine; NA: non-applicable
Table 116.12 Monotherapy with gemcitabine Author and year Entity (n)
Drugs
Dose (mg/m2), Protocol
Response Rate (%)
Median Survival (mo)
1-YSR (%)
1000 d 1,8,15 / 4 week 1200 d 1,8,15 / 4 week 1000 d 1,8,15 / 4 week 1000 d 1,8,15 / 4 week 1000 d 1,8,15 / 4 week 1000 d 1,8,15 / 4 week 1000 d 1,8,15 / 4 week 800 every week 1000 d 1,8 / 3 week 1000 d 1,8,15 / 4 week 100 c.i. d 1,8,15 / 4 week 1500 FDR d 1,8,15 / 4 week 1000 FDR d 1 / 1 week 2200 d 1 / 2 week
8 16 22 33 30 36 13 30 26 18 6
6 6.5 8 6.5 9.3 7.5 7.2 14 13.1 7.6 7.5
NA NA 22 26 NA 33 17 57 50 25 34
0
5
0
15 22
10 11.5
26 44
(Mezger et al.. 1998) [248] (Raderer et al. 1999) [315] (Gebbia et al. 2001) [114] (Arroyo et al. 2001) [17] (Kubicka et al. 2001) [212] (Gallardo et al. 2001) [112] (Lin et al. 2003) [227] (Tsavaris et al. 2004) [387] (Park et al. 2005) [286] (Okusaka et al. 2006)[275] (von Delius et al. 2005) [396] (Eng et al. 2004) [91]
BC BC BDC/ GBC BDC/ GBC ICC/ECC GBC BDC BDC/ GBC BDC/ GBC BC BDC/ GBC
13 19 18 42 23 26 24 30 23 40 18
Gem Gem Gem Gem Gem Gem Gem Gem Gem Gem Gem
BDC/ GBC
15
Gem
(Gelibter et al. 2005) [115] (Penz et al. 2001) [298]
BC BC
40 32
Gem Gem
BC: biliary carcinoma; BDC: bile duct carcinoma; GBC: gallbladder carcinoma; ICC: intrahepatic cholangiocarcinoma; ECC: extrahepatic cholangiocarcinoma; c.i.: continuous infusion (24 h); Gem: Gemcitabine; FDR: fixed dose rate; NA: non-applicable
Table 116.13 Monotherapy with topoisomerase-inhibitors Author and year Entity (n) Drugs (Sanz-Altamira et al. 2001) [333] (Alberts et al. 2002) [10] (Abou-Alfa et al. 2005) [2]
BC
25
CPT-11
BDC/GBC
36
CPT-11
BDC/GBC
42
Exatecan
Dose (mg/m2), Protocol
Response Rate (%)
Median Survival (mo)
1-YSR (%)
125 d 1,8,15,22 / 6 week 125/100 d 1,8,15,22 / 6 week 0.5 d 1–5 / 3 week
8
10
NA
7
32
8 5
BC: biliary carcinoma; BDC: bile duct carcinoma; GBC: gallbladder carcinoma; CPT-11: Irinotecan; NA: non-applicable
Extrahepatic Cholangiocarcinoma
1545
Table 116.14 Combination therapy with fluoropyrimidines and gemcitabine Author and year Entity (n) Drugs Dose (mg/m2), Protocol (Iyer et al. 2007) [163]
BDC/GBC
12
(Knox et al. 2005) [197]
BDC/GBC
45
(Iqbal et al. 2006) [154]
BDC/GBC
(Cho et al. 2005) [64]
BDC/GBC
44
(Chang et al. 2005) [52] (Knox et al. 2004) [198]
BDC GBC BDC/GBC
20 11 27
(Alberts et al. 2005) [9]
BDC/GBC
42
(Gebbia et al. 2001) [114] BC
22
(Hsu et al. 2004) [148]
30
BDC/GBC
Gem Cap Gem Cap Gem Cap
1000 d 1,8 / 3 week 1300 d 1–14 / 3 week 1000 d 1,8 / 3 week 1300 d 1–14 / 3 week 1000 d 1,8 / 3 week 1300 d 1–14 / 3 week
Gem Cap Gem Cap Gem 5-FU Gem 5-FU LV Gem 5-FU 5-FU LV Gem 5-FU LV
1000 d 1,8 / 3 week 1300 d 1–14 / 3 week 1000 d 1, 8, 15 / 4 week 1660 d 1–21 / 4 week 900 d 1,8,15 / 4 week 200 c.i. d 1–21 / 4 week 1000 d 1,8,15 / 4 week 600b d 1,8,15 / 4 week 25 d 1,8,15 / 4 week 1000 d 1,8 / 3 week 400b d 1,8 / 3 week 600 c.i. d1,8 / 3 week 100 800 d 1,8,15 / 4 week 200 c.i. d 1,8,15 / 4 week 300 d 1,8,15 / 4 week
Response rate (%)
Median survival (mo)
1-YSR (%)
17
14
58
31
14
49
18
7
NA
32
14
58
15 9 33
7.8
NA
5.3
26
10
9.7
36
36
11
36
21
4.7
NA
BC: biliary carcinoma; BDC: bile duct carcinoma; GBC: gallbladder carcinoma; b: bolus; c.i.: continuous infusion (24 h); Gem: Gemcitabine; Cap: Capecitabine; LV: Leucocorin; NA: non-applicable
Table 116.15 Combination therapy with fluoropyrimidines and platinum-derivatives Author, Year Entity [n] Drugs Dose (mg/m2), Protocol (Ducreux et al. 1998) [81]
BC
25
(Taieb et al. 2002) [365]
BC
29
(Kobayashi et al. 2006) [200]
BDC/GBC
42
(Kim et al. 2003) [189]
BDC/GBC
42
(Glover et al. 2005) [122]
BC
15
(Hong et al. 2007) [145]
BDC/GBC
32
(Nehls et al. 2006) [266]
BDC/GBC
65
(Nehls et al. 2002) [265]
BDC/GBC
16
(Sanz-Altamira et al. 1998) [332]
BC
14
5-FU CDDP CDDP LV 5-FU 5-FU 5-FU CDDP Cap CDDP Cap Oxali Cap CDDP Cap Oxali Oxali LV 5-FU Carbo LV 5-FU
1000 c.i. d 1–5 / 4 week 100 d 2 / 4 week 50 d 2 / 2 week 200 d 1 / 2 week 400b d 1 / 2 week 600 c.i. d 1–2 / 2 week 160 c.i. d 1–7 / 1 week 60 d 1,4 / 1 week 2500 d 1–14 / 3 week 60 d 1 / 3 week 1500 d 1–14 / 3 week 130 d 1 / 3 week 2500 d 1–14 / 3 week 60 d 1 / 3 week 2000 d 1–14 / 3 week 130 d 1 / 3 week 85 d 1 / 2 week 500 d 1 / 2 week 1500–2000 d 1–2/2 week 300 d 1 / 4 week 25 d 1–4 / 4 week 400 d 1–4 / 4 week
Response Rate [%]
Median Survival [mo]
24
10
34
9.5
43
7.5
21
9.1
27
NA
41
12.4
20
NA
19
9.5
21
5.0
BC: biliary carcinoma; BDC: bile duct carcinoma; GBC: gallbladder carcinoma; b: bolus; c.i.: continuous infusion (24 h); CDDP: Cisplatin; Oxali: Oxaliplatin; Carbo: Carboplatin; Gem: Gemcitabine; Cap: Capecitabine; LV: Leucocorin; NA: non-applicable
1546
116
Table 116.16 Combination therapy with fluoropyrimidines and topoisomerase-inhibitors Author, Year Entity [n] Drugs Dose (mg/m2), Protocol
(Feisthammel et al. 2007) [95]
ICC/ GBC
30
CPT-11 5-FU/ LV
80 d 1,8,15,22,39,46 / 8 week
Malignant Tumors
Response Rate [%]
Median Survival [mo]
1-YSR [%]
10
5.5/9.1
25
2000 c.i. d 1,8,15, 22,39,46 / 8 week ICC: intrahepatic cholangiocarcinoma; GBC: gallbladder carcinoma; CPT-11: Irinotecan; LV: Leucovorin; c.i.: continuous infusion (24 h)
Table 116.17 Combination Therapy with Gemcitabine and Platinum-Derivatives Author, Year Entity [n] Drugs Dose (mg/m2), Protocol (Malik et al. 2003) [240]
GBC
8
(Thongprasert et al. 2005) [378]
BDC/GBC
43
(Misra et al. 2005) [251]
GBC
40
(Gebbia et al. 2005) [113]
BDC/GBC
24
(Giuliani et al. 2006) [120]
BDC/GBC
38
(Doval et al. 2004) [77]
GBC
30
(Lee et al. 2006) [220]
BDC
24
(Kim et al. 2006) [188]
BC
29
(Park et al. 2006) [284]
BC
27
(Abid et al. 2003) [1]
GBC
36
(Reyes-Vidal et al. 2003) [325]
GBC
44
(Julka et al. 2006) [173]
GBC
20
(Andre et al. 2004) [14]*
BDC/GBC
33
(Harder et al. 2006) [133]
BC
31
(Charoentum et al. 2007) [55]
BC
42
(Lee et al. 2007a) [221]
BDC/GBC
39
(Wagner et al. 2006) [398]
GBC
35
Gem CDDP Gem
1000 d 1, 8 / 3 week 70 d 1 / 3 week 1250 d 1,8 / 3 week
CDDP Gem CDDP Gem Oxali Gem CDDP Gem CDDP Gem CDDP Gem CDDP Gem CDDP Gem CDDP Gem
75 d 1 / 3 week 1000 d 1, 8, 15 / 4 week 80 d 16,17 1000 d 1, 8 / 3 week 100 d 1 / 3 week 1000 d 1,8 / 3 week 75–80 d 1 / 3 week 1000 d 1,8 / 3 week 70 d 1 / 3 week 1000 d 1,8 / 3 week 70 d 1 / 3 week 1250 d 1,8 / 3 week 60 d 1 / 3 week 1000 d 1,8,15 / 4 week 75 d 1 / 4 week 1250 d 1,8 / 3 week 70 d 1 / 3 week 1250 d 1,8 / 3 week
CDDP Gem Carbo Gem Oxali Gem Oxali Gem CDDP Gem CDDP Gem Oxali 5-FU
35 d 1,8 / 3 week 1000 d 1,8 / 3 week AUC 5 d 1 / 3 week 1000 FDR d 1 / 2 week 100 d 2 / 2 week 1000 d 1,8,15 / 4 week 100 d 1,15 / 4 week 1250 d 1,8 / 3 week 75 d 1 / 3 week 1250 d 1,8 / 3 week 70 d 1 / 3 week 900 d 1,8 / 3 week 65 d 1,8 / 3 week 1500 d 1,8 / 3 week
Response Rate [%]
Median Survival [mo]
1-YSR [%]
64
10
NA
28
9
NA
55
8
NA
50
10
NA
32
8+
37
5
18
21
9.3
NA
35
11
NA
33
10
36
25
5.7
NA
46
7
NA
35
7.9
43
33/22
15.4/7.6
57/31
26
11
NA
21
10.8
40
17
8.6
30
NA
9.9
30
BC: biliary carcinoma; BDC: bile duct carcinoma; GBC: gallbladder carcinoma; AUC: area under the curve; FDR: fixed dose rate; CDDP: Cisplatin; Oxali: Oxaliplatin; Carbo: Carboplatin; Gem: Gemcitabine; NA: non-applicable * Separate analysis for patients in poor general condition with bilirubin > 3x upper limit of normal or second line chemotherapy
Extrahepatic Cholangiocarcinoma
1547
Table 116.18 Radiation therapy for biliary carcinoma Author, Year [n] (Shinchi et al. 2000) [346] (Zheng et al. 2006) [430] (Ohnishi et al. 1995) [273] (Lee et al. 1997) [219] (Shin et al. 2003) [345]
30 38 14 15 17 14 30
(Schleicher et al. 2002) [336] (Milella et al. 1998) [249]
(Meyers and Jones 1988) [247]
10 12 28 28 27
(Ishii et al. 2004) [156] (Kuvshinoff et al. 1995) [214] (Takamura et al. 2003) [368] (Eschelman et al. 1996) [92] (Foo et al. 1997) [101] (Vallis et al. 1996) [394] (Genzalez Gonzalez et al. 1999) [124] (Kamada et al. 1996) [176] (Tsujino et al. 1995) [388] (Fritz et al. 1994) [105] (Lu et al. 2002) [234]
25 12 93 11 24 38 38 54 27 30 18
(Bowling et al. 1996) [37]
Entity
EBRT Dose [Gy]
ILBT Dose [Gy]
Median Survival [mo]
HC ICC HC ECC ECC ECC HC HC ECC ECC HC HC ECC ECC ECC HC ECC ECC ECC BDC HC ECC ECC ECC ECC
Yes 50 50–60 + 50.4 (36–55) 50.4 (36–55) 30 30 + + 30 − 30–45 − 30–50 50.4 50 45 (25–56) 50.4 23.8 (22.5–55) 60–68 7.5–80 45 (12–50) 30–45 45
− − − + − 15 − 40 − + 60 − 30–50 30–50 24–40 20 39.2 (27–50) 25 (15–31) 20 40 22–25 (n=19) 20–95 7–95 20–45 7–21
10.6
8
3.9 9.1 11.5 14.3 10 7 14.3 3.6 9.3 14.5 12 22.6 12.8 15 10.4 12.4 13 10 12.2
HC: Hilar cholangiocarcinoma; BDC: bile duct carcinoma; ICC: intrahepatic cholangiocarcinoma; ECC: extrahepatic cholangiocarcinoma; NA: non-applicable
Table 116.19 Intraluminal brachytherapy for biliary carcinoma Author, Year [n] Entity ILBT [Gy] (Bruha et al. 2001) [41] (Chen et al. 2004) [59] (Dvorak et al. 2002) [84] (Leung et al. 1996) [225] (Kocak et al. 2005) [204] (Fletcher et al. 1983) [99]
17 11 14 20 13 16 8 19
HC GBC BDC BDC BDC/GBC BDC ECC HC/GBC
30 30 12–28 − 36–42 NA 20 44.7
Stent Patency [Months]
Median Survival [mo]
SEMS (13.9) SEMS (7.3) SEMS (12.6) SEMS (8.3) NA NA SEMS (5) Drainage (4.2)
11.9 7 9.4 6 9.2 23 5.5 11
HC: Hilar cholangiocarcinoma; BDC: bile duct carcinoma; GBC: gallbladder carcinoma; ICC: intrahepatic cholangiocarcinoma; ECC: extrahepatic cholangiocarcinoma; NA: non-applicable
Future Directions of Palliation Progress in PDT In the future, further progress may be made by using photosensitizers with a higher penetration depth for PDT than the currently used Photofrin™ and Photosan™, whose effect is limited to is 4 – 4.5 mm. Temoporfin
(Foscan™), with a strong absorption at 652 nm, or tetrahydroporphyrin tetratosylat (THPTS) with a strong absorption at 760 nm may be good candidates. Further modifications of Foscan™ like a liposomal formulation (Foslip™) or pegylation (Fospeg™) aim to reduce photosensitizer dose, side effects and costs. In addition to the development of new photosensitizers, other innovative ideas are currently under investigation. For
1548
116
Table 116.20 Chemoradiation for biliary carcinoma Author, Year [n] Entity
(Urego et al. 1999) [11] [392] (Morganti et al. 2000) [257] (Deodato et al. 2006) [72] (Park et al. 2006) [287] (Schoppmeyer et al. 2006) [338] (Matsumoto et al. 2004) [243] (Ben-Josef et al. 2005) [25] (Nomura et al. 2002) [270]
Malignant Tumors
EBRT [Gy]
ILBT [Gy]
Chemotherapy
Median Survival [mo]
24 34 20 22 19 11
ECC BDC BDC ECC ECC ECC
46 42–54.6 39.6–50.4 39.6–50.4 45 49.6
25 − 30–50 30–50 − −
5-FU (+ FAM/MMC) 5-FU/LV, IFN, (Taxol) 5-FU 5-FU Doxifluridin + Paclitaxel Gemcitabine
12 14 21.2 23 14 8,2
23 46 5 12
HC ICC ECC ECC
41.4 60,75 − < 40–59.4
− − 10–30 10–30
Epirubicin, MMC, 5-FU i.a. Floxuridin i.a. − 5-FU, CDDP, Adriamycin
19,5 13,3 4,6 16,2
HC: Hilar cholangiocarcinoma; BDC: bile duct carcinoma; GBC: gallbladder carcinoma; ICC: intrahepatic cholangiocarcinoma; ECC: extrahepatic cholangiocarcinoma; FAM: 5-FU/Adriamycin/Mitomycin C; LV: Leukovorin; IFNα: Interferon α; MMC: Mitomycin C; CDDP: Cisplatin; NA: non-applicable
instance, fractionated drug-dose PDT regimens were reported to result in a superior therapeutic effect, compared to single-dose regimens, and were able to induce long-term tumor growth control. Moreover, the use of specific targeting carriers, such as conjugated antibodies directed to tumor-associated antigens or vascular antigens are supposed to direct the photosensitizer to a certain cell type or compartment. Others suggest the use of different advanced delivery systems, such as ligand-based targeting with insulin, epidermal growth factor or adenoviral proteins, protease-mediated drug delivery, photosensitizing adenoviruses, water-soluble polymer carriers, and pH-responsive polymeric micelles. A completely different approach is the protection of normal tissue with drugs like WR-2721 and WR-77913 from possible PDT side effects if the photosensitizer is used in a high dose [415].
Progress in Chemotherapy S-1 is a novel orally administered drug that is a combination of tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP), and oteracil potassium in a 1:0.4:1 molar concentration ratio. CDHP is a competitive inhibitor of DPD, which is involved in the degradation of 5-FU, and acts to maintain efficacious concentrations of 5-FU in plasma and tumour tissues. Oteracil potassium, a competitive inhibitor of orotate phosphoribosyltransferase, inhibits the phosphorylation of 5-FU in the gastrointestinal tract, reducing the serious gastrointestinal toxicity associated with 5-FU. A phase II study investigated the
efficacy and safety of S-1 in patients with biliary tract cancer. Four patients achieved a partial response, giving an overall response rate of 21%. The median time-toprogression and median overall survival period were 3.7 and 8.3 months, respectively. S-1 was well tolerated in patients with this disease [391]. Uracil-tegafur (UFT) is an orally administered drug that is a combination of uracil and tegafur in a 4:1 molar concentration ratio. Uracil prevents degradation of 5-FU by inhibiting dihydropyrimidine dehydrogenase (DPD), which leads to an increased level of 5-FU in plasma and tumor tissues. A phase II study of UFT in patients with advanced biliary tract cancer was performed. Only one patient (5%) achieved a partial response with a duration of 2.0 months and six further patients (32%) showed stable disease. The authors concluded, that UFT appeared to have little activity as a single agent in treating patients with advanced biliary tract cancer [152]. A subsequent early phase II trial of UFT plus doxorubicin demonstrated moderate activity against advanced biliary tract cancer with an objective response rate of 12.5% and 54% stable disease [111]. Becatecarin (XL119, rebeccamycin analog) is a novel anti-tumor antibiotic with both topoisomerase I and II activity, as well as DNA intercalating properties. In a phase I trial the presence of a second peak during the elimination phase as well as a high concentration of becatecarin in biliary fluid compared with the corresponding plasma measurement was suggestive of enterohepatic circulation [78]. Encouraging responses and prolonged stable disease were observed in patients
Extrahepatic Cholangiocarcinoma
with biliary cancers and prompted a phase II trial. Response rate was 7% (11% including unconfirmed responses) and tumor control rate 44%. Preliminary observations were suggestive of enhanced clinical benefit with near doubling of survival as compared to historical controls [79]. However, the phase III trial was terminated early after enrollment of the first 225 of up to 600 planned patients due to no clear indication of efficacy benefit in the investigational arm. In addition, differences regarding early deaths, survival, treatment duration, and the number of serious adverse events in favor of the comparator arm (5-FU) were noted. The multitargeted antifolate pemetrexed is a novel antifolate that inhibits at least three enzymes involved in folate metabolism and DNA synthesis. These enzymes are thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase. The implication of these enzyme targets in the cytotoxicity of pemetrexed is the inhibition of both pyrimidine and purine pathways and is supported by the fact that both thymidine and hypoxanthine are required to circumvent cellular death caused by pemetrexed. Four patients with biliary tract cancer have been enrolled in a phase I trial of pemetrexed plus gemcitabine. Objective response was observed in two patients with cholangiocarcinoma [4]. Recently phase II results of the NCCTG phase I/II trial (N9943) of gemcitabine and pemetrexed in patients with biliary tract cancer were presented at ASCO 2007 in Chicago. Median survival was 6.3 months and median time-to-progression was 3.8 months. In conclusion, results of this trial were similar to what would be expected with gemcitabine alone [246]. Davanat™ is a carbohydrate polysaccharide polymer composed of mannose and galactose. Its mechanism of action is based upon binding to lectins on the cell surface. It is theorized that davanat targets specific lectin receptors (galectins) that are over-expressed on cancer cells. Current research indicates that galectins affect cell development and play important roles in cancer, including tumor cell survival, angiogenesis and tumor metastasis. In pre-clinical studies co-administration of davanat with 5-FU increased efficacy and decreased toxicity compared to 5-FU alone. Two international phase II trials, both designed as first-line therapies in colorectal and biliary cancers, administering Davanat™ in combination with 5-FU are currently recruiting patients. Bendamustine is a bifunctional alkylating agent combining a purine antagonist with an alkylating nitrogen mustard group. Its antineoplastic and cytotoxic
1549
properties are attributable mainly to crosslinking of the DNA single and double strands by alkylation. This leads to a disturbance of the matrix function of DNA and to hampered DNA synthesis. Bendamustine has activity as single-agent therapy or in combination with other cytotoxic drugs in the treatment of plasmocytoma, chronic lymphocytic leukemia, non-Hodgkin’s lymphoma, and breast cancer. We performed a pilot study to evaluate the safety and tolerability of bendamustine in patients with advanced hilar bile duct cancer and impaired liver function [337]. Six patients with histologically proven, unresectable adenocarcinoma of the hilar bile duct were treated with bendamustine 140 mg/m2 intravenously on day 1 of the first cycle and with bendamustine 100 mg/m2 on days 1 and 2 of the second to fourth cycle. Treatment cycles were repeated every 21 days. Primary endpoint was the safety and tolerability of the treatment; secondary endpoints were response rate, time to progression and overall survival. Transient lymphopenia grade 3 occurred in all six patients. No other grade 3 or 4 toxicities were present. The most common nonhematologic toxicity was mouth dryness grade 2 in six patients. Three patients had stable disease. No partial or complete responses were observed. Median time to progression was 3.3 months; median overall survival was 6 months. Our study demonstrated that bendamustine can be safely administered in patients with hilar bile duct cancer and impaired liver function. A potential role of bendamustine in combination therapies for bile duct cancer will be a subject of further trials.
Molecular Targeted Therapy Receptor tyrosine kinases (TKs) have emerged as clinically useful drug target molecules for treating biliary tract cancer [416]. Imatinib mesilate (STI-571, Gleevec™), an inhibitor of c-kit receptor, which was primarily designed to treat chronic myeloid leukemia, exerts marked effects on tumor growth inhibition in vitro and in vivo [63, 177, 413]. The epidermal growth factor receptor (EGFR) family, which is involved in cell proliferation, metastasis and angiogenesis, is another important target [16, 253]. In 2006, Philip and colleagues published a manuscript describing a phase II study of EGFR-1 (ErbB-1, HER- 1) inhibitor erlotinib in patients with advanced
1550
biliary cancer [301]. The primary objective of this study was to determine the proportion of patients with advanced biliary cancer who were progression-free at 6 months. Patients with either unresectable or metastatic disease were studied. Only one prior systemic or locoregional therapy was allowed. Erlotinib was administered continuously at a dose of 150 mg per day orally. Fortytwo patients with advanced biliary cancers were enrolled and 57% of patients had received prior chemotherapy. EGFR-1 expression by immunohistochemistry in tumor cells was detected in 29 (81%) of the 36 assessable patients. Seven of the patients (17%) were progression free at 6 months. Three patients had partial response with a duration of 4, 4, and 14 months, respectively. All responding patients had mild (grade 1/2) skin rash and two patients had positive tumoral EGFR-1 expression. Three patients (7%) had toxicity-related dose reductions of erlotinib due to grade 2/3 skin rash. These results suggest a therapeutic benefit for EGFR blockade with erlotinib in patients with biliary cancer. In addition, the dual EGFR-1/EGFR-2 (ErbB-2, HER-2) inhibitor NVP-AEE788 demonstrated significant in vitro and in vivo effects on tumor growth inhibition [412]. In the same year, Safran et al presented a two-stage, phase I evaluation of GW572016 (lapatinib), an orally active small molecule that reversibly inhibits EGFR-1 and EGFR-2 tyrosine kinases at GI ASCO. Patients with advanced adenocarcinoma of the pancreas or bile ducts were treated with GW572016 and either weekly gemcitabine (1 g/m2/week, 3 weeks on, 1 week off) or GemOx (gemcitabine 1 g/m2 over 100 minutes and oxaliplatin 100 mg/m2, every 14 days). Cohort 1: weekly gemcitabine + GW572016, 1,000 mg/day. Cohort 2: weekly gemcitabine + GW572016, 1,500 mg/day. Cohort 3: GemOx + GW572016 1,000 mg/day. Cohort 4: GemOx + GW572016 1,500 mg/day. Twenty-five patients had been treated [pancreatic cancer (n = 18), biliary cancer (n = 7)]. One of 11 patients in cohort 2 had grade 3 diarrhea. Dose limiting grade 3 nausea occurred in 2 of 5 patients in cohort 4. Two patients had a temporary decrease in cardiac ejection fraction. Five of 22 evaluable patients (23%) responded and median survival (n = 24) was 10 months. It was concluded that GW572016 at 1,500 mg/day can be administered will full dosage gemcitabine. The MTD of GW572016 was 1,000 mg/ day with GemOx. Dramatic responses had been demonstrated in patients with diffuse liver and peritoneal metastases suggesting that EGFR-1/ EGFR-2 signaling may be important in pancreaticobiliary cancers. Further
116
Malignant Tumors
evaluation of GW572016 in pancreaticobiliary cancer was recommended. In contrast, Ramanathan et al did not detect any activity of GW572016 monotherapy (1,500 mg daily orally) in patients with biliary tract cancer, showing a median survival of 5.2 months [318]. The expression level of EGFR-1 and EGFR-2 may have important implications for the treatment of different types of biliary tract cancer with EGFR inhibitors. According to Thomas et al, biliary tract cancer expresses EGFR-1 and EGFR-2 receptors in only 8% and 30% and EGFR-2 gene amplification was only present in 22% [377]. Intrahepatic cholangiocarcinoma, which was the main tumor in the study by Ramanathan et al, had no EGFR-1 expression and EGFR-2 gene amplification at all [318]. In contrast, studies examining only extrahepatic cholangiocarcinoma detected EGFR-1 and EGFR-2 receptor expression in 32–43% and 65–84% [271, 412, 431]. A relatively new experimental approach may be the combination of different targeting strategies, such as EGFR-1 and MAPK inhibition or dual EGFR-1/ EGFR-2 and Hedgehog inhibition [170, 171]. In addition, in vitro EGFR-1 inhibition with ZD1839 (gefitinib, Iressa) enhances the effect of radiotherapy [253]. Phase II studies examining the combination of gemcitabine, oxaliplatin and angiogenesis inhibitor bevazicumab (GemOx-B) in unresectable or metastatic biliary tract cancer/gallbladder cancer are in progress, but as yet a final conclusion regarding the efficacy of this regime cannot be drawn. Other promising new drugs, currently under preclinical and clinical evaluation, are cyclooxygenase-2 (COX2) inhibitors, mammalian target of rapamycin (m-TOR) inhibitors, MAPK inhibitors, proteasome inhibitors, multikinase inhibitor sorafenib, histondeacetylase (HDAC) inhibitors, anti-interleukin-6 receptor antibodies, hepatocyte growth factor (HGF) antagonists, somatostatin analogues, peroxisome proliferator-activated receptor-γ (PPARγ) ligands, γ-aminobutyric acid (GABA), antisense oligonucleotides against aspartyl (asparaginyl) β-hydroxylase (AAH), adoptive immunotherapy against MUC-1-positive target tumor cells, interferon-γ, tumor necrosis factor-related apoptosisinducing ligand (TRAIL)/Apo2L ± triptolide as sensitizer, adenovirus vector expressing p27kip1, RGD-modified COX-2 promoter driven herpes simplex virus thymidine kinase (HSV-TK) adenoviral expression vectors, tauroursodeoxycholate, and tannic acid [18, 36, 87, 149, 170, 281, 393, 414].
Extrahepatic Cholangiocarcinoma
Recurrent Extrahepatic Cholangiocarcinoma The prognosis for any treated cancer patient with progressing, recurring, or relapsing extrahepatic bile duct cancer is poor. Deciding on further treatment depends on many factors, including prior treatment and site of recurrence, as well as individual patient considerations. Relief of recurrent jaundice will usually improve quality of life. Clinical trials are appropriate and should be considered when possible in patients with recurrent extrahepatic cholangiocarcinoma.
Management of Tumor Complications Malignant gastric outlet obstruction or duodenal obstruction is a complication of advanced hepatobiliary carcinomas with an incidence of about 25% [335]. It usually represents a terminal event, but also grossly impairs patients’ quality of life. Relief of obstruction to improve symptoms as well as to allow enteral feeding, thereby improving weight and possibly increasing life expectancy, is the primary aim in these patients. Surgical bypass is the standard treatment with a reported success rate up to 90%. The procedure, however, carries a high complication rate of 25–35% and a perioperative mortality of approximately 2% [226]. A procedure that prolongs hospital stay and increases costs dramatically may not always be appropriate, especially in terminally ill patients with a poor clinical condition. Previous endoscopic interventions like balloon dilatation or laser recanalization provide only transient success, resulting in high reocclusion rates. Based on the experiences in palliation of obstructive esophageal and biliary tract cancer, enteral SEMS have been also used for malignant gastric outlet and duodenal obstructions since the early 1990s. In contrast to surgical bypass surgery, endoscopic placement of duodenal SEMS is a minimally invasive procedure that may result in shorter hospitalization time and lower costs. However, some studies reported complications that may increase length of hospital stay, especially tumor ingrowth, tumor overgrowth and stent dislocation. In our own prospective study, comprising 20 patients with biliary-tract-cancer (7 gallbladder, 13 Klatskin tumors), successful stent placement was achieved in all patients [335]. An additional stent was required in six cases (4 occlusions, 2
1551
dislocations). Median survival was 20.5 weeks, no treatment related deaths occurred. Twenty-eight biliary stent exchanges were performed in 13/20 (65%) patients. Erosive reflux esophagitis improved in 11/12 (92%) cases. After 4 weeks, all 17 surviving patients tolerated soft-solid or solid food, while 13/17 (77%) tolerated a more solid diet (p < 0.001, gastric-outletobstruction-scoring-system). Twelve of 17 (71%) patients gained a median of 1.5 kg weight (p = 0.001). The median Karnofsky-Index increased from 50% to 60% in 13/17 (77%) patients. In conclusion, SEMS are a safe, efficacious and minimally invasive treatment option for palliation of duodenal obstruction in biliary tract cancer. Technical complications can be managed endoscopically and the bile duct remains accessible for endoluminal treatment.
Prognostic Indicators in Patients with Hilar Cholangiocarcinoma Two recent studies identified surgical resection, C-reactive protein (CRP) and bilirubin at time of diagnosis as important prognostic factors for survival in patients with hilar cholangiocarcinoma [119, 403]. In contrast, age, tumor stage according to BismuthCorlette classification, and types of intervention were not significant parameters for survival. In surgical patients with hilar cholangiocarcinoma, residual tumor classification and grading seem to be the most important prognostic factors. There are controversial data on the prognostic significance of involved lymph nodes. Out of 10 surgical studies, tumor stage (UICC or AJCC staging system) was not shown to be an independent prognostic parameter in eight series [139, 167, 192, 209, 268, 340, 417]. It proved to be of prognostic significance in two reports [205, 302]. Vascular tumor invasion in resected specimens, a main component of the pT category and UICC classification from 2002, did not prove to be a significant factor for survival in multivariate analysis in recent studies [168, 182, 192, 205, 209, 302]. In two series, vascular invasion influenced survival on the basis of univariate analysis, and in the investigation by Ebata et al macroscopic but not microscopic portal vein invasion proved to be an independent prognostic variable [85, 168, 302].
1552
Finally, microvessel density in tumors may be an important prognostic parameter for survival [255].
Malignant Tumors of the Ampulla of Vater Definition Periampullary carcinomas arise within 2 cm of the major duodenal papilla. Primary ampullary neoplasms can arise from epithelium of the common bile duct, the pancreatic duct, or the duodenal mucosa. The American Joint Committee on Cancer (AJCC) and UICC (Union Internationale Contre le Cancer) have designated staging by the TNM classification of 2002 (Table 116.4) [354].
Epidemiology Malignant primary tumors of the papilla of Vater are very rare with an incidence of approximately six cases per million. They account for only 6% of lesions that arise in the periampullary region. Since the 1980s, largely through increased use of endoscopy, malignant ampullary tumors are more frequently recognized. The average age at diagnosis of sporadic ampullary carcinoma is 60–70 years.
Etiology and Pathogenesis Strong evidence supports the adenoma-to-carcinoma sequence, which is similar to the progression in colon cancer [126]. Adenomas are considered precancerous and usually occur within the 5th or 6th decade (see Chapter 115). Patients with familial adenomatous polyposis (FAP), an autosomal dominant disease, are predisposed to duodenal adenomas, especially near the ampulla. There is a 100- to 200-fold increased risk of adenocarcinoma [296]. This is also true for patients with hereditary non-polyposis colorectal cancer (HNPCC).
116
Malignant Tumors
K-RAS mutations are an early event in ampullary carcinogenesis, with an incidence of 37%. High expression of COX-2 has been detected in 78% of ampullary carcinomas.
Pathology Ninety percent of ampullary malignancies are adenocarcinomas. Five percent of gastrointestinal malignancies are ampullary or periampullary adenocarcinomas. They may arise from villous adenomas or villoglandular polyps; there is usually a co-existing adenoma present.
Clinical Manifestations Ampullary tumors are relatively rare, but the occurrence of biliary obstruction early in the disease course facilitates diagnosis. Nonspecific symptoms, such as weight loss, vague abdominal pain, dyspepsia, malaise, fever, and anorexia have all been described. Ampullary tumors can cause heme-positive stools and may lead in some patients to iron-deficiency anemia.
Diagnosis With technological advances, methods of diagnosis, treatment, and management of ampullary tumors are constantly evolving. However, despite rapid improvements in these areas, preoperative differentiation between adenomas and adenocarcinomas remains difficult (Fig. 116.9a). Transabdominal ultrasound is usually the first-line imaging test performed when obstructive jaundice is suspected. CT and MRI are useful for determining metastatic disease, although these imaging modalities are poor for detecting small ampullary tumors. Endoscopic ultrasound (Fig. 116.9c) is the test of choice for local staging [46]. MRCP may take over the diagnostic role of ERCP. Nevertheless, the value of ERCP lies in its ability to visualize the ampulla directly, to rule out other causes of obstruction, to obtain tissue samples, and to decompress the biliary system (Fig. 116.9b). Forceps biopsy specimens can accurately
Malignant Tumors of the Ampulla of Vater
1553
c
a
b
*
**
Fig. 116.9 Patient with ampullary carcinoma. (a) Endoscopic view, (b) ERCP, depicting a dilated bile (single asterix) and pancreatic duct (double asterix), and (c) endoscopic ultrasound (EUS) staging (uT3uN+) (white arrows depict tumor, lymph node not shown)
detect the presence or absence of adenomatous changes, but they have a high false negative rate for adenocarcinoma, ranging from 25% to 60%. Therefore, some authors advocate a two-stage approach for lesions that appear to arise from within the ampulla. Sphincterotomy is initially performed during the first endoscopic procedure. A second procedure is done 7–10 days later to obtain forceps biopsy and cytology specimens. Further improvements with flow cytometry and immunocytochemistry may improve diagnostic capabilities in the future. Serum tumor markers are not specific for ampullary carcinomas and have limited diagnostic application.
Intraductal ultrasonography (IDUS) and magnification endoscopy with narrow-band imaging (NBI) may become useful supplemental diagnostic tools.
Differential Diagnosis Differential diagnoses include duodenal adenocarcinoma, leiomyosarcoma, gastrointestinal stromal tumor, lymphoma, pancreatic carcinoma and distal bile duct carcinoma invading the ampulla of Vater, intraductal
1554
papillary mucinous neoplasm (IPMN), ampullary hamartoma, gangliocytic paraganglioma, neuroendocrine tumors, ectopic pancreatic tissue, fibroadenoma, and Brunner’s gland hyperplasia (BGH).
Therapy and Prognosis An oncological resection of cancer of the ampulla by means of a pylorus-preserving partial pancreaticoduodenectomy or the Kausch-Whipple resection is the surgical procedure of choice. In a large study, the 3- and 5-year survival rates were 72% and 52%, respectively, in patients with R0 resections [22]. Two recent studies display even a better overall 5-year survival rate of 68% [42, 418]. In patients with low-risk cancer in stages pTis and pT1 N0 M0, G1 or G2, local resection with ampullectomy including local lymph node dissection is debated [307]. In these cases, annual or semiannual upper endoscopic follow-up surveillance is recommended for early detection or recurrence. With regard to other treatments, chemotherapy and radiation should only be used in the context of controlled trials. Poor prognostic factors are: high stage, tumor size 2.5 cm or more, perineural invasion, angiolymphatic invasion, invasion of muscle of sphincter of Oddi, nodal metastases, signet-ring histology, poor differentiation, and positive margins. Papillary histology is regarded a favorable prognostic factor.
References 1. Abid L, Oukkal M, Berkane S, et al (2003) Phase II trial with the gemcitabine and cisplatin combination in the treatment of locally advanced and metastatic gall bladder carcinoma. Proc ASCO (abstract 1302) 2. Abou-Alfa GK, Rowinsky EK, Patt YZ, et al (2005) A Phase II study of intravenous exatecan administered daily for 5 days, every 3 weeks to patients with biliary tract cancers. Am J Clin Oncol 28: 334–9 3. Adamek HE, Albert J, Weitz M, et al (1998) A prospective evaluation of magnetic resonance cholangiopancreatography in patients with suspected bile duct obstruction. Gut 43: 680–3 4. Adjei AA, Erlichman C, Sloan JA, et al (2000) Phase I and pharmacologic study of sequences of gemcitabine and the multitargeted antifolate agent in patients with advanced solid tumors. J Clin Oncol 18: 1748–57
116
Malignant Tumors
5. Ahrendt SA, Eisenberger CF, Yip L, et al (1999) Chromosome 9p21 loss and p16 inactivation in primary sclerosing cholangitis-associated cholangiocarcinoma. J Surg Res 84: 88–93 6. Ahrendt SA, Rashid A, Chow JT, et al (2000) p53 overexpression and K-ras gene mutations in primary sclerosing cholangitis-associated biliary tract cancer. J Hepatobiliary Pancreat Surg 7: 426–31 7. Ahrens W, Timmer A, Vyberg M, et al (2007) Risk factors for extrahepatic biliary tract carcinoma in men: medical conditions and lifestyle: results from a European multicentre case-control study. Eur J Gastroenterol Hepatol 19: 623–30 8. Akosa AB, Barker F, Desa L, et al (1995) Cytologic diagnosis in the management of gallbladder carcinoma. Acta Cytol 39: 494–8 9. Alberts SR, Al-Khatib H, Mahoney MR, et al (2005) Gemcitabine, 5-fluorouracil, and leucovorin in advanced biliary tract and gallbladder carcinoma: a North Central Cancer Treatment Group phase II trial. Cancer 103: 111–8 10. Alberts SR, Fishkin PA, Burgart LJ, et al (2002) CPT-11 for bile-duct and gallbladder carcinoma: a phase II North Central Cancer Treatment Group (NCCTG) study. Int J Gastrointest Cancer 32: 107–14 11. Alden ME, Mohiuddin M (1994) The impact of radiation dose in combined external beam and intraluminal Ir-192 brachytherapy for bile duct cancer. Int J Radiat Oncol Biol Phys 28: 945–51 12. Aldridge MC, Bismuth H (1990) Gallbladder cancer: the polyp-cancer sequence. Br J Surg 77: 363–4 13. Anderson CD, Rice MH, Pinson CW, et al (2004) Fluorodeoxyglucose PET imaging in the evaluation of gallbladder carcinoma and cholangiocarcinoma. J Gastrointest Surg 8: 90–7 14. Andre T, Tournigand C, Rosmorduc O, et al (2004) Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study. Ann Oncol 15: 1339–43 15. Angulo P, Pearce DH, Johnson CD, et al (2000) Magnetic resonance cholangiography in patients with biliary disease: its role in primary sclerosing cholangitis. J Hepatol 33: 520–7 16. Ariyama H, Qin B, Baba E, et al (2006) Gefitinib, a selective EGFR tyrosine kinase inhibitor, induces apoptosis through activation of Bax in human gallbladder adenocarcinoma cells. J Cell Biochem 97: 724–34 17. Arroyo G, Gallardo J, Rubio B, et al (2001) Gemcitabine in advanced biliary tract cancer. Experience from Chile and Argentina in phase II trials. Proc ASCO (abstract 626) 18. Baradari V, Hopfner M, Huether A, et al (2007) Histone deacetylase inhibitor MS-275 alone or combined with bortezomib or sorafenib exhibits strong antiproliferative action in human cholangiocarcinoma cells. World J Gastroenterol 13: 4458–66 19. Baron TH (2001) Expandable metal stents for the treatment of cancerous obstruction of the gastrointestinal tract. N Engl J Med 344: 1681–7 20. Baton O, Azoulay D, Adam DV, et al (2007) Major hepatectomy for hilar cholangiocarcinoma type 3 and 4: prognostic factors and longterm outcomes. J Am Coll Surg 204: 250–60 21. Bauditz J, Schade T, Wermke W (2007) [Sonographic diagnosis of hilar cholangiocarcinomas by the use of contrast agents.]. Ultraschall Med 28: 161–7
References 22. Beger HG, Treitschke F, Gansauge F, et al (1999) Tumor of the ampulla of Vater: experience with local or radical resection in 171 consecutively treated patients. Arch Surg 134: 526–32 23. Belghiti J, Clavien PA, Gadzijev E, et al (2000) The Brisbane 2000 Terminology of Liver Anatomy and Resections. HPB 2: 333–339 24. Benckert C, Jonas S, Cramer T, et al (2003) Transforming growth factor beta 1 stimulates vascular endothelial growth factor gene transcription in human cholangiocellular carcinoma cells. Cancer Res 63: 1083–92 25. Ben-Josef E, Normolle D, Ensminger WD, et al (2005) Phase II trial of high-dose conformal radiation therapy with concurrent hepatic artery floxuridine for unresectable intrahepatic malignancies. J Clin Oncol 23: 8739–47 26. Ben-Menachem T (2007) Risk factors for cholangiocarcinoma. Eur J Gastroenterol Hepatol 19: 615–7 27. Bergquist A, Glaumann H, Persson B, et al (1998) Risk factors and clinical presentation of hepatobiliary carcinoma in patients with primary sclerosing cholangitis: a case-control study. Hepatology 27: 311–6 28. Bergquist A, Glaumann H, Stal P, et al (2001) Biliary dysplasia, cell proliferation and nuclear DNA-fragmentation in primary sclerosing cholangitis with and without cholangiocarcinoma. J Intern Med 249: 69–75 29. Berr F, Tannapfel A, Lamesch P, et al (2000a) Neoadjuvant photodynamic therapy before curative resection of proximal bile duct carcinoma. J Hepatol 32: 352–7 30. Berr F, Wiedmann M, Tannapfel A, et al (2000b) Photodynamic therapy for advanced bile duct cancer: evidence for improved palliation and extended survival. Hepatology 31: 291–8 31. Bettschart V, Clayton RA, Parks RW, et al (2002) Cholangiocarcinoma arising after biliary-enteric drainage procedures for benign disease. Gut 51: 128–9 32. Birkmeyer JD, Siewers AE, Finlayson EV, et al (2002) Hospital volume and surgical mortality in the United States. N Engl J Med 346: 1128–37 33. Birkmeyer JD, Stukel TA, Siewers AE, et al (2003) Surgeon volume and operative mortality in the United States. N Engl J Med 349: 2117–27 34. Bismuth H, Corlette MB (1975) Intrahepatic cholangioenteric anastomosis in carcinoma of the hilus of the liver. Surg Gynecol Obstet 140: 170–8 35. Bismuth H, Nakache R, Diamond T (1992) Management strategies in resection for hilar cholangiocarcinoma. Ann Surg 215: 31–8 36. Bluethner T, Niederhagen M, Caca K, et al (2007) Inhibition of histone deacetylase for the treatment of biliary tract cancer: A new effective pharmacological approach. World J Gastroenterol 13: 4761–70 37. Bowling TE, Galbraith SM, Hatfield AR, et al (1996) A retrospective comparison of endoscopic stenting alone with stenting and radiotherapy in non-resectable cholangiocarcinoma. Gut 39: 852–5 38. Broden G, Bengtsson L (1980) Biliary carcinoma associated with methyldopa therapy. Acta Chir Scand Suppl 500: 7–12 39. Broome U, Olsson R, Loof L, et al (1996) Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis. Gut 38: 610–5 40. Brugge WR (2005) Endoscopic techniques to diagnose and manage biliary tumors. J Clin Oncol 23: 4561–5
1555 41. Bruha R, Petrtyl J, Kubecova M, et al (2001) Intraluminal brachytherapy and selfexpandable stents in nonresectable biliary malignancies – the question of long-term palliation. Hepatogastroenterology 48: 631–7 42. Bucher P, Chassot G, Durmishi Y, et al (2007) Long-term results of surgical treatment of Vater’s ampulla neoplasms. Hepatogastroenterology 54: 1239–42 43. Burmester E, Niehaus J, Leineweber T, et al (2003) EUScholangio-drainage of the bile duct: report of 4 cases. Gastrointest Endosc 57: 246–51 44. Burris HA 3rd, Moore MJ, Andersen J, et al (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15: 2403–13 45. Caca K, Feisthammel J, Klee K, et al (2002) Inactivation of the INK4a/ARF locus and p53 in sporadic extrahepatic bile duct cancers and bile tract cancer cell lines. Int J Cancer 97: 481–8 46. Cannon ME, Carpenter SL, Elta GH, et al (1999) EUS compared with CT, magnetic resonance imaging, and angiography and the influence of biliary stenting on staging accuracy of ampullary neoplasms. Gastrointest Endosc 50: 27–33 47. Caplin M, Khan K, Savage K, et al (1999) Expression and processing of gastrin in hepatocellular carcinoma, fibrolamellar carcinoma and cholangiocarcinoma. J Hepatol 30: 519–26 48. Capussotti L, Muratore A, Polastri R, et al (2002) Liver resection for hilar cholangiocarcinoma: in-hospital mortality and longterm survival. J Am Coll Surg 195: 641–7 49. Carriaga MT, Henson DE (1995) Liver, gallbladder, extrahepatic bile ducts, and pancreas. Cancer 75: 171–90 50. Castro MP (1998) Efficacy of gemcitabine in the treatment of patients with gallbladder carcinoma: a case report. Cancer 82: 639–41 51. Chalasani N, Baluyut A, Ismail A, et al (2000) Cholangiocarcinoma in patients with primary sclerosing cholangitis: a multicenter case-control study. Hepatology 31: 7–11 52. Chang H, Ryu M, Lee J, et al (2005) Phase II trial of gemcitabine plus capecitabine in patients with advanced biliary tract cancer. J Clin Oncol (ASCO 2005) 23: (abstract 4173) 53. Chapman RW (1999) Risk factors for biliary tract carcinogenesis. Ann Oncol 10 Suppl 4: 308–11 54. Chariyalertsak S, Sirikulchayanonta V, Mayer D, et al (2001) Aberrant cyclooxygenase isozyme expression in human intrahepatic cholangiocarcinoma. Gut 48: 80–6 55. Charoentum C, Thongprasert S, Chewaskulyong B, et al (2007) Experience with gemcitabine and cisplatin in the therapy of inoperable and metastatic cholangiocarcinoma. World J Gastroenterol 13: 2852–4 56. Chaudhary A, Dhar P, Tomey S, et al (1997) Segment III cholangiojejunostomy for carcinoma of the gallbladder. World J Surg 21: 866–70; discussion 870–1 57. Chen JS, Jan YY, Lin YC, et al (1998) Weekly 24 h infusion of high-dose 5-fluorouracil and leucovorin in patients with biliary tract carcinomas. Anticancer Drugs 9: 393–7 58. Chen JS, Yang TS, Lin YC, et al (2003) A phase II trial of tegafur-uracil plus leucovorin (LV) in the treatment of advanced biliary tract carcinomas. Jpn J Clin Oncol 33: 353–6 59. Chen Y, Wang XL, Yan ZP, et al (2004) HDR-192Ir intraluminal brachytherapy in treatment of malignant obstructive jaundice. World J Gastroenterol 10: 3506–10
1556 60. Cheon YK, Cho YD, Moon JH, et al (2007) Diagnostic utility of interleukin-6 (IL-6) for primary bile duct cancer and changes in serum IL-6 levels following photodynamic therapy. Am J Gastroenterol 102: 2164–70 61. Cherqui D, Benoist S, Malassagne B, et al (2000) Major liver resection for carcinoma in jaundiced patients without preoperative biliary drainage. Arch Surg 135: 302–8 62. Chijiiwa K, Koga A (1993) Surgical management and longterm follow-up of patients with choledochal cysts. Am J Surg 165: 238–42 63. Chiorean MV, Guicciardi ME, Yoon JH, et al (2004) Imatinib mesylate induces apoptosis in human cholangiocarcinoma cells. Liver Int 24: 687–95 64. Cho JY, Paik YH, Chang YS, et al (2005) Capecitabine combined with gemcitabine (CapGem) as first-line treatment in patients with advanced/metastatic biliary tract carcinoma. Cancer 104: 2753–8 65. Choi CW, Choi IK, Seo JH, et al (2000) Effects of 5-fluorouracil and leucovorin in the treatment of pancreatic-biliary tract adenocarcinomas. Am J Clin Oncol 23: 425–8 66. Chow NH, Huang SM, Chan SH, et al (1995) Significance of c-erbB-2 expression in normal and neoplastic epithelium of biliary tract. Anticancer Res 15: 1055–9 67. Chow WH, Johansen C, Gridley G, et al (1999) Gallstones, cholecystectomy and risk of cancers of the liver, biliary tract and pancreas. Br J Cancer 79: 640–4 68. Cunningham D, Chau I, Stocken D, et al (2005) Phase III randomised comparison of gemcitabine (GEM) versus gemcitabine plus capecitabine (GEM-CAP) in patients with advanced pancreatic cancer. Eur J Cancer Suppl 3: 4 69. de Groen PC, Gores GJ, LaRusso NF, et al (1999) Biliary tract cancers. N Engl J Med 341: 1368–78 70. De Palma GD, Galloro G, Siciliano S, et al (2001) Unilateral versus bilateral endoscopic hepatic duct drainage in patients with malignant hilar biliary obstruction: results of a prospective, randomized, and controlled study. Gastrointest Endosc 53: 547–53 71. Della Torre G, Pasquini G, Pilotti S, et al (2000) TP53 mutations and mdm2 protein overexpression in cholangiocarcinomas. Diagn Mol Pathol 9: 41–6 72. Deodato F, Clemente G, Mattiucci GC, et al (2006) Chemoradiation and brachytherapy in biliary tract carcinoma: long-term results. Int J Radiat Oncol Biol Phys 64: 483–8 73. Deviere J, Baize M, de Toeuf J, et al (1988) Long-term follow-up of patients with hilar malignant stricture treated by endoscopic internal biliary drainage. Gastrointest Endosc 34: 95–101 74. Doctor N, Dick R, Rai R, et al (1999) Results of percutaneous plastic stents for malignant distal biliary obstruction following failed endoscopic stent insertion and comparison with current literature on expandable metallic stents. Eur J Gastroenterol Hepatol 11: 775–80 75. Donato F, Gelatti U, Tagger A, et al (2001) Intrahepatic cholangiocarcinoma and hepatitis C and B virus infection, alcohol intake, and hepatolithiasis: a case-control study in Italy. Cancer Causes Control 12: 959–64 76. Dougherty TJ, Gomer CJ, Henderson BW, et al (1998) Photodynamic therapy. J Natl Cancer Inst 90: 889–905 77. Doval DC, Sekhon JS, Gupta SK, et al (2004) A phase II study of gemcitabine and cisplatin in chemotherapy-naive, unresectable gall bladder cancer. Br J Cancer 90: 1516–20
116
Malignant Tumors
78. Dowlati A, Hoppel CL, Ingalls ST, et al (2001) Phase I clinical and pharmacokinetic study of rebeccamycin analog NSC 655649 given daily for five consecutive days. J Clin Oncol 19: 2309–18 79. Dowlati A, Posey J, Ramanathan RK, et al (2003) Multicenter phase II and pharmacokinetic study of rebeccamycin analogue (RA) in advanced biliary cancers. Proc Am Soc Clin Oncol 22: (abstract 1070) 80. Ducreux M, Liguory C, Lefebvre JF, et al (1992) Management of malignant hilar biliary obstruction by endoscopy. Results and prognostic factors. Dig Dis Sci 37: 778–83 81. Ducreux M, Rougier P, Fandi A, et al (1998) Effective treatment of advanced biliary tract carcinoma using 5-fluorouracil continuous infusion with cisplatin. Ann Oncol 9: 653–6 82. Ducreux M, Van Cutsem E, Van Laethem JL, et al (2005) A randomised phase II trial of weekly high-dose 5-fluorouracil with and without folinic acid and cisplatin in patients with advanced biliary tract carcinoma: results of the 40955 EORTC trial. Eur J Cancer 41: 398–403 83. Dumoulin FL, Gerhardt T, Fuchs S, et al (2003) Phase II study of photodynamic therapy and metal stent as palliative treatment for nonresectable hilar cholangiocarcinoma. Gastrointest Endosc 57: 860–7 84. Dvorak J, Jandik P, Melichar B, et al (2002) Intraluminal high dose rate brachytherapy in the treatment of bile duct and gallbladder carcinomas. Hepatogastroenterology 49: 916–7 85. Ebata T, Nagino M, Kamiya J, et al (2003) Hepatectomy with portal vein resection for hilar cholangiocarcinoma: audit of 52 consecutive cases. Ann Surg 238: 720–7 86. Eckel F, Schmid RM (2007) Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials. Br J Cancer 96: 896–902 87. El-Khoueiry AB, Rankin C, Lenz HJ, et al (2007) SWOG 0514: A phase II study of sorafenib (BAY 43–9006) as single agent in patients (pts) with unresectable or metastatic gallbladder cancer or cholangiocarcinomas. J Clin Oncol, 2007 ASCO Annual Meeting Proceedings Part I Vol 25, No. 18S (June 20 Supplement):(abstract 4639) 88. Ellis EF, Gordon PR, Gottlieb LS (1978) Oral contraceptives and cholangiocarcinoma. Lancet 1: 207 89. Ellis PA, Norman A, Hill A, et al (1995) Epirubicin, cisplatin and infusional 5-fluorouracil (5-FU) (ECF) in hepatobiliary tumours. Eur J Cancer 31A: 1594–8 90. Endo K, Ashida K, Miyake N, et al (2001) E-cadherin gene mutations in human intrahepatic cholangiocarcinoma. J Pathol 193: 310–7 91. Eng C, Ramathan RK, Wong MK, et al (2004) A Phase II trial of fixed dose rate gemcitabine in patients with advanced biliary tree carcinoma. Am J Clin Oncol 27: 565–9 92. Eschelman DJ, Shapiro MJ, Bonn J, et al (1996) Malignant biliary duct obstruction: long-term experience with Gianturco stents and combined-modality radiation therapy. Radiology 200: 717–24 93. Falkson G, MacIntyre JM, Moertel CG (1984) Eastern Cooperative Oncology Group experience with chemotherapy for inoperable gallbladder and bile duct cancer. Cancer 54: 965–9 94. Farley DR, Weaver AL, Nagorney DM (1995) “Natural history” of unresected cholangiocarcinoma: patient outcome after noncurative intervention. Mayo Clin Proc 70: 425–9
References 95. Feisthammel J, Schoppmeyer K, Mössner J, et al (2007) Irinotecan with 5-FU/FA in advanced biliary tract adenocarcinomas: a multicenter phase II trial. Am J Clin Oncol 30: 319–24 96. Feldmann G, Nattermann J, Nischalke HD, et al (2006) Detection of human aspartyl (asparaginyl) beta-hydroxylase and homeobox B7 mRNA in brush cytology specimens from patients with bile duct cancer. Endoscopy 38: 604–9 97. Fiorentino M, D’Errico A, Altimari A, et al (1999) High levels of BCL-2 messenger RNA detected by in situ hybridization in human hepatocellular and cholangiocellular carcinomas. Diagn Mol Pathol 8: 189–94 98. Fleming ID, Cooper JS, Henson DE, et al (1997) AJCC cancer staging manual, 5th ed. Lippincott-Raven, Philadelphia, PA 99. Fletcher MS, Brinkley D, Dawson JL, et al (1983) Treatment of hilar carcinoma by bile drainage combined with internal radiotherapy using 192iridium wire. Br J Surg 70: 733–5 100. Fong Y, Blumgart LH, Lin E, et al (1996) Outcome of treatment for distal bile duct cancer. Br J Surg 83: 1712–5 101. Foo ML, Gunderson LL, Bender CE, et al (1997) External radiation therapy and transcatheter iridium in the treatment of extrahepatic bile duct carcinoma. Int J Radiat Oncol Biol Phys 39: 929–35 102. Freeman ML, Overby C (2003) Selective MRCP and CT-targeted drainage of malignant hilar biliary obstruction with self-expanding metallic stents. Gastrointest Endosc 58: 41–9 103. Fritscher-Ravens A, Bohuslavizki KH, Broering DC, et al (2001) FDG PET in the diagnosis of hilar cholangiocarcinoma. Nucl Med Commun 22: 1277–85 104. Fritscher-Ravens A, Broering DC, Knoefel WT, et al (2004) EUS-guided fine-needle aspiration of suspected hilar cholangiocarcinoma in potentially operable patients with negative brush cytology. Am J Gastroenterol 99: 45–51 105. Fritz P, Brambs HJ, Schraube P, et al (1994) Combined external beam radiotherapy and intraluminal high dose rate brachytherapy on bile duct carcinomas. Int J Radiat Oncol Biol Phys 29: 855–61 106. Fujita N, Noda Y, Kobayashi G, et al (1999) Diagnosis of the depth of invasion of gallbladder carcinoma by EUS. Gastrointest Endosc 50: 659–63 107. Fujita N, Noda Y, Kobayashi G, et al (1998) Staging of bile duct carcinoma by EUS and IDUS. Endoscopy 30(Suppl 1): A132–4 108. Fulcher AS and Turner MA (2002) MR cholangiopancreatography. Radiol Clin North Am 40: 1363–76 109. Furubo S, Harada K, Shimonishi T, et al (1999) Protein expression and genetic alterations of p53 and ras in intrahepatic cholangiocarcinoma. Histopathology 35: 230–40 110. Furukawa H, Kosuge T, Shimada K, et al (1998) Small polypoid lesions of the gallbladder: differential diagnosis and surgical indications by helical computed tomography. Arch Surg 133: 735–9 111. Furuse J, Okusaka T, Funakoshi A, et al (2006) Early phase II study of uracil-tegafur plus doxorubicin in patients with unresectable advanced biliary tract cancer. Jpn J Clin Oncol 36: 552–6 112. Gallardo JO, Rubio B, Fodor M, et al (2001) A phase II study of gemcitabine in gallbladder carcinoma. Ann Oncol 12: 1403–6
1557 113. Gebbia N, Verderame F, Di Leo R, et al (2005) A phase II study of Oxaliplatin (O) and Gemcitabine (G) first line chemotherapy in patients with advanced biliary tract cancers. Proc ASCO 2005 23:(abstract 4132) 114. Gebbia V, Giuliani F, Maiello E, et al (2001) Treatment of inoperable and/or metastatic biliary tree carcinomas with single-agent gemcitabine or in combination with levofolinic acid and infusional fluorouracil: results of a multicenter phase II study. J Clin Oncol 19: 4089–91 115. Gelibter A, Malaguti P, Di Cosimo S, et al (2005) Fixed dose-rate gemcitabine infusion as first-line treatment for advanced-stage carcinoma of the pancreas and biliary tree. Cancer 104: 1237–45 116. Gerhards MF, van Gulik TM, de Wit LT, et al (2000) Evaluation of morbidity and mortality after resection for hilar cholangiocarcinoma – a single center experience. Surgery 127: 395–404 117. Gerhards MF, van Gulik TM, Gonzalez Gonzalez D, et al (2003) Results of postoperative radiotherapy for resectable hilar cholangiocarcinoma. World J Surg 27: 173–9 118. Gerhards MF, Vos P, van Gulik TM, et al (2001) Incidence of benign lesions in patients resected for suspicious hilar obstruction. Br J Surg 88: 48–51 119. Gerhardt T, Milz S, Schepke M, et al (2006) C-reactive protein is a prognostic indicator in patients with perihilar cholangiocarcinoma. World J Gastroenterol 12: 5495–500 120. Giuliani F, Gebbia V, Maiello E, et al (2006) Gemcitabine and cisplatin for inoperable and/or metastatic biliary tree carcinomas: a multicenter phase II study of the Gruppo Oncologico dell’Italia Meridionale (GOIM). Ann Oncol 17(Suppl 7): vii73–vii77 121. Glimelius B, Hoffman K, Sjoden PO, et al (1996) Chemotherapy improves survival and quality of life in ad vanced pancreatic and biliary cancer. Ann Oncol 7: 593–600 122. Glover KY, Thomas MB, Brown TD, et al (2005) A Phase II Study of Oxaliplatin and Capecitabine (XELOX) in Patients with Unresectable Cholangiocarcinoma, including Carcinoma of the Gallbladder and Biliary Tract. J Clin Oncol (ASCO 2005) 23: (abstract 4123) 123. Golematis B, Giannopoulos A, Papchristou DN, et al (1981) Sclerosing cholangitis of the bifurcation of the common hepatic duct. Am J Gastroenterol 75: 370–2 124. Gonzalez Gonzalez D, Gouma DJ, Rauws EA, et al (1999) Role of radiotherapy, in particular intraluminal brachytherapy, in the treatment of proximal bile duct carcinoma. Ann Oncol 10 Suppl 4: 215–20 125. Gores GJ (2003) Cholangiocarcinoma: current concepts and insights. Hepatology 37: 961–9 126. Gouma DJ, Obertop H, Vismans J, et al (1987) Progression of a benign epithelial ampullary tumor to adenocarcinoma. Surgery 101: 501–4 127. Hadjis NS, Blenkharn JI, Alexander N, et al (1990) Outcome of radical surgery in hilar cholangiocarcinoma. Surgery 107: 597–604 128. Halm U, Schiefke I, Fleig WE, et al (2001) Ofloxacin and ursodeoxycholic acid versus ursodeoxycholic acid alone to prevent occlusion of biliary stents: a prospective, randomized trial. Endoscopy 33: 491–4 129. Han C, Demetris AJ, Wu T (2004) Cyclooxygenase-2 and prostaglandin E2 promote cholangiocarcinoma cell growth and invasion through EP1 receptor-mediated activation of
1558
130. 131.
132.
133.
134.
135.
136.
137.
138.
139.
140. 141.
142.
143.
144.
145.
146.
147.
116 epidermal growth factor receptor and AKT. Hepatology 40: 301A (abstract 318) Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100: 57–70 Hann LE, Schwartz LH, Panicek DM, et al (1998) Tumor involvement in hepatic veins: comparison of MR imaging and US for preoperative assessment. Radiology 206: 651–6 Harada K, Zen Y, Kanemori Y, et al (2001) Human REG I gene is up-regulated in intrahepatic cholangiocarcinoma and its precursor lesions. Hepatology 33: 1036–42 Harder J, Riecken B, Kummer O, et al (2006) Outpatient chemotherapy with gemcitabine and oxaliplatin in patients with biliary tract cancer. Br J Cancer 95: 848–52 Harewood GC, Baron TH, Rumalla A, et al (2005) Pilot study to assess patient outcomes following endoscopic application of photodynamic therapy for advanced cholangiocarcinoma. J Gastroenterol Hepatol 20: 415–20 Harnois DM, Que FG, Celli A, et al (1997) Bcl-2 is overexpressed and alters the threshold for apoptosis in a cholangiocarcinoma cell line. Hepatology 26: 884–90 Harvey JH, Smith FP, Schein PS (1984) 5-Fluorouracil, mitomycin, and doxorubicin (FAM) in carcinoma of the biliary tract. J Clin Oncol 2: 1245–8 Heinrich PC, Behrmann I, Haan S, et al (2003) Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 374: 1–20 Hejna M, Pruckmayer M, Raderer M (1998) The role of chemotherapy and radiation in the management of biliary cancer: a review of the literature. Eur J Cancer 34: 977–86 Hemming AW, Reed AI, Fujita S, et al (2005) Surgical management of hilar cholangiocarcinoma. Ann Surg 241: 693–9; discussion 699–702 Henderson BW, Dougherty TJ (1992) How does photodynamic therapy work? Photochem Photobiol 55: 145–57 Henson DE, Albores-Saavedra J, Corle D (1992) Carcinoma of the extrahepatic bile ducts. Histologic types, stage of disease, grade, and survival rates. Cancer 70: 1498–501 Hintze RE, Abou-Rebyeh H, Adler A, et al (2001) Magnetic resonance cholangiopancreatography-guided unilateral endoscopic stent placement for Klatskin tumors. Gastrointest Endosc 53: 40–6 Hoang MP, Murakata LA, Padilla-Rodriguez AL, et al (2001) Metaplastic lesions of the extrahepatic bile ducts: a morphologic and immunohistochemical study. Mod Pathol 14: 1119–25 Hochwald SN, Burke EC, Jarnagin WR, et al (1999) Association of preoperative biliary stenting with increased postoperative infectious complications in proximal cholangiocarcinoma. Arch Surg 134: 261–6 Hong YS, Lee J, Lee SC, et al (2007) Phase II study of capecitabine and cisplatin in previously untreated advanced biliary tract cancer. Cancer Chemother Pharmacol 60: 321–8 Horie S, Endo K, Kawasaki H, et al (2000) Overexpression of MDM2 protein in intrahepatic cholangiocarcinoma: relationship with p53 overexpression, Ki-67 labeling, and clinicopathological features. Virchows Arch 437: 25–30 Houry S, Haccart V, Huguier M, et al (1999) Gallbladder cancer: role of radiation therapy. Hepatogastroenterology 46: 1578–84
Malignant Tumors
148. Hsu C, Shen YC, Yang CH, et al (2004) Weekly gemcitabine plus 24-h infusion of high-dose 5-fluorouracil/leucovorin for locally advanced or metastatic carcinoma of the biliary tract. Br J Cancer 90: 1715–9 149. Huether A, Hopfner M, Baradari V, et al (2007) Sorafenib alone or as combination therapy for growth control of cholangiocarcinoma. Biochem Pharmacol 73: 1308–17 150. Hultcrantz R, Olsson R, Danielsson A, et al (1999) A 3-year prospective study on serum tumor markers used for detecting cholangiocarcinoma in patients with primary sclerosing cholangitis. J Hepatol 30: 669–73 151. Ijitsma A, Appeltans BM, de Jong KP, et al (2004) Extrahepatic bile duct resection in combination with liver resection for hilar cholangiocarcinoma: a report of 42 cases. J Gastrointest Surg 8: 686–94 152. Ikeda M, Okusaka T, Ueno H, et al (2005) A phase II trial of Uracil-tegafur (UFT) in patients with advanced biliary tract carcinoma. Jpn J Clin Oncol 35: 439–43 153. Ince N, de la Monte SM, Wands JR (2000) Overexpression of human aspartyl (asparaginyl) beta-hydroxylase is associated with malignant transformation. Cancer Res 60: 1261–6 154. Iqbal S, McCoy H, Lenz H (2006) SWOG S0202: A phase II trial of gemcitabine and capecitabine in patients (pts) with unresectable or metastatic gallbladder cancer or cholangiocarcinoma. J Clin Oncol, 2006 ASCO Annual Meeting Proceedings Part I Vol 24, No. 18S (June 20 Supplement):(abstract 4134) 155. Isayama H, Komatsu Y, Tsujino T, et al (2004) A prospective randomised study of “covered” versus “uncovered” diamond stents for the management of distal malignant biliary obstruction. Gut 53: 729–34 156. Ishii H, Furuse J, Nagase M, et al (2004) Relief of jaundice by external beam radiotherapy and intraluminal brachytherapy in patients with extrahepatic cholangiocarcinoma: results without stenting. Hepatogastroenterology 51: 954–7 157. Isomoto H, Kobayashi S, Werneburg NW, et al (2005) Interleukin 6 upregulates myeloid cell leukemia-1 expression through a STAT3 pathway in cholangiocarcinoma cells. Hepatology 42: 1329–38 158. Isomoto H, Mott JL, Kobayashi S, et al (2007) Sustained IL-6/STAT-3 signaling in cholangiocarcinoma cells due to SOCS-3 epigenetic silencing. Gastroenterology 132: 384–96 159. Ito Y, Miyoshi E, Takeda T, et al (2000) ets-1 expression in extrahepatic bile duct carcinoma and cholangiocellular carcinoma. Oncology 58: 248–52 160. Ito Y, Takeda T, Sasaki Y, et al (2000) Bcl-2 expression in cholangiocellular carcinoma is inversely correlated with biologically aggressive phenotypes. Oncology 59: 63–7 161. Itoi T, Shinohara Y, Takeda K, et al (2000) Detection of telomerase activity in biopsy specimens for diagnosis of biliary tract cancers. Gastrointest Endosc 52: 380–6 162. Iwatsuki S, Todo S, Marsh JW, et al (1998) Treatment of hilar cholangiocarcinoma (Klatskin tumors) with hepatic resection or transplantation. J Am Coll Surg 187: 358–64 163. Iyer RV, Gibbs J, Kuvshinoff B, et al (2007) A Phase II Study of Gemcitabine and Capecitabine in Advanced Cholangiocarcinoma and Carcinoma of the Gallbladder: A Single-Institution Prospective Study. Ann Surg Oncol 14(11): 3202–09 164. Jaiswal M, LaRusso NF, Burgart LJ, et al (2000) Inflammatory cytokines induce DNA damage and inhibit
References
165.
166.
167.
168.
169. 170.
171.
172.
173.
174.
175.
176.
177.
178.
179.
180.
181.
DNA repair in cholangiocarcinoma cells by a nitric oxidedependent mechanism. Cancer Res 60: 184–90 Jaiswal M, LaRusso NF, Gores GJ (2001) Nitric oxide in gastrointestinal epithelial cell carcinogenesis: linking inflammation to oncogenesis. Am J Physiol Gastrointest Liver Physiol 281: G626–34 Jang JY, Kim SW, Park do J, et al (2005) Actual long-term outcome of extrahepatic bile duct cancer after surgical resection. Ann Surg 241: 77–84 Jarnagin WR, Bowne W, Klimstra DS, et al (2005) Papillary phenotype confers improved survival after resection of hilar cholangiocarcinoma. Ann Surg 241: 703–12; discussion 712–4 Jarnagin WR, Fong Y, DeMatteo RP, et al (2001) Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg 234: 507–17; discussion 517–9 Jarnagin WR, Shoup M (2004) Surgical management of cholangiocarcinoma. Semin Liver Dis 24: 189–99 Jimeno A, Rubio-Viqueira B, Amador ML, et al (2007) Dual mitogen-activated protein kinase and epidermal growth factor receptor inhibition in biliary and pancreatic cancer. Mol Cancer Ther 6: 1079–88 Jinawath A, Akiyama Y, Sripa B, et al (2007) Dual blockade of the Hedgehog and ERK1/2 pathways coordinately decreases proliferation and survival of cholangiocarcinoma cells. J Cancer Res Clin Oncol 133: 271–8 Jonas S, Mittler J, Pascher A, et al (2005) Extended indications in living-donor liver transplantation: bile duct cancer. Transplantation 80: S101–4 Julka PK, Puri T, Rath GK (2006) A phase II study of gemcitabine and carboplatin combination chemotherapy in gallbladder carcinoma. Hepatobiliary Pancreat Dis Int 5: 110–4 Kaassis M, Boyer J, Dumas R, et al (2003) Plastic or metal stents for malignant stricture of the common bile duct? Results of a randomized prospective study. Gastrointest Endosc 57: 178–82 Kadakia SC, Starnes E (1992) Comparison of 10 French gauge stent with 11.5 French gauge stent in patients with biliary tract diseases. Gastrointest Endosc 38: 454–9 Kamada T, Saitou H, Takamura A, et al (1996) The role of radiotherapy in the management of extrahepatic bile duct cancer: an analysis of 145 consecutive patients treated with intraluminal and/or external beam radiotherapy. Int J Radiat Oncol Biol Phys 34: 767–74 Kamenz T, Caca K, Bluthner T, et al (2006) Expression of c-kit receptor in human cholangiocarcinoma and in vivo treatment with imatinib mesilate in chimeric mice. World J Gastroenterol 12: 1583–90 Kamisawa T, Tu Y, Egawa N, et al (2005) Thermo-chemoradiotherapy for advanced bile duct carcinoma. World J Gastroenterol 11: 4206–9 Kang YK, Kim WH, Lee HW, et al (1999) Mutation of p53 and K-ras, and loss of heterozygosity of APC in intrahepatic cholangiocarcinoma. Lab Invest 79: 477–83 Kapoor VK, Pradeep R, Haribhakti SP, et al (1996) Intrahepatic segment III cholangiojejunostomy in advanced carcinoma of the gallbladder. Br J Surg 83: 1709–11 Kawahara N, Ono M, Taguchi K, et al (1998) Enhanced expression of thrombospondin-1 and hypovascularity in human cholangiocarcinoma. Hepatology 28: 1512–7
1559 182. Kawasaki S, Imamura H, Kobayashi A, et al (2003) Results of surgical resection for patients with hilar bile duct cancer: application of extended hepatectomy after biliary drainage and hemihepatic portal vein embolization. Ann Surg 238: 84–92 183. Keiding S, Hansen SB, Rasmussen HH, et al (1998) Detection of cholangiocarcinoma in primary sclerosing cholangitis by positron emission tomography. Hepatology 28: 700–6 184. Kelley ST, Bloomston M, Serafini F, et al (2004) Cholangiocarcinoma: advocate an aggressive operative approach with adjuvant chemotherapy. Am Surg 70: 743– 8; discussion 748–9 185. Khan SA, Davidson BR, Goldin R, et al (2002) Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut 51(Suppl 6):VI1–9 186. Khan SA, Taylor-Robinson SD, Toledano MB, et al (2002) Changing international trends in mortality rates for liver, biliary and pancreatic tumours. J Hepatol 37: 806–13 187. Kim EK, Lee SK, Kim WW (2002) Does laparoscopic surgery have a role in the treatment of gallbladder cancer? J Hepatobiliary Pancreat Surg 9: 559–63 188. Kim ST, Park JO, Lee J, et al (2006) A Phase II study of gemcitabine and cisplatin in advanced biliary tract cancer. Cancer 106: 1339–46 189. Kim TW, Chang HM, Kang HJ, et al (2003) Phase II study of capecitabine plus cisplatin as first-line chemotherapy in advanced biliary cancer. Ann Oncol 14: 1115–20 190. Kitagawa Y, Nagino M, Kamiya J, et al (2001) Lymph node metastasis from hilar cholangiocarcinoma: audit of 110 patients who underwent regional and paraaortic node dissection. Ann Surg 233: 385–92 191. Klebl F, Endlicher E, Kullmann F (2006) [Palliative therapy in cholangio- and gallbladder carcinoma]. Z Gastroenterol 44: 587–98 192. Klempnauer J, Ridder GJ, von Wasielewski R, et al (1997) Resectional surgery of hilar cholangiocarcinoma: a multivariate analysis of prognostic factors. J Clin Oncol 15: 947–54 193. Klempnauer J, Ridder GJ, Werner M, et al (1997) What constitutes long-term survival after surgery for hilar cholangiocarcinoma? Cancer 79: 26–34 194. Kluge R, Schmidt F, Caca K, et al (2001) Positron emission tomography with [(18)F]fluoro-2-deoxy-D-glucose for diagnosis and staging of bile duct cancer. Hepatology 33: 1029–35 195. Klump B, Hsieh CJ, Dette S, et al (2003) Promoter methylation of INK4a/ARF as detected in bile-significance for the differential diagnosis in biliary disease. Clin Cancer Res 9: 1773–8 196. Knoefel WT, Prenzel KL, Peiper M, et al (2003) Klatskin tumors and Klatskin mimicking lesions of the biliary tree. Eur J Surg Oncol 29: 658–61 197. Knox JJ, Hedley D, Oza A, et al (2005) Combining gemcitabine and capecitabine in patients with advanced biliary cancer: a phase II trial. J Clin Oncol 23: 2332–8 198. Knox JJ, Hedley D, Oza A, et al (2004) Gemcitabine concurrent with continuous infusional 5-fluorouracil in advanced biliary cancers: a review of the Princess Margaret Hospital experience. Ann Oncol 15: 770–4 199. Knyrim K, Wagner HJ, Pausch J, et al (1993) A prospective, randomized, controlled trial of metal stents for malignant obstruction of the common bile duct. Endoscopy 25: 207–12
1560 200. Kobayashi K, Tsuji A, Morita S, et al (2006) A phase II study of LFP therapy (5-FU (5-fluorourasil) continuous infusion (CVI) and Low-dose consecutive (Cisplatin) CDDP) in advanced biliary tract carcinoma. BMC Cancer 6: 121 201. Kobayashi M, Ikeda K, Saitoh S, et al (2000) Incidence of primary cholangiocellular carcinoma of the liver in japanese patients with hepatitis C virus-related cirrhosis. Cancer 88: 2471–7 202. Kobayashi S, Werneburg N, Bronk SF, et al (2004) Interleukin-6 (Il-6) increases myeloid cell leukemia-1 (Mcl-1) via an AKT signaling pathway i cholangiocarcinoma: therapeutic implications for AKT inhibitors. Hepatology 40: 364A (abstract 461) 203. Kobayashi T, Harada K, Miwa K, et al (2005) Helicobacter genus DNA fragments are commonly detectable in bile from patients with extrahepatic biliary diseases and associated with their pathogenesis. Dig Dis Sci 50: 862–7 204. Kocak Z, Ozkan H, Adli M, et al (2005) Intraluminal brachytherapy with metallic stenting in the palliative treatment of malignant obstruction of the bile duct. Radiat Med 23: 200–7 205. Kondo S, Hirano S, Ambo Y, et al (2004) Forty consecutive resections of hilar cholangiocarcinoma with no postoperative mortality and no positive ductal margins: results of a prospective study. Ann Surg 240: 95–101 206. Kondo S, Nimura Y, Hayakawa N, et al (2000) Regional and para-aortic lymphadenectomy in radical surgery for advanced gallbladder carcinoma. Br J Surg 87: 418–22 207. Kornek GV, Schuell B, Laengle F, et al (2004) Mitomycin C in combination with capecitabine or biweekly high-dose gemcitabine in patients with advanced biliary tract cancer: a randomised phase II trial. Ann Oncol 15: 478–83 208. Kornfeld D, Ekbom A, Ihre T (1997) Survival and risk of cholangiocarcinoma in patients with primary sclerosing cholangitis. A population-based study. Scand J Gastroenterol 32: 1042–5 209. Kosuge T, Yamamoto J, Shimada K, et al (1999) Improved surgical results for hilar cholangiocarcinoma with procedures including major hepatic resection. Ann Surg 230: 663–71 210. Kraas E, Frauenschuh D, Farke S (2002) Intraoperative suspicion of gallbladder carcinoma in laparoscopic surgery: what to do? Dig Surg 19: 489–93 211. Kresl JJ, Schild SE, Henning GT, et al (2002) Adjuvant external beam radiation therapy with concurrent chemotherapy in the management of gallbladder carcinoma. Int J Radiat Oncol Biol Phys 52: 167–75 212. Kubicka S, Rudolph KL, Tietze MK, et al (2001) Phase II study of systemic gemcitabine chemotherapy for advanced unresectable hepatobiliary carcinomas. Hepatogastroenterology 48: 783–9 213. Kuhn R, Hribaschek A, Eichelmann K, et al (2002) Outpatient therapy with gemcitabine and docetaxel for gallbladder, biliary, and cholangio-carcinomas. Invest New Drugs 20: 351–6 214. Kuvshinoff BW, Armstrong JG, Fong Y, et al (1995) Palliation of irresectable hilar cholangiocarcinoma with biliary drainage and radiotherapy. Br J Surg 82: 1522–5 215. Lammer J, Neumayer K (1986) Biliary drainage endoprostheses: experience with 201 placements. Radiology 159: 625–9 216. Launois B, Terblanche J, Lakehal M, et al (1999) Proximal bile duct cancer: high resectability rate and 5-year survival. Ann Surg 230: 266–75
116
Malignant Tumors
217. Lavaissiere L, Jia S, Nishiyama M, et al (1996) Overexpression of human aspartyl(asparaginyl)betahydroxylase in hepatocellular carcinoma and cholangiocarcinoma. J Clin Invest 98: 1313–23 218. Lazcano-Ponce EC, Miquel JF, Munoz N, et al (2001) Epidemiology and molecular pathology of gallbladder cancer. CA Cancer J Clin 51: 349–64 219. Lee CK, Barrios BR, Bjarnason H (1997) Biliary tree malignancies: the University of Minnesota experience. J Surg Oncol 65: 298–305 220. Lee GW, Kang JH, Kim HG, et al (2006) Combination chemotherapy with gemcitabine and cisplatin as first-line treatment for immunohistochemically proven cholangiocarcinoma. Am J Clin Oncol 29: 127–31 221. Lee J, Kim TY, Lee MA, et al (2007) Phase II trial of gemcitabine combined with cisplatin in patients with inoperable biliary tract carcinomas. Cancer Chemother Pharmacol 60: 321–8 222. Lee JH, Kang DH, Kim JY, et al (2007) Endoscopic bilateral metal stent placement for advanced hilar cholangiocarcinoma: a pilot study of a newly designed Y stent. Gastrointest Endosc 66: 364–9 223. Leelawat K, Leelawat S, Ratanachu-Ek T, et al (2006) Circulating hTERT mRNA as a tumor marker in cholangiocarcinoma patients. World J Gastroenterol 12: 4195–8 224. Lempinen M, Isoniemi H, Makisalo H, et al (2007) Enhanced detection of cholangiocarcinoma with serum trypsinogen-2 in patients with severe bile duct strictures. J Hepatol 47(5): 677–83 225. Leung J, Guiney M, Das R (1996) Intraluminal brachytherapy in bile duct carcinomas. Aust N Z J Surg 66: 74–7 226. Lillemoe KD, Cameron JL, Hardacre JM, et al (1999) Is prophylactic gastrojejunostomy indicated for unresectable periampullary cancer? A prospective randomized trial. Ann Surg 230: 322–8; discussion 328–30 227. Lin MH, Chen JS, Chen HH, et al (2003) A phase II trial of gemcitabine in the treatment of advanced bile duct and periampullary carcinomas. Chemotherapy 49: 154–8 228. Lipsett PA, Pitt HA, Colombani PM, et al (1994) Choledochal cyst disease. A changing pattern of presentation. Ann Surg 220: 644–52 229. Liu CL, Fan ST, Lo CM, et al (2006) Improved operative and survival outcomes of surgical treatment for hilar cholangiocarcinoma. Br J Surg 93: 1488–94 230. Liu CL, Lo CM, Lai EC, et al (1998) Endoscopic retrograde cholangiopancreatography and endoscopic endoprosthesis insertion in patients with Klatskin tumors. Arch Surg 133: 293–6 231. Liu XF, Kong FM, Xu Z, et al (2007) Promoter hypermethylation of death-associated protein kinase gene in cholangiocarcinoma. Hepatobiliary Pancreat Dis Int 6: 407–11 232. Lopera JE, Soto JA, Munera F (2001) Malignant hilar and perihilar biliary obstruction: use of MR cholangiography to define the extent of biliary ductal involvement and plan percutaneous interventions. Radiology 220: 90–6 233. Lowenfels AB, Norman J (1978) Isoniazid and bile duct cancer. JAMA 240: 434–5 234. Lu JJ, Bains YS, Abdel-Wahab M, et al (2002) High-doserate remote afterloading intracavitary brachytherapy for the treatment of extrahepatic biliary duct carcinoma. Cancer J 8: 74–8
References 235. Lundberg O, Kristoffersson A (1999) Port site metastases from gallbladder cancer after laparoscopic cholecystectomy. Results of a Swedish survey and review of published reports. Eur J Surg 165: 215–22 236. Luzar B, Poljak M, Cor A, et al (2005) Expression of human telomerase catalytic protein in gallbladder carcinogenesis. J Clin Pathol 58: 820–5 237. Maeda T, Sepe P, Lahousse S, et al (2003) Antisense oligodeoxynucleotides directed against aspartyl (asparaginyl) beta-hydroxylase suppress migration of cholangiocarcinoma cells. J Hepatol 38: 615–22 238. Maeda T, Taguchi K, Aishima S, et al (2004) Clinicopathological correlates of aspartyl (asparaginyl) beta-hydroxylase over-expression in cholangiocarcinoma. Cancer Detect Prev 28: 313–8 239. Malik IA, Aziz Z (2003) Prospective evaluation of efficacy and toxicity of 5-fu and folinic acid (Mayo Clinic regimen) in patients with advanced cancer of the gallbladder. Am J Clin Oncol 26: 124–6 240. Malik IA, Aziz Z, Zaidi SH, et al (2003) Gemcitabine and cisplatin is a highly effective combination chemotherapy in patients with advanced cancer of the gallbladder. Am J Clin Oncol 26: 174–7 241. Manfredi R, Brizi MG, Masselli G, et al (2001) Malignant biliary hilar stenosis: MR cholangiography compared with direct cholangiography. Radiol Med (Torino) 102: 48–54 242. Mani S, Sciortino D, Samuels B, et al (1999) Phase II trial of uracil/tegafur (UFT) plus leucovorin in patients with advanced biliary carcinoma. Invest New Drugs 17: 97–101 243. Matsumoto S, Kiyosue H, Komatsu E, et al (2004) Radiotherapy combined with transarterial infusion chemotherapy and concurrent infusion of a vasoconstrictor agent for nonresectable advanced hepatic hilar duct carcinoma. Cancer 100: 2422–9 244. McCaughan JS, Jr., Mertens BF, Cho C, et al (1991) Photodynamic therapy to treat tumors of the extrahepatic biliary ducts. A case report. Arch Surg 126: 111–3 245. McMasters KM, Tuttle TM, Leach SD, et al (1997) Neoadjuvant chemoradiation for extrahepatic cholangiocarcinoma. Am J Surg 174: 605–8; discussion 608–9 246. McWilliams RR, Foster NR, Quevedo FJ, et al (2007) NCCTG phase I/II trial (N9943) of gemcitabine and pemetrexed in patients with biliary tract or gallbladder carcinoma: Phase II results. J Clin Oncol, 25(Suppl 18): A-4578 247. Meyers WC, Jones RS (1988) Internal radiation for bile duct cancer. World J Surg 12: 99–104 248. Mezger J, Sauerbruch T, Ko Y, et al (1998) Phase II study with Gemcitabine in Gallbladder and Biliary Tract Carcinomas. Onkologie 21: 232–234 249. Milella M, Salvetti M, Cerrotta A, et al (1998) Interventional radiology and radiotherapy for inoperable cholangiocarcinoma of the extrahepatic bile ducts. Tumori 84: 467–71 250. Misra S, Chaturvedi A, Goel MM, et al (2000) Overexpression of p53 protein in gallbladder carcinoma in North India. Eur J Surg Oncol 26: 164–7 251. Misra S, Chaturvedi A, Misra NC (2005) Gemcitabine(G) plus Cisplatin (C) in advanced carcinoma gallbladder–a large single center experience. J Clin Oncol (ASCO 2005) 23:(abstract 4136) 252. Misra S, Chaturvedi A, Misra NC, et al (2003) Carcinoma of the gallbladder. Lancet Oncol 4: 167–76
1561 253. Miyata H, Sasaki T, Kuwahara K, et al (2006) The effects of ZD1839 (Iressa), a highly selective EGFR tyrosine kinase inhibitor, as a radiosensitiser in bile duct carcinoma cell lines. Int J Oncol 28: 915–21 254. Miyazaki M, Ito H, Nakagawa K, et al (1998) Aggressive surgical approaches to hilar cholangiocarcinoma: hepatic or local resection? Surgery 123: 131–6 255. Mobius C, Demuth C, Aigner T, et al (2007) Evaluation of VEGF A expression and microvascular density as prognostic factors in extrahepatic cholangiocarcinoma. Eur J Surg Oncol 33: 1025–9 256. Montemaggi P, Costamagna G, Dobelbower RR, et al (1995) Intraluminal brachytherapy in the treatment of pancreas and bile duct carcinoma. Int J Radiat Oncol Biol Phys 32: 437–43 257. Morganti AG, Trodella L, Valentini V, et al (2000) Combined modality treatment in unresectable extrahepatic biliary carcinoma. Int J Radiat Oncol Biol Phys 46: 913–9 258. Mueller PR, Ferrucci JT, Jr., Teplick SK, et al (1985) Biliary stent endoprosthesis: analysis of complications in 113 patients. Radiology 156: 637–9 259. Murata H, Tsuji S, Tsujii M, et al (2004) Helicobacter bilis infection in biliary tract cancer. Aliment Pharmacol Ther 20(Suppl 1): 90–4 260. Nagorney DM, Donohue JH, Farnell MB, et al (1993) Outcomes after curative resections of cholangiocarcinoma. Arch Surg 128: 871–7; discussion 877–9 261. Nakeeb A, Pitt HA, Sohn TA, et al (1996) Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg 224: 463–73; discussion 473–5 262. Nakeeb A, Tran KQ, Black MJ, et al (2002) Improved survival in resected biliary malignancies. Surgery 132: 555– 63; discission 563–4 263. Nanashima A, Yamaguchi H, Shibasaki S, et al (2004) Adjuvant photodynamic therapy for bile duct carcinoma after surgery: a preliminary study. J Gastroenterol 39: 1095–101 264. Nathan H, Pawlik TM, Wolfgang CL, et al (2007) Trends in Survival after Surgery for Cholangiocarcinoma: A 30-Year Population-Based SEER Database Analysis. J Gastrointest Surg 265. Nehls O, Klump B, Arkenau HT, et al (2002) Oxaliplatin, fluorouracil and leucovorin for advanced biliary system adenocarcinomas: a prospective phase II trial. Br J Cancer 87: 702–4 266. Nehls O, Oettle H, Hartmann J-T, et al (2006) A prospective multicenter phase II trial of capecitabine plus oxaliplatin (CapOx) in advanced biliary system adenocarcinomas: The final results. Proc ASCO 2006 24:abstract 4136 267. Nesbit GM, Johnson CD, James EM, et al (1988) Cholangiocarcinoma: diagnosis and evaluation of resectability by CT and sonography as procedures complementary to cholangiography. AJR Am J Roentgenol 151: 933–8 268. Neuhaus P, Jonas S, Bechstein WO, et al (1999) Extended resections for hilar cholangiocarcinoma. Ann Surg 230: 808–18; discussion 819 269. Nichols JC, Gores GJ, LaRusso NF, et al (1993) Diagnostic role of serum CA 19–9 for cholangiocarcinoma in patients with primary sclerosing cholangitis. Mayo Clin Proc 68: 874–9 270. Nomura M, Yamakado K, Nomoto Y, et al (2002) Clinical efficacy of brachytherapy combined with external-beam
1562
271.
271.
273.
274.
275.
276. 277.
278.
279.
280.
281.
282.
283.
284.
285.
286.
287.
116 radiotherapy and repeated arterial infusion chemotherapy in patients with unresectable extrahepatic bile duct cancer. Int J Oncol 20: 325–31 Ogasawara S, Yano H, Higaki K, et al (2001) Expression of angiogenic factors, basic fibroblast growth factor and vascular endothelial growth factor, in human biliary tract carcinoma cell lines. Hepatol Res 20: 97–113 Ogo Y, Nio Y, Yano S, et al (2006) Immunohistochemical expression of HER-1 and HER-2 in extrahepatic biliary carcinoma. Anticancer Res 26: 763–70 Ohnishi H, Asada M, Shichijo Y, et al (1995) External radiotherapy for biliary decompression of hilar cholangiocarcinoma. Hepatogastroenterology 42: 265–8 Okamoto M, Okamoto H, Kitahara F, et al (1999) Ultrasonographic evidence of association of polyps and stones with gallbladder cancer. Am J Gastroenterol 94: 446–50 Okusaka T, Ishii H, Funakoshi A, et al (2006) Phase II study of single-agent gemcitabine in patients with advanced biliary tract cancer. Cancer Chemother Pharmacol 57: 647–53 Ortner MA (2000) Photodynamic therapy of cholangiocarcinoma cancer. Gastrointest Endosc Clin N Am 10: 481–6 Ortner MA, Liebetruth J, Schreiber S, et al (1998) Photodynamic therapy of nonresectable cholangiocarcinoma. Gastroenterology 114: 536–42 Ortner MEJ, Caca K, Berr F, et al (2003) Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study. Gastroenterology 125: 1355–1363 Ouchi K, Mikuni J, Kakugawa Y (2002) Laparoscopic cholecystectomy for gallbladder carcinoma: results of a Japanese survey of 498 patients. J Hepatobiliary Pancreat Surg 9: 256–60 Pan G, Ahn EY, Chen Y, et al (2007) Reciprocal co-expression of Fas and Fas ligand in human cholangiocarcinoma. Int J Oncol 31: 843–50 Panichakul T, Intachote P, Wongkajorsilp A, et al (2006) Triptolide sensitizes resistant cholangiocarcinoma cells to TRAIL-induced apoptosis. Anticancer Res 26: 259–65 Paolucci V, Schaeff B, Schneider M, et al (1999) Tumor seeding following laparoscopy: international survey. World J Surg 23: 989–95; discussion 996–7 Papakostas P, Kouroussis C, Androulakis N, et al (2001) First-line chemotherapy with docetaxel for unresectable or metastatic carcinoma of the biliary tract. A multicentre phase II study. Eur J Cancer 37: 1833–8 Park BK, Kim YJ, Park JY, et al (2006) Phase II study of gemcitabine and cisplatin in advanced biliary tract cancer. J Gastroenterol Hepatol 21: 999–1003 Park do H, Kim MH, Choi JS, et al (2006) Covered versus uncovered wallstent for malignant extrahepatic biliary obstruction: a cohort comparative analysis. Clin Gastroenterol Hepatol 4: 790–6 Park JS, Oh SY, Kim SH, et al (2005) Single-agent gemcitabine in the treatment of advanced biliary tract cancers: a phase II study. Jpn J Clin Oncol 35: 68–73 Park JY, Park SW, Chung JB, et al (2006) Concurrent chemoradiotherapy with doxifluridine and paclitaxel for extrahepatic bile duct cancer. Am J Clin Oncol 29: 240–5
Malignant Tumors
288. Park MS, Kim TK, Kim KW, et al (2004) Differentiation of extrahepatic bile duct cholangiocarcinoma from benign stricture: findings at MRCP versus ERCP. Radiology 233: 234–40 289. Parkin DM, Srivatanakul P, Khlat M, et al (1991) Liver cancer in Thailand. I. A case-control study of cholangiocarcinoma. Int J Cancer 48: 323–8 290. Patel AH, Harnois DM, Klee GG, et al (2000) The utility of CA 19–9 in the diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis. Am J Gastroenterol 95: 204–7 291. Patel T (2006) Cholangiocarcinoma. Nat Clin Pract Gastroenterol Hepatol 3: 33–42 292. Patel T (2001) Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology 33: 1353–7 293. Patt YZ, Hassan MM, Aguayo A, et al (2004) Oral capecitabine for the treatment of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma. Cancer 101: 578–86 294. Patt YZ, Hassan MM, Lozano RD, et al (2001) Phase II trial of cisplatin, interferon alpha-2b, doxorubicin, and 5-fluorouracil for biliary tract cancer. Clin Cancer Res 7: 3375–80 295. Patt YZ, Jones DV, Jr., Hoque A, et al (1996) Phase II trial of intravenous flourouracil and subcutaneous interferon alfa-2b for biliary tract cancer. J Clin Oncol 14: 2311–5 296. Pauli RM, Pauli ME and Hall JG (1980) Gardner syndrome and periampullary malignancy. Am J Med Genet 6: 205–19 297. Pazdur R, Royce ME, Rodriguez GI, et al (1999) Phase II trial of docetaxel for cholangiocarcinoma. Am J Clin Oncol 22: 78–81 298. Penz M, Kornek GV, Raderer M, et al (2001) Phase II trial of two-weekly gemcitabine in patients with advanced biliary tract cancer. Ann Oncol 12: 183–6 299. Pereira SP, Ragunath K, Devlin J, et al (2005) Preliminary results of a phase II trial to examine the safety and efficacy of porfimer sodium photodynamic therapy (PDT) in locally advanced biliary tract carcinoma (BTC). J Clin Oncol 23: abstract 4180 (ASCO) 300. Petrowsky H, Wildbrett P, Husarik DB, et al (2006) Impact of integrated positron emission tomography and computed tomography on staging and management of gallbladder cancer and cholangiocarcinoma. J Hepatol 45: 43–50 301. Philip PA, Mahoney MR, Allmer C, et al (2006) Phase II study of erlotinib in patients with advanced biliary cancer. J Clin Oncol 24: 3069–74 302. Pichlmayr R, Weimann A, Klempnauer J, et al (1996) Surgical treatment in proximal bile duct cancer. A singlecenter experience. Ann Surg 224: 628–38 303. Piehler JM and Crichlow RW (1978) Primary carcinoma of the gallbladder. Surg Gynecol Obstet 147: 929–42 304. Pitt HA, Nakeeb A, Abrams RA, et al (1995) Perihilar cholangiocarcinoma. Postoperative radiotherapy does not improve survival. Ann Surg 221: 788–97; discussion 797–8 305. Polydorou AA, Cairns SR, Dowsett JF, et al (1991) Palliation of proximal malignant biliary obstruction by endoscopic endoprosthesis insertion. Gut 32: 685–9 306. Polydorou AA, Chisholm EM, Romanos AA, et al (1989) A comparison of right versus left hepatic duct endoprosthesis insertion in malignant hilar biliary obstruction. Endoscopy 21: 266–71
References 307. Posner S, Colletti L, Knol J, et al (2000) Safety and longterm efficacy of transduodenal excision for tumors of the ampulla of Vater. Surgery 128: 694–701 308. Prasad G, Wang KK, Baron TH, et al (2005) Factors predicting Survival in patients with cholangiocarcinoma treated with photodynamic therapy. Gastroenterology abstract (DDW 2005) 309. Prasad GA, Wang KK, Baron TH, et al (2007) Factors associated with increased survival after photodynamic therapy for cholangiocarcinoma. Clin Gastroenterol Hepatol 5: 743–8 310. Prat F, Chapat O, Ducot B, et al (1998) A randomized trial of endoscopic drainage methods for inoperable malignant strictures of the common bile duct. Gastrointest Endosc 47: 1–7 311. Prytz H, Keiding S, Bjornsson E, et al (2006) Dynamic FDG-PET is useful for detection of cholangiocarcinoma in patients with PSC listed for liver transplantation. Hepatology 44: 1572–80 312. Qualman SJ, Haupt HM, Bauer TW, et al (1984) Adenocarcinoma of the hepatic duct junction. A reappraisal of the histologic criteria of malignancy. Cancer 53: 1545–51 313. Que FG, Phan VA, Phan VH, et al (1999) Cholangiocarcinomas express Fas ligand and disable the Fas receptor. Hepatology 30: 1398–404 314. Radaeva S, Ferreira-Gonzalez A, Sirica AE (1999) Overexpression of C-NEU and C-MET during rat liver cholangiocarcinogenesis: A link between biliary intestinal metaplasia and mucin-producing cholangiocarcinoma. Hepatology 29: 1453–62 315. Raderer M, Hejna MH, Valencak JB, et al (1999) Two consecutive phase II studies of 5-fluorouracil/leucovorin/mitomycin C and of gemcitabine in patients with advanced biliary cancer. Oncology 56: 177–80 316. Raju GS, Sud R, Elfert AA, et al (2006) Biliary drainage by using stents without a central lumen: a pilot study. Gastrointest Endosc 63: 317–20 317. Ramage JK, Donaghy A, Farrant JM, et al (1995) Serum tumor markers for the diagnosis of cholangiocarcinoma in primary sclerosing cholangitis. Gastroenterology 108: 865–9 318. Ramanathan RK, Belani CP, Singh DA, et al (2006) Phase II study of lapatinib, a dual inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase 1 and 2 (Her2/Neu) in patients (pts) with advanced biliary tree cancer (BTC) or hepatocellular cancer (HCC). A California Consortium (CCC-P) Trial. J Clin Oncol, 2006 ASCO Annual Meeting Proceedings Part I Vol 24(No. 18S) (June 20 Supplement):(abstract 4010) 319. Randi G, Franceschi S, La Vecchia C (2006) Gallbladder cancer worldwide: geographical distribution and risk factors. Int J Cancer 118: 1591–602 320. Rao S, Cunningham D, Hawkins RE, et al (2005) Phase III study of 5FU, etoposide and leucovorin (FELV) compared to epirubicin, cisplatin and 5FU (ECF) in previously untreated patients with advanced biliary cancer. Br J Cancer 92: 1650–4 321. Rea DJ, Heimbach JK, Rosen CB, et al (2005) Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg 242: 451–8; discussion 458–61
1563 322. Redaelli CA, Buchler MW, Schilling MK, et al (1997) High coincidence of Mirizzi syndrome and gallbladder carcinoma. Surgery 121: 58–63 323. Reding R, Buard JL, Lebeau G, et al (1991) Surgical management of 552 carcinomas of the extrahepatic bile ducts (gallbladder and periampullary tumors excluded). Results of the French Surgical Association Survey. Ann Surg 213: 236–41 324. Reinhardt MJ, Strunk H, Gerhardt T, et al (2005) Detection of Klatskin’s tumor in extrahepatic bile duct strictures using delayed 18F-FDG PET/CT: preliminary results for 22 patient studies. J Nucl Med 46: 1158–63 325. Reyes-Vidal J, Gallardo J, Yanez E, et al (2003) Gemcitabine (G) and cisplatin (C) in the treatment of patients (pts) with unresectable or metastatic gallbladder cancer: Results of the phase II GOCCHI study 2000–13. Proc Am Soc Clin Oncol (ASCO 2003) 22: 273 (abstract 1095) 326. Robles R, Figueras J, Turrion VS, et al (2004) Spanish experience in liver transplantation for hilar and peripheral cholangiocarcinoma. Ann Surg 239: 265–71 327. Rumalla A, Baron TH, Leontovich O, et al (2001a) Improved diagnostic yield of endoscopic biliary brush cytology by digital image analysis. Mayo Clin Proc 76: 29–33 328. Rumalla A, Baron TH, Wang KK, et al (2001b) Endoscopic application of photodynamic therapy for cholangiocarcinoma. Gastrointest Endosc 53: 500–4 329. Sadamoto Y, Kubo H, Harada N, et al (2003) Preoperative diagnosis and staging of gallbladder carcinoma by EUS. Gastrointest Endosc 58: 536–41 330. Sagawa N, Kondo S, Morikawa T, et al (2005) Effectiveness of radiation therapy after surgery for hilar cholangiocarcinoma. Surg Today 35: 548–52 331. Sano T, Shimada K, Sakamoto Y, et al (2006) One hundred two consecutive hepatobiliary resections for perihilar cholangiocarcinoma with zero mortality. Ann Surg 244: 240–7 332. Sanz-Altamira PM, Ferrante K, Jenkins RL, et al (1998) A phase II trial of 5-fluorouracil, leucovorin, and carboplatin in patients with unresectable biliary tree carcinoma. Cancer 82: 2321–5 333. Sanz-Altamira PM, O’Reilly E, Stuart KE, et al (2001) A phase II trial of irinotecan (CPT-11) for unresectable biliary tree carcinoma. Ann Oncol 12: 501–4 334. Satyanarayana A, Manns MP, Rudolph KL (2004) Telomeres and telomerase: a dual role in hepatocarcinogenesis. Hepatology 40: 276–83 335. Schiefke I, Zabel-Langhennig A, Wiedmann M, et al (2003) Self-expandable metallic stents for malignant duodenal obstruction caused by biliary tract cancer. Gastrointest Endosc 58: 213–9 336. Schleicher UM, Staatz G, Alzen G, et al (2002) Combined external beam and intraluminal radiotherapy for irresectable Klatskin tumors. Strahlenther Onkol 178: 682–7 337. Schoppmeyer K, Kreth F, Wiedmann M, et al (2007) A pilot study of bendamustine in advanced bile duct cancer. Anticancer Drugs 18: 697–702 338. Schoppmeyer K, Miethe S, Wiedmann M, et al (2006) Radiochemotherapy followed by gemcitabine and capecitabine in extrahepatic bile duct cancer: a phase I/II trial. Am J Clin Oncol 29: 576–82
1564 339. Schwartz LH, Black J, Fong Y, et al (2002) Gallbladder carcinoma: findings at MR imaging with MR cholangiopancreatography. J Comput Assist Tomogr 26: 405–10 340. Seyama Y, Kubota K, Sano K, et al (2003) Long-term outcome of extended hemihepatectomy for hilar bile duct cancer with no mortality and high survival rate. Ann Surg 238: 73–83 341. Shi JS, Zhou LS, Han Y, et al (2004) Expression of tumor necrosis factor and its receptor in gallstone and gallbladder carcinoma tissue. Hepatobiliary Pancreat Dis Int 3: 448–52 342. Shim CS, Cheon YK, Cha SW, et al (2005) Prospective study of the effectiveness of percutaneous transhepatic photodynamic therapy for advanced bile duct cancer and the role of intraductal ultrasonography in response assessment. Endoscopy 37: 425–33 343. Shimonishi T, Isse K, Shibata F, et al (2000) Up-regulation of fas ligand at early stages and down-regulation of Fas at progressed stages of intrahepatic cholangiocarcinoma reflect evasion from immune surveillance. Hepatology 32: 761–9 344. Shin HR, Lee CU, Park HJ, et al (1996) Hepatitis B and C virus, Clonorchis sinensis for the risk of liver cancer: a case-control study in Pusan, Korea. Int J Epidemiol 25: 933–40 345. Shin HS, Seong J, Kim WC, et al (2003) Combination of external beam irradiation and high-dose-rate intraluminal brachytherapy for inoperable carcinoma of the extrahepatic bile ducts. Int J Radiat Oncol Biol Phys 57: 105–12 346. Shinchi H, Takao S, Nishida H, et al (2000) Length and quality of survival following external beam radiotherapy combined with expandable metallic stent for unresectable hilar cholangiocarcinoma. J Surg Oncol 75: 89–94 347. Shirai Y, Yoshida K, Tsukada K, et al (1992) Inapparent carcinoma of the gallbladder. An appraisal of a radical second operation after simple cholecystectomy. Ann Surg 215: 326–31 348. Shoup M, Fong Y (2002) Surgical indications and extent of resection in gallbladder cancer. Surg Oncol Clin N Am 11: 985–94 349. Sicklick JK, Choti MA (2005) Controversies in the surgical management of cholangiocarcinoma and gallbladder cancer. Semin Oncol 32: S112–7 350. Sirica AE, Lai GH, Zhang Z (2001) Biliary cancer growth factor pathways, cyclo-oxygenase-2 and potential therapeutic strategies. J Gastroenterol Hepatol 16: 363–72 351. Slattery JM, Sahani DV (2006) What is the current stateof-the-art imaging for detection and staging of cholangiocarcinoma? Oncologist 11: 913–22 352. Smadja C, Bowley NB, Benjamin IS, et al (1983) Idiopathic localized bile duct strictures: relationship to primary sclerosing cholangitis. Am J Surg 146: 404–8 353. Smoron GL (1977) Radiation therapy of carcinoma of gallbladder and biliary tract. Cancer 40: 1422–4 354. Sobin LH, Wittekind C (eds) (2002) UICC: TNM Classification of Malignant Tumors. 6th ed. Wiley-Liss, New York, pp 74–85 355. Sobin LH, Wittekind C (eds) (1997) UICC: TNM classification of malignant tumors, 5th ed. Wiley-Liss, New York, pp 81–3 356. Soderlund C, Linder S (2006) Covered metal versus plastic stents for malignant common bile duct stenosis: a prospective, randomized, controlled trial. Gastrointest Endosc 63: 986–95
116
Malignant Tumors
357. Sorensen HT, Friis S, Olsen JH, et al (1998) Risk of liver and other types of cancer in patients with cirrhosis: a nationwide cohort study in Denmark. Hepatology 28: 921–5 358. Speer AG, Cotton PB, MacRae KD (1988) Endoscopic management of malignant biliary obstruction: stents of 10 French gauge are preferable to stents of 8 French gauge. Gastrointest Endosc 34: 412–7 359. Speer AG, Cotton PB, Russell RC, et al (1987) Randomised trial of endoscopic versus percutaneous stent insertion in malignant obstructive jaundice. Lancet 2: 57–62 360. Standfield NJ, Salisbury JR, Howard ER (1989) Benign non-traumatic inflammatory strictures of the extrahepatic biliary system. Br J Surg 76: 849–52 361. Strom BL, Soloway RD, Rios-Dalenz JL, et al (1995) Risk factors for gallbladder cancer. An international collaborative case-control study. Cancer 76: 1747–56 362. Sturm PD, Baas IO, Clement MJ, et al (1998) Alterations of the p53 tumor-suppressor gene and K-ras oncogene in perihilar cholangiocarcinomas from a high-incidence area. Int J Cancer 78: 695–8 363. Sun CD, Zhang BY, Wu LQ, et al (2005) Laparoscopic cholecystectomy for treatment of unexpected early-stage gallbladder cancer. J Surg Oncol 91: 253–7 364. Suzuki S, Yokoi Y, Kurachi K, et al (2004) Appraisal of surgical treatment for pT2 gallbladder carcinomas. World J Surg 28: 160–5 365. Taieb J, Mitry E, Boige V, et al (2002) Optimization of 5-fluorouracil (5-FU)/cisplatin combination chemotherapy with a new schedule of leucovorin, 5-FU and cisplatin (LV5FU2-P regimen) in patients with biliary tract carcinoma. Ann Oncol 13: 1192–6 366.Takada T, Amano H, Yasuda H, et al (2002) Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer 95: 1685–95 367. Takada T, Kato H, Matsushiro T, et al (1994) Comparison of 5-fluorouracil, doxorubicin and mitomycin C with 5-fluorouracil alone in the treatment of pancreatic-biliary carcinomas. Oncology 51: 396–400 368. Takamura A, Saito H, Kamada T, et al (2003) Intraluminal low-dose-rate 192Ir brachytherapy combined with external beam radiotherapy and biliary stenting for unresectable extrahepatic bile duct carcinoma. Int J Radiat Oncol Biol Phys 57: 1357–65 369. Takeda Y, Hasuike Y, Kashiwazaki M, et al (2004) [Adjuvant arterial infusion chemotherapy for patients with biliary cancer]. Gan To Kagaku Ryoho 31: 1835–7 370. Tanaka S, Sugimachi K, Kameyama T, et al (2003) Human WISP1v, a member of the CCN family, is associated with invasive cholangiocarcinoma. Hepatology 37: 1122–9 371. Tanimura Y, Kokuryo T, Tsunoda N, et al (2005) Tumor necrosis factor alpha promotes invasiveness of cholangiocarcinoma cells via its receptor, TNFR2. Cancer Lett 219: 205–13 372. Tannapfel A, Benicke M, Katalinic A, et al (2000) Frequency of p16(INK4A) alterations and K-ras mutations in intrahepatic cholangiocarcinoma of the liver. Gut 47: 721–7 373. Taylor-Robinson SD, Toledano MB, Arora S, et al (2001) Increase in mortality rates from intrahepatic cholangiocarcinoma in England and Wales 1968–1998. Gut 48: 816–20
References 374. Terada T, Okada Y, Nakanuma Y (1996) Expression of immunoreactive matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in human normal livers and primary liver tumors. Hepatology 23: 1341–4 375. Terada T, Ueyama J, Ukita Y, et al (2000) Protein expression of double-stranded RNA-activated protein kinase (PKR) in intrahepatic bile ducts in normal adult livers, fetal livers, primary biliary cirrhosis, hepatolithiasis and intrahepatic cholangiocarcinoma. Liver 20: 450–7 376. Tham TC, Carr-Locke DL, Vandervoort J, et al (1998) Management of occluded biliary Wallstents. Gut 42: 703–7 377. Thomas M, Tarco E, Trivedi S, et al (2006) Amplification of HER-2/neu (erbB2) gene expression in gallbladder (GBC) and in bile duct cancer (BDC) (biliary tract cancer, BTC). J Clin Oncol, 2006 ASCO Annual Meeting Proceedings Part I Vol 24(No. 18S) (June 20 Supplement):(abstract 4011) 378. Thongprasert S, Napapan S, Charoentum C, et al (2005) Phase II study of gemcitabine and cisplatin as first-line chemotherapy in inoperable biliary tract carcinoma. Ann Oncol 16: 279–81 379. Tischendorf JJ, Kruger M, Trautwein C, et al (2006) Cholangioscopic characterization of dominant bile duct stenoses in patients with primary sclerosing cholangitis. Endoscopy 38: 665–9 380. Tocchi A, Mazzoni G, Liotta G, et al (2001) Late development of bile duct cancer in patients who had biliary-enteric drainage for benign disease: a follow-up study of more than 1,000 patients. Ann Surg 234: 210–4 381. Todoroki T, Iwasaki Y, Orii K, et al (1991) Resection combined with intraoperative radiation therapy (IORT) for stage IV (TNM) gallbladder carcinoma. World J Surg 15: 357–66 382. Todoroki T, Kawamoto T, Koike N, et al (2000) Radical resection of hilar bile duct carcinoma and predictors of survival. Br J Surg 87: 306–13 383. Tojima Y, Nagino M, Ebata T, et al (2003) Immunohistochemically demonstrated lymph node micrometastasis and prognosis in patients with otherwise node-negative hilar cholangiocarcinoma. Ann Surg 237: 201–7 384. Tomimatsu M, Ishiguro N, Taniai M, et al (1993) Hepatitis C virus antibody in patients with primary liver cancer (hepatocellular carcinoma, cholangiocarcinoma, and combined hepatocellular-cholangiocarcinoma) in Japan. Cancer 72: 683–8 385. Torok NJ, Higuchi H, Bronk S, et al (2002) Nitric oxide inhibits apoptosis downstream of cytochrome C release by nitrosylating caspase 9. Cancer Res 62: 1648–53 386. Tringali A, Mutignani M, Perri V, et al (2003) A prospective, randomized multicenter trial comparing DoubleLayer and polyethylene stents for malignant distal common bile duct strictures. Endoscopy 35: 992–7 387. Tsavaris N, Kosmas C, Gouveris P, et al (2004) Weekly gemcitabine for the treatment of biliary tract and gallbladder cancer. Invest New Drugs 22: 193–8 388. Tsujino K, Landry JC, Smith RG, et al (1995) Definitive radiation therapy for extrahepatic bile duct carcinoma. Radiology 196: 275–80 389. Tsukada K, Kurosaki I, Uchida K, et al (1997) Lymph node spread from carcinoma of the gallbladder. Cancer 80: 661–7 390. Tullo A, D’Erchia AM, Honda K, et al (2000) New p53 mutations in hilar cholangiocarcinoma. Eur J Clin Invest 30: 798–803
1565 391. Ueno H, Okusaka T, Ikeda M, et al (2004) Phase II study of S-1 in patients with advanced biliary tract cancer. Br J Cancer 91: 1769–74 392. Urego M, Flickinger JC, Carr BI (1999) Radiotherapy and multimodality management of cholangiocarcinoma. Int J Radiat Oncol Biol Phys 44: 121–6 393. Ustundag Y, Bronk SF, Gores GJ (2007) Proteasome inhibition-induces endoplasmic reticulum dysfunction and cell death of human cholangiocarcinoma cells. World J Gastroenterol 13: 851–7 394. Vallis KA, Benjamin IS, Munro AJ, et al (1996) External beam and intraluminal radiotherapy for locally advanced bile duct cancer: role and tolerability. Radiother Oncol 41: 61–6 395. van Berkel AM, Boland C, Redekop WK, et al (1998) A prospective randomized trial of Teflon versus polyethylene stents for distal malignant biliary obstruction. Endoscopy 30: 681–6 396. von Delius S, Lersch C, Schulte-Frohlinde E, et al (2005) Phase II trial of weekly 24-hour infusion of gemcitabine in patients with advanced gallbladder and biliary tract carcinoma. BMC Cancer 5: 61 397. Wade TP, Prasad CN, Virgo KS, et al (1997) Experience with distal bile duct cancers in U.S. Veterans Affairs hospitals: 1987–1991. J Surg Oncol 64: 242–5 398. Wagner AD, Buechner-Steudel P, Schmalenberg H, et al (2006) Gemcitabine, oxaliplatin and weekly high-dose 5-FU as a 24-hr-infusion in chemonaive patients with advanced or metastatic carcinoma of the gallbladder: Preliminary results of a multicenter phase II-study. J Clin Oncol, 2006 ASCO Annual Meeting Proceedings Part I Vol 24(No. 18S) (June 20 Supplement):(abstract 4129) 399. Wagner HJ, Knyrim K, Vakil N, et al (1993) Plastic endoprostheses versus metal stents in the palliative treatment of malignant hilar biliary obstruction. A prospective and randomized trial. Endoscopy 25: 213–8 400. Wakai T, Shirai Y, Hatakeyama K (2002) Radical second resection provides survival benefit for patients with T2 gallbladder carcinoma first discovered after laparoscopic cholecystectomy. World J Surg 26: 867–71 401. Wakai T, Shirai Y, Yokoyama N, et al (2001) Early gallbladder carcinoma does not warrant radical resection. Br J Surg 88: 675–8 402. Watanapa P, Watanapa WB (2002) Liver fluke-associated cholangiocarcinoma. Br J Surg 89: 962–70 403. Weber A, Landrock S, Schneider J, et al (2007) Long-term outcome and prognostic factors of patients with hilar cholangiocarcinoma. World J Gastroenterol 13: 1422–6 404. Wehbe H, Henson R, Meng F, et al (2006) Interleukin-6 contributes to growth in cholangiocarcinoma cells by aberrant promoter methylation and gene expression. Cancer Res 66: 10517–24 405. Welzel TM, Graubard BI, El-Serag HB, et al (2007) Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based case-control study. Clin Gastroenterol Hepatol 5: 1221–8 406. Welzel TM, McGlynn KA, Hsing AW, et al (2006) Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinoma in the United States. J Natl Cancer Inst 98: 873–5 407. West J, Wood H, Logan RF, et al (2006) Trends in the incidence of primary liver and biliary tract cancers in England and Wales 1971–2001. Br J Cancer 94: 1751–8
1566 408. Wibbenmeyer LA, Wade TP, Chen RC, et al (1995) Laparoscopic cholecystectomy can disseminate in situ carcinoma of the gallbladder. J Am Coll Surg 181: 504–10 409. Wideroff L, Gridley G, Mellemkjaer L, et al (1997) Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in Denmark. J Natl Cancer Inst 89: 1360–5 410. Wiedmann M, Berr F, Schiefke I, et al (2004) Photodynamic therapy in patients with non-resectable hilar cholangiocarcinoma: 5-year follow-up of a prospective phase II study. Gastrointest Endosc 60: 68–75 411. Wiedmann M, Caca K, Berr F, et al (2003) Neoadjuvant photodynamic therapy as a new approach to treating hilar cholangiocarcinoma: a phase II pilot study. Cancer 97: 2783–90 412. Wiedmann M, Feisthammel J, Bluthner T, et al (2006) Novel targeted approaches to treating biliary tract cancer: the dual epidermal growth factor receptor and ErbB-2 tyrosine kinase inhibitor NVP-AEE788 is more efficient than the epidermal growth factor receptor inhibitors gefitinib and erlotinib. Anticancer Drugs 17: 783–95 413. Wiedmann M, Kreth F, Feisthammel J, et al (2003) Imatinib mesylate (STI571; Glivec) – a new approach in the treatment of biliary tract cancer? Anticancer Drugs 14: 751–60 414. Wiedmann M, Mössner J (2007) Experimental strategies to treating biliary tract cancer. In: Whitten (Ed.) Cancer of the gallbladder: New research, Nova Science Publishers, Hauppauge, NY 415. Wiedmann MW, Caca K (2004) General principles of photodynamic therapy (PDT) and gastrointestinal applications. Curr Pharm Biotechnol 5: 397–408 416. Wiedmann MW, Caca K (2005) Molecularly targeted therapy for gastrointestinal cancer. Curr Cancer Drug Targets 5: 171–93 417. Witzigmann H, Berr F, Ringel U, et al (2006) Surgical and palliative management and outcome in 184 patients with hilar cholangiocarcinoma: palliative photodynamic therapy plus stenting is comparable to R1/R2 resection. Ann Surg 244: 230–239 418. Woo SM, Ryu JK, Lee SH, et al (2007) Recurrence and prognostic factors of ampullary carcinoma after radical resection: comparison with distal extrahepatic cholangiocarcinoma. Ann Surg Oncol 14: 3195–201 419. Yamaguchi K, Chijiiwa K, Saiki S, et al (1997) Retrospective analysis of 70 operations for gallbladder carcinoma. Br J Surg 84: 200–4 420. Yeh CN, Jan YY, Chen MF (2004) Management of unsuspected gallbladder carcinoma discovered during or following laparoscopic cholecystectomy. Am Surg 70: 256–8 421. Yeh TS, Jan YY, Tseng JH, et al (2000) Malignant perihilar biliary obstruction: magnetic resonance cholangiopancreatographic findings. Am J Gastroenterol 95: 432–40
116
Malignant Tumors
422. Yeo CJ, Pitt HA, Cameron JL (1997) Bile duct carcinoma: outcome, prognosis and follow-up. In: Terblanche J (ed) Hepatobiliary malignancy, Edwards Arnold, London, pp 479–84 423. Yoon JH, Werneburg NW, Higuchi H, et al (2002) Bile acids inhibit Mcl-1 protein turnover via an epidermal growth factor receptor/Raf-1-dependent mechanism. Cancer Res 62: 6500–5 424. Yoon WJ, Lee JK, Lee KH, et al (2006) A comparison of covered and uncovered Wallstents for the management of distal malignant biliary obstruction. Gastrointest Endosc 63: 996–1000 425. Yoshida T, Matsumoto T, Sasaki A, et al (2002) Prognostic factors after pancreatoduodenectomy with extended lymphadenectomy for distal bile duct cancer. Arch Surg 137: 69–73 426. Yoshida T, Sugai T, Habano W, et al (2000) Microsatellite instability in gallbladder carcinoma: two independent genetic pathways of gallbladder carcinogenesis. J Gastroenterol 35: 768–74 427. Yoshimitsu K, Honda H, Kaneko K, et al (1997) Dynamic MRI of the gallbladder lesions: differentiation of benign from malignant. J Magn Reson Imaging 7: 696–701 428. Zatonski WA, Lowenfels AB, Boyle P, et al (1997) Epidemiologic aspects of gallbladder cancer: a case-control study of the SEARCH Program of the International Agency for Research on Cancer. J Natl Cancer Inst 89: 1132–8 429. Zech CJ, Schoenberg SO, Reiser M, et al (2004) Crosssectional imaging of biliary tumors: current clinical status and future developments. Eur Radiol 14: 1174–87 430. Zeng ZC, Tang ZY, Fan J, et al (2006) Consideration of the role of radiotherapy for unresectable intrahepatic cholangiocarcinoma: a retrospective analysis of 75 patients. Cancer J 12: 113–22 431. Zheng J, Zhu YM (2007) Expression of c-erbB-2 protooncogene in extrahepatic cholangiocarcinoma and its clinical significance. Hepatobiliary Pancreat Dis Int 6: 412–5 432. Zidi SH, Prat F, Le Guen O, et al (2000) Performance characteristics of magnetic resonance cholangiography in the staging of malignant hilar strictures. Gut 46: 103–6 433. Zoepf T, Jakobs R, Arnold JC, et al (2005) Palliation of nonresectable bile duct cancer: improved survival after photodynamic therapy. Am J Gastroenterol 100: 2426–30 434. Zoepf T, Jakobs R, Arnold JC, et al (2001a) Photodynamic therapy for palliation of nonresectable bile duct cancer – preliminary results with a new diode laser system. Am J Gastroenterol 96: 2093–7 435. Zoepf T, Jakobs R, Rosenbaum A, et al (2001b) Photodynamic therapy with 5-aminolevulinic acid is not effective in bile duct cancer. Gastrointest Endosc 54: 763–6
Index
A AA-amyloid, 1106–1107 ABC transporters, 65 Abdomen, auscultation, 312 Abdominal pain, 531–536 Abetalipoproteinemia, 1184 Abscesses, 390–391 amebic, 418, 420 bacterial, 417–418 hepatic, 831 pylephlebitic, 832 Absorption, 1190 Absorptive phase, 81, 134 Acalculous cholecystitis, 869 Acanthocytosis, 1028 Accelerated starvation, 1197 Accessory liver lobe(s), 621 Aceruloplasminemia, 93, 1046 Acetaldehyde dehydrogenase acetaldehyde, 1128 hepatic, 1119 Acetaldehyde-protein adducts, 1129 Acetaminophen, 932, 1228 Acetaminophen intoxication, 934 Acetic acid injection, 1363 Acetylation, 128 Acetyl-CoA carboxylase, 87 Acidophilic necrosis, 210 Acinus, complex, 18 Acrodermatitis papulosa, 314, 747 ACTH, 160 Actin filamentous, 32 filaments, 19 globular, 32 Actinomycetaceae, 835 Actinomycosis, 835 Active septa, 258 Activity index, histological, 729–730 Acute alcoholic hepatitis, 1388 Acute cholecystitis, 393 pathogenetic mechanisms, 1472 Acute fatty liver of pregnancy course, 1265 definition, 1263 diagnosis, 1264
differential diagnosis, 1264–1265 epidemiology, 1263 etiology, 1263–1264 pathogenesis, 1263–1264 pathology, 1264 prognosis, 1265 therapy, 1265 Acute hepatic congestion, 641 Acute hepatic porphyrias, 1088 Acute hepatitis, 1387–1388 Acute hepatitis C, therapy, 801 Acute intermittent porphyria, 1078, 1080 Acute leukemia, 1249 Acute liver failure (ALF), 1388 acetaminophen intoxication, 934 acid-base balance, 942 acute fatty liver, 937 acute tubular necrosis, 941 APACHE-II-score, 933 autoimmune hepatitis, 937 Budd-Chiari syndrome, 937 cardiovascular system, 941 causes, 932 coagulation disorders, 942 definition, 931 drug-induced liver injury (DILI), 935 epidemiology, 931 etiology, 931–932 general considerations, 933 hemodynamics, 941 hepatocyte transplantation, 944 hepatorenal syndrome, 941 hyperdynamic circulation, 941 infections, 940–941 liver replacement, 943 liver transplantation, 943–944 metabolic disorders, 942 model for endstage liver disease (MELD) score, 933 multi-organ-failure (MOF), 941 mushroom poisoning, 934–935 N-acetyl-cysteine, 934 nutrition, 942–943 pregnancy, 937 prognosis, 932–933 refractory shock, 941
1567
1568 renal failure, 941–942 therapy, 937–944 viral hepatitis, 935–936 Wilson’s disease, 936–937 Acute phase proteins negative, 150 positive, 150 Acute phase reaction, 150–151 Acute porphyrias, 1079–1080, 1084–1087, 1089–1090 differential diagnosis, 1087 therapy, 1089 Acute rejection, 284 BANFF grading, 285 Acute variceal hemorrhage antibiotic prophylaxis, 983 balloon tamponade, 983–984 band ligation, 983 octreotide, 983 recombinant coagulation factor VIIa (rFVIIa), 983 sclerotherapy, 983 somatostatin, 983 terlipressin, 982 therapy, 982–984 vasopressin, 982 Adaptation, cellular, 219–233 Adaptins, 73 Adefovir, 778 Adefovir dipivoxil, 708–709, 770–772 resistance, 779 results of treatment, 771–772 Adenomas, 458 ampullary, 1516 bile duct, 1288–1289 hepatocellular, 379, 382–384, 408–412, 430, 556, 1276–1279 telangiectatic, 1277 Adenomatosis, 1508, 1511 miliary hepatocellular, 1280 Adenosine, 57, 58 Adenoviruses, 827 Adhesion molecules, 33 Adiponectin, 1159–1160 Adrenal cortical hormones, 160 Adrenoleucodystrophy, neonatal, 1185 Adrenomedullin, 607 Advanced glycosylation end products (AGE), 154 African iron overload, 1046 Aggrecan, 45 AIDS-cholangiopathy, 846 Alagille’s syndrome, 309, 629, 1093–1094 AL-amyloid, 1106 Alanine aminotransferase, 320, 541 Alanine cycle, 81 Albinterferon, 802 Albumin, 226, 327–328 Albumin dialysis, extracorporeal, 1015 Alcohol, 1190 absorption, 1114 annual consumption, 1113 associated diseases, 1113 drug metabolism, 1119 gastric first pass metabolism, 1114–1116
Index Alcohol dehydrogenases, 1115–1117 Alcoholic cirrhosis, 1120 acetaldehyde, 1144 chicken wire fibrosis, 1144 clinical findings, 1144–1145 definition, 1142 differential diagnosis, 1145 epidemiology, 1142 histopathology, 1144 natural course, 1145 pathogenesis, 1142–1144 prognosis, 1145 survival rates, 1145 therapy, 1145–1146 transient elastography, 1145 Alcoholic fatty liver, 1120 alcohol oxidation, 1122 complications, 1125–1126 definition, 1121–1122 diagnosis, 1122 differential diagnosis, 1125 epidemiology, 1122 histopathology, 1123–1124 overweight, 1122 pathogenesis, 1122–1123 prognosis, 1126 sterol regulatory element binding protein, 1123 therapy, 1126 Alcoholic foamy degeneration, 224 Alcoholic hepatitis, 238, 544 Alcoholic hepatitis index, 1137 Alcoholic hepatocellular cancer, 1120 Alcoholic liver disease, 1111–1148, 1358–1359 epidemiology, 1120 guidelines, 1140 hepatocarcinogenesis, 1147 laboratory parameters, 1136 natural course, 1120 nutritional status, 1121 nutritional therapy, 1140 pathogenesis, 1130 retinoids, 1121 risk factors, 1120–1121 Alcoholic steatohepatitis, 364, 1120 abstinence, 1138–1139 antioxidants, 1140 clinical findings, 1135–1136 complications, 1137 CYP2E1, 1132 cytokines, 1131 definition, 1127 differential diagnosis, 1136–1137 drugs, 1140–1141 endotoxin, 1131 enteral nutrition, 1139 extracorporeal liver support, 1141 free fatty acids, 1132 giant mitochondria, 1135 glucocorticosteroids, 1140–1141 histomorphology, 1127 histopathology, 1134–1135 imaging, 1136
Index laboratory findings, 1136 liver transplantation, 1141–1142 Mallory-Denk bodies, 1134 malnutrition, 1139 natural course, 1137–1138 nutritional therapy, 1139–1140 parenteral nutrition, 1139–1140 pathophysiology, 1127–1134 pentoxifylline, 1141 perivenular sclerosis, 1135 prognosis, 1137–1138 proteasome inhibitors, 1134 therapy, 1138–1142 TNFa antibodies, 1141 tumor necrosis factor a, 1131 ubiquitin-proteasome pathway, 1134 Alcohol metabolism, hepatic, 1116–1119 ALD/NAFLD index, 1137 Aldosterone, 606 Alkaline phosphatase, 324–325, 540, 546, 547 Alligator bile syndrome, 1185 Allograft rejection acute, 284 chronic, 284 Alpers–Huttenlocher’s syndrome, 1186 Amanita phalloides, 180, 934, 935 antidotes, 935 therapy, 935 a-Amanitine, 1229 Amantadine, 714, 802 Amatoxins, 934 Amebiasis course, 845 definition, 843 diagnosis, 844 differential diagnosis, 845 epidemiology, 843–844 etiology, 844 pathogenesis, 844 pathology, 844 prognosis, 845 therapy, 845–846 Amiloride, 971 Amino acids, 82–83 glucogenic, 79, 83 imbalance, 1009–1010 ketogenic, 83 Aminopyrine breath test assessment, 342 confounding factors, 341 principle and technique, 341 side effects, 341–342 Aminotransferase levels extrahepatic causes of, 545 unexplained elevations, 548 Aminotransferases, 320–322, 540, 542 normal values, 538 synopsis, 322 Amiodarone, 225 Ammonia, 84, 329 Ammonia metabolism, 1008 Ammonium, detoxification of, 134–135
1569 Amoxicillin-clavulanate, 932 Ampulla of Vater benign tumors, 1514–1517 malignant tumors, 1554–1556 Ampullary adenomas, 1514 Ampullary carcinomas, 459–460 TNM, 1528 UICC-classification, 1528 Ampullectomy, 1516 Amyloid, 654 globular, 226 Amyloidoses, localized, 1106 Amyloidosis, 1251 classification, 1106 definition, 1105–1106 familial, 1106 hepatic, 1107–1108 primary, 1106 secondary, 1106 Amyloid P component, 1105 Amylopectinosis, 225, 1182 Anabolic androgenic steroids, 1249 Anastomoses arterio-portal, 21, 56 Anatomy descriptive, 11–13 functional, 13–14 microscopic, 15–47 Andersen’s disease, 225, 1182 Androgenic steroids, 580 Anemia, 796 aplastic, 796, 1028 dilutional, 1028 hemolytic, 803, 1028 megaloblastic, 1028 sideroblastic, 1028 Angina, intestinal, 535 Angiogenesis, 160 Angiokeratoma corporis diffusum, 1183 Angiolipoma, 1298 Angiomyolipoma definition, 1298 diagnosis, 1300 epidemiology, 1298 pathology, 1298–1299 therapy, 1300 Angiomyomyelolipoma, 1298 Angiosarcomas, 204 anabolic steroids, 1340 arsenic, 1340 copper, 1340 course, 1341 definition, 1340 diagnosis, 1341 differential diagnosis, 1341 epidemiology, 1340 etiology, 1340 Fowler’s solution, 1340 hereditary hemochromatosis, 1340 pathogenesis, 1340 pathology, 1340–1341 polyvinyl chloride, 1340
1570 prognosis, 1341 therapy, 1342 thorium dioxide, 1340 thorotrast, 1340 vinyl chloride, 1340 von Recklinghausen’s disease, 1340 Angiotensin converting enzyme, 1240 Angiotensin II, 596, 606 Anitimitochondrial antibodies immunofluorescence reactivities, 350 occurrence and significance, 350–351 target antigens, 350 Anomalies, vascular, 637 Anorectal varices, 976 Anorexia, 306 Anorexia nervosa, 1251 Anthracotic pigment, 230 Antibiotics, nonabsorbable, 1014 Antibodies antimitochondrial, 899 antinuclear, 900 Antibodies, against asialoglycoprotein-receptor detection systems, 353 occurrence and significance, 353 target antigens, 353 Antibodies, against liver cytosol type 1 immunofluorescence reactivities, 352–353 occurrence and significance, 353 target antigens, 352 Antibodies, against liver-kidney-microsomes immunofluorescence reactivities, 351 occurrence and significance, 351–352 target antigens, 351 Antibodies, against soluble liver antigen/liver-pancreas antigen occurrence and significance, 352 target antigens, 352 Antidepressants, 581, 1230 Antigen presenting cells, 145 Antihistamines, 580 Antineutrophil cytoplasmic antibodies immunofluorescence reactivities, 354 occurrence and significance, 354 target antigens, 353–354 Antinuclear antibodies, 900 immunofluorescence reactivities, 347 occurrence and significance, 347–349 target antigens, 347 Antioxidants, 178–180 Antiphospholipid antibody syndrome, 1250 Antiports, 64 Antipyrine clearance assessment, 341 confounding factors, 340 principle and technique, 340 side effects, 341 Antisense-oligodeoxynucleotides, 716–717 Antisense-oligonucleotides, 710–711, 1406 a1-Antitrypsin, 226, 1071 structure, 1072 a1-Antitrypsin deficiency, 544, 1071–1076 clinical manifestations, 1073–1075 course, 1075
Index definition, 1072 differential diagnosis, 1075 epidemiology, 1072 etiology, 1072–1073 immunohistochemical staining, 1073 intracytoplasmic inclusions, 1073 laboratory findings, 1075 neonatal cholestasis, 1074 pathogenesis, 1072–1073 pathology, 1073 prognosis, 1075 therapy, 1075–1076 a1-Antitrypsin phenotypes, 1073 Apical sodium bile acid transporter, 1425 Aplastic anemia, 748, 796 Apolipoproteins, 90 Apoptosis, 209, 236 Fas-induced, 215 liver diseases, 217–218 molecular mechanisms, 214–217 morphology, 214 regulation, 217 Apoptosome, 216 Apoptotic bodies, 720, 728, 1163 APRI index, 263 Aquaporins, 70, 566 Arachidonic acid, 85 Arboviruses, 828 Arenaviruses, 828–829 Arginine-vasopressin, 606, 607 Arias syndrome, 588 Arsenic, 1340 Arterial flow, 365 Arterial underfilling, 606 Arterial vascular malformations, 365 Arteries interlobar, 21 interlobular, 21 Arteriohepatic dysplasia, 1093–1094 Arterioles, terminal hepatic, 21 Arteriopathy plexogenic, 1021 rejection, 668 xanthomatous, 668 Arterioportal fistula, 666 Arterioportal shunts, 378 Arteritis, 667–668 Artery, hepatic. See Hepatic arterty(ies) Ascites, 312, 470, 1395 abdominal sonography, 609 bed rest, 970 benign, 610 biochemical findings, 610 cardiac, 604 causes, 604 chylous, 604, 611 cirrhotic, 605 cloudy, 604 complications, 612, 969 definition, 603 diet, 970 different forms, 961
Index differential diagnosis, 611–612 dilutional hyponatremia, 970 diuretic-intractable, 974 diuretic-resistant, 613, 974 diuretics, 970–971 errors in the treatment, 973 etiology, 603–604 fine-needle aspiration, 609 formation, 605 hemorrhagic, 604 history, 609 infected, 612 inflammatory, 604 large-volume paracentesis (LVP), 972–973 malignant, 604, 610 paracentesis, 609 pathogenesis, 604–605 portal hypertensive, 604 prognosis, 612–613 refractory, 613, 973–974 serous, 604 simple, 613 stepped care approach, 970 tense, 613 types, 969 uncomplicated, 969 Ascites formation, theories, 608–609 Ascitic fluid, cytologic examination, 611 Asialoglycoprotein receptor, 82 Aspartate aminotransferase, 320, 541 Aspergillosis, 860 Asterixis, 315–316, 1010 Asteroid bodies, 1240 Astrocyte function, 1007–1009 swelling, 1008 Atazanavir, 1216 Atoimmune regulator, 885 Atresia, biliary, 628–630 Atrial natriuretic peptides, 607 Autoantibodies, 345–354, 883 in liver diseases, 346 naturally occurring, 345–346 pathologic, 345–346 patterns, 349 Autoimmune cholangitis, 909–910, 926 Autoimmune hepatitis (AIH), 195, 237, 276–277, 364, 543, 925 autoantibodies, 888 clinical presentation, 886–887 course and prognosis, 889 definition, 881 diagnosis, 883–884 differential diagnosis, 888–889 epidemiology, 881–882 etiology, 882 extrahepatic diseases, 887 genetic factors, 882–883 immunologic factors, 882 immunosuppressive therapy, 889 laboratory findings, 887–888 pathogenesis, 882
1571 pathology, 883 relapses, 891 scoring system, 278, 885 standard treatment, 890 subtypes, 883, 886 therapy, 889–892 Type I, 884 Type II, 884–885 Type III, 886 treatment failure, 891 Autoimmune overlap syndromes, 925–927 Autoimmune pancreatitis, 1249 Autoimmune polyglandular syndrome type I, 885 Autoimmune reactions, 194–195 Autoimmune thyroiditis, 748 Autoregulation, 56–58 Azathioprine, 1374 B Babesiosis, 846 Bacillary angiomatosis, 835 Bacillary peliosis, 835 Bacterial cholangitis antibiotics, 1498 prophylaxis, 1499 treatment, 1497 Bacterial infections, 994–998 Ballooning degeneration, 207 Balloon occlusion technique, 517 Balloon tamponade, 983–984 BANFF grading, 285 Banknote skin, 314 Barcelona Clinic liver cancer staging classification, 1325 Baroreceptors, high pressure, 606 Bartonella (Rochalimaea) henselae, 650, 835 Basiliximab, 1374 Bassen–Kornzweig syndrome, 1184 Bcl-2, 217 Beau’s lines, 315 Benign bile duct tumors epithelial tumors, 1512 non-epithelial tumors, 1512 pathology, 1512 tumor-like Lesions, 1512 Benign gallbladder tumors epithelial tumors, 1508 non-epithelial tumors, 1508 pathology, 1508–1509 tumor-like lesions, 1508 Benign recurrent intrahepatic cholestasis, 1097–1098 Benign tumors of ampulla, pathology, 1514–1515 Betaglycan, 45 Biglycan, 45 Big spleen syndrome, 847 Bile bacteria, 1495–1496 canalicular, 562, 565 composition, 103 ductal, 562, 565 formation, 104 functions, 104 hepatic, 562
1572 lithogenic, 119–122 metabolism, 103 secretion, 567 Bile acids, 104, 107–108, 327, 547, 1258, 1423, 1476 enterohepatic circulation, 116–117 extraction, 135–136 genetic disturbances, 124 hypercholeretic, 114 monohydroxylated, 123 primary, 107 reabsorption, 118 secondary, 108–109 tertiary, 108–109 toxic, 123 transcellular transport, 118 transporter, 117 uptake, 66, 117–118 Bile acid synthesis, 107–108 Bile canaliculi, 19 Bile duct adenoma clinical manifestations, 1288 definition, 1288 differential diagnosis, 1288–1289 histology, 1288 therapy, 1289 Bile duct lesions, ischemia-induced, 574 Bile ducts aberrant, 1433 accessory, 1433 anomalies, 625–630 carcinoma, 1487 cystically dilated, 556 cystic dilatations, 1434 cysts, 1434–1435 decompression, 1498 extrahepatic, 395–399, 1418–1421 hilar, 20 interlobular, 40 intrahepatic, 19 motility disorders, 1441–1454 obstruction, 586, 1496 segmental, 20 septal, 20, 40 strictures, 458, 1445 terminal, 9, 20 Bile duct stones, 441, 1445 clinics, 1484 complications, 1485–1487 diagnosis, 1484–1485 endoscopically unextractable, 1489 endoscopic retrograde cholangio-pancreaticography, 1484 endoscopic stone extraction, 1487–1488 endosonography, 1484 epidemiology, 1483–1484 magnetic resonance cholangio-pancreatography, 1484 percutaneous transhepatic cholangiography, 1485 primary, 1460 secondary, 1460 surgery, 1490 treatment, 1487–1491 ultrasound, 1484
Index Bile ductules/ ductuli, 19, 40 Bile flow bile acid dependent, 564 bile acid independent, 564 Bile formation, 137, 139 Bile infarcts, 243, 569 Bile lakes, 243, 569 Bile leaks, 444 Bile lipids, 105–106 Bile salt export pump, 108 Bile salts, 104, 107–108 Bile secretion, 113 functional regulation, 115–116 Biliary atresia congenital, 1435–1436 embryonic-fetal type, 629 extrahepatic, 628 intrahepatic, 628 perinatal form, 629 Biliary cancer, 503–505 chemotherapy, 1544 Biliary carcinoma, intraluminal brachytherapy, 1549 Biliary cirrhosis, 569 Biliary colic, 1475 Biliary cystadenoma definition, 1289 diagnosis, 1289–1290 differential diagnosis, 1290 epidemiology, 1289 pathology, 1289 therapy, 1290 Biliary ductopenia causes, 922 course, 924 definition, 921 diagnosis, 924 differential diagnosis, 924 drugs, 923 epidemiology, 921 etiology, 921–923 pathogenesis, 921–923 pathology, 923–924 prognosis, 924 therapy, 924 Biliary epithelial cells, 40, 146–147 intrahepatic, 136 Biliary infections, 1495–1503 Biliary microhamartomas, 1288 Biliary obstruction, histopathology, 241–245 Biliary pain, 535–536 Biliary pancreatitis, 1474, 1486–1487 Biliary papillomatosis definition, 1291 diagnosis, 1291 differential diagnosis, 1291 epidemiology, 1291 etiology, 1291 pathogenesis, 1291 prognosis, 1291 therapy, 1291 Biliary stenosis, 1435–1436
Index Biliary strictures benign, 442 malignant, 442–444 Biliary tract surgery, 1392, 1499 Biliopathy, portal hypertensive, 988 Bilirubin, 105–106, 330–331 delta fraction, 331 direct reacting, 330 encephalopathy, 587 excretion, 112 indirect reacting, 330 metabolism, 103–124 synthesis, 110 transport, 110 unconjugated, 110 uptake, 110 Bilirubinostasis, 242, 569 Bilitranslocase, 110, 113 Bilovenous fistulas, 446 Bilrubin, 230 Bioinactivation, 128 Biotransformation, 132, 1211 hepatic, 127–130 Bismuth-Corlette-classification, 1527 Bisphosphonates, 582, 1030 Black pigment stones, 1460, 1464–1465 Blastomycosis, 860–861 Bleeding signs, 314 Blood flow hepatic, 55–56 portal, 596–597 portal venous, 366 retrograde portal venous, 367 splanchnic, 596–597 Blood pool scintigraphy acquisition technology, 426–427 interpretation, 427 principle, 426 Blood vessels, intrahepatic, 21 Blue lunulae, 315 Boas sign, 1472 Bodies multivesicular, 30, 31 residual, 30 Bone disease metabolic, 570 posttransplant, 1030 Borreliae, 835–836 Botulinum toxin, 1450–1451 Boutonneuse fever, 839 Bouveret syndrome, 1474 Brain natriuretic peptides, 607 Branched chain amino acids, 1202 Branching enzyme, 80 Breakthrough clinical, 777 virological, 777 Breast milk jaundice, 587 BRIC 1, 1095, 1097–1098 BRIC 2, 1098 Bridging necrosis, 721
1573 Bromosulphthalein test assessment, 335 confounding factors, 335 principle and technique, 335 side effects, 335 Bronchobiliary fistulas, 625 Brown pigment stones, 1460, 1465–1467 Brucellae, 836 Brunner’s gland hyperplasia, 1514 Budd-Chiari syndrome, 370, 642–645 causes of, 643 Bumetanide, 972 Bunyaviruses, 828 Burkholderia pseudomallei, 836 Byler’s disease, 124, 1095 Byler’s syndrome, 1095 C Cachexia, 310 Cadherins, 25 Caffeine clearance assessment, 340 confounding factors, 340 principle and technique, 339–340 side effects, 340 CAGE test, 1136 Calcineurin inhibitors, 1373 Calcitonin, 160, 1031 Calcium-bilirubinate stones, 1460 Caliciviruses, 674 C17-alkylated steroids, 1276 Calpains, 177 Campylobacter species, 836 Canalicular multispecific organic anion transporter, 112 Canals of Hering, 9, 19 Cancer biliary, 503–505 gallbladder, 1521–1526 Cancer of the Liver Italian Program, 1324–1325 Candidiasis biliary tract, 860 hepatic, 859 hepatosplenic, 859 Capillarization of sinusoids, 654 Capsule endoscopy, esophageal, 977 Capsule, hepatic, 8 Caput medusae, 310 Carbamazepine, 1276 Carbamoyl-phosphate synthetase, 85 Carbohydrate homeostasis, 80–82 Carbohydrate metabolism, 139–140 regulation, 80 Carbohydrate response element binding protein, 87 Carbohydrates, 76, 225–226 Carbon monoxide (CO), 55, 58 Carbon tetrachloride (CCl4), 189, 190 Carcinoembryonic antigen (CEA), 19 Carcinoids, 1350 Carcinomas ampullary, 459–460 cholangiocellular, 397–398, 434
1574 common bile duct, 459 fibrolamellar, 1337–1338 gallbladder, 1474 hepatocellular, 412–413, 432, 433, 502–503, 1307–1329 Cardiac natriuretic peptides, 607 Cardiac surgery, 1393 Cardiomyopathy, cirrhotic, 1025 Carnitine shuttle, 87 Caroli’s disease, 627–628 Caroli’s syndrome, 627–628 Carrier proteins, 63 Carvedilol, 981 Caspase, 216 Caspase activity, 752 Castleman’s disease, 825 Catalase, 179 Catalase, hepatic, 1119 Catecholamines, 160 Caudate lobe. See Lobe, caudate Cavernous transformation, 368 Celiac disease, 545, 1248 Cell cycle, 163–164 Cell death, 174, 209 programmed, 209 Cell edema, 554 osmotic, 207 Cell injury, 174 Cell membrane, 25 Cell proliferation, 157, 163–164 Cell shrinkage, 138–140 Cell swelling, hydropic, 207 Cell types, 22–23 Cellular adaptation, 219–233 Cell volume, 137, 138, 140 Central hyaline sclerosis, 258, 645 Central vein, 16 Cerebral edema, 938 Cerebral hypertension, 938–940 drug therapy, 939–940 supportive therapy, 940 therapeutic measures, 939 Cerebrotendinous xanthomatosis, 1184 Ceroid pigment, 229–230 Ceruloplasmin, 93, 1037 Cestodes, 1502 Chalk milk bile, 1473 Channels, 63 Chaperones, 177 Chaperonins, 177 Charcot-Gombault infarcts, 243 Charcot’s triad, 1486 Chelators, 1057 Chelidonium majus, 574 Chenodeoxycholic acid, 107 Cherry red spots, 979 Chilaiditi’s syndrome, 439, 622 Child-Turcotte-Pugh score, 289–290 Chlamydiae, 836 Cholangiocarcinoma, 443, 1361 biliary papillomatosis, 1528 Bismuth-Corlette-classification, 1527 definition, 1526
Index epidemiology, 1526–1528 etiology, 1528–1529 extrahepatic, 1526–1554 fluoropyrimidines, 1546 gemcitabine, 1546 intrahepatic, 413–414 oncogenes, 1528 pathogenesis, 1528–1529 topoisomerase-inhibitors, 1546 Cholangiocellular carcinomas, 434 color Doppler imaging, 397 contrast enhanced ultrasound, 398 conventional B-mode ultrasound., 397 Cholangiocytes, 9 proliferation, 159 secretion, 1425 Cholangiodysplasia, 626 Cholangiography endoscopic retrograde, 437–446 percutaneous transhepatic, 437–446 Cholangiohepatitis, oriental, 627 Cholangioles, periportal, 19 Cholangiolitis, 568 Cholangiopathies, 568 AIDS-related, 575 cavernoma-associated, 658 ischemic, 574–575, 665 oriental, 445 Cholangioscopy, 449–453 percutaneous-transhepatic, 451–452 peroral, 450–451 Cholangitis, 445–446, 470, 1486 acute, 445, 568 ascending, 244 autoimmune, 909–910 bacterial, 1495–1500 chronic non-suppurative destructive, 895 fungal, 1500 immunglobulin G4 associated, 916 parasitic, 1500–1501 primary sclerosing, 363, 911–917 recurrent pyogenic, 445, 627 secondary sclerosing, 397 small duct, 245 suppurative, 244 treatment, 1489 tuberculous, 838 Cholangitis lenta, 245 Cholate stasis, 209, 243, 569 Cholecystectomy, 1477–1479 conventional, 1477 laparoscopic, 444, 1477 Cholecystitis acalculous, 393, 577, 869, 1472 acute, 393–394 acute bacterial, 1471–1473 chronic, 394, 1473 emphysematous, 393, 1473 Cholecystolithiasis, 393 complications, 1471–1474 Cholecystolithotomy, 1479 Cholecystostomy, 1479
Index Choledochal cysts, 395–396, 625 Choledocholithiasis, 396–397, 442, 458–459 endoscopic therapy, 1488 treatment, 1487–1491 Cholehepatic shunt, 565 Cholelithiasis asymptomatic, 1470 symptomatic, 1470–1471 Cholelitholysis, 1490–1491 Choleresis, 114 secretin-induced, 566 Cholestasis, 122 canalicular, 576 causes, 563 classification, 559–562 cystic fibrosis, 579 definition, 559 drug-induced, 574 drugs, 563 ductular, 576 endotoxin-induced, 197–198 etiology, 559–562 graft versus host disease, 577–578 histopathology, 568 imaging techniques, 572–573 intrahepatic, 585, 1093–1098 laboratory findings, 571–572 liver transplantation, 578 pathogenesis, 562–568 postoperative, 576–577 pregnancy, 578–579 progressive familial intrahepatic, 124 radiation-induced, 568 sarcoidosis, 577 sepsis-associated, 575–576 Cholestasis of pregnancy, intrahepatic, 1096 Cholestatic patterns, 320, 546–547 Cholestatic reaction, 241–246 Cholesterol, 89, 224–225 biosynthesis, 106 synthesis, 88 transport, 106 Cholesterol-7a-hydroxylase, 107 Cholesterol concrements, 1460 Cholesterol ester storage disease, 1184 Cholesterolosis, 394, 1508 Cholesterol polyps, 1509 Cholesterol stones diabetics, 1462 drugs, 1462 gallbladder motility, 1464 gallbladder mucus, 1463 genetic factors, 1462 hormonal aspects, 1462 hyperinsulinemia, 1462 hypomotility, 1462 lith genes, 1462 lithogenic bile, 1462 microliths, 1463 multilamellar vesicles, 1464 nucleation factors, 1463 obesity, 1462
1575 Cholesterol transport, reverse, 92 Cholesteryl ester transfer proteins, 92 Cholestyramine, 579, 1260 Cholinesterase, 326–327 Chondroitin sulfate, 45 Chronic biliary disease, staging, 280 Chronic granulomatous disease, 1251 Chronic hepatic porphyria, 1088–1090 Chronic hepatitis, 272–277 grading, 272–276, 729–731 semi-quantitative scoring, 729 staging, 272–276, 729–731 Chronic hepatitis B age, 754–755 coinfections, 756–757 HBeAg-negative, 751–752 HBeAg-positive, 750 HBV genotype, 755 HBV/HCV coinfection, 756 HBV/HDV coinfection, 756 HBV/HIV coinfection, 756 immunosuppression, 755 natural history, 754 viral load, 755–756 Chronic hepatitis C, 712–717, 728 extrahepatic manifestations, 793–797 therapy, 801–805 Chronic inflammatory bowel disease, 1248 Chronic liver disease, 498–501 surgery, 1388–1390 Chronic lobular hepatitis, 723 Chronic lymphocytic leukemia, 1250 Chronic myelocytic leukemia, 1249 Chronic viral hepatitis, 1388–1389 Chylomicrons, 90 Chylous ascites, 611 Circulation enterohepatic, 584 hepatic, 55–58 hyperdynamic, 596 Circulatory dysfunction, post-paracentesis, 973 Cirrhose cardiaque, 649 Cirrhosis, 543, 949–964 alcoholic, 955, 958, 1142–1146 biliary, 569 cryptogenic, 950 incomplete septal, 954 Indian childhood, 961 macronodular, 953–954 malnutrition, 1190 micronodular, 952–953 mixed forms, 954 monoacinar, 953 multiacinar, 953 primary biliary, 282, 362–363, 895 secondary biliary, 243 survival, 963 Cirrhotic cardiomyopathy (CC), 1025 Clathrin, 73 Claudin, 690 Clevudine, 774 Clinical breakthrough, 777
1576 Clomiphene, 1276 Clonorchis sinensis, 627, 1511 Clostridium perfringens, 836–837 Clotting factors, 328–329 deficiency of, 1029 CMV hepatitis, 825 COACH syndrome, 626 Coagulative necrosis, 210 Coagulopathy, 1394–1395 hepatic, 1029 Coated pits, 72 Coatomers, 72 Coccidioidomycosis, 860–861 Colestipol, 579 Collagen, 39, 42 biosynthesis, 43 bundles, 42 fibrils, 42 degradation, 44 structure, 42 types, 43–44 Collagenases, 44, 254 Collapse fsibrosis, 258 Collaterals, portosystemic, 600 Colloidal scintigraphy acquisition technology, 426 interpretation, 426 principle, 425–426 Colon cancer, 505 Colopathy, portal hypertensive, 988 Color Doppler imaging (CDI), 365 Combination therapy contraindications, 803–804 side effects, 803–804 Common bile duct carcinoma, 459 duplication, 1433 Compartment of uncoupling receptor and ligand (CURL), 71, 73 Complex lipids, synthesis, 88 Computed tomography, 405–421 Confluent necrosis, 721 Congenital erythropoietic porphyria, 1082, 1087, 1091 Congestion acute hepatic, 641 chronic hepatic, 641–642 Congestive heart failure, 367–368 Congo red staining, 1108 Conjugation reactions, 128 Connexins, 26 Copper, 92–93, 201–202, 228, 1035 excretion, urinary, 1038 hepatic, 1040 overload, 202 transport, 1036 Cori cycle, 81 Coronaviruses, 829 Corset liver, 622 Cotransport, Na+/HCO3¯, 71 Councilman bodies, 828 Covalently closed circular, 746
Index Cowdry A, 824 Cowdry B, 824 Coxiella burnetii, 839 Coxsackie virus, 827 CpG-Oligo(deoxy)nucleotides, 712–713 Crigler–Najjar syndrome type I/II, 587–588 Crigler–Najjar type I/II, 586 Cristae, 30 Critical flicker frequency, 1011 Cross talk hepatocyte-cholangiocyte, 1425 viral, 194 Cruveilhier-von-Baumgarten disease, 637 Cruveilhier-von Baumgarten syndrome, 600, 637 Cryoglobulinemia, 793–794 Cryoglobulins, 794 Cryptococcosis, 860 Cryptosporidiosis, 846 Cyanoacrylate, 985 Cyclin, 159 Cyclin-dependent kinases, 165 Cyclosporin A, 1217 Cyclosporine, 1354, 1373 Cystadenoma, biliary, 1289–1290 Cystadenomas, 1511 Cystic duct anomalies, 1429–1432 long, 1445 Cystic fibrosis, 364, 568, 579, 1096 clinical manifestations, 1102 course, 1102–1103 definition, 1101 epidemiology, 1101 etiology, 1101–1102 hepatobiliary manifestations, 1102 pathogenesis, 1101–1102 pathology, 1102 prognosis, 1102–1103 therapy, 1103 Cystic fibrosis transmembrane regulator (CFTR), 1101 Cystinosis, 1185, 1251 Cysts, 555 Cytochrome P452, 1118 isoenzymes, 130 mixed function, 128 Cytochrome P450 system, 1213 Cytokeratins 20, 1291 Cytokeratins, 32 Cytokines, 35, 142–149, 151, 253 proinflammatory, 147 Cytomegalovirus, 233, 825–826 Cytomegalovirus infection, 869 Cytoplasmic deposits, 208 Cytoskeleton, 31–32, 66 Cytosolic enzymes, 539 Cytosoloic function, 334
D Daclizumab, 1374 Dcytb protein, 1048
Index Death domain, Fas-associated, 215 Death inducing signaling complex, 215 Debranching enzyme, 80 Decorin, 45 Defects in fatty acid oxidation, 1186 Deferasirox, 1057, 1064 Deferoxamine, 1057, 1064 Deferoxamine testing, 1049 Degeneration alcoholic foamy, 224 feathery, 209, 243, 569 pseudoxanthomatous, 209 vacuolar, 207 Delayed early genes, 165 Delta-bilirubin, 331, 584 Deltaviridae, 683 Dendritic cells (DC), 145, 149 Dengue virus, 828 Deposits extracellular, 554 intracellular, 219–233, 554 intracytoplasmic, 224–232 Depression, 804 De Ritis quotient, 321, 541 Dermatan sulfate, 45 Dermatologic disorders, 795–796 Desmet’s score, 274, 275 Desmin, 37 Desmosomes, 25 Detoxification, 127 Development, embryonic, 7–10 Dexamethasone, 580, 1260 Diabetes mellitus, 1249 gestational, 748 hepatogenous, 1027 Diabetic hepatosclerosis, 654 Diabetic microangiopathy, 654 Diacytosis, 66 Dietary supplements, 1202 Diffusion facilitated, 63 free, 63 Dilatation, sinusoidal, 649–650 Dioxygenases, 127 Direct hepatotoxins, 1223, 1224 Disarray, lobular, 720 Discoidin domain receptors (DDRs), 255 Discriminant function, 291–292 Disse, space of, 17 Distal cholangiocarcinoma resection, 1535–1536 survival, 1535 Diuretic therapy, practical approach, 972 Diverticulum, hepatic, 7, 8 DNA, 746 ligase, 180 polymerase, 180 repair, enzymes of, 180 vaccination, 710, 1407 vaccines, 713 DNA-glycosylases, 180
1577 Doppler indices, 365–366 Doppler ultrasound, 364–371 Doss-porphyria, 1080–1081 Double target sign, 417 Doughnut granuloma, 249, 1237 Downhill-varices, 976 D-penicillamine, 1040 Dronabinol, 581 Drug-induced, 189–190 Drug-induced liver injury, 189–190, 875–876, 1223–1230 Drug metabolism age, 1212 factors affecting, 1211–1220 gender, 1212 genetic factors, 1212–1217 hepatic, 1211–1220 pharmacogenetics, 1213 phase I, 1213 phase II, 1213 Drugs, 544–545, 577 biliary excretion, 1217–1218 high hepatic clearance, 1218 low hepatic clearance, 1218 toxicity, 1211–1220 Dubin–Johnson pigment, 228–229, 1277 Dubin–Johnson syndrome, 584, 586, 589, 1096 Ductal plate, 9 Ductal plate malformations, 625, 626 Ductopenia, biliary, 921–924 Ducts of Luschka, 392 Ductular hepatocytes, 158 Ductular proliferation, 1285 Ductular reaction, 41, 245–246, 721 Duct, venous, 13 Dupuytren’s contracture, 316 Dynactin, 66 Dynein, 32, 66 Dysfunction granulocyte, 1028 sexual, 307, 797, 1026 sphincter of Oddi, 1445–1451 thyroid, 1026–1027 Dyskinesia, sphincter of Oddi, 523, 1446, 1451–1454 Dysplasia large cell, 724, 1313–1314 small cell, 724, 1314 Dysplastic foci, nodules, 1314 E Ebola virus, 829 Echinococcal disease, 420–421 Echoviruses, 827 Eclampsia, 1267 Ectasia, gastric antral vascular, 987 Ectopy, 621–622 Edema, cerebral, 938 Ehrlichiae, 837 Ehrlichiosis, 837 Elastin, 42, 44–45 Elastosis perforans serpiginosa, 1040
1578 Electrohydraulic lithotripsy, 1489 Eltrombopag, 796 Embryonal sarcoma course, 1346 definition, 1345 diagnosis, 1346 differential diagnosis, 1346 epidemiology, 1345 etiology, 1345 pathogenesis, 1345 pathology, 1345 prognosis, 1346 therapy, 1346 Embryonic development. See Development, embryonic Emtricitabine, 774 resistance, 780 Encephalopathy, 1395–1396 hepatic, 315, 938, 1005–1015 portosystemic, 306 Endocrine cells, 1421 Endocytosis, 66 receptor mediated, 72 Endogenous pathway, 91 Endonuclease, 180 Endoplasmic reticulum, 27 Endoplasmic reticulum stress, 173–180, 1158 defense mechanisms, 177 Endoscopic retrograde cholangiopancreaticography, 1499 Endoscopic sphincterotomy complications, 1488 results, 1488 Endoscopic therapy, 443 Endoscopic ultrasonography gallbladder diseases, 460 liver diseases, 460 Endoscopoic retrograde cholangiography, complications, 446 Endosomes, 30, 73 Endothelial cells, sinusoidal, 17, 32–34, 57 Endothelin-1 (ET-1), 254–255 Endothelins, 57, 58, 596, 606, 607 Endotoxins, 35, 197–198 End-stage renal disease, 483 Energy, 1196 Energy metabolism, 1191 Entactin, 47 Entecavir, 709, 772–773, 779 resistance, 779 results of treatment, 772–773 Enterohepatic circulation, 584 Enteropathy, portal hypertensive, 988 Enteroviruses, 827 Enzymes, 319–327 branching, 80 clearance, 539 cytosolic, 539 debranching, 80 hepatitic patterns, 540 induction, 580 inhibitors, 714
Index mitochondrial, 539 organ distribution, 541 patterns of injury, 540–548 Epidermal growth factor (EGF), 161 Epithelial tumors, 1275 Epithelioid granuloma, 248 Epithelioid hemangioendothelioma course, 1344 definition, 1343 diagnosis, 1344 differential diagnosis, 1344 epidemiology, 1343 etiology, 1343 pathogenesis, 1343 pathology, 1343–1344 prognosis, 1344 therapy, 1344–1345 Epitope vaccine, 713–714 Eplerenone, 971 Epstein-Barr virus, 826–827 Erdheim–Chester disease, 1251 Erectile dysfunction, 1026 Erythema infectiosum, 829 Erythrophagocytosis, 231, 654 Erythropoiesis, ineffective, 330, 587 Erythropoietic and X-linked protoporphyria, 1082 Erythropoietic protoporphyria, 1078, 1084, 1086–1088, 1090–1091 Esophageal varices acute bleeding, 980 anatomy, 976 b-blockers, 979, 980 bleeding, 978–979 carvedilol, 981 cherry red spots, 979 course, 978 definition, 976 diagnosis, 977–978 endoscopic grading, 977 endoscopic ultrasound, 977 epidemiology, 976 etiology, 976 multiband ligation, 981 nitrates, 981 octreotide, 981 pathophysiology, 976 preprimary prophylaxis, 979–980 primary prophylaxis, 980 prognosis, 978 prophylaxis, 979 red wale marks, 979 sclerotherapy, 981 secondary prophylaxis, 980 therapy, 979 white nipple sign, 979 Essential thrombocytopenia, 1249 Ethanol bacterial metabolism, 1119 carcinogenesis, 1119 gastric first pass metabolism, 1114–1116
Index metabolic diseases, 1117 Euchromatin, 26 EUS-miniprobes, 456–457 Exchange pump, HCO3¯/Cl¯, 71 Exocytosis non-triggered or constitutive, 65 triggered or nonconstitutive, 65 Exogenous pathway, 90 Extracellular matrix (ECM) , 42, 159, 255 Extracorporeal shock wave lithotripsy, 1489 Extrahepatic bile ducts, 395–399 anatomy, 1415 anomalies, 1433–1436 benign strictures, 1437 benign tumors, 1511–1514 cell types, 1419 electron microscopy, 1419 embryonic development, 1415 form anomalies, 1434–1436 microscopy, 1419 physiology, 1424–1425 Extrahepatic biliary tract, anomalies, 1429–1432 Extrahepatic cholangiocarcinoma adenocarcinomas, 1529 chemoradiation, 1545–1549 chemotherapy, 1543–1545 clinical manifestations, 1529 complications, 1553 diagnosis, 1529–1531 differential diagnosis, 1531–1532 endoprostheses, 1538 histologic types, 1529 mesenchymal tumors, 1529 molecular targeted therapy, 1551–1552 palliative management, 1538–1549 palliative radiotherapy, 1545 pathology, 1529 prognosis, 1532–1554 recurrent, 1553 stenting, 1538–1540 surgical palliation, 1543 survival rates, 1534 therapy, 1532–1554 TNM, 1527 UICC-classification, 1527 Extrahepatic disease, hepatic involvement, 1247–1251 F Fabry’s disease, 1183 Facies alcoholica, 309 False neurotransmitters, 1009–1010 Familial amyloidosis, 1106 Familial high density lipoprotein deficiency, 1184 Family history, 301 Farnesoid X receptor, 108 Fas-dependent cell death, 193, 194 Fas-ligand, 192 Fas-receptor, 215 Fatigue, 305, 571, 582 Fat-soap-stones, 1466 Fat storing cells, 36
1579 Fatty acid degradation, 86–87 essential, 85 b-oxidation, 86 polyunsaturated, 176 synthesis, 87 transport protein, 86 Fatty acid-binding proteins, 86, 119 Fatty acid synthase, 87 Fatty liver, 224, 277–280 pathophysiology, 1158 Fatty liver disease, nonalcoholic, 544, 1153 Fat vacuoles, 37 FDG-PET/-CT, 432–435 Feathery degeneration, 209, 243, 569 Felty’s syndrome, 1250 Fenestrae, 33 Fenton-reaction, 175, 179 Ferrokinetic measurements, 1049 Ferroportin, 1061 Ferroportin 1, 1048 Ferroportin disease, 1061–1063 Ferroportin mutants, 1062 Fetor hepaticus, 310, 1010 Fever, 307 hemorrhagic, 828 Fibers, parasympathetic, 22 Fibril banded, 42 proteins, 1105 Fibrinogen, 226 Fibrinogen storage disease, 226 Fibrin ring granulomas, 249, 1237 Fibroblast growth factors (FGF), 9, 162 Fibrogenesis, 252 biomarkers, 262–263 Fibrogenic reaction, 251–266 Fibro index, 263 Fibrolamellar carcinoma calcifications, 1337 collagen bundles, 1337 definition, 1337 diagnosis, 1337 differential diagnosis, 1337 epidemiology, 1337 immunocytochemical staining, 1337 mitochondrial hyperplasia, 1337 pathology, 1337 prognosis, 1338 survival rates, 1338 treatment, 1338 Fibromodulin, 45 Fibromyosarcoma, 1350 Fibronectin, 46 Fibropolycystic diseases, 626 Fibropolycystic liver diseases, 625 Fibrosing cholestatic hepatitis, 726, 729 Fibrosis biomarkers, 264 centrilobular, 258 indices, 263
1580 patterns, 260 pericellular, 257–258 periductal, 256 periportal, 256–257 perisinusoidal, 257–258 portal, 256–257 scores, 263 semiquantitative scoring system, 283–284 therapeutic approaches, 263–266 transmembrane conductance regulator, 65 Fibrotest, 263 Fibrous septa, 258 Fibrous tumors, 1301–1303 Filaments, intermediate, 32 Filoviruses, 829 Fine needle aspiration, ultrasound guided, 469 Fitz-Hugh-Curtis syndrome, 612, 836, 837 Flapping tremor, 1010 Flaviviridae, 686 Flaviviruses, 828 Floating gallbladder, 1430 Florid bile duct lesion, 897 Fluid volume, extracellular, 605–608 Fluorescence patterns, 347, 348 Fluoropyrimidines, 1546 Focal liver lesions, 371–391, 429–432, 553–557 Focal nodular hyperplasia, 379–382, 407, 430, 556 color Doppler imaging, 380 contrast-enhanced ultrasound, 380–381 CT-scanning, 1286 definition, 1284 diagnosis, 1285–1286 differential diagnosis, 1286–1287 epidemiology, 1284 etiology, 1284 hepatobiliary scanning, 1286 imaging, 1286 magnetic resonance imaging, 1286 natural history, 1287 pathogenesis, 1284 pathology, 1284–1285 prognosis, 1287 telangiectatic, 1277, 1285 therapy, 1287 ultrasonography, 1286 variant forms, 1285 Focal steatosis, 1298 ultrasound, 1298 Focus dysplastic, 1314 iron-free, 1314 Forbe’s/Cori’s disease, 1182 Foreign bodies, 230–231 Foreign body granulomas, 247 Forns index, 263 Fowler’s solution, 1340 Francisella tularensis, 837 Free radicals, 173–180 Free water excretion, 613 Fresh frozen plasma (FFP), 942 Fructose, 76
Index Fructose 1,6-biphosphatase, 79 Fructose intolerance, 1182 Fulminant hepatic failure, 482 Fulminant hepatitis, 721 Fungal infections, 859–861 Furosemide, 971 G Gabapentin, 581 Galactose, 76 Galactose-breath test, 338 Galactose elimination capacity assessment, 338 confounding factors, 338 principle and technique, 337–338 side effects, 338 Gallbladder adenomas, 1508 agenesis, 1429 anatomy, 1415 anomalies, 626, 1429–1432 benign tumors, 1507–1511 benign tumors, epidemiology, 1507–1508 bile, 105, 1423 bile excretion, 1423–1424 bile storage, 1423–1424 carcinoma, 395, 1474 duplication, 1430 embryonic development, 1415 empyema, 1473 examination, 311 hydrops, 1473 hypoplastic, 1102 left-sided, 1431 motility, 1424 numerical anomalies, 1429–1430 physiology, 1423 polyps, 395 positional anomalies, 1430–1431 sludge, 1467 stricture, 1431 tumors, classification, 1507 variations, 1430 varices, 988 Gallbladder cancer adenocarcinoma, 1523 adjuvant treatment, 1525 chemotherapy, 1526 cholelithiasis, 1522 clinical manifestations, 1523 diagnosis, 1523–1524 differential diagnosis, 1524 epidemiology, 1521 etiology, 1522–1523 external-beam radiation therapy, 1525 gallbladder polyps, 1522 histologic types, 1523 K-RAS mutations, 1523 lymphadenectomy, 1525 palliative treatment, 1525–1526 pathogenesis, 1522–1523
Index pathology, 1523 prognosis, 1524–1526 recurrent, 1526 therapy, 1524–1526 TNM-classification, 1522 UICC-classification, 1522 Gallbladder disease, 391–395 congenital anomalies, 392–393 Gallbladder stones cholecystography, 1468 computed tomography, 1469 endoscopic ultrasound, 1469 epidemiology, 1459–1461 etiology, 1461–1467 intravenous cholecystography, 1469 magnetic resonance cholangiography, 1469 natural course, 1469–1470 oral cholecystography, 1468 pathogenesis, 1461–1467 percutaneous transhepatic cholangiography, 1469 radiological techniques, 1467–1469 ultrasound, 1467 Gallstone disease, ultrasound findings, 1467 Gallstone(s) prevalence, 1460 prophylaxis, 1474–1475 therapy, 1475–1479 g-Aminobutyric acid (GABA), 1009–1010 Gamma-glutamyl transferase, 323–324 Gangliocytic paraganglioma, 1514 Gangliosidosis, 1183 Gap junctions, 25–26 Gas embolism, portal vein, 661 Gastric antral vascular ectasia (GAVE), 987 Gastric cancer, 506 Gastric varices, 985–986 Gastroesophageal varices, 600, 985 Gastrointestinal symptoms, 306 Gastropathy, portal hypertensive, 986–987 Gaucher cells, 225 Gaucher's disease, 225, 1183 Gelatinases, 44 Gemcitabine, 1546 Generalized pustular psoriasis, 1251 Genes augmentation, 1407 delayed early, 165 expression, 1405 immediate early, 164, 165 repair, 1404 substitution, 1404 Gene therapy, 1403–1409 antiangiogenic, 1408 suicide, 1407–1408 Genetic classification, 1403 Genetic hemochromatosis mortality risk, 1053 survival of, 1051 Genetic immunization, 710 Genetic polymorphism, 1214 Genetic vaccination, 710
1581 Genome, mitochondrial, 30 Genotypic resistance, 777 GERL-compartment, 30 g-Globulins, 328 Ghrelin, 1160 Gianotti-Crosti syndrome, 747 Giant cells arteritis, 1250 hepatitis, postinfantile, 722 multinucleated, 232 Giardia lamblia, 846 Giardiasis, 846 Gilbert’s disease, drug toxicity, 1214 Gilbert’s syndrome, 586, 588–589, 1214 phenotype, 1214 Glands, peribiliary, 20 Glasgow alcoholic hepatitis index, 1138 Glazed tongue, 314 Glisson’s capsule, 12 Globular enhancement, 407 Glomerulonephritis, 748, 776, 794 Glucagon, 160 Glucagon resistance, 1191 Glucocerebrosides, 225 Glucokinase, 76, 78 Gluconeogenesis, 77–80 Glucose, 76 activated, 80 metabolism, 133–134 requirement, 1201–1202 transporter, 76 transport proteins, 64 Glucose homeostasis, alterations, 1027 Glucose 6-phosphatase, 79 Glucose 6-phosphate, 76 Glucuronidation, 111–112, 128 Glucuronidation enzymes, genetic organization, 1214–1215 Glutamate, 84 Glutamate dehydrogenase, 322, 541 Glutamatergic transmission, 1008 Glutamine, 84 Glutamine cycle, intercellular, 135 Glutamine synthesis, 1008 g-Glutamyl transferase, 540 g-Glutamyl transpeptidase, 546–547 Glutathione, 114 Glutathione peroxidase, 132 Glutathione-S-tranferase, 1121 Glycogen, 25, 225–226, 232–233 inclusions, 24 Glycogen metabolism, 79–80 Glycogenosis type II, 225 Glycogenosis type IV, 225 Glycogen storage diseases, 383–384, 1182, 1276 Glycolipids, 86 Glycolysis, 76–77, 80 Glycoproteins, adhesive, 42, 46 Glycosaminoglycans, 42 Glypican 3, 1317 Golgi apparatus, functions, 29
1582 Gonococcal sepsis, 837 Gonococci, 837 Graft-vs.-host disease, 1251 Granulocyte dysfunction, 1028 Granulomas caseating, 1236 doughnut, 249 epithelioid, 248 fibrin ring, 249, 725 foreign body, 247 hepatic, 1235–1238 histiocytic, 826 immune, 247 lymphohistiocytic, 248 mineral oil, 249 non-caseating, 1237 tuberculoid, 860 Granulomatous hepatitis, 248 Granulomatous phlebitis, 661 Granulomatous reaction, 247–249 Granuloma types, 247–248 Granzymes, 193 Greater celandine, 574 Ground-glass hepatocytes, 219–222 Ground-glass inculsions, 727 Growth factors epidermal, 161 fibroblast, 162 hepatocyte, 159, 161 insulin-like, 162 transforming, 162 vascular endothelial, 160 Growth hormone, 161 Günther’s disease, 1087, 1084 (Guenther’s on page 1084) Gynecomastia, 310 H Haber-Weiss-reaction, 175 Hair growth, 315 Hairpin ribozymes, 711 Hairy cell leukemia, 1250 Half and half nails, 315 Halothane, 1230 Hamartoma, mesenchymal, 1297 Hammerhead ribozymes, 711 Hantavirus, 828 Harmonic imaging, 374 Hashimoto’s thyroiditis, 795 HBsAg carrier, asymptomatic, 747 HBsAg carrier state, inactive, 752 HBV infection, silent, 756 HBx-antigen, 679 Heart failure, 1248 congestive, 367–368 Heat shock proteins (Hsp), 177 Heat stroke, 1251 Helicase inhibitors, 715 HELLP syndrome, 1251, 1263, 1268–1269 Hemangioendothelioma epithelioid, 1343–1345 infantile, 1295–1296
Index Hemangioma, 376–379, 407, 430–432, 556 atypical, 377 cavernous, 1292 color Doppler imaging, 376 contrast-enhanced ultrasound, 376–377 conventional B-mode ultrasound., 376 CT scan, 1293 definition, 1292 diagnosis, 1292–1294 diagnostic criteria, 377 differential diagnosis, 1294 epidemiology, 1292 fine needle biopsy, 1294 giant, 556, 1292 MRI, 1294 natural history, 1294–1295 pathology, 1292 prognosis, 1294–1295 sonography, 1293 treatment, 1295 Hemangiomatosis, diffuse systemic, 1292 Hematoma, 391 Hematopoiesis, extramedullary, 654 Heme carrier, 95 carrier protein 1, 94 Hemobilia, 444 Hemochromatosis, 96 classification, 1046 early diagnosis, 1051 hereditary, 544, 1045–1065 natural course, 1046 neonatal, 1047 secondary, 1046, 1047, 1063–1065 survival, 1051 Hemojuvelin, 1059 Hemolysis, 576–577, 586–587 Hemolytic anemia, 803 Hemophagocytic syndrome, 865, 1250 Hemorrhagic fevers, 828 Hemosiderin, 227–228 Hemostasis, 470 Hemozoin, 847 Henoch–Schönlein purpura, 1251 Hepaciviridae, 686 Hepadnaviruses, 675 Heparan sulfate, 45 Heparin, 45 Hepar lobatum, 621 Hepar succenturiatum, 621 Hepatic acetaldehyde dehydrogenase, 1119 Hepatic amyloidosis course, 1108 diagnosis, 1107–1108 differential diagnosis, 1108 pathology, 1107 prognosis, 1108 Hepatic arterty(ies), 21, 55, 366, 663–668 accessory, 637 aneurysms, 665–667 congentital anomalies, 663 occlusion, 663–664
Index Hepatic blood flow. See Blood flow, hepatic Hepatic candidiasis, 859 Hepatic catalase, 1119 Hepatic choristoma, 621 Hepatic circulation, 55–56. See also Circulation, hepatic autoregulation, 57 neural factors, 57 regulation, 56 resistance elements, 57 Hepatic clearance, 334 Hepatic coagulopathy, 1029 Hepatic copper, 1038 Hepatic diverticulum. See Diverticulum, hepatic Hepatic drug metabolism, 1211–1220 Hepatic encephalopathy, 315, 1197–1198 ammonia-lowering, 1014–1015 bacterial infections, 1006 bispectral index, 1011 branched chained amino acids (BCAA), 1013 clinical grading, 1011 clinical manifestations, 1010 course, 1012 definition, 1005 diabetes mellitus, 1006 diagnosis, 1010–1012 dietary protein, 1006 differential diagnosis, 1012 drugs, 1007 electrolyte disturbances, 1006–1007 epidemiology, 1005 etiology, 1005–1010 fluid, 1006–1007 gastrointestinal bleeding, 1006 grades, 938 lactitol, 1014 lactulose, 1014 liver transplantation, 1015 malnutrition, 1006 minimal, 1010 neuroimaging, 1011 nomenclature, 1006 nutritional measures, 1013 overt, 1010–1011 pathogenesis, 1005–1010 pathology, 1010 precipitating factors, 1005 prognosis, 1012 psychometric tests, 1011 therapy, 1012–1015 toxins, 1007 Hepatic failure, fulminant, 482 Hepatic granulomas, 1235–1238 causes, 1236 diagnosis, 1237 differential diagnosis, 1237–1238 drugs, 1236 pathogenesis, 1236–1237 pathology, 1236–1237 Hepatic growth, regulators, 160–163 Hepatic hydrothorax clinical manifestations, 1022 course, 1022
1583 definition, 1022 diagnosis, 1022 epidemiology, 1022 pathogenesis, 1022 prognosis, 1022 therapy, 1022 Hepatic iron index (HII), 292 Hepatic lipase, 91 Hepatic lymphangiomatosis, 1297 Hepatic metabolism. See Metabolism, hepatic Hepatic microcirculation, 1211 Hepatic nodule, 1321 Hepatic osteodystrophy (HO) clinical manifestations, 1030 definition, 1030 diagnosis, 1030 epidemiology, 1030 pathogenesis, 1030 therapy, 1030–1031 Hepatic pain, 536 Hepatic regeneration, 157–167 Hepatic resection, 444, 1394 Hepatic steatosis, drugs, 1126 Hepatic stellate cells (HSC), 146, 252–253 Hepatic stem cells, 159 Hepatic veins, 641–646 examination, 369–371 Hepatic venous pressure gradient, 517 Hepatitic patterns, 320, 540 Hepatitis alcoholic, 238, 544 autoimmune, 237, 276–277, 543, 881–892 chronic lobular, 723 chronic viral, 237 clinical manifestations, 733–734 cytomegalovirus, 825 diagnostics, 690–707 epidemiology, 733–734 fibrosing cholestatic, 726, 729 giant cell, 722, 824 granulomatous, 248 hypoxic, 664–665 interface, 212, 722 ischemic, 543 molecular biology, 672 necroinflammatory activity, 723 prevention, 733–734 steatoviral, 726 therapy, 733–734 viral, 542–543 Hepatitis A virus, 724–725 active immunization, 741–742 acute liver failure, 739–740 cholestasis, 726 cholestatic hepatitis, 739 clinical presentation, 736–737 diagnosis, 737–738 diagnostics, 690–691 differential diagnosis, 738–739 epidemiology, 734–736 extrahepatic manifestations, 737 fulminant hepatitis, 739–740
1584 genome organization, 673 genotypes, 673 immune globulin, 741 incidence, 735 incubation period, 735 laboratory findings, 737, 738, 747 molecular biology, 672 natural course, 739 passive immunization, 740 pathogenesis, 735 pathology, 724 postexposure prophylaxis, 740–741 preexposure prophylaxis, 740 prevention, 740–742 prognosis, 739 relapsing hepatitis, 739 risk and factors, 735, 742 serotypes, 673 therapy, 742 transmission, 735 vaccines, 742 Hepatitis B virus, 1359–1360 active immunization, 760–761 acute, 747 asian patients, 776 capsid proteins, 677–678 children, 776 chronic, 747–748 cirrhosis, 758 clinical manifestations, 747–749 coinfection, 775–776 complete therapeutic response, 762 core particles, 233 definition, 743 diagnosis, 692, 749 differential diagnosis, 749–750 drug resistance, 777–780 drug resistant mutants, 778 envelope proteins, 676–677 epidemiology, 743–745 exacerbation, 757 extrahepatic manifestations, 748–749 fibrosing cholestatic hepatitis, 776 fibrosis, 725 fulminant, 754 genome organization, 675–676 genotypes, 679, 744 goals of therapy, 762–763 HBeAg seroconversion, 757 HBsAg seroconversion, 757 HBV/HCV coinfection, 775 HBV/HDV coinfection, 775 HBV/HIV coinfection, 775 hepatitis B immunology, 682 hepatitis flares, 757–758 hepatocellular carcinoma, 758–759 immune clearance phase, 746 immune globulin, 759 immune prophylaxis, 759 immune response, 682–683, 746 immune tolerant phase, 746 incubation period, 745
Index indications for therapy, 763 interferons, 764–768 laboratory findings, 738, 747 liver biopsy, 749 liver fibrosis, 758 liver transplantation, 776 major patterns, 750 molecular biology, 675 molecular diagnosis, 695–698 mutants, 750 natural course, 747, 753–759 non-replicative phase, 746, 747 nonresponders, 777–780 occult infection, 752–753 passive immunization, 759–760 pathogenesis, 745–746 pathology, 725 polymerase, 679 postexposure prophylaxis, 759 prevention, 759–761 prognosis, 753–759 progression, 758 reactivation, 747, 761 reactivation phase, 746 replication cycle, 679–682 seroconversion, 760 serological markers, 693 serotypes, 679 special therapeutic problems, 775–780 spontaneous resolution, 757 stages, 746–747 standard interferons, 764–765 surface antigen, 694 transmission, 744 treatment and guidelines, 761–774 vaccination, 760–761 vaccine escape mutants, 761 variants, 679, 750 Hepatitis B virus infection acute, 698 chronic, 698–699 Hepatitis C virus, 1359 acute hepatitis C, 792 a1-antitrypsin deficiency, 800 biochemical breakthrough, 801 biochemical response, 801 children, 799, 807 chronic hepatitis C, 792–793 cirrhosis, 798 clinical manifestations, 791–797 coinfection, 799 diabetes mellitus, 800 diagnosis, 701–702, 791–797 end-of-treatment response, 801 end-stage renal disease, 807 epidemiology, 788–789 escape mutants, 791 ethnic groups, 808 fulminant hepatitis, 798 genome organization, 686–687 genotypes, 689 HBV/HCV coinfection, 799
Index hepatocellular carcinoma, 798–799 HIV/HCV coinfection, 800 immune pathogenesis, 790 individualizing treatment, 804–805 intravenous drug users, 808 iron overload, 791 liver cirrhosis, 807 malignant lymphoma, 1347 molecular biology, 686 molecular tests, 701 natural course, 797–800 needle stick injury, 800–801 new approaches to treatment, 805 nonresponders, 805–807 non-structural proteins, 688–689 normal aminotransferases, 799 NS 5A gene, 688 pathogenesis, 789–791 persistently normal aminotransferase levels, 805 porphyria cutanea tarda, 800 postexposure prophylaxis, 801 pregnancy, 799 prevention, 800–801 prognosis, 797–800 quasispecies, 687–688 recurrent disease, 807 relapsers, 805–807 replication cycle, 689–690 results of treatment, 804 serotypes, 689 steatosis, 791 stopping rules, 803 structural proteins, 688 sustained viral response, 801 therapeutic problems, 805–808 therapy, 801–808 transmission, 789 virologic breakthrough, 801 virologic relapse, 801 virologic response, 801 Hepatitis-delta (D) virus, 683, 699–701, 729 antigen, 684–685 clinical manifestations, 817 coinfection with HBV, 817 diagnosis, 699, 817 epidemiology, 816 genetic heterogeneity, 816 genotypes, 684 immunology, 685–686 molecular biology, 683–684 molecular diagnosis, 700–701 natural course, 817–818 pathogenesis, 816 prevention, 818 prognosis, 817–818 quasispecies, 816 replication, 685 serology, 699–700 superinfection, 817 therapy, 818 Hepatitis E virus, 729, 1265 cholestatic variant, 820
1585 clinical presentation, 820 diagnosis, 691–692, 820 differential diagnosis, 820 epidemiology, 819 fulminant, 820 genome organization, 674 genotypes, 674–675 incubation period, 819 molecular biology, 674 morphology, 674 natural course, 820 pathogenesis, 820 prevention, 820–821 prognosis, 820 replication, 675 seroprevalence, 819 serotypes, 674–675 superinfection, 820 therapy, 821 Hepatitis G virus, 733 Hepatoallergens, 1224 Hepatobiliary scintigraphy, 1449 acquisition technology, 427 interpretation, 428–429 principle, 427 Hepatoblastoma course, 1339 definition, 1338 diagnosis, 1339 epidemiology, 1338 pathology, 1338 prognosis, 1339 therapy, 1339 Hepatoblasts, 7–9 Hepatocavopathy, obliterative, 643 Hepatocellular adenoma, 379, 382–384, 408–412, 430 color Doppler imaging, 382 contrast-enhanced ultrasound, 382 conventional B-mode ultrasound, 382 definition, 1276 diagnosis, 1277–1278 differential diagnosis, 382–383, 1278 dynamic CT, 1278 epidemiology, 1276 etiology, 1276 MRI imaging, 1278 pathogenesis, 1276 pathology, 1277 prognosis, 1279 therapy, 1279 ultrasonography, 1278 Hepatocellular carcinoma, 412–413, 432, 433, 502–503, 557, 758–759, 1361–1364 ablative techniques, 1327–1328 acinar, 1315 advanced stage, 1325 aflatoxin B1, 1312–1313 alcoholic liver disease, 1308 anabolic androgenic steroids, 1309 angiotensinogen, 1317 Aspergillus flavus, 1312
1586 Barcelona clinic liver cancer(BCLC) staging classification, 1325 betel nut, 1312 bile droplets, 1317 Cancer of the Liver Italian Program, 1324–1325 carcinosarcoma, 1316 chemotherapy, 1329 chronic HBV infection, 1308 chronic hepatitis B virus infection, 1311 chronic hepatitis C, 1308 chronic hepatitis C virus infection, 1312 chronic necroinflammation, 1310 clear cell, 1316 clinical findings, 1148 clinical manifestations, 1317 color Doppler imaging, 386 contrast-enhanced ultrasound, 386–387 conventional B-mode ultrasound, 386 cryoablation, 1328 cytokeratin immunostaining, 1317 definition, 1307 des-g-carboxy-prothrombin, 1318 diabetes mellitus, 1309 diagnosis and therapy, 1148, 1317–1321 diarrhea, 1317 differential diagnosis, 1321 diffuse type, 1315 dysplastic foci, 1314 dysplastic nodules, 1314 early stage, 1325 endoglin, 1318 end-stage disease, 1325 epidemiology, 1146–1147, 1307–1308 epigenetic modification, 1310 erythrocytosis, 1317 ethnic factors, 1308 etiology, 1308–1310 a1-fetoprotein, 1317, 1318 fibrolamellar, 1316 gene expression profiles, 1314 genetic susceptibility, 1310 glutamine synthetase, 1318 glycogen storage disease, 1309 glypican 3, 1317, 1318 grading, 1317 gross anatomy, 1315 ground glass inclusions, 1317 growth factors, 1310 growth patterns, 1315 HCV core protein, 1312 heat shock protein 72, 1318 hepatic porphyrias, 1309 hepatitis B carriers, 1326 Hep Par 1, 1317 hereditary hemochromatosis, 1309 hereditary tyrosinemia, 1309 high grade dysplastic nodules, 1314 high incidence areas, 1307 hormonal therapy, 1329 hyaline inclusion bodies, 1316 hypercalcemia, 1317
Index hypertension, 1317 hypoglycemia, 1317 imaging, 1319 incidence, 1307 insulin resistance states, 1308 intermediate stage, 1325 intracellular inclusions, 1316–1317 iron-free foci, 1314 Japan integrated staging score, 1325 laboratory findings, 1317–1318 large cell dysplasia, 1313–1314 liver cell dysplasia, 1313–1314 liver cell-like, 1316 liver cirrhosis, 1308, 1312 liver transplantation, 1327 low grade dysplastic nodules, 1314 macroregenerative nodules, 1313 Mallory–Denk bodies, 1317 membranous obstruction of the inferior vena cava, 1309 microcystine, 1312 microscopic anatomy, 1315–1317 Milan criteria, 1327 molecular pathogenesis, 1310 molecular prognostication, 1322 mortality trend, 1322 multinodular type, 1315 nodule in nodule, 1313 non-hepatitis B cirrhosis, 1326 occult hepatitis C, 1312 Okuda staging system, 1323–1324 oncocytic, 1316 oral contraceptives, 1309 overall survival, 1322 pale bodies, 1317 paraneoplastic syndrome, 1317 parathyroid hormone-related protein, 1317 pathogenesis, 1147–1148, 1310–1313 pathology, 1313–1317 pedunculated HCC, 1315 percutaneous ethanol injection, 1327, 1328 pleomorphic, 1316 precancerous lesions, 1313 prevention, 1326 prognosis, 1321–1325 protein profiling, 1318 pseudoglandular, 1315 pseudosarcomatous, 1316 radiation therapy, 1328 radiofrequency ablation, 1327, 1328 risk factors, 1309 sarcomatoid, 1316 scirrhous, 1316 sclerosing hepatic carcinoma, 1316 screening, 1326 small cell dysplasia, 1314 small HCC, 1315 solid, 1316 sorafenib, 1329 spindle cell, 1316 staging, 1321–1325 staging systems, 1323
Index stem cell, 1311 surgical resection, 1326–1327 surveillance, 1320, 1326 survival, 1321 survivin, 1317 telomere hypothesis, 1310 therapy, 1326–1329 TNM system, 1323, 1324 Tokyo score, 1325 trabecular, 1315 transarterial chemoembolization, 1327, 1328 tumor stage, 1323 uninodular, 1315 vasoactive intestinal peptide, 1317 Hepatocellular injury, 540 Hepatocellular siderosis, grading, 283 Hepatocellular transport. See Transport, hepatocellular Hepatocerebral syndrome, 1186 Hepatocystin, 634 Hepatocyte(s), 23–25 ballooned, 720 ductular, 158 ground glass, 219–222 induced, 221 oncocytic, 722 periportal, 134 perivenous, 134 prolapse, 646 proliferation, 1276 swelling, 138 transplantation, 1405 volumetric composition, 23 Hepatocyte growth factor (HGF), 35, 159, 161 Hepatoerythropoietic porphyria, 1086 Hepatolithiasis, therapy, 1490 Hepatomegaly, 310–311 approach to the patient, 553–551 Hepatopathies, mitochondrial, 1186 Hepatoportal sclerosis, 252, 659–660, 865 Hepatoptosis, 622 Hepatopulmonary syndrome, 1369 clinical manifestations, 1018–1019 course, 1019 definition, 1017 diagnosis, 1018–1019 diagnostic criteria, 1019 differential diagnosis, 1019 epidemiology, 1017 etiology, 1017–1018 grading, 1019 pathogenesis, 1017–1018 pathology, 1018 prognosis, 1019 therapy, 1019–1020 Hepatorenal reflex, 22 Hepatorenal syndrome, 608 clinical manifestations, 1001–1002 course, 1002 definition, 999 diagnosis, 1001–1002 diagnostic criteria, 1001
1587 differential diagnosis, 1002 epidemiology, 999 etiology, 999–1001 hemodialysis, 1003–1004 liver transplantation, 1004 midodrine, 1003 noradrenaline, 1003 octreotide, 1003 ornipressin, 1003 pathogenesis, 999–1001 predictive factors, 1000 prognosis, 1002 survival, 1002 terlipressin, 1003 therapy, 1003–1004 type 1, 1001 type 2, 1001–1002 vasopressin, 1003 Hepatosplenic candidiasis, 859 Hepato-splenic g/d T-cell lymphomas, 1347 Hepatotoxicity, predictable, 1228 Hepatotoxic pathway, 1223 Hepatotoxins, 189, 1224 Hepcidin, 96, 1048, 1059 Hepeviridae, 674 Hephaestin, 94 Hep Par 1, 1317 Heptaporphyrins, 1083 Hereditary coproporphyria, 1080 Hereditary hemochromatosis, 544, 1045–1065 arrhythmias, 1055 arthropathy, 1055–1056 cardiomyopathy, 1055 chondrocalcinosis, 1055 diabetes mellitus, 1054–1055 differential diagnosis, 1052 early diagnosis, 1050–1052 endocrine abnormalities, 1056 gastric inhibitory peptide, 1054 genetic tests, 1050 heart disease, 1055 hyperinsulinemia, 1054 hypogonadism, 1056 insulin resistance, 1054 prognosis, 1058 screening, 1050–1052 sexual impotence, 1056 staging, 283 testicular failure, 1056 therapy, 1056–1058 Hereditary hemorrhagic telangiectasia, 637, 1248, 1294 Hering, canals, 41 Herpes simplex hepatitis, 1265 Herpes simplex virus, 233, 823–824 Herpes viruses, 823–827 Her’s disease, 1182 Heterochromatin, 26 Heterogeneity functional, 131 structural, 131 Hexose monophosphate shunt, 77
1588 HFE gene, 1047 HFE hemochromatosis diagnosis, 1048–1050 epidemiology, 1047–1048 etiology, 1048 history, 1047 laboratory tests, 1048–1049 pathogenesis, 1048 type 1, 1047–1052 High clearance substances, 1218 High density lipoproteins, 92 Hilar cholangiocarcinoma adjuvant therapy, 1536 liver transplantation, 1535 photodynamic therapy, 1540–1543 prognostic indicators, 1553–1554 resection, 1533–1535 survival, 1535 Histiocytoma, fibrous, 1349 Histological activity index, 729–730 Histoplasmomas, 860 Histoplasmosis, 860, 869 HIV cholangiopathy, 1501–1503 HIV-infection, 865 drug-induced liver injury, 875 Hepatitis A, 866 Hepatitis B, 866–867 Hepatitis C, 867–868 Hepatitis D, 867 hepatocellular carcinoma, 873 Kapsi’s sarcoma, 873–874 malignant lymphomas, 874 opportunistic infections, 869 viral hepatitis, 865–866 HMG-CoA lyase, 89 HMG-CoA reductase, 88 HMG-CoA synthase, 89 Hodgkin’s lymphoma, 748, 1250 Homocystinuria, 1185 Hormone sensitive lipase, 91 Hourglass gallbladder, 392 Human herpesvirus 6, 824 Human herpesvirus 7, 824 Human herpesvirus 8, 825 Hurler’s disease, 1276 Hyalin droplets, 221 Hyaluronic acid, 45, 46 4-Hydoxynonenal, 176 Hydration, liver cell, 137–140 Hydropic change, 207 Hydrothorax, hepatic, 1022 Hydroxyl-ethyl-radicals, 1128 Hydroxyl radical, 174 Hydroxyproline, 42, 44 Hyperammonemia, 1009 Hyperbilirubinemia, 584, 585 Hypercholesterolemia, familial, 224 Hyperdynamic circulation, 596 clinical manifestations, 1024–1025 differential diagnosis, 1024 pathogenesis, 1024
Index therapy, 1025 Hyperferritinemia, 792 Hyperferritinemia-cataract syndrome, 1063 Hyperfibrinolysis, 1029 Hyper-g-globulinemia, 328, 883 Hypericum perforatum, 1217 Hyperlipidemia, 582 Hyperpigmentation, 314 Hyperplasia Brunner’s glands, 1514 focal nodular, 379, 407, 430, 556, 1284–1287 liver cell, 554 mitochondrial, 722 nodular regenerative, 391, 1280–1283 Hypersensitivity reactions, 189 Hypertension cerebral, 938–940 intracranial, 938–939 portal, 366–367, 518 portopulmonary, 1020–1022 Hyperthyroidism, 1249 Hypertrichosis, 315 Hypoechoeic areas, focal, 360 Hypogonadism, 1026 Hypopigmentation, 314 Hypoplastic gallbladder, 1429 Hypothermia, 940 Hypothyroidism, 1249 Hypoxemia, 1019 Hypoxia, 181 Hypoxic hepatitis, 664–665 Hypoxic liver injury, 181–183 Hypoxic vacuoles, 208 I Icterus, 312–313 Idiosyncrasy, 189, 1224 Idiosyncratic toxicity, 189 Ileopathy, portal hypertensive, 988 Immune granulomas, 247 Immune mediated, liver injury, 191–195 Immune phagocytosis, 142 Immune reactions, antiviral, 192–194 Immune responses, intrahepatic, 149–150 Immune therapy, 1408 Immune thrombocytopenic purpura, 796 Immunglobulin G4 associated cholangitis (IAC), 916 Immunodeficiency, 1276 Immunofluorescence microscopy, 346 Immunoglobulin A nephropathy, 748 Immunoglobulins, 226 biliary, 147–148 Immunologic tolerance, 148–149 Immunomodulatory drugs, 709–710 Incidentalomas, 555 Inclusions Cowdry type A, 233 Cowdry type B, 233 ground-glass, 727 intracellular, 219–233 intracytoplasmic, 224–232
Index nuclear, 27, 232 viral, 233 Indian childhood cirrhosis, 961 Indinavir, 1216 Indirect hepatotoxicity, 1223 Indirect hepatotoxins, 1224 Indocyanine green test assessment, 336–337 confounding factors, 336 principle and technique, 336 side effects, 336 Induced hepatocytes, 221 Ineffective erythropioesis, 587 Infantile hemangioendothelioma definition, 1295 diagnosis, 1295–1296 epidemiology, 1295 pathology, 1295 therapy, 1296 Infections bacteria, 831–841 biliary, 1495–1503 fungal, 859–861 protozoal, 843–848 Inferior vena cava, thrombosis, 556 Inflammation endotoxin-induced, 197 portal vein, 660–661 Inflammatory bowel disease, 545 Inflammatory myofibroblastic tumor, 1301 Inflammatory pseudotumor, 391 definition, 1301 diagnosis, 1302–1303 differential diagnosis, 1303 epidemiology, 1301 etiology, 1301–1302 pathogenesis, 1301–1302 pathology, 1302 prognosis, 1303 therapy, 1303 Inflammatory reactions, 236–239 Injury hepatocellular, 540 hypoxic, 664 infiltrative, 548 Innervation peptidergic, 22 sympathetic, 22 Inosine monophosphate dehydrogenase, 712 Insulin, 160 Insulin-like growth factors (IGF), 162 Insulin resistance, 1027 Integrins, 47 Interface hepatitis, 212, 722, 883 Interfering peptides, 1406 Interferon(s), 771, 801–802 actions, 764 adverse reactions, 766 contraindications, 767 side effects, 803 Interleukin 6 (IL-6), 163
1589 Interleukin 15 (IL-15), 163 Interleukin-11, recombinant, 796 Intermediale density lipoproteins, 91 Intestinal angina, 535 Intracellular deposits, 219–233 Intracellular inclusions, 219–233 Intracellular pH. See pH intracellular Intracranial hypertension, 939–940 Intracranial pressure, 938–939 Intrahepatic cholestasis, inherited syndromes, 1093–1098 Intrahepatic cholestasis of pregnancy, 578 course, 1259–1260 definition, 1257 diagnosis, 1258–1259 differential diagnosis, 1259 epidemiology, 1257 etiology, 1258 fetal injury, 1260 imaging, 1259 pathogenesis, 1258 pathology, 1258 premature labor, 1260 prognosis, 1259–1260 therapy, 1260 Intrahepatic gallbladder, 1430 Intravascular coagulation, disseminated, 1029 Irinotecan metabolism, 1215 toxicity, 1215 Irinotecan toxicity, 1215 Iron, 201–202, 227–228 absorption, 99 carrier, 1048 exporter ferroportin 1, 94 metabolism, 93 regulatory proteins, 94 removal, 1057 Iron-free focus, 1314 Iron index, hepatic, 292 Iron overload, 201, 1045–1065 complications, 1052–1056 diseases, definition, 1046–1047 hepatic, 282–283 therapy, 1057 Ischemia, 181–183, 577, 664 Ischemia-reperfusion injury, 185–186 Ischemic cholangiopathy, 574–575, 665 Ischemic hepatitis, 543 Ischemic liver injury, 181–183 Ishak score, 730 Isocitrate dehydrogenase, 327 Isoniazide, 1230 Itching, 571 Ito cells, 8, 36, 252–253 Ito cell tumor, 1304 Ivemark’s syndrome, 626 J JAK2 tyrosine kinase, 642 Japan integrated staging score, 1325 Jaundice, 312–313
1590 breast milk classification, 583 definition, 582 diagnosis, 584–586 differential diagnosis, 584–586 etiology, 582–584 idiopathic dyserythropietic, 587 pathogenesis, 582–584 physiologic Jeune’s syndrome, 626 Junin virus, 829 Juvenile hemochromatosis diagnosis, 1059 natural history, 1059 treatment, 1059–1060 Juvenile hereditary hemochromatosis pathophysiology, 1058–1059 prevalence, 1058 K Kala-Azar, 846 Kaposi’s sarcoma, 1349–1350 Kaposis’s sarcoma, 825 Kasabach–Merrit syndrome, 1293 Kasai classification, 1435 Kausch–Whipple resection, 1556 Kayser–Fleischer rings, 316, 1037 KDEL-receptors, 72 Keratan sulfate, 45 Kernicterus, 587 Ketogenesis, 89 Ketone bodies, 89 Kinesin, 32, 66 King’s college criteria, 289, 292, 933 Klatskin-mimicking lesions, 1532 Klatskin tumor(s), 442, 1361, 1532 Klinefelter’s syndrome, 1276 Knodell’s score, 273 K-sparing diuretics, 971 Kupffer cells, 34–35, 136, 140, 142 Kwashiorkor, 1188 L Laboratory parameters, 319–331 Labrea fever, 224 Lactate dehydrogenase, 323 Lactulose, 984 Lafora bodies, 219, 222 Laminin, 46–47 Lamivudine, 708, 768–771 duration of treatment, 768–769 predictors of response, 769 resistance, 777–779 results of treatment, 769–770 Langerhans cell histiocytosis, 1251 Laparoscopy complications, 496 contraindications, 490 equipment, 491–492 risk profile, 495–498 technique, 489–490
Index Lassavirus, 828 LDL receptor, 91 LDL receptor related protein, 91 Lead intoxication, 1085 differential diagnosis, 1087 Lecithin:cholesterol acyltransferase (LCAT), 92 Legionella pneumophila, 837 Legionnaire’s disease, 837 Leiomyomas, 1304 Leiomyosarcoma, 1350 Leishmaniasis, 846 Leptin, 39, 255, 1159 Leptospira, 837–838 Leptospirosis, 837 Lesions, precancerous, 1313 Leucin aminopeptidase, 326 Leucocytoclastic vasculitis, 748 Leukopenia, 1028 Lichen planus, 314–315 Ligament coronary, 12 falciform, 12 hepatorenal, 12 triangular, 13 venous, 13 Ligandins, 110, 584 Light chains, nonamyloidotic, 654 Lille model, 289, 291–292 Limit dextrinosis, 1182 Lindsay nails, 315 Linoleic acid, 85, 89 Linolenic acid, 85 Linton-Nachlas-tube, 984 Lipase hepatic, 91 hormone sensitive, 91 Lipids, 85–86, 224–225 homeostasis, 89 peroxidation, 175–176, 1158 Lipocytes, 36 Lipodystrophy syndrome, 876 Lipofuscin, 228 Lipogranulomas, 249, 1237 Lipoma, 1298 Lipomatous tumors, 1298 Lipomelanin, 1277 Lipopolysaccharide, bacterial, 149 Lipoprotein lipase, 90 Lipoproteins, 89–92 high density, 91 low density, 91 very low density, 91, 92 Lipoprotein X, 546 Liposarcoma, 1350 Liposomes, 121 Liquid crystals, 121 Listeria monocytogenes, 838 Listeriosis, 994 Lithocholic acid, 109 Litholysis contact, 1476, 1477
Index oral, 1475–1476 Lithotripsy, 1489 extracorporeal shock wave, 1476–1477 intracorporeal electrohydraulic, 442 Liver agenesis, 622 aging, 153–155 atrophy, 622 cysts, 631–633 extraabdominal location, 622 hemodynamic parameters, 56 hypoplasia, 622 immune organ, 141–151 intraabdominal displacement, 622 malformations, 621–622 malpositions, 621–622 palpation, 310–311 percussion, 310–311 span, 310–311 transposition, 622 Liver abscess, 555, 1486 amebic, 843–848 bacterial, 831–841 causes, 833 course, 834 definition, 832 diagnosis, 833–834 differential diagnosis, 834 epidemiology, 832 etiology, 832–833 pathogenesis, 832–833 prognosis, 834 therapy, 834–835 Liver acinus, 15–16, 18 Liver ageing, drug metabolism, 155 Liver bile, 104 Liver biopsy, 259–261, 554 biopsy technique, 478 complications and mortality, 479 contraindications, 477 indications, 476–477 percutaneous, 463–470 success rate, 476 transjugular, 476 transvenous, 475–484 Liver bud, 7, 8 Liver carcinoma, 1053 Liver cell adenoma, 556 adenomatosis, 1277 death, 209–218 degeneration, 207–209 dysplasia, 724, 1313–1314 hydration, 137–140 hyperplasia, 554 injury, 236 Liver cell death, ischemic, 182 Liver cell mass functional, 334 Liver cell rosettes, 212, 238, 242 regenerative, 722
1591 Liver cirrhosis, 360–361, 1052–1053 a1-antitrypsin deficiency, 955 APACHE III-score, 963 bacterial infections, 994–998 biliary cirrhosis, 955 capillarization of sinusoids, 951 cardiovascular, 1024–1025 causes, 950 cell death, 950–951 Child-Pugh stages, 958 chronic viral hepatitis B, 954 chronic viral hepatitis C, 955 circulatory disturbances, 951 clinical manifestations, 955–959 clonidine, 976 coagulopathy, 1028–1029 compensated, 962 complications, 967–988, 994–1015, 1017–1022, 1024–1031, 1245 course, 962–963 decompensated, 962 definition, 949 diagnosis, 955–961 differential diagnosis, 961–962 endocrine alterations, 1026–1027 endoscopic ultrasonography (EUS), 960 epidemiology, 949 etiology, 950–952 a1-fetoprotein, 962 hematologic alterations, 1028–1029 hemodynamic alterations, 951 hepatocellular carcinoma (HCC), 962 hepatocyte growth, 951–952 hepatocyte prolifection, 951 hereditary hemochromatosis, 955 histological findings, 954–955 hyperdynamic circulation, 958 imaging, 960–961 interface hepatitis, 954 intrahepatic vascular shunts, 951 laboratory findings, 959–960 laparoscopy, 960 liver biopsy, 960 liver cell failure, 956 liver transplantation, 975 magnetic resonance imaging, 960 malnutrition, 956 MELD score, 963 muscular complications, 1031 nodule, 1321 obesity, 962 opeative risk stratification, 1390 operative mortality, 1386, 1392 outcome, 962 pathogenesis, 950–952 pathology, 952–955 physical findings, 958 portal hypertension, 956 prognosis, 520, 962–963 pseudolobuli, 951 pulmonary complications, 1017–1022
1592 scanning, 960 screening, 962 sexual dysfunction, 1026 sonography, 960 surgical risk, 1390 terlipressin, 976 therapy, 963–964 thyroid dysfunction, 1026–1027 transient elastography, 960 vasoconstrictor drugs, 975 vasopressin receptor antagonists, 975 venous outflow obstruction, 955 Wilson’s disease, 955 Liver cirrhotic, mass lesion, 1320 Liver cyst(s), 376 acquired, 632 classification, 632 congenital, 632 Liver damage drug-induced, 277 oxidative, 176–177 toxic, 189 Liver diseases(s) alcoholic, 1111–1148, 1358–1359 autoimmune, 886, 888, 889 categories, 302 chronic, 498–501 fibropolycystic, 625 gene therapy, 1404 molecular prevention, 1408–1409 monogenic, 1404 nutrition, 1187–1203 nutritional therapy, 1196 operative risk, 1385–1394 polycystic, 633–635 surgery, 1383 Liver enzymes abnormal, 537–550 approach to the patient, 548–550 Liver failure, 571 acute, 931–944 Liver fibrosis congenital, 625–627 resolution, 256 Liver fibrosis, 251 Liver flap, 1010 Liver function, test, 333–342 Liver heterotopia, 621 Liver injury cholestasis-induced, 199 cholestatic, 1225 drug-induced, 189–190, 1223–1230 endotoxin mediated, 197–198 enzyme patterns, 320 hepatocellular, 1225 hepatotoxic, 1224–1225 histological patterns, 1225–1227 hypoxic, 181–183, 664 idiosyncratic, 1224, 1225, 1230 ischemic, 181–183 laboratory parameters, 1225
Index metal-induced, 201–202 mixed, 1225 toxic, 1224 Liver-iron-index, 1049 Liver lesions cystic, 555 diagnostic approach, 554–555 differential diagnosis, 555–557 focal, 371–391, 429–432, 553–557 solid, 555 Liver lobule, 15–16 Liver regeneration alternate pathways, 167 molecular mechanisms, 164–166 morphology, 158–159 multi-step model, 166 pathologic, 158 physiologic, 158 reparative, 158 termination, 167 Liver, segments, 13 Liver size determination, 553 etiology, 554 pathogenesis, 554 Liver stiffness, 262 Liver transplantation, 444, 1353–1379 acute cellular rejection, 1375 age, 1368–1369 alcoholic liver disease, 1358–1359 antibodies, 1374 a1-antitrypsin disease, 1364 arterial hypertension, 1375–1376 aspergillus infection, 1378 azathioprine, 1374 bacteremia, 1378 bacterial infection, 1377 basiliximab, 1374 bile duct cast syndrome, 1376 bile duct obstruction, 1376 bile leaks, 1376 biliary complications, 1376 Budd–Chiari syndrome, 1364 candidiasis, 1378 cardiopulmonary contraindications, 1369 Child-Pugh classification, 1356 cholangiocarcinoma, 1361 cholestatic liver disease, 1360 contraindications, 1368–1370 corticosteroids, 1374 cyclosporine, 1373 cytomegalovirus infection, 1378 daclizumab, 1374 delisting criteria, 1371 delta MELD, 1356 diabetes mellitus, 1375 evaluation, 1355, 1366–1368 expected survival, 1357 fulminant hepatic failure, 1364–1365 fungal infection, 1378 hepatic malignancy in children, 1366
Index hepatitis B, 1359–1360 hepatitis C, 1359 hepatitis in children, 1366 hepatocellular carcinoma, 1361–1364 hepatopulmonary syndrome, 1369 hereditary hemochromatiosis, 1364 HIV infection, 1369–1370 hypercoagulable state, 1364 immunosuppression, 1373 indications, 1357–1366 infection, 1377–1378 infectious contraindications, 1369–1370 Klatskin tumor, 1361 listing, 1355, 1366–1368 living donor liver transplantation, 1363, 1371–1372 malignant diseases of the liver, 1360–1364 medical evaluations, 1355 metabolic liver disease, 1364 minimal listing criteria, 1357–1358 mycophenolate mofetil, 1374 opportunistic infection, 1377 organ allocation, 1355, 1356 pediatric cholestatic diseases, 1365–1366 pediatric end stage liver disease, 1356 pediatric metabolic liver diseases, 1366 perioperative period, 1372–1373 portal vein thrombosis, 1364 posttransplantation infection, 1377 posttransplant period, 1372–1378 pretransplant workup, 1367 primary biliary cirrhosis, 1360 primary sclerosing cholangitis, 1360 prioritization, 1356 psychosocial contraindications, 1369 psychosocial evaluations, 1355 rapamycin, 1374 recurrent disease, 1376–1377 rejection, 1375 retransplantation in children, 1366 scoring systems, 1356 tacrolimus, 1373 timing of transplantation, 1370–1371 vascular complication, 1376 vascular disease of the liver, 1364 veno-occlusive disease, 1364 viral hepatitis, 1359–1360 viral infection, 1378 waiting list, 1356, 1370–1371 Wilson’s disease, 1364 Liver transplant, in child, 1365–1366 Liver transplant recipients, 483–484 Liver tumors, 372–374 secondary, 505–509 Liver weight, 157 Living donor liver transplantation, 1363, 1371–1372 LKM-1 autoantibodies, 793 Lobe, caudate, 13, 14, 645 hypertrophy, 556 Lobe, quadrate, 13 Longitudinal scan, 456
1593 Loop diuretics, 971 L-ornithine-L-aspartate (LOLA), 1014 Low clearance substances, 1218 Low density lipoproteins, 91 Low-T3 syndrome, 1026 LPAC syndrome, 1095 Lunulae, blue, 315 Lyme disease, 835 Lymphadenopathy, perihepatic, 361, 362 Lymphangioma, 1297 Lymphangiomatosis, hepatic, 1297 Lymphatics, 21–22 Lymph nodes, 21 Lymphocytes ab-T cell receptor (ab-TCR), 143–144 gd-T cell receptor (gd-TCR), 144 intrahepatic, 142–145 large granulated, 40, 144 Lymphocytosis, intrasinusoidal, 826 Lymphohistiocytic granuloma, 248 Lymphoid aggregate, 638 Lymphoma color Doppler imaging, 390 contrast enhanced ultrasound, 390 conventional B-mode ultrasound, 390 Lysosomes, 29–30 functions, 30 Lytic necrosis, 210
M Machupovirus, 829 Macrocytosis, 1028 Macroenzymes, 321, 545 Macronodular cirrhosis, 953–954 Macrophage activating syndrome, 1250 Macrophages, ceroid storing, 211 Macroregenerative nodules, 1313 Maddrey index, 289, 291–292 Maddrey score, 1137 Magnetic resonance imaging, 405–421 Malabsorption, 570, 581 Malacoplakia, 1508 Malaria, 847 Malarial pigment, 230 Malformations, arterial vascular, 365 Malignant cells, dissemination, 469 Malignant fibrous histiocytoma, 1349 Malignant lymphoma B-cell, 1347 gd-lymphoma, 1347 primary hepatic, 1347–1348 T-cell, 1347 Malignant teratomas, 1350 Malignant tumors, 1305–1350 Mallory-Denk bodies, 226–227 Mall, space of, 21 Malnutrition, 1187–1203 cirrhosis, 1190 definition, 1188–1189 pathophysiology, 1190–1193
1594 patterns, 1189 prognosis, 1193–1194 Malondialdehyde, 176, 1130 Maltese cross structures, 1084 Manganese superoxide dismutase, 1121 Mannitol, 939 Mannose/N-acetylglucosamine receptor, 33 Manometry complications, 526–527 contraindications, 524 equipment, 524 indications, 523–524 normal findings, 525–526 pathological findings, 526 sphincter of Oddi, 1447 technique, 524–525 Marasmus, 1188 Marburg virus, 829 Massive necrosis, 721 Matrix components, 42 Matrix, extracellular, 159 Matrix-metalloproteinases (MMPs), tissue inhibitors of, 44, 255 Mauriac syndrome, 226 Mayo risk score, 289, 291 McArdle’s syndrome, 1182 Measles virus, 827 Mechanical lithotripsy, 1489 Meckel–Gruber’s syndrome, 626 Medical history, 302–303 Mediteranean spotted fever, 839 Megamitochondria, 222–224, 1128 Melanin, 230 Melioidosis, 836 Membrane canalicular, 25 hepatocellular, 62 lateral, 25 sinusoidal, 25 Membranoproliferative glomerulonephritis, 794 Membranous glomerulonephritis, 748 Menghini needle, 465 Mercaptanes, 1009 Mesenchymal hamartoma, 1297 Metabolic diseases amino acid metabolism, 1185 carbohydrate metabolism, 1182 lipid metabolism, 1183–1184 Metabolic syndrome, 1154–1160 Metabolism, hepatic, 75–99 Metachromatic leucodystrophy, 1184 Metallochaperons, 93 Metalloproteinases, 159, 254 Metalloproteinases, tissue inhibitors of, 44 Metalloproteinases-1 tissue inhibitors of, 254 Metallothioneins, 93 Metals, 227–228 Metal stents self-expanding, 443, 1539 Metal transporter 1, 94
Index Metastases, 414–419, 430, 432, 434–435, 556 color Doppler imaging, 387 contrast enhanced ultrasound, 387–388 conventional B-mode ultrasound, 387 neuroendocrine, 388–390 METAVIR score, 273 Methotrexate toxicity, 278 Methylation, 128 Methyl-tertiary-butyl ether, 1477, 1490 Meulengracht’s disease, 588 Micellar concentration, 119 Michaelis Gutman, inclusion bodies, 1509 Microabscesses, miliary, 838 Microbodies, 30 Microbubbles, 373 Microcirculatory units, hepatic, 16 Microfilaments, 32 Microgallbladder, 392 Microhamartomas, biliary, 1288 Micronodular cirrhosis, 952–953 Microsomal enzymes induction, 1217 inhibition, 1217 Microsomal ethanol oxidizing system, 1116–1119 Microsomal function, 334 Microsomal transfer protein, 90, 1157 Microtubules, 32 Microvesicular steatosis, 1265 Milan criteria, 1327 Milwaukee criteria, 1446 Mineral oil granulomas, 249 Mirizzi syndrome, 441, 1445, 1474 Mitochondria, 30 matrix, 31 Mitochondrial enzymes, 539 Mitochondrial hepatopathies, 1186 Mitochondrial hyperplasia, 722 Mitochondriosis, 222 Mixed function oxygenase, 1217 Mixed micelle, 121 Model for end-stage liver disease (MELD), 289–291, 1137, 1354 Molecular adsorbents recirculation system (MARS), 943 Monoacinar cirrhosis, 953 Monoethylglycinexylidide test assessment, 339 confounding factors, 339 principle and technique, 338 side effects, 339 Mononeuritis multiplex, 797 Monooxygenases microsomal, 127 mixed reaction, 128 Morula cells, 224 Motor proteins, 32, 66 Mucin carbohydrate antigens, 1291 Mucin core proteins, 1291 Mucormycosis, 860 Muehrcke lines, 315 Multiacinar cirrhosis, 953 Multiband ligation, 981
Index Multi drug resistance, 65 Multi-drug resistance-associated protein 2, 69, 108 Multidrug resistance protein, 112 Multilobular necrosis, 721 Multiple myeloma, 1250 Multiseptate gallbladder, 1431 Muralium duplex, 8 Muralium simplex, 8 Murphy’s sign, 536, 1472 Muscle cramps, 307, 1031 Muscular complications, 1031 Mushroom poisoning, 934–935 Mutants, dominant-negative, 711–712 Mycobacteria, 838–839 Mycobacteriosis, atypical, 839 Mycobacterium avium intracellulare, 249, 838, 869 Mycobacterium leprae, 838 Mycobacterium tuberculosis, 249, 838 Mycophenolate mofetil, 1374 Mycoplasma pneumoniae, 839 Myofibroblastic tumor, inflammatory, 1301–1303 Myostatin, 1193
N N-acetylcysteine (NAC), 934 N-acetyl-p-benzoquinone-imine (NAPQI), 934 Nadolol, 980, 981 NADPH oxidase, 186 Nail changes, 315 Naloxone, 580 Naltrexone, 580 Na-taurocholate cotransporter, 68 Natriuretic peptides, 606 Natural killer cells, 144–145, 194 Natural killer T cells, 144 Nausea, 306 Navajo neurohepatopathy, 1186 Necroinflammatory reaction, 235–239 Necrosis, 209 acidophilic, 210 bridging, 212 coagulative, 210 confluent, 211–212 lytic, 210 massive (panlobular), 211 multilobular, 211 patterns, 210 piecemeal, 212 porto-venous, 212 single cell, 210–211 submassive, 211 surgical, 212–213 veno-venous, 212 zonal, 211 Nectins, 46 Nematode cholangitis, 1500–1501 Nematodes, 1502 Neonatal hemochromatosis, 1047 Nerves, 22 parasympathetic, 22
1595 sympathetic, 22 Network, microtrabecular, 31 Neural factors, 57 Neurofibromatosis, 1251 Neurogenic pain, 535 Neurologic-psychiatric changes, 315–316 Neuropathy, 797 Neuropsychiatric symtpoms, 306 Neurotoxins, 1007–1009 Neurotransmission, opioidergic, 580 Neurotransmitters, false, 1009–1010 Nidogen, 47 Niemann–Pick disease, 1183 Nieman-Pick type C disease, 224 Nitrates, 981 Nitric oxide (NO), 57, 58, 174, 596, 606, 607 Nitrogen, 1196 Nitrogen compounds, 83–85 Nocardiosis, 835 Nodular panniculitis, 315 Nodular regenerative hyperplasia, 391 conditions associated, 1280 definition, 1280 diagnosis, 1282 differential diagnosis, 1282 epidemiology, 1280 etiology, 1280–1281 natural history, 1282–1283 pathogenesis, 1281 pathology, 1281–1282 prognosis, 1282–1283 therapy, 1283 Nodular transformation, partial, 1281 Nodules dysplastic, 557, 1314 hepatic, 1321 macroregenerative, 1313 regenerative, 557 Nodule in nodule, 1313 Non-acute porphyrias, 1081–1082 Nonalcoholic fatty liver disease (NAFLD), 544, 1153–1174, 1393 bariatric surgery, 1174 carbohydrate response element binding protein, 1156 causes, 1155 children, 1154 chronic hepatitis C, 1154 clinical manifestations, 1163–1164 clinical scoring system, 1164 definition, 1153 diagnosis, 1163–1165 differential diagnosis, 1165 drugs, 1154 epidemiology, 1153–1154 ethnic differences in, 1154 etiology, 1154–1155 gastrointestinal surgical procedures, 1154 glycogenated nuclei (Lochkerne), 1161 HCV genotype 1, 1160 HCV genotype 3, 1160 imaging, 1164–1165
1596 insulin resistance, 1156 laboratory findings, 1164 lifestyle modifications, 1166 lipogenesis, 1157 lipolysis, 1156 macrovesicular steatosis, 1161 metabolic syndrome, 1154 metformin, 1173 microsomal transfer protein, 1157 microvesicular steatosis, 1161 natural course, 1165–1166 obesity, 1154 pathogenesis, 1155–1161 pathology, 1161–1163 peroxisomal proliferator activated receptors, 1166 pharmacological therapy, 1166–1173 polycystic ovary syndrome, 1154 prognosis, 1165–1166 steatosis, 1161 sterol regulatory element-binding protein-1c, 1156 therapy, 1166–1174 thiazolidinediones, 1166 type 2 diabetes mellitus, 1154 visceral adipose tissue, 1157 Nonalcoholic steatohepatitis, 239, 364, 1153 adipocyte hormones, 1159 adiponectin, 1159–1160 endotoxin, 1159 fibrosis, 1162 genetic influences, 1160 ghrelin, 1160 hepatocyte injury, 1162 histology, 1163 histomorphology, 1127 inflammation, 1163 iron overload, 1160 leptin, 1159 mitochondrial alterations, 1159 resistin, 1160 visceral fat, 1159 Nonamyloidotic light chains, 654 Non-A-Non-B hepatitis, 686 Nonepithelial tumors, 1275 Non-essential aminoacids, 1198 Nonhepatotropic viruses, 823–829 Non-Hodgkin’s lymphoma, 796–797, 1250 Nonimmune phagocytosis, 142 Nonparenchymal cells, 136, 138, 140 Norepinephrine, 606 Nuclear changes, 232–233 Nuclear factor, hepatic, 9 Nuclear imaging, 425–435 Nuclear inclusions, 232 Nuclear swelling, 232 Nuclei, sanded, 233 Nucleos(t)ide analog, 708 Nucleosides, 768–774 5’-Nucleotidase, 325–326 Nucleotides, 768–774 Nucleus, 26 Nutrient intake, 1190
Index Nutrition, 1396 cholestasis, 573 total parenteral, 573–574 Nutritional assessment, 1194–1195 Nutritional interventions, 1198 Nutritional management alcoholic hepatitis, 1199 cirrhosis, 1199 fulminant hepatic failure, 1199–1200 guidelines, 1200 Nutritional requirement, 1196 Nutritional status, measurement, 1194 Nutritional supplements, 1202 Nutritional therapy, 1196
O Obesity, 1155–1160, 1189, 1203 Obliterative endarteritis, 667 Obliterative hepatocavopathy, 643 Obliterative portal venopathy, 1282 Obstructive sleep apnea, 1248 Occlusion, hepatic artery, 663–664 Octopamine, 1009 Octreotide, 981 Okuda staging system, 1323–1324 Oncocytic change, 222 Oncolytic viruses, 1408 ONKO PET, 433 Oral contraceptives, 1249, 1276 Organgefühl, 306, 535 Organic anion transporter multispecific canalicular, 112 Organic anion transporting polypeptides, 68 Organic anion transporting proteins, 564 Organic cation transporters, 68, 564 Organization, structural, 15 Oriental cholangiohepatitis, 627 Oriental cholangiopathy, 445 Ornithine transcarbamylase, 327 Orrego index, 1137, 1138 Orthodeoxia, 1017, 1018 Osler–Weber–Rendu syndrome, 313, 371, 637, 1252 Osmosignaling, 138 Osteodystrophy, hepatic, 1030–1031 Osteomalacia, 1030 Osteomyelofibrosis, 1249 Osteopenia, 581–582 Osteoporosis, 1030 Outflow obstruction, hepatic venous, 370 Oval cells, 41, 167 Ovarian insufficiency, 1026 Ovarian tumors, 1276 Overflow hypothesis, 608 Overlap syndromes, autoimmune, 925–927 Oxidases, 127, 128 b-Oxidation, 86, 87 Oxidative stress, 174–180, 1158 defense mechanisms, 177 2-Oxo-acid dehydrogenase enzymes, 350 Oxygen consumption, hepatic, 56
Index P Pain, 306 biliary, 535–536 causes, 534–536 clinical evaluation, 534–536 conduction, 532–533 epigastric, 534, 535 hepatic, 536 neurogenic, 535 origin, 531–532 referred, 533 right upper quadrant, 534, 535 somatic, 532, 533 types, 533 visceral, 532, 533 Palmar erythema, 313–314 Pancreatic cancer, 508–509 Pancreaticoduodenectomy, 1516 Pancreatitis, biliary, 1474 Panniculitis, nodular, 315 Papillary adenomas, 1512 Papillectomy, 1516 Papillomas, 458 Papillomatosis, 1511, 1512 biliary, 1291 Papulous acrodermatitis, 314 Paraaminosalicylic acid, 1230 Paracentesis large-volume, 972–973 practical approach, 973 Paracetamol, 1228 Paracoccidiomycosis, 860–861 Paramyxoviruses, 827 Parathyroid hormone, 161, 1031 Parenteral nutrition, 1202 Paroxysmal nocturnal hemoglobinuria, 1250 Partial nodular transformation, 1281 Partial therapeutic, response, 762 Partial thromboplastin time, 329 Parvoviruses, 829 Parvoviruses B19, 829 Passive septa, 258 Pattern recognition receptors (PRR), 149 Patterns of injury cholestatic, 540 hepatitic, 540 mixed, 540 Pearson’s syndrome, 1186 Pegylated interferon, 765–768 Peliosis hepatis, 650–651 Peliosis hepatic, bacillary, 869 Penicilliosis, 861 Penicillium marneffei1, 861 Pentose phosphate pathway, 77 PEP carboxylase, 79 Pepper-and-salt-stones, 1466 Peptidergic transmitters. See Transmitters, peptidergic Peptides natriuretic, 606, 607 vasodilating, 606, 607 Percutaneous ethanol, 1363
1597 Percutaneous transhepatic cholangiography, 1499 complications, 446 Perforin, 193 Performance status, 1323 Perfusion scintigraphy acquisition technology, 426–427 interpretation, 427 principle, 426 Peribiliary glands, hyperplasia, 1289 Pericytes, 36, 57 Pericytoma, spongiotic, 1304 Periductal fibrosis, 256 Perihepatitis gonorrhoica, 837 Perioperative care, 1394–1395 Perisinusoidal lesions, 654 Peritoneovenous shunt, 974 Peritonitis, spontaneous bacterial, 994–998 Perivenous sclerosis, 258 Perlecan, 45 Peroxisomal disorders, 1185 Peroxisome proliferator activated receptors (PPARs), 30 Peroxisomes, 30 PFIC. See Progressive familial intrahepatic cholestasis PFIC 1, 1095, 1097 PFIC 2, 1095, 1098 PFIC 3, 1098 Phagocytosis immune, 142 nonimmune, 142 Phalloidin, 189, 568, 1229 Phase II reactions, 127 Phase I reactions, 127 Phenobarbital, 580 Phenoles, 1009 Phenotypic resistance, 777 Phenylethanolamine, 1009 pH intracellular, 70–71 Phlebitis, granulomatous, 661 Phlebosclerosis, 659 Phlebotomy, 1056–1057 Phosphofructokinase, 78 Phospholipids, 86, 109–110, 225 Photosensitivity, cutaneous, 1086 Phototherapy, 581 pH-regulation, systemic, 135 Phrygian cap, 392, 1431 Phycomycosis, 860 Physical examination, 309–316 Physiologic jaundice, 587 Picornaviruses, 673 Piecemeal necrosis, 212, 236 Pigment, 228–230 anthracotic, 230 ceroid, 229–230 Dubin-Johnson, 228–229 malarial, 230 schistosomal, 230 wear and tear, 228 Pinocytosis, 66 Pit cells, 18, 39–40, 144 Plasma cell granuloma, 1301
1598 Plasma cell hepatitis, 883 Plasma membrane, 25 Plasmodium falciparum, 847 Platelet-derived growth factor (PDGF), 254 Platelets, 1028–1029 Platypnea, 1018 Plexogenic arteriopathy, 1021 Pneumococci, 839 Pneumocystis carinii (jiroveci), extrapulmonary, 869 Pneumoperitoneum, 492–494 POEMS syndrome, 554 Pohl score, 263 Polyarteritis nodosa, 667, 748, 794–795, 1250 Polycystic kidney disease, autosomal recessive, 633 Polycystic liver disease, autosomal dominant, 633 Polycystic ovary syndrome, 1276 Polycystin, 634 Polycythemia vera, 1249 Polyglandular syndrome, autoimmune, 885 Polyglucosan bodies, 226 Polymerase inhibitors, 715–716 Polymorphism, genetic, 129, 1214 Polyneuropathy, 748, 797 Polyps, gallbladder, 395 Pompe’s disease, 1182 Pontiac fever, 837 Porcelain gallbladder, 394, 1473 Pore complexes, nuclear, 26 Porphyria cutanea tarda, 795, 1078, 1081–1084, 1086, 1088–1090 iron overload, 1081 Porphyrias definition, 1077–1078 enzyme defects, 1078 epidemiology, 1078–1079 gene mutations, 1079 Porta hepatis, 13 Portal blood flow, sonographic determination, 599 Portal fibrosis, non-cirrhotic, 594 Portal flow, hepatofugal, 367 Portal hypertension, 366–367, 518 complications, 600 course and prognosis, 600 definition, 593 diagnosis, 597–600 differential diagnosis, 600 epidemiology, 593 etiology, 594 idiopathic, 659 non-cirrhotic, 594, 659, 961 pathogenesis, 595 therapy, 600–601 Portal hypertensive colopathy, 988 Portal hypertensive enteropathy, 988 Portal hypertensive gastropathy clinical manifestations, 986–987 course, 987 definition, 986 diagnosis, 986–987 differential diagnosis, 987 endoscopic changes, 987 epidemiology, 986
Index etiology, 986 pathogenesis, 986 pathology, 986 prognosis, 987 therapy, 988 Portal hypertensive ileopathy, 988 Portal pressure balloon occlusion technique, 517 circadian variations, 518 measurement, 515–520 normal values, 518 pathologic values, 518–519 Portal tracts, 16 Portal vein, 366, 657–663. See also Vein(s) cavernous transformation, 368, 637, 658 examination techniques, 368–369 fibrous obliteration, 637 gas embolism, 661 inflammation, 660–661 Portal vein thrombosis, 365, 368–379, 657 acute, 657–658 chronic, 658–659 etiology, 658 Portopulmonary hypertension clinical manifestations, 1021 course, 1021 definition, 1020 diagnosis, 1021 differential diagnosis, 1021 epidemiology, 1020 etiology, 1020–1021 pathogenesis, 1020–1021 pathology, 1021 prognosis, 1021 therapy, 1021–1022 Portosystemic collaterals, 600 Portosystemic encephalopathy, 306 Positron emission tomography (PET), 432 Postabsorptive phase, 81, 134 Postcholecystectomy syndrome, 1441–1445, 1478 Postoperative lesions, 444–445 Postoperative monitoring, 1396 Posttraumatic lesions, 444–445 Poulsen-Christoffersen lesion, 244 Precancerous lesions, 1313 Preeclampsia, 1267 Pregnancy acute fatty liver, 1263–1265 cholestasis, 1259 pruritus, 1259 Preoperative screening, 1394–1396 Pre-procollagen, 43 Pressure intracranial, 938–939 sinusoidal, 515 wedged hepatic, 515 Pretransplant workup, 1367 Primary amyloidosis, 1106 Primary, bile, 104 Primary biliary cirrhosis (PBC), 195, 362–363, 925 AMA negative, 899, 910 clinical presentation, 897–899
Index definition, 895 diagnosis, 897 differential diagnosis, 900 drugs, 902 environmental factors, 896 epidemiology, 895 etiology, 896 extrahepatic diseases, 899 genetic factors, 896 grading and staging, 282 immunologic factors, 896–897 infectious organisms, 896 laboratory findings, 899 liver transplantation, 903 Mayo-Risk-Score, 901 mitochondrial antigens, 899 natural course, 900 pathogenesis, 896 pathology, 897 prognosis, 900 serologic diagnosis, 899 staging, 897 therapy, 901 Primary hepatic malignant lymphoma course, 1348 diagnosis, 1347–1348 differential diagnosis, 1348 epidemiology, 1347 pathogenesis, 1347 pathology, 1347 prognosis, 1348 therapy, 1348 Primary liver tumors, classification, 1275 Primary sclerosing cholangitis (PSC), 363, 925 complications, 916 course, 916–917 definition, 911 diagnosis, 913 differential diagnosis, 915–916 epidemiology, 911–912 etiology and pathogenesis, 912 extrahepatic diseases, 914 genetic factors, 912 imaging, 914–915 immunological findings, 912 laboratory findings, 914 Mayo model, 916 pathology, 912–913 pericholangitis, 912 prognosis, 916–917 signs, 913 small duct variant, 912 staging, 913 survival, 916 symptoms, 913 therapy, 917 Priming phase, 165 Procollagen, 43 Proelastin, 44 Progenitor cells, 159 Progressive familial intrahepatic cholestasis, 1094–1098
1599 Proinflammatory cytokines, 1158 Prolactin, 161 Proliferative phase, 165 Proline, 42 Prometheus-system, 943 Propranolol, 980, 981 Prostacyclin, 596 Prostaglandins, 606, 607 Protease inhibitors, 715 Proteinase inhibitor, jaundice, 1216 Protein, dietary allowance, 1191 Protein-energy malnutrition, 1189, 1193 Protein metabolism, 1190–1191 Protein restriction, 1198 Proteins, 82–83, 226–227 acute phase, 150, 151 multidrug resistance-associated, 69 synthesis, 1192 turnover, 1191 vaccination, 709–710 vaccines, 713 Proteoglycans, 42, 45–46 Prothrombin time, 329 Protoporphyrin crystals, 230 Protozoal diseases, 843–848 Pruritus, 307, 571, 579–581 Pseudocapillarization, 154 Pseudocysts, 631 Pseudo-Gaucher cells, 225, 226 Pseudo-Lafora bodies, 222 Pseudolipoma, 1298 Pseudolymphoma, 1348 Pseudomonas, 836 Pseudotumor, inflammatory, 391 Psychiatric disorders, 797 Pulmonary fibrosis, 797 Pulsatile liver, 311 Pulsatility, portal vein, 367 Pump, 64–65 bile salt export, 69 electrogenic, 65 Purpura, palpable, 314 Pylephlebitis, 660–661 suppurative, 832 Pyrrolizidine alkaloids, 651 Pyruvate carboxylase, 79 Pyruvate kinase, 78 Q Q fever, 839 Quadrate lobe. See Lobe, quadrate Quinke’s triad, 445 R Radial scan, 456 Radiation-induced liver damage, 203–204 Radiation therapy, 1549 Radiofrequency ablation, 1363 Raloxifene, 1030 Rapamycin, 1374 Reactive oxygen species (ROS), 173–180, 1128
1600 Receptors, low pressure, 606 Receptosome, 73 Recombinant activated factor VII (rFVIIa), 942 Recombinant factor VIIa, 1394 Recurrent pyogenic cholangitis, 627 Red blood cells, 1028 Red wale marks, 979 Referred pain, 533 Reflex, hepatorenal, 22 Refractory ascites, 613 Refsum’s syndrome, infantile, 1185 Regan-isoenzyme, 325 Regeneration, hepatic, 157–167 Regulator, autoimmune, 885 Rejection arteriopathy, 668 Relapsing fever, 836 Remak’s plates, 17 Renal cell carcinoma, 1249 Renal dysfunction, 1395 Rendu–Weber–Osler disease, 1294 Renin-angiotensin-aldosterone (RAA) system, activation, 606 Reperfusion injury, 185–186 Resection, partial hepatic, 164 Residual bodies, 30, 1240 Residual nodules, 236 lipophagic, 249 Resistance elements, intrahepatic, 57 genotypic, 777 phenotypic, 777 Resistin, 1160 Respiratory syndrome, severe acute, 829 Restitution phase, 165 Retinoate X receptor, 92 Retinoic acid, 92 Retinoic acid receptor, 92 Retinoids, 92 Retinol-binding protein, 92 Retinol-binding protein 4, 792 Retrocytosis, 66 Reye’s syndrome, 825 Reynold’s pentad, 1486 Reynold’s syndrome, 1486 Rhabdomyosarcomas, 1350 Rheumatoid arthritis, 1250 Rhizomelic chondrodysplasia punctata, 1185 Ribavirin, 712, 802 contraindications, 803 weight-based, 805 Ribozymes, 711, 717, 1405–1406 Rickettsiae, 839 Riedel’s lobe, 12, 621 Rifampicin, 580, 1230 Rifampin, 580 Rimantadine, 714 RNA interference, 1406–1407 Rocky Mountain spotted fever, 839 Rokitansky-Aschoff sinuses, 392–393 Rosettes, liver cell, 212 Rotor syndrome, 586, 589–590 Rubella virus, 827
Index S Saccharomyces cerevisiae, 716 S-adenosyl-methionine, 581, 1117, 1264 Salmonellae, 839–840 Salt restriction, 1198 Sanded nuclei, 233, 726 Sandhoff’s disease, 1183 Sarcoid granulomas, 1238 Sarcoidosis, 249, 795, 1251 ascites, 1241 Budd-Chiari syndrome, 1242 cholestasis, 1241 cholestatic alterations, 1240 course, 1241–1242 definition, 1239 diagnosis, 1240–1241 differential diagnosis, 1241 epidemiology, 1239 granulomatous phlebitis, 1240 liver failure, 1242 necroinflammatory changes, 1240 pathogenesis, 1239–1240 pathology, 1240 portal hypertension, 1240 prognosis, 1241–1242 pseudotumors, 1240 sarcoidoma, 1241 therapy, 1242 Sarcoma, embryonal, 1345–1346 Scavenger cells, 135 Scavenger receptor, 33 Schaumann bodies, 1240 Scheuer’s score, 274 Schistosomal pigment, 230 Scintigraphy blood pool, 426–427 perfusion, 426–427 Sclerosing cholangitis primary, 445, 911–917 secondary, 397 Sclerosing hyaline necrosis, 645 Sclerosis central hyaline, 258, 645 hepatoportal, 252, 659–660, 865 perivenous, 258 Sclerotherapy, 982 Scoring systems clinical, 289–292 histopathological, 271–286 Scratch effects, 313 Scrotal edema, 309 Secondary amyloidosis, 1106 Secondary hemochromatosis, 1047 diagnosis, 1064 pathophysiology, 1063–1064 therapy, 1064–1065 Sengstaken-Blakemore-tube, 984 SEN virus, 733 Sepsis, 575–576 gonococcal, 837 Sepsis tuberculosa acutissima Landouzy, 838
Index Septa, interlobular, 16 Septicemia, 1251 Septum transversum, 8, 9 Serine proteases, 177 Serotonin, 161, 1009 Serotonin antagonists, 580 Serpines, 1071 Serum amyloid P, 1105 Serum-ascites-albumin gradient, 610 Serum copper, 1038 Serum sickness, 316 Sex hormones, 1276 Sexual dysfunction, 307, 797, 1026 Shigellae, 840 Shock liver, 1248 Short-bowel syndrome, 1249 Shunts intrahepatic vascular, 951 hyperbilirubinemia, 587 peritoneovenous, 974 transjugular intrahepatic, 371 transjugular intrahepatic portosystemic, 974–975 Shuttle-vesicles, 72 Sicca syndrome, 748 Sickle cell anemia, 654 Sickle cell disease, 1250 Siderosis, 227 Silibinin, 935 Sinusoidal cells, 22 Sinusoidal contents, changes, 654 Sinusoidal dilatation, 649–650 Sinusoidal endothelial cells Sinusoidal endothelial cells (SEC), 136, 140, 146 Sinusoidal obstruction syndrome, 203, 651–654 Sinusoidal pressure, 515 Sinusoids, 17, 649–654 capillarization, 257, 654 Situs inversus, 622 Sjögren’s syndrome, 795 Small hepatocellular carcinoma, 1315 Small interfering RNA, 1406 Small ubiquitin-related modifiers, 900 a-Smooth muscle actin, 37 Smooth muscle antibodies immunofluorescence reactivities, 349 occurrence and significance, 349–350 target antigens, 349 Sodium benzoate, 1014–1015 Sodium taurocholate cotransporting polypeptide, 564 Solitary fibrous tumor, 1301 Somatic pain, 532, 533 Sorbitol clearance assessment, 337 confounding factors, 337 principle and technique, 337 side effects, 337 Sorbitol dehydrogenase, 327 Space, perinuclear, 26 Spectrin, 66 SPECT technique, 429 Sphincter of Oddi
1601 anatomy, 1442 dysfunction, 1445–1451 manometry, 523–527, 1447 physiology, 1425 pressure phenomena, 525 Sphincter of Oddi dyskinesia, 1451–1454 classification, 1446 tests, 1446 Spider nevi, 313 Spider telangiectasia, 313 Spironolactone, 971 Spleen, examination, 311–312 Spongiotic pericytoma, 1304 Spontaneous bacterial peritonitis, 611 bacterial translocation, 995 clinical manifestations, 995 course, 996 definition, 994 diagnosis, 995–996 differential diagnosis, 996 epidemiology, 994 etiology, 994–995 laboratory findings, 995 microorganisms, 994 pathogenesis, 994–995 primary prophylaxis, 996–997 prognosis, 996 prophylaxis, 996–998 secondary prophylaxis, 998 therapy, 996–998 Spotty necrosis, 720 Squamous cell carcinomas, 1350 Staphylococcus aureus, 840 Starvation, 134 Stauffer’s syndrome, 1249 Steatohepatitis, 224, 277–280, 1158–1160 alcoholic, 1127–1142 nonalcoholic, 239, 1153 staging, 280 Steatosis, 360, 1156–1158 focal, 384–386, 556, 1298 hepatic, 1126 irregular, 556 macrovesicular, 224 microvesicular, 224, 1265 Steatoviral hepatitis, 726 Stellate cells, 8, 18, 36–39, 42, 57, 58 activation, 38 apoptosis, 39 extracellular matrix, 38 hepatic, 140 membrane receptors, 38 secretory products, 38 Stem cell factor (SCF), 163 Stem cells, hepatic, 40–41, 159 Sterol regulatory element-binding protein, 87, 92 St. John’s wort, 1217 Stone ileus, 1474 Stone perforation, 1474 Stones bile duct, 1483–1491
1602 black pigment, 1460 brown pigment, 1460 calcium-bilirubinate, 1460 chemical dissolution, 1490 cholesterol, 1460 gallbladder, 1459–1479 primary, 1460 secondary, 1460 Strawberry gallbladder, 1509 Strictures benign biliary, 442 bile duct, 444 malignant biliary, 442–444 Stromelysins, 44 Submassive necrosis, 721 Sulfation, 128 Summerskill–Tygstrup–Walsh syndrome, 1095, 1097–1098 Superoxide anion, 175 Superoxide dismutase, 179 Surgery bibilary tract, 1392–1393 cardiac, 1393 cardiopulmonary complications, 1384 contraindication, 1387–1388 effects on the liver, 1383 hemodynamic effects, 1384 hepatic, 1393–1394 hepatopulmonary syndrome, 1384 hypoxemia, 1384 portopulmonary hypertension, 1384 Surgical necrosis, 212–213 Survival genes, 177 Survivin, 1317 Swelling, nuclear, 232 Sympathetic nervous system, activation, 606 Symports, 64 Syndecan, 45 Synovitis, 748 Syphilis, 840 Systemic lupus erythematosus, 1250 Systemic mastocytosis, 1251
T Tachyoddia, 526 Tacrolimus, 1373 Tangier disease, 224, 225, 1184 Target cell, 1028 Tarui’s disease, 1182 Taste, distribution of, 306 Tay–Sachs disease, 1183 T cells alternative, 143 conventional, 143 unconventional, 143 Telbivudine, 709, 773 resistance, 779 results of treatment, 773 Telomerase, 153 Telomeres, 153 Tenascin, 46
Index Tenofovir, 709, 773–774, 778 Terlipressin, 942 Terry nails, 315 Testicular atrophy, 316 Tetracyclines, 1228 Tetrathiomolybdate, 1041 Thalassemia, 1063, 1276 Thalassemia major, 1250 Therapy, gallstone, 1475–1479 Thorium dioxide, 203, 204, 1340 Thorotrast, 203, 204 Thrombocytopenia, 804, 1028 Thrombomodulin, 45 Thrombosis, portal vein, 365, 368–369, 657 Thyroid disorders, 795 Thyroid dysfunction, 1026–1027 Thyroid hormones, 160 Tight junctions, 25 Tissue inhibitors of metalloproteinases, 44 T lymphocytes, 142 cytotoxic, 193–194 TNF-related apoptosis-inducing-ligand (TRAIL), 216–217 TNM staging system, 1323, 1324 a-Tocopherol, 178 Tocopherol-radical, 178 Togaviruses, 827–828 Tokyo score, 1325 Tolerance immunologic, 148–149 oral, 149 Toll-like receptors (TLR), 149 Topoisomerase-inhibitors, 1546 Torres bodies, 233, 828 Torsemide, 972 Total parenteral nutrition, 573–574 Toxemia of pregnancy clinical manifestations, 1268 complications, 1268 definition, 1267 diagnosis, 1268 epidemiology, 1267 etiology, 1267 HELLP syndrome, 1268–1269 imaging, 1268 laboratory findings, 1268 liver disease, 1267–1269 pathogenesis, 1267 pathology, 1268 prognosis, 1269 therapy, 1269 Toxicity, idiosyncratic, 189 Toxic liver injury, 189–190 Toxic shock syndrome, 840 Toxins, 544–545 Toxoplasmosis, 847–848 Transaminases. See Aminotransferases Transarterial chemoembolization, 1363 Transcription factors, 165 Transcytosis, 33, 66 Transfer protein, microsomal, 90 Transferrin receptor 1, 1060
Index Transferrin receptor 2, 96 Transferrin saturation, 1049 Transforming growth factor-a (TGF-a), 162, 254 Transforming growth factor-b1 (TGF-b1), 253–254 Transforming growth factor beta (TGF-b), 162 Transient elastography, 262, 598 Transjugular intrahepatic portosystemic shunt (TIPS), 371, 974–975 Transmitters, peptidergic, 22 Transplant, pathology, 284–285 Transport active, 64 hepatocellular, 61–74 passive, 63 vesicle, 65–66, 71–72 Transporters apical (canalicular), 69–70 apical sodium bile acid, 1425 basolateral (sinusoidal), 66–69 canalicular, 114 defects, genetic, 1095 hepatocellular, 66, 114 Transport processes, cellular, 62 Transport proteins, 63–64 Transport systems, 113 ATP-dependent, 565 ATP-independent, 565 cholangiocyte, 566 heptocellular, 564 Traube’s space, 311 Trematode cholangitis, 1501 Trematodes, 1502 Treponema pallidum, 840 Triamterene, 971 Trientine, 1040, 1041 Triglycerides, 86, 224 Tropheryma whipplei, 841 Tropical splenomegaly syndrome, 847 Tropoelastin, 44 Tru-Cut needle, 465 TT virus, 733 Tuberculosis, extrapulmonary, 869 Tubulin, 32 Tuft cell, 1420 Tularemia, 837 Tumor-like lesions, 1275 Tumor necrosis factor alpha (TNF-a), 162 Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 192, 194 Tumors epithelial, 1275 extrahepatic bile duct, 398–399 nonepithelial, 1275 primary, 1275 Turner’s syndrome, 1251 Type 3 hemochromatosis diagnosis, 1061 natural history, 1060–1061 pathophysiology, 1060 prevalence, 1060 therapy, 1061
1603 Type 4 hemochromatosis diagnosis, 1063 natural history, 1062–1063 pathophysiology, 1061–1062 prevalence, 1061–1062 therapy, 1063 Typhoid nodules, 840 Tyrosinemia, 1185 U Ubiquitin, 83, 178 Ubiquitination, 178 Ubiquitin proteasome pathway, 1134 UDP-glucuronosyl transferase, 1214 UGT1A gene locus, genetic variation, 1215 Ulcerative colitis, 748 Ultrasonography, 261–262, 359–399 diffuse liver disease, 360 Ultrasound contrast-enhanced, 374 transabdominal, 360 Ultrasound contrast agents, 373–374 Umbilical hernia, 310 Uncoupling protein-2, 178 Underfilling, arterial, 606 Underfilling hypothesis, 608–609 Undulin, 46 Unfolded protein response, 176–178 Uniports, 64 United Network for organ sharing, 1355 Urea, 84 cycle, 85 cycle disorders, 1185 Uremia, 1249 Urobilinogen, 112, 330 Uroporphyrin crystals, 230 Uroporphyrins, 1083 Ursodeoxycholic acid, 109, 580, 1260 Urticaria, 748 V Variccal band ligation, 981 Variceal bleeding predictors, 520, 978–979 Variceal hemorrhage primary prophylaxis, 980–982 recurrent, 984–985 secondary prophylaxis, 984 Variceal pressure, 976 Varicella-Zoster virus, 233, 825 Varices anorectal, 976 downhill, 976 esophageal, 976–985 gallbladder, 988 gastric, 985–986 gastro-esophageal, 600 Variegate porphyria, 1080 Vascular anomalies, 637 Vascular endothelial growth factor (VEGF), 160
1604 Vascular resistance, portal, 595 Vasoactive substances, 57–58 Vasoconstriction, intrahepatic, 596 Vasodilating peptides, 606, 607 Vasopressin, 161 Vein(s) centrilobular, 21 collecting, 21 perilobular, 21 portal, 21, 55 sublobular, 21 Venae spigelii, 645 Veno-occlusive disease, 370, 651 Venopathy, obliterative portal, 1282 Venous outflow, 365 Venules terminal hepatic, 18 terminal portal, 21 Veres needle, 489–494, 497 Versican, 45 Very low density lipoproteins, 91 Vesica fellea divisa, 1430 Vesica fellea duplex, 1430 Vesicles clathrin coated, 73 multilamellar, 121 unilamellar, 121 Vesicle transport. See Transport Vibrio vulnificus, 994 Vimentin, 37 Vim Silverman needles, 466 Vinyl chloride, 1340 Viral breakthrough, 770 Viral cross talk, 194 Viral hepatitis, 542–543, 577, 1359–1360 acute, 361, 542–543 chronic, 543 pathology, 720 treatment approaches, 707–717 Viral hepatitis C, chronic, 362 Viral inclusions, 233 intranuclear, 824 Viral infections, 671–821 Viral kinetic analysis, 805 Viramidine, 803 Virchow’s cells, 838 Viruses inactivation, intracellular, 194 nonhepatotropic, 823–829 Visceral pain, 532, 533 Vitamin A, 36, 38, 92, 570, 581 Vitamin D, 570, 581 Vitamin deficiency, 570 Vitamin E, 178, 570, 581 Vitamin K, 570, 581 Vitamins, 1197 Volume deficiency hypothesis, 608 Volumetric composition, 22 von Gierke’s disease, 1182 von Meyenburg complexes, 628, 1288
Index von Recklinghausen’s disease, 1251 VX-499, 712 W Watermelon stomach, 987 Wedged hepatic venous pressure, 515 Weight loss diet, 1203 Weil’s disease, 837 Whipple procedure, 1516 Whipple’s disease, 841, 1251 White nipple sign, 979 Wilson protein, 1036 Wilson’s disease, 544, 936–937 clinical presentation, 1036–1037 definition, 1035 diagnosis, 1036–1037 diagnostic findings, 1037–1039 differential diagnosis, 1039 epidemiology, 1035 etiology, 1035 family screening, 1039 fulminant hepatic failure, 1037, 1039 gene, 1035 Kayser-Fleischer rings, 1037 liver transplantation, 1042 molecular studies, 1038 neurological symptoms, 1037 pathogenesis, 1035 prognosis, 1039–1040 psychiatric abnormalities, 1037 survival rates, 1042 treatment, 1040–1042 Wilson’s disease protein, 93 Wolman’s disease, 224, 225, 1184 X Xanthelasmas, 314, 570 Xanthine oxidase, 186 Xanthoma cells, 244 Xanthomas, 570 Xanthomas, eruptive, 314 Xanthomatous arteriopathy, 668 Y Y-binding-protein, 119 Yellow fever, 233 Yellow fever virus, 828 Yersiniae, 841 Y-protein, 110 Z Zahn’s grooves, 622 Zellweger’s syndrome, 1185 Zieve’s syndrome, 1028, 1126 Zinc salts, 1040, 1041 Zonation, metabolic, 131, 132 Zonulae occludentes, 25 Z-protein, 110 Zygomycosis, 860
