Therapy of Digestive Disorders, Second Edition

Dedication This book is dedicated to all my colleagues and students for providing friendship and purpose, and to my en...

Author: M. Michael Wolfe MD | Gary L. Davis MD | Francis A. Farraye MD MSc | Ralph Giannella MD | Juan-R Malagelada MD | Michael L. Steer MD

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Dedication

This book is dedicated to all my colleagues and students for providing friendship and purpose, and to my entire family, and especially my children, Jessica, Matthew, and Aliza, for their inspiration, love, understanding, encouragement, unremitting sacrifice, and support, as well as the challenges they continuously provide.

Commissioning Editor: Karen Bowler Project Development Manager: Shuet-Kei Cheung Editorial Assistant: Katie McCormack Project Manager: Rory MacDonald Cover Designer: Jayne Jones Text Designer: Stewart Larking Illustration Manager: Mick Ruddy Illustrator: Antbits & Tim Loughhead Marketing Manager (UK/USA): Amy Hey & Laura Meiskey

An imprint of Elsevier Inc © 2000,WB Saunders Company. © 2006, Elsevier Inc. All rights reserved

First edition 2000 Second edition 2006

No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the Publishers. Permissions may be sought directly from Elsevier’s Health Sciences Rights Department, 1600 John F. Kennedy Boulevard, Suite 1800, Philadelphia, PA 19103-2899, USA: phone: (+1) 215 239 3804; fax: (+1) 215 239 3805; or, e-mail: [email protected] may also complete your request on-line via the Elsevier homepage (http://www.elsevier.com), by selecting ‘Support and contact’ and then ‘Copyright and Permission’. ISBN 1-4160-0317-7 This book is also available as a package of book and PDA software: ISBN 1-4160-0318-5 A PDA software version of this book is also available: ISBN 1-4160-0319-3 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging in Publication Data A catalog record for this book is available from the Library of Congress Notice Medical knowledge is constantly changing. Standard safety precautions must be followed, but as new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current product information provided by the manufacturer of each drug to be administered to verify the recommended dose, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on experience and knowledge of the patient, to determine dosages and the best treatment for each individual patient. Neither the Publisher nor the author assume any liability for any injury and/or damage to persons or property arising from this publication. The Publisher Printed in China Last digit is the print number: 9 8 7 6 5 4 3 2 1

Contributors Aijaz Ahmed MD Gastroenterology Fellow Hepatology Stanford University Medical Center Palo Alto, CA, USA

Lawrence J. Brandt MD Chief of Gastroenterology GI Division Montefiore Medical Center Bronx, NY, USA

Vicente Arroyo Perez MD Professor of Medicine, Director Institute for Digestive Diseases Hospital Clinic i Provincial de Barcelona Universitat de Barcelona Barcelona, Spain

Markus W. Büchler MD Professor of Surgery Department of Surgery University of Heidelberg Heidelberg, Germany

Bruce R. Bacon MD James F. King MD Endowed Chair in Gastroenterology Director, Division of Gastroenterology and Hepatology Saint Louis University School of Medicine St. Louis, MO, USA William F. Balistreri MD Director, Division of Gastroenterology, Hepatology & Nutrition Dorothy M.M. Kersten Professor of Pediatrics Cincinnati Children’s Hospital Medical Center Cincinatti, OH, USA Carl L. Berg MD Director of Hepatology Medical Director, Liver Transplantation Associate Professor of Medicine Digestive Health Center of Excellence University of Virginia Health System Charlottesville,VA, USA Adil E. Bharucha MD MBBS Associate Professor of Medicine Consultant Division of Gastroenterology & Hepatology Mayo Clinic Rochester Rochester, MN, USA Cheryl Blank DO Fellow Division of Pediatric Gastroenterology Children’s Hospital of Pittsburgh Pittsburgh, PA, USA Henry Worth Boyce MD Professor and Director Joy McCann Culverhouse Center for Swallowing Disorder University of South Florida College of Medicine Tampa, FL, USA

Jonathan F. Critchlow MD FACS Department of Anesthesia & Critical Care Beth Israel Deaconess Medical Centre Boston, MA, USA Srinivasan Dasarathy MD Assistant Professor of Medicine Case Western Reserve University Metro Health Medical Center Cleveland, OH, USA

Theresa A Byrne PhD Director of Research and Clinical Studies Nutritional Restart Center Hopkington, MA, USA

Bradley R. Davis MD Associate Professor of Surgery Division of Colon and Rectal Surgery University of Cincinnati Cincinnati, OH, USA

James H. Caldwell MD Professor, Internal Medicine (Digestive Diseases) Division of Digestive Disease The Ohio State University Hospital Columbus, OH, USA

Gary L. Davis MD Director Division of Hepatology Baylor University Medical Center Dallas,TX, USA

Michael Camilleri MD MRCP FACP FRCP FACG Atherton and Winifred W. Bean Professor, Professor of Medicine Mayo Clinic College of Medicine Rochester, MN, USA

John Del Valle MD Professor of Medicine Department of Internal Medicine University of Michigan Ann Arbor, MI, USA

Andrés Cárdenas MD MMSc Instructor in Medicine Harvard Medical School Beth Israel Deaconess Medical Center Boston, MA, USA Shivakumar Chitturi MD MRCP(UK) Consultant Hepatologist Department of Gastroenterology Apollo Hospitals Chennai, India

Carlo Di Lorenzo MD Chief, Division of Pediatric Gastroenterology Division of Pediatric Gastroenterology Columbus Children’s Hospital Columbus, OH, USA Ram Dickman MD Research Fellow GI Section Southern Arizona VA Health Care System Tucson, AZ, USA

Umesh Choudhry MD Professor of Gastroenterology Mease Hospitals Clearwater, FL, USA

Eric J. Dozois MD Assistant Professor Division of Colon and Rectal Surgery Mayo Clinic College of Medicine Rochester, MN, USA

M.T. Clandinin PLQ Professor of Agriculture, Food & Nutritional Sciences University of Alberta Edmonton, AB, Canada

Andrew W. DuPont MD Assistant Professor Division of Gastroenterology University of Texas Medical Branch Galveston,TX, USA

Ray E. Clouse MD Professor of Medicine and Psychiatry Division of Gastroenterology Washington University St Louis, MO, USA

Hashem B. El-Serag MD MPH Chief, Clinical Epidemiology and Outcomes, Gastroenterology Associate Professor of Medicine Baylor College of Medicine Houston,TX, USA

Contributors

x Francis A. Farraye MD MSc Associate Professor of Medicine and Clinical Director Section of Gastroenterology Boston University School of Medicine Boston, MA, USA

Stuart L.Goldberg MD Chief, Leukemia Service Clinical Associate Professor of Medicine Hackensack University Medical Center University of Medicine and Dentistry of New Jersey Hackensack, NJ, USA

Richard H. Hunt FRCP FRCPC FACG Professor of Medicine Division of Gastroenterology, Department of Medicine McMaster University Medical Centre Hamilton, Ontario, Canada

Geoffrey C. Farrell MD FRACP Department of Gastroenterology & Hepatology Westmead Hospital New South Wales, Australia

Richard C. Golding MD Senior Attending Physician Division of Gastroenterology Hackensack University Medical Center Hackensack, NJ, USA

Brian C. Jacobson MD MD MPH Associate Director of Endoscopy Boston University Medical Center Boston, MA, USA

Ronnie Fass MD FACP FACG Associate Professor of Medicine GI Section Southern Arizona VA Health Care System Tucson, AZ, USA David M. Felig MD Attending Physician Division of Gastroenterology Hackensack University Medical Center Hackensack, NJ, USA Stephen J. Ferzoco MD Assistant Professor of Surgery Department of Surgery Brigham and Women’s Hospital Boston, MA, USA Henry S. Fraimow MD Associate Professor of Medicine Division of Infectious Diseases Cooper University Hospital Camden, NJ, USA Ronald Fried MD Consultant for Gastroenterology and Hepatology Gastroenterology and Hepatology Merian-Iselin Spital Basel, Switzerland Sonia Friedman MD Instructor of Medicine, Harvard Medical School Gastroenterology Division Brigham and Women’s Hospital Boston, MA, USA Helmut M. Friess MD Professor of Surgery Department of Surgery University of Heidelberg Heidelberg, Germany Daniel Gelrud MD Assistant Professor of Medicine Department of Gastroenterology Jacobi Medical Center Bronx, NY, USA Ralph A. Giannella MD Mark Brown Professor of Medicine Division of Digestive Diseases University of Cincinnati College of Medicine Cincinnati, OH, USA Pere Ginés Gibert MD Associate Professor of Medicine, Chief of Liver Unit Hospital Clinic i Provincial de Barcelona Universitat de Barcelona Barcelona, Spain

Gregory J. Gores MD Professor of Medicine and Chief Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine Rochester, MN, USA Annette Grambihler MD Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine Rochester, MN, USA Norton J. Greenberger MD Clinical Professor of Medicine, Harvard Medical School Senior Physician, Brigham and Women’s Hospital, Division of Gastroenterology Brigham and Women’s Hospital Boston, MA, USA David Greenwald MD Associate Professor of Medicine Albert Einstein College of Medicine Associate Director, Division of Gastroenterology Montefiore Medical Center Bronx, NY, USA Francisco Guarner MD PhD Consultant of Gastroenterology Digestive System Research Unit Hospital Universitari Vall d’Hebron Barcelona, Spain J. Eileen Hay MBChB FRCP Professor of Medicine and Consultant Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine Rochester, MN, USA Ikuo Hirano MD Associate Professor of Medicine Gastroenterology Fellowship Training Director Division of Gastroenterology Northwestern University School of Medicine Chicago, IL, USA Richard Hodin MD Associate Professor of Surgery Department of Surgery Massachusetts General Hospital Boston, MA, USA Christopher S. Huang MD Instructor Gastro Medicine Boston University Medical Center Boston, MA, USA

Maureen M. Jonas MD Professor and Chairman of Internal Medicine Division of Gastroenterology The Children’s Hospital Boston, MA, USA Emmet B. Keeffe MD Professor of Medicine, Chief of Hepatology, Co-Director, Stanford University Medical Center Palo Alto, CA, USA Ciarán P. Kelly MD FRCPI FRCG Associate Professor of Medicine Department of Gastroenterology Beth Israel Deaconess Medical Center Boston, MA, USA Robert S. Klein MD Professor of Medicine, and Epidemiology & Population Health Department of Medicine Division of Infectious Diseases Montefiore Medical Center Bronx, NY, USA Samuel Klein MD Professor of Medicine & Nutritional Science Division of Gastroenterology Washington University School of Medicine St Louis, MO, USA Kenneth L. Koch MD Professor of Medicine, Section Head Section on Gastroenterology Wake Forest University School of Medicine Winston-Salem, NC, USA Patricia L. Kozuch MD Instructor of Medicine Department of Medicine The University of Chicago Division of Biological Sciences Chicago, IL, USA Edward L. Krawitt MD Professor of Medicine Department of Medicine University of Vermont Burlington,VT, USA J.Thomas LaMont MD Charlotte F. & Irving W. Rabb Professor of Medicine, Ha Chief, Division of Gastroenterology Beth Israel Deaconess Medical Center Boston, MA, USA

xi Lars Lundell MD PhD Professor of Surgery Department of Surgery Sahlgrens Hospital Gothenburg, Sweden

James Y.W. Lau MD Consultant, Division of Upper Gastrointestinal Surgery Department of Surgery Prince of Wales Hospital Hong Kong, China

Juan-R. Malagelada MD Professor Digestive Diseases Digestive Diseases Department Hospital Universitari Vall d’Hebron Barcelona, Spain

Konstantinos N. Lazaridis MD Assistant Professor of Medicine Center for Basic Research in Digestive Diseases Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine Rochester, MN, USA Mike A. Leonis MD PhD Research Instructor in Pediatrics, William E. Cooper Procter Scholar Division of Gastroenterology, Hepatology and Nutrition Department of Pediatrics Cincinatti, OH, USA Markus M. Lerch MD Professor of Medicine and Chair Department of Gastroenterology, Endocrinology and Nutrition Ernst-Moritz-Arndt Universität Greifswald Greifswald, Germany Wai K. Leung MD Associate Professor Department of Medicine & Therapeutics The Chinese University of Hong Kong Shatin Hong Kong, China David R. Lichtenstein MD Associate Professor of Medicine Director of Endoscopy Section of Gastroenterology Boston University School of Medicine Boston, MA, USA Gary R Lichtenstein MD Professor of Medicine, University of Pennsylvania School Director, Center for Inflammatory Bowel Diseases Hospital of the University of Pennsylvania Gastroenterology Division Philadelphia, PA, USA Keith D. Lindor MD Professor of Medicine and Dean Mayo Medical School Division of Gastroenterology and Hepatology Rochester, MN, USA Robert M. Lowe MD Educational Director of Gastroenterology Assistant Professor of Medicine Gastroenterology Boston Medical Center Boston, MA, USA

Paul Martin MD Professor of Medicine, Associate Director of the Division Recanati / Miller Transplantation Institute The Mount Sinai Hospital New York, NY, USA Jeffrey B. Matthews MD Christian R Holmes Professor and Chairman Department of Surgery University of Cincinnati Cincinnati, OH, USA Julia Mayerle MD Lecturer Department of Gastroenterology, Endocrinology and Nutrition Ernst-Moritz-Arndt Universität Greifswald Greifswald, Germany Arthur J. McCullough MD Director of Gastroenterology Department of Medicine MetroHealth Medical Center Cleveland, OH, USA James E. McGuigan MD Professor of Medicine Division of Gastroenterology, Hepatology and Nutrition University of Florida College of Medicine Gainesville, FL, USA Peter J. Milla MD Reader in Paediatric Gastroenterology Gastroenterology Unit Institute of Child Health London, UK Daniel S. Mishkin MD CM Instructor of Medicine Section of Gastroenterology Boston University Medical Center Boston, MA, USA Kevin D. Mullen MB FRCPI Professor of Medicine Case Western Reserve University and Consultant of Gastroenterology GI Division Metro Health Medical Center Cleveland, OH, USA

David R. Nelson MD Associate Professor Chief, Section of Hepatobiliary Diseases Director, Adult Liver Transplant Program Dept of Gastroenterology, Hepatology and Nutrition University of Florida Gainesville, FL, USA Enders K.W. Ng MD FRCS Assistant Dean (Clinical), Faculty of Medicine Professor and Chief, Upper Gastrointestinal Surgery Department of Surgery The Chinese University of Hong Kong Shatin Hong Kong, China David P. Nunes MB Director of Hepatology Boston University School of Medicine Boston, MA, USA Jaime Oviedo MD Assistant Professor of Medicine Gastroenterology Boston Medical Center Boston, MA, USA Sareh Parangi MD Assistant Professor of Surgery Department of Surgery Beth Israel-Deaconess Medical Center Boston, MA, USA John H. Pemberton MD Professor of Surgery Division of Colon and Rectal Surgery Mayo Clinic Rochester, MN, USA David A. Peura MD Associate Chief of Gastroenterology and Hepatology Professor of Medicine University of Virginia Charlottesville,VA, USA Gilda Porta MD Professor of Pediatrics University of Sao Paulo Sao Paulo, Brazil Charlene M. Prather MD Associate Professor of Medicine Saint Louis University School of Medicine Saint Louis, MO, USA Sarathchandra I. Reddy MD Instructor of Medicine, Harvard Medical School Gastroenterology Division Brigham and Women’s Hospital Boston, MA, USA Joachim Richter MD Assistant Professor of Medicine; Lecturer,Tropical and In Tropenmedizinische Ambulanz, Klinik für Gastroenterologi Universitätsklinikum Düsseldorf Düsseldorf, Germany

Contributors

Nicholas F. LaRusso MD Professor and Chairman of Internal Medicine Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine Rochester, MN, USA

Contributors

xii Malcolm K. Robinson MD Director, Metabolic Support Services Brigham and Women’s Hospital Assistant Professor of Surgery Harvard Medical School Department of Surgery Brigham and Women’s Hospital Boston, MA, USA Juan Rodés MD Professor of Medicine Hospital Clinic University of Barcelona Barcelona, Spain Janice G. Rothschild MD, FACS Assistant Professor of Surgery Department of Surgery Tufts-New England Medical Center Boston, MA, USA Richard I. Rothstein MD Professor of Medicine Assistant Dean Cont. Education Chief, Section of Gastroenterology Dartmouth-Hitchcock Medical Center Lebanon, NH, USA Deborah C. Rubin MD Professor of Medicine Department of Medicine Director, DDRCC Morphology Core Facility Washington State University School of Medicine St Louis, MO, USA Sherif Saadeh MD Staff Gastroenterologist & Transplant Hepatologist Division of Hepatology Department of Internal Medicine Baylor University Medical Center Dallas,TX, USA Arun J. Sanyal MBBS MD Charles Caravati Professor of Medicine Chairman, Division of Gastroenterology and Hepatology Medical College of Virginia Richmond,VA, USA Miguel Saps MD Division of Pediatric Gastroenterology Children’s Memorial Hospital of Chicago Chicago, IL, USA Lawrence J. Sauberman MD Assistant Professor of Medicine Gastroenterology Division Brigham and Women’s Hospital Boston, MA, USA Robert E. Schoen MD MPH Professor of Medicine and Epidemiology Division of Gastroenterology, Hepatology and Nutrition Pittsburgh, PA, USA

Paul C. Schroy III MD MPH Professor of Medicine Boston University School of Medicine Section of Gastroenterology Boston Medical Center Boston, MA, USA Douglas Simon MD FACG Professor of Clinical Medicine Department of Medicine Jacobi Medical Center Bronx, NY, USA Adam Slivka MD PhD Associate Professor of Medicine & Associate Chief of Gastroenterology, Hepatology & Nutrition UPMC Gastroenterology University of Pittsburgh Medical Center Pittsburgh, PA, USA Consuelo Soldevila-Pico MD Associate Professor of Medicine Department of Medicine University of Florida Gainesville, FL, USA David I. Soybel MD Associate Professor of Surgery Division of General and GI Surgery Brigham and Women’s Hospital Boston, MA, USA Stuart Jon Spechler MD Professor of Medicine University of Texas Southwestern Medical Center Chief, Division of Gastroenterology Dallas VA Medical Center Dallas,TX, USA Michael L. Steer MD Professor of Surgery, Chief of General Surgery Tufts University School of Medicine Tufts-New England Medical Center Boston, MA, USA Joseph J.Y. Sung MD PhD FRCP FRCPE FRACP FACP FHKAM FHKCP Professor of Medicine Chairman Department of Medicine and Therapeutics Director, Center for Emerging Infectious Diseases New Territories Hong Kong SAR Christina M. Surawicz MD Professor of Medicine Harborview Medical Center University of Washington Seattle, WA, USA Jan Tack MD PhD Professor of Medicine Head of Clinic, Department of Gastroenterology University Hospitals Leuven Leuven, Belgium

Jayant A.Talwalkar MD MPH Assistant Professor of Medicine Mayo Clinic College of Medicine Rochester, MN, USA Beth E.Taylor MS RD CNSD FCCM Nutrition Support Specialist Department of Food and Nutrition Barnes-Jewish Hospital Plaza St Louis, MO, USA A. B. R.Thomson MD FRCPC Professor or Medicine Department of Medicine University of Alberta Edmonton, AB, Canada Tram T. Tran MD Medical Director, Liver Transplant, Cedar Sinai Medical Assistant Professor of Medicine Geffen UCLA School of Medicine Los Angeles, CA, USA Jacques Van Dam MD PhD Professor and Chief of Clinical Gastroenterology Division of Gastroenterology and Hepatology Stanford University Medical Center Palo Alto, CA, USA C. Mel Wilcox MD Division of Gastroenterology and Hepatology University of Alabama Birmingham, AL, USA G. E.Wild MD PLQ Professor of Medicine University of Alberta Edmonton, AB, Canada Douglas W. Wilmore MD Professor of Surgery Harvard Medical School Department of Surgery Brigham and Women’s Hospital Boston, MA, USA Jacqueline L.Wolf MD Associate Professor of Medicine Division of Gastroenterology Beth Israel Deaconess Medical Center Boston, MA, USA M. Michael Wolfe MD Professor of Medicine and Chief, Section of Gastroenterology Boston University School of Medicine Boston, MA, USA Yuhong Yuan MD MSc PhD Research Associate Division of Gastroenterology, Department of Medicine McMaster University Medical Centre Hamilton, Ontario, Canada

Preface to the second edition During the past three decades, gastroenterologists and other healthcare workers engaged in the management of patients with digestive disorders have been witness to remarkable improvements in the understanding of the biology of these commonly encountered problems. Moreover, advancements in the elucidation of the pathogenesis of various digestive disorders and the exponential increase in therapeutic modalities for the treatment of these diseases have been unsurpassed during this same period of time. The universal availability of fiberoptic, and more recently video and wireless capsule, endoscopy and the widespread employment of minimally invasive surgery, have facilitated the ability of gastroenterologists and gastrointestinal surgeons to investigate and provide therapy for the multitude of persons suffering from the vast array of digestive disorders. This spectacular progress has enabled practitioners to extend the technological advances and improvements in pharmacological treatment to the masses, and in doing so, have diminished morbidity, improved survival, and enhanced the quality of life for the hundreds of millions of individuals afflicted with these diseases. One prominent example of our remarkable progress during this period of time is the management of gastroesophageal reflux disease (GERD). Beginning in the mid-1970s with the availability of the histamine H2-receptor antagonists and, more recently, the proton pump inhibitors, as well as surgical and endoscopic approaches to the disorder, the treatment of GERD has been revolutionized. A myriad of individuals, who previously received generally inadequate therapy, have benefited significantly by these remarkably effective and safe agents. The significance of gastrointestinal drug development is further evident by the bestowing of two Nobel Prizes in Medicine and Physiology for biomedical research that led to the development of two prominent classes of drugs that affect gastrointestinal function: the histamine H2-receptor antagonists and prostaglandins. Furthermore, the past decade has witnessed the development of a myriad of new classes of medication, including specific immunomodulators and other drugs used for the therapy of inflammatory bowel diseases, antiviral agents for the treatment of viral hepatitides, and neuromodulators for the management of irritable bowel syndrome and other motility disorders of the gastrointestinal tract. Along with these important advances comes the requisite requirement for practitioners to remain informed, a task generally accomplished by the availability of contemporary textbooks and other literature relevant to their interests and needs. Beginning with its inception and formulation and during the preparation of the second edition of this textbook, Therapy of Digestive Disorders was formulated to provide practitioners with an authoritative and evidence-based, yet practical, approach to the optimal management of individuals afflicted with specific digestive disorders. The text of each chapter focuses on diagnosis and treatment, with less emphasis placed on epidemiology and pathogenesis. Nevertheless, all treatment recommendations are based on the biology and pathophysiology of the specific disease entities. In addition to providing updates and expanding the topics included in the first

edition, several new chapters and sections and new features have been included in the second edition of this textbook. They include: (1) A chapter devoted in its entirety to the use of probiotics in the management of gastrointestinal disorders; (2) A section on the treatment of the ever-increasing problem of nonalcoholic fatty liver disease; (3) A chapter devoted to the management of gastrointestinal diseases in the elderly; (4) A chapter that focuses on the management of gastrointestinal diseases in children; (5) A chapter that considers the special and specific issues encountered during the management of pregnant women with acute and chronic digestive and hepatic disorders; (6) Owing to the significant recent advances in our understanding of their pathogenesis, as well as marked improvements in the therapy of inflammatory bowel diseases, separate chapters on the management of Crohn’s disease and ulcerative colitis; (7) All chapters now include succinct summaries with specific treatment recommendations; (8) Annotated references to help guide readers to the review of specific topics; (9) A PDA version of each chapter for rapid, bedside use. The full spectrum, from preventive measures to the therapy of complex and advanced disease states, is covered in depth, with the liberal use of tables and treatment algorithms to help guide clinicians. My distinguished colleagues and Section Editors – Doctors Gary L. Davis, Francis A. Farraye, Ralph A. Giannella, Juan-R. Malagelada, and Michael L. Steer – and all the outstanding authors have striven to emphasize, extend, and amplify specific treatment topics and have provided contemporary citations, several of which have been annotated, to further guide the examination of specific topics. In addition to their respective roles as objective authorities, the contributors have interjected their own personal expert opinion regarding the appropriate selection of management, including the proper dosing and administration of specific medication and the judicious employment of procedure-based diagnostic and therapeutic modalities. The target audience for this textbook includes gastroenterologists, gastrointestinal surgeons, and all practitioners who care for individuals afflicted with digestive disorders. The contributors have used utmost care and discrimination in presenting their materials, and the subject matter has been composed in a concise, yet thorough, format. Accordingly, medical students, internal medicine, family medicine, and surgery residents, and gastroenterology fellows will view this text as an invaluable adjunct to their educational needs, and it should be regarded as germane to the practices of primary care and emergency room physicians, intensivists, hospitalists, pharmacists, and other health care

Preface to the second edition

xiv professionals involved in the management of diseases of the alimentary tract and hepatobiliary systems. Therapy of Digestive Disorders is clearly the product of the enormous effort of its superb contributors, some of the most capable persons in the fields of gastroenterology, hepatology, gastrointestinal surgery, and other medical disciplines, defined in advance by their willingness to respond to the compelling need to share their knowledge and produce quality chapters despite their other endless commitments. These authors were selected primarily for their record of excellence as investigators, clinicians,

and educators. All are engaged in clinical or basic investigation and are particularly proficient in the application of basic scientific information to the realm of patient management. The Section Editors and I believe that the second edition of Therapy of Digestive Disorders has been built upon the high standards set forth in the initial text, and that the ultimate recipient of its excellence will be the patients with digestive disorders, whose care will optimized by the improved proficiency of their physicians. M. Michael Wolfe, M.D.

Preface to first edition The logarithmic increase in medical and technological advances used in the management of individuals with digestive disorders during the past two decades is unparalleled. The universal availability of fiberoptic instruments, and later video, endoscopic, and surgical instruments, has facilitated the ability of gastroenterologists and gastrointestinal surgeons to investigate and provide therapy for the multitude of individuals suffering from the vast array of digestive disorders. These spectacular technological advances have enabled practitioners to extend the use of noninvasive and minimally invasive methods to the masses, thereby producing diminished morbidity, improved survival, and probably most important, enhanced quality of life. Equally important to these remarkable achievements, however, was the development of a myriad of new classes of medication for the treatment of these diseases. Since the mid-1970s, with the introduction of H2 receptor antagonists, we have experienced a virtual explosion of new drugs that have revolutionized medical therapy for gastrointestinal illnesses. Since 1978, the leading individual drug used throughout the world has been one used to treat digestive disorders. The significance of their importance is further evident by the bestowing of two Nobel Prizes in Medicine and Physiology for biomedical research that led to the development of two prominent classes of drugs that affect gastrointestinal function: H2 antagonists and prostaglandins. Beginning with its inception and formulation and during the writing of this companion book, rather than emphasizing specific classes of medication, endoscopic intervention, or surgical procedures, Therapy of Digestive Disorders was developed to provide practitioners with an authoritative and evidence-based, yet practical, approach to the optimal management of individuals with specific digestive disorders. The full spectrum, from preventive measures to the treatment of complex and advanced disease states, is covered in depth, with liberal use of tables and treatment algorithms to help guide the clinician. Rather than merely reiterate

the content of Drs. Mark Feldman, Bruce F. Scharschmidt, and Marvin H. Sleisenger’s landmark Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, the authors here have striven to emphasize, extend, and amplify specific treatment topics and have provided up-to-date references to direct further examination of specific topics. Although the contributors have written their chapters as objective authorities, they have also interjected their expert opinions regarding the appropriate selection of therapeutic options, including the proper dosing and administration of specific medications and the judicious employment of diagnostic and procedure-based therapeutic modalities. The target audience for this text includes all practitioners who care for individuals with digestive disorders. The contributors have used utmost care and discrimination in presenting their materials, and the subject matter is thus appropriate not only for gastroenterologists and gastrointestinal surgeons, but also for medical and surgical residents, primary care and emergency department physicians, intensivists, and other health care professionals specializing in the management of diseases of the alimentary tract and hepatobiliary organs. The superb group of contributors assembled for this book were selected primarily for their record of excellence as investigators, clinicians, and teachers. All are engaged in clinical or basic investigation and are particularly proficient in the application of basic scientifc information to the realm of patient management. This book is clearly the product of the enormous effort of these individual authors, some of the most capable persons in the fields of gastroenterology, hepatology, and gastrointestinal surgery, defined in advance by their willingness to respond to the compelling need to share their knowledge and produce quality chapters despite their other endless commitments. M. Michael Wolfe

Acknowledgements I am most pleased to be afforded the opportunity to acknowledge the many teachers and mentors, all of whom have inspired me immeasurably during my training and career as an academic gastroenterologist. It is particularly gratifying for me to have been able to include my medical school advisor, Professor James H. Caldwell, as a contributor to the second edition of Therapy of Digestive Disorders. I also acknowledge the invaluable advice and counseling received over the years from the late Professor Walter Rubin, whose recent untimely death was a tragedy to all who revered him. Among the others who played an invaluable and instrumental role are Professors Donald Kaye, Phillip P. Toskes, James E. McGuigan, Gabriel M. Makhlouf, James W. Freston, William Silen, Eugene Braunwald, William W. Chin, and Joseph Loscalzo. I am deeply indebted to the Section Editors — Gary Davis, Frank Farraye, Ralph Giannella, Juan Malagelada, and Mike Steer — for their diligence and efforts in assembling a distinguished, talented, and exceptional group of authors. As a result of their outstanding contributions, we have succeeded in compiling a contemporary textbook that combines a scholarly review of every individual topic with practical guidelines for the management of the wide array of digestive disorders. The ultimate beneficiaries of their efforts will be the hundreds of millions of patients with gastrointestinal diseases, who will receive the most optimal and contemporary care available. In addition to the Section Editors and authors, the successful completion of the second edition of Therapy of Digestive Disorders would not have been possible without the invaluable support of the group of dedicated professionals and assistants. I would like to express my sincere appreciation to Carolyn Dumas, my assistant in the Section of Gastoenterology at Boston University School of Medicine, and to Erin Medley, who provided technical assistance. A special debt of gratitude goes to Linda Neville, Administrator in the Section of Gastroenterology, who helped maintain the excellence of the daily operations of the GI Section when my attention was diverted by the formidable challenges faced during

the preparation of a textbook of this magnitude. I thank Joanne Scott, Henrietta Preston, and especially Shuet-Kei Cheung, Project Managers at Elsevier, who approached the formidable task of serving as liaison between the chapter authors, Section Editors, and Elsevier with enthusiasm and zeal, and who made my tasks tolerable by streamlining all the various protocols and processes involved with editing the textbook. In addition to the Project Managers, this project would not have been possible without the support of Sue Hodgson, Publisher at Elsevier, and Karen Bowler, Senior Acquisitions Editor. Finally, a special debt of gratitude goes to Rolla Couchman, Senior Acquisitions Editor at Elsevier, who served as a friend and as an earnest and enthusiastic professional throughout the course of this textbook’s inception, planning, organization, and composition. Finally, I wish to express my personal appreciation to my fellows and colleagues within the Section of Gastroenterology and in the Department of Medicine for their collegiality and friendship. I have been blessed to have the opportunity to work with an unparalleled group of dedicated and accomplished physicians and scientists, who have devoted their careers and lives to research, education, and patient care and for maintaining an environment conducive to creativity and scholarship. I offer my extreme gratitude to my research collaborators and to the devoted members of my laboratory, Mike Boylan, Lisa Jepeal, Diane Song, Carlton Moore, Min Yao, Wei Zhou, Albert Chang, Jon Simon, Tom Liu, and Cherrell Wilson. Their diligent and resolute efforts have consistently produced research of the highest quality that have culminated in publications in most prestigious scientific journals. Lastly, I thank my father, my late mother, sister, brother, wife, and children for their endless patience, encouragement, support, and understanding throughout not only the preparation of this textbook, but during my education and career. M. Michael Wolfe

SECTION ONE MODES OF THERAPY

1

CHAPTER ONE

Molecular and cellular targets in therapy of acid-related diseases James E. McGuigan

INTRODUCTION History From early recorded antiquity, acid has been thought to be present in the human stomach. Greek scholars more than 2300 years ago remarked on epigastric pain, heartburn, and sour eruptions as potentially caused by problems with the stomach. Celsus, 3 centuries later, concluded that some foods were acidic and recommended that ‘if the stomach is infested with an ulcer…acid is to be avoided.’ Proof that hydrochloric acid was the acidic material in the stomach awaited the scientific documentation of William Prout in his elegant presentation before the Royal Society in London in 1823 and published the following year entitled ‘On the Nature of Acid and Saline Matters Usually Existing in the Stomach of Animals.’1 Hippocrates was reported to have introduced the term ‘pepsis’ to describe the process of digestion, far in advance of the much later applications of derivatives of the term to appreciation of the intimate interrelationships of pepsin with gastric acid and to acid-related diseases. An assortment of clinical symptoms and disorders have been thought to be associated with hydrochloric acid secretion by the stomach. Recognition of acid-related diseases prompted the application of a variety of lifestyle measures, diets, and pharmacological approaches intended to reduce the potentially harmful effects of hydrochloric acid secreted by the stomach. Lifestyle adjustments appeared to offer some adjunctive value for patients with acid-related disorders, but alone provided limited benefits. Various dietary manipulations, although transiently attracting their proponents, proved to be of little value in management of those patients. Major efforts have been directed to the treatment of acid-related diseases by pharmacological agents directed to neutralize secreted gastric acid or, more recently, to inhibit its secretion. Surgical procedures were also developed to reduce gastric acid secretion, principally by gastric resection and/or by interruption of the vagus nerves, recognizing the integral role of the vagus in stimulation of hydrochloric acid secretion by the stomach. Until the latter part of the twentieth century, pharmacologic treatment of acid-related disorders was of limited effectiveness. Antacid preparations of various composition partially neutralized secreted gastric acid, but because of their relatively short residence in the gastric lumen, they proved to be of no prolonged benefit; if sustained effects were sought, frequent repetitive dosing was required. Anticholinergic agents were found

to inhibit gastric acid secretion, but for the most part only marginally and with predictable adverse side effects, which prevented their dosing in sufficiently potent quantities. The treatment of acid-related diseases was revolutionized by the conception, development, and introduction of H2-receptor antagonists.2–6 It had long been appreciated that histamine, present in many tissues and organs, including the stomach, was a potent stimulant of gastric acid secretion. However, its role in regulation of acid secretion by the stomach was controversial. Histamine had been used as a provocative stimulant to assess the capacity of the stomach to secrete acid, an effect that could not be inhibited by traditional histamine receptor (histamine 1 receptor) antagonists. This observation predicted and stimulated the search for a separate class of histamine receptors, which if inhibited specifically, would reduce acid secretion by the stomach. The development of structural analogs of histamine that inhibited gastric acid secretion by competitive inhibition of the receptors in the absence of other antihistaminic effects validated the concept and for which Sir James Black was awarded a Nobel Prize in 1988.2 Cimetidine, the first of this class of agents (H2-receptor antagonists) which competitively inhibited these histamine2 receptors was introduced in the United States in 1977 for clinical use in reducing gastric acid secretion.3 More potent and more prolonged inhibition of gastric acid secretion was achieved subsequently by development of antagonists of the parietal cell hydrogen potassium ATPase (H+, K+ATPase), which constitutes the parietal cell’s final exchange mechanism for hydrogen and potassium ions, resulting in its secretion of hydrochloric acid. Omeprazole was the first clinically available member of this class of inhibitors of H+, K+-ATPase, now commonly referred to as proton pump inhibitors (PPIs).7,8 Omeprazole was introduced in the United States in 1989. This chapter will address the neurohumoral regulation of gastric acid secretion and the pharmacologic agents that are used to inhibit gastric acid secretion in the therapy and prevention of acid-related diseases. It will also describe and discuss the molecular and cellular targets of these acid inhibitory agents, as well the behavior of those cells which predispose their susceptibility to these pharmacologic agents and the regulation of acid secretion by these and other factors.

Acid-related diseases A variety of diseases and disorders are viewed as acid-related diseases. In each of these conditions hydrochloric acid secreted by

Molecular and Cellular Targets in Therapy of Acid-related Diseases

4 the stomach is believed to play a crucial pathogenic role. Although similar in this regard, the various acid-related diseases differ in other important aspects. In some instances, acid-related diseases result as a direct consequence of excessive secretion of gastric hydrochloric acid. In other examples, the diseases are caused by diminished mucosal defense mechanisms, rendering the tissues susceptible to injury by secreted gastric acid, usually in patients with normal or often decreased gastric acid secretion. Finally, some acid-related disorders may result from variably, but often modestly, increased gastric acid secretion coupled with some deficiency of mucosal defense. The Zollinger-Ellison syndrome (gastrinoma) is certainly the prototypic consequence of pure gastric acid hypersecretion (see Ch. 20). Although gastric acid plays a role, ulcers associated with nonsteroidal antiinflammatory drugs appear to develop principally because of deficient mucosal defense, as does stress-related mucosal ulceration (see Ch. 19). Acid-related diseases include gastric ulcer, associated with normal or reduced gastric acid secretion, and duodenal ulcer, usually with normal or modestly increased gastric acid secretion, and are often accompanied by some reduction of mucosal defense (see Chs 18 and 20). Gastroesophageal reflux disease is also an acid-related disease that results from gastric hydrochloric acid refluxing into the esophagus, which is less well equipped to defend itself from gastric acid than the relatively richly defended normal stomach and most proximal duodenum (see Ch. 13). Supra-esophageal reflux disorders also appear to be produced by gastric acid contact with tissues possessing relatively insufficient mucosal defense mechanisms. The role of gastric acid in the pathogenesis of nonulcer dyspepsia is less clearly defined.9 Although most patients with acid-related diseases do not have gastric acid hypersecretion, therapy used in prevention and cure of these diseases is directed principally to reduction of hydrochloric secretion by the stomach and the avoidance of its corrosive effects on the gastrointestinal tract.

CELLULAR TARGETS Parietal cells The cells responsible for secretion of hydrochloric acid by the stomach are gastric parietal cells.10,11 These cells are present in glands, often referred to as parietal cell glands or oxyntic glands, which are located principally in the body and fundus of the stomach. Parietal cells are the most frequent cell type found in oxyntic glands. Parietal cells are located singly or in clusters in the mid and slightly deeper portions of the glands. Parietal cells are surface epithelial cells with their mucosal apical surfaces facing the gland lumen. They have a basolateral membrane, which surrounds the remainder of the cell and includes the serosal surface on which the cell is situated. The basolateral membranes of parietal cells contain prominent tight junctions. Parietal cells have several different classes of receptors on their basolateral cell membranes that participate in the regulation of stimulation and inhibition of gastric acid secretion (Fig. 1.1).11 Parietal cells are somewhat plump and flask shaped, with wide bases and much thinner conical apices abutting the gland lumen, and are primarily secretory, rather than absorptive, cells. In the resting state and in response to stimulation, the extensive canalicular system of the parietal cell is in continuity with the

Stimulation

Inhibition HCI Ca G

Gq G Gq Ca

EP3

G GS

cAMP SS

M3 H2

EGF

•

Fig. 1.1 A model of the receptors present on the basolateral surface of the parietal cell and their intracellular effects. Gq and Gs, trimeric G proteins; cAMP, cyclic adenosine monophosphate; G, G protein; M3, muscarinic receptor; H2, histamine receptor; EGF, epidermal growth factor; SS, somatostatin; EP3, subtype of prostaglandin.

gland lumen (Fig. 1.2). The secretory canaliculi are infoldings of the apical membranes of the parietal cells and serve as the channels by which the cells empty their secretory products into the gland lumen. The major secretory products of parietal cells are hydrochloric acid and intrinsic factor, the latter playing an important role in the promotion of active absorption of cyanocobalamin (vitamin B12 ). The parietal cell has a prominent nucleus and cytoplasm containing abundant mitochondria. Parietal cells are extremely active metabolically, requiring vigorous mitochondrial synthesis of adenosine triphosphate (ATP), which serves as the source of energy that drives gastric acid secretion. The mitochondria occupy approximately one-third of the cytoplasm of parietal cells. During the resting state, the remainder of parietal cell cytoplasm is filled with an extensive tubulovesicular system, containing numerous membrane-containing tubules.11,12 Immunolabeling has demonstrated the presence of the H+, K+-ATPase (proton pump) on the tubules of the tubulovesicular system.12 In the resting (unstimulated) parietal cell, the secretory canaliculi have short and stubby microvilli (see Fig. 1.2). After stimulation, parietal cells expand their intracellular canalicular membranes and exhibit dramatic changes in the appearance of their canalicular membrane microvilli, which become long and slender (Fig. 1.3). When the parietal cell is stimulated (i.e., after eating), the tubules of the tubulovesicles located in the parietal cell cytoplasm fuse with cell membranes of the microvilli projecting on the luminal surface of the secretory canaliculi, inducing an enormous expansion of the canalicular luminal surface area (see Figs 1.2, 1.3). These changes also result in translocation of H+, K+-ATPase from its sequestered position of insertion in the tubular membranes within the parietal cell cytoplasm to the luminal surfaces of its secretory canaliculi. Immunolabeling using high-pressure freezing (HPF) techniques has demonstrated substantial increases in the labeling density of H+, K+-ATPase on the canalicular membranes of parietal cells after stimulation compared with resting parietal cells.12

5

Golgi complex

Tubulovesicular membrane

Intracellular canaliculus

Basal folds

Mitochondria

Basement lamina

Enterochromaffin-like cells Enterochromaffin-like (ECL) cells are located close to parietal cells in the oxyntic gland areas in the body and fundus of the stomach, found exclusively in oxyntic glands. In contrast to parietal cells, ECL cells are not luminal epithelial cells. Although ECL cells are located near parietal cells, they are positioned beneath the epithelial cell layer and do not have a cell surface exposed to the gland lumen. ECL cells contain prominent eccentrically located nuclei and have numerous cytoplasmic extensions. The cytoplasm is also packed with conspicuous vacuoles containing the biogenic amine histamine. ECL cells are responsible for synthesis and secretion of histamine, a potent stimulus of gastric acid secretion.9,13,14 Stimulation of the ECL cell induces the synthesis and activity of parietal cell histidine decarboxylase (HDC), the enzyme responsible for histamine synthesis. Through synthesis and release of histamine, ECL cells play a crucial role in the stimulation of gastric acid secretion. The ECL cell is distinct from mast cells, which are also found in the oxyntic mucosa. Mast cells, like ECL cells, contain histamine but do not participate in the regulatory stimulation of gastric acid secretion. ECL cells possess receptors in their plasma membranes for gastrin, somatostatin, galanin, and pituitary adenylate cyclase activating polypeptide (PACAP), all of which participate in regulation of histamine release.

REGULATION OF GASTRIC ACID SECRETION The secretion of hydrochloric acid by the stomach is highly regulated by multiple endocrine, neurocrine, paracrine, enterchromaffin-like cells and autocrine mechanisms responsible for its stimulation and its inhibition.

Endocrine factors The polypeptide hormone gastrin in the most potent known stimulant of gastric acid secretion. The ingestion of food constitutes the principal physiological stimulus to gastrin release from gastrin-containing G cells located in the gastric antral mucosa, resulting in the stimulation of gastric acid secretion.15 Gastrin is released into the circulation when the intraluminal pH increases above 3.5–4.0 and in response to protein ingestion and specifically in response to the peptide and amino acid products of protein digestion. Intact protein does not stimulate gastrin release, and ingested fat and carbohydrate inhibit gastrin release. Aromatic amino acid products of protein hydrolysis such as tryosine and phenylalanine are particularly potent in stimulating gastrin release. Gastrin released into the circulation in response to stimulation binds to specific gastrin receptors (CCK-2 receptors) on the membrane surfaces of ECL cells, which are located in intimate proximity to parietal cells. Gastrin binding to ECL cells

Regulation of Gastric Acid Secretion

•

Fig. 1.2 Electron photomicrograph of parietal cell in the resting (unstimulated) state demonstrating abundant cytoplasmic tubulovesicular membranes to which proton pumps – hydrogen potassium ATPase (H+, K+-ATPase) are inserted.


6

•

Golgi complex

Intracellular canaliculus

Fig. 1.3 Electron photomicrograph of stimulated parietal cell demonstrating translocation of the tubulovesicular membranes (containing proton pumps) to the intracellular secretory canalicular membranes, facilitating pump exposure to the highly acidic canalicular lumen.

Mitochondria

Tubulovesicular membrane

Basal folds Intracellular canaliculus Basement lamina

results in increases in intracellular calcium, which induces transcription of histidine decarboxylase, resulting in enhanced synthesis and secretion of histamine. Histamine released from stimulated ECL cells binds to histamine 2 receptors, which are located on the basolateral membranes of parietal cells, resulting in the stimulation of hydrochloric acid secretion. Stimulation of ECL cells, evoking histamine release and histamine-mediated stimulation of parietal cell secretion, is the most important mechanism by which gastrin stimulates hydrochloric acid secretion. The role and importance of direct binding of gastrin to parietal cells are controversial and clearly of less importance than gastrin induction of histamine-stimulated acid secretion by parietal cells. In addition to its stimulation of release by gastrin, histamine release from ECL cells may also be stimulated by PACAP.9 This neuropeptide, which is structurally related to vasoactive intestinal peptide (VIP), is localized to enteric nerves distributed throughout the gastrointestinal tract, including the stomach. PACAP administration increases intracellular calcium concentrations and cyclic AMP in ECL cells, resulting in histamine release. A variety of mechanisms are operative in inhibiting gastrin release and in inhibiting parietal cell secretion of acid.15 The most important physiologic peptide inhibitor of gastrin release and gastric acid secretion is somatostatin.16 Somatostatin is a peptide hormone and a neuropeptide widely distributed throughout the body in neurons of the central, peripheral, and enteric

nervous systems and in endocrine cells (D cells). Local release of somatostatin directly inhibits G cells, ECL cells, and parietal cells. In the gastric antrum, somatostatin is present in D cells located in close proximity to gastrin-containing G cells. Antral D cells are classified as open cells since they have a cell surface that is exposed to the contents of the antral gland lumen. In addition to somatostatin-containing D cells in the antrum, somatostatincontaining cells are also located in the body and fundus of the stomach. D cells in the body and fundus of the stomach differ from those in the antrum in that they are closed-type D cells, not having a surface facing the oxyntic gland lumen. Somatostatin decreases gastric acid secretion by both direct and indirect mechanisms. D cells inhibit gastrin release by a paracrine mechanism in which somatostatin released from cytoplasmic extensions from D cells binds to somatostatin receptors located on the basolateral membrane surfaces of antral G cells. By decreasing gastrin release, somatostatin inhibits gastrin-mediated secretion of hydrochloric acid by parietal cells. Somatostatin, released from cytoplasmic extensions of D cells located close to ECL cells, binds to its receptors on these cells, inhibiting histamine synthesis and release and thereby directly reducing histamine stimulated gastric acid secretion. Finally, somatostatin released from D cells in close proximity to parietal cells binds to somatostatin receptors located on the basolateral membranes of parietal cells, resulting in direct inhibition of parietal cell secretion of hydrochloric acid.15

7

Neurocrine factors The regulation of gastric acid secretion involves both stimulatory and inhibitory neurocrine mechanisms. The vagus nerves provide the principal neural stimulation of parietal cells.18 Acetylcholine released from vagal cholinergic nerve fibers binds to cholinergic muscarinic (M3) receptors located on the basolateral membranes of parietal cells.19,20 (There are five different cholinergic muscarinic receptors – M1 through M5 receptors – each with different specificity.) Cholinergic stimulation via these receptors increases parietal cell intracellular calcium concentrations by opening plasma membrane calcium channels for calcium entry into parietal cells and by promoting release of calcium from intracellular stores. These increases in cytoplasmic calcium result in the stimulation of gastric acid secretion, and blockade of cholinergic muscarinic receptors decreases gastric acid secretion. There are also inhibitory cholinergic receptors on D cells, by which vagal stimulation promotes gastric acid secretion by the inhibition of somatostatin release. Gastric acid secretion is also influenced by other neural mechanisms and neuropeptides. Gastrin release is stimulated by the neuropeptide gastrin-releasing peptide (GRP), as well as by PACAP and galanin. PACAP has at least two separate and opposing effects on gastric acid secretion. As stated above, PACAP increases gastric acid secretion by stimulating ECL cells to release histamine. PACAP also binds to VIP receptors on D cells, stimulating somatostatin release and inhibiting gastric acid secretion. PACAP has no effect on gastrin release from antral G cells. Galanin is a 29 amino acid neuropeptide that inhibits gastrin-stimulated gastric acid secretion. Galanin inhibits both gastrin release from antral G cells and histamine release from ECL cells, but does not inhibit cholinergic stimulation of gastric acid secretion.

imbedded in the basolateral membranes of parietal cells.21 This receptor possesses seven transmembrane domains with three cytoplasmic loops and three loops located on the external surface of the membrane, as demonstrated in Figure 1.4. The H2 receptor has an extracellular amino terminal-linked glycosylation site and an extended intracellular carboxy-terminal peptide segment and is comprised of 359 amino acids. H2 receptors are structurally and functionally distinct from histamine 1 receptors, which account for many allergic-type responses to histamine. Antihistaminic agents that engage H1 receptors have negligible effects on gastric acid secretion. The site to which histamine and H2-receptor antagonists are thought to bind is believed to be located on the external surface of the middle of the extracellular loop located between the fourth and fifth transmembrane segments and to the surface of the transmembrane segments 3 and 5 of the H2 receptor.22 Histamine stimulation of parietal cells is mediated principally by intracellular cyclic AMP. Binding of histamine to parietal cell H2 receptors results in their coupling to a stimulatory G protein (Gs), which activates adenylate cyclase, thereby increasing intracellular cyclic AMP. The increase in intracellular cyclic AMP is also accompanied by increases in intracellular calcium, which exert a limited signal interaction with a Gq trimeric G protein. It has been hypothesized that both cyclic AMP and calcium signals are required because cyclic AMP is necessary for the activation of H+, K+-ATPase, and increases in intracellular calcium appear to be necessary to provide for redistribution of the enzyme in its attachment to the secretory canaliculi. In addition to their presence on parietal cell membranes, H2 receptors have been found on membranes of smooth muscle and cardiac myocytes. Cardiac arrhythmias, cardiac arrest, and atrioventricular conduction abnormalities have been reported rarely in patients being treated with H2-receptor antagonists. Most of those patients were very seriously ill and often they had received the H2-receptor antagonists by rapid intravenous infusion.23 The H2 receptor in the cell membrane of the parietal cell is the most important receptor involved in stimulation of parietal cell secretion. It is responsible for the stimulation of basal acid output and for gastric acid secretory responses to feeding, principally mediated through gastrin. In addition to H2 receptors, there are other stimulatory receptors on parietal cells, including the M3 receptor for acetylcholine and the CCK-2 receptor for gastrin (see Fig. 1.1). However, unlike the parietal cell H2 receptor, the CCK-2 receptor is believed to promote gastric acid secretion principally through elevations in parietal cell cytoplasmic calcium, with a very minor role played by cyclic AMP.

RECEPTORS INVOLVED IN REGULATION OF GASTRIC ACID SECRETION Gastrin receptors H2 receptors A variety of receptors participate in acid secretory regulation by inhibition or stimulation of gastric acid secretion. As stated above, histamine plays the dominant role in stimulating gastric acid secretion by its binding to and stimulating H2 receptors located on the basolateral membranes of parietal cells.12,14 Parietal cell H2 receptors are responsible for the greatest portion of the stimulation of the acid secretory response to gastrin. The H2 receptor of the parietal cell is a member of the seven transmembrane G protein-coupled receptor superfamily and is

Binding of gastrin to its receptor on the surrounding cell membranes of ECL cells stimulates histamine synthesis and secretion, resulting in parietal cell activation and gastric acid secretion. Gastrin binding to its receptor induces acid secretion by increases in intracellular calcium by an inositol 1,4,5triphosphate (IP3) mechanism. The receptors to which gastrin binds have been classified CCK-2 (also known as CCK-B) because of their relative structural homology to cholecystokinin (CCK) receptors. Gastrin stimulation of acid secretion does require a small increase in cyclic AMP, whereas cholinergic receptor activation of the parietal cell requires only increases in parietal

Receptors Involved in Regulation of Gastric Acid Secretion

Somatostatin is also the prime mediator of the negative feedback inhibitory control of gastric acid secretion. Acidification of the gastric luminal contents (to pH 90%. After intravenous administration, H2RAs are eliminated principally through renal excretion, and the bioavailability of each of the H2RAs approximates 100%. All H2RAs but nizatidine are available as intravenous formulations in the US. No reductions in the doses of these drugs are required based exclusively on hepatic insufficiency, whereas dose reductions are usually recommended for most patients with clinically significant renal insufficiency.28 Cimetidine and ranitidine are metabolized by the hepatic cytochrome P450 mixed function oxidase system. For this reason, these H2RAs may compete with other drugs which are metabolized by the same P450 enzyme system.29,30 Potential drug interactions include, among others, those with warfarin, lidocaine, quinidine, phenytoin, and theophylline. Some drug interactions have been reported in patients who have been treated with cimetidine, with somewhat fewer interactions having been observed with ranitidine. Because nizatidine and famotidine are metabolized by different enzyme systems, they are not associated with the potential increases in blood levels of those drugs. In addition to their presence on gastric parietal cells, H2 receptors have also been identified on suppressor T lymphocytes.31 Antiandrogenic effects, principally in the forms of impotence and gynecomastia, have been reported in patients receiving very high doses of cimetidine, but not the other H2RAs, most often in treatment of patients with the Zollinger-Ellison syndrome. Central nervous system symptoms have been reported rarely in patients receiving H2 receptor antagonists.32 These have been noted most often in seriously ill, mostly elderly patients, commonly in intensive care settings, and it is uncertain whether these very unusual associations actually represent adverse effects from these agents.32 Bone marrow suppression has been reported as a very uncommon side effect of treatment with H2RAs and is believed to represent an idiosyncratic mechanism. Rarely, drug administration has been associated with some asymptomatic increases in serum liver aminotransferase levels. However, these increased levels return to normal after the drugs are discontinued and do not appear to represent hepatic disease.33 H2RAs compete with creatinine for renal tubular excretion, and as a result, their administration has occasionally been associated with small increases in serum creatinine levels.34 These increases are transient and disappear after discontinuation of therapy. With the exception of famotidine, H2RAs inhibit gastric mucosal alcohol dehydrogenase and may thus increase blood alcohol levels.35 However, because >90% of alcohol dehydrogenase is hepatic in origin, these increases in blood alcohol concentrations tend to be small and are rarely of clinical significance. Gastric acid secretory rebound has been reported after discontinuation of chronic H2RA therapy of 1–9 months’ duration.36,37 Acid secretory rebound after the cessation of therapy is usually brief and has been reported to be resolved by 9 days after stopping the drug. Gastric acid rebound may occur as a result of upregulation of parietal cell H2 receptors due to receptor antagonism.


12 CH2 CF3 O CH3

CH3 O CH3

CH3

N

N

Omeprazole N

Lansoprazole

SO NH

N

•

CH3 O

CH3 O

CH3 OCH2 CH2 CH2O CH3

N SO

N

Pantoprazole

NH

N

CH3O

Rabeprazole

SO NH

N

Fig. 1.6 Structures of proton pump inhibitors. (Esomeprazole is the S-isomer of omeprazole.) They are all ampholytic weak bases and accumulate as prodrugs in the secretory canaliculus of the active parietal cell.They are activated by acid to form the reactive sulfenamide derivative.

SO NH

CHF2O

exclusively in the very low pH of the canaliculi of the actively secreting parietal cell. The protonated form of the PPI as a weak base is membrane impermeable and thus accumulates in the acidic compartment at a concentration depending on the gradient between the pH and the pKa of the weak base. The pKa of PPIs is sufficiently low to prevent their accumulation in other relatively acidic intracellular compartments, such as lysomes or secretory granules, which have a pH of 4.5–5. After the PPI prodrugs have been concentrated by the acid gradient-dependent mechanism, they undergo acid catalyzed protonation, converting the prodrugs to the active thiophilic sulfenamide form of the proton pump inhibitor (Fig. 1.7). At a pH erythromycin >clarithromycin >oleandomycin). Two major mechanisms for erythromycin’s effects on motility have been reported: stimulation of motilin receptors and a cholinergic mechanism. Erythromycin activates L-type calcium channels, increasing intracellular calcium and causing contraction of single muscle cells.14

Clinical efficacy Erythromycin stimulates gastric emptying in normal subjects and in patients with diabetic gastroparesis.15 Erythromycin (200 mg i.v.) increased the rate of emptying of liquids and solids. In postvagotomy or idiopathic gastroparesis, similar results are obtained with intravenous and oral preparations of the drug. Erythromycin can stimulate intense fundic16 and antral contractions,17,18 resulting in the dumping of solids out of the stomach. This may be a disadvantage since nontriturated solids, unprepared for chemical digestion, are delivered to the small bowel.19 On the other hand, this property is utilized in clinical practice when nondigestible solids (e.g., bezoars, tubes, blood clot) need to be emptied from the stomach. The long-term efficacy of erythromycin is less clear, as downregulation of the motilin receptor may reduce its efficacy. However, one study noted sustained effects for a median time of >6 months when dosages were titrated to permit continued use

without intolerable side effects.20 The dose of erythromycin has to be selected carefully according to the indication; there is evidence that doses lower than 2 mg/kg are needed to induce phase III of the MMC,21 and may be preferable for small bowel dysmotility. The standard dose used to induce clearance of gastric residue is 3 mg/kg i.v. In patients with gastroparesis who develop recurrent bezoars, i.v. erythromycin (3 mg/kg every 8 hr) induces highly propulsive gastric contractions and dumps nondigestible debris out of the stomach.22 Intravenous erythromycin can also be used to facilitate placement of nasoduodenal tubes. Erythromycin at low doses (40 mg i.v.) has been shown to increase contractile events in the small intestine.22 Higher doses (350–400 mg i.v.) appear to decrease small intestinal activity. In patients with pseudo-obstruction or ileus, intravenous erythromycin, at doses ranging from 40 to 250 mg, increased duodenal contractions.23 Short-term oral administration of erythromycin (40 mg t.i.d.) has also been shown to be beneficial in few patients with chronic intestinal pseudo-obstruction and in a patient with intestinal scleroderma.24 There are anecdotal reports of i.v. erythromycin use in acute colonic pseudo-obstruction.25 Erythromycin combined with octreotide was effective in inducing motility and reducing symptoms in an open trial of patients with chronic intestinal pseudo-obstruction (neuropathic or myopathic).26 New synthetic motilin agonists that are devoid of antibiotic activity constitute a promising addition to the clinical armamentarium in the treatment of disorders of gastric motility. The most clear indication for their use is in the short-term treatment of gastroparesis, though it is also possible that these medications will be indicated for other acute gastrointestinal motility disorders such as acute colonic pseudo-obstruction or postoperative ileus. For longer-term treatment, new agents are being developed that are not likely to induce tolerance and lose efficacy over a few days or weeks. Formal trials are under way.

Serotonergic agents 5-hydroxytryptamine (5-HT, serotonin) mediates several physiological functions throughout the gastrointestinal tract through several different types of receptors (Fig. 2.3).

5-HT4 AGONISTS Tegaserod Tegaserod is an aminoguanidine indole derivative of serotonin that acts as a selective agonist at 5-HT4 receptors.27

Mechanism of action Tegaserod activates 5-HT4 receptors located on excitatory cholinergic neurons of the gastrointestinal tract and probably also on intrinsic primary afferent neurons that are important for activation of the peristaltic reflex. It increases gastrointestinal motility in animal models,28 healthy male volunteers29 and in patients with constipation-predominant irritable bowel syndrome,30 and it may reduce visceral sensation in experimental animal models of visceral hyperalgesia31 and in humans.32 Tegaserod is absorbed rapidly after oral administration and distributes widely into tissues. No important drug interactions have been identified.33 No dose adjustment for age or gender is recommended in tegaserod therapy.34

23 A

5HT4 receptor

5HT4 receptor 5HT3 receptor

5HT1D receptor

5HT1A receptor

Excitatory Cholinergic Motor neuron

Inhibitory Nitrergic Motor neuron

ACh

NO

Contraction

Relaxation

5-HT3 receptors on extrinsic vagal afferents, DRG and vomiting center

B

Vagal afferents Vagal nuclei

DRG

Sympathetic S2,3,4

Extrinsic first order neuron

Intrinsic primary afferent neuron

5HT4 receptor

Gut mucosa 5-HT release from mucosal EC cells

Clinical efficacy Tegaserod, 6 mg, b.i.d., reduces pain and discomfort in the abdominal area, and reduces bloating and constipation. Three studies have appeared in the peer-reviewed literature.35–37 Improvement of symptoms, particularly constipation, may occur within 1 or 2 weeks of the start of treatment. The efficacy of tegaserod beyond 12 weeks has not been studied extensively.

Adverse effects The adverse event reported most often in association with tegaserod compared to placebo was diarrhea (9% of patients receiving tegaserod compared to 4% of patients receiving placebo). The discontinuation rate from clinical studies due to diarrhea was 1.6%.38 Other adverse events such as abdominal pain, flatulence, and headaches appear to be no more frequent with tegaserod than placebo. Safety with long-term use appears good.39

neurons, and it possibly acts directly on smooth muscle.40,41 Metoclopramide increases lower esophageal sphincter pressure when administered parenterally. Metoclopramide accelerates gastric emptying, relaxes the pyloric sphincter, and increases jejunal peristalsis. Metoclopramide (10 mg, 30 min before meals) increases gastric emptying in diabetic and idiopathic gastroparesis.40 The symptomatic benefit of metoclopramide in patients with gastroparesis is not always accompanied by a significant acceleration of gastric emptying.42 Metoclopramide crosses the blood–brain barrier and has direct effects on the vomiting center.

Clinical efficacy

Metoclopramide

For a decade, cisapride had largely supplanted the use of metoclopramide as an oral prokinetic agent. Side effects occur in approximately 20% of patients given metoclopramide at therapeutic doses.40 However, with the absence of cisapride and the insufficient studies to date with alternatives such as domperidone and tegaserod, metoclopramide is being used more extensively again. As metoclopramide can be given subcutaneously or parenterally, it has a secondary role (after i.v. erythromycin) during episodes of severe nausea and vomiting when the patient is unable to tolerate oral medications. It can also be administered long-term by the subcutaneous route in patients with gastroparesis.43

Mechanism of action

Adverse effects

Metoclopramide antagonizes dopamine at central and peripheral receptor sites. It also activates 5-HT4 receptors on cholinergic

Common side effects include anxiety, restlessness, and drowsiness. Extrapyramidal reactions are less common and are usually

Other potential indications There are several other preliminary reports suggesting the potential use of tegaserod for other conditions, notably chronic constipation, gastroparesis, and functional dyspepsia.

5-HT4 Agonists

•

Fig. 2.3 Summary of the actions of the main currently available serotonergic agents affecting motor (A) or sensory (B) functions.

Pharmacology and Therapeutics for Motor and Sensory Disorders of the Gut

24 reversible with diphenhydramine. Tardive dyskinesia is rare,44 but may be irreversible when it occurs.

NOVEL 5-HT4 AGONISTS IN DEVELOPMENT Renzapride Mechanism of action Renzapride is a full agonist at 5-hydroxytryptamine 4 (5-HT4) receptors45 and is also an antagonist of 5-HT2B and 5-HT3 receptors.46,47 The 5-HT4 receptor action mediates increased gut transit rate and perhaps also contributes to the alleviation of symptoms attributed to disordered gastrointestinal motility46 in constipation-predominant IBS. Activating 5-HT4 receptors is thought to result in an increase in adenylate cyclase activity that subsequently leads to release of acetylcholine from postsynaptic neurons.47

Clinical efficacy Evidence for renzapride’s promise in the treatment of IBS is based on two promising phase IIb trials in constipation-predominant IBS or mixed symptom IBS, which was recently presented in abstract form.48,49 A pharmacodynamic study showed that 4 mg renzapride accelerated ascending colon emptying and there was a significant dose-related acceleration of colonic transit in patients with constipation-predominant IBS in whom an evacuation disorder was excluded. The acceleration of transit was associated with an improvement in stool consistency and ease of stool passage during a two-week treatment period.50

5-HT3 AGONISTS These receptors are located in the motor and sensory apparatus of the rodent gut51,52 and are the target for antiemetic medications (see section on antagonists below), as well as being antagonized by alosetron and cilansetron in the treatment of IBS. Interestingly, a recent study has shown that an agonist at the 5-HT3 receptor, MKC 733, slightly delays stomach emptying of liquids and transfer of solids from the proximal stomach, but it significantly accelerates small bowel transit in healthy volunteers.53 The presumed mechanism of action is activation of cholinergic neurons to stimulate contractions. MKC 733 increased the number of migrating motor complexes recorded in the antrum and duodenum (p30% of body protein, fat depletion >70% of body fat stores, and body size (body mass index [BMI] of 50 years and 43% in younger patients.38 Duration of illness, baseline radiographic features, initial symptom severity, and gender have not been shown to be predictive of response. The clinical definition of response is another important variable between studies. Most studies utilized a scoring system incorporating the symptoms of dysphagia, chest pain, and regurgitation. Response was variably defined in some studies by an absolute point score and in others as achievement of a percent improvement in the symptom score.

Botulinum toxin

Limitations

Botulinum toxin was first used in the treatment of neurologic and ophthalmologic disorders affecting skeletal muscle in the 1970s. It is a protein synthesized by Clostridium botulinum that acts at the nerve terminals of the neuromuscular junction by cleaving SNAP-25, a cytoplasmic protein involved in the exocytosis of acetylcholine-containing presynaptic vesicles, thus leading to muscular paralysis. Selective loss of inhibitory neural function in achalasia with preservation of excitatory, cholinergic innervation has been demonstrated in achalasia (see Fig. 15.2). The intact cholinergic neurons constitute a therapeutic target for botulinum toxin. Pasricha et al. introduced the use of botulinum toxin for achalasia in 1995 in a randomized, placebo-controlled trial in 21 patients,28 demonstrating symptom improvement in 82% after botulinum toxin injection compared with 10% in those received placebo. Significant reductions in LES pressure and improved esophageal radionuclide retention were also demonstrated. This trial was followed by a prospective, long-term followup study of 31 patients that reported a response in two-thirds of patients at a mean follow-up of 2.4 years.38

Most studies have emphasized the clinical efficacy of botulinum toxin therapy for relief of symptoms. Objective measures of response to therapy such as a reduction of lower esophageal sphincter pressure and improvement in esophageal emptying by barium swallow or radionuclide emptying scans, have demonstrated statistically significant, but clinically modest, results. While an approximate 40% reduction in basal LES pressure has been reported, the residual LES pressure post botulinum toxin has averaged approximately 20 mmHg. This residual pressure is clinically relevant as post-treatment LES pressure has been shown to be an important predictor of response to therapy and the need for future therapy. Similarly, studies incorporating measures of esophageal emptying by means of barium radiography or nuclear scintigraphy have demonstrated statistically significant, but modest, improvements in esophageal transit. The apparent disproportionate symptom and objective functional improvement has led to the speculation that botulinum toxin may also be affecting afferent neural function, resulting in impairment of visceral sensation. Highlighting this point is the study by Vaezi et al., a randomized study comparing botulinum toxin with pneumatic dilation. At 1 month post therapy, the response rates were similar. At 1 year, however, 70% of patients treated with pneumatic dilation and only 32% of patients treated with botulinum toxin were in symptomatic remission.27 Four other randomized studies comparing botulinum toxin to pneumatic dilation have also demonstrated significantly greater symptom and objective esophageal functional improvement with pneumatic dilation.40–43 Although the Vaezi study did not allow for repeated injections of botulinum toxin, the lower response rate was seen at nearly all intermediate time points beyond 2 months. Of greater concern was the observation that objective parameters of esophageal function, including LES pressure and esophageal emptying by barium swallow, did not significantly improve after botulinum toxin, while substantial reductions were seen after pneumatic dilation. While many patients treated with botulinum toxin showed a decrement in LES pressure following treatment, onethird of the patients were noted to have a paradoxical increase in LES pressure. These results conflict with the majority of other

Response rates and predictors of success Botulinum toxin has emerged as a novel therapy that is both easy and safe to administer. To date, there have been over 15 prospective studies involving over 450 patients from around the world that have examined the efficacy of botulinum toxin. Response rates at 1 month following administration average 78% (range 63–90%). The clinical response decreases to 58% (range 25–78%) at 6 months and to 49% (range 15–64%) at 12 months (see Table 15.2). It should be noted that the 12-month data was strongly influenced by a single, multicenter study of 118 patients by Annese et al. that reported the highest response rate of 64%.46 The transient efficacy of botulinum toxin and the wide range of reported response rates are apparent. With repeated injections, the response rates reported in limited studies are similar or lower to that achieved with the initial injection. This observation implies that with repeated injections, the absolute number of patient responders decreases. The diminishing effect may be due to the development of protective antibodies against the botulinum toxin

231 Table 15.3 Botulinum toxin (Botx) injection technique for achalasia 1. Botx is stored at or below –5°C until ready for use.

Indications

2. Botx is contraindicated in patients with an allergy to eggs.

Given these limitations to the efficacy and durability of response, botulinum toxin is generally reserved for use for patients who are not candidates for more invasive treatments with pneumatic dilation or Heller myotomy. Such patients might include elderly patients with comorbidities and patients awaiting more definitive therapy. Given the concerns of modest objective esophageal functional improvement in spite of symptom improvement, some assessment of esophageal emptying following botulinum toxin is reasonable. Recent reports have also raised concerns about adverse effects of botulinum toxin therapy on subsequent esophagomyotomy. These reports have noted technical difficulty with the surgical procedure, with a risk of intraoperative esophageal perforation perhaps secondary to obliteration of tissue planes from an inflammatory reaction created by the biologic agent.44,45 However, other studies have not confirmed this observation, and previous botulinum toxin therapy does not appear to affect the overall outcome of surgery should it be indicated.

3. Reconstitute Botx 100 IU with 5 mL of preservative-free normal saline immediately prior to use (yields 20 IU per mL). Care is taken to avoid excess agitation and frothing of Botx during the process.

Dosing and technique of administration The optimal dose of botulinum toxin therapy was examined by Annese and colleagues.46 In this multicenter study from Italy, 118 patients were randomized to treatment with 50, 100, and 200 units of botulinum toxin. Responders to the 100 unit dose were administered a second 100 units after 30 days. At a mean follow-up of 12 months, relapse was seen in 19% treated with the double injections of 100 units compared with 47% and 43% for the 50 and 200 unit doses, respectively. The effect of intermittent versus scheduled dosing of botulinum toxin on clinical efficacy has not been studied. Other potential variations on technique of administration of botulinum toxin include retrograde injection into the gastric aspect of the LES under retroflexed positioning of the endoscope and EUS guidance of the injections. Neither of these techniques has been shown to have increased efficacy over the standard botulinum toxin administration method. A suggested protocol for use of botulinum toxin is given in Table 15.3.

Side effects Botulinum toxin injection for achalasia has been extremely safe. Concerns about potential muscular paralysis have not been realized in the gastrointestinal or neurological applications as the doses used are 20 to 30 times less than the per kilogram lethal dose reported in primates. Transient chest pain is usually mild and has been reported in approximately 20% of patients. Significant heartburn is reported in approximately 5–10% of patients. Isolated case reports of potential adverse events have included heart block, urinary retention, and pneumothorax.

Pneumatic dilation Dilation system Dilation of the esophagus is the oldest form of therapy for achalasia with the earliest use credited to the use of a whale bone by Willis in 1674. Since that time, a number of different techniques have been employed, all with the purpose of mechanically disrupting the LES. Bougienage using dilators with diameters of

4. Five-millimeter sclerotherapy catheter/needle is primed with Botx. A preservative-free normal saline flush is used to expel the final 1–2 mL of Botx from the catheter. 5. Standard upper endoscopy is performed with aspiration of any retained esophageal contents and close inspection of the gastroesophageal junction and cardia. 6. Injection is performed into the proximal aspect of the constriction or ‘rosette’ at the gastroesophageal junction. This typically is located 1–2 cm proximal to the squamocolumnar junction.The needle is angled at approximately 45° to penetrate the muscularis propria and avoid a submucosal injection. Four quadrant injections are performed for a total of 80 to 100 IU. 7. Standard postendoscopy recovery with follow up at 4 weeks with consideration for objective assessment of esophageal emptying.

less than 60 French had been advocated in the past but have since been supplanted by use of pneumatic or mechanical dilators with diameters exceeding 90 French (see Table 15.2). A more recent retrospective study compared symptom response following 56-French mercury bougienage with pneumatic dilation and reported responses of 50% and 83%, respectively.47 While the smaller diameter bougienage is clearly inferior to pneumatic dilation, it is a safer procedure and might be considered in patients at high risk for more invasive therapies, either as an alternative or perhaps in combination with botulinum toxin. Currently, the Rigiflex™ pneumatic dilator (Boston Scientific Corp, Boston, MA) is the most widely used and readily available dilating system for achalasia (Fig. 15.4). The polyethylene balloon is noncompliant and is available in three sizes designed to inflate to fixed diameters of 3, 3.5, or 4 cm. This system offers a safety advantage over earlier compliant, latex balloons that delivered variable diameters depending upon inflation pressure.

Dilation technique and predictors of success Kadakia and Wong reported the results of 47 patients treated with the Rigiflex™ system using a stepwise approach, in which dilation was started with a 3 cm balloon with progression to a 3.5 cm and 4 cm balloon for patients not responding to prior dilator size.48,49 In this series, 62% of patients responded to a 3 cm balloon, with 45% of the nonresponders achieving success with a 3.5 cm balloon. Six patients went on to receive a 4 cm dilation, with 67% responding, yielding an overall response to dilation of 93% over a mean follow-up period of 47 months (range 3–72 months). Over 20 retrospective and prospective studies have been reported on the effectiveness of pneumatic dilation for achalasia using the Rigiflex™ balloon dilator. The overall response rates,

Therapy

published series that have reported a consistent and statistically significant decrease in LES pressure among treated patients, although two abstracts also reported a lack of improvement following botulinum toxin.

Management of Achalasia

232

•

Fig. 15.4 Pneumatic dilation for achalasia using Rigiflex balloon dilator.The left panel shows an uninflated balloon being positioned across the gastroesophageal junction.The four radio opaque rings are centered upon the junction that is visualized endoscopically and generally situated at the level of the diaphragm.The right panel depicts the balloon being inflated, with evidence of a constriction or waist created at the midpoint of the balloon (arrow) due to the LES.

defined by good to excellent relief of symptoms, averages 85% (range 70–92%) with mean follow-up period of 20 months (see Table 15.2). As discussed below, a marked decrement in the response rate has been noted in several, recent, long-term followup studies of pneumatic dilation using balloon dilators that are no longer available. It is therefore reasonable to expect that the response rate in Table 15.2 will decrease with long-term followup studies using the Rigiflex™ system. A protocol for pneumatic dilation is listed in Table 15.4.49 While the use of the Rigiflex™ dilators with an approach that incorporates stepwise increments in balloon diameter has been accepted, a number of methodological issues have not been standardized. The use of conscious sedation, pressure to which the balloon is inflated, duration of balloon inflation, and number of inflations per session are variables that could affect patient outcomes and complications. The use of conscious sedation could theoretically decrease the efficacy of pneumatic dilation through relaxation of the lower esophageal sphincter. Arguing against this possibility is the uncontrolled observation that the response rates in studies using conscious sedation are similar to those not employing sedation.29,48 The importance of specific dilation parameters have been addressed in a small number of prospective studies. Khan and Castell randomized 81 patients to either 60or 6-second dilation with a 3 cm Rigiflex™ dilator and found similar symptom improvement in both groups at 6 month followup.50 Kim and colleagues reported a study of 14 patients randomized to different balloon sizes, one or two inflations per session, and differing inflation times.51 The problem with these studies is that the small sample sizes limit their statistical power to detect significant differences. Nevertheless, the limited prospective and retrospective studies have not shown that inflation times, inflation duration, or number of inflations significantly affect outcomes.

Studies examining clinical and technical factors have identified age, balloon diameter, post-dilation lower esophageal sphincter pressure, clearance of barium on esophagram, and prior dilation as predictors of success following pneumatic dilation. Similar to the botulinum toxin experience, several studies have reported that older patients respond better than younger patients. Eckardt found a 2-year remission rate of 29% in patients under 40 compared with 67% for those over 40.29 In this same study, a Browne-McHardy pneumatic dilator was used, and balloon diameter of less than 3.6 cm was associated with a 31% response compared with 68% for diameter greater than 3.6 cm. Postdilation LES pressure of 50 and presence of vigorous achalasia. Objective measures of esophageal function do not improve to the same degree as seen with pneumatic dilation. Moreover, the response to botulinum toxin wanes with time and repeated injections have been associated with a decrease in the number of patient responders.Therefore, botulinum toxin is recommended for patients who are poor candidates for more invasive therapies due to medical comorbidities. 4. Pneumatic dilation using the Rigiflex™ balloon is an accepted first line-therapy for achalasia, with reported response rates of 85% at 1–2 years and perforation rates averaging 2.6%. Predictors of response include larger balloon diameter and age >40. A graded approach is recommended that starts with a 3 cm balloon, with incremental balloon diameters reserved for nonresponders. Long-term follow-up studies suggest that the effectiveness of pneumatic dilation diminishes over time, with an approximate 40% remission rate at 5 years even with repeated dilations. 5. Based on limited, mostly uncontrolled observations, laparoscopic Heller myotomy is the most effective therapy for achalasia with response rates of 90% reported from centers with large patient experiences. Improvements in surgical approach have resulted in shortened hospital stays approximating 1 day. Furthermore, the benefits of the minimally invasive surgical approach are not available to patients who have perforations resulting from pneumatic dilation, as these require a traditional thoracotomy. Laparoscopic Heller myotomy is a recommended primary therapy at centers having surgical experience with the procedure, especially for younger patients. Complications of gastroesophageal reflux occur and can be treated with proton pump inhibitor therapy.

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89. De Palma GD, et al. Self-expanding metal stents for endoscopic treatment of esophageal achalasia unresponsive to conventional treatments. Long-term results in eight patients. Endoscopy 2001; 33(12):1027–1030.

110. Donahue PE, et al. Esophagocardiomyotomy – floppy Nissen fundoplication effectively treats achalasia without causing esophageal obstruction. Surgery 1994; 116(4):719–724; discussion 724–725.

90. Sandler RS, et al. The risk of esophageal cancer in patients with achalasia. A population-based study. JAMA 1995; 274(17): 1359–1362.

111. Sariyannis C, Mullard KS. Oesophagomyotomy for achalasia of the cardia. Thorax 1975; 30(5):539–542.

91. Dunaway PM, Wong RK. Risk and surveillance intervals for squamous cell carcinoma in achalasia. Gastrointest Endosc Clin N Am, 2001; 11(2):425–434. 92. [No authors listed]. The role of endoscopy in the surveillance of premalignant conditions of the upper gastrointestinal tract. Gastrointest Endosc 1998; 48(6):663–668. 93. Cuilliere C, et al. Achalasia: outcome of patients treated with intrasphincteric injection of botulinum toxin. Gut 1997; 41(1):87–92. 94. Fishman VM, et al. Symptomatic improvement in achalasia after botulinum toxin injection of the lower esophageal sphincter. Am J Gastroenterol 1996; 91(9):1724–1730. 95. Kolbasnik J, et al. Long-term efficacy of botulinum toxin in classical achalasia: a prospective study. Am J Gastroenterol 1999; 94(12):3434–3439.

112. Stipa S, et al. Heller-Belsey and Heller-Nissen operations for achalasia of the esophagus. Surg Gynecol Obstet 1990; 170(3):212–216. 113. Castrini G, Pappalardo G, Mobarhan S. New approach to esophagocardiomyotomy: report of forty cases. J Thoracic Cardiovasc Surg 1982; 84(4):575–578. 114. Okike N, et al. Esophagomyotomy versus forceful dilation for achalasia of the esophagus: results in 899 patients. Ann Thorac Surg 1979; 28(2):119–125. 115. Pai GP, et al. Two decades of experience with modified Heller’s myotomy for achalasia. Ann Thoracic Surg 1984; 38(3):201–206. 116. Ellis FH Jr. Oesophagomyotomy for achalasia: a 22-year experience. Br J Surg 1993; 80(7):882–885. 117. Jara FM, et al. Long-term results of esophagomyotomy for achalasia of esophagus. Arch Surg 1979; 114(8):935–936.

96. Gordon JM, Eaker EY. Prospective study of esophageal botulinum toxin injection in high-risk achalasia patients. Am J Gastroenterol 1997; 92:1812–1816.

118. Menzies-Gow N, Gummer JW, Edwards DA. Results of Heller’s operation for achalasia of the cardia. Br J Surg 1978; 65(7):483–485.

97. Neubrand M. Long-term results and prognostic factors in the treatment of achalasia with botulinum toxin [see comment]. Endoscopy 2002; 34(7):519–523.

119. Mattioli S, et al. Surgery for esophageal achalasia. long-term results with three different techniques. Hepato-Gastroenterol 1996; 43(9):492–500.

98. Barkin JS, et al. Forceful balloon dilation: an outpatient procedure for achalasia. Gastrointest Endosc 1990; 36(2):123–126.

120. Di Simone MP, et al. Onset timing of delayed complications and criteria of follow-up after operation for esophageal achalasia. Ann Thoracic Surg 1996; 61(4):1106–1110; discussion 1110–1111.

99. Stark GA, et al. Prospective randomized comparison of BrownMcHardy and microvasive balloon dilators in treatment of achalasia. Am J Gastroenterol 1990; 85(10):1322–1326.

121. Gallone L, Peri G, Galliera M. Proximal gastric vagotomy and anterior fundoplication as complementary procedures to Heller’s operation for achalasia. Surg Gynecol Obstet 1982; 155(3):337–341.

References

79. Malthaner RA, et al. Long-term results in surgically managed esophageal achalasia. Ann Thoracic Surg 1994; 58(5):1343–1346; discussion 1346–1347.


240 122. Rosati R, et al. Laparoscopic approach to esophageal achalasia. Am J Surg 1995; 169(4):424–427.

129. Mitchell PC, et al. Laparoscopic cardiomyotomy with a Dor patch for achalasia. Can J Surg 1995; 38(5):445–448.

123. Picciocchi A, et al. Surgical treatment of achalasia: a retrospective comparative study. Surg Today 1993; 23(10):855–859.

130. Morino M, et al. Laparoscopic Heller cardiomyotomy with intraoperative manometry in the management of oesophageal achalasia. Int Surg 1995; 80(4):332–335.

124. Murray GF, et al. Selective application of fundoplication in achalasia. Ann Thoracic Surg 1984; 37(3):185–188. 125. Cosentini E, et al. Achalasia. Results of myotomy and antireflux operation after failed dilatations. Arch Surg 1997; 132(2):143–147. 126. Hunter JG, et al. Laparoscopic Heller myotomy and fundoplication for achalasia. Ann Surg 1997; 225(6):655–664; discussion 664–665. 127. Pandolfo N, et al. Manometric assessment of Heller-Dor operation for esophageal achalasia. Hepato-Gastroenterol 1996; 43(7): 160–166. 128. Robertson GS, Johnstone JM. Laparoscopic Heller’s cardiomyotomy without an antireflux procedure. Surg Endosc 1995; 9(7):781–785.

131. Rosati R, et al. Evaluating results of laparoscopic surgery for esophageal achalasia. Surg Endosc 1998; 12(3):270–273. 132. Yamamura MS, et al. Laparoscopic Heller myotomy and anterior fundoplication for achalasia results in a high degree of patient satisfaction. Arch Surg 2000; 135(8):902–906. 133. Stewart KC, et al. Thoracoscopic versus laparoscopic modified Heller myotomy for achalasia: efficacy and safety in 87 patients. J Am Coll Surg 1999; 189(2):164–169; discussion 169–170. 134. Dempsey DT, et al. Comparison of outcomes following open and laparoscopic esophagomyotomy for achalasia. Surg Endosc 1999; 13(8):747–750.

SECTION THREE MANAGEMENT OF ESOPHAGEAL DISORDERS

16

CHAPTER SIXTEEN

Treatment of esophageal disorders caused by medications, caustic ingestion, foreign bodies and trauma Umesh Choudhry and Henry Worth Boyce

ESOPHAGEAL INJURY CAUSED BY MEDICATIONS Introduction Esophageal injury due to ‘pills’ was first reported by Pemberton in 1970.1 Since then, nearly 100 drugs have been reported to incite injury to the esophageal mucosa (Table 16.1).2–4 Drugs that have been most reported to cause esophageal injury include potassium chloride (especially the slow release, wax matrix form), tetracycline, doxycycline, quinidine gluconate, ferrous sulfate, nonsteroidal antiinflammatory drugs (NSAIDs) and more recently, alendronate, zidovudine, rifampin and lansoprazole.5,6 Emepronium, a common cause of drug-induced esophageal damage (DIED) in parts of Europe, is not available in the United States. Esophageal injury caused by medications can be classified into two categories. The first type of injury is an acute, superficial injury of a short duration. Spontaneous healing after discontinuation of the offending agent is the rule. The second type of injury is characterized by deep, intramural inflammation and ulceration, which heals by stricture formation. The late sequelae of this latter type of injury are difficult to treat and place considerable limitations on the patient’s lifestyle.

Pathogenesis The pathogenesis of DIED is best understood by examining the properties of the drug formulation, the shape and form in which the drug is swallowed, the habitus and characteristics of the patient who ingests the medication, and the functional status/anatomy of the esophagus. The most critical factor in the development of DIED is the contact time of the injurious drug with the esophageal mucosa.

Agent factors The drug delivery vehicle, whether pill or capsule, is important because the latter can adhere to the esophageal wall and dissolve slowly, thereby increasing the contact time of the drug with the mucosa. The hygroscopic property of gelatin capsules and their sticky surface allows them to adhere to the mucosa. Thus, doxycycline tablets were found to be less ulcerogenic than the capsule form of the same medication.7 Large tablets, especially those larger than 13 mm in size are more likely to get lodged at a site of

‘physiological narrowing’ in the esophagus, such as at the aortic arch level.8,9 Oval-shaped, film-coated tablets traverse the esophagus easier than round, uncoated tablets.9 The chemical nature of the drug is another important factor. Some medications such as doxycycline, ferrous sulfate, ascorbic acid, or aspirin cause esophageal damage due to their acidic nature.7,10–12 Aspirin may also increase the permeability of the mucosal barrier, allowing H+ ions into the cells.13 Although other medications, such as quinidine gluconate and potassium chloride, have a neutral pH, they incite damage by the hyperosmolar solution produced by dissolution of the drug.14 Direct thermal injury may be produced by dissolving of the agent/medication, as occurred in the case of Clinitest (copper sulfate) tablets. These tablets, now off the market, were used for detecting urine glucose in diabetics and were ingested accidentally or deliberately.15

Host factors DIED is more common in the elderly, debilitated population because they take more medications and are typically in a recumbent position for longer periods of time. These patients also secrete a reduced amount of saliva. In healthy adults, more than one ounce (30 cc) of water is required to swallow and reliably pass a 13 mm tablet promptly into the stomach.16 Therefore, when medications are ingested without or with an insufficient amount of liquid, the chance they will persist in the esophagus is increased.17–19 Even when the esophageal lumen is normal, elderly patients or those confined to a bed are at a higher risk for medications adhering to their esophageal mucosa, due to protracted recumbency.9,18 In addition, poor memory or visual impairment may interfere with their ability to read and comprehend the instructions on the package.

Esophageal factors In addition to the natural propensity for medicines to traverse the sites of anatomical narrowing in the esophagus (cervical esophagus, aortic arch level, and lower esophageal sphincter), underlying esophageal pathology, such as abnormal esophageal motility, a pre-existing stricture, or cardiomegaly (left atrial esophageal compression), may compound the risk of injury due to medications. Hiatal hernias, a very common condition in Western populations, have been shown to reduce the transit of ingested pills.20 Similarly, a Schatzki ring less than 13 mm in diameter may contribute to the delayed transit of tablets.11

Treatment of Esophageal Disorders caused by Medications, Caustic Ingestion, Foreign Bodies and Trauma

242 Table 16.1 Various drugs causing esophageal disease Class of drug Major offenders Potassium chloride (delayed release)

achalasia.2,7 Prevention and treatment strategies are summarized in Table 16.2.

Agents

Slow K & other KCI formulations

Antiarrythmics

Quinidine gluconate, quinidine sulfate

Antiosteoclastic

Alendronate

Diuretic

Furosemide

Antibiotics

Doxycycline, other tetracyclines, penicillin, clindamycin

Antiinflammatory drugs

Aspirin, indomethacin, piroxicam ibuprofen

Other offenders Antiviral agents

Zidovudine

Vitamins

Ascorbic acid, multivitamins

Iron preparations

Ferrous sulfate/succinate

Miscellaneous

Mexiletine, captopril, theophylline, warfarin,

Agents not available in the United States

Emepronium bromide, pinaverium

Prevention of drug-induced esophageal damage Esophageal injury due to medications is entirely preventable. The lack of knowledge of physicians, pharmacists, and patients is the biggest hurdle in preventing this injury. Dissemination of information regarding the injurious potential of various medications is therefore essential. Pharmaceutical companies have the primary responsibility of informing and educating the medical community, using unambiguous language, about the injurious potential of drugs. Package inserts of such medications should contain explicit instructions regarding their use. All physicians and nursing personnel should similarly educate patients, hospital/nursing, home personnel, and caregivers at all levels. Although potassium chloride (Slow-K) was identified as being injurious to the esophagus over 30 years ago, many internists and cardiologists remain unaware of this potential problem with potassium chloride.1 Patients should be warned prior to initiation of therapy with these high-risk agents. Periodically during therapy, a careful history for odynophagia, retrosternal pain, and dysphagia should be obtained. Special attention should be given to patients who are taking multiple medications. Medications that reduce salivary secretions or esophageal peristalsis (e.g., antihistamines, anticholinergics) are likely to increase the contact time of injurious medications with esophageal mucosa, thereby worsening the damage. All patients should be advised to take medications in an upright posture, take at least 2–3 oz water with each tablet, and to remain upright for at least 15 minutes after ingestion.21 When medications are prescribed to be taken at bedtime, patients should be informed that ‘at bedtime’ does not mean at the time of recumbency, but rather 15 minutes or longer before assuming a recumbent position. Liquid preparations should be used for bedridden patients and patients with preexisting esophageal lesions such as strictures, diverticula, and

Diagnosis and treatment of drug-induced esophageal damage in the acute phase As previously outlined, an accurate history leads to an early diagnosis in most cases. Patients with DIED present most often with a burning retrosternal pain (60–70%).4 Odynophagia is the second most common symptom (50–74%); however, dysphagia is relatively infrequent and usually is reported when there is a significant luminal compromise during the later stages of injury.22 Pain, odynophagia, and dysphagia can develop within hours to 10 days after the initiation of the medication. The first and foremost step in this phase of injury is to identify the offending agent and discontinue its use. If a pill is found adherent to the mucosa or impacted in the esophageal lumen on a barium swallow, early endoscopy may be required for its removal. Symptomatic treatment using antacids, topical xylocaine gel or a combination and oral analgesics are useful in alleviating pain. These combinations may be named variously in different hospitals as ‘GI cocktail,’ ‘Kessler’s solution’ or ‘magic mouthwash.’ They are usually short acting and must be administered frequently. Sucralfate, H2-blockers, and proton pump inhibitors have also been used to promote the healing of acid reflux-related ulceration/erosion of the esophagus, although their efficacy in treatment of DIED has not been established.2,3,23 No further diagnostic evaluation for acute symptoms is recommended in younger patients without immune deficiency states.3,8 If symptoms persist or worsen despite the above measures, the patient should undergo an esophagogastroduodenoscopy (EGD). A double-contrast barium esophagogram may be helpful as an initial study, but EGD has the advantage of revealing more mucosal detail. It also provides a more accurate assessment of the degree of injury and gives an opportunity for biopsy. Impacted tablets/capsules, if encountered, can also be removed at the time of the procedure. In 99% of cases, mucosal abnormalities are found on EGD and commonly include a single, shallow, discrete ulcer with exudate at the level of the aortic arch or circumferential mucosal ulceration or nodularity of the mid esophagus with an adherent clot.4,24

Table 16.2 DIED: prevention and treatment strategies Prevention Physician/pharmacist education Patient education: upright posture and 100 cc water Modification of pill size/shape Substitution of pills by elixir or orally dissolving formulations Avoid concurrent use of offending agents Treatment during acute phase Cessation of offending agent Symptomatic treatment: topical and oral analgesics, antacids, sucralfate Treatment after stricture formation Esophageal dilation Intralesional triamcinolone injection: questionable benefit Surgery: almost never required

243

Management of delayed sequelae of drug-induced esophageal damage When medications cause a deep ulceration of the esophageal wall, the healing phase is prolonged and slow. Persistent symptoms often indicate complications such as stricture formation, bleeding, or perforation.19 The medications usually implicated in this type of injury include a delayed-release wax-matrix form of potassium chloride (Slow-K), quinidine gluconate (Quinaglute), and indomethacin. A recent addition to this list is the daily dosing version of bisphosphonate: alendronate (Fosamax 10 mg).27,29,30 When patients present with continued symptoms and a history of ingestion of one of the above mentioned ‘serious offenders,’ it is important to proceed with an early endoscopy due to the serious transmural injury caused by these agents.31,32 If active ulceration is identified by barium study or EGD, acid suppression in the form of H2-blockers or proton pump inhibitors is indicated in patients with gastroesophageal reflux. Esophageal dilation is postponed until inflammation/ulceration is completely healed. Esophageal dilation in the presence of ulceration is often ineffective and may be associated with complications.33 Once inflammation is resolved and stricture formation is confirmed, the stricture should be dilated early and frequently, to prevent contraction of the cicatrix.19,26 Unfortunately, patients may be seen by gastroenterologists months to years after the initiation of these medications because some drugs such as potassium chloride and quinidine gluconate may not cause odynophagia or retrosternal pain. In other cases, repeated complaints of dysphagia are often ignored until a tight, fibrotic stricture develops, at which point esophageal dilation becomes very difficult. These patients require multiple sessions of esophageal dilation performed at 1–2 week intervals, usually over several months.26 Almost all patients show gratifying results and have nearly complete resolution of symptoms after adequate esophageal luminal patency has been restored. Since multiple sessions of esophageal dilation are anticipated, the pathophysiology of the condition and treatment plan should be discussed in detail with the patient. The patient may be given appointments for several sessions of dilation in advance to assure proper treatment intervals. The median number of dilation sessions required over 6–12 months to achieve adequate lumen patency for severe quinidine gluconate-related strictures at our center is 14. Dilation over a wire guide is the preferred method for these strictures. Several investigators have described the use of intralesional injections of triamcinolone in ‘refractory’ strictures.34–39 A MEDLINE review of the use of intralesional steroids revealed several case reports, primarily in patients with corrosive strictures, one retrospective study, and one randomized prospective study (in abstract

form) of patients with reflux strictures.34–39 All report a decrease in the frequency of dilation after intralesional steroids. However, none of these reports defined ‘stricture’ relative to the degree of active inflammation present, and only one patient had a DIEDrelated stricture. Intralesional injection of steroids is simple and safe, with no serious reported adverse effects. However, it is useful only for strictures less than 1 cm in length. A 23–26-gauge endoscopic needle (sclerotherapy needle) is used to inject 40 mg/mL strength triamcinolone or a larger volume of diluted strength. Four quadrant injections of 0.5 mL each are made at the time of each dilation. The benefit shown with the use of intralesional steroids has likely been due to their antiinflammatory property. However, satisfactory results can be achieved with conventional dilation performed with a proper technique. There is currently no proof that steroid injections relieve obstructions in chronic fibrotic strictures not associated with active inflammation. We ascribe the therapeutic success to the elimination of inflammation, discontinuation of the offending agent, and wire-guided dilation under fluoroscopy. The use of intralesional steroids is not recommended as a standard therapy in patients with DIED.

Role of surgery/stents Surgery has no proven role in the treatment of DIED, except when perforation or uncontrollable bleeding occurs. All strictures can be successfully managed by wire-guided dilation. The use of selfexpanding metal or nonmetallic stents for benign esophageal strictures has been evaluated over the past few years. The experience to date suggests that this approach leads to significant complications and should be avoided in patients with significant life expectancy and who have other treatment alternatives.40,41

ESOPHAGEAL INJURY CAUSED BY CANCER CHEMOTHERAPY Introduction Cancer chemotherapy alone or in conjunction with radiation therapy often results in esophageal damage. The damage is often diffuse and similar to mucosal injury that occurs elsewhere in the body.42,43 Patients typically present with severe odynophagia and dysphagia. Intense nausea and vomiting are caused by the chemotherapeutic agents and reduce the ability of the patient to ingest oral liquids. On endoscopy, diffuse erythema with exudation is seen throughout the esophagus. Bleeding may occur and may be potentiated by thrombocytopenia or coagulopathy secondary to bone marrow suppression. Immunosuppression may also result in opportunistic esophageal infections due to Candida, herpes simplex virus, or cytomegalovirus.

Symptomatic treatment Amelioration of retrosternal pain and odynophagia is the first goal of treatment, followed by treatment to promote healing. Topical analgesics are often useful for the mucositis that nearly always accompanies esophagitis. Viscous xylocaine can provide some measure of relief, albeit short-lived, from pain and odynophagia. Due to its short duration of action, xylocaine jelly alone or in combination with antacids needs to be given at frequent intervals (every 1–2 hours, up to a maximum of 8 doses of 15 mL in

Esophageal Injury Caused by Cancer Chemotherapy

The mucosa above and below this lesion is generally normal,7,25 although on occasion, a distal esophageal ulceration maybe be found, especially in the presence of a pre-existing reflux-related injury.26,27 Pill remnants or pigmentation of the mucosa may also be seen. On histological examination, the pigmentation has been shown to be due to impregnated crystals of the offending medication, viz., ferrous sulfate or doxycycline.28 Most cases of DIED improve with cessation of the offending medication plus symptomatic therapy in the acute phase and do not require any further treatment.29 Pre-existing lesions, when identified, should be managed appropriately for complete resolution of symptoms.


244 24 hours). Oral/parenteral pain medications may be required, in addition to topical analgesics. When used, it is best to prescribe these medications as alcohol-free suspensions since alcohol typically exacerbates pain and odynophagia. Combinations of acetaminophen and codeine or hydromorphone are useful in this situation. Cryotherapy using ice chips in the mouth has been used to prevent oral mucositis in patients receiving chemotherapy.44 Similarly, sucralfate has been studied in prevention and treatment of chemotherapy-induced stomatitis.45 It is uncertain if sucralfate has any proven effect in the treatment of chemotherapy-associated esophagitis. Because acid suppression therapy using H2-blockers or proton pump inhibitors is traditionally used for reflux esophagitis or peptic ulcer disease, these medications are often used in patients with esophagitis due to chemotherapy despite lack of any substantial evidence indicating a benefit.46 Supportive measures such as adequate nutrition and hydration by the parenteral route or a thin nasogastric tube for enteral feeding are important. It is preferable to pass the nasogastric tube under fluoroscopic guidance. Acid suppression by either an H2-blocker or a proton pump inhibitor should be given during nasogastric intubation.

ESOPHAGEAL INJURY CAUSED BY LYE/CAUSTIC SUBSTANCE INGESTION Introduction Lye-based liquid household cleaners have been commercially available in the United States since 1967. Accidental and intentional ingestion of these substances has resulted in serious morbidity during the past three decades. It is estimated that caustic ingestion and foreign body aspiration are the third most common causes of pediatric death in this country.47 Nearly 26 000 episodes of caustic substance ingestion occur in the United States every year. Nearly 17 000 of these involve children, 50% of whom are under the 4 years of age. Adults and adolescents account for 20% cases, the majority of which are suicidal gestures. The agents most often reported to be involved in these cases are shown in Table 16.3.

Table 16.3 Common household corrosives Brand name/product

Chemical name

Red Devil Drain Opener

Sodium hydroxide (96–100%)

Crystalline Drano

Sodium hydroxide (50%)

Clinitest tablets

Sodium hydroxide (50%)

Liquid Drano

Sodium hydroxide (2–10%)

Signs and symptoms of caustic injury Several large series of caustic ingestion esophageal injuries have been reported.48–50 The signs and symptoms reported include nausea, vomiting, dysphagia, refusal to drink, drooling, and stridor. None of these signs and symptoms appears to accurately predict the degree of injury. Crain and colleagues reported that the presence of two or more of the serious signs/symptoms, namely vomiting, drooling, or stridor, indicated a 50% chance of esophageal injury.50,51

Pathogenesis Vancura and colleagues, using a cat model, demonstrated that alkali at a pH of 12.5 produces esophageal ulceration.52 Liquid lye, frequently available in the form of drain cleaner, produces its injury by liquefaction necrosis and is thus able to quickly spread into the esophageal and gastric mucosa, thereby producing widespread penetrating injuries. Bacterial infection regularly occurs and potentiates the injury. Acidic caustic substances (except hydrofluoric acid), in contrast, result in coagulation necrosis and form a thick eschar, which may protect the mucosal layers from damage. By 10 days after caustic injury, granulation tissue begins to replace the necrotic tissue, and fibroblast proliferation and scar formation begin by the third week after injury. Caustic ingestion may cause serious systemic effects by causing airway edema and obstruction, resulting in hypoxia and hypercapnia. Metabolic disturbances can occur and require immediate attention. Infection usually complicates the clinical scenario in cases of esophageal perforation.

Prevention of corrosive injury In most instances, injury due to corrosive substances is preventable. Educating the public regarding proper storage of these agents away from the reach of infants and children and possibly from suicidal adolescents is required as a continuous effort. Educating prospective parents during prenatal classes when their attention level is heightened may be another strategy. Efforts from industry are needed to minimize the corrosive component of household cleaning solutions. Proper labeling and addition of colors to these agents can prevent their being mistaken for water. In addition to household cleaners, corrosive alkali is present in cylindrical and button batteries. There is thus a need for manufacturing leak-proof battery casings, as merely sucking on a battery by a child has been reported to result in esophageal burns.53 Some countries such as Norway have taken a lead in this matter and have banned the sale of alkaline corrosives as household cleaners. Ironically, acid injuries now account for a majority of cases in Finland.54

Mr. Clean liquid

Sodium carbonate

Top Job liquid

Sodium carbonate/ammonia

Phases of corrosive injury

Liquid clorox

Sodium hypochlorite (5.25%)

Three phases of corrosive injury have been described.55 A thorough understanding of these phases is important in planning a therapeutic strategy.

Lysol deodorizing cleaner

Ammonium chloride (2.7%)

Swish toilet bowl cleaner

Ammonium chloride (1.25%)

Dish water detergents

A combination of sodium hypochlorite, bicarbonate, phosphate, silicate (pH: 12.5)

Battery fluid

Sulphuric acid

Acute phase The first 72 hours after the ingestion of the corrosive substance constitute the acute phase. It is characterized by the initiation of an inflammatory response and vessel thrombosis. Invasion of the

245

Subacute phase This phase spans from 3 days to 3 weeks post corrosive ingestion. An intense inflammatory response and further vascular thrombosis occurs during this phase, resulting in sloughing of the superficial layers of mucosa and ulceration. Granulation tissue formation, fibroblast infiltration, and collagen deposition also occur and may be accompanied by significant hemorrhage. The risk of esophageal perforation is increased, especially with blind instrumentation such as nasogastric intubation during this phase.

Chronic phase Beginning at about 3 weeks post ingestion, the chronic or late phase of corrosive injury is marked by scar retraction, continued fibrosis, mucosal re-epithelialization and possible tracheoesophageal fistula formation. Stricture formation occurs in up to 30% of patients with corrosive esophageal injury, typically in patients with second and third degree injury.56 These patients have been estimated to have a greater than 1000-fold increase in the incidence of squamous cell carcinoma of the esophagus 15–20 years after corrosive ingestion,57,58 and periodic surveillance should thus be considered in this group after 15 years. The use of Lugol iodine chromoendoscopy will delineate foci of dysplasia or cancer and can enhance early diagnosis.

Treatment in the acute phase Patients who can give a reliable history of accidental ingestion, are asymptomatic, have no evidence of oropharyngeal burns, or have only a questionable history of corrosive ingestion may be observed in the emergency room or during an overnight hospital stay. In contrast, patients who show signs of acute injury, may have ingested large amounts of corrosive substances or are suicidal should be admitted to the intensive care unit for observation, further diagnostic tests, and treatment. In either situation, early endoscopy will provide an accurate assessment of the degree of injury.

Airway protection Emergency tracheostomy or endotracheal intubation is indicated in patients with stridor, hoarseness, or inability to speak. It should be borne in mind that the onset of respiratory symptoms may be delayed up to 24 hours. PA and lateral chest X-rays should be obtained initially and repeated, based on the patient’s condition, since aspiration pneumonia is a risk in these patients.

Most patients need to be kept NPO in view of the possibility of endoscopy or surgery. Patients who are able to swallow their saliva, do not have any respiratory symptoms, or in whom urgent endoscopy is not contemplated may be allowed ice chips or sips of water.

Endoscopic evaluation and management As stated above, signs and symptoms do not generally predict the severity of damage. Since treatment options depend greatly on the assessment of injury (Table 16.4), endoscopic examination should be carried out as early as possible. This strategy also minimizes the risk of perforation. Endoscopy should be done 24–48 hours post ingestion or sooner if respiratory and hemodynamic parameters are stable. More than 50% of patients with a history of caustic ingestion are found to have no evidence of esophageal injury on an early endoscopy.49,50,60,61 The extent of the endoscopic examination has also been debated. In the past, when endoscopes were rigid, a limited examination within the first 24 hours was favored to avoid perforations.62,63 Endoscopists terminated the exam at the level of the first burn site. With the availability of small-caliber flexible video endoscopes, endoscopy under direct vision is considered safe during any phase of the illness in the absence of obvious evidence of perforation.64 Some authors recommend gently guiding the instrument through areas of superficial injury and continuing examination until areas of possible full-thickness necrosis are encountered, an approach that allows complete evaluation of the upper gastrointestinal tract and has been reported to be safe.65–67 If severe full-thickness necrosis is encountered, the examination is terminated and intensive care observation continued for signs of esophageal or gastric perforation. Endoscopic management strategy is summarized in Table 16.5.

Nasogastric tube placement There have been reports in which acute corrosive injury was managed conservatively by the insertion of a nasogastric tube.68 Although no controlled data are available regarding this approach, the nasogastric tube appears to act as a stent and prevents complete occlusion of the lumen and assures access for dilation guidewire

Table 16.4 Endoscopic grades of corrosive injury 1st degree

Erythema, edema, erosions (bleeding)

2nd degree

Intense erythema, blebs, and deep erosions with exudate

3rd degree

Epithelial loss, ulceration, necrosis, exudate and eschar

Supportive treatment Appropriate management of hypotension and shock may be required in the form of intravenous fluids or pressor agents. Surgical consultation should be obtained early in cases of severe esophageal injury as emergency surgery is indicated if evidence of esophageal, gastric, or other visceral perforation is present. Signs of esophageal perforation include pneumomediastinum, subcutaneous emphysema, crepitus, dyspnea, and severe chest or abdominal pain. Care should be taken to avoid the use of emetic agents as they may precipitate additional esophageal and oropharyngeal injury and lead to perforation. The use of neutralizing agents is contraindicated as neutralization reactions lead to heat production and may further aggravate the injury.59

Table 16.5 Endoscopic management of corrosive injury General anesthesia usually not required Early endoscopy post stabilization Complete, diligent examination of the esophagus and stomach Repeat EGD after 2 weeks Initiate dilation before 3 weeks if evidence of stricture Savary dilation over guide wire under fluoroscopy is optimal technique for initial therapy

Esophageal Injury Caused by Lye/Caustic Substance Ingestion

esophageal wall by bacteria and polymorphonuclear leukocytes takes place during this phase.


246 placement. If a nasogastric tube is used, it should be connected to low intermittent suction to avoid gastric distention. Measures to prevent acid reflux such as elevation of the head of the bed and acid suppression should also be employed during intubation. Some authors favor this approach if severe esophageal damage has been ruled out by endoscopy. In our opinion, when nasogastric intubation is considered appropriate, the concomitant use of an intravenous proton pump inhibitor is indicated. It is safer to place the nasogastric or nasoduodenal tube under fluoroscopic guidance or over a wire placed through the endoscope after evaluation has been completed. If the nasogastric tube tip is modified prior to placement by removing the blind end tip and smoothing the cut edges, guidewire insertion at the time of dilation can be done through the tube with safe post-dilation replacement of the nasogastric tube over the guidewire.

Use of corticosteroids, antibiotics, and early dilation Since 1950, the use of systemic corticosteroids has been advocated in the acute and subacute phases of injury. Spain and colleagues reported a reduction in the degree of inflammation in an animal model.69 However, Anderson and colleagues, in a prospective study, refuted this claim and reported no improvement in the steroidtreated group.60 This debate may have been rekindled by a recent study by Bautista et al., who showed dexamethasone to be superior to prednisone in preventing strictures and reducing burn severity at 3 weeks. The dexamethasone-treated group also needed fewer dilations.70 Barring this study, the prevailing belief at the present time is that steroids do not play a role in the treatment of corrosive injury.71,72 The positive effect of dexamethasone in children may also be related to the fact that children, unlike suicidal adults, are brought to the hospital very early during the postingestion period. Antibiotics alone have not been shown to be of any benefit in the treatment of corrosive injury. Their use has been limited to the prevention of septic complications in patients on intravenous corticosteroids.73 Broad-spectrum antibiotic therapy is indicated in patients with signs of esophageal or gastric perforation. Esophageal dilation carried out in the subacute phase may be associated with an increased risk of perforation.74,75 In contrast to traditional thinking, esophageal dilation using proper technique and fluoroscopic control may be safe even during the subacute phase. Early dilation and the prevention of stricture formation forms the basis of the modified Salzer technique described by Palmer.67,76 Using fluoroscopic guidance and proper technique, the patient receives a nasogastric tube within a few hours of the corrosive ingestion. Wire-guided esophageal dilation is then initiated on the third day after an endoscopic examination, with the dilator size chosen based on the age of the patient. Adult patients may be started with a 12 or 13 mm dilator (5–6 mm for a child); the dilation may be gradually progressed by 1–2 mm to reach a 15 mm diameter by the end of the first month. The dilation is discontinued if fresh blood is seen on the dilator. Dilations are carried out at least two or three times per week for several weeks in order to prevent stricture formation. Dilations predictably meet more resistance by the fourth week. The diameter of the lumen and frequency of dilation sessions should be determined by the resistance experienced on passage of each dilator. A progressively less frequent dilation schedule should be set for the next several months to years, using either wire-guided dilation or Maloney bougie dilation under fluoroscopic control to maintain lumen diameter between 15 and 18 mm. Periodic radiographic and endoscopic evaluations

should be continued as indicated for dysphagia and surveillance for the remainder of the patient’s life.

Total parenteral nutrition Maintenance of nutrition is of utmost importance in seriously ill patients. Feeding through the nasogastric tube may not be possible in patients with severe (grade 3) injury or in patients with impending perforation. These patients should receive early total parenteral nutrition (TPN) to avoid malnutrition, while allowing the gastrointestinal tract to rest and heal. DiConstanzo and colleagues reported that TPN protects the damaged mucosa.77 TPN may also be required during the perioperative period in patients who require surgery.

Surgery Esophagectomy should be performed when evidence of perforation related to the acute-phase injury is present. When endoscopic examination reveals extensive gastric necrosis, most authors recommend esophagectomy with gastrectomy and anastomosis, as either a oneor two-stage operation. Surgery is performed with the presumption that esophageal perforation is imminent in this situation. Zargar and colleagues proposed a modified classification system for corrosive injury and further subdivided second and third degree injury into grades 2a, 2b, 3a, and 3b. Patients with grade 1 (erythema and edema) and grade 2a injury (friability, hemorrhages, erosions, and superficial ulceration) did not develop any complications. Grade 2b (deep discrete or circumferential ulcers) or deeper injury was associated with complications. Patients with small and scattered areas of necrosis could be managed conservatively in the acute phase. Only 25% of these patients required surgery at a later stage. They recommend emergent esophagectomy only for patients with extensive necrosis (stage 3b).64 Laparotomy may be needed for an evaluation of the depth of injury in some patients with extensive second or third degree injury. It also provides the option for the placement of a feeding gastrostomy tube and a continuous #4 silk suture, which may be utilized for retrograde dilation should it become necessary at a later date.

Treatment during chronic phase In patients with severe esophageal injury, strictures typically develop within 3 to 4 weeks. Earlier frequent dilation serves to minimize this risk.76 A barium esophagogram should be obtained at this time to assess the degree of stricture formation, the site of strictures, and contour of esophageal lumen. A solid bolus challenge may be required for accurate assessment if no stricture is apparent with liquid barium. A detailed regimen of wire-guided esophageal dilation needs to be planned as outlined above in the section on DIED. The dilation strategy should, however, take into account that the transmural fibrosis seen in this condition makes the esophageal wall prone to tearing and perforation. These patients may have pseudodiverticulum formation and require a much more careful approach. It is prudent to begin with a dilator size just below the estimated lumen diameter (by barium esophagogram) and advance only one or two millimeters in dilator diameter in the beginning. The rate of dilator size progression is determined by the resistance encountered, as well as operator experience. Some authors have shown a decrease in the need for repeated dilation when intralesional injections of triamcinolone were used in both pediatric and adult population.38,39 The mechanism by which

247 batteries are less than 15 mm in diameter, with 62.5% being 11.6 mm in diameter (range 7–23 mm).79–81,83 Disc batteries should be considered as a foreign body with severe corrosive properties or a corrosive chemical delivered as a small pellet. Contrary to early belief, Litovitz did not find the severity of injury to be dependent on the electrical status of the battery in a study of 1718 cases in which the battery status and outcome were both known. Instead, they found that lithium batteries with their larger size and higher voltage (3 volts) were associated with more severe damage.

Detection and treatment of late complications Prevention As discussed above, patients with a history of corrosive injury to their esophagus have been estimated to have a 1000 times higher incidence of squamous cell carcinoma.57,58 It may thus be reasonable to perform periodic surveillance endoscopies with Lugol staining chromoendoscopy in these patients starting 15 years after injury. However, no studies are available to prove or disprove the usefulness, cost-effectiveness or the proper interval of endoscopic surveillance.

TREATMENT ISSUES SPECIFIC TO MINIATURE (BUTTON) BATTERY INGESTION Introduction The ingestion of ‘button’ batteries follows the old axiom that ‘toddlers put in their mouth what they get their hands on.’ ‘Button’ battery ingestion represents a relatively new phenomenon. These miniaturized alkaline batteries have rapidly replaced the older cylindrical cells (Fig. 16.1). With electronic toys and quartz watches replacing their mechanical counterparts, these batteries are present in every modern household. They contain a highly concentrated solution of potassium or sodium hydroxide and potentially toxic compounds of mercury and zinc, lithium and cadmium. Over a 10-year period (1982–1992), 2320 cases of button battery ingestion were reported to the National Button Battery Ingestion Hotline at Georgetown University Hospital’s National Poison Center (202-625-3333).79–81

Pathogenesis

Precautions required to prevent ingestion of button batteries are similar to those needed for any foreign body ingestion. However, due to their potential for causing rapid damage, it is extremely important to keep these batteries out of reach of children. Sixtysix percent of battery ingestions occur in children younger than 6 years of age.79–81 Children who use a hearing aid require closer supervision because nearly one-half of the reported ingestions involve these batteries. Education of audiologists, parents, and children may help reduce these events. Design improvements and industry involvement can likely eliminate this threat. It may be prudent for the manufacturers to use smaller batteries, which are less likely to get impacted in the esophagus. Further miniaturization and the development of batteries that do not contain corrosive materials may eliminate this damage in the coming decades. The development of one such battery was reported in the lay press by researchers at Johns Hopkins University.

Management Foreign body identification Prompt identification and location of the battery is the most important first step in this condition. Once a possible case is brought to the notice of a physician, posteroanterior and lateral chest radiographs should be promptly obtained. A ‘double-density’ opacity is usually produced by a disc battery.84 The edges of a battery are more rounded than that those of a coin. An abdominal radiograph is also indicated initially to search for other foreign objects that may have been ingested.

Removal

The major mechanism of injury to the esophagus is the leakage of the caustic alkaline solution from the button battery. Esophageal mucosal damage may occur within 1 hour of ingestion, and the degree of damage correlates directly to the duration of contact with the mucosa.82 The risk of impaction of a disc battery in the esophagus depends on its size, being more likely with batteries larger than 20 mm in diameter. Fortunately, 97% of the ingested

If the battery is lodged in the esophagus, a prompt endoscopic extraction is mandatory. No neutralizing agents have been found to be useful to prevent or decrease esophageal damage while the patient is in transit to a medical center.85 Emetic agents are generally ineffective and should not be used. Although Foley catheter balloon-assisted removal of foreign bodies is considered safe in patients with a disease-free esophagus, this method is not

•

11 mm

17 mm

18 mm

21 mm

24 mm

Fig. 16.1 A photograph of an 11 mm disc battery and common coins, showing the rounded edges of the battery that make its retrieval using forceps difficult.The caustic material leaks out from the gap between front and back covers. The coins have elevated edges, which enable them to be grasped with alligator/rat-tooth forceps.

Treatment Issues Specific to Miniature (Button) Battery Ingestion

intralesional steroids benefit in this condition is not clearly understood. Often patients not properly treated by adequate dilation early in the chronic phase, or who are later neglected during follow-up, will require a series of careful dilation sessions to achieve and sustain adequate esophageal patency. Collagen synthesis inhibitors may have a role in this condition; such agents, however, are currently under investigation and no data presently support their use.78


248 recommended for disc batteries due to a lack of control.86–88 The use of a magnetic probe for the removal of button batteries has been reported in European countries.89 A protocol for the management of ingested button batteries is presented in Table 16.6. Most reviews do not recommend any intervention for batteries that have arrived in the stomach or more distally at the time of diagnosis.88–90 However, more recent experience tends to suggest that polyethyline glycol solution preparations may be used safely to flush the battery more quickly.91

Endoscopic intervention Oral removal by endoscopy is the treatment of choice for button batteries lodged in the esophagus. General anesthesia or monitored anesthesia care with protection of the airway may be required in infants and children, while adolescents and adults may be able to undergo endoscopy using intravenous sedation. A bronchoscopy prior to endoscopy should be performed if more than 4 hours have elapsed since the ingestion of battery to identify a fistula that may form as a result of full-thickness injury to the anterior esophageal and posterior tracheal walls. Endoscopic removal of disc batteries from the esophagus is challenging. General principles employed in the removal of disc batteries are similar to those followed for any other foreign body retrieval with the exception of need for removal as early as possible (Table 16.7). Because of their rounded edges, these batteries are difficult to grasp securely with foreign-body forceps or snares. If the exact size and type of the battery is identified, the choice of instrument can be made by prior rehearsal. Common US coins and a disc battery are shown in Figure 16.1. Forceps with magnetic properties may be more useful in these situations, but are not currently available. An overtube may be used to protect the airway or to prevent dropping the battery as it traverses the cricopharyngeal sphincter. A Dormier basket as used for gallstone retrieval

Table 16.6 Management protocol for esophageal button battery History: establish accurate size and time of ingestion Initial X-ray (posterior-anterior and lateral chest X-ray plus abdominal X-ray) Esophageal battery: emergent endoscopic retrieval Identify the chemical system: mercury levels only when battery disintegrated For help call (202) 625-3333 in the United States or contact your physician immediately

Table 16.7 Indications for emergent removal of ingested foreign body Respiratory distress Foreign body at the cricopharyngeus level

or the Roth Retrieval Net used to retrieve colon polyps may be helpful. Only 33% of attempted removals have been reported as successful.81 If retrieval is not possible, the battery can be gently pushed into the stomach and removal attempted from the stomach. However, this maneuver should only be done if the lumen beyond the battery is clearly visible, adequately patent, and free of any pathology. If retrieval is not possible even from the stomach, the battery should be left in the stomach and a follow-up radiograph obtained at 48 hours to follow the passage of the battery. Although Willis and Ho reported the perforation of a Meckel’s diverticulum by an ingested disc battery, no further intervention is generally required if the battery has passed beyond the pylorus by 48 hours and if no symptoms are reported.90

Role of surgery Early surgery may be indicated if a perforation, full-thickness injury, or fistula formation is detected by endoscopy and/or bronchoscopy. The management is then the same as that of perforation due to any foreign body.

Post-retrieval measures If a battery has been removed uneventfully without full-thickness damage evident on endoscopy, no further intervention may be required. In patients where progression to full-thickness burn or fistula formation may be likely, a barium swallow using thin barium may be performed during the next 24–48 hours. This study may be repeated in the next several days to delineate stricture formation. Treatment with proton pump inhibitors or sucralfate may be useful if mucosal erosion is seen. The use of laxatives or prokinetics to promote the passage of a gastrointestinal button battery is not recommended since most batteries are excreted within 72 hours.88

ESOPHAGEAL FOREIGN BODIES (NONFOOD) Foreign body ingestion results in approximately 1500 deaths annually in the United States. A large majority of foreign body ingestions occur in children, edentulous elderly, prisoners, and psychiatric patients. In a recent series of 414 adult patients with ingested foreign bodies, 38% were nonfood-related objects. Seventy-five percent of these objects were found in the esophagus (36% cervical, 19.8% mid-esophagus, and 19.1% distal esophagus).92 Nonfood foreign bodies are ingested primarily by children.93 These include coins, components of toys, crayons, and small household items such as pens, paper clips, and safety pins. College students have a propensity for accidental ingestion of coins as a consequence of a flip and oral catch game often played under the influence of alcohol. Prisoners, on the other hand, have been reported to indulge in recurrent (3–10%), deliberate ingestion of many types of foreign bodies for secondary gain.95,96 Nearly 75% of all documented ingested foreign bodies are lodged in the esophagus at the time of diagnosis.97

Inability to swallow secretions Evidence of perforation Button battery ingestion Sharp object ingestion

Pathogenesis Children ingest foreign bodies while playing with them, while the elderly who ingest foreign bodies most often have their palatal

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Prevention of foreign body ingestion is far more cost-effective than their extraction. Coins and small objects that can be swallowed should be kept out of the reach of infants and small children. A similar strategy for close supervision should be adopted for the mentally retarded and elderly patients.

reported to be 100% successful in a small number of patients. This approach may represent a simple strategy, but its safety and efficacy needs to be further tested by a larger study.103 Other effervescent agents that release large quantities of CO2 upon ingestion have also been used, with success rates of 75%.104 However, because effervescent agents in the setting of complete obstruction have resulted in perforation, their use can not be recommended. Their use may be safe prior to endoscopy in patients with nontoxic, blunt/round, small-caliber foreign bodies in the absence of preexisting esophageal pathology. A technique usually reported by radiologists and not favored by most gastroenterologists involves the use of a Foley catheter for the removal of esophageal foreign bodies. This technique has been widely reported in emergency medicine and in the pediatric literature and employs the passage of a Foley catheter under fluoroscopic guidance, followed by inflation of its balloon distal to the ingested object.105–107 The catheter is then withdrawn, thus removing the foreign body. This technique has been shown to be safe in the pediatric population, where pre-existing esophageal pathology is generally not encountered. The technique has an obvious cost advantage because it obviates the need for an endoscopy and minimizes the period of observation in a hospital or emergency room. The primary risk of this strategy is the lack of control when the object passes the hypopharynx. This risk may be overcome either by the use of endotracheal intubation or placing the patient in a Trendelenburg position. In a survey of pediatric radiologists, Campbell and colleagues reported 2500 successful foreign body removals, with only one complication.108 The use of this method is limited to blunt objects within 12 hours of ingestion.105 Gastroenterologists prefer endoscopy over the Foley balloon catheter, perhaps due to their experience with endoscopy and lack of experience with Foley catheter technique.94,109 Because esophageal disease is so common in patients with esophageal foreign bodies, an endoscopy should be performed in all cases. The blind passage of an esophageal bougie to push the foreign body into the stomach has been described, but should not be done because of the high risk for perforation and the ready availability of safer alternatives.110 Thompson and colleagues recently described another nonendoscopic technique for the removal of gastric and esophageal metallic foreign bodies, using a magnetic orogastric tube.111,112 Although their reported success rate was >90%, lack of control is once again an issue. The technique, however, has the potential of being useful as an adjunct to endoscopy and overtube placement.

Removal of esophageal foreign bodies

Endoscopic removal

Diagnosis A history of definite ingestion by the patient/witness or in its absence other associated signs of dysphagia, odynophagia, sialorrhea, chest discomfort, or constitutional, signs of perforation may all point to the diagnosis of foreign body ingestion. Radiography is of paramount importance as most ingested foreign bodies are radiopaque. Since 1982, at the insistence of pediatricians and radiologists, all North American coins have been minted with radiopaque metals.98 It is important to obtain two axis (AP and lateral) views to estimate the exact location, size, and shape of the object. However, plain films have false-negative rates up to 47% in the detection of foreign bodies.99 When the suspicion is strong, but plain radiography fails to identify a foreign body, barium contrast radiography is often useful. However, barium should be avoided in patients suspected to have total esophageal obstruction. Also, barium may be retained in enough quantity with incomplete obstruction to hinder endoscopic examination. Radiographic diagnosis assists the endoscopist in planning the procedure and selecting the timing and equipment for retrieval.94,97 It may also rule out or confirm a suspicion of perforation. CT scanning of the neck and chest with soft tissue and bone windows provide better contrast and are more useful in foreign body detection.100 Flexible video endoscopy has the advantage of combining diagnostic and therapeutic capabilities. Extreme care should be exercised by the endoscopist during the procedure. It is critical that the passage of the endoscope and accessories be done under constant direct vision and never blindly into or beyond a foreign body.

Prevention

Nonendoscopic management In a retrospective study of esophageal foreign bodies, Crysdale and colleagues101 reported that 7.8% passed spontaneously within 24 hours, while another 2.5% passed with the use of pharmacological agents. In contrast, Tibbling and Stenquist reported a spontaneous passage rate of 21% within 24 hours,102 which further increased to 29% if endoscopy was delayed beyond 24 hours. Spontaneous passage is almost universal once the foreign body has reached beyond the lower esophageal sphincter. Nonendoscopic approaches can be divided into two categories: those that promote the passage of the object distally and those aimed at extraction of the object. Distal passage is promoted primarily by pharmacological means using agents that relax the lower esophageal sphincter. The use of a carbonated drink has been

Rigid esophagoscopy was most widely used for foreign body removal prior to the 1960s and 1970s. However, the availability of flexible fiberoptic endoscopes, and more recently video endoscopy, has brought about a revolution in this field. The diameter of the endoscopes has become progressively smaller, thereby making flexible endoscopy favored for the removal of foreign bodies. Gastroenterologists today are primarily trained in, and prefer to use, flexible video endoscopes, a preference that is widely supported.93–95,97,113 In his report of 242 foreign body removals, Webb used a flexible endoscope in 211 (87%) cases.93 Similarly, in a 15-year review of foreign body management, Weiss and colleagues employed flexible endoscopy in 111 of the 132 cases where endoscopic removal was carried out, with a success rate of 90%. In addition, flexible endoscopy has the advantage of being safer, with a reported perforation rate less than one-half that of rigid esophagoscopy (0.9%

Esophageal Foreign Bodies (Nonfood)

sensation reduced or eliminated by a denture plate. One such example is the aluminum foil wrapping on medications with the medication enclosed, which has resulted in esophageal perforation. Although uncommon in children, adults who have esophageal foreign bodies impacted in the esophagus have underlying lesions of the esophagus in up to 88% of cases.95


250 versus 2%).95,110 Rigid endoscopy retains a role for the removal of foreign bodies impacted in the hypopharynx and cricopharyngeus (upper esophageal sphincter) and in those not removable by a flexible endoscope.

Table 16.8 Esophageal foreign body

Suitable extraction accessories

Preparation for endoscopy

Coin

Roth net, alligator forceps, rat-tooth forceps, snare, basket,TTS balloon, magnetic probe (if available)

Button battery

Roth retrieval net, Dormier basket, magnetic probe

Thumb tacks

Alligator forceps, rat-tooth forceps

Sharp objects (pins, needles, toothpicks, blades, open safety pins, fish bone)

Overtube, hooded sheath, snare, alligator forceps

Marbles, seeds, eraser

Baskets, snare, polyp retriever

Food bolus (meat)

Overtube Stiegman-Goff adaptor, Dormier basket

Indications for emergent foreign body retrieval are summarized in Table 16.7. While performing endoscopy for removal of foreign bodies, one must ascertain that the patient is completely cooperative or adequately sedated and properly monitored, with ample assistance and equipment available to the endoscopist. If intravenous conscious sedation does not achieve this objective, monitored anesthesia care (MAC) using short-acting intravenous agents, such as propofol, is preferred. MAC is especially useful when endotracheal intubation is required for airway protection. Availability of the surgical team, if needed, should be ascertained before beginning any foreign body removal, especially when dealing with sharp object or button battery ingestion or when the object was ingested more than 24 hours previously.

Equipment selection Most experts in this field practice and recommend a proper selection of equipment and planning (i.e., a ‘dry run’), using accessories to practice grasping a similar foreign body prior to the actual procedure.94,97 This process provides the endoscopist and the endoscopy assistant a feel for both the eventualities that might occur during the retrieval and the suitability of the accessory equipment to be used.

Accessories Various accessories have enhanced the ability of the endoscopist in successful retrieval of ingested foreign bodies safely (Table 16.8). These include: overtube, alligator forceps, rat-tooth forceps, (both manufactured by Olympus America Inc., Lake Success, NY), Roth retrieval net, (US Endoscopy Group, Inc., Mentor, Ohio), polypectomy

snare, Dormier basket, tripod, hooded sheath, and the StiegmanGoff adaptor for variceal band ligation (Figs 16.2–16.4). Of these, the plastic overtube is a versatile, multipurpose accessory that should be stocked in every endoscopy unit (Fig. 16.2). It also allows multiple passages of the endoscope with lesser patient discomfort. When back-loaded on an endoscope and advanced after the endoscope tip is beyond the cricopharyngeus, it can be advanced over the scope to provide airway protection. However, injury can occur due to trapping of the mucosa between either an endoscope or a Maloney dilator used as an obturator to introduce the overtube.114 Introduction of the overtube should be performed gently and carefully regardless of the obturator (endoscope or rubber bougie) used. A 44 French size Maloney dilator is used as the obturator for

•

Overtubes. Fig. 16.2 (A) Conventional, black, straight overtube with sharp inner edge; (B and C) Newer variety, curved, clear plastic (20 cm long) overtubes. Note their round (B) and tapered (C) distal ends. (D) Friction tip (Stiegmann-Goff) adaptor for variceal ligation and meat bolus extraction.

A

B

C

D

251

A

B

C

D

•

A dual exposure Fig. 16.4 photograph showing: (A) rat-tooth forceps, (B) alligator forceps, and (C) alligator forceps with rat-tooth jaws.These accessories are useful in removal of a variety of foreign bodies.

A

B

C

passing one standard model of overtube in patients without esophageal foreign bodies; however, this blind overtube passage should not be used for fear of push injury when an esophageal foreign body is suspected. Sharp objects, such as pins, needles, blades and wires, can be withdrawn into the tube, thus protecting the esophageal mucosa from damage. Coins, the most common foreign bodies ingested by children, are best removed using an alligator or a rat-tooth forceps or a Dormier basket (Figs 16.3, 16.4). These forceps have sharp jaws that appose well to grasp an object

with rough and vertical edges. Button batteries, on the other hand, have rounded edges that are difficult to grasp with forceps. In an in vivo comparison of various accessories, Faigel and colleagues demonstrated that button batteries could be removed only by using either a basket or a Roth Retrieval Net (Fig. 16.3), whereas the snare was the best instrument for removing toothpicks and thumb tacks.115 A through-the-scope (TTS) balloon may at times be used to remove a foreign body under direct visualization via a two-channel operating endoscope, or as

Esophageal Foreign Bodies (Nonfood)

•

Photograph showing: Fig. 16.3 (A) Snare, (B) Roth Retrieval Net, (C) polyp retriever, and (D) Dormier basket.


252 a means of opening the lumen distal to a foreign body in the grasp of a snare or forceps.

Body packer syndrome (cocaine-loaded foreign body) The popularity of cocaine as a recreational drug within the United States has resulted in increased smuggling of this drug across international borders. Its abundant availability in South American countries and the enormous cost difference between these countries and United States has resulted in people devising ingenious ways to smuggle the drug. ‘Body packing’ or ingesting cocaine-filled latex condoms is one such ingenious method used to conceal the illicit material. Each pack generally contains up to 5 grams of cocaine. Once the ‘packer’ arrives at his destination, the ingested pack is retrieved after it is passed in feces. The clinical significance of this crime strikes home when the scheme does not proceed as planned. Complications of this ingestion usually arise when the packages rupture or are not passed in the feces within 24–48 hours. Esophageal impaction with these packages is rare, but may occur as with any ingested foreign bodies. Johnson and Landreneau reported a case of esophageal obstruction and perforation due to ingested marijuana packs by a prisoner in Missouri.116 The cocaine/drug packs are unique in that endoscopic removal should not be attempted because it may lead to perforation of the pack and release of a fatal dose of the drug. Whenever detected, these packs are best managed surgically. The general condition of the patient merits intensive observation and supportive care if some or all of the packs have traversed the esophagus.

TREATMENT OF FOOD BOLUS IMPACTION Introduction A food bolus represents a specific type of foreign body, and most studies deal with the accidentally swallowed, unchewed or unprepared food bolus as a part of ingested foreign bodies. We deal with the specific aspects of management of food bolus separately due to the unique characteristics of this foreign body. Impacted food bolus is the most common type of foreign body encountered in adults. In a large majority of cases, a food bolus impacts in the esophagus due to an underlying disorder. The impacted food is usually a piece of meat that is swallowed without careful chewing. Hence, the commonly used terms include ‘meat impaction’ or ‘steakhouse syndrome.’

Pathogenesis A distal esophageal ring or a stricture is usually present that prevents the passage of the bolus into the stomach. Patients frequently present several hours after dining at a restaurant or having a big holiday meal. Meat boluses impacted for over 12 hours or those that contain slivers of bone create a higher risk for esophageal perforation during attempts at removal.

Diagnosis/treatment As discussed in the section on foreign bodies above, diagnosis is often apparent from the history. Most patients receive glucagon,

nitroglycerine, or similar medications in the emergency room before a gastroenterologist is consulted. The statistics presented above for success of these agents in foreign bodies are applicable to the impacted food bolus. Recent experience with glucagon has not been very gratifying. Although esophageal perforation was reported with the use of papain as early as 1968,117 the use of meat tenderizers (a very reduced concentration of papain) was common in emergency rooms long after that.118 The use of this agent should no longer be considered a standard treatment. Papain, the active ingredient in meat tenderizer, has no effect on normal mucosa, but contact with inflamed mucosa may incite a marked increase in inflammation,117 and mural digestion may occur if the tissue is ischemic. Because of its chemical nature and contact with saliva, a food bolus impacted in the esophagus undergoes progressive degradation with passage of time. This feature is of importance in planning its extraction. If the patient can handle salivary secretions, emergent endoscopy is not necessary. Observation and sedation may allow spontaneous passage of the food bolus.93 If urgent endoscopy is performed, a meat bolus ingested recently can potentially be extracted in one piece using a snare or a basket. However, if more than 12 hours have elapsed since the consumption of the meal, the meat may have become very soft and fragmented. Under such circumstances, multiple passages of the endoscope may be required, necessitating the use of an overtube.94 The standard forceps and snare accessories often are inadequate for removing such impactions. Saeed and colleagues in 1990 reported the use of the StiegmanGoff band ligator tip as an accessory for meat bolus extraction (see Fig. 16.2D).119 This technique produces a suction cup at the tip of the endoscope, thus facilitating removal of a soft food bolus. Despite disintegration with the usual instrumentation, the bolus can be suctioned and anchored into this cup during the passage across the cricopharyngeus. Homemade endoscope tip adaptors fashioned from plastic tubing were, however, in use even prior to this report. The newer variety transparent variceal band ligator adaptors are even more suitable for this task as they do not occlude the endoscopist’s field of vision. Other aspects of meat bolus extraction are generally identical to those of ingested foreign bodies. Any bolus that completely occludes the lumen and prevents visual inspection of the lumen beyond the bolus should not be blindly pushed ahead with the endoscope or any accessory instrument because of an increased risk of perforation.

Treatment of the underlying disorders An underlying esophageal structural abnormality is present in up to 80% of adults with foreign body impaction in the esophagus. An appropriate therapy of the underlying lesion may thus prevent future recurrences. The lesion most often encountered is a refluxinduced esophageal stricture. Mosca et al. found associated pathology in 83 (30.7%) of their patients (stricture, 50; hiatal hernia, 11; achalasia, 11; and Schatzki ring, varices, diverticula, and cancer, 11).92 If the ingested object or food bolus is present for more than 12 hours and the esophageal mucosa shows signs of ischemia/ inflammation, esophageal dilation should be deferred for at least 1–2 weeks after foreign body removal. A malignant lesion should be appropriately managed. Patients with psychiatric disorders should receive prompt help via psychiatric consultation and should be appropriately treated because of the risk of repeated ingestion or other suicide attempts.

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Introduction Traumatic injury to the esophagus can be classified into two groups based on etiological mechanisms. The first and far more frequent is the extrinsic group, which includes instrumentation, such as endoscopy, dilation, surgery, foreign bodies, and thermal ablation of lesions. Recognition of complication risk and efforts at prevention are the key elements in avoiding perforation.120 The second and less common group is due to intrinsic causes, which includes MalloryWeiss tear, Boerhaave’s syndrome, and malignant strictures.

Pathogenesis Various etiological factors involved in trauma to the esophagus are summarized in Table 16.9. Instruments such as endoscopes, bougies, hydrostatic or pneumatic balloon dilators, guidewires, tips of hydrostatic (TTS) dilators, and other accessories all may cause disruption of the wall of the esophagus due to a shearing or radial force or a direct puncture. Owing to its unique anatomic characteristic of lacking the serosal layer, the esophagus is especially susceptible to these forces. Trauma during or after surgery, on the other hand, may be either direct laceration or disruption of vascular supply at the time of surgery resulting in an ischemic injury, which finally results in perforation. Modalities such as thermal lasers, multipolar coagulation and heater probe, or photodynamic laser therapy (PDT) may traumatize the esophagus by direct burn

or deep desiccation, which eventually results in necrosis of the tissue and perforation. Barotrauma or forceful distention may take place due to excessive insufflation of air during various procedures, especially in the setting of complete obstruction.

Prevention Esophageal injury due to instrumentation may increase as newer procedures, instruments, and techniques are adopted for achieving hemostasis and performing esophageal dilation, as well as with the advent of endoscopic antireflux procedures. In our view, adequate emphasis on prevention of iatrogenic injury is likely the most important part of management. The following section deals with issues important for the prevention of iatrogenic esophageal injury.

Barium esophagogram

Table 16.9 Esophageal trauma: etiology

‘Cost containment’ issues have also resulted in the endoscopist often not having the luxury of, or making the effort to, obtain a barium esophagogram study prior to endoscopic intervention for stenotic lesions. Identification of pre-existing lesions prior to endoscopy by barium swallow is, however, useful. The value of a barium esophagogram being available prior to endoscopy in stenotic lesions of the esophagus cannot be overemphasized. A detailed history may help in selecting the cases where a barium study must be obtained before endoscopy is attempted. A barium esophagogram helps to identify the site, length, and contour of the stricture. It also alerts the endoscopist to the possibility of more than one stenotic lesion with different characteristics being present in one patient. A barium study will identify necrotic cavities in an esophageal carcinoma prior to endoscopy, dilation, or stent placement that otherwise might be interpreted as a perforation when done following the procedure.

Extraluminal etiologies Penetrating wounds

Issues relating to fluoroscopy, wire guidance and TTS balloons

Blunt trauma Operative injury Through-the-wall suture Disruption of blood supply Laparoscope/other instruments Intraluminal etiologies Intrinsic Mallory-Weiss tear Boerhaave syndrome Esophageal malignancy Ulceration Extrinsic Foreign bodies/nonendoscopic instrumentation Bone/pin ingestion, endotracheal, nasogastric, orogastric tube placement Endoscopic instrumentation Dilation, guidewire/endoprosthesis placement, balloon tip Pneumatic dilation, sclerotherapy, laser or electrocoagulation, overtubes

Several developments in the evolution of endoscopy have resulted in esophageal dilation being done routinely without the use of fluoroscopy. These include time constraints, commercial promotion to employ newer TTS balloons for esophageal dilation, the demonstrated safety of esophageal dilation in simple, distal, peptic strictures without the use of fluoroscopy, and the advent of officeor outpatient center-based endoscopy. All have led to the general belief that fluoroscopy may be superfluous for most esophageal strictures. However, fluoroscopy helps in completing a safe, effective dilation of esophageal stricture and is of utmost value when the endoscopist is not familiar with the severity of the lesion. We prefer that patients be in a supine position for this procedure, especially when using fluoroscopy, which helps in the correct anatomical identification of landmarks and helps in following the course of the dilator accurately. Availability of excellent C-arms with digital image quality has brought fluoroscopy out of hospital radiology departments and into modern endoscopy units, thereby making it easily accessible. Esophageal dilation under wire guidance has made esophageal dilation safer and, in the authors’ view, should be the method of choice for most dilation procedures. The wire placement should either be endoscope assisted or under fluoroscopic guidance or both. Advancement of the Savary wire or a thinner, floppy wire under fluoroscopy may prevent inadvertent injury when a patient has

Traumatic Injury to the Esophagus

TRAUMATIC INJURY TO THE ESOPHAGUS


254 luminal abnormalities, such as a Zenker diverticulum, cricopharyngeal bar, epiphrenic diverticulum or large hiatal hernia. The Savary wire, although flexible at its tip, has been reported to cause perforation of the gastric or duodenal wall when not fixed diligently in position during advancement of the dilator. Injury occurs when the flexible tip is completely flexed or the wire bent acutely, and force is exerted either at the junction of the flexible tip and stiff steel wire or against the point of the bent wire. Due to its thickness and relative rigidity, the tip may also traverse severely inflamed, friable tissue planes if not observed carefully during endoscopy or under fluoroscopy. Esophageal TTS hydrostatic balloons have gained increased popularity in recent times for the dilation of esophageal strictures. Although far more expensive than bougie-type dilators, aggressive marketing and relative ease of use form the basis of their increased usage. These balloons, however, have a long, semi-firm tapered tip, which is often several centimeters away from the view of the endoscope (Fig. 16.5). The tip is prone to causing injury to the mucosa in the presence of inflammation, friability, or carcinoma, especially when the endoscope is being repositioned or with respiratory excursion. This possibility is even more important with longer balloons or when a stenotic lesion does not allow the passage of the endoscope to direct safe passage of the balloon dilator tip. The tip should be carefully observed at the time of advancement and at every point when the balloon or the endoscope is advanced. Development of an even more flexible tip may address this problem. Regardless, the endoscopist and the assistant need to diligently fix the endoscope at the mouth and the balloon catheter at the insertion port of the endoscope, which should prevent inadvertent movement of the balloon dilator or its tip during inflation. Another concern is the use of these hydrostatic balloons to dilate strictures due to causes likely associated with deep transmural injury and fibrosis, such as those related to radiation and caustic injury. In our opinion, wire-guided dilation or Maloney dilators under fluoroscopic control are safest in these patients.

Issues relating to thermal or other ablative modalities Adhering to safe levels of power settings while performing thermoablation procedures and becoming familiar with new equipment prior to use may prevent accidental deep burns. Testing the power settings in vitro on comparable animal tissue or in vivo in the stomach (which has a thicker wall) immediately before use may prevent deeper esophageal burns or perforation. Using lower power settings when the tissue is inflamed or treating raised lesions and avoiding excavated lesions may also be helpful. The depth of ablation achieved with equipment made by different manufacturers may differ even with similar settings. Early experience with the radiofrequency technique for treatment of gastroesophageal reflux (STRETTA™) has reportedly resulted in perforation, although added experience has improved its safety profile. The Endo Cinch™ device technique has recently been reported to have caused a perforation of the distal esophagus that was managed laparoscopically.121 It is obvious that these techniques are best used by adequately trained operators who perform these procedures regularly.

Issues relating to overtubes and foreign-body removal During endoscopy, intubation and advancement of the endoscope should be done under direct visualization. While attempting foreign body retrieval, the overtube should not be passed until the foreign body and esophageal mucosa have been examined. The use of an overtube should be avoided if possible, but not at the cost of compromising the airway. However, overtubes are important in the protection of the airway and should be used when indicated. Mucosal injuries related to passage of overtubes can be minimized by placing the overtube in warm water prior to insertion and passing the overtube over a proper diameter bougie.122,123 The largest bougie that can be comfortably moved in and out of the overtube should be used. The use of the newer variety 60F/20 cm length tube with a filed, blunt, rounded leading edge may further reduce this trauma.124 Inadequate sedation and inability of the assistant to hold the overtube in place are two factors that may precipitate accidental,

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Fig. 16.5 Photograph showing tip of a TTS balloon.The tip (arrow) can traverse through inflamed, necrotic, or even normal tissue, with sufficient force, during blind placement and cause perforation if caution is not exercised.

255

Management of perforation of the esophagus Causes of esophageal perforation have been listed along with causes of esophageal trauma in Table 16.9. Whatever the cause, esophageal trauma and perforation constitute an emergency and require rapid diagnosis and treatment. The signs and symptoms usually depend on the cause, location, and extent of perforation (Fig. 16.7). Patients usually present with tachycardia, chest pain, shortness of breath, and vomiting, and may have subcutaneous or mediastinal emphysema. Efficient management of esophageal perforation begins with an accurate history in high-risk cases. The classic scenario is of a patient presenting after consuming a large meal that includes alcohol, followed by vomiting and/or severe bouts of coughing, chest pain, and dysphagia. Subtle presentations may include a history of consumption of carbonated drinks/beer with forceful retching, blunt trauma to the chest during a fist fight or accident, swallowing a sharp bone or object, or severe coughing episodes. Symptoms of pleuritic chest pain with radiation to shoulder, neck or jaw, or epigastric pain in a patient with the abovementioned history should alert physicians to the possibility of esophageal perforation. This possibility is especially important for the physicians evaluating patients during the night or in walk-in

clinics, where several hours may elapse before the patient is likely to be seen by another physician. Early detection and evaluation of suspicious symptoms with chest radiographs and barium esophagogram can be invaluable in improving the eventual outcome. Radiographic studies may show subcutaneous emphysema (Fig. 16.8), mediastinal widening, pneumothorax, pleural effusion, or an air–fluid level in the mediastinum. Typically, a water-soluble contrast (Gastrograffin®, meglumine diatrizoate) swallow should be performed if esophageal perforation is suspected. This study should be the first radiographic procedure done for the evaluation of a suspected perforation after a PA and lateral chest X-ray. If negative, a barium esophagogram using a limited volume of thin barium is more likely to reveal small perforations and should be done. If perforation is still suspected, a CT scan will prove most sensitive for revealing barium outside the esophageal lumen. Once esophageal perforation is suspected, regardless of whether initial studies are negative, a thoracic surgeon with significant experience in performing esophageal surgery should be contacted promptly. Preferably, the surgeon should be alerted to the possibility of esophageal perforation and be available on call even before a relatively high-risk procedure, such as pneumatic balloon dilation for achalasia, is actually performed. The patient with suspected esophageal perforation is best managed in the hospital under close observation with surgical consultation until perforation is excluded. Nontransmural tears of the esophagus can be successfully managed conservatively and patients discharged within 3 to 4 days.125 Occasionally, limited/nontransmural tears may extend after delayed weakening of the wall by infection or by high intrathoracic pressures generated by gagging, vomiting, or coughing. Thus, the diagnosis should be reviewed and diagnostic studies repeated if the clinical condition of the patient does not improve rapidly. Esophageal perforation occurring after endoscopy or dilation is considered by some authors to represent a different entity. Although surgery forms the mainstay of therapy, several studies have reported successful management of these patients by conservative

•

Fig. 16.6 Photograph showing the cut internal bumper of a gastrostomy tube.The relatively sharp tube end can cause mucosal injury. Retrieval direction (arrow) should be with the sharp end trailing.

Traumatic Injury to the Esophagus

uncontrolled, and repetitive repositioning or advancement of the overtube, thereby increasing the chances of mucosal injury. The older, larger, longer, and stiffer overtube (see Fig. 16.2A) should be considered obsolete and removed from the endoscopy units. As described above, while removing foreign bodies, the sharper end should always be trailing (Fig. 16.6) in order to avoid accidental puncture of the mucosa. Removal of a PEG tube mushroom should be done by the external traction method whenever possible. Cutting of the internal bumper and snare-assisted retrieval should only be done when one-step external traction removal is not possible. If not retrieved carefully, these bumpers can result in esophageal perforation.


256

•

Algorithm for management of Fig. 16.7 esophageal perforation.

Possible etiologies Endoscopy Dilation Intubation Trauma

Vomiting Foreign body Caustic ingestion

Symptoms and signs suggest perforation Pain – chest, neck, abdomen *Tachycardia, dyspnea, hypotension, fever, subcutaneous emphysema Assure availability of or consult with experienced esophageal surgeon

Admit for evaluation and observation

Establish IV access

PA-lateral radiographs chest, neck, abdomen

Diagnostic of perforation

Water soluble contrast esophagram

Negative

Decision for surgery vs. medical therapy


Barium esophagram (thin, small volume)


Negative

CT chest

Overnight hospital observation

treatment, using intravenous fluids and antibiotics.126–131 Mortality is generally low compared to noniatrogenic patient groups, although morbidity is higher in patients with delayed (>24 hours) identification of perforation.132 If the patient is not a surgical candidate and has a limited life span, as in patients with esophageal cancer, immediate placement of a plastic or coated metal expandable endoprosthesis is an option, with 60–90% chances of survival.133,134 Despite these reports, it must be emphasized that such patients require close observation, preferably in the intensive care unit, aggressive supportive care, broad-spectrum antibiotic therapy and an alternative source of nutrition. Surgery should be considered if clinical improvement does not continue. There has been one case report where perforation following pneumatic balloon dilation for achalasia was treated endoscopically using a metallic clip.135 In the future, laparoscopic surgery may also play a larger role in the management of small, clean, iatrogenic perforations that are detected early.120 Perforation due to noniatrogenic trauma is best managed by early surgical repair.136 Historically, patients undergoing early surgery

Negative

have had a better outcome. Mortality rates as high as 56% with delayed recognition of esophageal perforation are reported.137,138 More recent reports, although maintaining the trend of poor prognosis for patients with delayed detection, show a comparatively better outcome in both groups.139 Most patients are able to avoid esophagectomy. Some of these studies also support conservative management for noniatrogenic perforations. The studies that have evaluated a conservative approach for this group of patients report success in patients with hypopharyngeal perforations.139 Others who have evaluated this form of treatment with thoracic esophageal perforations have selected larger perforations for surgical treatment.133 There is also a chance of reporting bias where failures of conservative approach may not be reported. In addition, as emphasized by Pasricha et al., it is quite difficult to predict that a small perforation selected for conservative management will not progress to cause extensive mediastinitis.138 Thus, early surgery should still be considered the treatment of choice for most patients, with conservative treatment reserved for selected cases (Table 16.10).

257

Table 16.10 Selection guidelines for nonoperative management of esophageal perforation Minimal pain Absence of shock Mild to moderate fever or leukocytosis No clinical evidence of sepsis A confined cavity that drains well into the esophagus Delayed diagnosis >24 hours, no progression or patient improving Adapted from Pasricha et al.119

SUMMARY Nearly 100 drugs have been reported to cause injury to the esophageal mucosa. Such injury may be an acute, superficial injury that heals rapidly or deep, intramural ulceration, which heals by stricture formation. Esophageal injury caused by medications is entirely preventable. A periodic, careful history for odynophagia, retrosternal pain, and dysphagia should be obtained. Concomitant therapy with anticholinergics should be avoided, and liquid preparations should be used for bed-confined patients or those with esophageal strictures, diverticula, or dysmotility. Early barium swallow

or endoscopy is indicated, and symptomatic treatment using antacids, topical xylocaine gel, or both are useful. Drug-induced deep esophageal ulcers are slow to heal and acid suppression is indicated. Tight, fibrotic strictures may require diligent, multiple fluoroscopic and wire-guided dilations, while intralesional corticosteroid injections and surgery have no proven role. Esophageal damage caused by chemotherapy and chemoradiation therapy is often diffuse and involves long segments. Pain control followed by healing is the goal of therapy; viscous lidocaine, systemic analgesics, sucralfate, and PPIs appear to provide benefit. Lye-based liquid household cleaners along with foreign body aspiration are the third most common cause of pediatric death in the United States. Industry-wide voluntary and legislative efforts are needed for effective prevention. These patients typically present with nausea, vomiting, dysphagia, refusal to drink, drooling, and stridor. In the first 72 hours after ingestion, airway protection is the primary goal. Management in the intensive care unit with intravenous fluids, pressors, and antibiotics is useful. Early surgical consultation is needed when viscous perforation is suspected. In the absence of perforation, early endoscopy with a small, flexible endoscope is safe and necessary for assessment of severity. Acute corrosive injury may be managed conservatively with broadspectrum antibiotics, thin-caliber nasogastric suction tube placement, and intensive care management with arguable success. Esophageal dilation carried out in the subacute phase (3 days to 3 weeks) is risky but may be successful. Frequent, painfully diligent sessions over several months may be needed.

Summary

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Fig. 16.8 A radiograph of the neck showing diffuse subcutaneous emphysema.The patient had a microperforation following esophageal dilation for Zenker diverticulum and prominent cricopharyngeal bar.


258 Due to their potential for causing rapid damage, button batteries must be kept out of the reach of children. Prompt identification and location of the battery by radiography is the most important first step. If the battery is lodged in the esophagus, a prompt endoscopic extraction is mandatory, using a basket or a net device as the method of choice. Airway protection by endotracheal intubation and the use of an overtube are critical. Neutralizing agents and emetic agents are generally ineffective. Early surgery may be indicated if a perforation, full-thickness injury, or fistula formation is detected by endoscopy. Similarly, other foreign bodies or food bolus require emergent removal in the presence of respiratory distress, location of the foreign body at the cricopharyngeus level, inability to swallow secretions, sharp object ingestion, or evidence of perforation. With increasing availability of diagnostic and therapeutic endoscopy, iatrogenic trauma to the esophagus has become more common. Endoscopic ablation of esophageal lesions by thermoablative techniques, photodynamic therapy, and radiofrequency devices has added a new dimension to the iatrogenic esophageal injury. Nevertheless, management principles remain the same, with prompt identification of the injury being the key. Although the use of conservative management is being reported, surgical repair remains the mainstay of management when perforation is strongly suspected.

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85. Tanaka J, Yamashita M, Yamashita M, et al. Effects of tap water on esophageal burns in dogs from button lithium batteries. Vet Hum Toxicol 1999; 41(5)279. 86. Harned RK, Strain JD, Hay TC, et al. Esophageal foreign bodies: safety and efficacy of Foley catheter extraction of coins. Am J Roentgenology 1997; 168:443. 87. Sigalet D, Lees G. Tracheoesophageal injury secondary to disc battery ingestion. J Ped Surg 1988; 23(11):996.

107. Ginaldi S. Removal of esophageal foreign bodies using a Foley catheter in adults. Am J Emerg Med 1985; 3(1):64. 108. Campbell JB, Condon VR. Catheter removal of blunt esophageal foreign bodies in children. Survey of the Society for Pediatric Radiology. Pediatr Radiol 1989; 19(6–7):361. A nonoperative, low-risk technique is reported successful in 98 of 100 children with blunt esophageal foreign bodies.

88. Studley JGN, Linehan IP, Ogilvie AL, et al. Swallowed button batteries: is there a consensus on management? Gut 1990; 31(8):867.

109. Berggreen PJ, Harrison ME, Sanowski RA, et al. Techniques and complications of esophageal foreign body extraction in children and adults. Gastrointest Endosc 1993; 39(5):626.

89. McDermott VG, Taylor T, Wyatt JP, et al. Orogastric magnet removal of ingested disc batteries. J Pediatr Surg 1995; 30(1):29.

110. Shaffer RD, Klug T. A comparative study of techniques for esophageal foreign body removal with special emphasis on meat bolus obstruction. Wisconsin Med J 1981; 80(11):33.

90. Willis GA, Ho WC. Perforation of Meckel’s diverticulum by an alkaline hearing aid battery. Can Med Assoc J 1982; 126(5):497. 91. Namasivayam S. Button battery ingestion: a solution to a management dilemma. Pediatr Surg Int 1999; 15(5–6):383. 92. Mosca S, Manes G, Martino R, et al. Endoscopic management of foreign bodies in the upper gastrointestinal tract: report of series of 414 adult patients. Endoscopy 2001; 33:692. 93. Webb WA. Management of foreign bodies of the upper gastrointestinal tract: update. Gastrointest Endosc 1995; 41(1):39. Management of 242 foreign bodies of the upper gastrointestinal tract (181 in the esophagus), without morbidity or mortality, is reviewed. 94. Weiss KL, Brady PG, LaFontaine P. Management of ingested foreign objects and food bolus impactions [Abstract]. Gastrointest Endosc 1996; 43:361. 95. Rosenow EC. Foreign bodies of the esophagus. In: Payne WS, Olsen AM, eds. The esophagus. Philadelphia: Lea & Febiger; 1974:159. 96. Webb WA, Mc Daniel L, Jones L. Foreign bodies of the upper gastrointestinal tract: current management. South Med J 1984; 77:1083. 97. Quinn PG, Connors PJ. The role of upper gastrointestinal endoscopy in foreign body removal. Gastrointest Endosc Clin N Am 1994; 4(3):571. 98. Neilson IR. Ingestion of coins and batteries. Peds in Review 1995; 16(1):35. 99. Herranz-Gonzalez J, Martinez-Vidal J, et al. Esophageal foreign bodies in adults. Otolaryngol Head Neck Surg 1991; 105(5):649. 100. Braverman I, Gomori JM, Polv O, et al. The role of CT imaging in the evaluation of cervical esophageal foreign bodies. J Otolaryngol 1993; 22(4):311.

111. Thompson N, Lowe-Pansford F, Mant AK, et al. Button battery ingestion: a review. Adverse Drug React Toxicol Rev 1990; 93:157. 112. Paulson EK, Jaffe RB. Metallic foreign bodies in the stomach: fluoroscopic removal with a magnetic orogastric tube. Radiology 1990; 174(1):191. 113. Brady PG. Esophageal foreign bodies. Gastroenterol Clin North Am 1991; 20(4):691. 114. Sanowski RA, Harrison ME, Young MF, et al. Foreign body extraction in the gastrointestinal tract. In: Sivak MV Jr, ed. Gastroenterologic endoscopy. Philadelphia: WB Saunders; 2000:801–812. An excellent review of endoscopic techniques for removal of esophagal and gastric foreign bodies. 115. Faigel DO, Stotland BR, Kochman ML, et al. Device choice and experience level in endoscopic foreign object retrieval: an in vivo study (Abstract). Gastrointest Endosc 1996; 43:334. 116. Johnson JA, Landreneau RJ. Esophageal obstruction and mediastinitis: a hard pill to swallow for drug smugglers. Am Surgeon 1991; 57(11):723 117. Holsinger JW, Fuson RL, Sealy WC. Esophageal perforation following meat impaction and papain ingestion. JAMA 1968; 204:188. 118. Goldner F, Danley D. Enzymatic digestion of esophageal meat impaction. A study of Adolph’s Meat Tenderizer. Dig Dis Sci 1985; 30(5):456. 119. Saeed ZA, Michaletz PA, Feiner SD, et al. A new endoscopic method for managing food impaction in the esophagus. Endoscopy 1990; 22:226. 120. Tulman AB, Boyce HW. Complications of esophageal dilation and guidelines for their prevention. Gastrointest Endosc 1981; 27:229.

261 130. Shaffer HA., Valenzuela G, Mittal RK. Esophageal perforation: a reassessment of the criteria for choosing medical or surgical therapy. Arch Intern Med 1992; 152(4):757.

122. Baehr PH, McDonald GB. Esophageal disorders caused by infection, systemic illness, medications, radiation, and trauma. In: Feldman M, Scharschmidt B, eds. Sleisenger and Fordtran’s gastrointestinal and liver disease. 6th edn. Chapter 334. Philadelphia: WB Saunders; 1997:519.

131. Reeder LB, DeFilippi VJ, Ferguson MK. Current results of therapy for esophageal perforation. Am J Surg 1995; 169(6):615. 132. Port JL, Kent MS, Bacchetta M, et al. Thoracic esophageal perforations: A decade of experience. Ann Thorac Surg 2003; 75:1071.

123. Berkelhammer C, Madhav G, Lyons S, et al. Pinch injury during overtube placement in upper endoscopy. Gastrointest Endosc 1993; 39(2):186.

133. Wesdorp IC. Treatment of instrumental esophageal perforation. Gut 1984; 25(4):398.

124. Dennert B, Ramirez FC, Sanowski RA. A prospective evaluation of the endoscopic spectrum of overtube-related esophageal mucosal injury. Gastrointest Endosc 1997; 45(2):134.

134. Hine KR, Atkinson M. The diagnosis and management of perforations of esophagus and pharynx sustained during intubation of neoplastic esophageal strictures. Dig Dis Sci 1986; 31(6):571.

125. Molina EG. Conservative management of esophageal nontransmural tears after pneumatic dilation for achalasia. Am J Gastroenterol 1996; 91(1):15. 126. Lo AY, Surik B, Ghazi A. Nonoperative management of esophageal perforation secondary to balloon dilation. Surg Endosc 1993; 7(6):529. 127. Dolgin SR, Wykoff TW, Kumar NR, et al. Conservative medical management of traumatic pharyngoesophageal perforations. Ann Otol Rhinol Laryngol 1992; 101(3):209. 128. Sawyer R, Phillips C, Vakil N. Short- and long-term outcome of esophageal perforation. Gastrointest Endosc 1995; 41(2):130. This is an important report on the long-term outcome in patients who suffer endoscopically related esophageal perforation. A low mortality is related to early diagnosis and therapy. 129. El-Newihi HM, Mihas AA. Esophageal perforation as a complication of endoscopic overtube insertion (Letter). Am J Gastroenterol 1994; 89(6):953.

135. Wewalka FW, Clodi PH, Haidinger D. Endoscopic clipping of esophageal perforation after pneumatic dilation for achalasia. Endoscopy 1995; 27(8):608. 136. Weiman DS. Non-iatrogenic esophageal trauma. Ann Thorac Surg 1995; 59(4):845. 137. Moghissi K, Pender D. Instrumental perforations of the esophagus and their management. Thorax 1988; 43(8):642. 138. Pasricha P, Fleischer D, Kalloo A. Endoscopic perforations of the upper digestive tract: A review of their pathogenesis, prevention and management. Gastroenterology 1994; 106(3):787. A state-of-the-art review of all aspects of instrumental perforations of the esophagus and upper gastrointestinal tract. Important reading for all who perform endoscopy. 139. Stanley RB, Armstrong WB, Fetterman BL, et al. Management of external penetrating injuries into the hypopharyngeal-cervical funnel. J Trauma 1997; 42:675.

References

121. Tuebergen D, Rijcken E, Senninger N. Esophageal perforation as a complication of Endo Cinch endolumenal gastroplication. Endoscopy 2004; 36(7):663.

SECTION THREE MANAGEMENT OF ESOPHAGEAL DISORDERS

CHAPTER SEVENTEEN

17

Approach to the patient with esophageal cancer Brian C. Jacobson and Jacques Van Dam

INTRODUCTION Esophageal cancer (EC) is the eighth most frequent cancer worldwide, but ranks sixth in cancer mortality with more than 90% of cases resulting in death.1 Of the estimated 14 000 new cases of esophageal cancer in the United States each year,2 the vast majority are either squamous cell carcinoma (SCC) or adenocarcinoma (ADC), with occasional cases of endocrine tumors, carcinoid tumors, choriocarcinomas, small cell carcinoma, and metastatic cancers.3 The incidence of SCC has been declining gradually over the past few decades while that of ADC has been increasing steadily in both the United States and Europe.4,5 Men have a greater lifetime risk for developing EC, and incidence rises steadily with age.6 Black men in the United States have a nearly fivefold increased risk of SCC compared to non-Hispanic white men, while non-Hispanic white men have a fourfold increased risk for AC compared to black men.7 Squamous cell carcinoma has been strongly linked to chronic heavy alcohol and tobacco exposure6,8,9 while the majority of cases of AC are associated with Barrett’s esophagus and gastroesophageal reflux disease.10,11 Other risk factors for SCC include poverty;8,12 frequent consumption of salt-pickled or smoke-cured foods, sun-dried foods, and moldy foods;9 diets deficient in fruits and vegetables;9 regular consumption of extremely hot beverages;13–15 a history of esophageal stricture following caustic ingestion;16 achalasia;17 type A tylosis (diffuse palmoplantar keratoderma);18,19 prior radiation therapy to the chest;20 and a current or prior history of SCC of the upper aerodigestive tract.21,22 Increased body mass index, tobacco, and alcohol use appear to be independent risk factors for ADC8,23–26

DIAGNOSIS History, physical examination, and laboratory testing The majority of EC are diagnosed only after symptoms arise, with only a small percentage found in the setting of surveillance programs, such as for Barrett’s esophagus (see below).27 Patients with EC typically present with dysphagia when eating solid food. Unfortunately, this symptom, as well as a report of weight loss, is often indicative of advanced disease. Other symptoms may suggest invasion of surrounding structures, such as hoarseness from involvement of the recurrent laryngeal nerve, or cough and

pneumonia from a tracheoesophageal fistula. The physical examination is usually normal, but may reveal evidence of rapid weight loss and malnutrition, supraclavicular or axillary lymph node involvement, pleural effusion, and hepatomegaly. There are no laboratory tests specific for EC, although iron deficiency may be present if the tumor has resulted in chronic blood loss. Typically, there are no tumor markers used to diagnose EC, monitor therapy, or survey for early recurrence.

Barium esophagogram An esophagogram or ‘barium swallow’ performed to evaluate dysphagia may be the initial diagnostic study demonstrating EC. The esophagogram will define the location of the tumor, the degree and length of stenotic regions, and the presence of fistulae. Tumors may appear as a space-occupying lesion or an irregular stricture. Early lesions may appear as nodular regions or small ulcers.28

Endoscopy Esophagogastroduodenoscopy (EGD) remains the primary method for visualizing esophageal masses and for directing biopsies. Typically, EC will appear as a fungating mass or a stricture with nodularity and friable mucosa (Fig. 17.1). Occasionally, a highgrade malignant stricture will prevent passage of a standard endoscope. When available, an ultrathin endoscope with an insertion tube diameter of 5.3–6 mm may traverse the stricture and allow complete examination of the esophagus and stomach.29,30 In order to highlight pathology otherwise difficult to visualize by standard endoscopy, vital staining, or chromoendoscopy, can be used. This entails the application of a dye to the gastrointestinal mucosa, and the two most commonly used stains in the esophagus are iodine and methylene blue. Iodide solutions such as Lugol’s iodine stain the glycogen-rich prickle cell layer of the esophageal squamous epithelium. Dysplastic epithelium lacks the glycogen-rich granules present in this epithelial layer and therefore fails to stain.31 Iodine chromoendoscopy may detect early squamous cell carcinomas of the esophagus that might otherwise be undetected with standard endoscopy.32–35 Iodine chromoendoscopy may also be helpful in defining the extent of an esophageal SCC.32,36 During iodine chromoendoscopy patients may experience heartburn, tingling in the chest, or nausea and the technique should be avoided in patients with an allergy to iodine.37

Approach to the Patient with Esophageal Cancer

264

•

Fig. 17.1 (A) Fungating esophageal adenocarcinoma. A fungating adenocarcinoma can be seen arising from the wall of the esophagus. Barrett’s esophagus is demonstrated as well (asterisk). (B) This squamous cell carcinoma presented as a tight malignant stricture in the mid-esophagus.

A

B

Topically applied methylene blue stains mucin within goblet cells and is therefore useful in highlighting Barrett’s epithelium amid normal squamous cell-lined esophageal epithelium.38–40 As Barrett’s epithelium becomes dysplastic, there is a loss of goblet cells and a decreased uptake of dye, which results in highlighting poorly stained dysplastic regions amid more strongly staining nondysplastic mucosa. While methylene blue chromoendoscopy may be useful during Barrett’s esophagus surveillance, it has no established role in the diagnosis of adenocarcinoma.

be enrolled in a surveillance endoscopy program.16 Prospective studies of screening endoscopy have detected high-grade dysplasia or esophageal SCC among 5% of patients with a history of head and neck cancer21,22,53–57 and among 4% of patients with a history of chronic, excessive alcohol and tobacco use.35,58–60 It is not clear whether screening or surveillance among these high-risk populations provides a survival benefit61,62 or is cost-effective.63,64

Tissue acquisition

The best prognostic indicator for patients with EC is the extent, or stage, of disease at the time of diagnosis. Five-year survival is 50–80% for stage I EC, 10–40% for stage II EC, 10–15% for stage III EC, and 90%) than for T1 and T2 tumors (65%).72 However, the use of high-frequency

265

TNM Stage

Definition

T1m

Tumor confined to the mucosa, including the lamina propria

T1sm

Tumor invades the submucosa

T2

Tumor invades into, but not through, the muscularis propria

T3

Tumor extends through the muscularis propria into the adventitia

T4

Tumor invades adjacent structures

N0

No lymph node involvement

N1

Regional nodes involved

M0

No metastatic disease

M1a

Malignant celiac lymph nodes (in distal esophageal cancer) or cervical lymph nodes (in proximal esophageal cancer)

M1b

Distant metastases

Overall Stage I

T1 N0 M0

IIa

T2 or T3, N0

IIb

T1,T2, or T3, N1

III

T3 N1 or T4 N0 or T4 N1

IVa

M1a

IVb

M1b

Adapted from references 68 and 69.

(15–30 MHz) ultrasound catheter probes for staging T1 and T2 tumors improves the accuracy to 83–92%.73–75 Therefore, the T stage of superficial esophageal tumors should be determined using a high-frequency catheter probe whenever possible.

When examining lymph nodes by EUS, particular findings may predict malignant nodal involvement, including a hypoechoic echotexture, a sharply demarcated border, a rounded contour, and a size greater than 1 cm.76,77 While these individual findings are predictive, sensitivity exceeds 80% only when all four are present, although this occurs in the minority of cases.76,78,79 Fine needle aspiration (FNA) of nodes improves the accuracy of EUS for determining N stage and should be performed regularly as part of the staging EUS.79,80 One study demonstrated that three FNA passes were needed to ensure 100% sensitivity.81 A general caveat is to avoid traversal of the primary tumor by the FNA needle, which can result in a false-positive nodal aspirate. EUS for esophageal cancer staging should include an assessment of celiac axis lymph nodes as the spread of malignancy to these nodes is considered evidence of advanced disease and may impact management. However, a stricture that restricts passage of an echoendoscope is present in 29% of cases,82 and indicates a lesion with advanced T stage.83 Failure to traverse a malignant stricture results in significantly decreased accuracy for both T and N staging.83,84 When available, catheter ultrasound probes may be used to traverse the stricture and attempt complete T and N staging;74,85 however lower frequency probes (i.e., 12 MHz) should be used.86 A 7.5 MHz nonoptical, 7 mm, wire-guided esophagoprobe has also been used to complete staging in the setting of malignant strictures.82,87 Dilation of the stricture may permit passage of a standard echoendoscope. Savary-Gilliard and balloon dilators have been used with perforation rates ranging from 0% to 24%,83,88–90 but may not permit passage of the echoendoscope in all cases.84,88,89 Residual inflammation and fibrosis after chemotherapy and radiation therapy makes EUS too inaccurate to be recommended as a tool for post-therapy restaging.91–95

Positron emission tomography Positron emission tomography (PET) with fluoro-deoxy-glucose (FDG) adds little to the T staging of tumors, but may be accurate

•

A

B

C

D

(A) EUS image of a T1 esophageal Fig. 17.2 cancer. A mass is seen extending into the hyperechoic submucosa (SM) at the region indicated by the asterisk.The hypoechoic muscularis propria (MP) is not involved. (B) EUS image of a T2 esophageal cancer. A mass replaces the entire circumference of the esophageal wall, obliterating distinctions between mucosa, submucosa, and muscularis propria. However, the confines of the adventitia remain as a bright line surrounding the cancer. (C) EUS image of a T3 esophageal cancer. A mass can be seen extending through the esophageal wall into the surrounding adventitia (asterisk). Malignant lymph nodes are also seen (N). (D) EUS image of a T4 esophageal cancer. There is loss of the interface between the esophagus and the aorta indicating invasion.

Staging

Table 17.1 TNM staging of esophageal cancer

Approach to the Patient with Esophageal Cancer

266 in detecting malignant adenopathy and may be superior to conventional imaging for detecting occult metastases.96 PET scanning may also prove useful in monitoring response to therapy, but its role in this setting remains preliminary.

Detecting cancer recurrence Any patient presenting with signs or symptoms of local recurrence after resection of esophageal cancer should undergo endoscopy as part of their evaluation. In this setting, standard endoscopy can yield a diagnosis of recurrent disease in 40% of patients.97 However, recurrence is often extramucosal and therefore missed with standard endoscopy. EUS has been shown to detect cancer with a positive predictive value of 75–100%.97,98 While surveillance EUS after cancer resection may detect recurrent cancer, it remains unproven whether this practice has any impact on survival.98

THERAPY Treatment for EC is stage-specific and, in some cases, institutionspecific. Different modalities of treatment have been used, including surgery, radiotherapy (RT), chemotherapy, chemoradiotherapy (CRT), and endoscopic therapy. Cancer confined to the esophagus (T1/T2, N0) is generally treated with a primary resection. Cancer with extension through the esophageal wall (T3) or with regional lymph node involvement is usually treated with CRT and subsequent resection when possible. Metastatic disease is treated with palliative measures.

Surgery Surgery remains the gold standard of treatment for esophageal cancers. The rationale for surgical resection is the potential removal of all neoplastic tissue, including any and all involved lymph nodes. Because EC tends to spread along submucosal planes, limited longitudinal resections are not as effective as more extensive resections. The proximal extent of resection should extend at least 10 cm above macroscopically visible tumor, and the distal margin should be at least 5 cm below the tumor.70 Radial margins are dictated by the location, with tumors at the esophagogastric junction often requiring resection of portions of the diaphragm. One of two different procedures are typically performed.99 The transhiatal operation is done completely through the abdominal cavity without complete lymph node resection.100 The other operation involves an incision into both the chest and abdomen (transthoracic esophagecetomy with extended en-bloc lymphadenectomy) with better exposure, resulting in a more traditional ‘cancer operation.’ In this latter procedure, an esophagogastric anastomosis is created within the chest (the Ivor-Lewis technique) or within the neck (the three-field technique). The transthoracic esophagectomy is associated with greater morbidity (but not mortality), and does not conclusively prolong 5-year survival.101 Curative resections (no microscopic disease present at surgical margins) are possible in 54–69% of cases.6 Even with improved surgical technique and perioperative management, complication rates range 20–40% and operative mortality ranges 3–10%.102–104 Major complications commonly seen include infection, anastamotic leaks, and cardiopulmonary complications.

Whether surgery alone is sufficient for curative management of EC remains controversial. Obviously, a resection with positive margins or failure to remove involved lymph nodes is not sufficient. However, there may be a role for adjuvant or neoadjuvant therapy, especially in cases where a curative resection is not obtained (see below). For patients with tumors in the cervical esophagus, surgery is often deferred because of the likelihood of early spread to lymph nodes in the neck. However, in some institutions resection is attempted and includes an extensive neck dissection. The proper selection of patients for surgery should include accurate staging including CT and EUS to exclude patients with T4 or M1 disease. However, selection must also include a thorough preoperative assessment to limit perioperative mortality. This selection process usually includes a detailed medical history and physical examination and often involves consultation with cardiologists, pulmonologists, and anesthesiologists.

Radiation therapy No trials have randomized patients to radiation therapy (RT) alone versus surgery alone. Uncontrolled series of cases have been published in which patients with high operative risks received RT as their only therapy for SCC. A review of these series found no survival advantage of RT over surgery, but 5-year survival was only 6%.105 In addition, while primary RT avoids operative morbidity, it may still be associated with local complications such as stricture formation and tracheoesophageal fistulae. Studies have also examined whether preoperative RT provides benefit compared with surgery alone. A meta-analysis combined five randomized trials of preoperative RT versus surgery and included 1147 patients with a median follow-up of 9 years.106 This analysis found no significant survival advantage for RT in this setting. Currently, RT is more commonly used in combination with chemotherapy, either before surgery or for nonoperative candidates. In addition, patients with positive resection margins may receive postoperative RT. Radiation therapy has also been used as palliation for malignant dysphagia in nonoperative candidates, but may take several weeks before symptomatic improvement is realized.

Chemotherapy and chemoradiotherapy Chemotherapy alone is not generally used for curative intent. In patients with localized disease, combination chemoradiotherapy (CRT) using RT and cisplatin/fluorouracil-based regimens may lead to long-term survival in 14–26% of patients.107,108 A rigorous review of the literature found that CRT provides an absolute reduction in cancer mortality of 7% compared with RT alone, at least within the first 2 years of treatment.109 CRT is associated with significantly more toxicity than RT alone, and the possibility of toxicity should be considered in any treatment decision-making process. In the setting of proximal esophageal SCC, surgery is often difficult, and CRT has been shown to offer complete pathological response rates in excess of 20%.70 In this setting, CRT may be a reasonable option in lieu of surgery. In a long-term follow-up study of CRT without a surgical arm, persistent or local/regional recurrence failures accounted for the majority of deaths, suggesting that the addition of surgery might improve overall survival.107 However, it remains unclear whether the addition of CRT prior to or following a curative resection is

267

ROLE OF ENDOSCOPY IN TREATMENT Effective endoscopic methods are utilized for the treatment of early EC and for the palliation of advanced EC. Definitive treatment of early lesions is limited to those with superficial T1 lesions; i.e., tumors confined to the mucosa. In the United States, endoscopic resection or destruction of early cancer is generally reserved for poor operative candidates or those patients who refuse surgery. However, as more data are collected, endoscopic procedures may emerge as reasonable therapeutic options for more patients. As for palliation, endoscopic techniques are currently the primary means for managing malignant dysphagia and tracheoesophageal fistulae.71

Endoscopic mucosal resection Endoscopic mucosal resection (EMR) removes a region of mucosa, superficial submucosa, and occasionally deep submucosa. Four principal techniques are presently used for EMR of early cancer: (1) the inject and cut; (2) the inject, lift, and cut; (3) cap-assisted EMR (EMRC); and (4) EMR with ligation (EMRL).120 These methods typically involve the injection of saline into the

submucosa below the lesion to provide a cushion of fluid between the mucosa and the muscularis propria, which serves two purposes: (1) the cushion protects the muscularis propria from thermal injury as a relatively large region of mucosa is removed, and (2) lesions that fail to lift on a cushion of saline are more likely to involve the deeper submucosal layer (termed the ‘nonlifting sign’121), and therefore may not be appropriate for EMR. Once saline has been injected into the submucosa, the lesion is removed by snare excision alone (inject and cut), by being lifted through an open snare using a double-channel endoscope and a grasping forceps prior to snare excision (the inject, lift, and cut), by being aspirated into a variceal banding cap prior to application of a snare (EMRC), or by applying a variceal band ligator to the lesion prior to snare excision (EMRL). After EMR, a second immediate EMR of adjacent residual tumor is possible, and the addition of chromoendoscopy helps determine whether a second EMR is required by delineating tumor margins. The selection of patients for EMR requires EUS to confirm that the tumor is confined to the mucosa and to exclude the presence of suspicious lymph nodes. Lymph node involvement is rare (70%, often approaching 100%, while in the US resistance ranges from 25% to 50%.94–96 The mechanism of metronidazole resistance appears due to a point mutation(s) that prevents the reduction of the drug to its active metabolite.43 Metronidazole-resistant strains do not remove oxygen from the site of metronidazole reduction, thereby preventing antibiotic activation. Increasing the dose of metronidazole or giving the drug with bismuth can eradicate some resistant strains, suggesting that imidizole ‘resistance’ is not an absolute phenomenon. However, because of the widespread emergence of metronidazoleresistant strains, an effective nonmetronidazole-containing regimen such as PPI-AC should be the primary treatment of choice. Macrolide resistance is considerably less prevalent than imidizole resistance, ranging from 5% to 10% in most surveys, and it appears to affect all antibiotics in the drug class (erythromycin, clarithromycin, azithromycin, etc.).94–96 Its mechanism has been better characterized and involves point mutations within the conserved loop of the 23S strand of ribosomal RNA. Polymerase chain reaction (PCR) methods that detect these point

Treatment of H. Pylori Infection

renders this combination clinically ineffective. Treatment failure also can lead to emerging resistance to both antibiotics, which can complicate subsequent therapy. Because imidizole resistance among H. pylori even in the US is quite common and macrolide resistance so clinically relevant, it is best to avoid co-administration of metronidazole and clarithromycin except in patients who are penicillin sensitive. The combination of a PPI, amoxicillin, and clarithromycin (PPIAC) is the most popular and widely recommended treatment for H. pylori worldwide. A 7–14 day course of PPI-AC cures infection in approximately 85% of individuals, especially when using the higher 500 mg dose of clarithromycin.66,84–87 This level of treatment effectiveness is significantly superior to dual treatments and generally better than other PPI or bismuth-based triple therapies. While macrolide resistance does negatively impact treatment success with PPI-AC,66 imidizole resistance and rarely encountered penicillin resistance do not significantly influence treatment. When azithromycin is used in place of clarithromycin, success of treatment is less consistent. A higher dose of clarithromycin (500 mg) and longer treatment (10–14 days) seem to increase cure rate. However, outside the US, to reduce cost and improve compliance, 7-day treatment with 250 mg clarithromycin is common and generally successful. Shorter course PPI-AC treatment is less often used in the US, but based on comparative studies, the FDA recently approved a 1-week H. pylori treatment in patients with ulcer disease (rabeprazole 20 mg, amoxicillin 1g, and clarithromycin 500 mg all twice daily). Other FDA-approved combinations and durations of treatment of H. pylori infection in the setting of ulcer disease include amoxicillin (1 g twice daily), clarithromycin (500 mg twice daily) along with lansoprazole (30 mg twice daily for 10 or 14 days), omeprazole (20 mg twice daily for 10 days), or esomeprazole (40 mg once daily for 10 days). Extensive international experience with pantoprazole, amoxicillin, and clarithromycin supports the efficacy of this combination as well, although this specific regimen is not currently approved by the FDA. Lansoprazole-AC is marketed as Prevpac™, a compliance packaging containing each day’s component medication in 14 individual blister packs. Side effects with a PPI-AC regimen are generally those associated with the individual components previously described, usually mild, less common than with PPI-CM or BMT, and rarely require discontinuing treatment. Because the clarithromycin component of PPI-based treatments is expensive, other antibiotics have been substituted to decrease cost. Omeprazole 20 mg, amoxicillin 1 g, and metronidazole 500 mg each dosed twice daily for two weeks (OAM) is one such less expensive regimen that is particularly popular in the United Kingdom. The efficacy of PPI-AM ranges between 70% and 90%, but can be considerably less when treating metronidazole-resistant organisms.88 A shorter duration of therapy (1 week) results in less consistent cure of infection. Despite its lower cost, PPI-AM is not recommended for primary H. pylori treatment because imidizole resistance significantly affects treatment success and because more effective regimens are available.

Treatment of Helicobacter pylori Infection

284 mutations can identify macrolide resistant strains of H. pylori in gastric juice and biopsies, but such methods are not clinically available at this time.97 Unlike resistance to metronidazole, which can be ‘overcome’ in some instances by administering a higher dose of medication, macrolide resistance is permanent and negatively impacts treatment, even when the dose of antibiotic is increased. In fact, primary macrolide resistance is likely a major cause of treatment failure with clarithromycin-containing threedrug regimens.66,93 Following initial treatment failure with dualor triple-drug clarithromycin-containing regimens, secondary macrolide resistance commonly develops. To minimize emergence of secondary resistance, macrolides should not be used alone or in dual therapies. Moreover, it is best to avoid using clarithromycin and metronidazole together since treatment failure would likely result in dual antibiotic resistance, a situation which would complicate subsequent treatment. To date, H. pylori resistance to amoxicillin and tetracycline has not been a clinical problem. In fact, resistance to these antibiotics is so uncommon that most laboratories do not routinely perform sensitivity testing. Quinilone resistance is more common and may increase as quinilones are used more frequently in re-treatment or rescue regimens. A recent analysis evaluated H. pylori resistance rates to the commonly used antibiotics (Fig. 18.7) and patient demographic characteristics associated with antibiotic resistance.94

Recurrence and re-treatment of H. pylori infection If successfully treated, adults rarely become reinfected with H. pylori. Even in regions of the world where the prevalence of infection is high, recurrence is generally 60% of cases, quadruple therapy is cumbersome to take, and its success is influenced by imidizole resistance, although the higher 500 mg dose of metronidazole appears to overwhelm resistant bacteria. The metronidazole dose contained in Helidac™ is only 250 mg so when using this packaged combination, additional medication must be prescribed to ensure sufficient metronidazole, especially during re-treatment. In areas of the world where it is available, furazolidone 100 mg can be substituted for metronidazole in quadruple therapy as another means to counteract antibiotic resistance.102 Other simpler, but more expensive re-treatment regimens are being used especially outside the US, but experience with these newer regimens is limited. One promising regimen includes PPI, amoxicillin 1 g, and levafloxicin 250 mg b.i.d. for 10–14 days.103 Optimistic reports suggest >80% success in curing persistent H. pylori. Another suggested re-treatment regimen consists of a PPI, rifabutin 150 mg, and amoxicillin 1 g twice daily for 10–14 days. This ‘rescue’ therapy reportedly eliminates infection in >80% of patients failing one or two courses of more traditional treatments.104

FUTURE TREATMENTS FOR H. PYLORI Host immune responses to H. pylori not only cause tissue injury, but are also central to any vaccination strategy. Since the organism can survive the immune response to natural infection, the development of an effective vaccine faces significant challenges. However, preliminary studies suggest that immunization with crude bacterial extracts and recombinant subunits of the bacterial enzymes urease and catalase can protect animals from H. pylori exposure.105,106 Efforts are also underway to develop a therapeutic vaccine intended to augment the natural immune response to infection.107,108 A therapeutic vaccine could promote spontaneous clearance of infection and/or improve the efficacy of antibiotic regimens. An effective therapeutic vaccine could also obviate the widespread use of antibiotics and reduce the emergence of antibiotic-resistant organisms. While preliminary results of human testing of a urease antigen and inactivated whole-cell

285

Recommendations regarding management of H. pylori Working parties from the US,37 Europe,36,112 and the Asian Pacific region38 have each developed guidelines intended to assist physicians within their respective localities to appropriately manage H. pylori infection. Specific management recommendations are based on factors such as community prevalence and seriousness of H. pylori-related disease and the likelihood of altering its clinical course with treatment.

United States guidelines for management of H. pylori infection37 The most recent US guidelines propose testing for H. pylori infection only if subsequent treatment is planned. Appropriate indications for testing and treatment include patients with present or past uncomplicated or complicated gastric or duodenal ulcer, those with gastric MALT lymphoma, or following resection of early gastric cancer. A decision to test a patient with functional or uninvestigated dyspepsia should be made on a case-by-case basis. The guidelines specifically emphasize the lack of data sufficient to recommend routine testing of asymptomatic individuals or those receiving chronic PPI therapy (the latter is a suggestion of the European working group). Diagnostic tests should be tailored to the clinical situation. When endoscopy is not clinically necessary, either serology or a urea breath test is a suitable test. If endoscopy is indicated for patient care, then it is appropriate to obtain a biopsy for diagnosis, but routine culture is not recommended. A PPI or RBC, clarithromycin and amoxicillin or metronidazole or PPI, bismuth, metronidazole and tetracycline given for 2 weeks are recommended therapies. Confirming the cure of infection is suggested for those with complicated ulcer disease, MALT lymphoma, or recurrent symptoms. These guidelines were established in 1997, and while they remain generally applicable, several modifications and additions may be appropriate. For example, serology is now known to be less accurate when the prevalence of H. pylori infection is low, a situation common to many regions of the US.30 Therefore, if serology is used to screen for H. pylori infection, a positive serology test result should be confirmed by a more accurate breath or stool test before initiating treatment.113 With the widespread availability of these accurate noninvasive tests, it is now also appropriate to document cure of infection in everyone at least 4 weeks following treatment.114 Initial treatment should be for 10–14 days with a PPI, clarithromycin, and amoxicillin unless the patient is allergic or intolerant of one of the medications. Bismuth-based treatments are now considered second-line therapy. The indications for testing remain well founded, but should be expanded to include other situations. Given the recent information about H. pylori and genetic susceptibility to gastric

cancer, it is not unreasonable to test individuals, even those with no symptoms, who have first-degree relatives with gastric adenocarcinoma or those of Japanese descent.115 Recent data question the benefit of H. pylori testing in patients with dyspepsia, especially in regions where the prevalence of infection and serious infection-associated diseases are low.116

International management of H. pylori infection consensus and disagreement Similarities between the European36,112 and US guidelines37 include the treatment of individuals with active or past ulcer disease, MALT lymphoma, or early gastric cancer. Differences include recommended testing of patients with evidence of severe endoscopic or atrophic gastritis and those prescribed long-term PPIs for gastroesophageal reflux disease. Further variations, although not strongly evidence based, include testing young otherwise healthy patients with uninvestigated dyspepsia, persons with functional dyspepsia, those with a family history of gastric cancer, or individuals initiating NSAID therapy. The development of Asian Pacific recommendations poses a challenge since they need to be applicable in localities with diverse rates of H. pylori infection and associated diseases.38 In harmony with other regional guidelines, testing those with active or past ulcer disease, MALT lymphoma, and early gastric cancer is suggested. The Asian Pacific working group asserts that asymptomatic individuals, those receiving NSAIDs or those solely with a family history of gastric cancer do not need to be routinely tested for H. pylori. They also suggest that young healthy individuals with dyspeptic complaints can be initially tested noninvasively for H. pylori, but should symptoms not improve, such individuals should have prompt endoscopy because of the high prevalence of gastric cancer in Asian countries. Diagnosis and treatment recommendations from both Europe and Asian Pacific region support endoscopic diagnosis of H. pylori, since ulcer and gastric cancer, which are more prevalent than in the US, need to be excluded. When noninvasive testing is used, a breath test is preferred to serology. As in the US, the treatment regimen of choice in Europe and the Asian Pacific region is a PPI with amoxicillin, and clarithromycin; however, a 7-day course of treatment has been deemed sufficient.

PERSONAL RECOMMENDATIONS FOR H. PYLORI MANAGEMENT Testing for H. pylori is appropriate in any patient with an active or past history of duodenal ulcer irrespective of NSAID use (Fig. 18.8). Those with MALT lymphoma, or early gastric cancer, both rare conditions in the US, are also candidates for testing. Although not supported by evidence, individuals at higher risk for gastric cancer, such as those of Japanese descent or with a first-degree relative with gastric cancer, should be tested. H. pylori in those with uninvestigated or functional dyspepsia, especially if symptoms are unresponsive to empiric acid suppressive treatments, should be approached on a case-by-case basis, but in practice testing for infection is inevitable. Routine testing of patients with GERD, asymptomatic users of aspirin or NSAIDs, or other asymptomatic individuals is not warranted. Non-invasive testing for H. pylori is the most cost-effective approach. Preferred tests are a urea breath or stool test, but if serology is used, a positive result should be confirmed by another

Personal Recommendations for H. Pylori Management

vaccines using heat-labile enterotoxin of E. coli as an adjuvant have been reported,109,110 it is unlikely that an effective, safe vaccine will be available for clinical use in the near future. Now that the H. pylori genome has been sequenced, scientists can identify ‘pylori-specific’ metabolic mechanisms to target with therapeutic pharmaceuticals. Such a strategy offers the opportunity to eradicate H. pylori, while sparing other endogenous organisms. A number of possible candidates for specific targeting are being investigated.111


286 Indications for testing for H. pylori: declining strength of evidence Uninvestigated dyspepsia Functional dyspepsia First beginning HSAIDs Family history of gastric cancer

Active or past ulcer MALT lymphoma Early gastric cancer

Endoscopy not clinically indicated

•

Fig. 18.8 Current recommendations for H. pylori management.

Chronic PPI treatment Atrophic gastritis

Endoscopy clinically indicated

HP stool antigen test or Urea breath test Serology only if HP prevalence high

Biopsy urease test or histology Culture not routinely indicated

Test for HP cure with stool or breath test

PPI amoxicillin clarithromycin PPI metronidizole clarithromycin if allergic to penicillin

Rescue therapies

Retreatment based on initial treatment that failed

Alternative rescue therapy

PPI amoxicillin and levofloxacin or PPI amoxicillin and rifabutin

Bismuth based quadruple therapy or PPI amoxicillin metronidizole or PPI amoxicillin

Bismuth based quadruple therapy with furazolidone

method before starting treatment. Endoscopic testing (i.e., urease test or histology) is appropriate when a procedure is indicated for clinical reasons, but bacterial culture is rarely necessary. All patients should be retested at least 4–6 weeks after treatment to confirm cure. The treatment of choice is a PPI with amoxicillin and clarithromycin each twice daily for 10–14 days. Metronidazole should be substituted for amoxicillin only if the patient is allergic to penicillin. If initial treatment fails, re-treatment with 14 days of bismuth-based quadruple therapy with high-dose metronidazole (500 mg) is the next best option. ‘Rescue therapy’ is reserved for third or fourth treatment courses. Experience is limited with rescue regimens, but the author favors the PPI, amoxicillin, levofloxacin combination in the rare patient who fails courses of more conventional therapies.

SUMMARY Infection with Helicobacter pylori is common worldwide, but in many countries such as the United States its incidence is declining. Accompanying this decline is a reduction in associated clinical conditions such as ulcer disease and gastric cancer. Several general principles underlie the management of H. pylori. Test and treat only those most likely to benefit. Use a diagnostic test that is accurate, cost-effective, and provides necessary clinical information. Choose an effective, simple, well-tolerated treatment regimen that is less likely influenced by the presence of antibiotic-resistant organisms. Treatment duration and drug dosage should be sufficient to guarantee maximal efficacy since the ‘true costs’ of managing H. pylori are related to the consequences of failed eradication rather than to direct expense of medication (Table 18.1). Given

Table 18.1 FDA-approved regimens for treatment of H. pylori in patients with ulcer disease Regimen

Comment

PPI amoxicillin 1 g clarithromycin 500 mg twice daily for 7–14 days

Treatment regimen of choice

PPI clarithromycin 500 mg twice daily for 14 days

Not recommended

PPI amoxicillin 1 g three times daily for 14 days

Not first-line, but may be useful as re-treatment

Bismuth 2 tabs metronidazole 250 mg tetracycline 500 mg four times daily for 14 days with acid suppressing medication

Not first-line – appropriate for re-treatment but if used need 500 mg metronidazole

RBC twice and clarithromycin 500 mg three times daily for 14 days

RBC not available in the US

287

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109. Michetti P, Kreiss C, Kotloff KL, et al. Oral immunization with urease and Escherichia coli heat-labile enterotoxin is safe and immunogenic in Helicobacter pylori-infected adults. Gastroenterology 1999; 116:804–812.

114. Fendrick AM, Chey WD, Margaret N, et al. Symptom status and the desire for Helicobacter pylori confirmatory testing after eradication therapy in patients with peptic ulcer disease. Am J Med 1999;1 07:133–136.

110. Kotloff KL, Sztein MB, Wasserman SS, et al. Safety and immunogenicity of oral inactivated whole-cell Helicobacter pylori vaccine with adjuvant among volunteers with or without subclinical infection. Infect Immun 2001; 69:3581–3590.

115. Parsonnet J, Harris RA, Hack HM, et al. Modelling costeffectiveness of Helicobacter pylori screening to prevent gastric cancer: a mandate for clinical trials. Lancet 1996; 348:150–154.

111. Chalker AF, Minehart HW, Hughes NJ, et al. Systematic identification of selective essential genes in Helicobacter pylori by genome prioritization and allelic replacement mutagenesis. J. Bacteriol 2001; 183:1259–1268.

116. Ladabaum U, Chey WD, Scheiman JM, et al. Reappraisal of noninvasive management strategies for uninvestigated dyspepsia: a cost-minimization analysis. Aliment Pharmacol Ther 2002; 16:1491–1501.

SECTION FOUR MANAGEMENT OF GASTRODUODENAL DISORDERS

19

CHAPTER NINETEEN Therapy and prevention of NSAID-related gastrointestinal disorders Jaime Oviedo and M. Michael Wolfe

INTRODUCTION History More than a century has passed since Felix Hoffman, at the suggestion of Hermann Dreser, the chief pharmacologist at Bayer Corporation, synthesized acetylsalicylic acid as the first nonsteroidal antiinflammatory drug (NSAID).1,2 The compound was named ‘aspirin,’3 and it later proved to be a convenient method for the delivery of salicylic acid to treat rheumatic diseases, pain, and fever.2 The first reports providing endoscopic evidence that aspirin carried the potential to induce gastric mucosal damage in humans date to 1938.4 Since that time, numerous reports have corroborated these findings,5–9 and the subsequent introduction of many potent agents with even greater toxicity, such as indomethacin, phenylbutazone, and piroxicam, led to an increase in the occurrence of NSAID-induced gastroduodenal injury and provided the motivation for the development of effective NSAIDs with a more favorable safety profile. Starting in the early 1970s, numerous new NSAIDs were developed that were purportedly free of gastrointestinal (GI) toxicity. However, because few, if any, of these agents are entirely innocuous, newer compounds were developed to improve the safety profile of NSAIDs while maintaining their antiinflammatory and analgesic properties.

NSAIDS and gastrointestinal toxicity: epidemiology and scope of the problem NSAIDs are one of the most commonly used medications worldwide. In the United States alone, more than 70 million NSAID prescriptions and 30 billion over-the-counter preparations are sold every year.10 Although NSAIDs are generally well tolerated, adverse GI events occur in a small, but significant, percentage of patients, resulting in substantial morbidity and mortality. Adverse effects from NSAIDs range from dyspepsia to serious GI complications that may lead to hospitalization and considerable use of resources. The prevalence of dyspepsia while taking NSAIDs may be as high as 50% in some series,11,12 depending on variations in the terminology used to report GI symptoms. In a recent meta-analysis using a strict definition based on epigastric pain-related symptoms, NSAIDs increased the risk of dyspepsia by 36%.13 Nearly 15% of patients with rheumatoid arthritis (RA) will choose to discontinue NSAID therapy as a result of dyspepsia and other GI symptoms.13

The risk of serious GI complications in patients with RA and osteoarthritis (OA) taking NSAIDs has been estimated at 13 and 7.3 per 1000 patients per year, respectively.14 The risk of NSAIDinduced ulceration and complications is dose-related and increases with age, the concomitant use of corticosteroids or anticoagulants, higher doses of NSAIDs, including the use of more than one NSAID, and a history of prior ulcer disease or serious systemic disorders.10,15–17 The mortality rate attributed to NSAID-related GI toxicity is 0.22% per year, with an annual relative risk of 4.21, compared with the risk for persons not using NSAIDs.17 NSAIDs are used regularly by at least 13 million people with arthritides in the US, with a world market for NSAIDs rapidly growing from US$6 billion per year in the mid-1990s,1 to US$10 billion in 2000.18 The annual direct costs of managing NSAID-related GI complications exceeds US$2 billion.19

PATHOGENESIS OF NSAID-INDUCED GI TOXICITY More than 90% of gastroduodenal ulcers are associated with the use of NSAIDs or with chronic infection with the bacterium Helicobacter pylori (H. pylori). NSAID-related gastrointestinal damage is, however, not limited to the stomach and duodenum, as these agents are capable of causing injury throughout the length of the GI tract.20,21 Although NSAID-induced esophageal injury has been reported infrequently, some reports have described pill esophagitis and ulceration associated with the ingestion of these acidic compounds.22–24 An association between aspirin and NSAID use (including over-the-counter NSAIDs and low-dose aspirin) and esophageal strictures, specially in older individuals, has also been reported.25 Finally, NSAIDs have been shown to produce a so-called enterocolopathy, which is characterized by a protein- and blood-losing enteropathy, colonic injury resembling inflammatory bowel disease, and the development of small intestinal ulcers, diaphragms, and strictures (Table 19.1).26–28 This chapter will focus on injury to the upper GI tract. Damage to the gastroduodenal mucosa occurs as a result of both the topical and systemic effects of NSAIDs.10 Mucosal injury is initiated topically by the acidic properties of aspirin and many other NSAIDs. In addition, topical mucosal injury may occur as a result of indirect mechanisms mediated through the biliary excretion and subsequent duodenogastric reflux of active NSAID metabolites.29 Although topical injury caused by NSAIDs contributes to the development of gastroduodenal mucosal injury, the systemic effects

Therapy and Prevention of NSAID-related Gastrointestinal Disorders

292 Table 19.1 Adverse effects of aspirin and NSAIDs on the gastrointestinal tract Esophagus Pill esophagitis/ulceration Esophageal strictures Stomach and duodenum Gastroduodenal ulcers Small bowel Protein/blood-losing enteropathy Ulcerations Diaphragm Strictures Colon Colitis Colonic perforation Colonic ulcers/bleeding Diaphragm-like strictures ? Inflammatory bowel disease (onset and reactivation) ? Development of collagenous colitis

of these agents appear to play the dominant role.1 For example, gastroduodenal ulcers occur with equal frequency using entericcoated NSAID preparations and cutaneous gels, and following rectal and parenteral administration of these agents.26–30 These systemic effects are largely the result of the inhibition of endogenous prostaglandin (PG) synthesis, although decreased production of other factors such as nitric oxide (NO), trefoil peptides, and calcitonin gene-related peptide may also be involved. While the entire process by which a reduction in mucosal PG synthesis generates mucosal injury has not been fully elucidated, PGs play a major role by stimulating several local components of the normal defensive properties inherent to the gastroduodenal mucosa (Table 19.2).23,31 PGs also inhibit acid secretion by reducing the generation of cyclic AMP by the gastric parietal cell.32 Prostaglandins are derived from arachidonic acid, which originates from cell membrane phospholipids through the action of phospholipase A2. The metabolism of arachidonic acid to

prostaglandins and leukotrienes is catalyzed by the cyclooxygenase (COX) pathway and the 5-lipoxygenase (LOX) pathway, respectively (Fig. 19.1).1,19,29 Two related but unique isoforms of COX, designated COX-1 and COX-2, have been demonstrated in mammalian cells.33,34 Despite their structural similarities, each is encoded by distinct genes that differ with regard to their distribution and expression in tissues; the COX-1 gene is primarily expressed constitutively, while the COX-2 gene is inducible.10 COX-1 appears to function as a ‘housekeeping’ enzyme in most tissues, including the gastric mucosa, the kidneys, and platelets, whereas the expression of COX-2 can be induced by inflammatory stimuli and mitogens in many different types of tissue, including macrophages and synovial cells.35 It has thus been suggested that the antiinflammatory properties of NSAIDs are mediated through the inhibition of COX-2, whereas adverse effects, such as gastroduodenal ulceration, occur as a result of effects on the constitutively expressed COX-1 (Fig. 19.2).33,35 The discovery of the two COX isoforms led to the development of COX-2-specific inhibitors, drugs that maintain their antiinflammatory properties while preserving the biosynthesis of protective prostaglandins. Standard NSAIDs differ in their relative inhibitory potency against COX-1 and COX-2, ranging from high selectivity ratios favoring COX-1 inhibition to nearly equivalent suppression of both isoforms (Fig. 19.3). The important role of COX-1 in protecting the gastroduodenal mucosa is supported by studies showing that the greatest degree of damage to the gastroduodenal mucosa is generally caused by NSAIDs that preferentially inhibit COX-1, such as naproxen, piroxicam, sulindac, and indomethacin.36

RISK FACTORS FOR NSAID-RELATED UPPER GI CLINICAL EVENTS Because dyspeptic symptoms are not a reliable warning sign for the development of serious NSAID-related mucosal injury, it is crucial to identify patients who are at increased risk of developing serious GI events associated with NSAID therapy.10 Several factors have been reported to significantly increase the risk of developing NSAID-associated GI events (Table 19.3). Important clinical

Phospholipids Phospholipase A2 Arachidonic acid

Table 19.2 Mucosal protective properties inherent to the gastroduodenal mucosa

Cyclooxygenase (COX-1 and COX-2)

Lipooxygenase

Cyclic endoperoxides

5-HPETE

Pre-epithelial Enhancement of mucus secretion Increase in bicarbonate ion secretion

Prostacyclin

Thromboxane A2

Leukotrienes

Epithelial Increase in mucosal blood flow Prostaglandins

Enhancement of intercellular tight junctions Decrease in transmembrane H+ ion permeation Subepithelial Increase in rate of cell restitution, i.e., epithelial cell renewal

•

Fig. 19.1 Biosynthesis of prostaglandins and leukotrienes via the cyclooxygenase and lipoxygenase pathways, respectively.The immediate precursor, arachidonic acid, is derived from membrane phospholipids.

293

COX-1 Housekeeping gene (constitutive)

-

COX-2 Inflammatory gene (inductable)

Proven Age (older than 60 years)

-

History of ulcer or GI complications Concomitant anticoagulation therapy Concomitant corticosteroid use

Corticosteroids

NSAIDs

High dose of NSAID or use of more than one NSAID Serious systemic disorder Duration and severity of arthritis

Gastric function Vascular homeostasis Renal function

Possible Concomitant infection with Helicobacter pylori

Mitogenesis/growth Female reproduction

Cigarette smoking Ethanol abuse

•

Fig. 19.2 Depiction of the two cyclooxygenase (COX) isoenzymes that catalyze the synthesis of tissue prostaglandins from arachidonic acid. COX-1 is expressed constitutively and maintains normal homeostasis, including gastric mucosal defense. In contrast, COX-2, the inflammatory gene, is inducible. Although both pathways can be variably inhibited by different nonsteroidal antiinflammatory drugs (NSAIDs), only the COX-2 gene contains a corticosteroid-responsive repressor element in its promoter.

Aspirin

3.12

Naproxen

1.79

Indomethacin

1.78

Ibuprofen

1.69

Nabumetone

0.64

Etodolac

0.11

Celecoxib

0.11

Meloxicam

0.09

Rofecoxib

0.05 0.00

0.50

1.00

1.50

2.00

2..50

3..00

3.50

Ratio – IC50 for COX-2 to IC50 for COX-1

•

Fig. 19.3 Selectivity of COX-2 inhibitors. Comparison of in vivo concentration (IC50) ratios (COX-2: COX-1) of selective and nonselective NSAIDs. A lower ratio indicates increased selectivity for COX-2. (Adapted from Feldman M, McMahon AT. Do cyclooxygenase-2 inhibitors provide benefits similar to those of traditional NSAIDs, with less gastrointestinal toxicity? Ann Intern Med 2000; 132:134–143; with permission.)

factors that are validated in multiple studies include increasing age, history of ulcer or GI complications, concomitant anticoagulation therapy, concomitant corticosteroid use, and high-dose NSAID use.10,37 Advanced age has consistently been found to represent one of the primary risk factors for GI events.10,37 The likelihood of serious events appears to increase in linear fashion, with no significant increase in ulcer bleeding reported among patients aged 35–49

and a 2.9-fold increase in patients aged 50–64 years.38 Furthermore, mortality due to upper GI hemorrhage, the most common ulcer complication associated with NSAID use, increases logarithmically with age.39 While advanced age represents a definite risk, gender-related differences probably do not,15 and previous suggestions to the contrary likely reflect an increased use of NSAIDs by women.23,40 A prior history of gastroduodenal ulcer or GI events may be the most important risk factor for future events.23,37 A meta-analysis of 10 case-control studies reported an OR of 4.8 (95% CI, 4.1–5.6) for patients with a prior history of a GI event.41 In addition, a history of ulcer or ulcer complications increases the risk of future GI events in all patients, regardless of their NSAID use.37 Concomitant use of oral anticoagulants has been reported to increase the risk of hospitalization for bleeding ulcers in NSAID users >65 years old 12.7 times (95% CI, 6.3–25), while the risk in NSAID users not receiving anticoagulants was 4.0 (95% CI, 3.4–4.8).42,43 Although corticosteroid use alone does not appear to increase the risk of ulcer or ulcer complications,44 the concomitant use of a corticosteroid and NSAIDs increases the risk of GI events by 10-fold.16 A meta-analysis of three studies reported an OR for upper GI bleeding of 1.8 (95% CI, 1.2–2.8) for steroid use compared with no steroid use in NSAID users.15 Several studies have documented that the risk of upper GI complications increases proportionally to the NSAID dose employed.45–47 The magnitude of the relative risk varies among the different studies, but increases consistently in a linear fashion. While several epidemiological studies have suggested that the risk of GI complications is highest in the first month of NSAID use,37,48 and that adaptation occurs with time,41 other studies indicate that the risk of NSAID-associated GI hemorrhage remains constant or increases steadily over an extended period of observation.49,50 Therefore, elderly patients who might require high-dose NSAID therapy for a short period or those who might use them intermittently appear to be at highest risk. Other less well-validated risk factors for the occurrence of NSAID-related upper GI injury include: systemic comorbidities, disability and severity of RA, H. pylori infection, type of NSAID use, and presence of dyspepsia. Although supporting data are limited, the presence of concurrent illnesses, such as heart disease,

Risk Factors for NSAID-Related Upper GI Clinical Events

Table 19.3 Risk factors for development of NSAIDassociated mucosal injury

Arachidonic acid

Therapy and Prevention of NSAID-related Gastrointestinal Disorders

294 appears to increase the risk of developing NSAID-associated GI events. Furthermore, the presence of comorbidities in patients who develop complications such as GI bleeding will significantly increase the risk of death due to the complication.51 A multivariate analysis of the MUCOSA trial suggested a modest increase of GI events in NSAID users with heart disease (OR 1.8; 95% CI, 1.1–3.2),17 but apparently not with other comorbid conditions.37,52 In a different report, both heart failure and diabetes were found to increase the likelihood of ulcer bleeding in NSAID users.53 However, a recent multivariate analysis of the Vioxx Gastrointestinal Outcomes Research (VIGOR) study found no evidence of an increased risk of NSAID-related GI complications in patients with heart disease.43 Although not consistently identified as predictors of GI events, severity of disability and duration of RA has been found to represent significant risk factors in several multivariate analyses.43,45,52

Helicobacter pylori Helicobacter pylori and NSAIDs are both recognized risk factors for the development of ulcer disease, but whether a synergistic relationship between the presence of this organism and NSAID use plays a role in the development of ulcers or ulcer complications is controversial. Most,54–57 but not all,58,59 studies have found these two risk factors to be independent. For example, Chan et al.59 treated H. pylori-infected patients with naproxen with or without H. pylori eradication therapy for 8 weeks. The study found that individuals treated for H. pylori before they began taking naproxen had significantly fewer ulcers (7%) than patients who were given naproxen only (26%). Although the authors concluded that the eradication of H. pylori reduces the occurrence of NSAID-induced ulcers, antimicrobial therapy used in this study included the use of a bismuth compound, which possesses ulcerhealing properties independent of its effects on the bacterium.60 Other case-control studies have been performed to assess the interaction of H. pylori and NSAID use in ulcer bleeding. Although Aalykke et al. reported a borderline significant increase in H. pylori infection among NSAID users with ulcer bleeding (OR, 1.8; 95% CI, 1.0–3.2),61 other studies do not show a significant increase in bleeding with H. pylori infection,62–65 and some studies suggest a possible protective effect of H. pylori in ulcer bleeding, especially gastric ulcer bleeding.62,64,65 In conclusion, most studies do not support the contention that H. pylori infection increases the risk of ulcer formation in individuals receiving NSAIDs. Because both NSAID use and H. pylori infection are independent risk factors for ulcer disease, they should be removed when possible in individual patients.37

Risk with individual NSAIDs While all NSAIDs currently in use possess the capacity to induce GI mucosal injury, the relative risk varies among the various preparations. These differences may be due to several factors, including variations in relative potency for inhibiting prostaglandin synthesis, duration of action, systemic absorption, drug solubility in gastric juices, and pH-dependent partition in the gastroduodenal mucosa.23 Several studies have reported the greatest risk of complications with piroxicam15,27,46 and ketorolac,66 and relatively low risk with the use of ibuprofen. Griffin et al.47 reported relative risks for ulcer formation with several NSAIDs ranging

from a low of 2.3 for ibuprofen to a high of 8.7 for meclofenamate. A meta-analysis by Gabriel et al.15 and a case control study by Henry et al.27 found the greatest risk of complications with piroxicam, with progressively lower risk ratios for indomethacin, aspirin, naproxen, and ibuprofen. A study by Garcia-Rodriguez and Jick46 also found piroxicam to carry the greatest relative risk for developing hemorrhage or perforation. In their study, however, the NSAID with the least likelihood of precipitating an ulcer complication, ibuprofen, still carried a relative risk of 2.9 (Table 19.4).46 Of those nonselective NSAIDs commonly used, ibuprofen appears to carry the lowest risk of developing gastroduodenal ulcers,67 and low-dose ibuprofen preparations available without prescription in the US are associated with a relative risk of ulcer complications that approaches placebo rates. Other potential, but unproven, risk factors for NSAID-induced ulcers include smoking and alcohol use. Smoking is an established risk factor in gastroduodenal ulceration and is associated with delayed ulcer healing, but whether smoking (or ethanol) increases this risk in NSAID users is unknown. Nevertheless, owing to other health benefits, cigarette smoking and excessive consumption of ethanol should be discouraged in individuals taking NSAIDs.

Dyspepsia Although at least 20% of patients who are receiving long-term therapy with aspirin or NSAIDs for arthritis or coronary prophylaxis experience dyspepsia during the course of treatment, dyspeptic symptoms do not predict the presence of gastroduodenal mucosal injury.10,11,23,68,69 As many as 50% of patients with NSAID-related dyspepsia may have a normal-appearing gastroduodenal mucosa on endoscopy,10 and conversely, nearly 60% of individuals hospitalized for NSAID-related GI hemorrhage,70 and up to 70% of patients with arthritis and NSAID-related ulcers report no preceding symptoms.11 High doses of any NSAID, as well as any dose of indomethacin, meclofenamate, or piroxicam, increase the risk of dyspepsia by about 3-fold.71 Whether COX-2 selective inhibitors decrease the prevalence of dyspepsia has not been determined. A recent study by

Table 19.4 Relative risks of upper gastrointestinal tract events in users of individual NSAIDs compared with nonusers Drug

Relative risk (95% CI)

Ibuprofen

1.9 (1.6–2.2)

Aspirin

1.6 (1.3–2.5)

Diclofenac

3.3 (2.8–3.9)

Sulindac

3.6 (2.8–4.7)

Naproxen

4.0 (3.5–4.6)

Indomethacin

4.6 (3.8–5.5)

Ketoprofen

4.6 (3.3–6.4)

Piroxicam

6.3 (5.5–7.2)

Ketorolac

24.7 (9.6–63.5)

Data from Garcia Rodriguez66; Henry197; Hernandez-Diaz198.

295

TREATMENT Treatment of NSAID-related dyspepsia H2-receptor antagonists Dyspeptic symptoms are commonly reported by patients taking NSAIDs and include heartburn, abdominal pain, nausea, abdominal distention, and anorexia. In a prospective, double-blind European study,74 127 symptomatic individuals using NSAIDs without significant endoscopic abnormalities were randomized to treatment with either cimetidine 400 mg twice daily or placebo. Ninety-five percent of the patients had upper abdominal pain, 60% percent had nausea, and 75% had heartburn. While only 49% of those receiving placebo reported resolution of their symptoms, 72% of those receiving cimetidine reported complete symptomatic remission. In a second study, van Groenendael et al.75 investigated the efficacy of ranitidine 150 mg twice daily in treating NSAID-related dyspeptic symptoms in patients with RA and osteoarthritis (OA). Among those without endoscopic evidence of any mucosal damage, only 6% and 26% of patients treated with placebo and ranitidine, respectively, had complete disappearance of their dyspeptic symptoms. In another study, Taha et al.76 compared placebo with two different doses of famotidine in the prevention of gastroduodenal ulcers in RA and OA patients receiving NSAIDs. As a secondary goal of the study, the effects of famotidine on dyspeptic symptoms were evaluated. At baseline, approximately 30% of patients reported abdominal pain, and at the end of the 24-week study nearly the same percentage of patients (29%) receiving placebo reported abdominal pain. In those randomly assigned to receive famotidine, pain was reported in 19% of those taking famotidine 20 mg twice daily and in 17% taking 40 mg twice daily, reductions of 36.6% and 43.3%, respectively.76 Taking into account differences in methodology, these studies appear to provide evidence for the beneficial effects of H2-receptor antagonists (H2RAs), and it would thus seem reasonable to recommend the use of low doses of H2RAs for symptomatic relief of dyspeptic symptoms associated with the use of NSAIDs. Although the initial regimen of an H2RA should generally be low dose (e.g., cimetidine 400 mg, ranitidine or nizatidine 150 mg, or famotidine 20 mg, all twice daily), dosing should be flexible and must be optimized to meet the individual needs of each specific patient.

Proton pump inhibitors In a study by Ekstrom,77 patients with no or mild dyspepsia, and with a need for continuous NSAID treatment, were randomized to receive either 20 mg omeprazole once daily or placebo. Gastroduodenal ulcers, erosions, and dyspeptic symptoms were evaluated after 1 and 3 months. The development of moderate to severe dyspepsia requiring active treatment, either alone or in

combination with ulcers or erosions, occurred in 15.3% (15 of 85) of patients treated with omeprazole and 35.6% of those who received placebo. A double-blind trial comparing omeprazole 20 mg once daily and ranitidine 150 mg twice daily in NSAID users demonstrated that omeprazole was significantly more effective than ranitidine in decreasing the incidence of dyspepsia. Over a 4-week period, the proportion of patients with moderate to severe upper GI symptoms decreased from 52% to 6% in those receiving omeprazole, compared to a reduction from 50% to 12% in those taking ranitidine (p80

30 mg/vial

Delayed-release capsules/ disintegrating tables, 15 mg, 30 mg; delay released suspensions, 15 mg, 30 mg/packet

Lansoprazole

Not approved 40 mg q.d. for 4–8 wks

Not approved

Maintenance therapy of DU#

Active benign GU

Risk reduction of NSAIDs associated GU

15 mg q.d. up to 12 wk

30 mg q.d. up to 8 wks for benign GU or NSAID associated GU

15 mg q.d.

FDA-approved label use of oral preparations for adult peptic ulcer diseases Active DU 20 mg q.d. for 4 wk, some 15 mg q.d. for 4 wk patients may required another 4 wk

CYP2C19

Metabolic enzymes

95

Protein binding (%) 77

0.5–1

Elimination half-life (h) in normal metabolizers*

23

0.5–3.5

Time to peak plasma concentration (h)*

Billiary/feces

30–40

Bioavailability (%)*

Route of elimination Renal

No

Intravenous injection

Preparation (may be varied by manufacturers) Oral Delayed-release capsules, 10 mg, 20 mg, 40 mg; delayed release tablets, 20 mg

Variable

Not approved

Not approved

Not approved

Not approved

CYP2C19, CYP3A4. minor: CYP2D6, 2C9

18

71

98

1

2.5

77

40 mg/vial

Delayed-release tablets, 20 mg, 40 mg

Pantoprazole

Not approved

Not approved

Not approved

20 mg q.d. up to 4 wk

CYP3A4, CYP2C19

10

90

96.3

1–2

2–5

52

No

Delayed-release tablets, 20 mg

Rabeprazole

Table 20.5 Comparison of five PPIs used in North America for peptic ulcer diseases and pathological hypersecretory

20 mg or 40 mg q.d. up to 6 months

Not approved

Not approved

Not approved

CYP2C19, CYP3A4

20

80

97

1–1.5

1.5

64

20 mg, 40 mg/vial

Delayed-release capsules, 20 mg, 40 mg

Esomeprazole

Treatment of Non-NSAID and Non-H. Pylori Gastroduodenal Ulcers and Hypersecretory States

322

60 mg q.d. Up to 120 mg t.i.d. Some patients have been treated for >5 years

Pathological hypersecretory conditions, starting and maintaining dose §

60 mg q.d. Up to 90 mg b.i.d. Some patients have been treated for >4 years

Lansoprazole

Diazepam, phenytoin, warfarin, clarithromycin, sucralfate

Drug interactions (exclude drugs effect by the change in gastric pH)

Theophylline, sucralfate

30 mg t.i.d. ⫻ 14 days None

Not approved

Not approved

40 mg b.i.d. Up to 240 mg/day. Some patients have been treated for >2 years

Pantoprazole

Clarithromycin

Not approved

20 mg b.i.d. ⫻ 7 days

60 mg q.d. Up to 60 mg b.i.d. Some patients have been treated for 1 year

Rabeprazole

Diazepam clarithromycin

Not approved

40 mg q.d. ⫻ 10 days

Not approved

Esomeprazole

Management of Gastric and Duodenal Ulcer

* Average values after an oral dose. # Control studies have not extended beyond 12 months. § Dose should be adjusted to individual patient need. DU, duodenal ulcer; GU, gastric ulcer; q.d., once daily; b.i.d., twice daily; t.i.d., three times daily; h.s., at bedtime; wk, week. Table is summarized from most recent approved individual product monograph/label listed on the Food and Drug Administration (FDA) website (http://www.fda.gov/cder/index.html, accessed on April, 2005).

40 mg q.d. for 14 days

In dual therapy

H. pylori eradication for infectious patients with active DU or DU history In triple therapy 20 mg b.i.d. for 10 days 30 mg b.i.d. ⫻ 10–14 days

Omeprazole

Variable

Table 20.5 Comparison of five PPIs used in North American for peptic ulcer diseases and pathological hypersecretory—Cont’d

323

Effect on acid and pepsin secretion PPIs are prodrugs that require protonation to their active moiety. They are activated when the local pH decreases below their respective pKa (54 for omeprazole, esomeprazole, lansoprazole, and pantoprazole; 55 for rabeprazole).31,96 The antisecretory effect of PPIs is dose-dependent, and the rapidity of onset of action depends on the bioavailability of the individual PPI.95,97–101 All PPIs seem comparable with regard to the inhibition of gastric acid secretion, but there are differences in PPI pharmacokinetic and pharmacodynamic profiles that result in differences in the degree of acid suppression and the speed of onset of acid inhibition, which may have clinical implications for symptom relief as well as healing of peptic ulcer and esophagitis.96 An in vitro study suggests that rabeprazole produces the most rapid inhibition of H+/K+-ATPase, followed by lansoprazole, omeprazole, then pantoprazole,102 which may be a result of the pKa of the PPIs and the pH to which they are exposed. Lansoprazole has a high oral bioavailability and achieves maximum effect on pH on day one of dosing.98 Single comparator studies have shown that lansoprazole,41 pantoprazole,103 and rabeprazole,104 provide significantly higher mean intragastric pH and longer duration of antisecretory effect than omeprazole in healthy subjects. Lansoprazole also produces a faster onset and greater degree of acid inhibition than pantoprazole.105 In a double-blind, crossover study in 18 H. pylori-negative healthy volunteers, the onset of antisecretory action occurred within 2 hours without significant difference for lansoprazole, omeprazole MUPS, omeprazole capsule, pantoprazole, and rabeprazole (p=0.6).106 Rabeprazole and lansoprazole showed significantly greater control of daytime and nighttime pH than comparators (Fig. 20.2). Nonetheless, the slightly more rapid onset of acid inhibition of a given PPI has not been shown to have clinically significant importance in peptic ulcer healing rate. Compared with omeprazole, esomeprazole, the s-isomer of omeprazole, has increased bioavailability and is metabolized more slowly, and the area under the plasma concentration-time curve (AUC), which is related to the antisecretory effect for esomeprazole 20 mg, is about 180% of that for omeprazole 20 mg. Esomeprazole 20 mg and 40 mg has been shown to provide superior acid suppression when compared with omeprazole 20 mg with regard to consistency among individuals, duration over 24 hours, and overall impact on pH.107 In addition, the increased dose is correlated with a more rapid onset and greater degree of acid suppression.101 Crossover studies of gastric pH in GERD patients and healthy volunteers have shown esomeprazole 40 mg once daily is significantly more effective than other PPIs at standard doses on both day 1 and day 5.101 However, there are no direct comparisons between

esomeprazole and any other PPIs conducted in patients with peptic ulcer, and whether differences between PPIs on day 5 are related to clinical end points relevant to peptic ulcer healing remains unknown. PPIs are most effective when the parietal cell is activated in response to a meal when the H+K+-ATPase is inserted into the secretory canaliculus. PPIs should therefore be taken to 1 hour before a meal, for example with a first dose before breakfast, and second dose, if and when required, before the evening meal.31 All the PPIs require accumulation and acid activation, and with the exception of lansoprazole,98 steady-state is usually not achieved for several days. Once-daily dosing with a PPI achieved 66% of steady-state inhibition of MAO after 5 days, and administration twice daily for the first 2–3 days can provide more rapid maximal acid secretory inhibition.108 Sporadically taken PPIs are unlikely to provide adequate acid inhibition.31 The effect of PPIs on peptic activity can be achieved by direct and indirect mechanisms. PPIs decrease pepsin output and reduce secretory volume, which directly inhibits peptic activity.109,110 In contrast, increasing intragastric pH to above 4 indirectly eliminates peptic activity because activation of pepsin is highly pH dependent.111 This effect on pH may partly explain the difference between PPIs and H2RAs in healing peptic ulcer and particularly esophagitis because the intragastric pH achieved with H2RAs over a 24-hour period still allows pepsin to retain proteolytic activity.111

Effect on ulcer healing Despite different recommended doses of PPIs, at equivalent dose, they provide similar healing rates when used for the treatment of peptic ulcer. Omeprazole was the first PPI and was shown to be superior to H2RAs in suppressing gastric acid secretion, healing peptic ulcers, and relieving symptoms.61–63,97 Omeprazole, 20 mg in the morning, suppresses 90% of 24-hour intragastric acidity, 88% of nocturnal acidity, and 92% of daytime acidity. The best acid suppression profile achieved with H2RAs is with ranitidine, 300 mg at bedtime, which inhibits 24-hour intragastric acidity by only 68%, nocturnal acidity by 90%, and daytime acidity by 50% (see Table 20.4).61 Although a reduction in nocturnal acidity is an important determinant for ulcer healing, suppression of 24-hour intragastric acidity has proved to be more critical. If intragastric pH can be maintained above 3 for a period of 18–20 hours of the day, the healing rate of DU approximates 100% at 4 weeks (Fig. 20.3).62 The length of treatment also plays a critical role. The healing rate achieved with omeprazole, 20 mg daily, at 4 weeks can be approached by H2RAs if the treatment is extended to 8 weeks.61

•

** *** Median time (hours)

Treatment of Non-NSAID and Non-H. Pylori Gastroduodenal Ulcers and Hypersecretory States

324

16

13.1

* ** ***

12 8

8

pH>3 pH>4

** ***

** 11.2 *** 7.4

6.9

4.9

4

5.8

5.7 2.9

3

2.7

0.9

0 RAB

LAN

PAN

OME Cap

OME MUPS

PBO

Fig. 20.2 Median time (hours) at pH >3, pH >4 of different proton pump inhibitors in healthy volunteers (n=18). RAB, rabeprazole; LAN, lansoprazole; PAN, pantoprazole; OME, omeprazole; Cap: capsule; MUPS, multiple unit pellet system. * p ) 0.03 vs. LAN; **, p ) 0.03 vs. PAN; ***, p ) 0.02 vs. OME Cap; †, p ) 0.04 vs. OME MUPS; ‡, p ) 0.04 vs. PBO. (Data from Pantoflickova D, Dorta G, Ravic M, et al. Acid inhibition on the first day of dosing: comparison of four proton pump inhibitors.Aliment Pharmacol Ther 2003; 17:1507–1514.)

325

22

Suppression (hours)

20 18 100

16 90

14 12

70

10

60 50

8

40 30 20

6

10 0

4 0

2

4 Weeks

6

8

•

Fig. 20.3 Contour plot of the duodenal ulcer healing rate predicted by the duration of suppression above a fixed pH threshold and the duration of therapy. Dashed lines indicate that if intragastric pH can be maintained above pH 3 or 4 for a period of 520 hours of the day, the healing rate of DU approximates 100% at 4 weeks. (Reprinted from Burget DW et al, Gastroenterology 1990; 99:345–351. © 1990, with permission from The American Gastroenterological Association.)

Omeprazole: Two meta-analyses have shown a clear advantage for omeprazole over various dosing regimens of H2RAs in the healing of peptic ulcers.78,112 In a meta-analysis of 30 studies, Eriksson and colleagues showed a significant advantage of omeprazole 20 mg over ranitidine and cimetidine at recommended doses in healing DU at 2 and 4 weeks and GU at 4 and 8 weeks.112 As shown in Table 20.6, 11–12% more duodenal ulcer patients were healed with omeprazole than with H2RAs at 4 weeks, and 7–10% more GU healed at 8 weeks. In addition to rapid ulcer healing, omeprazole provides significantly faster relief of symptoms than H2RAs. After 2 weeks, 9–14% more patients with peptic ulcer were symptom free with omeprazole than with H2RAs.112 This advantage was more dramatic for daytime than

evening symptoms, thus suggesting a pharmacologic difference between these two classes of drugs as discussed previously. Omeprazole 40 mg/day was significantly superior to omeprazole 20 mg/day in healing GU at both 4 and 8 weeks.113 Lansoprazole: Lansoprazole has a mechanism of action similar to that of omeprazole but has improved bioavailability, resulting in faster and greater suppression of acid secretion than does omeprazole in approved therapeutic doses. Like omeprazole, studies with lansoprazole show consistent superiority over H2RAs in healing peptic ulcer and relieving symptoms.114 In a metaanalysis of five randomized clinical trials comparing the effect of lansoprazole 30 mg in the morning with ranitidine 300 mg at bedtime or famotidine, 40 mg at bedtime, for the treatment of acute DU, significantly more ulcers were healed with lansoprazole than with H2RAs.115 The pooled healing rates were 60% and 85% for lansoprazole at 2 and 4 weeks, respectively, whereas the corresponding figures for the H2RAs were 40% and 75%. Lansoprazole also led to rapid and greater symptom relief of abdominal pain. In patients with GU, lansoprazole is significantly better than H2RAs in comparative clinical trials. Data from a meta-analysis of five published and eight unpublished randomized controlled trials showed that 33% more patients were healed at 4 weeks (RR, 1.33, 95% CI, 1.19–1.49) and 12% more patients healed at 8 weeks (RR, 1.12, 95% CI, 1.06–1.19) with lansoprazole than with H2RAs.116 Intragastric pH was maintained above 3 for significantly longer in active GU patients treated with lansoprazole than with famotidine.81 Lansoprazole has a more rapid onset of action than omeprazole when tested in healthy volunteers.117 Clinical trials comparing the effect of lansoprazole 30 mg daily with omeprazole 20 mg daily for healing ulcer have shown that they are similar in ulcer healing rate at 4 weeks. In two studies, the DU healing rates were 93.9% and 97.7%, respectively, in the lansoprazole group and were 97.5% and 96.7%, respectively, in the omeprazole group, with similar efficacy in maintenance of ulcer healing over 18 months.118,119 However, one study showed that at 2 weeks lansoprazole healed significantly more ulcers than omeprazole (71% versus 55%, p=0.045),120 which is explained by the faster onset of antisecretory effect of lansoprazole98 and the earlier time point. Faster pain relief was also seen in the lansoprazole group. Lansoprazole 30 mg/day also healed significantly more patients with GU than omeprazole 20 mg/day at 8 weeks (93% versus

Table 20.6 Comparison of omeprazole with ranitidine and cimetidine in healing peptic ulcer

Ulcer

Omeprazole n %

Ranitidine n %

Difference (95% CI)

Omeprazole n %

Cimetidine n %

Difference (95% CI)

Duodenal 2 wk 1532

62

1531

47

15 (12–19)*

674

63

689

42

21 (15–26)*

4 wk

1441

88

1448

77

11 (8–14)*

661

86

671

74

12 (8–17)*

Gastric 4 wk

374

69

369

59

10 (3–17) *

102

73

87

58

15 (2–29)*

8 wk

374

86

369

79

7 (1–12)*

102

85

87

75

10 (–2;21)

Data were analyzed on an intent-to-treat basis. n, total number of patients; CI, confidence interval. * p80

1940–47

687

33

2

1953–67

2149

48

1967–68

817

49

1972–78

583

1984–86

1017

1993

4185

Mortality #

Age standardized mortality ratio (95% CI)

9.9

147 (109–195)

8

8.9

110 (95–126)

9

10.6

122 (100–146)

NA

NA

10.3

–

63

18

11.8

68

27

11.0

CI, confidence intervals; NA, Not available; # emergency admissions only.

91 (73–112) 100 (reference value)

Upper Gastrointestinal Bleeding

338 Table 21.2 Final diagnosis of the cause of upper gastrointestinal bleeding in 2225 patients Diagnosis

Percentage of total diagnoses (%)

Duodenal ulcer

24.3

Gastric erosions

23.4

Gastric ulcer

21.3

Varices

10.3

Mallory-Weiss tear

7.2

Esophagitis

6.3

Erosive duodenitis

5.8

Neoplasm

2.9

Stomal ulcer

1.8

Esophageal ulcer

1.7

Miscellaneous

6.8

(Reprinted from Silverstein FE et al, Gastrointestinal Endoscopy 1981; 27:73. © 1981, with permission from The American Society for Gastrointestinal Endoscopy.)

INITIAL MANAGEMENT Patients with acute bleeding should be evaluated immediately on presentation. A rapid assessment should be performed to establish whether: (1) the airway is compromised, (2) there is active bleeding, and (3) the patient is hypovolemic. Orthostatic vital signs can help in the determination of lesser degrees of intravascular volume depletion. Postural hypotension is often present and indicates a 10–20% reduction in blood volume. Fluid resuscitation takes priority in the presence of any of the above signs, and venous access via one or more wide-bore cannulas is essential. Blood is drawn for typing and cross-matching in addition to testing for hemoglobin level, hematocrit, platelet count, and coagulation profiles. Patients with severe acute bleeding require admission to a high dependency or intensive care unit. Those with significant cardiopulmonary disease are fragile patients and may require intense monitoring that includes central venous pressure measurements. Intravascular volume should be promptly replenished with crystalloid solutions to maintain organ perfusion, and supplemental oxygen should be administered to augment oxygen-carrying capacity of blood. Patients’ vital signs, including blood pressure, pulse rate, and urine output, must be closely monitored. After initial volume replacement with crystalloid, unstable vital signs and evidence of ongoing bleeding, such as fresh hematemesis, are requisites for early blood transfusion. Serial hematocrit measurements provide estimates on the dilution of blood. Packed erythrocytes are generally administered, reserving whole-blood transfusion for the unusual circumstances of massive bleeding. Abnormal coagulation profiles require specific correction with fresh-frozen plasma and platelets, as is the case in many patients with liver cirrhosis. After stabilization with the restoration of intravascular volume, history taking, physical examination, and investigation can proceed in the usual order. A history of chronic liver disease and signs of portal hypertension denote the possibility of variceal

bleeding, which requires specific therapy, such as the administration of vasoactive drugs and antibiotics prior to endoscopy. Previous aortic surgery in the presence of massive bleeding raises the concern of an aortoenteric fistula. Those with signs of ongoing bleeding after initial resuscitation, such as fresh hematemesis or fresh hematochezia and hypovolemic shock, should undergo urgent endoscopy to localize the source of bleeding and for possible endoscopic therapy. Hematemesis indicates that bleeding originates from a site proximal to the ligament of Treitz. A history of fresh hematemesis usually implies a significant bleed. On the other hand, coffee grounds emesis often indicates that active bleeding may have ceased. Melena occurs when hemoglobin is converted to hematin and other hemochromes by bacterial degradation, and the ingestion of as little as 200 mL of blood can produce melenic stool. Although melena generally connotes bleeding proximal to the ligament of Treitz, bleeding from small bowel or proximal colon may also cause melena, especially when colonic transit is slow. A mildly elevated level of blood urea nitrogen (BUN) is another indication of upper GI bleeding, which is due to the absorption of blood via the intestinal tract. Hypovolemia may also account for the transient azotemia.6 Massive upper GI bleeding can present as hematochezia, although it is more often a sign of lower GI bleeding. However, 11% of patients with rapid bleeding from an upper GI source pass bright red blood rectally because of rapid GI transit.7 In a patient with fresh rectal bleeding and hypovolemia, placement of a nasogastric tube or early endoscopic examination should be offered to differentiate bleeding from an upper or a lower GI source. The routine insertion of a nasogastric tube prior to endoscopy may not be necessary. Nasogastric tube placement with lavage prior to endoscopy is often ineffective, as blood tends to form clots and may thus be difficult to aspirate. Bleeding lesions often locate at the lesser gastric curvature, angular notch, gastric antrum, or bulbar duodenum while blood generally pools in the gastric fundus and corpus. An endoscopic examination is often possible and adequate with suction aspiration and patient positioning. The insertion of a nasogastric tube is associated with a small risk of aspiration, particularly among obtunded patients. In occasions when the source of GI bleeding is uncertain, the insertion of a nasogastric tube can help to confirm an upper GI bleeding source with the presence of gross blood or coffee ground-like substances in the gastric aspirate. In contrast, a clear nasogastric aspirate does not exclude upper GI bleeding inasmuch as bleeding may be episodic or the lesion located distal to the stomach in the presence of a competent pylorus, preventing retrograde reflux of blood from duodenum. In a study by Cuellar and colleagues, only 53% of patients with a positive nasogastric aspirate were actively bleeding when endoscopy was performed, and 20% of patients with a clear aspirate were found to be actively bleeding at endoscopy.8 Nevertheless, the nature of nasogastric aspirates can serve as a prognostic indicator, as highlighted in the ASGE survey.9 A clear nasogastric aspirate was associated with a mortality rate of 6%, which increased to 18% when the aspirate was grossly bloody. When both a bloody aspirate and fresh hematochezia are present, the mortality rises to around 30%. Gross blood in the nasogastric aspirate indicates ongoing and often massive bleeding and mandates emergency intervention. Early endoscopy is usually defined as performance of the examination within 24 hours of patient’s admission. This

339

Risk stratification In about 80% of patients, bleeding has stopped spontaneously upon presentation.4 In the remaining 20% of patients, bleeding would continue or recur during their hospitalization. The mortality in this group increases as much as eightfold compared to those without further bleeding. It is therefore mandatory that patients who are at risk be identified. Several risk stratification schemes with validation have been published. Most are composite scoring systems incorporating both clinical and endoscopic parameters. Such a scheme should aid in the clinical decisions for both (1) the need for urgent intervention as patients must be triaged before endoscopy, and (2) predicting continued or recurrent bleeding in the context of endoscopic therapy. The latter is important as alternate treatment strategies should be readily available to prevent recurrent bleeding. From the National United Kingdom audit, Rockall et al. derived an admission score and postendoscopy scores from 4185 admissions and validated these scores with data from 1625 patients (Table 21.3) in their ability to predict recurrent bleeding and death.18 The scoring system consists of age, comorbidity, the presence of shock, and endoscopic findings. A total score of 3 or less is associated with an excellent prognosis, while a score 8 or above is associated with a high risk of death. Blatchford et al. used simple clinical and biochemical parameters to derive a score to predict the need for intervention to control bleeding.19 The score was modeled on the clinical process rather than treatment outcome. The risk markers of BUN, hemoglobin, systolic blood pressure, pulse rate, the presence of

melena or syncope, and evidence of hepatic or cardiac disease with assigned numerical values are used and easy to remember. The full score can be used to determine the required level of care upon the patient’s admission and to identify those who may need urgent treatment. In the Canadian Consensus Conference Statements, Barkun et al. reviewed studies over the last decade that used multivariate analyses to formulate risk schemes.20 Similar to most scoring systems, they concluded that older age, poor health status or comorbid illness, continued or recurrent bleeding, fresh hematemesis or hematochezia, and the onset of bleeding in hospitalized patients (those admitted for reasons other than upper GI bleeding) represented poor prognostic factors and predicted death. Clinical prognosticators of increased risk for recurrent bleeding are listed in Table 21.4. Of note, endoscopic factors including active bleeding, major stigmata of recent hemorrhage, ulcers greater than 2 cm in size, and location in proximity to large arteries are the factors that predict recurrent bleeding.

Stigmata of hemorrhage Endoscopic features of an ulcer are important prognostic indicators. The presence of stigmata of recent bleeding in an ulcer confirms the source of bleeding. Three decades ago, Forrest and Finlayson categorized ulcers into those that were actively bleeding, those that showed stigmata of recent bleeding, and those that had a clean base.21 The nomenclature has since been in widespread use. Forrest class I ulcers are those with active bleeding, which can be either spurting (Forrest class IA) (Fig. 21.1) or oozing (Forrest class IB). Stigmata of recent bleeding belong to Forrest class II: non-bleeding visible vessel, IIA; adherent clots, IIB; and flat pigmented spots, IIC (Figs 21.2, 21.3 , 21.4). Ulcers with a clean base belong to Forrest III (Fig. 21.5). Laine and Peterson summarized endoscopic findings from cohort studies in which endoscopic therapy was not used and correlated the appearance with risk of recurrent bleeding, requirement for surgery, and risk of mortality (Table 21.5).22 There are, however,

Table 21.3 The Rockall risk score scheme Score Variable

0

1

2

Age (years)

3 cm or ‘porcelain gallbladder’).39 Whether diabetic patients with asymptomatic gallstones should undergo prophylactic cholecystectomy is discussed below.

setting. When open cholecystectomy was the gold standard operation, it was common to allow patients with acute cholecystitis to ‘cool down’ with medical management, and then operate electively several weeks later. A recent meta-analysis of prospective randomized trials demonstrated no significant difference in rates of operative and perioperative complications between early and delayed cholecystectomy (both open and laparoscopic) for uncomplicated acute cholecystitis.50 Moreover, early surgery was not associated with an increased risk of choledocholithiasis encountered during surgery or of retained stones post cholecystectomy. Total hospital stay was significantly shorter in the early surgery group, especially for patients undergoing open cholecystectomy. Another important finding from this meta-analysis was that over 20% of patients randomized to delayed surgery failed to respond to medical management or suffered recurrent cholecystitis in the interval period, leading to unplanned urgent surgery in more than 50%. Finally, the conversion rate from laparoscopic to open cholecystectomy was lower in early compared to delayed surgery. Overall, early surgery (within 48–72 hours) should be considered the preferred strategy for patients with uncomplicated acute cholecystitis.50

Nonsurgical treatment options Surgical treatment Cholecystectomy is the treatment of choice for symptomatic or complicated gallstone disease. Laparoscopic cholecystectomy has replaced open cholecystectomy as the ‘gold standard’ operation for uncomplicated symptomatic gallstones, conferring benefits of lower morbidity and mortality, shorter length of stay, and lower hospital costs.40,41 Only recently has laparoscopic cholecystectomy become accepted in the treatment of acute cholecystitis.42–44 In one of the few published prospective, randomized trials comparing laparoscopic versus open cholecystectomy for acute cholecystitis, the laparoscopic approach was associated with a significant reduction in complication rate, duration of hospital stay, and sick leave.44 However, the rate of conversion to open cholecystectomy was 16%, mainly due to technical difficulties related to unclear anatomy. In contrast, elective surgery for uncomplicated symptomatic gallstone disease has a much lower rate of conversion, generally ranging 4–7%.45,46 Factors associated with an increased likelihood of conversion to open cholecystectomy in the setting of acute cholecystitis include age >60, male gender, delay in operation (>48 hours from presentation), leukocytosis, obesity, presence of multiple comorbidities, and radiographic evidence of pericholecystic collections or a thickened gallbladder (> 5 mm).42,46–49 Patients who are poor candidates for laparoscopic cholecystectomy include those with generalized peritonitis, septic shock from cholangitis, severe acute pancreatitis, end-stage cirrhosis, and gallbladder cancer.41 Prior upper abdominal surgery can make laparoscopic cholecystectomy more difficult, but is not an absolute contraindication.

Timing of surgery The optimal timing of cholecystectomy for acute cholecystitis has long been a subject of controversy, recently fueled by the increased acceptance of laparoscopic cholecystectomy in this

The role for nonsurgical treatment of gallstone disease has decreased in recent years with the advances in laparoscopic cholecystectomy. However, nonsurgical treatment, primarily with oral bile acid therapy, direct contact dissolution, and/or extracorporeal shock wave lithotripsy, remains an effective alternative to cholecystectomy in selected patients with symptomatic gallstone disease who refuse surgery or are not fit for surgery. Percutaneous cholecystostomy as a treatment option for high-risk patients with acute cholecystitis is also discussed in this section.

Oral bile acid therapy Oral bile acid therapy with chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA) has been shown to be effective in dissolving cholesterol gallstones. These agents reduce cholesterol saturation and effect dissolution by a number of mechanisms, such as inhibiting biliary secretion of cholesterol, enriching the bile acid pool, promoting liquid crystal formation and transferring cholesterol into micelles and vesicles. A meta-analysis found that UDCA in doses greater than 7 mg/kg/day taken for at least 6 months dissolved radiolucent gallstones in 37% of patients.51 Long-term use of UDCA has also been shown to reduce the risk of biliary pain and acute cholecystitis in patients with symptomatic gallstones.52 The effectiveness of oral bile acid therapy is highly dependent on proper patient selection, taking into account gallbladder function and gallstone size, number, and composition. Favorable criteria include small stone size (250 U/L has a PPV of over 75%.78 Finally, noninvasive imaging, generally with ultrasonography, is useful in predicting the presence of choledocholithiasis. A CBD stone visualized on ultrasound is highly specific and increases the likelihood of choledocholithiasis over 13-fold;73 however, this finding has a sensitivity of only 40–50%.74,79 Ultrasound evidence of CBD dilation is also a strong predictor, increasing the likelihood of choledocholithiasis nearly 7-fold.73,80 Although not commonly used for this indication, radionuclide cholescintigraphy has been reported to be very accurate in diagnosing CBD obstruction,81 with a sensitivity and specificity of 83–84% for choledocholithiasis.74 Overall, the three most powerful clinical, noninvasive predictors of choledocholithiasis are cholangitis, preoperative jaundice, and identification of common bile duct stones on ultrasound.73 Since no single test is completely accurate in predicting CBD stones, the decision whether further diagnostic testing is warranted should be based on the integration of clinical, biochemical, and radiographic information.

Diagnostic imaging studies Endoscopic retrograde cholangiopancreatography Direct cholangiography is the ‘gold standard’ diagnostic test for the detection of choledocholithiasis. This can be performed via percutaneous transhepatic cholangiography (PTC), intraoperative

Common Bile Duct Stones

Stone recurrence occurs in 50–60% of patients after 11 years of follow-up, with a plateau after 5–9 years.57,58 The presence of multiple stones before dissolution therapy is associated with a higher risk of recurrence.58

Biliary Tract Stones

400 Table 25.2 Predictors of choledocholithiasis Category

Condition

Sensitivity

Specificity

Positive likelihood ratio

Clinical

Cholangitis Jaundice Pancreatitis Cholecystitis

0.11–0.42 0.36–0.69 0.10–0.12 0.50

0.99 0.89–0.97 0.95 0.76

18.3 10.1 2.1 1.6

Biochemical

Bilirubin Alkaline phosphatase Amylase

0.69–0.77 0.57–0.70 0.11

0.88 0.86 0.95

4.8 2.6 1.5

Radiographic

CBD stone on ultrasound Dilated CBD on ultrasound HIDA scan: partial/complete obstruction

0.38–0.50 0.42–0.85 0.83

0.97–1.00 0.82–0.96 0.84

13.6 6.9 –

Data from Abboud 199673, and Bose 200174.

cholangiography (IOC), or endoscopic retrograde cholangiopancreatography (ERCP). Of these, ERCP is currently the most commonly used; in experienced hands, ERCP has a sensitivity, specificity, and accuracy each exceeding 95%, and can detect stones as small as 2 mm in diameter (Fig. 25.4).82 An advantage of ERCP is the ability to perform endoscopic sphincterotomy and stone extraction at the time of diagnosis (see below). However, there is a small but significant risk of complications including pancreatitis, hemorrhage, perforation, and cholangitis, as well as adverse reactions to sedatives and cardiopulmonary dysfunction.83 Most prospective studies report an overall short-term complication rate for ERCP with or without sphincterotomy of 5–10%.84–86 Therefore, because of these risks, along with recent advances in noninvasive imaging, the use of ERCP in many institutions has become limited to therapeutic, rather than purely diagnostic, indications. It remains the initial test of choice for the treatment of patients with a high likelihood of choledocholithiasis based on clinical, biochemical, and radiographic data.82 As such, ERCP is the preferred test in patients with cholangitis and/or severe gallstone pancreatitis because these patients benefit from early therapeutic intervention.87–89

II anastomosis, Roux-en-Y anastomosis), in whom ERCP may be difficult or impossible. The major limitation of MRCP is that it is a purely diagnostic test and has no therapeutic capability. Therefore, its optimal use is as a screening examination for the detection or exclusion of CBD stones in patients with a low or intermediate probability of harboring stones, sparing such patients a potentially unnecessary ERCP.90

Endoscopic ultrasound Endoscopic ultrasound (EUS) is another alternative to ERCP, with the advantages of being less invasive and having a lower risk of complications.94 For the diagnosis of choledocholithiasis, EUS is comparable to ERCP and MRCP with respect to sensitivity, specificity, and positive and negative predictive values.82,95,96 The CBD can also be imaged via intraductal ultrasound (IDUS) using

Magnetic resonance cholangiopancreatography Since its introduction over a decade ago, magnetic resonance cholangiopancreatography (MRCP) has evolved into a highly accurate, noninvasive method of imaging the biliary tree (Fig. 25.5).90 Current techniques can image the entire biliary system in a single breath-hold and provide high spatial resolution. Studies examining the performance of MRCP for the diagnosis of choledocholithiasis have generally used ERCP as the reference standard. Recent studies have shown good concordance between the two modalities, with sensitivities and specificities both exceeding 90% for MRCP.79,91,92 The sensitivity of MRCP varies according to the size of the stone, ranging from approximately 70% for 3–5 mm stones, to 90% for 6–10 mm stones, to 100% for stones larger than 10 mm in diameter.93 The major advantages of MRCP are that it is noninvasive and eliminates the risks associated with sedation, instrumentation, contrast administration, and ionizing radiation. Moreover, MRCP can provide complete evaluation of the biliary tree in patients with surgically altered upper gastrointestinal tracts (e.g., Billroth

•

Fig. 25.4 Endoscopic retrograde cholangiopancreatography demonstrating two large stones in the common bile duct (arrows), corresponding to the images shown in Figure 25.5.

401

Surgical treatment

TREATMENT OF COMMON BILE DUCT STONES

When laparoscopic cholecystectomy replaced open surgery as the preferred treatment of symptomatic gallstones, it was initially unclear whether laparoscopic IOC and LCBDE would be feasible, safe, and cost-effective. Accumulating experience from specialty centers has demonstrated successful duct clearance rates exceeding 90%, with relatively low morbidity rates of approximately 8–10%.103,104 LCBDE has the advantage of being a one-stage procedure for patients with choledocholithiasis, thereby avoiding the risks of ERCP and sphincterotomy without compromising effectiveness of bile duct clearance, and conferring the additional benefits of shorter hospital stay and reduced costs.105,106 Two laparoscopic approaches to LCBDE have been developed: transcystic and transductal (via choledochotomy). The former approach is generally preferred when feasible, because it is less invasive and results in shorter hospital stay than transductal LCBDE.107 CBD stones documented on laparoscopic IOC can then be retrieved with wire baskets, with or without the use of choledochoscopy or fluoroscopy. Intraoperative electrohydraulic or laser lithotripsy techniques are available but have not been widely used. If LCBDE is unsuccessful, biliary drainage can be achieved by placing a transcystic duct catheter inserted through a separate abdominal wall puncture, or by placing a standard T tube or biliary stent via choledochotomy. Alternatively, the procedure can be converted to open CBD exploration unless expert endoscopists are available, in which case postoperative ERCP should be performed.

Endoscopic treatment

Percutaneous treatment

ERCP with endoscopic sphincterotomy and stone extraction has become the primary therapeutic modality for choledocholithiasis, with success rates exceeding 80% using standard techniques.98 Advanced techniques for difficult bile duct stones, including mechanical, electrohydraulic, laser, or extracorporeal shockwave lithotripsy, increase the success rate to nearly 100%.98,99 Standard techniques for endoscopic treatment of choledocholithiasis include ERCP with sphincterotomy, usually in combination with balloon or wire basket stone extraction. Endoscopic papillary balloon dilation (EPBD) has been proposed as an alternative to sphincterotomy, with a purported benefit of preserving sphincter of Oddi function. EPBD should be considered in selected patients with cirrhosis, coagulopathy, or altered anatomy (e.g., large periampullary diverticulum or Billroth II anatomy).100 However, endoscopic sphincterotomy remains the preferred technique

Percutaneous treatment of CBD stones should be considered when surgical and endoscopic modalities fail, are unavailable, or cannot be safely performed. Several percutaneous methods of duct clearance have been performed with success rates of 75–90%, including basket extraction, mechanical lithotripsy, and ESWL or electrohydraulic lithotripsy under cholangioscopic guidance. Stones smaller than 1 cm can also be pushed through the papilla following transhepatic papillary balloon dilation.108–110 A ‘rendezvous’ procedure can be performed if the ampulla can be reached endoscopically but retrograde cannulation is unsuccessful. In this approach, a guidewire is placed percutaneously into the bile ducts, traversing the papilla into the duodenum. This facilitates localization and cannulation of the papilla, allowing endoscopic sphincterotomy and stone extraction to be safely completed.111

•

Fig. 25.5 Magnetic resonance cholangiopancreatography demonstrating multiple common bile duct stones (arrows), which were subsequently confirmed and removed during endoscopic retrograde cholangiopancreatography (Fig. 25.4).

a high-frequency catheter US probe inserted through the accessory channel of a standard endoscope or duodenoscope. In conjunction with ERCP, IDUS significantly increases diagnostic accuracy compared to ERCP alone, especially in the presence of a dilated CBD.97 Given its safety and excellent negative predictive value, EUS is considered a first-line diagnostic test in patients who are at low or intermediate risk for choledocholithiasis.82 However, because of limitations in EUS training, experience, and availability, as well as the continued refinement of MRCP technology, EUS has not been widely adopted for this indication.

Treatment of Common Bile Duct Stones

because of higher rates of successful stone clearance and possibly lower rates of procedure-induced pancreatitis compared to EPBD.101 Endoscopic biliary stenting is an effective temporizing measure in cases of difficult bile duct stones that cannot be extracted by standard techniques. Stenting provides immediate biliary drainage, and occasionally leads to stone resolution or fragmentation, permitting subsequent endoscopic extraction.102 Stenting has also been used as the sole therapy for difficult CBD stones, but because of the risk of late complications, particularly cholangitis, this should be restricted to highly selected patients unfit for other more definitive treatments.


402

SPECIAL CONSIDERATIONS Gallbladder sludge Gallbladder sludge is composed of suspension of cholesterol monohydrate crystals, calcium bilirubinate, and other calcium salts embedded in gallbladder mucus. Specific clinical situations commonly associated with sludge formation include pregnancy, rapid weight loss, prolonged fasting, long-term parenteral nutrition, bone marrow or solid organ transplantation, and the use ceftriaxone and octreotide. Sludge is usually diagnosed on abdominal ultrasound, where it appears as low-level echoes that layer dependently without acoustic shadows. However, the sensitivity of transabdominal ultrasound for sludge is only about 55%.112 Direct microscopic examination of bile, although less clinically applicable, is more sensitive than ultrasonography, and is considered the diagnostic gold standard. The natural history of sludge is variable, with three main clinical outcomes: complete resolution, a waxing and waning course, and gallstone formation.113 Like gallstones, sludge is most often asymptomatic; elimination of precipitating factors and expectant observation are recommended in this situation. However, sludge can also be complicated by biliary colic (in approximately 10% of patients), and less commonly by acute pancreatitis, cholangitis, and cholecystitis. Once symptoms or complications occur, cholecystectomy should be considered as the definitive therapy. Alternatively, oral bile acid dissolution therapy with UDCA can be attempted, although its long-term efficacy has not been proven.

Acute cholangitis Acute cholangitis occurs as a result of biliary stasis and infection, and is most commonly due to choledocholithiasis. The classic presentation of acute cholangitis is characterized by Charcot’s triad of fever, right upper quadrant pain, and jaundice, which is seen in approximately 50–75% of patients.114 The presence of hypotension and altered mental status (Reynold’s pentad) indicates severe infection termed suppurative cholangitis. All patients with acute cholangitis should be treated with broadspectrum antibiotics to cover against Gram-negative aerobic enteric organisms (Escherichia coli, Klebsiella, Enterobacter), Grampositive Enterococcus, and anaerobic bacteria (Bacteroides fragilis, Clostridium perfringens). Urgent biliary decompression is required in patients with suppurative cholangitis and those who fail to respond to antibiotic therapy (approximately 20% of patients), whereas decompression can be safely delayed in patients who respond to antibiotics.115 Urgent endoscopic decompression should also be considered for patients with adverse prognostic indicators, such as the presence of comorbid medical conditions, thrombocytopenia, azotemia, and hypoalbuminemia. The preferred method of biliary decompression is via ERCP, which has been shown to reduce morbidity and mortality rates compared to surgical therapy.116

Gallstone pancreatitis Gallstone disease is one of the most common causes of acute pancreatitis in North America and Western Europe. Most patients

have a mild clinical course and can be conservatively managed with intravenous fluids, bowel rest, and analgesia. Elective cholecystectomy should then be performed once the acute illness has resolved, preferably during the same admission.117 Patients with gallstone pancreatitis who have evidence of biliary obstruction, those who deteriorate after an initial mild attack, or those presenting with severe pancreatitis at the outset should be considered for urgent ERCP.98 Pooled data from four randomized, controlled trials have demonstrated a convincing role for early ERCP and sphincterotomy (within 72 hours of presentation) in patients with severe gallstone pancreatitis.87,89,118,119 A metaanalysis of these trials found statistically significant reductions in overall complications and mortality in patients treated with early ERCP with sphincterotomy compared with those treated conservatively.120 There is no clear benefit in patients with mild pancreatitis, or in those without obstructive jaundice.98,118 Cholecystectomy should be performed following an episode of acute gallstone pancreatitis, but can be safely delayed after sphincterotomy. Endoscopic sphincterotomy is a viable alternative to cholecystectomy for the prevention of recurrent gallstone pancreatitis in high surgical risk patients.121 Depending on length of follow-up, recurrence rates of gallstone pancreatitis following sphincterotomy with gallbladder in situ are low, ranging 0–5%.121–123 However, sphincterotomy cannot prevent future episodes of other biliary complications such as recurrent biliary colic and acute cholecystitis if a stone-containing gallbladder remains intact (see below).

Gallbladder in situ The clinical course of patients with gallbladder in situ following endoscopic sphincterotomy and bile duct clearance is controversial, hence the issue of ‘prophylactic’ cholecystectomy remains a matter of debate. Several retrospective and nonrandomized prospective studies with varying duration of follow-up have reported symptomatic recurrence or cholecystectomy rates ranging 5–20%, lending support both for and against the need for prophylactic cholecystectomy.124–127 A recent prospective randomized trial compared a ‘wait and see’ approach with prophylactic laparoscopic cholecystectomy following endoscopic sphincterotomy in patients with proven gallbladder stones.128 This study found that after a median follow-up of 30 months, 47% of patients being followed expectantly developed at least one recurrent biliary event, most commonly uncomplicated pain, compared to 2% of patients who underwent cholecystectomy. Acute cholecystitis occurred in 12% of patients in the former group, and 37% required ‘on demand’ cholecystectomy. Possible risk factors for recurrence of biliary complications following sphincterotomy with gallbladder in situ include bile duct diameter >15 mm, periampullary diverticula, diabetes, acute cholangitis or gallstone pancreatitis at the time of sphincterotomy, nonfilling of the gallbladder on cholangiography, and brown pigment stones at initial ERCP.123,124,128–130

Pregnancy Alterations in cholesterol secretion and gallbladder motility are thought to contribute to an increased risk of gallstones and biliary sludge during pregnancy. Biliary colic develops in up to a third of pregnant women with gallstones.131,132 Symptomatic

403 bile aspiration into the ERCP catheter (rather than contrast injection), shielding the pelvis with lead, and avoiding hard copy radiographs.135,136

Diabetes Early studies suggested that diabetic patients with gallstones were at increased risk for severe complications from acute cholecystitis, and had higher morbidity and mortality rates from cholecystectomy.137 Specific complications such as perforation, gangrenous cholecystitis, and emphysematous cholecystitis have been reported to occur in up to 20–40% of diabetics.138 Increased susceptibility

Suspected gallstone disease/biliary complication

Noninvasive evaluation (U/S, labs)

Biliary colic, uncomplicated

Is patient fit for surgery?

No

Acute cholecystitis

Cholangitis

Gallstone pancreatitis

Medical management: consider percutaneous cholecystostomy in unstable patients

IV antibiotics, supportive care

Access severity of pancreatitis

ERCP (emergent if patient deteriorates)

Yes

Mild

Severe

ERCP

Nonsurgical treatment

CCY CCY Assess likelihood of choledocholithiasis

Intermediate

Low

CCY +/– IOC

Negative

MRCP or EUS

High

Positive

ERCP

CCY Follow clinically

IOC (–), or no IOC

IOC (+)

CBDE

Fig. 25.6

Postoperative ERCP

• Algorithm outlining the authors’ recommendations for the management of gallstones

Special Considerations

gallstone disease can be managed conservatively in the majority of cases, with definitive therapy deferred until the postpartum period. However, endoscopic and/or surgical therapy are indicated when biliary complications arise, including acute cholecystitis unresponsive to medical therapy, choledocholithiasis, and severe gallstone pancreatitis.133 With early involvement of the obstetrics team, perioperative fetal monitoring, and the appropriate use of tocolytic agents, laparoscopic cholecystectomy can be safely performed during any stage of pregnancy.134 Similarly, ERCP and sphincterotomy are safe during pregnancy, but measures should be taken to minimize radiation exposure to the fetus, such as limiting fluoroscopy time or confirming biliary cannulation by


404 Table 25.3 Author’s recommendations for the management of gallstones Gallstones Ultrasonography is the diagnostic test of choice for cholelithiasis and acute cholecystitis. Observation is recommended for the vast majority of patients with asymptomatic gallstones. Laparoscopic cholecystectomy is the treatment of choice for symptomatic cholelithiasis, and can be safely performed for acute cholecystitis by surgeons with expertise in laparoscopic surgery. Early cholecystectomy (within 48–72 hours) is the preferred treatment approach for patients with acute, uncomplicated cholecystitis. Common bile duct stones Cholangitis, jaundice, and identification of common bile duct stones on noninvasive imaging are the best predictors of choledocholithiasis. ERCP should be reserved for therapeutic indications, but remains the test of choice for treatment of patients with a high likelihood of choledocholithiasis and patients with cholangitis or severe gallstone pancreatitis. MRCP, EUS, or IOC is recommended when the probability of choledocholithiasis is intermediate. Common bile duct stones can then be removed by pre- or postoperative ERCP, or intraoperatively by LCBDE, depending on local expertise.

SUMMARY Recommendations for the management of gallstones are summarized in Table 25.3 and in Figure 25.6.

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92. Griffin N, Wastle ML, Dunn WK, et al. Magnetic resonance cholangiopancreatography versus endoscopic retrograde cholangiopancreatography in the diagnosis of choledocholithiasis. Eur J Gastroenterol Hepatol 2003; 15:809–813. 93. Sugiyama M, Atomi Y, Hachiya J. Magnetic resonance cholangiography using half-Fourier acquisition for diagnosing choledocholithiasis. Am J Gastroenterol 1998; 93:1886–1890. 94. Sivak MV Jr. EUS for bile duct stones: how does it compare with ERCP? Gastrointest Endosc 2002; 56:S175–S177. 95. Prat F, Amouyal G, Amouyal P, et al. Prospective controlled study of endoscopic ultrasonography and endoscopic retrograde cholangiography in patients with suspected common-bile duct lithiasis. Lancet 1996; 347:75–79. 96. NIH state-of-the-science statement on endoscopic retrograde cholangiopancreatography (ERCP) for diagnosis and therapy. NIH Consens State Sci Statements 2002; 19:1–26. 97. Das A, Isenberg G, Wong RC, et al. Wire-guided intraductal US: an adjunct to ERCP in the management of bile duct stones. Gastrointest Endosc 2001; 54:31–36. 98. Carr-Locke DL. Therapeutic role of ERCP in the management of suspected common bile duct stones. Gastrointest Endosc 2002; 56:S170–S174. 99. Binmoeller KF, Bruckner M, Thonke F, et al. Treatment of difficult bile duct stones using mechanical, electrohydraulic and extracorporeal shock wave lithotripsy. Endoscopy 1993; 25:201–206. 100. Park DH, Kim MH, Lee SK, et al. Endoscopic sphincterotomy vs. endoscopic papillary balloon dilation for choledocholithiasis in patients with liver cirrhosis and coagulopathy. Gastrointest Endosc 2004; 60:180–185. 101. Arnold JC, Benz C, Martin WR, et al. Endoscopic papillary balloon dilation vs. sphincterotomy for removal of common bile duct stones: a prospective randomized pilot study. Endoscopy 2001; 33:563–567. 102. Katsinelos P, Galanis I, Pilpilidis I, et al. The effect of indwelling endoprosthesis on stone size or fragmentation after long-term treatment with biliary stenting for large stones. Surg Endosc 2003; 17:1552–1555. 103. Petelin JB. Laparoscopic common bile duct exploration. Surg Endosc 2003; 17:1705–1715. 104. Dorman JP, Franklin ME Jr, Glass JL. Laparoscopic common bile duct exploration by choledochotomy. An effective and efficient method of treatment of choledocholithiasis. Surg Endosc 1998; 12:926–928. 105. Urbach DR, Khajanchee YS, Jobe BA, et al. Cost-effective management of common bile duct stones: a decision analysis of the use of endoscopic retrograde cholangiopancreatography (ERCP), intraoperative cholangiography, and laparoscopic bile duct exploration. Surg Endosc 2001; 15:4–13. 106. Cuschieri A, Croce E, Faggioni A, et al. EAES ductal stone study. Preliminary findings of multi-center prospective randomized trial comparing two-stage vs single-stage management. Surg Endosc 1996; 10:1130–1135. 107. Petelin JB. Surgical management of common bile duct stones. Gastrointest Endosc 2002; 56:S183–S189. 108. van der Velden JJ, Berger MY, Bonjer HJ, et al. Percutaneous treatment of bile duct stones in patients treated unsuccessfully with endoscopic retrograde procedures. Gastrointest Endosc 2000; 51:418–422.

109. Ogawa K, Ohkubo H, Abe W, et al. Percutaneous transhepatic small-caliber choledochoscopic lithotomy: a safe and effective technique for percutaneous transhepatic common bile duct exploration in high-risk elderly patients. J Hepatobiliary Pancreat Surg 2002; 9:213–217. 110. Moon JH, Cho YD, Ryu CB, et al. The role of percutaneous transhepatic papillary balloon dilation in percutaneous choledochoscopic lithotomy. Gastrointest Endosc 2001; 54:232–236. 111. Shorvon PJ, Cotton PB, Mason RR, et al. Percutaneous transhepatic assistance for duodenoscopic sphincterotomy. Gut 1985; 26:1373–1376. 112. Ko CW, Sekijima JH, Lee SP. Biliary sludge. Ann Intern Med 1999; 130:301–311. 113. Lee SP, Maher K, Nicholls JF. Origin and fate of biliary sludge. Gastroenterology 1988; 94:170–176. 114. Saik RP, Greenburg AG, Farris JM, et al. Spectrum of cholangitis. Am J Surg 1975; 130:143–150. 115. Boender J, Nix GA, de Ridder MA, et al. Endoscopic sphincterotomy and biliary drainage in patients with cholangitis due to common bile duct stones. Am J Gastroenterol 1995; 90:233–238. 116. Lai EC, Mok FP, Tan ES, et al. Endoscopic biliary drainage for severe acute cholangitis. N Engl J Med 1992; 326:1582–1586. This randomized trial performed in Hong Kong compared surgical decompression of the biliary tract with endoscopic biliary drainage for the treatment of severe acute cholangitis.The study demonstrated significant advantages to endoscopic drainage with respect to complication rate, frequency of residual stones, and mortality rate. These findings strongly support the use of endoscopic drainage as first line therapy for acute cholangitis secondary to choledocholithiasis. 117. Kelly TR, Wagner DS. Gallstone pancreatitis: a prospective randomized trial of the timing of surgery. Surgery 1988; 104:600–605. 118. Folsch UR, Nitsche R, Ludtke R, et al. Early ERCP and papillotomy compared with conservative treatment for acute biliary pancreatitis. The German Study Group on Acute Biliary Pancreatitis. N Engl J Med 1997; 336:237–242. 119. Nowak A, Nowakowska-Dulawa E, Marek T, et al. Final results of the prospective, randomized, controlled study on endoscopic sphincterotomy versus conventional management in acute biliary pancreatitis (Abstract). Gastroenterology 1995; 108:A380. 120. Sharma VK, Howden CW. Metaanalysis of randomized controlled trials of endoscopic retrograde cholangiography and endoscopic sphincterotomy for the treatment of acute biliary pancreatitis. Am J Gastroenterol 1999; 94:3211–3214. This meta-analysis reviewed data from four published randomized controlled trials comparing ERCP and sphincterotomy with conservative management for acute biliary pancreatitis.This study demonstrated that pooled data from these studies showed a statistically significant reduction in the rate of complications from acute biliary pancreatitis in patients treated with ERCP. Furthermore, there was a statistically significant reduction in mortality in patients treated with ERCP compared with conservative management.The authors predicted that approximately eight patients would need to be treated with ERCP to prevent one complication, and approximately 26 patients would need to be treated to prevent one death. 121. Kaw M, Al-Antably Y, Kaw P. Management of gallstone pancreatitis: cholecystectomy or ERCP and endoscopic sphincterotomy. Gastrointest Endosc 2002; 56:61–65. 122. Uomo G, Manes G, Laccetti M, et al. Endoscopic sphincterotomy and recurrence of acute pancreatitis in gallstone patients considered unfit for surgery. Pancreas 1997; 14:28–31.

References

91. Soto JA, Alvarez O, Munera F, et al. Diagnosing bile duct stones: comparison of unenhanced helical CT, oral contrast-enhanced CT cholangiography, and MR cholangiography. AJR Am J Roentgenol 2000; 175:1127–1134.


408 123. Davidson BR, Neoptolemos JP, Carr-Locke DL. Endoscopic sphincterotomy for common bile duct calculi in patients with gall bladder in situ considered unfit for surgery. Gut 1988; 29:114–120. 124. Hammarstrom LE, Holmin T, Stridbeck H. Endoscopic treatment of bile duct calculi in patients with gallbladder in situ: long-term outcome and factors. Scand J Gastroenterol 1996; 31:294–301. 125. Yi SY. Recurrence of biliary symptoms after endoscopic sphincterotomy for choledocholithiasis in patients with gallbladder stones. J Gastroenterol Hepatol 2000; 15:661–664. 126. Targarona EM, Ayuso RM, Bordas JM, et al. Randomised trial of endoscopic sphincterotomy with gallbladder left in situ versus open surgery for common bile duct calculi in high-risk patients. Lancet 1996; 347:926–929. 127. Lai KH, Lin LF, Lo GH, et al. Does cholecystectomy after endoscopic sphincterotomy prevent the recurrence of biliary complications? Gastrointest Endosc 1999; 49:483–487. 128. Boerma D, Rauws EA, Keulemans YC, et al. Wait-and-see policy or laparoscopic cholecystectomy after endoscopic sphincterotomy for bile-duct stones: a randomised trial. Lancet 2002; 360:761–765. This prospective study of 120 patients addressed the issue of whether patients with gallbladder stones should undergo cholecystectomy following endoscopic sphincterotomy and extraction of common bile duct stones. Patients were randomized to either expectant management or laparoscopic cholecystectomy. The study demonstrated a high rate of recurrent biliary symptoms (47%) among patients managed expectantly, compared to that in patients who underwent cholecystectomy (2%).The authors therefore concluded that cholecystectomy after sphincterotomy and bile duct clearance in patients with gallbladder in situ was the preferred strategy. 129. Pereira-Lima JC, Jakobs R, Winter UH, et al. Long-term results (7 to 10 years) of endoscopic papillotomy for choledocholithiasis. Multivariate analysis of prognostic factors for the recurrence of biliary symptoms. Gastrointest Endosc 1998; 48:457–464. 130. Hill J, Martin DF, Tweedle DE. Risks of leaving the gallbladder in situ after endoscopic sphincterotomy for bile duct stones. Br J Surg 1991; 78:554–557. 131. Maringhini A, Ciambra M, Baccelliere P, et al. Biliary sludge and gallstones in pregnancy: incidence, risk factors, and natural history. Ann Intern Med 1993; 119:116–120.

134. Cosenza CA, Saffari B, Jabbour N, et al. Surgical management of biliary gallstone disease during pregnancy. Am J Surg 1999; 178:545–548. 135. Tham TC, Vandervoort J, Wong RC, et al. Safety of ERCP during pregnancy. Am J Gastroenterol 2003; 98:308–311. 136. Tarnasky PR, Simmons DC, Schwartz AG, et al. Safe delivery of bile duct stones during pregnancy. Am J Gastroenterol 2003; 98:2100–2101. 137. Mundth ED. Cholecystitis and diabetes mellitus. N Engl J Med 1962; 267:642–646. 138. Schein CJ. Acute cholecystitis in the diabetic. Am J Gastroenterol 1969; 51:511–515. 139. Shpitz B, Sigal A, Kaufman Z, et al. Acute cholecystitis in diabetic patients. Am Surg 1995; 61:964–967. 140. Ransohoff DF, Miller GL, Forsythe SB, et al. Outcome of acute cholecystitis in patients with diabetes mellitus. Ann Intern Med 1987; 106:829–832. 141. Landau O, Deutsch AA, Kott I, et al. The risk of cholecystectomy for acute cholecystitis in diabetic patients. Hepatogastroenterology 1992; 39:437–438. 142. Aucott JN, Cooper GS, Bloom AD, et al. Management of gallstones in diabetic patients. Arch Intern Med 1993; 153:1053–1058. 143. Del Favero G, Caroli A, Meggiato T, et al. Natural history of gallstones in non-insulin-dependent diabetes mellitus. A prospective 5-year follow-up. Dig Dis Sci 1994; 39: 1704–1707. 144. Del Olmo JA, Garcia F, Serra MA, et al. Prevalence and incidence of gallstones in liver cirrhosis. Scand J Gastroenterol 1997; 32:1061–1065. 145. Acalovschi M, Badea R, Dumitrascu D, et al. Prevalence of gallstones in liver cirrhosis: a sonographic survey. Am J Gastroenterol 1988; 83:954–956. 146. Conte D, Fraquelli M, Fornari F, et al. Close relation between cirrhosis and gallstones: cross-sectional and longitudinal survey. Arch Intern Med 1999; 159:49–52. 147. Acalovschi M, Blendea D, Feier C, et al. Risk factors for symptomatic gallstones in patients with liver cirrhosis: a casecontrol study. Am J Gastroenterol 2003; 98:1856–1860.

132. Valdivieso V, Covarrubias C, Siegel F, et al. Pregnancy and cholelithiasis: pathogenesis and natural course of gallstones diagnosed in early puerperium. Hepatology 1993; 17:1–4.

148. Poggio JL, Rowland CM, Gores GJ, et al. A comparison of laparoscopic and open cholecystectomy in patients with compensated cirrhosis and symptomatic gallstone disease. Surgery 2000; 127:405–411.

133. Sungler P, Heinerman PM, Steiner H, et al. Laparoscopic cholecystectomy and interventional endoscopy for gallstone complications during pregnancy. Surg Endosc 2000; 14:267–271.

149. Ishizaki Y, Bandai Y, Shimomura K, et al. Management of gallstones in cirrhotic patients. Surg Today 1993; 23:36–39.

SECTION FIVE MANAGEMENT OF PANCREATICOBILIARY DISORDERS

CHAPTER TWENTY-SIX

26

Primary sclerosing cholangitis Konstantinos N. Lazaridis and Nicholas F. LaRusso

INTRODUCTION

Pathogenesis

Primary sclerosing cholangitis (PSC) is a chronic, progressive cholestatic hepatobiliary disease of unknown cause.1,2 PSC is characterized by concentric, obliterative fibrosis of both the intraand extrahepatic bile ducts resulting in destruction of the biliary tree and subsequently in biliary cirrhosis.1,2 PSC is diagnosed after exclusion of secondary sclerosing cholangitis, in which bile duct injury is caused by identifiable etiologies (Table 26.1).

PSC is a heterogeneous disease. To date, the etiopathogenesis of PSC remains elusive. It is believed that the interaction of genetic elements and environmental exposures is pivotal in the pathogenesis of PSC. Figure 26.1 represents a working hypothesis of the environmental and genetic interplay that leads to PSC and may explain the disease’s multifactorial etiology and heterogeneous presentation.

Epidemiology

Genetic factors

Over the last 3 decades, the frequency of PSC diagnosis has increased. This is likely because of an enhanced awareness of PSC among physicians in addition to extensive use of endoscopic retrograde cholangiopancreatography (ERCP) in clinical practice. PSC affects primarily young men during their fourth decade of life.1,2 In the United States, population-based estimates reported an age-adjusted incidence of PSC to be 1.25 and 0.54 per 100 000 person-years in men and women, respectively.3 From the same study, the prevalence of PSC was calculated to be 20.9 and 6.3 per 100 000 of men and women, respectively.3 About 75–80% of patients of northern European origin with PSC suffer from inflammatory bowel disease. In this group, chronic ulcerative colitis (CUC) is more common (590%) than Crohn’s disease (510%). Of interest, only 2–6% of patients with CUC have or will develop PSC.1,2

Table 26.1 Causes of secondary sclerosing cholangitis AIDS-associated cholangiopathy Amyloidosis Bile duct neoplasm (in the absence of PSC) Chemicals/drugs (i.e., 5-fluorouracil) Choledocholithiasis Congenital bile duct abnormalities (i.e., Caroli’s disease) Iatrogenic biliary strictures/trauma Ischemic strictures of bile ducts AIDS, acquired immunodeficiency syndrome.

The fact that genetic factors predispose to the development of PSC is evident by reports of familial PSC cases4,5 and the association of specific HLA haplotypes (i.e., B8, DR3) with PSC patients compared to matched controls.2 In the last 3 years, additional genetic polymorphisms have been implicated in the pathogenesis of PSC. For example, a functional variant of stromelysin (i.e., matrix metalloproteinase 3) has been shown to affect PSC susceptibility and disease progression;6 moreover, a functional polymorphism of the MICA gene (major histocompatibility complex [MHC] class I related – MIC gene family) was reported to have a role in PSC susceptibility.7

Environmental factors and associated diseases Environmental elements such as copper and infectious agents (i.e., CMV), have been implicated in the development of PSC. Copper was postulated to participate in the pathogenesis of PSC because of the excessive copper found in the hepatic parenchyma of patients with PSC. Nevertheless, a causative role for copper in PSC development is unlikely given the elevated hepatic copper concentration reported in other chronic cholestatic liver diseases. Moreover, the notion that PSC progresses in spite of a decrease in hepatic copper following chelation therapy with D-penicillamine argues against this hypothesis.8 Viruses such as cytomegalovirus and reovirus type 3 have also been postulated to cause PSC. To date, however, proven evidence to support involvement of these microorganisms in PSC pathogenesis is lacking. The association between CUC and PSC has been confirmed by many studies. Nonetheless, the proposal that increased colonic permeability, due to CUC, and the resulting enhanced absorption of luminal contents (i.e., toxins, bacteria, inflammatory mediators) leads to the inflammation of bile ducts in PSC remain unproven. In fact, the development of PSC in the absence of CUC (520% of patients) and the failure of proctocolectomy to modify

410 Primary Sclerosing Cholangitis

Laboratory findings, imaging of the biliary tree, and histologic staging of primary sclerosing cholangitis Gene A

Gene B

Gene X

Environment

PSC Heterogeneity

•

Fig. 26.1 The interaction of genetic variants located at different loci (arrows) with the environment is proposed to account for the heterogeneity of PSC pathogenesis, clinical presentation and progression.

The laboratory profile of patients with PSC includes a threeto fourfold elevation of serum alkaline phosphatase of at least 6 months duration. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and serum bilirubin are mildly elevated and may fluctuate.1 Serologic tests for antimitochondrial antibodies are generally negative.9 Serum copper and ceruloplasmin levels, and urine and hepatic copper values may be abnormal. ERCP reveals diffusely distributed, short, annular strictures with intervening segments of dilated ducts (beading) affecting both the intra- and extrahepatic biliary tree (Fig. 26.2). Magnetic resonance cholangiography (MRC) offers comparable accuracy to ERCP, in addition to reduced cost, as the initial test for the diagnosis of PSC.10 The histologic staging of PSC is shown on Table 26.2.

Diagnosis

the natural history of PSC argue against a direct causative mechanism between these two entities. Humoral and cellular immune abnormalities have been described in patients with PSC implying that altered immunity is involved in its pathogenesis. Whether distorted immunity is linked to PSC causation or is just an epiphenomenon of its pathogenesis remains unclear. Humoral alterations in PSC include: (1) hypergammaglobulinemia with increased serum immunoglobulin M levels; (2) decreased clearance of circulating immune complexes; (3) increased complement activation; and (4) increased titer of autoantibodies (i.e., antineutrophil cytoplasmic antibodies, antinuclear antibodies).1 Cell-mediated abnormalities of immunity in PSC include: (1) decline of the total number of T cells involving mainly the suppressor/cytotoxic (CD 8) and less frequently the helper (CD 4) T lymphocytes; and (2) aberrant expression of HLA class II antigens by biliary epithelia.1 At present, the consensus working hypothesis of PSC pathogenesis proposes that the disease develops in a genetically predisposed individual following exposure(s) to a biliary insult that causes progressive destruction of bile ducts. Moreover, we now know that the cholangiocyte, the epithelial cell that lines the intra- and extrahepatic bile ducts, is the target cell in PSC.

The diagnosis of PSC is usually based on the following criteria: (1) elevated serum alkaline phosphatase level of at least 6 months duration; (2) characteristic cholangiographic findings of the bile ducts (see Fig. 26.2); and (3) exclusion of secondary sclerosing cholangitis (see Table 26.1). Liver biopsy is not always necessary for the diagnosis. In a recent study, involving 79 PSC patients who underwent liver biopsy with a previously established PSC diagnosis by cholangiography, the biopsy result itself did not affect the clinical management in 78 out of 79 PSC patients.11 Nevertheless, liver biopsy is required in PSC patients suspected to have the ‘overlap syndrome’ (i.e., coexistence of PSC with autoimmune hepatitis) or ‘small duct PSC’ (i.e., patients with normal ERCP but cholestatic pattern of liver enzymes). Liver biopsy is also indicated for staging PSC prior to entry into therapeutic trials. The differential diagnosis of PSC should include secondary sclerosing cholangitis (see Table 26.1), primary biliary cirrhosis, chronic

CLINICOPATHOLOGICAL FEATURES AND DIAGNOSIS Clinicopathological features Symptoms and signs The clinical presentation of PSC is heterogeneous. The asymptomatic individual has incidentally detected abnormal liver blood tests. The symptomatic patient presents with signs/symptoms/ complications of end-stage hepatic disease. A commonly encountered clinical scenario is a patient with CUC who presents with a cholestatic pattern of liver enzyme changes. Symptomatic patients have fatigue (75%), pruritus (70%), hepatomegaly (55%), jaundice (50%), weight loss (40%), splenomegaly (30%), and skin hyperpigmentation (25%).1

•

Typical ERCP findings of PSC. Multifocal stricturing and Fig. 26.2 dilatation of intra- and extrahepatic bile ducts.

411

TREATMENT

Portal stage (stage I)

Portal edema, inflammation, ductal proliferation; abnormalities do not extend beyond the limiting plate.

Periportal stage (stage II)

Periportal fibrosis, inflammation with or without ductular proliferation; piecemeal necrosis may be present.

The management of PSC should be multifaceted. PSC causes chronic, debilitating symptoms and complications of end-stage liver disease. To date, we lack an effective, specific treatment for the underlying disorder. Gastroenterologists are the primary physicians that treat patients with PSC. However, the complexity of the disease requires a team management approach that also involves interventional radiologists and surgeons in order to treat the spectrum of PSC manifestations and complications. Figure 26.3 provides an algorithm for the treatment of PSC.

Septal stage (stage III)

Septal fibrosis or bridging necrosis can be identified.

Medical treatment

Cirrhotic stage (stage IV)

Biliary cirrhosis.

active hepatitis, idiopathic adulthood ductopenia, and overlap syndrome.

NATURAL HISTORY AND COMPLICATIONS Natural history PSC is an insidious and progressive disease. Although some patients with early-stage PSC are asymptomatic, most will advance over time to develop complications of chronic cholestasis and end-stage liver disease. In the absence of liver transplantation, the median survival from the time of diagnosis is about 12 years; even asymptomatic patients have decreased survival compared to matched controls.12 Children with PSC have a natural history that is comparable to adults. The median survival for children, in the absence of liver transplantation, was reported to be 12.7 years and the overall survival was significantly shorter despite attempted pharmacological treatment.13 Prognostic models in PSC have been devised to predict survival, assess efficiency of therapeutic trials, and identify the ideal timing for liver transplantation. In the revised Mayo natural history model for PSC, five independent, reproducible parameters, namely age, bilirubin, albumin, aspartate aminotransferase, and history of variceal bleeding, were used to estimate the survival of patients with PSC.14 This model’s advantage is the avoidance of liver biopsy in estimating patient survival.

Complications The complications of PSC can be divided into two groups. The first consists of the non-specific complications related to endstage liver disease and it includes chronic cholestasis and liver failure, steatorrhea and fat-soluble vitamin deficiency, hepatic osteodystrophy, decompensated cirrhosis, and portal hypertension. The second group of complications includes those more directly related to PSC (i.e., cholelithiasis, choledocholithiasis, dominant biliary stricture(s), recurrent bacterial cholangitis, cholangiocarcinoma, and peristomal varices). The latter occurs in patients with coexistent PSC and CUC who have undergone proctocolectomy and ileostomy.

The management of PSC should simultaneously focus on: (1) treatment of non-specific PSC complications, (2) therapy of specific PSC complications, and (3) approaches to ameliorate the progression of the underlying hepatobiliary disease.

Treatment of non-specific complications of PSC Pruritus Patients with advanced-stage PSC frequently complain of intense pruritus. To alleviate this distressing symptom many medical therapies have been used.1 Cholestyramine, a nonabsorbable bile acid binding resin, is thought to work by lessening the intestinal absorption of bile acids. The recommended dose of cholestyramine (4 g four times per day) must be given at least 2 hours before or after other medications because their intestinal absorption can be inhibited by this resin. Phenobarbital (120–160 mg per day) have been used in addition to cholestyramine to control nocturnal pruritus. Ursodeoxycholic acid (i.e., ursodiol), a hydrophilic bile acid that likely replaces hydrophobic, toxic bile acids in bile, may also alleviate pruritus in PSC patients at a dose of 13–15 mg per kg of body weight per day, divided in two doses. Antihistamines (i.e., hydroxyzine and diphenhydramine) can be used as supplements to cholestyramine or ursodeoxycholic acid particularly for nocturnal pruritus because of their sedative properties. Rifampin, which works by competing for the hepatocyte uptake of bile acids and by inducing hepatic microsomal enzymes, may also improve pruritus. Rifampin is administered orally at 300–600 mg per day. The potential side effects of rifampin (i.e., drug-induced hepatitis) make it a second-line agent for pruritus. Opiate antagonists such as naloxone, nalmefene, and naltrexone have shown promise in alleviating pruritus.15 More aggressive treatments for intractable pruritus include the use of plasmapheresis, phototherapy, and orthotopic liver transplantation.

Steatorrhea, fat-soluble vitamin deficiency, and hepatic osteodystrophy Because prolonged cholestasis results in decreased intestinal bile acid concentration, patients with advanced-stage PSC may develop steatorrhea. However, PSC patients who present with steatorrhea should be evaluated for other concurrent causes of the latter such as pancreatic insufficiency and celiac sprue.16 Steatorrhea, due to intralumenal bile acid deficiency, may improve by lowering the dietary fat intake to 540 g per day, and by substituting medium-chain triglycerides for dietary long-chain triglycerides.

Treatment

Table 26.2 Staging of primary sclerosing cholangitis by liver histology

Primary Sclerosing Cholangitis

412 PSC

(Consider liver biopsy to rule out overlap syndrome)

Consider participation in therapeutic trials

Stage III, IV

Stage I, II

Consider OLT

Symptoms, signs and complications of PSC

Pruritus

Steatorrhea

Osteoporosis

• Cholestyramine ± Phenobarbital • UDCA ± Antihistamines • Rifampin • Opiate antagonists • Plasmapheresis/ Phototherapy • Consider OLT

Exclude celiac sprue, pancreatic insufficiency

• Obtain bone scan density • Calcium • Vitamin D • Estrogen

• Lower dietary fat • Add mediumchain triglycerides • Monitor and supplement with fat-soluble vitamins

Dominant biliary strictures(s) • Biopsy/ cytology (i.e., DIA, FISH) • Dilitation • Temporary stenting • Consider OLT • Consider reconstructive biliary surgery

Jaundice

Biliary stones

Recurrent bacterial cholangitis

Symptomatic cholelithiasis

• Antibiotics • Biliary lavage

• Cholecystectomy

Cholangiocarcinoma

• Consider • Extraction surgical • Biliary lavage resection • Consider OLT in selected liver transplant centres

Complications of decompensated cirrhosis and portal hypertension

Hepatic encephalopathy

Ascites/ spontaneous bacterial peritonitis

Variceal bleeding

• Lactulose • Dietary restrictions

• Sodium restrictions • Diuretics • Antibiotics

• β-blockers • Variceal obliteration • TIPS

Follow-up evaluations

Stable status

Intractable symptoms, signs, and complications of PSC

Consider OLT

•

Fig. 26.3 Algorithm for the management of primary sclerosing cholangitis (PSC). UDCA, ursodeoxycholic acid; OLT, orthotopic liver transplantation; DIA, digital image analysis; FISH, fluorescence in situ hybridization;TIPS, transjugular intrahepatic portosystemic shunt

Fat-soluble vitamin (i.e., A, D, E, K) deficiencies have been described in PSC.17 Vitamin A deficiency can cause ‘night blindness.’ In PSC patients with vitamin A deficiency, oral supplementation with 25 000–50 000 U of vitamin A two to three times per week is recommended. Serum levels of vitamin A must

be monitored in treated patients to avoid hepatotoxicity. The main bone disease in patients with PSC is osteoporosis.18 Special consideration must be given in advanced-stage PSC patients who have moderate to severe osteopenia since about 50% have bone mineral density below the fracture threshold.18 Patients should

413

Decompensated cirrhosis and portal hypertension Patients with advanced-stage PSC develop complications of decompensated cirrhosis and portal hypertension including ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, and variceal bleeding. These complications should be managed expectantly as in other end-stage liver diseases. The PSC patient with decompensated cirrhosis and associated complications should receive standard medical therapy (i.e., sodium restriction, lactulose, diuretics, beta blockers) and endoscopic evaluation (i.e., periodic surveillance for esophageal varices and, if needed, variceal obliteration). However, as PSC progresses, these complications become intractable and orthotopic liver transplantation remains the single best therapeutic option.

Treatment of specific complications of PSC Cholelithiasis and choledocholithiasis About 30% of PSC patients will develop cholelithiasis and/or choledocholithiasis due to the chronic, progressive nature of intrahepatic and extrahepatic cholestasis. Patients with PSC who present with symptoms and signs of biliary stone disease and a biochemical profile of worsening cholestasis should be evaluated for cholecystitis and/or choledocholithiasis. If the diagnosis of choledocholithiasis is made, ERCP with endoscopic sphincterectomy and removal of biliary stones is the therapeutic intervention of choice. Symptomatic gallbladder disease in PSC patients should be treated with cholecystectomy. Of note, the presence of a luminal gallbladder mass that cannot be attributed to gallstones needs special attention. In a Mayo Clinic study of 102 patients with PSC who underwent cholecystectomy, 14 of 102 (13.7%) were found to have gallbladder mass of which eight (57%) were malignant (i.e., adenocarcinoma).19 Therefore, in patients with PSC and suspected gallbladder polyps of any size, cholecystectomy is strongly recommended.

Dominant biliary stricture(s) and recurrent bacterial cholangitis Dominant biliary stricture(s) develop in 10–20% of PSC patients during the course of their disease. PSC patients with dominant biliary stricture(s) present with acute onset or worsening of jaundice and pruritus. Dominant biliary stricture(s) should be evaluated by ERCP or percutaneous transhepatic cholangiography (PTC) to visualize the biliary tree and permit brushing as well as biopsies of the involved area(s) to exclude cholangiocarcinoma. Biliary aspirate specimens should be sent for standard cytology, digital imaging analysis (DIA), and fluorescence in situ hybridization (FISH). The latter two laboratory tests have improved the diagnostic accuracy for cholangiocarcinoma (see below).

The therapeutic management of dominant biliary stricture(s) and/or recurrent bacterial cholangitis should include a balanced combination of dilatation and stenting interventions, biliary lavage, and the preventive use of antibiotics. The preferred approach of intervention (i.e., ERCP versus PTC) depends on stricture characteristics (i.e., location, length), and availability/ local experience with the related procedures. The majority of biliary strictures are amenable to ERCP. Endoscopic cholangioplasty (i.e., balloon dilation) of dominant biliary stricture(s) followed by stenting improves patient symptoms. However, the long-term effect of this approach on disease progression and need for liver transplantation has not been examined. PTC is the suggested method of approaching the biliary tree for mechanical treatment of biliary strictures that affect intrahepatic ducts, in patients with history of Roux-en-Y gastrojejunostomy, and in cases of failed endoscopic approaches. Intravenous antibiotics are strongly recommended immediately prior to mechanical manipulation of the biliary tree and oral antibiotic treatment should be continued for 7–10 days following ERCP or PTC. Ciprofloxacin is the antibiotic that is most frequently used in our practice because of its high biliary secretion and broad spectrum of bacterial coverage. PSC patients with frequent episodes of bacterial cholangitis should also be given ciprofloxacin prophylactically to prevent recurrence or reduce its severity. Recurrent bacterial cholangitis in patients with PSC is not always the result of dominant biliary stricture(s). It has been proposed that edema, inflammatory exudation, and debris in the biliary tree can result in temporary stenosis of bile ducts leading to obstruction and recurrent bacterial cholangitis. Since these events are thought to be transient and more likely reversible, biliary lavage has been devised as an endoscopic modality to flush out potential irritants from the biliary tree. After cannulation of the biliary system, the ducts are irrigated with either saline or with saline plus steroids in an attempt to achieve a topical antiinflammatory effect.

Cholangiocarcinoma PSC is considered to be a premalignant condition since adenocarcinoma of the bile ducts occurs in 8–15% of patients.2 The estimated annual incidence of cholangiocarcinoma in patients with PSC is 51.5%.20 The development of cholangiocarcinoma in PSC is frequently heralded by weight loss, abdominal discomfort/pain, and rapid deterioration of liver function tests. The median survival after the diagnosis of cholangiocarcinoma is short (56 months). Patients at high risk for this tumor are those with a prolonged history of CUC and advancedstage PSC. Early detection of cholangiocarcinoma in PSC patients is hampered by the low sensitivity/specificity of diagnostic techniques including fine needle biopsy and brush cytology of bile ducts. CA-19-9, a serum glycoprotein, is a useful marker of cholangiocarcinoma but it may be elevated in pancreatic malignancies and in bacterial cholangitis. In spite of this, periodic testing of CA-19-9 in PSC patients is recommended and a progressive CA-19-9 increase should make one suspect that cholangiocarcinoma has developed. New modalities that may aid in the diagnosis of cholangiocarcinoma include digital imaging analysis (DIA) and fluorescence in situ hybridization (FISH) of bile duct cytology specimens. These two tests have improved the diagnostic yield of cholangiocarcinoma when compared to standard biliary cytology.20,21

Treatment

receive supportive therapy including: (1) calcium supplements; (2) replenishment with vitamin D (25 000–50 000 U of vitamin D two to three times per week intramuscularly) when low serum levels are detected; and (3) use of estrogens. PSC patients deficient in vitamin K have prolonged prothrombin time. In these cases, a testing oral dose of 10 mg of vitamin K should be administered. If empiric treatment improves prothrombin time, then patients should be started on a maintenance dose of 5–10 mg of watersoluble vitamin K per day. Vitamin E should be replaced if its serum level is reduced. The recommended oral dose of vitamin E is 100–200 mg per day.

Primary Sclerosing Cholangitis

414 Liver resection for cholangiocarcinoma is limited to only those few patients who are diagnosed at early stages. Unfortunately, chemotherapy and radiation therapy are not effective in treating cholangiocarcinoma. Liver transplantation for cholangiocarcinoma has had disappointing results with a 5-year survival rate of 70 yr Glucose >220 mg/100 mL WBC >18 000/mm3 LDH >40 IU/L AST >250 U/100 mL

Hct fall >10 BUN elevation >2 mg/100 mL Ca2+ >8 mg/100 mL Base deficit >5 mEq/L Fluid sequestration >4L

Nongallstone pancreatitis Age >55 yr Glucose >200 mg/100 mL WBC >16 000/mm3 LDH >350 IU/L AST >250 U/100 mL Number of factors 0–2 3–4 5–6 7–8 Adapted from references 19, 59.

Hct fall >10 BUN elevation >5 mg/100 mL Ca2+ >8 mg/100 mL Base deficit >4 mEq/L Fluid sequestration >6L PaO2 >55 mmHg Mortality 3 pathological side branches of the main pancreatic duct

Two of the following pathological findings: Cysts Duct irregularities Focal acute pancreatitis Heterogeneity of the parenchyma Increased echogenity of the ductal wall Intraductal filling defects Gland enlargement

Grade II, moderate

> 3 pathological side branches of the pancreatic duct + dilated main pancreatic duct

All above-mentioned findings

Grade III, severe

Grade II plus one or more of the following findings: Cyst >10 mm Intraductal filling defects Calcification Obstruction or strictures of the pancreatic duct Dilatation of the pancreatic duct as well as irregularities Contiguous neighboring organ invasion

Chronic Pancreatitis

432 Table 28.3 Sensitivity and specificity of routinely employed techniques for the diagnosis of chronic pancreatitis (after ref. 55) Diagnostic tool

Sensitivity

Specificity

Transabdominal ultrasound

48–90%

75–90%

Contrast enhanced CT scan

56–95%

85–90%

ERCP

68–93%

89–97%

Endosonography

88–100%

90–100%

Fecal elastase-1

50–93%

62–93%

Serum pancreolauryl test

70–82%

70–87%

Secretin-cholecystokinin test

80–90%

90–95%

The wide range of percentages given for specificity and sensitivity of diagnostic procedures results from a heterogeneous cohort of patients as well as the different mix of severity of cases in the studies used. Furthermore, a gold standard has so far not been defined.

maldigestion can be found in about one-third of all patients with chronic pancreatitis. Reduced exocrine function often precedes morphological changes and, therefore, sensitivity for the detection of early changes is higher for pancreatic function tests than for imaging studies. Several tests of exocrine pancreatic function are well established in the diagnostic evaluation of patients suspected to have chronic pancreatitis. The approaches can be divided into those that are direct and those that are indirect. When pancreatic function is measured directly, the stimulated secretion of pancreatic juice is collected via a nasoduodenal tube and then the enzymes and bicarbonate are quantitated. Indirect methods detect decreased secretion by measuring the amount of pancreatic enzymes in stool or serum or, alternatively, they evaluate the digestion of synthetic substrates by pancreatic enzymes (Table 28.4). The disadvantage of indirect tests for pancreatic function is that they cannot distinguish between structural or functional abnormalities. The situation after gastrectomy can serve as a good example. In this case, an impaired synchrony of pancreatic secretion and the gastrointestinal passage of food may lead to clinical exocrine insufficiency or abnormal function tests without primary damage of the pancreas (pancreatico-cibale asynchrony).68

Direct pancreatic function tests Secretin-cholecystokinin-test: Pancreatic enzyme activity as well as bicarbonate concentration are measured in the duodenal juice after stimulation with the enterohormones secretin (1 CU/kg, i.v.) and cholecystokinin (CCK 25–100 ng/kg). This requires passing a nasoduodenal tube that has two lumena. The proximal one is used to remove gastric secretions and to prevent gastric juice from stimulating pancreatic secretion. The second lumen is placed beyond the ligament of Treitz and fractions, containing duodenal juice, are aspirated every 15 min. The secretin-cholecystokinin test is the gold standard for pancreatic function testing. Its overall sensitivity and specificity is 90%. Even though the secretincholecystokinin test is the most accurate assay for pancreatic function, only few specialized centers routinely use this technique for clinical studies. The cost of testing one patient is about US$150. Furthermore, 2 days of labor by the technician are

Table 28.4 Direct and indirect pancreatic function tests Pancreatic function test Direct

Secretin-cholecystokinin test Endoscopic secretin test

Indirect

Serum tests: Pancreolauryl test NBT-PABA test (discontinued) Fecal tests: Fecal elastase-1 Chymotrypsin Stool weight Fecal fat quantification

required to prepare the test and to do the analysis.69–71 Some authors use a standardized test meal (Lund test) rather than hormone stimulation of the exocrine pancreas but this more ‘physiological’ approach is, ultimately, less sensitive in detecting early functional changes and bicarbonate cannot be measured in the collected chyme.

Indirect pancreatic function tests Fecal elastase-1: Pancreatic elastase accounts for 6% of all proteins in pancreatic juice. Compared to other serine proteases, this enzyme is highly stable during its passage through the gut and can be detected in stool (median concentration of 1200 ␮g/g). Fecal elastase is measured using an enzyme linked immunoassay (ELISA) and there are polyclonal and monoclonal test kits commercially available. The ELISAs employed have been extensively evaluated for cross-reactivity between species and none has been found. It is therefore not necessary for the patient to discontinue enzyme supplementation treatment with animal-derived enzyme preparations. To measure fecal elastase, only small amounts of stool are required (100 mg) and it is not necessary to test multiple samples because interassay variability is low (8–15%). The overall sensitivity of fecal elastase testing is 63% for mild exocrine insufficiency and it rises to 100% for intermediate and severe exocrine insufficiency if compared to the gold standard of the secretin-cholecystokinin test.72,73 Pancreolauryl: The serum pancreolauryl test (PLT) is the most widely accepted oral indirect pancreatic function test for detecting and grading the functional impairment of the gland. The test involves ingestion of fluorescein dilaureate (0.25 mmol) with a standardized breakfast (20 g bread, 20 g butter, and 200 ml tea). The fluorescein dilaureate is cleaved in the duodenum by pancreatic esterases and fluorescein, absorbed from the intestine, can be photometrically measured in the patient’s urine or serum after defined time intervals. Before performing this pancreatic function test, the patient must discontinue enzyme supplementation as orally taken enzymes interfere with testing, leading to false-negative results. The pancreolauryl test can also quantify severe exocrine insufficiency via a diminished increase in serum fluorescein or in dialysis fluid of patients with renal insufficiency.74 The sensitivity is 82% with a specificity of 91% for severe exocrine insufficiency. Mild exocrine insufficiency can only be detected with a sensitivity of 51%. The PLT is regarded as an indirect noninvasive pancreatic function test of high clinical relevance.75

433 negatively affect the course of chronic pancreatitis because of their effect on the sphincter of Oddi are unwarranted. Some authors prefer meperidine over other opiates in pancreatitis but this alleged advantage has not been studied in controlled trials. Tramadolsulphate, as an alternative to other opiates, should not be considered in patients with acute or chronic pancreatitis because, according to the authors’ personal experience, nausea and vomiting are common side effects in this group of patients. As many patients with chronic pancreatitis are drug addicts, a rigid scheme of pain medication is more effective than medication on demand. Several studies have suggested that enzyme supplementation is associated with pain relief. A randomized, placebo controlled study, however, has not shown such a beneficial effect (Table 28.5).77,78

TREATMENT STRATEGIES

Nutrition and pancreatic enzyme supplementation

The aim of medical treatment of chronic pancreatitis is the compensation of exocrine and endocrine pancreatic insufficiency. It is, therefore, dominated by attempts to control maldigestion, steatorrhea, weight loss, and blood glucose levels and to achieve adequate pain management. The role and prognostic value of psychosocial care with the aim of discontinuing alcohol abuse in patients with chronic pancreatitis should not be underestimated.

Pain management Following intrapancreatic protease activation or tissue necrosis, inflammatory mediators are locally released. These not only facilitate and sustain the inflammatory process, but they can also exert a direct effect on sensory fibers of the celiac plexus (T5–T9), thus triggering visceral pain, which is a common symptom in patients with chronic pancreatitis. Adequate pain relief is therefore one of the most important and urgent treatment goals. There are several concepts to pain treatment which need to be carefully evaluated on an individual basis. In principle, pain management for chronic pancreatitis follows the guidelines of the WHO for the treatment of chronic pain. The combination of a nonsteroidal analgesic with a centrally active drug should initially be considered. Concerns that morphine analogues may

Diabetes mellitus associated with chronic pancreatitis Diabetes mellitus is an independent predictor of mortality in patients with chronic pancreatitis. Morbidity and mortality due to diabetes mellitus may occur from progressive microangiopathic complications or from more acute complications such as treatment-induced hypoglycemia, particularly in those patients with an inadequate glucagon reserve. Ketoacidosis is relatively unusual. This may be due to the fact that insulin secretion has not entirely ceased when glucagon secretion is already reduced. The underlying pathophysiology of diabetes in chronic pancreatitis is the loss of insulin secretion. Oral antidiabetic agents, therefore, have no role in the treatment of diabetes due to chronic pancreatitis. Control of blood sugar levels should be achieved with exogenous insulin. Guidelines for the treatment and monitoring of the secondary organ failure of type I diabetes mellitus can be used for the treatment of pancreatitis-induced diabetes, but the insulin doses required are usually lower.79,80

Enzyme supplementation is clinically indicated if patients suffering from chronic pancreatitis lose more than 10% of their body weight, excrete more than 15 g/d fat with their stool, or suffer from clinical symptoms of dyspepsia or meteorism. Treatment of the pain and meteorism associated with chronic pancreatitis and meteorism are two situations in which pancreatic enzymes can be used on an individual basis but there is no conclusive evidence of benefit from controlled trials. Four types of pancreatic enzyme preparation are currently available. Most commercial preparation consists of pancreatin, which is the shock-frozen powdered extract of porcine pancreas containing lipase, amylase, trypsin, and chymotrypsin. Enzyme supplements are not absorbed from the gastrointestinal tract. Rather, they are inactivated by enteral bacterial flora or digestive secretion and fecally eliminated. Administration of acid-stable, encapsulated microspheres or microtablets filled with pancreatic enzymes has greatly increased the efficacy of enzyme supplementation in chronic pancreatitis. Patients with documented exocrine insufficiency should eat three main meals a day and three snacks in between. In general, 25 000 to 50 000 IU of lipase should be ingested simultaneously along with a main meal and 25 000 IU of lipase along with the snacks. They should not be taken either

Treatment Strategies

Fecal fat: Fecal fat quantification by the classical Van de Kamer (alcohol extraction) technique is the standard for establishing the presence of steatorrhea, i.e., characteristic symptom of reduced exocrine function. The test is performed by collecting stool over 3 days during which oral fat intake is 80–100 g/d. After a 90% loss of exocrine function, fat excretion in stool significantly increases as a sign of fat maldigestion. A mild or intermediate impairment of exocrine function is usually clinically compensated. Pancreatic endocrine function should be evaluated by fasting and 1 h postprandial blood glucose levels and oral glucose tolerance testing as well as HbA1C according to the guidelines of the WHO for the diagnosis of diabetes mellitus. In addition to an evaluation of exocrine and endocrine function, considerable attention should be paid to the etiology of the disease. Recent results from molecular and genetic studies suggest that a significant number of patients with chronic pancreatitis suffer from a genetically determined or inherited disease. This is mainly true for patients who were formerly classified as suffering from idiopathic pancreatitis, for patients with an onset of the disease before the age of 25, or for those with a positive family history for chronic pancreatitis or pancreatic cancer. Patients who suffer from chronic pancreatitis due to mutations in the cationic trypsinogen gene are burdened with a 70- to 140-fold increased risk of developing pancreatic cancer, particularly if they smoke. Whether this is also true for patients who carry SPINK-1 or CFTR mutations needs to be determined. Genetic testing for trypsinogen gene mutations can be recommended for chronic pancreatitis patients who have first-degree relatives suffering from pancreatitis or pancreatic cancer, and for patients with chronic pancreatitis or recurrent bouts of acute pancreatitis before the age of 25 years and no identifiable risk factor.76 Genetic testing for clinically unaffected relatives is not indicated and should only be performed within ethics committee-approved research protocols.


434 Table 28.5 Dosage of pain medication in chronic pancreatitis according to the AGA guidelines77 Generic

Dosage

Maximal dosage/day

Paracetamol

2–3 ⫻ 500–1000 mg

4000 mg

Metamizol

1–4 ⫻ 500–1000 mg

4000 mg

Tramadol

4 ⫻ 100 mg, 2–3 200 mg (ret)

400 mg (600 mg ret)

Buprenorphin

3–4 ⫻ 0.2–0.4 mg

6–9 ␮g/kg bodyweight

Pentazocin

6–7 ⫻50 mg

360 mg

Tilidin

3 ⫻50–200 mg

600 mg

Morphine

Dependent on the effect on pain relief

No maximal dosage given

Levopromazin

3–5 ⫻ 10 mg

300 mg

Clomipramin

1 ⫻ 50–100 mg

100 mg

before or after the meals. When gastric hyperacidity is present, proton pump inhibitors or H2 antagonists should be prescribed to delay enzyme inactivation. In cases of progressive maldigestion and steatorrhea, it can be necessary to supplement lipid-soluble vitamins parenterally. In cases of severe exocrine insufficiency, one-third of the daily caloric intake can be met by administration of medium-chain triglycerides, which do not require lipolysis by lipase for absorption. While this is clinically effective, MCT fat is usually disliked by the patients because of its poor taste. The efficacy of enzyme supplementation is demonstrated by the improvement of symptoms and not by laboratory tests.67,81–85

Endoscopic therapy Common bile duct stenting: Many studies which have investigated the natural course of chronic pancreatitis have shown that 30–60% of all patients undergo surgical intervention at some point in the disease process. However, this varies greatly among countries depending whether chronic pancreatitis patients are initially seen by surgeons (e.g., UK, high rate of operations) or physicians (e.g., Switzerland, low rate of operations). Approximately two-thirds of all patients can be managed conservatively or with endoscopic intervention. In 10–40% of patients, a stenosis of the common bile duct occurs that requires either endoscopic or surgical intervention. Either endoscopic or surgical intervention is clinically indicated if the patient presents with jaundice or recurrent bouts of cholangitis, to prevent secondary biliary cirrhosis. It may also allow the clinician to determine whether the common bile duct stenosis in chronic pancreatitis is the cause of pain. Several studies have examined the cost-effectiveness and the outcome of stenting of the common bile duct. They have concluded that endotherapy is initially equivalent to surgery for short-term symptom control and immediate decongestion but that only one-third of patients benefit in the long term. On the other hand, endotherapy is less invasive and is probably associated with less severe complications than surgery. It can thus be offered to patients as initial treatment with an immediate effect and an approximately 30% chance of a long-term benefit. It may be required as an emergency procedure for patients with cholangitis or as the definitive treatment for patients unfit for surgery. However, it needs to be kept in mind that long-term

insertion of biliary stent can also increase the risk of cholangitis and biliary sepsis. For several decades clinicians used antibiotics or ursodeoxycholic acid to prevent clogging of the endoprostheses. Even antibiotic-coated stents were used for this purpose. It has recently been shown that this treatment does not reliably extend the patency of plastic stents. The only way to effectively prevent stent clogging is to insert a large-bore endoprosthesis and to replace the stent at least every three months. The insertion of self-expanding metal wire stents is clinically not indicated for the treatment of benign bile duct strictures in patients with chronic pancreatitis (Table 28.6).63,86–90 Stenting of the main pancreatic duct: Whether endoscopic decompression of Wirsung’s duct is clinically indicated in the treatment of chronic pancreatitis patients with a dominant stenosis is still a matter of debate. No single prospective randomized controlled trial has shown a beneficial therapeutic effect on the metabolic complications of chronic pancreatitis after ductal decompression by endoprosthesis. The primary outcome of pain relief was addressed in a study by Dite and coworkers. They showed, in a prospective, randomized trial comparing endoscopic and surgical therapy for pain management in chronic pancreatitis, that surgery is superior to endotherapy for long-term pain relief but immediate pain relief can be achieved by endoscopic decompression.88 A beneficial effect of endoscopic stenting was confirmed by a large retrospective multicenter study enrolling 1000 patients on an intention to treat basis.90 Pain relief was achieved in this cohort in 65% after endoscopic decompression of the pancreatic duct and patients remained pain-free over the

Table 28.6 Indications for endoscopic biliary stenting For symptomatic relief of cholestasis and jaundice To drain infected bile and treat or prevent cholangitis To gain time for repression of a reversible inflammatory process or pseudocyst To prevent secondary biliary cirrhosis To differentiate between pancreatic pain and pain caused by biliary obstruction

435

Surgical management Surgical treatment for chronic pancreatitis is clinically indicated if intractable upper abdominal pain is refractory to conservative pain management or when organ complications occur. If pain is the leading symptom and imaging studies exclude other secondary complications of chronic pancreatitis, bilateral thoracoscopic splanchnicectomy can be performed for pain control. In 1943 Mallet-Guy described pancreatic denervation in the treatment of chronic pancreatitis pain. In 1993 the technique was rediscovered and modified as a video-endoscopic-assisted, minimally invasive treatment procedure. In a prospective randomized single-center study, it has been shown that bilateral thoracoscopic splanchnicectomy can lead to effective long-term pain relief with only 7% morbidity in patients who achieve temporary pain relief from peridural analgesia.100–102 In addition to refractory pain, the indications for surgery in chronic pancreatitis are closely related to complications that result from an enlarged, inflamed pancreatic head. These include obstruction of the common bile duct, stenosis of the pancreatic duct, obstruction of the duodenal loop and, in rare cases, compression of the portal vein. It should also be noted that in a retrospective analysis the incidence of pancreatic malignancy was 6–14% in a cohort of more than 200 patients with chronic pancreatitis who were originally operated on for an inflammatory mass in the head of the pancreas.103 One recent study has shown that early surgical intervention can delay the loss of exocrine and endocrine function in patients with chronic pancreatitis.104 Surgical procedures include drainage operations, organ preserving procedures, and major pancreatic resections. The classical Kausch-Whipple procedure was long regarded as the standard procedure for chronic calcifying pancreatitis. During the last two decades it has been steadily replaced by more procedures which are more organ-preserving, such as the pylorus-preserving Whipple procedure according to Longmire-Traverso (pp-Whipple), the duodenum preserving pancreatic head resection (DPPHR) according to Beger and, when extended by a longitudinal pancreaticojejunostomy by the socalled Frey procedure.105 When deciding upon a suitable surgical procedure, one must distinguish between two different disease manifestations of chronic pancreatitis: large duct disease in which the duct of Wirsung is dilated to more than 7 mm; and small duct disease without a dilated pancreatic duct. In large duct disease, drainage procedures such as the longitudinal pancreaticojejunostomy according to Partington-Rochelle or a Puestow procedure can be performed. Both procedures are employed when pain generation is considered to be the result of increased intrapancreatic ductal and parenchymal pressure. Both include a Roux-en-Y jejunal loop to decompress the pancreatic main duct and the duct of Santorini along with the parenchyma. The procedures are associated with low perioperative morbidity and mortality, but long-term pain relief can be achieved in only 60% of cases.106 Because the inflamed pancreatic head is regarded as the pacemaker for the generation of pancreatic pain, and because most pancreatic islets are found in the pancreatic tail, a pancreatic left resection is rarely considered as an option. It is clinically indicated only for persistent or complicated pancreatic pseudocysts or for chronic pancreatitis confined to the tail of the gland.

Treatment Strategies

observation period of at least 2 years. However, there is evidence that stenting of the pancreatic main duct can damage the ductal epithelium, causing a continuous inflammatory stimulus that subsequently progresses to fibrosis and stricturing of the duct.88 Due to its low degree of invasiveness and its immediate success in pain management, endotherapy can be offered as a first-line treatment. Surgery could then follow after stent failure or in cases of recurrence. For patients with intraductal pancreatic stones, a nasopancreatic drain should be inserted before extracorporeal shock wave lithotripsy of the stones and endoscopic removal of the fragments.55,91–94 Pancreatic pseudocysts which impress the stomach wall can be drained by endoscopic ultrasound-guided, pigtail drainage into the stomach. Extracorporal shock wave lithotripsy for pancreatic duct stones: Before the introduction of extracoporal shock wave lithotripsy (ESWL) in 1989, open surgery was the only option for treating pancreatic duct stones which were not accessible to endoscopic removal. Several retrospective studies have since investigated the clincal benefit of ESWL for the treatment of pancreatic duct stones. These studies were not able to demonstrate an advantage for ESWL when compared to surgical intervention. We therefore conclude that ESWL is technically feasible, it is associated with a low complication rate, a low morbidity, and nearly no mortality and it results in an immediate benefit for the patient if technically successful. The results of long-term studies, however, favor surgical intervention.88,95,96 Endoscopic treatment of pancreatic pseudocysts: Approximately 25% of patients with chronic pancreatitis develop pancreatic pseudocysts, mainly after an acute episode of the disease. This number is derived from a Swiss longitudinal study investigating the incidence of pseudocysts in a cohort of 245 patients with alcoholic chronic pancreatitis.1 In the first 6 weeks 40% of pancreatic pseudocysts resolve spontaneously, while in 20% of cases complications such as bacterial superinfection, compression of neighboring organs, hemorrhage, persistent inflammation of the pancreas, or rupture of the pancreatic pseudocyst can occur. If a pseudocyst persists for more than 12 weeks, spontaneous regression is unlikely and the complication rate rises to 60%. Several recent studies have documented that the rate of complications rises when the diameter of the pseudocysts exceeds 5 cm. Smaller cysts and asymptomatic cysts can be safely monitored for at least 12 weeks. When pseudocysts become symptomatic or when they persist for more than 3 months, either surgical or endoscopic decompression should be considered. Endoscopic and surgical drainage procedures have both been shown to be effective in terms of technical feasibility and recurrence rate. In general, endoscopic intervention is used as a first-line treatment because it is less invasive and has a lower morbidity. Endoscopic drainage can be performed via the gastric or intestinal wall or through the pancreatic duct. The lowest complication rate is achieved if the pseudocyst can be drained into the stomach via a pigtail catheter. Although percutaneous pseudocyst drainage was first performed in 1867 and can be safely performed using ultrasound- or CTguided techniques, it has been more or less abandoned because of the higher risk of secondary infection, the risk of persistent pancreatic fistulas, and the high recurrence rate. The percutaneous complication rate is twice that of internal endoscopic or surgical drainage.97–99


436 Classical resective procedures can also be successfully performed in patients with small duct disease. For many years, a pancreaticoduodenectomy (Kausch-Whipple procedure), was regarded as the standard surgical procedure for chronic pancreatitis with complications arising from the pancreatic head, even if the results were burdened with a high perioperative morbidity and mortality rate of up to 44%. More recent studies have shown that hospital mortality has fallen to below 5% and that it may be less than 1% in large specialized centers. Although the classical KauschWhipple resection is successful in achieving pain relief in chronic pancreatitis, it is unfortunately associated with a high postoperative morbidity and a poorer long-term surgical result. The Kausch-Whipple procedure is associated with a number of side effects which may alter quality of life. Dysbalanced intestinal motility, including dumping, frequently results from the procedure. Peptic ulcers can arise at the site of the anastomosis as a result of gastrin secretion in the remaining stomach, and reflux of bile occurs due to the removal of the pylorus. Many patients complain about dyspeptic symptoms. In approximately 20% of patients, endocrine function gradually declines after the KauschWhipple operation, and the resulting diabetes mellitus is responsible for much of the late postoperative morbidity and mortality. To address the drawbacks of the classical Kausch-Whipple operation, during the last two decades organ-preserving techniques such as the pylorus-preserving Whipple have evolved as an attempt to minimize the disadvantages of the classical procedure. Dumping as well as peptic ulcers and reflux of bile is reduced by the ppWhipple procedure, and the continuity of the gastrointestinal tract is less affected. Up to 90% of all patients gain weight after the pp-Whipple but up to 50% of patients still suffer from delayed gastric emptying associated with a delayed weight gain and a slightly increased risk of developing cholangitis. However, 45% of patients still lose their remaining exocrine and endocrine function regardless of the operation. Originally, the pp-Whipple procedure was created to treat pancreatic malignancies with adequate oncological radicality. In general, an extended resection, as in the Whipple procedure, is clinically not indicated for a benign disorder such as chronic pancreatitis. In 1972 H.G. Beger established the so-called duodenum preserving pancreatic head resection as a new surgical approach to chronic pancreatitis. With this procedure the anatomical structures of the gastrointestinal tract are not altered and their continuity is not disturbed. In a high-volume single center, duodenum preserving pancreatic head resection was noted to result in pain relief over 5 years in 80% of cases and the perioperative mortality was 0.7%. More than 70% of patients were resocialized into daily work routine and, only in rare cases, the loss of endocrine function progressed.103 In 1985 Frey and Smith extended the duodenum preserving pancreatic head resection by adding a longitudinal pancreaticojejunostomy and, in this manner, combined the organ preserving surgical procedure with a drainage operation.107 In a randomized prospective single-center study with a median observation period of 2.5 years, the Beger procedure and the Frey procedure were shown to result in equivalent postoperative outcome.108 In 1998 Izbicki suggested a modification of the Frey procedure for the treatment of chronic pancreatitis without a dilatated pancreatic duct.109 He performed a V-shaped resection of the ventral pancreas to drain the second- and third-order pancreatic ducts via a longitudinal pancreaticojejunostomy. In a small group

of patients and with an observation period of 30 months he was able to show that his modification resulted in complete pain relief in 95% of cases. In 67%, the quality of life increased and the procedure was associated with a low perioperative morbidity rate of 15.4% and no mortality rate.109 Recently, Büchler et al. modified the Beger procedure to allow the resection of the pancreatic head without transection of the gland over the superior mesenteric vein. In this manner the risk of bleeding complications (especially in patients with portal hypertension) is thought to be minimized while still allowing an excision of the pancreatic head.110 Future randomized prospective trials will have to evaluate the more recently modified techniques. It is still a matter of debate whether a prophylactic perioperative application of somatostatin analogues can reduce the rate of leakage from the pancreaticojejunostomy. Leakage at that anastomosis results in an increased mortality and frequently requires interventional treatment. The incidence of leakage at the site of the pancreaticojejunostomy is reported to be 0–30%. In 2001, Li-Ling and Irving demonstrated, in a meta-analysis of all randomized trials, a significant reduction of pancreatic fistulas when a somatostatin analogue was perioperatively administered. The rate of reduction in leakage at the site of anastomosis was as high as 40%.111 The route of application and the duration required are still being discussed but three doses of 100 ␮g of sandostatin a day for at least 5–7 days is often regarded as the standard protocol.112 In summary, the most widely accepted organ-preserving technique is now the duodenum preserving pancreatic head resection and this procedure should be preferred for the surgical treatment of chronic pancreatitis with complications arising from the pancreatic head.87,103,104,110

SUMMARY With an incidence of 8.2 and a prevalence of 27.4 per 100 000 population, chronic pancreatitis represents a frequent disorder of the gastrointestinal tract. In the past, chronic pancreatitis was considered to be mostly associated with chronic alcohol abuse. During the past two decades idiopathic chronic pancreatitis and, moreover, hereditary pancreatitis have been recognized as distinct disease entities. Hereditary pancreatitis is an autosomal dominant disorder with an 80% penetrance. It is associated with recurrent episodes of pancreatitis starting in early childhood and associated with an increased risk of pancreatic cancer. The pathophysiology of chronic and hereditary pancreatitis is not fully understood. Patients suffering from chronic pancreatitis present with beltlike abdominal pain, weight loss, steatorrhea, and, often, diabetes mellitus. Usually the diagnosis is made by a combination of imaging procedures such as ultrasound and endoscopic retrograde cholangiopancreatography, and exocrine and endocrine function tests. Therapy is presently restricted to symptom control for the lack of a causal treatment strategy. Thirty to 60% of all patients develop disease-associated complications such as persistent pain, strictures of the common bile duct, or pancreatic duct stones that may require either endoscopic or surgical treatment. Figures 28.2 and 28.3 provide algorithms for the diagnosis of chronic pancreatitis and treatment of chronic pancreatitis, respectively.

437

Patient’s history

Clinical criteria Upper abdominal pain, steatorrhea, weight loss, diabetes mellitus

Clinical examination

Imaging criteria

Functional criteria

Ultrasound

Exocrine

Endocrine

Indirect function tests

ERCP

EUS

CT

MRT-MRCP Direct function tests

Etiological criteria Genetic testing if hereditary pancreatitis is suspected or patient is 70

Adapted from Jensen RT, Norton JA11 and Arnold R, et al.26

Zollinger-Ellison Syndrome and other Neuroendocrine Tumors

470 Pancreatic neuroendocrine tumors may be sporadic (nonfamilial) or develop as part of the MEN I syndrome.5–9 MEN I (Werner’s syndrome) is inherited as an autosomal dominant disorder with a high degree of penetrance. It is characterized by neoplasms or hyperplasia involving the parathyroid glands, pancreas, pituitary and, less commonly, the adrenal cortex and thyroid gland. Gastrinomas are the most frequent tumor associated with MEN I. The genetic defect predisposing to MEN I has been mapped to the long arm of chromosome 11 (11q11-q13). Establishing the diagnosis of MEN I (strong family history, multiple organ involvement) is essential since family screening is mandatory in this disorder. The gene responsible for MEN I has been cloned10 and will ultimately facilitate genetic screening for this disorder. The presence of MEN I will impact the surgical approach to the patient, as will become evident when the treatment of gastrinomas is reviewed below. Awareness of the signs and symptoms associated with these rare tumors in addition to a high level of suspicion by the clinician provides the elements needed for the establishment of an early diagnosis. Early detection will enhance the likelihood of definitive surgical therapy, which is particularly important when one considers that the likelihood of these tumors being malignant exceeds 50%. A detailed review of the clinical features of pancreatic endocrine tumors is beyond the scope of this chapter, and several comprehensive reviews of this subject are available.4,5,11–14 The following is a brief summary of several salient clinical features of these rare syndromes.

Specific syndromes

Neck of gallbladder

Neck of pancreas Junction of 2nd and 3rd portion of duodenum

•

Fig. 31.1 Gastrinoma triangle.This hypothetical triangle is defined as the confluence of the cystic and common bile ducts superiorly, junction of the second and third portions of the duodenum inferiorly and junction of the neck and body of the pancreas medially. Adapted with permission from Stabile BE, et al.15

Zollinger-Ellison syndrome Severe peptic ulcer diathesis secondary to gastric acid hypersecretion due to autonomous gastrin release from a non-␤ cell endocrine tumor (gastrinoma) defines the components of the Zollinger-Ellison syndrome.5,6 Early on, Zollinger-Ellison syndrome was typified by aggressive and refractory ulceration in which total gastrectomy provided the only chance for enhancing survival. Advances in medical and surgical approaches have converted Zollinger-Ellison syndrome into a disease that, if identified early, can be cured by surgical resection in up to 30–34% of patients with sporadic (non-MEN I related) disease. The true incidence of gastrinoma is unknown, but in the United States it is estimated to be present in 0.1–1% of individuals with peptic ulcer disease. There is a slight predominance of males over females, and the majority of patients are diagnosed between the age of 30 and 50 years. Gastrinomas are classified into sporadic tumors (60–80%) and those associated with multiple endocrine neoplasia type I (MEN I, see below).9 Greater than 80% of these neoplasms are found within the hypothetical gastrinoma triangle, defined as the confluence of the cystic and common bile ducts superiorly, junction of the second and third portions of the duodenum inferiorly, and junction of the neck and body of the pancreas medially (Fig. 31.1).15 Duodenal tumors constitute the most common nonpancreatic lesions, with recent studies suggesting that as many as 50% of gastrinomas are found in this location. In excess of 60–80% of tumors are considered malignant, with up to 30–50% of patients having multiple lesions or metastatic disease at presentation.6 Peptic ulcer is the most common clinical manifestation, occurring in over 90% of gastrinoma patients. Suspicion of a gastrinoma

should arise in patients with ulcers in unusual locations (second part of the duodenum and beyond), ulcers refractory to standard medical therapy, ulcer reoccurrence after acid reducing surgery, or ulcers presenting with frank complications (bleeding, obstruction, and perforation). Symptoms of esophageal origin are present in up to two-thirds of Zollinger-Ellison patients, with a spectrum ranging from mild esophagitis to frank ulceration with stricture and Barrett’s mucosa. Diarrhea is the next most common clinical manifestation, being present in as many as 50% of patients, with the etiology being multifactorial, resulting from marked volume overload to the small bowel, pancreatic enzyme inactivation and bile salt precipitation by acid overload, and mild damage of the intestinal epithelial surface by acid. Gastrinomas can develop in the presence of MEN I syndrome in approximately 25% of patients.9 An additional distinguishing feature in Zollinger-Ellison patients with MEN-I is the higher incidence of gastric carcinoid tumor development (as compared to patients with sporadic gastrinomas). Moreover, gastrinomas tend to be smaller, multiple, and located in the duodenal wall more often then what is seen in patients with sporadic disease. Establishing the diagnosis of MEN I is critical not only from the standpoint of providing genetic counseling to the patient and his/her family, but also from the surgical approach recommended (see below). Recent success in controlling gastric acid hypersecretion in this group of patients (see Ch. 20) has shifted emphasis of therapy towards providing a surgical cure. Detecting the primary tumor

471

Insulinoma Insulinomas are the most common symptomatic endocrine tumor of the pancreas.11–14,16 The clinical features are secondary to hypoglycemia resulting from the autonomous release of insulin from the neoplasm. Symptoms are frequently associated with fasting and are most commonly of the neuroglycopenic variety (mild personality changes, confusion, drowsiness, visual disturbance, coma) as opposed to the signs and symptoms related to compensatory catecholamine release (diaphoresis, pallor, tachycardia). Insulinomas are generally solitary benign tumors of the pancreas (70–80%) that are often amenable to resection. The diagnosis requires documenting hypoglycemia in the presence of inappropriately elevated plasma insulin levels. An in-hospital fast (up to 72 hours) coupled with monitoring of blood glucose and insulin levels is the most effective way of establishing the diagnosis. This test is positive for insulinoma if serum insulin levels are stable or increase during hypoglycemia (blood sugar 90%), with more than 60% being malignant. The diagnosis depends on establishing the presence of secretory diarrhea (>700 mL/day, which persists during fasting and is isotonic) in association with elevated plasma VIP levels (normal levels = 0–170 pg/mL).

Glucagonoma Excessive release of glucagon from a pancreatic neoplasm account for the signs and symptoms associated with this syndrome.4,11–14,17–19 Clinical manifestations include a characteristic rash (migratory necrolytic erythema, 70–85%), glucose intolerance or diabetes (85%), hypoaminoacidemia (80–90%), weight loss (85%), anemia (85%), diarrhea (15%), thromboembolic phenomena (20%), and glossitis (15%). The rash progresses over 7–14 days from erythematous macules to fluid-filled bullae followed by central necrosis, scaly eczematoid lesions, and central clearing and scaling. The lesions occur most commonly in areas of friction, as well as on the face and distal extremities. The mechanism for rash development is unclear. Glucagonomas occur almost exclusively in the pancreas (body and tail) and are large (>5 cm), with the majority

having evidence of metastasis (liver) at the time of presentation. Delay in diagnosis is probably related to the insidious signs and symptoms. Diagnosis depends on the presence of elevated plasma glucagon level (normal levels = 0–150 pg/mL) in the appropriate clinical scenario. Several causes of increased glucagon levels have been described (diabetes mellitus, renal failure, cirrhosis, acute injury, bacteremia, and Cushing’s syndrome), and thus a plasma glucagon level should exceed 500 pg/mL for the diagnosis of this endocrine neoplasm.

Somatostatinoma Release of somatostatin from an endocrine neoplasm originating from either the pancreas or the small intestine typifies this syndrome.4,11–14 The variable clinical presentation has led to some controversy regarding the existence of a distinct somatostatinoma syndrome. The triad of symptoms most frequently encountered in pancreatic somatostatinoma patients includes gallstones (95%), diabetes mellitus (95%), diarrhea (92%). Other manifestations include weight loss (90%), hypochlorhydria (85%), and steatorrhea (80%). With intestinal neoplasms, weight loss (70%), gallbladder disease (40%), and diarrhea (38%) are the most commonly encountered clinical manifestations with diabetes (20%), hypochlorhydria (17%), and steatorrhea (12%) following thereafter. As with gastrinomas, somatostatinomas are frequently found in extrapancreatic sites (44% small intestine) as well as in the pancreas (56%, usually head of pancreas). Similar to VIP and glucagon producing tumors, somatostatinomas are large (≈5 cm in diameter) at the time of diagnosis. The diagnosis requires a high level of suspicion (clinical triad: gallstone, diabetes, and diarrhea) coupled with an elevated plasma somatostatin level.

GRFoma This more recently described neoplasm (1982) usually originates in the pancreas and secretes high levels of growth hormonereleasing factor (GRF).4,11–14 The most common clinical manifestations are those associated with acromegaly (large extremities, coarsening of facial features, oily skin, malodorous perspiration, hypertrichosis, voice changes, visceral hypertrophy, and glucose intolerance). Forty percent of these cases have been associated with Zollinger-Ellison syndrome, and approximately 30% are associated with MEN I syndrome. Patients frequently have a large pancreatic mass (>5 cm) with evidence of metastasis to the liver at the time of presentation in approximately one-third of the cases. The diagnosis depends on identifying an elevated plasma GRF level in a patient with the appropriate clinical presentation. A summary of the salient clinical features corresponding to the different endocrine neoplasms is outlined in Table 31.1.

THERAPY As is the case with solid tumors in general, the only chance at curing these indolent neoplasms is through surgical resection. Despite this concept, additional considerations must be brought to light when approaching the treatment of individuals with these rare neoplasms. Specifically, the clinician needs to ameliorate the potentially life-threatening sequelae and often incapacitating symptoms related to hormone overproduction. This principle will be critically important in managing the patient who is awaiting localization studies while anticipating surgery, and in individuals who are deemed unresectable because of metastatic disease. Recent

Therapy

and excluding metastatic disease is critical in view of this paradigm shift.


472 work demonstrating the direct impact of tumor extent on survival,20–24 coupled with the limited success of medical therapy in controlling progression of metastatic disease, serves to further reinforce the importance of early diagnosis, localization, and surgical resection of these indolent, yet often relentless, neoplasms. The following section will review the medical and surgical management of endocrine tumors of the pancreas. In view of the potential applicability of somatostatin analogues to the diagnosis and therapy of the majority of these tumors, the first portion of this section will review the pharmacology of these novel compounds. Subsequent sections will focus on the medical and surgical therapy of specific syndromes.

Gastrointestinal actions of somatostatin Ala

Gly

Cys

Lys

Phe

Phe Trp

S S Cys

Lys Ser

Thr

Phe

Somatostatin

D-Phe Cys

Phe D-Trp

S S

Somatostatin analogues

Thr-ol Cys

Understanding the biology of peptide hormone receptors expressed on neuroendocrine tumors has ushered in an exciting paradigm for the treatment of these rare neoplasms.24 For example, development of stable somatostatin analogues (see below) has revolutionized the therapy of functional endocrine tumors. Over 80% of neuroendocrine tumors (with the exception of insulinomas) express somatostatin receptors. Octreotide24–28 and lanreotide28,29 are two examples of analogues that have reached clinical utility. The former is available in the United States and has been used extensively for the therapy of functioning secretory tumors. Somatostatin was first isolated as a 14-amino-acid peptide from ovine hypothalamus by Brazeau and colleagues during their search for a factor involved in regulating pituitary growth hormone release. Subsequent to this discovery, somatostatin was found distributed throughout the body in areas extending from the nervous system to the gastrointestinal tract. Moreover, five subtypes of somatostatin receptors have been described and cloned, each having a characteristic structure, distribution, and biological function.24,28 Somatostatin is unique because it exerts a wide array of inhibitory actions on multiple physiologic functions (Fig. 31.2). Early studies using native somatostatin for the therapy of secretory diarrhea were promising, but the peptide’s short halflife (approximately 2 minutes) limited its practical utility. Advances in peptide hormone biochemistry have facilitated the engineering of the chemically stable analogue of somatostatin, octreotide. Octreotide is a synthetic eight-amino-acid peptide designed on the basis of the structural components of somatostatin that are essential for its biological activity (see Fig. 31.2).25,26,28 In addition to retaining biological activity, octreotide has a longer plasma half-life than its native counterpart (90 minutes as compared to 2 minutes). Octreotide exerts its action by binding to the somatostatin receptor subtype 2.24 Due to its poor intestinal absorption, this analogue must be administered parenterally, reaching peak plasma levels approximately one hour after subcutaneous injection, with maximal clinical efficacy noted 2 hours after administration. Initial reports suggest that hepatic extraction can account for 30–40% of octreotide metabolism, while approximately 11–30% of the parent compound is recovered from the urine and less than 2% appears unchanged in feces. Prolonged plasma clearance of octreotide has been demonstrated in patients with renal failure on hemodialysis, and the dose should thus be adjusted accordingly. From the standpoint of its biological activity, in vitro studies have demonstrated that the inhibitory effect of octreotide on cellular function is equal to or slightly greater than that of native

Asn

Lys Thr

Octreotide

Thr

Inhibits • Gastric endocrine and exocrine secretion • Pancreatic endocrine and exocrine secretion •Gallbladder contractility • Bile flow • Splanchnic blood flow • Tissue growth and proliferation • Gastrointestinal transit time Stimulates • Water and electrolyte absorption

•

Structure and gastrointestinal actions of somatostatin and Fig. 31.2 octreotide. Shaded amino acids are important for biological activity. (Reprinted from Maton PN, Gardner JD, Jensen RT, Digestive Disorder Science, 1989; 34:285. © 1989 with permission from Springer Science and Business Media.)

somatostatin. In contrast, in vivo studies reveal that the stable analogue is three times, 23 times, and 80 times more potent than somatostatin in mediating inhibition of insulin, glucagon, and gastric acid secretion, respectively. The enhanced potency of octreotide in vivo is most likely due to its prolonged stability in plasma. A large number of clinical trials have demonstrated the efficacy of octreotide in ameliorating the signs and symptoms of several pancreatic neuroendocrine tumors of the pancreas (see below). Moreover the potential antiproliferative effects of this compound have led to its use as an antitumoral agent. The recent development of radiolabeled octreotide has added a new dimension to this compound as a diagnostic/staging tool and more interestingly as a nuclear probe for tumor therapy.24 A consensus statement regarding dosing schedules for octreotide has been published.30 In the case of VIPoma and other secretory diarrhea related to neuroendocrine tumors, octreotide should be started at a dose of 100–150 ␮g/day and increased to 200 ␮g every 8 hours if the response is not adequate. If the patient is still refractory, 100 ␮g increments per dose can be administered to a maximum 1500 ␮g per day. If control of symptoms is achieved, a gradual decrease in the dose after 2–3 weeks of therapy can be initiated. The dose should be decreased by 25 ␮g/injection per week. In patients with severe or life threatening signs and symptoms, the initial dose (100 ␮g) can be administered intravenously followed by a continuous infusion of 50 ␮g/hour. Once symptoms are controlled, a change to subcutaneous octreotide should be initiated. A long-acting form of octreotide has been developed and is presently available for use in the United States and Europe.28,31 The compound (Sandostatin LAR®) consists of octreotide prepared in a slow-release formulation that can be administered as an intramuscular depot injection once per month. Early studies in patients with carcinoid tumors suggest that symptom control is achieved by 7–14 days of administration.31 The compound is available in 10-, 20- and 30-mg doses (as compared to microgram dosing for octreotide). One suggested approach to using this compound is to begin the patient on short-acting octreotide as

473

Medical therapy of specific syndromes Zollinger-Ellison syndrome The cornerstone to the therapy of gastrinoma patients is aggressive control of gastric acid secretion.4,20,33 Prior to the advent of inhibitors of gastric acid secretion (histamine H2-receptor antagonists, proton pump inhibitors), the only option for these patients was total gastrectomy. The advent of potent antisecretory agents, in particular proton pump inhibitors (PPIs), has dramatically changed the approach to these patients.4,33,34 (See Chapters 1 and 20 for a review on the treatment of ZollingerEllison syndrome with inhibitors of gastric acid secretion.) In general, therapy is aimed at decreasing basal acid secretion to 2 months) should be monitored for gallstone development. The low rate of symptomatic disease does not warrant prophylactic cholecystectomy, but may be a consideration in patients undergoing surgery for a different reason (debulking, etc.).


474 first line of therapy must be aimed at correcting the fluid and electrolyte abnormalities since these can be quite severe and potentially fatal. Subsequently, control of the large-volume diarrhea is essential. A host of therapeutic modalities have been used in an effort to decrease high stool outputs related to VIPoma. These options have included high-dose prednisone (>60 mg/day),47–49 which has been shown to decrease the diarrhea in a significant percentage of patients. Other agents reserved for patients that are intolerant to prednisone have included indomethacin,50,51 clonidine, lithium,52 phenothiazines,53 propranolol,54 and loperamide. Unfortunately, patients are not uniformly responsive to any one of these drugs. Octreotide has also proven most useful in ameliorating the signs and symptoms related to VIPoma. Early studies demonstrated significant improvement in patient’s diarrhea after treatment with native somatostatin administered by continuous infusion, but the short plasma half-life limited its practical utility.55–58 Subsequent studies have confirmed that octreotide can decrease diarrhea in over 80% of VIPoma patients.59–62 Of interest, there have been several patients who improved symptomatically with octreotide and continued to have elevated plasma VIP levels. Some have suggested that synthesis of VIP in the tumor may have been altered such that a biologically less active molecular form was released from the neoplasm.63 This observation also reinforces the concept that the inhibitory effect of somatostatin is multifactorial and is not limited to its effect on secretogogue release from the neoplasm. In summary, over 80% of VIPoma patients treated with octreotide have experienced significant symptomatic improvement. The dosage utilized has ranged from 100 to 1500 ␮g/day, and the duration of therapy for some has been as long as 38 months.64 These observations indicate that octreotide is the most effective drug available for the treatment of this disorder. Experience with the long-acting form of octreotide in patients with VIPoma, as well as the subsequent tumors reviewed in this chapter, is limited, but the anticipation is that it will also provide a useful addition to the treatment of these patients.

Glucagonomas The presentation of glucagonoma patients can be quite indolent and escape detection for many years, with more than 60% being metastatic at the time of diagnosis. As in the case of other neuroendocrine tumors, surgical resection provides the only possibility for cure. Unfortunately, surgery is not often feasible in view of metastatic disease being present at diagnosis. A surgical procedure will often be recommended, and preoperative correction of hypoaminoacidemia (malnutrition) and anemia seem warranted. Some have described improvement of the severe rash with total parenteral nutrition and zinc replacement, although this approach remains controversial. Thirty percent of patients may present with thromboembolic phenomena including pulmonary emboli,17,18,65 and measures should thus be taken to prevent venous thrombosis, especially if the patient is awaiting surgery. These measures should include low-dose subcutaneous heparin and/or compression stockings.13 If distal pancreatectomy with splenectomy is contemplated, a pneumococcal vaccine should be administered.13 Both native somatostatin and octreotide have been utilized in the treatment of glucagonoma patients with some success. Over 17 glucagonoma patients have been treated with the stable analogue in doses ranging 50–450 ␮g per day,66–68 with greater than 50% experiencing resolution of the rash and greater

than 60% of subjects having a reduction in plasma glucagon levels. Approximately one-half of these patients received octreotide for more than 6 months. Of note, octreotide had little effect on tumor size and diabetes.

Somatostatinoma, GRFoma The indolent and variable presentation of somatostatinomas make medical therapy difficult to generalize. The most common clinical sequelae related to pancreatic lesions that will often lead to medical attention include diabetes mellitus (95%), gallbladder disease, and diarrhea. Each of these may be managed prior to establishing an association with a somatostatin-producing tumor. The role of octreotide has not been examined extensively in this disorder. GRFomas most often present with signs and symptoms of acromegaly. It is important to consider this type of tumor in patients with peptic ulcer disease and acromegaly in view of the known association with Zollinger-Ellison syndrome. In such cases, acid suppressive therapy will be critical in the management of these individuals (see Ch. 20). Octreotide has been utilized successfully in patients with GRFomas, decreasing plasma levels of GRF, and reducing symptoms70–73 in 100% of a small number of patients treated. Although limited, the data available suggest that octreotide is the drug of choice in patients with this neoplasm.

Surgical therapy of nonmetastatic disease As outlined throughout this chapter, the only possibility for longterm cure in patients with neuroendocrine tumors is surgical resection of the neoplasm. The potential for curative resection will vary according to the specific tumor type. In addition, the presence of MEN I will impact the surgical approach taken. The rare incidence of these neoplasms, coupled with the fact that these tumors may be small, multiple, and in difficult areas to locate, makes it imperative that the procedure be performed by a surgeon experienced in the resection of neuroendocrine tumors. The last decade has witnessed a steady increase in the tools available to assist in the preoperative localization of these sometimes difficult to find tumors. A review of these modalities and their application to the different tumor types is beyond the scope of this chapter. The advent of endoscopic ultrasonography (EUS) (Fig. 31.3)74,75 and somatostatin receptor scintigraphy (Octreoscan®) (Fig. 31.4)76–78 has complemented and even supplanted the more traditional modalities, including extracorporeal ultrasound, CT scanning, nuclear magnetic resonance imaging (MRI), and angiography. Somatostatin receptor scintigraphy should generally be the first modality utilized to localize gastrinomas since it is more sensitive than CT scanning, ultrasound, MRI, and angiography combined in localizing primary tumors and as sensitive as all these

•

B

T

Fig. 31.3 Endoscopic ultrasound in a patient with the ZollingerEllison syndrome demonstrating a tumor (T) in the head of the pancreas.

475

Tumor

lying neoplasm lead to cure rates below 10%. Recent advances in early tumor detection and improved understanding of tumor distribution has led to 10-year disease-free intervals as high as 34% in sporadic gastrinoma patients undergoing surgery.79 A positive outcome is highly dependent on the experience of the surgical team treating these rare tumors. Surgical therapy of gastrinoma patients with MEN I remains controversial and is related to the difficulty in rendering these patients disease free with surgery. In contrast to the encouraging postoperative results observed in patients with sporadic disease, only 6% of MEN I patients are disease free 5 years after an operation. Some groups suggest surgery only if a clearly identifiable, nonmetastatic lesion is documented by structural studies. Others advocate a more aggressive approach, where all patients free of hepatic metastasis are explored and all detected tumors in the duodenum resected, followed by enucleation of lesions in the pancreatic head, with a distal pancreatectomy to follow. The outcome of the two approaches has not been clearly established. In contrast to insulinomas and gastrinomas, greater than 50% of glucagonomas have metastasized by the time of diagnosis,19 with an even greater percentage having extensive disease at the time of operation. Similar odds of having metastatic disease holds true for VIPoma, somatostatinoma, GRFoma, and nonfunctioning tumors, and the long-term benefit of surgical resection has thus not been clearly established in these patients.

Therapy of metastatic disease modalities in detecting metastatic disease. EUS has been found to be as accurate as somatostatin receptor scintigraphy in localizing gastrinomas and more sensitive in localizing insulinomas. EUS is often used to confirm and more specifically localize gastrinomas after localization by initial somatostatin receptor scintigraphy. A summary of the sensitivity of the various modalities used for localizing insulinomas and gastrinomas is summarized in Table 31.2. It is essential that all patients with documented biochemical evidence of a neuroendocrine tumor undergo detailed evaluation in an effort to localize the tumor and determine the extent of involvement (metastatic versus nonmetastatic). As discussed above, the tumor with greatest potential for surgical cure is an insulinoma. Between 75% and 95% of insulinoma patients can be cured with surgery.11–16 As in the case of insulinomas, the ultimate goal of surgery in gastrinoma patients is to provide a definitive cure. No longer is total gastrectomy routinely required in these patients. Early attempts at resection of the under-

Table 31.2 Sensitivity of multiple imaging modalities in detecting primary gastrinomas and insulinomas

Imaging procedure

Sensitivity (%) Gastrinoma Insulinoma

EUS

11/14 (79)

13/14 (93)

SRS

12/14 (86)

2/14 (14)

CT

4/14 (29)

3/14 (21)

US

4/14 (29)

1/14 (7)

MRI

4/14 (29)

1/14 (7)

Adapted from Zimmer T, et al. Gut 1996; 39:562–568.

Despite the steady advances made in the diagnosis, localization, and therapeutic modalities pertinent to neuroendocrine tumors of the pancreas, issues regarding the approach to unresectable or metastatic disease remain unresolved. The reasons include the rarity with which these tumors develop, their slow-growing nature and the somewhat limited information available regarding the natural history of these tumors. The advent of effective therapy for the control of symptoms and potential-life threatening complications of neuroendocrine tumors has now shifted the emphasis of treatment towards controlling the growth of metastatic disease, since mortality presently appears more directly related to the latter. Grama and coworkers80 retrospectively examined 85 patients with functional pancreatic neuroendocrine neoplasms. The tumor types and the corresponding median survival are summarized in Table 31.3. Forty-eight percent (41/85) had metastatic disease at the time of diagnosis. Of these, two-thirds died from tumor progression. Although there appears to be some differences in overall 5- and 10-year survival for individual tumors, the survival rates for all malignant tumors was 54% and 28%, respectively. With regard to gastrinoma patients, 5- and 10-year survival rates vary between 62–75% and 47–53%, respectively, for all patients.5,33 Individuals with the entire tumor resected or those with a negative laparotomy have 5- and 10-year survival rates in excess of 90%. Patients with incompletely resected tumors have a 5- and 10-year survival of 43% and 25%, respectively. Finally, survival in patients with hepatic metastasis is less than 20% survival at 5 years. Characteristics considered to be favorable prognostic indicators include primary duodenal wall tumors, isolated lymph node tumor, undetectable tumor upon surgical exploration, and possibly the presence of MEN I. Poor prognostic indicators include hepatic metastasis or the presence of Cushing’s syndrome

Therapy

•

Fig. 31.4 Octreoscan in a patient with the Zollinger-Ellison syndrome demonstrating a tumor within the gastrinoma triangle.


476 Table 31.3 Survival estimates for patients with malignant endocrine pancreatic tumors

Diagnosis

Survival (%) 5-year 10-year

Median survival (months)

Insulinoma

50

50

151

Gastrinoma

47

18

51

VIPoma

88

25

103

All malignant tumors*

54

28

68

* Including glucagonoma and somatostatinoma. Adapted from Grama D, et al.78

in a sporadic gastrinoma patient. The approach to patients with metastatic neuroendocrine tumors will vary somewhat according to the type of neoplasm. First, the control of signs and symptoms related to hormone excess is essential, as discussed above, and reversing or controlling tumor growth should follow. Unfortunately, the success rates of traditional chemoradiation therapeutic approaches have been highly variable and often of limited success in altering survival. The reason for poor outcome is unclear, but may be related to the relatively well-differentiated state of these tumor cells, making them less vulnerable to agents that depend on high cell proliferative rates for success. Moreover, the relatively prolonged survival of these patients (in comparison to adenocarcinoma of the pancreas), coupled with the rarity of these tumors and inconsistencies in defining response to treatment, makes the available data difficult to interpret. The limited success rates associated with classic cytotoxic agents in conjunction with the relatively high side effect profile associated with these agents has led to a host of relatively novel approaches to the therapy of patients with metastatic endocrine tumors. These have extended from the use of hormonal agents, such as octreotide, to liver transplantation. The approach will depend to some extent on the tumor type and to a significant extent on the clinical state of the patient in terms of signs, symptoms, and tumor growth. Most patients will qualify for a step-wise approach in which a combination of therapies will be utilized in an effort to ameliorate signs and symptoms of hormone excess and tumor growth. The following sections will summarize both medical and surgical approaches that have been utilized in the therapy of metastatic neuroendocrine tumors of the pancreas.

Medical therapy Hormonal therapy The expression of somatostatin receptors on a large number of neuroendocrine tumors,24,81 coupled with experimental data suggesting that this peptide has antiproliferative effects,82–86 led to the utilization of stable somatostatin analogues as antitumoral agents.14,27,35 Early reports using octreotide demonstrating tumor shrinkage were encouraging.87–90 Unfortunately, subsequent larger-scale studies have not been as convincing of the antitumoral effect of somatostatin analogues. In a retrospective report of 94 patients by Maton and colleagues,91 it was observed that tumor

size decreased, stabilized, or progressed in 13%, 63%, and 24% of patients, respectively. More recent prospective studies have documented modest tumor shrinkage and stabilization of the neoplasm.92 Arnold and coworkers26 prospectively examined 47 patients with documented tumor progression who were treated with octreotide (200 ␮g twice daily). Initial stabilization of tumor growth was observed in 40% of patients, and the disease state remained stable in 25% and 13% of patients for 12 and 36 months, respectively. The authors did not, however, observe tumor shrinkage in any of the patients tested. It has been postulated that the lack of antiproliferative effects of octreotide may have been due to the relatively low dose tested. A recent prospective multicenter trial addressed this question by examining the effect of octreotide at either 500 ␮g (23 patients) or 1000 ␮g three times daily (35 patients) in 58 patients with metastatic neuroendocrine tumors.27 Therapy was continued until evidence of tumor progression was noted. The majority of patients had carcinoid tumors, with only 12 individuals having other hormonal neoplasms. Although the population was heterogeneous, only two carcinoid patients showed an objective decrease in tumor size, with duration of response of 10 and 14 months, respectively. Tumor stabilization for 6 months was observed in 27 patients (22%). Of note, all of these patients had either carcinoid tumors or medullary thyroid carcinomas. In addition, the beneficial effects were not related to the octreotide dose utilized. The median overall survival was 22 months, but for the noncarcinoid tumor patients, survival was only 12 months. Lanreotide has also been utilized, in a preliminary fashion, as an antiproliferative agent in the treatment of metastatic neuroendocrine tumors.93 Faiss and colleagues report observing cessation of tumor growth in 46% of all patients with high-dose Lanreotide (5 mg three times daily). Unfortunately, the tumor types examined and the duration of response were not outlined in this preliminary report. In summary, it appears that stable analogues of somatostatin will not provide a significant antitumoral effect in patients with metastatic neuroendocrine tumors. At best, it appears that tumor stabilization is achievable at high doses, but the major benefit appears to be for carcinoid tumor patients. A novel therapeutic approach attempting to capitalize on the high level of somatostatin receptor expression on neuroendocrine tumors has recently been reported. In a phase I trial, Krenning and co-workers94 treated six end-stage neuroendocrine tumor patients with octreotide radionuclide therapy. These investigators utilized [111In-DTPA-D-Phe1] octreotide in cumulative doses as high as 53 GBq per patient. The group studied was heterogeneous, consisting of two pancreatic neuroendocrine tumors (one glucagonoma, one insulinoma), two medullary thyroid carcinomas, one carcinoid tumor, and one glomus tumor. No major side effects were reported (2-year follow-up) and a decrease in tumor size was observed in 3/6 patients (both neuroendocrine tumor patients). More recent studies utilizing [111In-DTPA°] octreotide in 20 patients with advanced disease demonstrated a decrease (30%) or stabilization (40%) of the tumor. Additional radioligands being piloted include 90Y-labeled octreotide and 177Lu-DOTA-Tyr3-octreotide. The potential of targeting therapy to metastatic endocrine tumors is an exciting modality with potential future applicability, but the overall impact, efficacy, and safety of this therapeutic approach requires treatment of a larger number of patients.12,95

477 Chemotherapy

The limited success of octreotide and chemotherapy (see below) in the therapy of metastatic endocrine tumors has led to studies examining the potential benefits of ␣-interferon in this clinical setting. Initially described as antiviral agents, these naturally occurring substances have been shown to inhibit cell proliferation and modulate an immune response in several systems. The initial report examining the effect of ␣-interferon in patients with carcinoid tumor was encouraging, showing a decrease in bioactive hormone production, but no effect on tumor size.96 Subsequent studies were more encouraging, suggesting not only a beneficial effect on hormone release, but in addition an antiproliferative effect.97–99 Oberg and coworkers performed a metaanalysis of available data obtained in 310 patients treated with ␣-interferon. They observed a partial remission (decrease in tumor size by >50%) and a biochemical response in 11% and 42% of patients, respectively. Unfortunately, the heterogeneous patient population examined and the variable dose of interferon utilized led to difficulty in deriving a definite conclusion from this analysis. When examining a population of patients with metastatic neuroendocrine tumors of the pancreas, a reduction in tumor size was observed in 12% of patients, while tumor stabilization was seen in 24% of individuals treated with 5 million units of interferon-␣ three times per week.98 Unfortunately, these encouraging results were not observed in two reports examining the efficacy of interferon-␣ in patients with VIPoma100 and Zollinger-Ellison syndrome.101 In these reports, no beneficial effect of interferon on tumor growth was detected. In summary, the efficacy of interferon in the therapy of neuroendocrine tumors of the pancreas is still somewhat controversial. It appears that the antiproliferative effect of these agents is rather limited and comparable to that observed with octreotide. The major disadvantage of the former is related to the potential adverse side effects, such as flu-like symptoms, neutropenia, and depression.96–101 The marginal benefit of interferon or octreotide alone on tumor growth, coupled with the observation that these compounds exert a biological response via different mechanisms,103 has led to several small trials examining the combination of these two agents. Nold and coworkers104 observed a partial response in one patient, stable disease in three, and progressive disease in three of seven patients with neuroendocrine tumors of the pancreas. These are preliminary results that are difficult to interpret due to the small number of patients examined, and the potential benefit of combination therapy thus awaits further trials. In view of the modest benefit of ␣-interferon and octreotide as inhibitors of tumor growth, additional combination therapies have been attempted. Saltz and coworkers undertook a phase II trial of ␣-interferon in combination with 5-fluorouracil (5-FU) in patients with advanced carcinoid (14 patients) and neuroendocrine tumors (7 patients).105 Of the neuroendocrine tumor patients, one had a partial response (8 months’ duration) and four patients had stable disease for a median of 13 months. Unfortunately, significant drug toxicity developed with 14 of 21 patients, requiring reduction in the interferon dose. This degree of toxicity was much higher than that observed with interferon alone or interferon in combination with octreotide. Therefore, these results do not support the use of combination interferon and 5-FU for the routine therapy of neuroendocrine tumors.

More than 26 studies examining over a dozen possible chemotherapeutic regimens for pancreatic endocrine tumors have been published. The large number of studies is in part a reflection of the difficulty in treating this type of metastatic disease. A detailed review of these reports is beyond the scope of this chapter, and reference is made to a recent thorough review of the subject by Jensen and Norton.11 Evaluating the efficacy of these different regimens is made difficult by the heterogeneous group of neoplasms included in each study. As is the case when assessing other treatment modalities, the relatively slow growth rate of these tumors, coupled with a somewhat limited understanding of their biology and natural history, limits to some extent interpretation of the available data. Despite these limitations, several general observations can be made regarding the use of chemotherapy in the therapy of metastatic neuroendocrine tumors of the pancreas. Multiple agents have been used with varying results. The most often used agent with the greatest success rate is the nitrourea antibiotic streptozotocin.106–112 As a single agent, this drug has been associated with an objective response in over 30% to as high as 60% of patients. The only additional single agent with this response rate is the analogue of streptozotocin, chlorozotocin.113,114 Combination therapy has been utilized in an effort to improve response rates. Moertel and coworkers compared streptozotocin plus doxorubicin to the former and 5-FU or to chlorozotocin alone in patients with metastatic pancreatic endocrine tumors.112 These investigators observed a response rate of 69% for streptozotocin plus doxorubicin, 45% for streptozotocin plus 5-FU, and 30% for chlorozotocin alone. Moreover, a significant improvement in survival with the strepto/doxo (2.2 versus 1.4 years) combination was observed when evaluating 105 patients treated. A significant advantage of combination therapy over single-agent treatment was also observed with streptozotocin plus 5-FU. Unfortunately, others115,116 have not observed similar response rates in gastrinoma patients, a discrepancy possibly due to inherent differences in the patients examined. Variation in response rates to chemotherapy may hold true for different neuroendocrine tumor types. For example, based on the above data, it appears that the combination of streptozotocin and doxorubicin would be the regimen of choice for the therapy of metastatic neuroendocrine tumors of the pancreas. Yet, when evaluating selected subgroups, a heterogeneous response can be observed. Metastatic VIPomas are reported to have response rates as high as 90% to streptozotocin.46 Dacarbazine, an agent with marginal benefit in several neuroendocrine tumors, has been reported to be extremely effective in the therapy of glucagonomas,117–121 leading to complete remission in selected cases. Side effect profiles will also vary among the different agents utilized. Nausea and vomiting are commonly observed in patients treated with streptozotocin or its derivative. Renal insufficiency occasionally leading to chronic renal failure (5–7%) has also been described with these compounds. In summary, it appears that streptozotocin in combination with doxorubicin may represent the best chemotherapeutic agents for the therapy of metastatic neuroendocrine tumors. In view of the more favorable toxicity profile of 5-FU, some recommend using this agent in place of doxorubicin.93 In patients with glucagonoma, dacarbazine may represent the best selection.

Therapy

Interferon

Hepatic artery embolization

Debulking

In light of the limited benefit of the above-listed therapies and the inevitable recurrence of signs and symptoms observed in these patients, alternative therapeutic options have been developed. One such option for neuroendocrine tumor patients with liver metastasis is hepatic artery occlusion.122–125 The rationale for this approach is based on several factors. Hepatic metastasis of neuroendocrine tumors tends to be highly vascular126,127 and predominantly supplied by the hepatic artery. Normal liver parenchyma receives 75–80% of its blood supply from the portal vein, thus protecting it from ischemic damage if one hepatic artery were to be occluded. The largest experience with this technique has been in patients with metastatic carcinoid tumor, but several studies have included metastatic pancreatic neuroendocrine tumor patients as well. Marlink and colleagues observed a prompt decrease in symptoms related to hormone secretion and a decrease in tumor size for varying intervals in 6/6 patients with metastatic pancreatic neuroendocrine tumors treated with this modality.125 Hepatic artery occlusion has also been combined with chemotherapy, achieving a complete symptomatic response in over 60% of patients treated.128 Ruszniewski et al.129 performed a prospective phase II study examining the efficacy of chemoembolization with doxoribicin in 24 patients with metastatic neuroendocrine tumors. Of these, five had pancreatic primaries (gastrinomas). Although results achieved with carcinoid patients were somewhat promising, only a minor response or tumor stabilization was observed in three of the pancreatic tumor patients. More encouraging results were achieved by Mavligit and coworkers,130 who observed >50% tumor regression, lasting 8–44 months in four of five patients treated with hepatic artery chemoembolization with cisplatin, followed by intra-arterial infusion of vinblastine. Complications related to hepatic artery embolization can vary from transient abdominal pain, nausea, and fever in greater than 90% of patients to hormonal crisis and renal insufficiency in a smaller percentage of patients. Death has been reported in 10 sample ratio units (SRU) by radioimmunoassay (RIA) (approximately 10 mIU/mL using the international standard). Complete protection is afforded in 82–98% of vaccinees receiving 3 doses.39 Anti-HBs titers decline progressively over time following successful vaccination. Between 15% and 40% of responders have titers 105 copies/mL

No treatment; monitor

≤ 2 ⫻ ULN

> 10 copies/mL

Treat if biopsy shows moderate or severe inflammation or advanced fibrosis

>2 ⫻ ULN

> 105 copies/mL

Treat; may observe HBeAg-positive patients for 3–6 months for spontaneous seroconversion Treat immediately for decompensation or worsening

5

Modified from the recommendations of the American Association for the Study of Liver Disease, European Association for the Study of the Liver, and the Asian-Pacific Association for the Study of the Liver.51–53

509

Condition

Recommendationa,b

HBeAg positive, HBV DNA >105 copies/mL

Pegylated IFN, LAM, or ADVc

HBeAg negative, HBV DNA >105 copies/mL

Pegylated IFN or ADV preferredc

Compensated cirrhosis

Pegylated IFN, LAM, or ADVc

Decompensated cirrhosis

LAM or ADVc

IFN nonresponder or IFN contraindication

LAM or ADVc

a b c

Modified from the recommendations of the American Association for the Study of Liver Disease. IFN, interferon; LAM, lamivudine; ADV, adefovir. Entecavir would also be an alternative when FDA approved.

Table 33.11 Advantages and disadvantages of currently available agents for treatment of chronic hepatitis B Agent

Advantages

Disadvantages

Standard interferon

Short course High seroconversion rate Durable response HBsAg loss common

Side effects Optimal duration unknown Less if ALT normal or patient immunosuppressed May cause decompensation in patients with advanced cirrhosis

Pegylated interferon

1 year duration High seroconversion rate Good response in HBeAg-negative chronic hepatitis B Durable response HBsAg loss common

High cost (though course short) Side effects Less if ALT normal or patient immunosuppressed May cause decompensation in patients with advanced cirrhosis

Lamivudine

Oral Well tolerated Inexpensive Safe/effective despite advanced liver disease or immune suppression

Low seroconversion rate Drug resistance common Requires long-term treatment HBsAg loss not common

Adefovir

Oral Well tolerated Lower drug resistance Active against lamivudine-resistant HBV Safe/effective despite advanced liver disease or immune suppression

Low seroconversion rate Not as potent as lamivudine Requires long-term treatment HBsAg loss not common

Entacavir

Oral Well tolerated Active against lamivudine-resistant HBV

Low seroconversion rate Requires long-term treatment

Tenofovira

Oral Well tolerated Extremely potent antiviral activity Active against lamivudine-resistant HBV

Low seroconversion rate Requires long-term treatment

Emtricitabinea

Oral Well tolerated No de novo resistance to date (except in patients already resistant to lamivudine)

Low seroconversion rate Not as potent as lamivudine Requires long-term treatment

a

Commercially available for HIV; no approved labeling for HBV.

synthesis, and amplifying specific (cytotoxic T lymphocyte) and nonspecific (natural killer cell) immune responses to viral proteins.54–57 Alpha-interferons was the first agent that was shown to have efficacy in the treatment of chronic viral hepatitis and several

recombinant forms, including pegylated forms of the parent compounds, are commercially available. Standard alpha-interferon was first shown to be effective for the treatment of chronic HBV infection about 15 years ago. Short courses (16–24 weeks) of

Hepatitis B

Table 33.10 Selection of treatment agents for chronic hepatitis B

Prophylaxis and Treatment of Viral Hepatitis

510 subcutaneous recombinant interferon-alfa-2b administered as 5 million units daily or ten million units administered three times per week appeared to be optimal and were equally effective, although the daily dosing regimen appeared to be better tolerated.50,55,58 Serum HBV DNA levels declined by as much as 75% during treatment.59 Serum ALT levels usually remained unchanged for the first 8–10 weeks of treatment, but there was often a flare in ALT activity between 10 and 16 weeks in about 70% of responding patients and this was frequently followed by the disappearance of HBV DNA by the older dot-blot hybridization techniques, loss of HBeAg, and normalization of serum ALT, in that order.50,58 Thus, it is important to recognize that an abrupt elevation of serum ALT during treatment is not an indication to adjust interferon dose or prematurely terminate therapy.58 Entry into the phase of low replication is thought to represent immunemediated clearance of the bulk of HBV-infected hepatocytes.55 It is worth noting an important change in terminology between the literature describing these early trials and more recent studies. These early studies utilized rather insensitive dot-blot hybridization techniques to detect HBV DNA and commonly described loss of HBV DNA on treatment and entry into a nonreplicative phase of infection. It is now clear that low levels of HBV replication, generally less than 104–5 copies per milliliter by the sensitive DNA amplification methods employed today, persist in such patients and therefore the term low replicative phase is preferable to noreplicative phase. Using this newer terminology, HBV DNA levels fell into the low replication range in approximately half of the patients treated with standard interferon.55 About 10% of these responders subsequently lost HBsAg within 6 months of seroconversion.58 Long-term follow-up studies demonstrated that about two-thirds of patients who responded to interferon eventually lost HBsAg and become HBV DNA negative by PCR;60 this is a feature unique to interferon treatment and not common with nucleosides (see below). Although patients who lose HBsAg and detectable HBV DNA might appear to be clinically cured, small amounts of integrated HBV DNA sequences remain sequestered in either the liver or extrahepatic sites in some of these individuals.61,62 Whether these are clinically relevant is not known. Pegylation of interferons has decreased clearance of the parent drug allowing for once per week dosing and more consistent plasma drug levels. Pegylated interferons have been approved for treatment of chronic hepatitis C (see below). Two recent trials examined the effectiveness of 48 weeks of treatment with peginterferon-alfa-2a (180 micrograms once per week) with or without the nucleoside lamivudine in patients with HBeAgnegative chronic hepatitis B and wild-type infection.63,64 Among the HBeAg-positive patients, HBeAg seroconversion occurred in 32% of subjects treated with pegylated interferon alone (27% if combined with lamivudine).63 HBV DNA decreased to and remained less than 100 000 copies per milliliter in 32%. Among HBeAg-negative subjects, HBV DNA decreased to and remained less than 20 000 copies per milliliter in 43% of subjects treated pegylated interferon alone (44% if combined with lamivudine).64 Loss of HBsAg and development of anti-HBs occurred in 2–3% of interferon-treated subjects within 6 months. Several factors influence the response to interferon therapy. Those who respond best include those with low levels of HBV replication (less than 200 pg/mL by the Abbott Genostics assay; note that available HBV DNA assays are not compared to a common standard and therefore their use for selecting patients

for treatment based on viral levels is limited) and high serum ALT levels (>100 IU/L).50 Side effects occur in most patients who receive interferon.65 These are usually confined to flu-like side effects such as fever, chills, myalgia, arthralgia, and headache. Tachyphylaxis to these symptoms generally occurs after the first few doses, but in some cases these side effects may persist at a low level throughout the treatment course.65 A mean weight loss of 2.5 kg, and a consistent 15% reduction in white cell and platelet counts has also been described.66 Leukopenia, granulocytopenia, and thrombocytopenia generally reach their nadir during the first 4 weeks of treatment. Thus, it is advisable to monitor these laboratory tests weekly during the first month and monthly thereafter during therapy. In general, interferon is well tolerated. About 10–20% of patients treated with standard interferons required temporary discontinuation of treatment or dose reductions because of side effects, usually leukopenia or thrombocytopenia, and 2–10% had to discontinue treatment altogether.65–67 Pegylated interferon appears to be similarly tolerated.63,67 It is interesting to note that intolerance is much less common in patients with chronic hepatitis B than in those with chronic hepatitis C, though the doses are similar.68 Contraindications to interferon therapy are relative. Treatment of patients with decompensated cirrhosis (coagulopathy, hypoalbuminemia, encephalopathy, ascites, or jaundice) requires considerable caution.69 Side effects include significant cytopenia and bacterial infections. Worsening hepatic failure due to the interferon-mediated flare in hepatitis may require timely liver transplantation. Interferon therapy in this high-risk population should similarly be carried out only by experienced clinicians with ready access to a liver transplant program. Caution should also be used when considering treatment in patients with autoimmune disorders, pre-existing cytopenia, severe depression or other psychiatric conditions, severe congestive cardiac diseases, poorly controlled diabetes, seizure disorders, an organ transplant, and autoimmune or potentially immune-mediated diseases including but not limited to rheumatoid arthritis, systemic lupus, inflammatory bowel disease, or neuropathy. The drug should not be used in pregnant women. Despite the gratifying viral responses reported with interferon treatment, the cost and associated side effects have hindered its acceptance as the preferred therapy. Thus, interferon was quickly replaced by well-tolerated oral reverse transcriptase inhibitors such as lamivudine and adefovir when these became commercially available.

Nucleoside analogues Nucleoside analogues are compounds that are thought to impair viral replication by competing with the natural substrate for binding to cellular DNA polymerases, thereby becoming incorporated into the nascent DNA chain and terminating DNA chain synthesis. Most nucleosides are phosphorylated by cytoplasmic enzymes to nucleoside 5′-triphosphates. However, the unique metabolic and pharmacologic properties of each nucleoside analogue make it difficult to predict their mechanisms of action, toxicity, or efficacy. A variety of nucleoside analogues have been studied as potential treatment for chronic hepatitis B. Many of these drugs have only been studied in small, controlled clinical trials. Adenine arabinoside (Ara-A) and its aqueous monophosphate derivative (Ara-AMP) are potent DNA polymerase inhibitors, but both agents were withdrawn from investigative use in the United States

511

Lamivudine Lamivudine (3TC), a cytosine analogue, is a potent in vitro inhibitor of HBV. Initial human trials showed dramatic reductions in HBV DNA levels in all recipients of a single daily dose of 100 mg or more.76 In contrast to interferon therapy, lamivudine is also associated with a relatively simultaneous fall in HBV DNA levels and serum ALT. As with all of the nucleoside analogues, the effects of short-term treatment with lamivudine are transient with detectable viral replication reappearing shortly after the drug is stopped.76 However, longer treatment duration (several hepatocyte half-lives) with lamivudine was associated with sustained suppression of virus in most patients. For example, HBeAg to anti-HBe seroconversion was 12%, 17%, 21%, and 40% after 3, 12, 18, and 36 months of treatment, respectively.76–79 HBV DNA suppression with HBeAg seroconversion is usually permanent, with 64% being maintained 3 years later and some of these patients may even lose HBsAg.80 Prolonged treatment-related suppression of virus results in histologic improvement and even loss of fibrosis in some patients.81 Lamivudine has an excellent safety record.82 The major drawback of the drug is the development of drug resistance which results in loss of response and, eventually, histologic progression.79,81,83 The likelihood of drug

Table 33.12 Relative antiviral potencies of nucleosides and nucleotides available or under study Drug

Drug status

log decrease HBV DNA

Pegylated interferon

Approved

3.5

Lamivudine (3TC)

Approved

4.4

Adefovir

Approved

3.5

Entecavir

Approved

4.6

Tenofovir

Approved (HIV only)

6.6

Emtricitabine (FTC)

Approved (HIV only)

3.0

Telbivudine (LdT)

Investigational

6.1

resistance is related to treatment duration increasing from 14% to 24% at one year, to 38% after 2 years, and to nearly 60% after 3 years.79,84

Adefovir dipivoxil Drug resistance to lamivudine results in HBV DNA breakthrough and can result in loss of any previously obtained benefit. Thus, it is important to have other agents that are active against the lamivudine-resistant strains of the virus. Adefovir dipivoxil is an orally bioavailable prodrug of adefovir, a phosphonate nucleotide analogue of adenosine monophosphate.85 It was originally developed for treatment of HIV but was associated with nephrotoxicity at the doses required to efficiently inhibit HIV.86 It is active against HBV at lower doses that do not result in renal injury, although its ability to inhibit HBV is not as great as lamivudine or the nucleosides discussed below (see Table 33.12). The major attraction of adefovir is its ability to inhibit lamivudine-resistant mutants of HBV.85 Large multicenter randomized controlled trials of adefovir compared to placebo have been conducted in patients with chronic hepatitis B.87,88 A 10 mg daily dose of adefovir for 48 weeks decreased HBV DNA levels by 3.52 and 3.91 logs from baseline for those with treatment naïve HBeAg-positive and HBeAg-negative chronic hepatitis B, respectively.87,88 The drug was well tolerated without evidence of renal or other toxicity at this dose. Although no breakthrough drug resistance was seen in these studies, substitutions within the polymerase coding region develop at low frequency.89 A small number of cases of drug resistance (≈2% after 2 years of treatment) have now been reported.85 Thus, it appears that the major advantage of adefovir is its ability to inhibit HBV DNA in patients with lamivudine-resistant mutations of the virus. However, the antiviral effect of adefovir can be inconsistent in such patients, especially those with high viral loads, so other antiviral agents such as tenofovir or entecavir might be preferable.90 It does not appear to have an advantage over lamivudine as primary therapy in treatment naïve patients and may not be as potent an antiviral agent. Nonetheless, some have recommended it over lamivudine since drug resistance is less common and the patients may not require monitoring of their virus levels as frequently. It is likely, however, that other antiviral agents will eventually replace adefovir.

Entecavir Entecavir is a cyclopentyl guanosine analogue that is a potent inhibitor of the HBV polymerase. In contrast to both lamivudine and adefovir, it is a selective inhibitor of HBV and has no activity against HIV or other DNA viruses.91 It is effective against both wild-type and lamivudine-resistant HBV, but is most effective against wild-type.92,93 It appears to be about 30 times more potent than lamivudine.94 It is highly bioavailable and administered once daily. A recent phase 3 multicenter study compared 48 weeks of entecavir at a dose of 0.5 mg per day to 100 mg of lamivudine in subjects with HBeAg-positive chronic hepatitis B.95 Among entecavir-treated subjects, the median fall in HBV DNA was almost 7 logs, HBV DNA became undetectable in 69%, and seroconversion occurred in 21% compared to 5.5 logs, 38%, and 18%, respectively, for lamivudine. An identically designed study compared 48 weeks of entecavir at a dose of 0.5 mg per day to 100 mg of lamivudine in subjects with HBeAg-negative chronic hepatitis B.96 HBV DNA decreased to less than 200 copies per milliliter

Hepatitis B

and western Europe because of neuromuscular toxicity and limited efficacy.70,71 Acyclovir and the more absorbable prodrug, 6-deoxyacyclovir, are appreciably safer compounds, but clinical experience has indicated that neither has significant activity against HBV.72,73 Ganciclovir may have more antiviral activity against hepatitis B.74 Famciclovir appears to have similar effects, but has the advantage of being orally administered. Dideoxynucleosides such as DDI have proven to be potent inhibitors of duck hepatitis B virus, a virus closely resembling the human hepatitis B virus.75 However, early studies in humans did not demonstrate activity. Ribavirin is a weak inhibitor of HBV replication. Fialuridine (FIAU), a fluoridated uracil which acts as a thymidine analogue, showed significant activity against HBV in cell culture and early short-term human trials. Unfortunately, the agent was associated with lethal toxicity when treatment was extended beyond 1 month. The relative potencies of the agents that are currently approved or under study are listed in Table 33.12, although potency alone does not determine their attractiveness as clinical agents.


512 in 89% of entecavir-treated subjects compared to 70% of lamivudine-treated. Entecavir-resistant mutations of HBV have not been identified yet in nucleoside-naïve patients, but emerged in 6% of lamivudine-resistant patients who received the drug.97 Entecavir was approved for use in chronic hepatitis B by the Food and Drug Administration in 2005.

Other antiviral agents Several other nucleosides with activity against HBV are currently under study and show promise.91 Tenofovir disoproxil fumarate is a nucleotide analogue, similar to adefovir, that is currently approved for the treatment of HIV but also has potent activity against HBV. Like adefovir, it is active against both wild-type and lamivudine-resistant HBV.98 However, in contrast to adefovir, tenofovir results in rapid and consistent early viral suppression even in patients with advanced liver disease or HIV coinfection.90 Emtricitabine (ETC) is a cytosine nucleoside analogue that is currently approved for use against HIV and has moderate (3 log) inhibitory activity against HBV. Resistance may limit its use as a single agent. Clevudine (L-FMAU) is a pyrimidine analogue that has selective inhibitory activity against HBV. Long-term dosing studies are underway. Telbivudine (LdT), an L-nucleoside thymidine analogue, is a member of a new class of natural ␤-L-configured nucleosides. It is a very potent and selective HBV inhibitor; most treated patients achieve a 4-log reduction in HBV DNA. Interestingly, studies in woodchucks suggest that combinations of ␤-L-nucleosides (e.g. LdC and LdT) may have additive or even synergistic inhibitory effects. Development of these and other agents will continue and it is likely over the next few years that some of these agents will join the list of nucleosides approved for use in patients with chronic hepatitis B.

Selection of therapeutic agents for chronic hepatitis B The approach to deciding whether to treat a patient with chronic hepatitis B is discussed above and summarized in Table 33.9. Although clinical trials have made a point to distinguish HBeAgpositive and HBeAg-negative patients with replicative chronic hepatitis B, this distinction is much less important in practice. Rather, the levels of HBV DNA and ALT, and sometimes the degree of histologic injury, are critical in making the decision to proceed with therapy (see Table 33.10). A possible exception might be to use a nucleoside with less chance of resistance when treating patients with HBeAg-negative chronic hepatitis B since therapy is often prolonged and resistance is likely with lamivudine; this remains controversial. The advantages and disadvantages of the available agents with efficacy in hepatitis B are listed in Table 33.11. Although interferons are attractive because of the finite duration of therapy, durability of response, and high clearance rate for HBsAg, the initial cost, and significant side effects of interferons have limited their acceptance. This may change with pegylated interferons. In contrast, nucleosides such as lamivudine, adefovir, and entecavir have been quickly accepted because of their ease of administration and lack of significant side effects. The major frustrations with these agents are the uncertain duration of use and the need to serially monitor for drug resistance. Fortunately, the latter has not limited

acceptance since a variety of active nucleosides are now available.

HEPATITIS D Hepatitis D virus (delta agent) infection occurs only in patients infected with the hepatitis B virus. Thus, protection against HBV is protective against hepatitis D. However, most cases of hepatitis D occur as superinfection in patients already infected with HBV. There is currently no effective passive or active immunoprophylaxis to protect the HBV-infected patient against this infection. HBIG will not confer protection against HDV superinfection in carriers of HBsAg. Since HDV is a viroid consisting of unenveloped single-stranded RNA, i.e. it does not have a viral protein envelope, it is unlikely that vaccines will be easily developed. Fortunately, delta infection is becoming uncommon.

Treatment options Interferons Early studies suggested that interferon had a limited role in the treatment of HDV infection. Interferon does not inhibit HDV replication,99 but conveys any benefit to the patient through inhibition of HBV. The antiviral effects are usually transient, i.e. are dependent upon ongoing therapy, and require high doses (9 MU three times per week for one year) for long periods of time.100,101 Interestingly, about half of treated patients have persistent ALT normalization and histologic improvement, despite persistent HDV viremia.99,101 Recently, the results of long-term follow-up of these biochemical responders were reported. Surprisingly, half of the patients with normal ALT levels after treatment still had normal ALT levels 14 years later and some had resolution of fibrosis.102 Both HBV and HDV replication decreased, or even ceased, in some of these patients. Thus, long-term (1 year) high-dose interferon is currently the only effective therapy for chronic hepatitis D. The goal of therapy is ALT normalization, but this may eventually result in viral clearance and histologic improvement. No data with pegylated interferons are available to date.

HEPATITIS C Hepatitis C virus infection currently accounts for only about 15% of cases of acute hepatitis in the United States. The estimated incidence of acute hepatitis C has fallen dramatically over the last two decades and it is now estimated that less than 30 000 new cases occur per year in the United States.103 However, chronic infection (persistent viremia) occurs in 50–90% of acutely infected individuals and chronic hepatitis (abnormal liver tests) develops in 60–70%. There are nearly 4 million chronically infected persons in the United States.104 Chronic hepatitis C is the most common cause of liver disease and the most common indication for liver transplantation. The hepatitis C virus is present in blood, and therefore it is most efficiently transmitted by parenteral routes. At present, injection drug use is the most common route of transmission, accounting for 60% of cases. Blood transfusion, a common source of infection in the past, is no longer a common route of acquisition. Hepatitis C can also be transmitted sexually and perinatally, though these routes are not as efficient as they are with hepatitis B.

513

Immune globulin Studies evaluating the efficacy of immunoglobulin administration in preventing HCV have yielded conflicting results.9 Three studies conducted in the 1970s examined the ability of immune globulin to reduce post-transfusion non-A, non-B hepatitis.105–107 Although two of these studies significantly reduced the incidence of icteric hepatitis, the overall risk of hepatitis was not changed.106,107 Several points regarding these studies must be emphasized. First, the risk of post-transfusion hepatitis was very high during the 1970s because of the use of commercial blood donors. It would be unlikely that any effect of immune globulin could be seen with the low rate of post-transfusion hepatitis that now exists since institution of voluntary blood donation and screening tests to eliminate HCV infection from the blood donor pool. Second, in one of these two studies, immune globulin was given before transfusion and its results are therefore not applicable to discussions of postexposure immunoprophylaxis.106 Finally, it must be recognized that extrapolation of post-transfusion studies to other types of exposure to HCV, e.g. needlestick injuries, is probably inappropriate since the risk of infection by other routes is only 2–3%.108 In short, there are currently no data to justify administration of immune globulin in hopes of preventing hepatitis C infection. Furthermore, current criteria for selecting plasma donors (anti-HCV negative) virtually guarantee that the titer of antibodies to HCV in IG preparations will be negligible. Some continue to recommend IG for postexposure prophylaxis since the risk of its use is low;6,13 however, the Advisory Committee on Immunization Practices has stated unequivocally that … IG does not protect against infection with HCV. Thus, available data do not support the use of IG for postexposure prophylaxis of hepatitis C. In contrast to ISG, a high titer anti-HCV immunoglobulin preparation has been shown to delay the onset of HCV infection in chimpanzees.109 Such preparations do not appear to prevent infection, however. A recent clinical trial of high-titer polyclonal anti-HCV prepared from pooled plasma did not prevent HCV reinfection of grafts following liver transplantation of patients with chronic hepatitis C.110 Based on the current lack of an effective immune globulin, persons with percutaneous exposure to HCV should be closely monitored for infection. At a minimum, this requires serial testing of serum ALT and anti-HCV. Serial HCV RNA determinations by PCR might be a more effective means of monitoring and would be expected to identify acute infection earlier, when it would be more amenable to interferon treatment (see below).111

Hepatitis C vaccines Development of an effective vaccine against HCV faces several obstacles. Most importantly, neutralizing antibodies against the hypervariable envelope proteins are isolate specific and therefore likely to provide only partial, if any, protection against a heterogeneous virus such as HCV.92 Furthermore, clinical testing of an HCV vaccine would be difficult since the current risk of infection is extremely low except in active injection drug users. These limitations in mind, several efforts toward developing hepatitis C vaccines have been undertaken. Several prototype HCV vaccines have been developed in an effort to prevent primary infection. Envelope glycoprotein vaccines can produce high titers of neutralizing antibodies and prevent primary infection in chimpanzees

challenged with low doses of the homologous strain of HCV and perhaps even with some heterologous strains.112,113 However, the heterogeneity of the viral envelope proteins is a major obstacle to making an effective envelope vaccine. Efforts to create a more effective vaccine using the relatively well-conserved HCV nucleocapsid (core) have been disappointing.114 Vaccination with HCV genes in plasmid or viral expression vectors induces a humoral immune response to core and cytotoxic T-lymphocyte activity in mice, but neutralizing antibodies are not produced.115–118 At this time, there are no promising candidates for a traditional vaccine for hepatitis C. An alternative approach is development of therapeutic vaccines aimed at improving or resolving established infection. Several companies are active in therapeutic vaccine research. Repeated courses of a recombinant HCV E1 vaccine over 3 years resulted in increased anti-E1 antibody levels, E1-specific T-cell responses, decreased serum ALT levels, and lack of histologic progression, though no change in HCV RNA was observed.119 This study was not controlled. Another study using a synthetic vaccine comprised of 5 peptides containing HLA-restricted cytotoxic T-helper epitopes of HCV and a T-cell adjuvant, poly-L-arginine, found that gamma interferon producing cytotoxic and helper T cells were induced in vaccine recipients but not in controls.120 Clinical response data are not yet available.

Treatment of acute and chronic infection The major goal of treatment of HCV infection is to prevent development of decompensated liver disease and death. This can be accomplished by preventing new infections, reducing the chance of acute infection progressing to chronic hepatitis, or effectively treating chronic infection. The goals in treating chronic hepatitis should include eradication or prolonged suppression of virus replication, reduction of hepatic inflammation, and, ultimately, slowing of the rate of progressive liver injury. Not all of these goals may be achievable in an individual patient.

Interferon in acute hepatitis C The goal of treating patients with acute hepatitis is termination of infection, thereby eliminating the risk of progressing to chronic infection or liver disease. Several studies have examined the role of IFN in patients with acute hepatitis C.121–124 Of these, four were randomized, controlled trials (three using recombinant alpha IFN for 3 months121–123 and one using beta IFN for 1 month).124 A recent meta-analysis of these studies demonstrated complete ALT response at the end of treatment in 69% of patients receiving IFN but only 29% of controls.125 Sustained response 12 months after completion of treatment was seen in 53% of IFN-treated patients and only 32% of untreated controls.125 Furthermore, serum HCV RNA was undetectable at the last follow-up in 41% of treated patients but only 4% of untreated controls. Thus, even a short course of IFN at standard doses reduces the proportion of patients developing chronic HCV infection (HCV RNA positive) from 96% to 59% and chronic hepatitis (elevated ALT) from 68% to 47%. Pegylated interferon either alone or in combination with ribavirin for 6 months cleared infection in 80–85% of cases compared to 36% of controls.126 While these results are encouraging, treatment of patients with acute HCV infection must be considered in the proper perspective. The incidence of acute hepatitis C in the United States has fallen

Hepatitis C

Immunoprophylaxis


514 dramatically to about 28 000 infections per year.127 Only a small proportion of these cases are symptomatic and recognized by either the patient or physician. Furthermore, there is no test to distinguish acute from chronic infection. Nonetheless, when acute hepatitis C is suspected, treatment should be strongly considered.

Interferon for chronic hepatitis C Interferon is the foundation of therapy for chronic hepatitis C. The efficacy of IFN in patients with chronic non-A, non-B hepatitis was first described in 1986, 3 years before the identification of HCV.128 Several subsequent reports confirmed that low doses of IFN-␣ improved liver tests and histology in patients with chronic hepatitis C.129–133 Over the last decade, interferon-based treatment regimens have become increasingly effective, and sustained viral response or clearance can now be achieved in approximately 55% of treated patients.134 Sustained viral response (SVR) is defined by undetectable HCV RNA by a sensitive amplification method, such as polymerase chain reaction (PCR) or transcription-mediated amplification (TMA), 6 months after completion of therapy. SVR is durable135 and associated with histologic improvement136,137 All patients with chronic hepatitis C should be considered for possible interferon treatment. If contraindications to therapy are not present (see below), then a quantitative HCV RNA level and viral genotype should be done (Table 33.13). At the present time, a pretreatment liver biopsy remains important in determining the degree of underlying liver injury because neither serum ALT, HCV RNA, nor symptoms correlate well with histologic activity.138,139 Liver biopsy provides an estimation of prognosis and is helpful in counseling the patient about the need and urgency for therapy. The National Institutes of Health Consensus Development Conference on Hepatitis C concluded that the need for treatment

Table 33.13 Selection of patients with chronic hepatitis C for treatment Indications Documented HCV infection (anti-HCV and HCV RNA positive) No contraindications to therapy Contraindications For interferon Significant cytopenia (relative) Major depression or other psychiatric disease Autoimmune diseases For ribavirin Inability to tolerate acute fall in hemoglobin Chronic anemia or hemolytic anemia Severe cardiac or pulmonary disease Elderly patients, particularly with risk factors for coronary disease Patients of childbearing potential not using adequate contraception Baseline assessment Quantitative HCV RNA HCV genotype Liver biopsy (optional) Note: See text for discussion of optimal treatment regimen. ALT, alanine aminotransferase; HCV, hepatitis C virus.

in patients with chronic hepatitis of moderate or severe histologic activity with or without fibrosis was unequivocal, while patients with mild activity and those with decompensated cirrhosis need to be considered on an individual basis after weighing such factors as projected prognosis, age, comorbid factors, and pre-existing cytopenia.140 However, as the efficacy of treatment regimens improves, it is likely the role of liver histology in helping determine the need for treatment will decrease. Initial therapy for chronic hepatitis C in the early 1990s consisted of standard interferon administered thrice weekly. SVR rates were low, averaging 6% to 16% for 6 to 12 months of therapy, respectively.125 The addition of the oral nucleoside ribavirin increased SVR rates to 33% and 44% for 6 and 12 months, respectively.141,142 Current therapy consists of pegylated interferon administered once per week plus daily ribavirin therapy.143,144 Overall SVR rates now average above 50%. The current recommendation for dose and duration have evolved from the large randomized studies of pegylated interferon and ribavirin143,144 and from a more recent study that examined a shorter duration of treatment and lower doses of ribavirin.138 The current recommendation for genotype 1, which accounts for about 70% of cases in the United States, is 12 months of pegylated interferon and ribavirin, the latter at a dose of 1000 mg for a subject weighing less than 75 kg and 1200 mg for those who weigh more. Genotypes 2 and 3 are more sensitive to interferon-based therapy and they require only 6 months of treatment and 800 mg of ribavirin per day. The typical response to interferon therapy is a rapid fall in serum ALT and HCV RNA.129 With current treatment regimens, HCV RNA levels decrease by at least 2 logs after 12 weeks of treatment in approximately 80% of patients (70% for genotype 1, 96% for genotypes 2 or 3) and are undetectable by PCR in most of these cases.139 Patients who do not decrease their HCV RNA level by at least 2 logs during the first 12 weeks of treatment (termed early viral response or EVR) will not respond to treatment and therapy can be stopped (Fig. 33.1).139 A fall in the serum ALT level typically occurs in parallel with the virologic response, and ALT often normalizes between 4 and 12 weeks after initiation of treatment.140,145,146 These biochemical and virologic changes are accompanied by histologic improvement.129,143,144,147 Once the prescribed duration of therapy has been completed, drugs should be stopped; there is currently no evidence that a longer course of therapy is helpful. Serum ALT and HCV RNA should be repeated 6 months after treatment is completed to determine whether an SVR has been achieved. SVR should be confirmed by HCV RNA testing again 1 year after completing therapy and yearly thereafter for at least 2 years in order to confirm a durable response. About half of patients with chronic hepatitis C who are treated with IFN fail to respond.125,129,143,144 Nonresponse is usually evident early in the treatment course as described above. It is important to recognize that not all nonresponders are the same in terms of their sensitivity to interferon-based regimens; HCV RNA may fall significantly and become nearly undetectable or may not change at all.129,146,148 The degree of initial interferon sensitivity probably provides a good estimate of the likelihood of response when new and more effective therapies are developed. It has long been noted that some patients without a complete virologic response will nevertheless show some histologic improvement.125,129 This appears to depend upon the ability of interferon to at least decrease the viral level since no such histologic

515

12 weeks

Genotype 1

Genotype 2 or 3

Retest quantitative HCV RNA

No need to test HCV RNA

reducing the complications of portal hypertension, and the rate of variceal bleeding in the control group appears to be high considering that they were supposed to be adequately beta blocked. However, another recent report suggests that interferon may decrease portal pressure and this might explain the observations in the COPILOT study.153 The results of other similar interferon maintenance studies will be of great interest in confirming these important observations and determining whether pegylated interferon maintenance might be an option in cirrhotic patients who fail to eradicate HCV with interferon-based therapies.

Factors that influence treatment response HCV RNA decreased ≥ 2 log vs baseline

HCV RNA undetectable

HCV RNA not decreased 2 logs

HCV RNA detectable

Repeat HCV RNA at 24 wk

Negative

Complete treatment

Positive

Discontinue treatment

Complete treatment

•

Fig. 33.1 Algorithm for monitoring antiviral treatment in patients with chronic hepatitis C.

improvement is seen in those who fail to suppress virus by at least 2 logs during therapy.148,149 Thus, there has been great interest in continuing therapy or retreating patients with histologically advanced disease, i.e. fibrosis or cirrhosis, in hopes of preventing disease progression. Certainly, all nonresponders, particularly those who decreased viral levels with their initial course of treatment, should be considered for re-treatment if advances in therapy, such as a new agent, evolve and are proven to be effective. However, retreatment with the same regimen is not effective and should not be considered in such patients. Very high doses of interferons or prolongation of therapy may improve overall outcomes, but these studies have not been controlled and require confirmation.150,151 Most interest recently has focused on maintenance interferon therapy. Several studies are underway to assess whether maintenance therapy with long-term, low-dose interferon is of benefit to patients with chronic hepatitis C and fibrosis who have failed to eradicate HCV with conventional antiviral therapy. These studies include the NIH-sponsored HALT-C trial, the international EPIC trial, and the COPILOT study. Only the COPILOT study has reported data so far.152 A 2-year interim analysis reported no difference between interferon-treated and control groups for death, hepatocellular carcinoma, or need for transplantation. However, by Kaplan-Meier analysis, the annual risk of variceal bleeding was 13.5% in the control group and 5% in the interferon group. These preliminary findings are the first data to suggest that low-dose maintenance interferon may be useful in preventing complications of cirrhosis, but the benefit appears to be confined to

Viral genotype is the most important factor influencing response to combination treatment (Table 33.14). In recent trials that evaluated a year of pegylated interferon and ribavirin in previously untreated patients, SVR was achieved in 41–42% of patients infected with genotype 1 and 66–75% of those with genotype 2 or 3.143,144 This led to a study to define the optimal dose of ribavirin and duration of therapy according to genotype.138 Patients with genotype 1 had the highest SVR with 48 weeks of therapy (51% versus 41% with 24 weeks at full-dose ribavirin) at a dose of 1000 to 1200 mg of ribavirin per day (51% versus 40% with a lower dose of ribavirin for 1 year). In contrast, patients with genotype 2 or 3 did as well with just 6 months of treatment and 800 mg per day of ribavirin (73% to 78% for all doses and durations studied). Preliminary reports from ongoing studies suggest that patients with genotype 2 or 3 who lose detectable HCV RNA after 4 weeks can be treated for just 14–16 weeks,154,155 but this needs confirmed in other trials before becoming standard clinical practice. The effect of HCV RNA before treatment influences response, but not to the same degree as viral genotype does. The effect is observed mainly in patients with genotype 1 infection. Those with pretreatment HCV RNA levels greater than 2 million copies per milliliter have an SVR of 30–39% compared to SVR of 56–68% in patients with lower levels of viremia.143,144 One study recently suggested that patients with genotype 3 and high viral loads had a poor response and should be treated with 48 weeks instead of 24 weeks of therapy,156 but analysis of larger clinical databases has failed to confirm the value of this suggestion.157

Table 33.14 Influence of pretreatment and treatment factors on response to pegylated interferon and ribavirin Increased SVR

Decreased SVR

Genotype 2 or 3

Genotype 1

HCV RNA 2 million copies/mL

Young

Bridging fibrosis or cirrhosis

Female gender

Male gender

Short duration of infection

Obesity

Early viral response

Hepatic steatosis Alcohol intake Poor adherence Early dose reductions

Hepatitis C

Pegylated IFN and ribavirin treatment Baseline genotype and quantitative HCV RNA


516 Fibrosis or cirrhosis, known to reduce the response to interferon alone, does not appear to reduce the sustained response quite as much with combination therapy (41–44% SVR in stage 3–4 disease versus 54–55% with stage 0–2).141–144,158 This is an important observation since these patients are at the greatest risk for developing hepatic decompensation if not treated.159 SVR is reduced, though to a far lesser extent than with the factors discuss above, by age, weight, alcohol use, and hepatic steatosis.143,144,160,161 SVR is not significantly influenced by ALT level (including normal ALT). There are currently no data to suggest that the response rates are significantly different with the two forms of pegylated interferon or with different brands of ribavirin. SVR is reduced in African-Americans and patients coinfected with HIV. Since African-Americans are predominantly infected with genotype 1, they might be expected to have lower SVR than the general population. However, even among those with genotype 1 the SVR in this group is lower than in non-Hispanic whites (19–26% versus 39–52%).162,163 The explanation for this difference in response remains elusive and may be related to genetic polymorphisms that influence immune responsiveness. Patients coinfected with HIV also have lower SVR than HIVnegative patients when treated with combination therapy. Three large clinical trials have clearly shown that SVR after a year of treatment with pegylated interferon and ribavirin is reduced compared to patients infected with HCV alone (27–40% overall; 14–29% in genotype 1).164–166 Somewhat surprisingly, patients infected with genotype 2 or 3 did quite well with SVR ranging from 43% to 73%.

Table 33.15 Management of drug toxicity in the treatment of chronic hepatitis C Drug-related problem

Management optionsa

Flu-like symptoms

Dose in evening Acetaminophen Oral fluids Activity

Nausea ± vomiting

Metaclopramide Phenothiazines Serotonin HT3 receptor antagonist

Fatigue

Treat anemia and depression Exercise SSRIs with stimulatory properties (e.g. flouxetine, sertaline) Bupropion Modafinil

Depression

SSRIs Counseling if poorly controlled

Anxiety

SSRI with sedating properties (e.g. low-dose venlafaxine)

Mania

Stop interferon and all antidepressants Emergency referral to psychiatry

Insomnia

Sleep hygiene Take second dose of ribavirin in early evening, not before bed Avoid stimulating SSRIs Diphenhydramine Short-acting hypnotics (e.g. zolpidem, zaleplon)

Anemia

Stop ribavirin if Hgb 3 months; interface hepatitis, bridging necrosis, cirrhosis; occasional autoantibodies

Diclofenac, nitrofurantoin, mesalamine, minocycline

Granulomatous hepatitis

Hepatic granulomas, raised liver enzymes especially SAP, GGT

Allopurinol, carbamazepine, quinine, hydralazine

Steatohepatitis

Steatosis, ballooning change, Mallory’s hyaline, pericellular or perisinusoidal fibrosis, cirrhosis

Amiodarone, perhexiline, tamoxifen

Cholestasis

See Table 37.4

Vascular disorders

Dilated sinusoids, peliosis hepatis, noncirrhotic portal hypertension, nodular regenerative hyperplasia, sinusoidal obstruction syndrome (veno-occlusive disease)

Anabolic steroids, oral contraceptives, cancer chemotherapy agents

Liver tumors

Focal nodular hyperplasia, hepatic adenoma, hepatocellular carcinoma, angiosarcoma

Anabolic steroids, oral contraceptives, vinyl chloride, arsenic, 6-thioguanine

GGT, gamma glutamyl transpeptidase; SAP, serum alkaline phosphatase; ALT, alanine aminotransferase; ULN, upper limit of normal; HAART, highly active antiretroviral therapy.

special features on liver biopsy (microvesicular steatosis, steatohepatitis, or granulomatous hepatitis), or characteristics of dose-dependency. Likewise, cholestatic drug reactions are grouped together based on duration (acute or chronic) or on histology (‘bland cholestasis,’ cholestatic hepatitis with or without significant bile duct injury) (Table 37.2). Syndromes of chronic cholestatic syndromes can closely mimic either primary biliary cirrhosis or sclerosing cholangitis. The range of hepatic lesions resulting from vascular injury includes hepatic sinusoidal dilatation, peliosis hepatis, through to sinusoidal obstruction syndrome (or veno-occlusive disease), nodular regenerative hyperplasia, and portal fibrosis with noncirrhotic portal hypertension. Finally, prolonged use of certain drugs can promote formation of hepatic neoplasms such as hepatic adenoma and, rarely, hepatocellular carcinoma and angiosarcoma (see Table 37.1).

Epidemiology Previous pharmacoepidemiological studies have estimated the incidence of drug-induced hepatitis at approximately 8.9 to 406 per million persons per year.21 The methodologies of these studies have been criticized for their retrospective design, lack of followup, and insufficient detail about viral hepatitis testing. Further, some of these reports have preceded the discovery of the hepatitis C virus. Contemporary estimates based on two prospective population-based French and Spanish studies cite lower figures, between 7.4 to 8 per million persons exposed per year.21,22 It is estimated that only about 10% of cases of serious liver injury are reported; the figures for milder reactions could be even

lower (2–4%).23 Regional differences in spontaneous drug reaction reporting also account for the heterogeneity in population-based estimates of hepatotoxicity. For example, when assessed from voluntary adverse reaction reports, the annual incidence of drug hepatotoxicity is 2.2 and 0.9 per 100 000 persons for Sweden and France, respectively.24 The occurrence of hepatic adverse reactions is nonlinear with time; most reactions occur within 6 months of drug ingestion, and most reports of hepatic adverse drug reactions are made within 2 years of approval of the new drug. Therefore, conventional indices such as incidence or prevalence are less meaningful than the risk of liver injury for an individual drug. This is expressed as frequency of reactions per persons exposed to a particular compound.25 For the majority of drugs, the risk of hepatotoxicity ranges from 1 in 1000 to 1 in 100 000 per persons exposed. The risk is even lower with drugs such as minocycline (1 in a million).8 However, these figures are only crude estimates. What is more important clinically is that hepatotoxicity can occur at greater frequencies (0.1–2%) in persons with particular sets of demographic, medical, and environmental risk factors (see below).

PATHOGENESIS Dose-dependent hepatotoxins Unlike several industrial compounds, only a small proportion of current drugs operate as dose-dependent hepatotoxins.2,3 Examples include acetaminophen, cancer chemotherapeutic agents such as busulfan and cyclophosphamide, and the antimalarial, amodiaquine. Dose-dependent hepatic injury occurs after a short

567

Syndrome

Clinical and biochemical features

Typical examples

Recent additions

Acute Cholestasis without hepatitis

Pruritus, SAP >3 ⫻ ULN, transient increase in ALT; bilirubin < 12 mg/dl

Estrogens, anabolic steroids

Infliximab Fosinopril

Cholestasis with hepatitis

Right upper quadrant or generalized abdominal pain; jaundice; can simulate acute cholangitis; SAP >3 ⫻ ULN in 70%, ALT 2–5 ⫻ ULN

Chlorpromazine, other phenothiazines, macrolides, amoxicillin-clavulanate, sulindac, oxypenicillins, azathioprine

Ticlopidine, irbesartan, gatifloxacin, levofloxacin, risperidone, glimepiride, pyritinol, rofecoxib

Cholestasis with bile duct injury

Features simulate acute cholangitis

Dextropropoxyphene, flucloxacillin

Terbinafine, ramipril, ciprofloxacin

Chronic Vanishing bile duct syndrome

Resembles primary biliary cirrhosis; antimitochondrial antibodies absent

Chlorpromazine, flucloxacillin, oxypenicillins

Ramipril

Large bile duct strictures

Resembles primary sclerosing cholangitis

Floxuridine, intralesional scolicidal agents (absolute alcohol, 2% formaldehyde, hypertonic saline)

latent period, usually within 1 to 5 days. Typical ALT values exceed 1000 IU/L and liver histology shows zonal, bridging, or massive hepatic necrosis. Dose-dependent toxins are endowed with ‘intrinsic hepatotoxic potential,’ implying that the circumstances in which they cause liver injury are predictable.3 Thus, hepatotoxicity occurs when their chemically reactive metabolites exceed a predetermined threshold. However, host factors can profoundly influence the formation of these metabolites, as well as ‘tissue resistance’ to their accumulation (such as antioxidant reserves). Acetaminophen (APAP) hepatotoxicity is a model of dosedependent hepatotoxicity. In keeping with this paradigm, liver injury occurs when a threshold dose is exceeded (150 mg/kg body weight). Onset of toxicity is rapid (24–48 hours) and marked elevation of ALT is characteristic. However, patients with a history of chronic alcohol excess are more likely to develop hepatotoxicity, sometimes with intake of regular (several days) doses regarded as within the therapeutic range (2–4 g/day).26 The actual risk of heightened susceptibility to paracetamol among alcoholics has been questioned by Prescott,26a but contemporary hepatologic practice supports a real association between excessive alcohol intake and instances of paracetamol induced severe liver injury, occasionally due to “therapeutic misadventure”. APAP undergoes metabolism to glucuronide and sulfate conjugates, which are excreted in the urine (Fig. 37.1). A reactive metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), is also formed by cytochrome P450 (CYP)-mediated oxidation, particu-

larly CYP2E1 and CYP3A4. NAPQI is readily detoxified by hepatic glutathione (GSH). Therefore, circumstances which favor NAPQI accumulation include hepatic GSH depletion (e.g., prolonged fasting) or induction of CYP2E1 (by fasting, isoniazid, chronic alcohol intake) and CYP3A4 (by anticonvulsants). Depletion of glucuronide or sulfate stores (fasting, intake of some other drugs) reduces the capacity to conjugate APAP, again favoring the CYPmediated oxidation pathway to form NAPQI. NAPQI alters hepatocyte membrane proteins directly or generates oxidative stress, leading to mitochondrial injury with cell death (whether by necrosis or apoptosis).27 The host innate immune system may also be involved in the pathogenesis of APAP liver injury.28 Replenishing intracellular GSH by administering thiol donors such as N-acetylcysteine (NAC) and methionine is the cornerstone of antidote therapy in management of patients with APAP hepatotoxicity.29

Idiosyncratic drug reactions Other than a few dose-dependent and some partial dose-dependent hepatotoxins (e.g., tacrine, dantrolene), the majority (over 95%) of drug-induced liver diseases are dose-independent or ‘idiosyncratic’ by nature. Broadly, idiosyncratic drug reactions are considered to have either a metabolic or an immunoallergic basis. Metabolic idiosyncrasy refers to liver injury resulting from drug or drug metabolite accumulation as a consequence of altered metabolic pathways (e.g., in persons with polymorphisms of drug

•

Acetaminophen

CYP2E1

GSH

Sulfation Glucuronidation

Mercapturic acid derivatives

NAC Methionine

NAPQI No GSH

Covalent binding/ oxidative stress (toxicity)

Metabolism of acetaminophen and Fig. 37.1 the role of NAPQI in liver injury. NAC and methionine ameliorate acetaminophen hepatotoxicity by replenishing hepatic glutathione. GSH, reduced hepatic glutathione; NAPQI, N-acetyl-p-benzoquinoneimine; NAC, N-acetylcysteine.

Pathogenesis

Table 37.2 Syndromes of drug-induced cholestasis

Drug-induced Hepatic Injury (Prevention)

568 metabolizing enzymes). In turn, there is activation of cell death pathways by mitochondrial injury, covalent binding to macromolecules, induction of oxidative stress, or interference with canalicular transporter functions. Both hepatocytes and hepatic nonparenchymal cells (e.g., Kupffer cells, endothelial cells, liver lymphocytes, stellate cells) may be involved. Troglitazone hepatotoxicity is a contemporary paradigm for likely metabolic idiosyncrasy. Like acetaminophen, troglitazone is principally conjugated with glucuronide and sulfate and also forms a potentially reactive quinone metabolite. However, in comparison with the parent compound, the quinone metabolite is less toxic.30,30a Troglitazone-associated mitochondrial injury, culminating in cell death (apoptosis or necrosis), has been suggested as a possible pathway to liver injury,30 but the evidence to support this suggestion has been challenged.30b Associated inhibition of the bile salt export pump could also induce apoptosis by promoting accumulation of bile salts (well known to cause apoptosis). Certain host factors may underlie troglitazone toxicity. Thus, those at risk were obese persons with type 2 diabetes, which are risk factors for nonalcoholic steatohepatitis but there is no convincing evidence that preexisting steatohepatitis with its associated oxidative stress and possible energy depletion, rendered the liver more susceptible to troglitazoneinduced injury.30b Drug–drug interactions could also have contributed to severe liver injury; co-administration of cholestasisinducing drugs (e.g., glibenclamide) could have aggravated troglitazone-induced bile salt retention,30 but direct evidence in favour of his proposition is also lacking.30b Immunoallergic idiosyncrasy has been implicated in some hepatic drug reactions, typically those accompanied by other allergic manifestations such as fever, skin rash, neutrophilia, and eosinophilia. The anticonvulsant hypersensitivity syndrome is a well-studied example of this pattern of toxicity. More recently, the term reactive metabolite syndrome has been preferred to emphasize the pathogenic role of drug metabolites in its development.31 Other drugs which have been associated with this syndrome include sulfonamides, allopurinol, dapsone, and minocycline. The clinical presentation is characterized by short latency (2–6 weeks), high-grade fever, pharyngitis, facial edema, lymphadenopathy, and skin reactions ranging from an exanthematous eruption to Stevens-Johnson syndrome and toxic epidermal necrolysis. Visceral involvement can occur; this includes interstitial nephritis, encephalitis or aseptic meningitis, pneumonitis, atypical lymphocytosis or cytopenias, and vasculitis. Cross-reactivity with similar drugs that can produce reactive metabolites and a positive family history of similar drug reactions (in 25%) indicate the genetic basis for this syndrome. It is hypothesized that drug metabolites form adducts with cellular proteins. The ensuing protein-adducts then provide a target for the host immune response that culminates in liver injury. However, drugs such as acetaminophen, which readily produce reactive metabolites, do not evoke such an immune response. Further, demonstration of a damage-inducing cytotoxic T-cell response has not been easy. A modified concept is the ‘danger hypothesis,’ which proposes that an immune (or tissue-specific inflammatory) response occurs only if the reactive metabolite also elicits danger signals by producing intracellular oxidative stress or necrosis.31

Drug-induced cholestasis Molecular characterization of hepatobiliary transport processes has provided insights into the pathogenesis of drug-induced

cholestasis.32,33 Thus, cholestasis could result from cis- or transinhibition of the bile salt export pump by such agents as cyclosporine A, rifampicin, estradiol, and troglitazone. Alternatively, drugs or their metabolites could cause covalent modification of canalicular transport proteins (e.g., diclofenac) or alter membrane fluidity. Individuals with genetic defects in transporter proteins, such as those with progressive familial cholestasis (defects in multidrug resistance protein-3) can develop cholestasis with drugs such as estrogens that inhibit the bile salt export pump or multidrug resistance-related protein (MRP)-2 (formerly known as canalicular multispecific organic anion transporter-cMOAT) function. The pathogenesis of chronic forms of cholestasis is unknown but immune mechanisms may be involved. This is supported by the observation that Stevens-Johnson syndrome, a disorder with an immunological basis has accompanied some cases of vanishing bile duct syndrome.34

Individual risk factors Underlying host and disease variables which influence the expression and severity of drug-induced hepatic injury are listed in Table 37.3. Overall, children are less susceptible to drug hepatotoxicity with the exceptions of valproic acid toxicity, Reye’s syndrome with aspirin, and cholestatic hepatitis caused by erythromycin estolate. The restriction of aspirin use for febrile illness in this age group has led to a dramatic decline in the incidence of Reye’s syndrome.35 By contrast, older patients are vulnerable to hepatic injury by way of increased exposure, altered drug disposition, and often drug–drug interactions due to polypharmacy. The reason for gender differences in hepatic drug reactions is unclear and cannot be explained merely by increased exposure. Women are over-represented in reports of drug-induced hepatitis, particularly in cases of chronic hepatitis. On the other hand, amoxicillin-clavulanate and azathioprine toxicity are more common in males. Both undernutrition and obesity can predispose to hepatotoxicity. Undernutrition is an independent risk factor for antituberculous therapy; dose recommendations are now strictly by body weight.36 On the other hand, obese individuals are more susceptible to halothane and methotrexate toxicity. In the case of methotrexate, the underlying nonalcoholic steatohepatitis may be important in the pathogenesis of the liver injury.37 Central obesity may also be a risk factor for tamoxifen-induced fatty liver disorders.38 The impact of underlying liver disease on hepatotoxicity is also illustrated by the interactions between chronic hepatitis B and antituberculous therapy (ATT) and of highly active antiretroviral therapy (HAART) with chronic hepatitis B (HBV) and C virus (HCV) infection. In a study from Taiwan, persons infected with HBV were more likely (35% versus 9%, respectively) to develop an ALT rise with ATT as compared to persons without HBV infection.39 Further, among those who developed liver injury, coinfected individuals had higher histological severity scores than those without HBV infection. By multiple logistic regression analysis, only age and hepatitis B surface antigen positivity were independent risk factors for liver injury (odds ratio 5.5, 95% CI, 2.1–14.3).39 Likewise, in some studies, a proportion of HAART recipients coinfected with HBV or HCV were at an increased risk of hepatotoxicity.40 In one study, the presence of chronic viral hepatitis B and C was associated with an increased risk of severe hepatotoxicity, especially among patients prescribed regimens

569

Risk factors

Representative agents

Importance

Age

Isoniazid, troglitazone, halothane, nitrofurantoin Valproic acid, salicylates

Age >60 increases frequency and severity of liver injury More common in children

Gender

Halothane, diclofenac, nitrofurantoin, dextropropoxyphene Azathioprine, amoxicillin-clavulanic acid

More common in women

Dose

Acetaminophen, salicylates Anticancer drugs, perhexiline, tacrine, oxypenicillins, dantrolene Methotrexate, vitamin A

Toxicity correlates with drug levels Partial relationship to dose

Halothane, phenytoin, sulfonamides

Family history of similar reactions; in vitro susceptibility tests in lymphocytes Strong HLA association Associated with inherited mitochondrial enzyme deficiencies

Genetic factors

More common in men

Total dose, frequency, and duration of exposure correlate with fibrosis risk

Amoxicillin-clavulanic acid Valproic acid Cross-sensitivity

Isoflurane, enflurane, halothane; erythromycin and other macrolides; diclofenac and ibuprofen

Relevant to prevention of drug-induced liver disease

Multiple drug therapy (polypharmacy) including drug interactions

Acetaminophen and isoniazid, zidovudine or phenytoin

Lower hepatotoxic dose threshold

Excessive alcohol use

Acetaminophen Isoniazid, methotrexate

Lower hepatotoxic dose threshold Increased risk of liver injury, fibrosis

Nutritional status Obesity Fasting

Halothane, troglitazone, tamoxifen, methotrexate Acetaminophen

Increased risk of liver injury, NASH or hepatic fibrosis Increased risk of liver injury

Pemoline Viral hepatitis B or C

Increased risk of liver injury Increased risk with HAART, antituberculosis treatment, ibuprofen

Methotrexate

Increased risk of hepatic fibrosis

Osteoarthritis

Diclofenac

Increased risk of liver injury

HIV/AIDS

Sulfonamides (cotrimoxazole)


Renal failure

Methotrexate

Increased risk of liver injury, fibrosis

Rheumatoid arthritis, SLE

Salicylates


NASH

Methotrexate

Increased risk of liver fibrosis

Pregnancy

Intravenous tetracycline

Increased risk of acute fatty liver of pregnancy

Organ and bone marrow transplantation

Azathioprine, thioguanine, busulfan

Increased risk of vascular toxicity

Liver disease

Other diseases Diabetes mellitus

HLA, human leukocyte antigen; NASH, nonalcoholic steatohepatitis; HAART, highly active antiretroviral therapy; HIV/AIDS, human immunodeficiency virus, acquired immunodeficiency syndrome; SLE, systemic lupus erythematosus.

Pharmacogenetics which excluded ritonavir (odds ratio, 3.7; 95% CI, 1.0–11.8); overall, around 12% of patients receiving a protease inhibitor developed liver injury.41 One suggested strategy to minimize hepatotoxicity associated with HAART includes use of a published algorithm based on ALT monitoring, signs and symptoms of hepatitis and/or mitochondrial toxicity.42 The other approach to this problem is to consider pretreatment of chronic viral hepatitis in HIV-infected patients prior to administration of HAART.43

Genetic factors are estimated to account for 20–95% of variations in drug disposition and effects.44,45 In more extreme examples, this may manifest as polymorphisms of drug metabolizing enzymes, drug receptors, or transporters.44 Pharmacogenetics deals with these variations in drug response with reference to single-gene or genome-based approaches to pharmacology (pharmacogenomics) or toxicology (toxicogenomics). With reference to drug-induced liver

Pathogenesis

Table 37.3 Risk factors for increased incidence and severity of drug-induced liver diseases


570 Table 37.4 Genetic polymorphisms and drug-induced liver disease Polymorphism

Phenotype

Drugs associated with increased hepatotoxicity

CYP2D6

Poor metabolizer

Perhexiline maleate

CYP2C19

Poor metabolizer

Atrium

CYP 2C9*3

Poor metabolizer

Leflunomide

CYP2E1

c1/c1 phenotype associated with increased CYP2E1 activity

Isoniazid

Glutathione S-transferase

Poor metabolizer (combined GST M1-T1 phenotype only)

Tacrine

Glutathione S-transferase

Poor metabolizer (GST M1 phenotype only)

Isoniazid

N-acetyl transferase 2

Slow acetylator status; other studies have shown fast acetylators to be at greater risk

Isoniazid

HLA associations

Absence of HLA-DQA1*0102 (OR 4.0) and presence of HLA-DQB1*0201

Antituberculous drugs

HLA-DRB1*1501, DRB5*0101, DQB1*0602

Amoxicillin-clavulanate

HLA-A33/B44/DR6

Tiopronin

injury, those polymorphisms that have been implicated in hepatotoxic reactions are listed in Table 37.4.46–49 However, the practical significance of these associations within the community has not been defined. One of the problems is the population-specific variation of each polymorphism; thus, independent validation is needed across different ethnic groups. Variations in immune response genes have been linked to certain forms of drug allergy. Again, reanalysis of putative preliminary associations in different populations or in larger studies has given rise to conflicting reports. Given these limitations, as well as cost considerations, the routine application of pharmacogenetic methods cannot yet be widely recommended.

DIAGNOSIS Clinical suspicion, causality assessment, scoring systems In the absence of confirmatory tests, the diagnosis of drug-induced liver disease is based on circumstantial evidence (Table 37.5).8 Key diagnostic points include the temporal profile of drug use, the response to drug withdrawal (dechallenge) and rechallenge. Generally, reactions occurring within 1–12 weeks of commencing

Table 37.5 Clinical features raising suspicion of drug-induced liver disease New drug introduced (within 1 to 6 months) Extrahepatic involvement; hypersensitivity features ‘Idiopathic’ acute hepatitis Chronic hepatitis without antibodies or hyperglobulinemia Mixed hepatocellular-cholestatic biochemical profile Cholestasis with normal biliary tract imaging Suggestive histologic features (see Table 37.6) Complex medical situations (e.g., intensive care unit), special risk categories (see Table 37.3) Concurrent herbal drug intake

a drug are considered most likely to represent drug toxicity. Latent periods of 12 weeks to 1 year are still compatible with drug toxicity, but are considered less likely. Other than certain forms of delayed toxicity, such as development of chronic hepatitis (e.g., minocycline), cirrhosis (e.g., methotrexate, arsenic) or hepatic neoplasia (e.g., oral contraceptives, anabolic steroids, arsenic), reactions occurring beyond 1 year of use are very unlikely to be medicationrelated. By contrast, re-exposure to the drug in previously sensitized persons may produce hepatotoxicity within hours or days. Such rechallenge, whether deliberate or inadvertent, is regarded as the gold standard when assigning causality to a particular agent. However, ethical considerations usually prevent its application because safer therapeutic alternatives may be available, and, more importantly, re-exposure can provoke severe reactions and even fatalities with drug reactions of an immunoallergic nature. Therefore, emphasis is placed on observation of the ‘dechallenge,’ i.e., the response to drug withdrawal. Accordingly, hepatocellular reactions may be categorized as ‘very suggestive’ or ‘suggestive’ if the liver enzymes decrease by 50% of excess above ULN within 8 days or 30 days, respectively. The time frame for improvement for ‘suggestive’ cholestatic reactions is extended to 180 days.50 Scoring systems to assign causality have been developed by consortia of experts in this field. Two such systems, the detailed CIOMS and a simpler modification, the clinical diagnostic scale (CDS) are in use.50,51 The components of these scores include: time to onset from drug commencement or drug discontinuation, course of the reaction after drug cessation, concomitant treatment, complete exclusion of non-drug-related causes, previous track record of the suspected drug, extrahepatic manifestations and response to rechallenge. Comparisons between the two systems showed poor concordance, with agreement in only 31% of cases.52 Agreement was better for hypersensitivity cases (perhaps due to the emphasis on extrahepatic features of drug hypersensitivity) but the overall performance of the CIOMS was better. The CDS has been criticized for its heavier weighting towards hypersensitivity reactions, bias towards recent drugs (25% of cells in infiltrate) Bile duct injury Granulomas, vascular lesions Features of severe steatohepatitis Presence of vitamin A deposits (autofluorescence)

Indications for liver biopsy Many instances of drug-induced liver injury are self-limiting. Liver biopsy is not usually performed in these individuals, particularly when improvement is evident or there is only a minor alteration in liver biochemical tests. However, liver biopsy may be useful in borderline cases to exclude other liver disorders or to provide corroborative evidence of drug toxicity; the latter may assume greater importance when a new pharmacologic or complementary/alternative medicine (CAM) agent not previously associated with liver injury is the most likely cause. Although a specific diagnosis can be rarely made, several histologic features raise the suspicion of a drug etiology (Table 37.6). The prognosis of drug injury can also be inferred in some instances. For example, detection of severe bile duct injury in cases of acute cholestatic hepatitis foreshadows the development of ductopenia and the possibility of prolonged cholestasis,56 while bridging or zonal necrosis is indicative of a surprisingly severe form of hepatocellular injury. Liver biopsy plays an important role in patients with risk factors for other forms of liver injury such as metabolic causes of fatty liver, in whom methotrexate is being considered. The risk–benefit ratio for liver biopsy needs to be assessed carefully for each individual, and informed consent is clearly essential.

GOALS OF PREVENTION Pharmacologic principles, patient and professional education, appreciation of special risk categories Preventing drug hepatotoxicity is a moral, ethical, and legal responsibility of every prescribing doctor. Since serious drug reactions are infrequent and often idiosyncratic, individual experience with dealing with such cases will be limited. Further, recognizing medication errors may not be sufficiently stressed during medical training; in one American survey, only 16% of interns received formal training during their clerkship.57 At the level of the prescriber, minimizing harm requires attention to core pharmacologic principles: appropriate drug, appropriate dose, considering safer alternatives (especially nonpharmacologic), avoid polypharmacy and appreciation of host and drug factors which heighten the influence of adverse drug effects (see Table 37.3). As discussed below, protocol ALT monitoring has its limitations and should never replace patient and physician education about drug toxicity. The increasing availability of drug information software (e.g., ePocrates®) on personal digital assistants in clinical practice or drug alerts in hospital network systems is an interesting contemporary trend; it could be hoped that such applications will help reduce prescribing errors and consequent drug toxicity, but this remains to be seen. From a hospital perspective, implementation of an automated computer-assisted laboratory result monitoring system is feasible.58,59 In a pilot project, 91% of all adverse reactions were identified, but the specificity of this computer-generated alert was low (23%), rendering the process of reaction identification ineffective. However, specificity of the computer-generated alert could be improved upon (to 76%) by incorporation of specific laboratory algorithms. Governmental initiatives may also have an impact on preventing or reducing drug-induced liver injury. For example, in the UK, restrictions on pack sizes of acetaminophen, and restricting sales (in 1998) changing the mode of packing, have been associated contemporaneously

Goals of Prevention

with a possible drug reaction. Discrepancies also exist between a physician’s (global) assessment of drug reactions, and achievement of a diagnosis through application of scoring systems.54 In one French study, complete agreement was observed in only 6% of the cases. Physicians were more likely to score reactions as ‘likely or very likely’ (60%), whereas causality was considered ‘likely’ in only 10% of the same case mix when the scoring system was used.54 Therefore, the exact place of scoring systems is not defined. Although they can be used as research tools and their use is being increasingly encouraged in case reports, individual assessment on a case-by-case basis remains critical.


572 with reduced requirement for liver transplantation (by 66%) and mortality (by 21%) after acetaminophen overdose although the contribution of the 1998 regulations to the reduction is unclear.60,60a

Drug screening, post-marketing surveillance The elaborate drug development process includes extensive toxicologic preclinical testing in animal models, followed by doseranging studies, phase II and finally phase III trials.11,11a Despite this, identification of idiosyncratic drug reactions is not always possible. This is because the number of participants in prerelease clinical trials (2000–3000) is much lower than typical frequencies of drug hepatotoxicity (1 in 10 000 above). The troglitazone story highlights this shortcoming.12a Thus, although approximately 2% of clinical trial recipients of troglitazone developed raised aminotransferases, no cases of acute liver failure were observed. Nonetheless, in the 5 years following its launch, over 90 cases of serious liver injury were reported to the FDA, leading to its ultimate withdrawal. Based on current estimates of troglitazone hepatotoxicity (50 per 220 per million person-years), it is obvious that such events could not have been adequately predicted from phase III trials.12,12a,30b The troglitazone experience underscores the importance of post-marketing surveillance. Prescribers are encouraged to report unusual or serious adverse events to drug licensing authorities (e.g., MEDWATCH database maintained by the Food and Drug Administration, USA). The information sought extends beyond prescribed drugs to other hepatotoxins, and in particular, to the hepatic reactions with some nutritional supplements (e.g., Lipokinetix)61 and CAM.62,63 Standardization, better documentation of efficacy, and similar procedures for approval as for other drugs has been suggested for these compounds.64

Common practice is to recommend drug withdrawal when ALT levels exceed 5 times ULN (roughly 250–300 IU/L). Alterations in bilirubin, prothrombin time, and onset of non-specific symptoms (nausea, anorexia, malaise, hepatic discomfort), jaundice or other signs of liver injury are much more important. Above all, educating the patient (and practitioners) about symptoms of hepatotoxicity is critical because the goal is to stop the offending drug as early as possible. The progressive nature and poor outcome of drug-induced liver injury, when patients continue their medications after the onset of symptoms, is a recurring theme in publications on drug hepatotoxicity. Other methods of monitoring for early detection of liver problems include performing liver biopsies to assess hepatic fibrosis (for methotrexate), and annual ultrasound examination of the liver to screen for hepatic adenoma formation (for danazol).67 Guidelines for performing liver biopsy in long-term methotrexate recipients have been published.68–70 Liver histology is obtained at baseline only in persons at risk, and particularly those with history of chronic excessive ethanol intake, baseline abnormalities of ALT, or strong risk factors for nonalcoholic fatty liver disease. For others, liver biopsy is considered when a cumulative amount of 1.5 grams is reached and for every 1–1.5 grams thereafter according to the result of the first liver biopsy. Aithal and colleagues have called for a revision in these guidelines. In their study, only 2.6% of recipients receiving a cumulative amount of 4 grams showed significant hepatic fibrosis.71 Further, the risk–benefit ratio of liver biopsy appeared unfavorable with complication rates of 4% in this cohort; notwithstanding that such a high rate of liver biopsy complications is not in accord with that currently accepted,72 the authors have suggested a higher threshold (cumulative dose, 5 grams) before liver biopsy.71 We partially agree with this view, with the exception of those with the aforementioned risk factors.

MANAGEMENT Protocol ALT monitoring Routine monitoring of liver tests (especially ALT) is often recommended for persons receiving long courses of treatment (>4 weeks). This is an established practice for drugs with an established track record of hepatotoxicity, such as isoniazid, methotrexate, etretinate, and other synthetic retinoids, ketoconazole and anticancer drugs. However, drugs that have low hepatotoxic potential cause a conundrum for patients and prescribers; in the case of the widely prescribed “statins” (3-hydroxy-3-methylglutarhyde coenzyme-A reductase inhibitors), the usefulness of this approach has been seriously questioned.66a,66b Several caveats apply to protocol ALT screening. Progression to acute liver failure can be rapid with certain drugs (e.g., troglitazone). Thus, monthly monitoring of ALT did not identify 19 (20%) of 94 cases of troglitazone-associated liver failure.12 Second, the threshold at which ‘injury’ occurs is not well defined. Raised aminotransferases more often occur transiently during drug intake, representing true ‘hepatic adaptation.’ Thus, liver test abnormalities may resolve without stopping treatment. Third, liver enzyme changes (outside of the stated ‘normal range’, the definition of which is controversial65) are also observed in persons receiving placebo during clinical trials. Finally, the costeffectiveness of such monitoring has never been documented, but has been questioned.66 In this context, recommendations of manufacturers for monitoring ALT (or AST) with drugs like minocycline and the statins is hard to endorse.

In mild cases, early recognition of drug toxicity and prompt withdrawal of the offending drug usually leads to a rapid and uneventful clinical recovery. Conversely, resolution (especially at the biochemical level) can be protracted in cholestatic reactions, and also with drugs that have a long half-life (amiodarone, vitamin A, ketoconazole, etretinate). A more variable set of outcomes pertains to individuals who develop severe liver injury. In some such cases, prolonged intensive support may be needed. Patients fulfilling standard criteria for liver transplantation73 should be considered for referral to a liver transplant center. Early discussion with transplant centers is critical, to facilitate transfer before an irretrievable clinical situation is reached and to allow time for obtaining a donor liver, assessing comorbidity and psychosocial issues.

Dose-dependent hepatotoxins In cases of dose-dependent hepatotoxicity, approaches to management include gastric lavage to remove unabsorbed drug (for acetaminophen, metals, and toxic mushrooms). Drug levels should be measured (acetaminophen, salicylates, metals). Acetaminophen (APAP) hepatotoxicity is the only form of druginduced liver disease for which a specific antidote is available.74 NAC is administered either orally (USA) or intravenously (Australia, Europe), but only the oral form of NAC is approved by

573

Dosing schedule for N-acetylcysteine

Idiosyncratic drug reactions Corticosteroids No controlled data are available for the role of corticosteroids in drug-induced liver disease. However, patients receiving corticosteroids for systemic hypersensitivity reactions (e.g., with allopurinol) have also shown improvement in biochemical and clinical manifestations of the coexisting liver injury. Likewise, corticosteroids have been used with apparent benefit in some cases of acute and chronic hepatitis due to diclofenac, piroxicam, methyldopa, minocycline, and the sulfa drugs.86–90 The literature abounds with instances of ‘corticosteroid-whitewash’ in cases of drug-induced jaundice, especially with cholestatic hepatitis; conversely, a partial response could mask another disorder (e.g., occult cholangiocarcinoma). Based on these considerations, the use of corticosteroids may be considered on a case-by-case basis based on the severity and duration of illness and careful assessment of comorbidity (diabetes mellitus, active sepsis, and other relative contraindications to steroid use). Further, the adequacy (complete or otherwise) of any response and the post-biopsy course all need to be considered with unusual diligence.

Ursodeoxycholic acid in the treatment of chronic cholestasis As with corticosteroids, controlled trials of efficacy for ursodeoxycholic acid (UDCA) are lacking. Anecdotally, UDCA has been used with success in predominantly cholestatic reactions with drugs such as cyclosporine in heart transplant recipients, amoxicillinclavulanate, flutamide, flucloxacillin, and ticlopidine.91–95 Therefore, it may be considered in protracted cases of cholestasis.

Oral N-acetylcysteine Oral dosing is an initial dose of 140 mg/kg, 70 mg/kg 4 hours later, and subsequent doses of 70 mg/kg every 4 hours for 17 doses. The unpleasant odor and flavor of NAC can be masked by administering it with fruit juice and by dilution of NAC to a 5% solution.

Intravenous N-acetylcysteine An initial loading dose of 150 mg/kg of NAC is given in 200 mL of 5% dextrose over 15 minutes, followed by 50 mL/kg in 500 mL of 5% dextrose over 4 hours. The maintenance dose is 100 mL/kg in 1 liter of 5% dextrose over 16 hours. Newer protocols include a 48-hour intravenous and a 20-hour oral protocol.82 The latter has been evaluated only in early presenters (within 8 hours of APAP ingestion). All regimens appear to be equally effective. Anaphylactoid reactions (flushing, wheezing, urticaria, rarely angioedema) are observed in 6–15% of intravenous NAC recipients. However, these reactions are usually mild, and rarely lead to treatment discontinuation. Minor reactions require no additional treatment (for flushing) or antihistaminics (for pruritus). The NAC infusion is temporarily discontinued if angioedema and respiratory distress develop. After antihistaminics are administered, the infusion can usually be resumed after 1 hour. Bronchial asthma is not an absolute contraindication to use of NAC. However, caution is advised because such persons are more likely to develop other adverse effects that can rarely be fatal.83–85 Oral methionine can also be used in early cases (within 10 hours) of APAP overdose. However, methionine can cause vomiting and is now usually restricted to persons with NAC hypersensitivity.

Liver transplantation Patients fulfilling standard liver transplant criteria (developed at King’s College Hospital, London) (Table 37.7) have a poor outcome and should be considered for liver transplantation.73,96,97 Other additions and modifications to these criteria have been suggested, but further appraisal is necessary (Table 37.8).98–101 Artificial liver support systems based on molecular adsorbent recirculating systems have shown benefit in uncontrolled studies, but remain investigational.102 Short-term transplant-free survival for acute liver failure induced by acetaminophen was significantly better than for nonacetaminophen-related cases (68% versus 25%, respectively).103 Of those undergoing liver transplantation, 75% could be discharged from hospital; 66% were alive at a median of 37 months (range 1–72 months).96

Table 37.7 Criteria for liver transplantation in acetaminophen-induced acute liver failure Arterial pH 300 ␮mol/L Prothrombin time >100 seconds (international normalized ratio >6.5) Grade III/IV encephalopathy (if all 3 of these occur within a 24-hour period)

Management

the FDA. An inhalant preparation of NAC can also be used for intravenous administration.75 Although the hepatotoxic dose of APAP is 150 mg/kg, APAP levels should be obtained within 24 hours in all patients who present. Physicians should consult a treatment nomogram (Rumack-Mathew, Prescott) in which the plasma APAP level is plotted against time since ingestion.76,77 NAC is commenced if plasma levels exceed the standard treatment line (drawn joining a level of 200 mg/L at 4 hours and 30 mg/L at 15 hours). The threshold for treatment is lowered in certain high-risk patient groups, such as those receiving enzymeinducing drugs (carbamazepine, phenytoin) or under conditions of hepatic glutathione depletion (fasting, anorexia nervosa, cancer cachexia). For these patients, a lower threshold treatment line is used (joining plasma APAP levels over 100 mg/L at 4 hours and 15 mg/L at 15 hours). The nomograms are less reliable after 15 hours of APAP ingestion and also in persons presenting with staggered overdoses or continued ingestion of APAP at moderately high levels for more than 48 hours. In these cases, treatment is initiated if the total dose of APAP exceeds 150 mg/kg or in any cases of doubt. The 4-hour APAP levels may be below treatment threshold with extended-release APAP overdoses; repeat measurement at 8 hours is suggested in these cases.78 The benefits of continuing NAC in late-presenters (beyond 24 hours of ingestion) are controversial.79,80 Improved cerebral outcome due to stabilization of vascular tone has been reported79 but others have refuted this.81 However, current practice in many liver units around the world is to continue NAC till recovery or liver transplantation.


574 Table 37.8 Other predictors of poor outcome in acetaminophen-induced liver failure Criteria

Significance

Comment

Blood lactate levels96

Poor outcome if blood lactate levels >3.5 mmol/L after early fluid resuscitation or if blood lactate levels >3.0 mmol/L after adequate fluid resuscitation

Timing of testing is critical.The significance of hyperlactatemia in a center accepting only late referrals may be different from a unit dealing with early cases. Independent validation is needed.

Acute physiology and chronic health evaluation (APACHE II) score97

Highest positive and lowest negative likelihood ratio in assessing need for liver transplantation

Single study only

Serum phosphate98–101

Hyperphosphatemia was found to be a predictor of nonsurvival

Sensitivity questioned. Addition to King’s College Hospital criteria73 improved sensitivity but decreased specificity, positive predictive value and accuracy.

Galactose elimination capacity102

Predictor of hepatic encephalopathy

Good sensitivity but low specificity

FUTURE DIRECTIONS Newer strategies include improvement of methods used in assessing the hepatotoxic potential of new compounds, using sophisticated monitoring tools once the drug is marketed, and also advances in the management of patients with drug-induced liver disease. High-throughput assays examining multiple cellular functions appear promising in efforts to predict hepatotoxicity at an early stage of drug development.104 Sophisticated tools to monitor specific organelle injury (e.g., mitochondrial injury with HAART) are being explored. Likewise, the role of noninvasive serum markers in estimating hepatic fibrosis is an area of study. Vector analysis of liver tests can detect early biochemical trends during clinical trials.105 The development of antibodies to drugcell adducts may facilitate diagnosis in cases of acute liver failure of uncertain cause.106 For example, in cases of APAP overdosage, such antibodies are present up to 1 week later when APAP levels are undetectable.106 An important spin-off from the Human Genome project is to accurately identify disease-producing genes in various populations. Polymorphisms of drug-metabolizing enzymes that promote drug toxicity will be increasingly sought before treatment is initiated. Such strategies are already in place for some drug reactions (e.g., thiopurine methyltransferase assays in persons receiving azathioprine to prevent marrow suppression but not liver reactions). At present, abrogating drug-induced liver injury is limited to drugs such as APAP. Potential newer targets include inhibition of apoptosis (caspase inhibitors).107 Global organ shortage has provided an impetus to developing temporary liver support systems, which allow sufficient time for recovery of the native liver. They provide extracorporeal hepatic support or act as filtering devices (e.g., molecular adsorbent recirculating system, MARS) to remove circulating hepatic toxins.102

of drug hepatotoxicity. Diagnosis is still based on circumstantial evidence and appropriate exclusion of other liver diseases. Use of scoring systems can facilitate uniformity in comparisons but are of little if any practical clinical value in diagnosis. Preventing liver injury relies on attention to pharmacologic principles, and patient and professional education. Spontaneous reporting of drug reactions to regulatory authorities is critical in collating evidence of drug toxicity. Protocol monitoring of liver tests should not and cannot replace patient education of hepatotoxic symptoms. Other than N-acetylcysteine for acetaminophen overdose, the management of drug hepatotoxicity is largely supportive. Liver transplantation may be required in severe cases, while ursodeoxycholic acid may have beneficial effects in some cases of severe and prolonged cholestasis. See Table 37.9 for the authors’ summary of recommendations for the management of drup-induced liver injury,

Table 37.9 Authors’ recommendations on management of drug-induced liver injury Early recognition and prompt discontinuation of the offending drug is critical to minimize progressive liver injury. All patients need baseline and continued monitoring for signs of acute liver failure. Oral or intravenous N-acetylcysteine is the preferred treatment for acetaminophen hepatotoxicity. Anecdotal evidence supports the use of corticosteroids in persons with coexisting hypersensitivity manifestations and liver injury. Uncontrolled data favor the use of ursodeoxycholic acid in severe and protracted cholestatic drug reactions.

SUMMARY

Supportive care is critical for all patients with drug-induced hepatic injury. Early liaison with liver transplant centers is encouraged in cases of acute liver failure.

Drug-induced liver injury remains an underrecognized, underreported, occasionally fatal form of adverse drug reaction. Numerous host-related factors can influence the risk and severity

Providing temporary support to the failing liver with extracorporeal liver support devices is yet to be FDA approved, but appears to be a promising future strategy.

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33. Stieger B, Fattinger K, Madon J, et al. Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile export pump (Bsep) of rat liver. Gastroenterology 2000; 118:422–430. 34. Srivastava M, Perez-Atayde A, Jonas MM. Drug-associated acuteonset vanishing bile duct and Stevens-Johnson syndromes in a child. Gastroenterology 1998; 115:743–746. 35. Autret-Leca E, Jonville-Bera AP, Llau ME, et al. Incidence of Reye’s syndrome in France: a hospital-based survey. J Clin Epidemiol 2001; 54:857–862. 36. Pande JN, Singh SP, Khilnani GC, et al. Risk factors for hepatotoxicity from antituberculosis drugs: a case-control study. Thorax 1996; 51:132–136.

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576 37. Langman G, Hall PM, Todd G. Role of non-alcoholic steatohepatitis in methotrexate-induced liver injury. J Gastroenterol Hepatol 2001; 16:1395–1401. 38. Farrell GC. Drugs and steatohepatitis. Semin Liver Dis 2002; 22:185–194. 39. Wong WM, Wu PC, Yuen MF, et al. Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection. Hepatology 2000; 31:201–206. 40. den Brinker M, Wit FW, Wertheim-van Dillen PM, et al. Hepatitis B and C virus co-infection and the risk for hepatotoxicity of highly active antiretroviral therapy in HIV-1 infection. AIDS 2000; 14:2895–2902. 41. Sulkowski MS, Thomas DL, Chaisson RE, et al. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA 2000; 283:74–80. 42. Sulkowski MS, Thomas DL. Hepatitis C in the HIV-infected person. Ann Intern Med 2003; 138:197–207. Guidelines for treatment of HCV/HIV coinfected patients and strategies to deal with abnormal liver tests in these patients. 43. Uberti-Fopa C, De Bona A, Morsica G, et al. Pretreatment of chronic active hepatitis C in patients coinfected with HIV and hepatitis C virus reduces the hepatotoxicity associated with subsequent antiretroviral therapy. J Acquir Immune Defic Syndr 2003; 33:146–152. 44. Givens RC, Watkins PB. Pharmacogenetics and clinical gastroenterology. Gastroenterology 2003; 125:240–248. A review of the possible applications of pharmacogenetics in minimizing gastrointestinal drug toxicity. 45. Evans WE, McLeod HL. Pharmacogenomics – drug disposition, drug targets, and side effects. N Engl J Med 2003; 348:538–549. 46. Larrey D, Pageaux GP. Genetic predisposition to drug-induced hepatotoxicity. J Hepatol 1997; 26(suppl 2):12–21. 47. Roy B, Chowdhury A, Kundu S, et al. Increased risk of antituberculosis drug-induced hepatotoxicity in individuals with glutathione S-transferase M1 ‘null’ mutation. J Gastroenterol Hepatol 2001; 16:1033–1037. 48. Huang YS, Chern HD, Su WJ, et al. Polymorphism of the Nacetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis. Hepatology 2002; 35:883–889. 49. Sharma SK, Balamurugan A, Saha PK, et al. Evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment. Am J Respir Crit Care Med 2002; 166:916–919.

55. Aithal GP, Rawlins MD, Day CP. Accuracy of hepatic adverse drug reaction reporting in one English health region. Br Med J 1999; 319:1541. An alternative liver disorder was observed in more than 50% of cases labeled as having drug-induced liver disease. 56. Degott C, Feldmann G, Larrey D, et al. Drug-induced prolonged cholestasis in adults: a histological semiquantitative study demonstrating progressive ductopenia. Hepatology 1992; 15:244–251. 57. Rosebraugh CJ, Honig PK, Yasuda SU, et al. Formal education about medication errors in internal medicine clerkships. JAMA 2001; 286:1019–1020. 58. Dormann H, Criegee-Rieck M, Neubert A, et al. Implementation of computer-assisted monitoring system for the detection of adverse drug reactions in gastroenterology. Aliment Pharmacol Ther 2004; 19:303–309. A pilot attempt at identifying adverse drug reactions in hospitalized patients by computer-generated alerts. 59. Azaz-Livshits T, Levy M, Sadan B, et al. Computerized surveillance of adverse drug reactions in hospital: pilot study. Br J Clin Pharmacol 1998; 45:309–314. 60. Hawton K, Townsend E, Deeks J, et al. Effects of legislation restricting pack sizes of paracetamol and salicylate on self poisoning in the United Kingdom: before and after study. Br Med J 2001; 322:1203–1207. 60a. Morgan O, Grifiths C, Majeed A. Impact of paracetamol pack size restrictions on poisoning from paracetamol in England and Wales: an observational study. J Public Health 2005; 27:19–24. 61. Favreau JT, Ryu ML, Braunstein G, et al. Severe hepatotoxicity associated with the dietary supplement LipoKinetix. Ann Intern Med 2002; 136:590–595. 62. Chitturi S, Farrell GC. Herbal hepatotoxicity: an expanding but poorly defined problem. J Gastroenterol Hepatol 2000; 15:1093–1099. 63. Stedman C. Herbal hepatotoxicity. Semin Liver Dis 2002; 22:195–206. 64. Lewis JD, Strom BL. Safety of dietary supplements with the free market. Ann Intern Med 2002; 136:616–618. Calls for stricter regulation of complementary/alternative medicines. 65. Kaplan MM. Alanine aminotransferase levels: what’s normal? [Editorial]. Ann Intern Med 2002; 137:49–51. 66. Tolman KG. The liver and lovastatin. Am J Cardiol 2002; 89:1374–1380.

50. Danan G, Benichou C. Causality assessment of adverse reactions to drugs–I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemol 1993; 46:1323–1330.

66a. Smith CC, Bernstein LI, Dains RB, et al. Screening for statinrelated toxicity: the yield of transaminase and creatine kinase measurement in a primary care setting. Arch Intern Med 2003; 163:688–692.

51. Maria VA, Victorino RM. Development and validation of a clinical scale for the diagnosis of drug induced hepatitis. Hepatology 1997; 26:664–669.

66b. Chalasami N, Statins and hepatotoxicity: focus on patients with fatty liver. Hepatology 2005; 41:690–695.

52. Lucena MI, Camargo R, Andrade RJ, et al. Comparison of two clinical scales for causality assessment in hepatotoxicity. Hepatology 2001; 33:123–130. Poor correlation of these two scales in causality assessment except in patients with associated hypersensitivity features.

67. Bork K, Pitton M, Harten P, et al. Hepatocellular adenomas in patients taking danazol for hereditary angio-oedema. Lancet 1999; 353:1066–1067. 68. Kremer JM, Alarcon GS, Lightfoot RW Jr, et al. Methotrexate for rheumatoid arthritis: suggested guidelines for monitoring liver toxicity. Arth Rheum 1994; 7:316–328.

53. Kaplowitz N. Causality assessment versus guilt-by-association in drug hepatotoxicity. Hepatology 2001; 33:308–310.

69. Roenigk HH, Auerbach R, Maibach HI, et al. Methotrexate in psoriasis: revised guidelines. J Am Acad Dermatol 1988; 19:145–156.

54. Miremont G, Haramburu F, Begaud B, et al. Adverse drug reactions: physicians’ opinions versus a causality assessment method. Eur J Clin Pharmacol 1994; 46:285–289.

70. Said S, Jeffes EW, Weinstein GD. Methotrexate. Clin Dermatol 1997; 15:781–797.

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72. Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med 2001; 344:495–500. 73. O’Grady JG, Alexander GJ, Hayllar KM, et al. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989; 97:439–445. 74. Chitturi S, Farrell GC. Drug-induced liver disease. Current treatment options in gastroenterology. Gastroenterology 2000; 3:457–462. 75. Dribben WH, Porto SM, Jeffords BK. Stability and microbiology of inhalant N-acetylcysteine used as an intravenous solution for the treatment of acetaminophen poisoning. Ann Emerg Med 2003; 42:9–13. 76. Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics 1975; 55:871–876. 77. Prescott LF, Illingworth RN, Critchley JAJH, et al. Intravenous N-acetylcysteine: the treatment of choice for paracetamol poisoning. Br Med J 1979; 2:1097–1100. 78. Zed PJ, Krenzelok EP. Treatment of acetaminophen overdose. Am J Health Syst Pharm 1999; 56:1081–1093. 79. Keays R, Harrison PM, Wendon JA, et al. Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. Br Med J 1991; 303:1026–1029. 80. Pajoumand A, Jalali N, Abdollahi M, et al. Successful treatment of acetaminophen overdose associated with hepatic failure. Hum Exp Toxicol 2003; 22:453–458. 81. Walsh TS, Hopton P, Philips BJ. The effect of N-acetylcysteine on oxygen transport and uptake in patients with fulminant hepatic failure. Hepatology 1998; 27:1332–1340. 82. Dargan PI, Jones AL. Management of paracetamol poisoning. Trends Pharmacol Sci 2003; 24:154–157. 83. Yip L, Dart RC, Hurlbut KM. Intravenous administration of oral N-acetylcysteine. Crit Care Med 1998; 26:40–43. 84. Appelboam AV, Dargan PI, Knighton J. Fatal anaphylactoid reaction to N-acetylcysteine: caution in patients with asthma. Emerg Med J 2002; 19:594–595. 85. Schmidt LE, Dalhoff K. Risk factors in the development of adverse reactions to N-acetylcysteine in patients with paracetamol poisoning. Br J Clin Pharmacol 2001; 51:87–91. 86. Iveson TJ, Ryley NG, Kelly PMA, et al. Diclofenac associated hepatitis. J Hepatol 1990; 10:85–89. 87. Shalev O, Mosseri M, Ariel I, et al. Methyldopa-induced immune hemolytic anemia and chronic active hepatitis. Arch Intern Med 1983; 143:592–593. 88. Gough A, Chapman S, Wagstaff K, et al. Minocycline induced autoimmune hepatitis and systemic lupus erythematosus-like syndrome. Br Med J 1996; 312:169–172. 89. Mitnick PD, Klein WJ Jr. Piroxicam-induced renal disease. Arch Intern Med 1984; 144:63–64. 90. Sterling MJ, Kane M, Grace ND. Pemoline-induced autoimmune hepatitis. Am J Gastroenterol 1996; 91:2233–2234. 91. Kallinowski B, Theilmann L, Zimmermann R, et al. Effective treatment of cyclosporine-induced cholestasis in heart-

transplanted patients treated with ursodeoxycholic acid. Transplantation 1991; 51:1128–1129. 92. Katsinelos P, Vasiliadis T, Xiarchos P, et al. Ursodeoxycholic acid (UDCA) for the treatment of amoxicillin-clavulanate potassium (Augmentin)-induced intra-hepatic cholestasis: report of two cases. Eur J Gastroenterol Hepatol 2000; 12:365–368. 93. Kojima M, Kamoi K, Ukimura O, et al. Clinical utility of ursodeoxycholic acid in preventing flutamide-induced hepatopathy in patients with prostate cancer: a preliminary study. Int J Urol 2002; 9:42–46. 94. Piotrowicz A, Polkey M, Wilkinson M. Ursodeoxycholic acid for the treatment of flucloxacillin-associated cholestasis. J Hepatol 1995; 22:119–120. 95. Leone N, Giordanino C, Baronio M, et al. Ticlopidine-induced cholestatic hepatitis successfully treated with corticosteroids: a case report. Hepatol Res 2004; 28:109–112. 96. Bernal W, Wendon J, Rela M, et al. Use and outcome of liver transplantation in acetaminophen-induced acute liver failure. Hepatology 1998; 27:1050–1055. 97. Bernal W, Donaldson N, Wyncoll D, et al. Blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure: a cohort study. Lancet 2002; 359:558–563. 98. Schmidt LE, Dalhoff K. Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity. Hepatology 2002; 36:659–665. 99. Bernal W, Wendon J. More on serum phosphate and prognosis of acute liver failure. Hepatology 2003; 38:533–534. 100. Gow PJ, Sood S, Angus PW. Serum phosphate as a predictor of outcome in acetaminophen-induced fulminant hepatic failure. Hepatology 2003; 37:711–712. 101. Schmidt LE, Ott P, Tygstrup N. Galactose elimination capacity as a prognostic marker in patients with severe acetaminophen-induced hepatotoxicity: 10 years’ experience. Clin Gastroenterol Hepatol 2004; 2:418–424. 102. Koivusalo AM, Yildirim Y, Vakkuri A, et al. Experience with albumin dialysis in five patients with severe overdoses of paracetamol. Acta Anaesthesiol Scand 2003; 47:1145–1150. Preliminary experience with an albumin-based dialysis in druginduced acute liver failure. 103. Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002; 137:947–954. 104. Sussman NL, Kelly JH. High throughput screening for druginduced liver disease-investigative and preemptive toxicology (Abstract). Hepatology 2003; 34(Suppl.1):702A. 105. Trost DC, Freston JW. Use of vector analysis of liver function tests to detect an early signal of hepatotoxicity of a drug in early clinical trials (Abstract). Hepatology 2003; 34(Suppl.1):698A. 106. Davern TJ, James LP, Fontana RJ, et al. Serum acetaminophen adducts reliably distinguish acetaminophen toxicity from other causes of acute liver failure (Abstract).Hepatology 2003; 34(Suppl.1):538A. 107. Hoglen NC, Fisher CD, Hirakawa BP, et al. IDN-6556, the first anti-apoptotic caspase inhibitor: preclinical efficacy and safety (Abstract). Hepatology 2003; 34(Suppl.1):579A.

References

71. Aithal GP, Haugk B, Das S, et al. Monitoring methotrexateinduced hepatic fibrosis in patients with psoriasis: are serial liver biopsies justified? Aliment Pharmacol Ther. 2004; 19:391–399.

SECTION SIX MANAGEMENT OF HEPATIC DISORDERS

38

CHAPTER THIRTY-EIGHT

Primary biliary cirrhosis Jayant A. Talwalkar and Keith D. Lindor

INTRODUCTION Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease of unknown etiology. The disease is characterized histologically by the presence of portal inflammation and necrosis of the interlobular and septal bile ducts. Progressive bile duct destruction is associated with the development of cirrhosis and end-stage liver disease requiring transplantation. The etiology of PBC remains unknown although evidence for an interaction between host and environmental factors is likely. PBC is commonly diagnosed among women in the fifth and sixth decade of life with a majority being asymptomatic at initial presentation. Serum antimitochondrial antibody (AMA) is present in 90–95% of affected patients. Medical therapy with ursodeoxycholic acid (UDCA) can halt disease progression in selected individuals and improves survival free of liver transplantation.

EPIDEMIOLOGY AND NATURAL HISTORY Primary biliary cirrhosis affects all races and has no specific geographic predilection. Women are primarily affected with a female to male ratio of 9:1. The median age of disease onset is 50 years but varies between 20 and 90 years. The annual incidence of PBC ranges between 2 and 24 cases per million population.1,2 Prevalence estimates range from 19 to 402 cases per million population.2–5 Potential risk factors for the development of PBC include cigarette smoking, history of extrahepatic autoimmune disease, history of urinary tract infection, and previous tonsillectomy.6,7 The risk for developing PBC among first-degree relatives of an index case is at least 10 times higher when compared to the general population risk, especially among daughters of affected women.8 For asymptomatic patients at diagnosis, the cumulative risk for developing symptoms is 50% at 5 years and 95% at 20 years of follow-up.9 The median time from serum AMA positivity to persistent serum liver test elevations is 5.6 years.10 Among patients with normal liver biochemistries and detectable serum AMA at diagnosis, a 40% rate of histologic disease progression is observed over a median of 11.4 years.10 Death from liver disease is less frequent in asymptomatic versus symptomatic patients.9 However, a lower overall median survival for asymptomatic patients is observed when compared to an age- and sex-matched healthy population in the absence of treatment.9,11 Disease

progression to end-stage liver failure is more likely to occur among symptomatic patients. Independent predictors of mortality for all patients include age, total bilirubin, albumin, prothrombin time, and severity of edema.12

PATHOGENESIS The major finding associated with immune system dysregulation in PBC is recognition of the antimitochondrial antibody. Serum AMA is directed against the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2) along the inner surface of biliary epithelial mitochondrial membrane.13 The reason for developing AMA specifically directed against inner mitochondrial membrane proteins of small intrahepatic bile ducts rather than other tissues is unknown. Furthermore, the occurrence of PBC in patients without AMA seropositivity remains incompletely understood.14 Arguments against direct cytotoxic activity from AMA include: (1) the persistence of antibody after liver transplantation without immediate disease recurrence; (2) the absence of correlation between serum antibody titer and hepatic involvement; (3) the absence of AMA in some patients with histologic confirmation of PBC; and (4) the ability to induce AMA by administration of recombinant PDC-E2 protein in animal models without causing PBC.15 The concept of ‘molecular mimicry’ wherein microbial infection induces cross-reactivity with self-antigens has been proposed as an underlying mechanism for PBC.16 A number of infectious agents including Escherichia coli (E. coli), Helicobacter species, Chlamydia pneumoniae, and retroviruses have been implicated yet findings to date remain non-specific to PBC.17,18 Evidence for an underlying viral infection is supported by electron microscopy of cholangiocytes and the increased frequency of serum antibodies to retroviral antigens in PBC.19 Alternate explanations for the development of PBC include fetal microchimerism,20 selenium deficiency,21 and impaired sulfoxidation of endogenous bile acids.22

DIAGNOSIS

(Figure 38.1)

Biochemical features The most characteristic biochemical abnormality in PBC is an elevated serum alkaline phosphatase (usually 3–4 times the upper limit of normal).23 Subjects with a positive serum AMA and histology compatible with PBC may rarely have normal serum

Primary Biliary Cirrhosis

580 AST ≥ 5 x ULN Alk phos < 1.5 x ULN AMA+

AST ≤ 5 x ULN AP ≥ 1.5 x ULN AMA+

•

Fig. 38.1 Proposed clinical algorithm for the diagnosis and treatment of PBC.

Elevated serum biochemistries (AP, AST elevations) No history of drug toxicity AST ≤ 5 x ULN Alk Phos ≤ 5 x ULN AMA– PBC No liver biopsy indicated

Liver biopsy

Liver biopsy

Other

PBC

Overlap syndrome with AIH

PBC

UDCA 13–15 mg/kg/day x 6 months

UDCA 13–15 mg/kg/day x 6 months

AP, AST, TB every 3 months x 2

AP, AST, TB every 3 months x 2

AP ≤ 1.5 x ULN

Alkaline phosphatase > 1.5 x ULN

AP ≤ 1.5 x ULN

Alkaline phosphatase > 1.5 x ULN

Continue UDCA

Refer for adjuvant treatment in clinical trial setting

Continue UDCA

Refer for adjuvant treatment in clinical trial setting

alkaline phosphatase levels.10 No association exists between the level of serum alkaline phosphatase elevation and prognosis prior to initiation of medical therapy. Modestly increased values for alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are common, but significant elevations (greater than 200 U/L) requires the exclusion of superimposed viral or druginduced hepatic injury. Serum total bilirubin levels often rise during disease progression but are commonly within normal limits at the time of diagnosis. Levels reaching 20 mg/dL are unusual but can be associated with advanced hepatic disease. Elevations in serum total bilirubin, hypoalbuminemia, and prolongations in prothrombin time are associated with poor clinical outcomes and often justify consideration for liver transplantation. Hypercholesterolemia is observed in up to 85% of cases at diagnosis. Serum IgM levels and bile acids (cholic acid, chenodeoxycholic acid) are also elevated in patients with PBC.23

Serologic features Between 90% and 95% of patients with the diagnosis of PBC have positive serum AMA in titers greater than or equal to 1:40.24 Although the AMA assay that is widely commercially available is not organ-specific, a titer at or above 1:40 remains highly sensitive (98%) as a diagnostic test.25 Of note, an estimated 8–10% of cases with autoimmune hepatitis26 and a small proportion of PSC

cases are AMA seropositive. PBC patients may also exhibit serum antinuclear antibody (ANA) and/or smooth muscle antibody (SMA) in 35–66% of cases.23 Some of thesepatients exhibit features of AMA-negative PBC (see below and also Chapter 34 for a description of overlap syndromes).27 Serum anticentromere antibodies in patients with scleroderma or the CREST syndrome occur in 10–15% of PBC cases.28 Other autoantibodies in PBC patients include rheumatoid factor (70%), antithyroid antibodies (40%), and anti-sp-100 antibodies (25%).23

Histologic features While the biochemical and serologic presentation described above usually confirms the diagnosis of PBC, a liver biopsy is needed for determining the stage of histologic disease at the time of diagnosis.29 Stage I PBC is associated with portal tract inflammation from predominantly lymphoplasmacytic infiltrates resulting in the destruction of septal and interlobular bile ducts up to 100 ␮m in diameter. Focal duct obliteration with granuloma formation has been termed the ‘florid duct lesion’ and is considered almost pathognomonic for PBC when present. Stage II PBC is consistent with an extension of portal tract infiltrates with associated lymphocytic cholangitis and interface hepatitis. Stage III PBC is dominated by the existence of septal or bridging fibrosis. The inflammatory features described with stage II disease are often

581 Table 38.2 Monitoring of patients with PBC

Overlap syndrome with autoimmune hepatitis

Serum vitamin A, D, and E levels at diagnosis

Selected patients with PBC may also have clinical and histologic features compatible with autoimmune hepatitis. An ‘overlap’ syndrome has been described in this situation with original estimates of frequency as high as 20%. Refinement of diagnostic criteria, however, has reduced the prevalence rate of this condition to 50% of interlobular bile ducts) becomes more common, resulting in progressive cholestasis. Stage IV disease is consistent with biliary cirrhosis. Nodular regeneration with extensive ductular proliferation resembling a ‘garland-shaped’ appearance is characteristic of advanced PBC.30,31

Primary Biliary Cirrhosis

582 extremely problematic. Both dry eyes and dry mouth are observed in patients with PBC. Secondary involvement of salivary and lacrimal glands with inflammation is thought to be the underlying cause. The majority of patients, however, do not satisfy criteria for the diagnosis of Sjögren’s syndrome. In contrast, patients with classical features of Sjögren’s syndrome and serum AMA positivity often develop PBC at a later date.52 Treatment is directed at symptomatic improvement using artificial tears and oral sialagogues as first-line agents. Topical cyclosporine for keratoconjunctivitis has not been tested in PBC.53 Oral pilocarpine and cemeviline, which have been used in patients with primary Sjögren’s syndrome, have not been extensively tested in PBC.54,55

Dyslipidemia Hypercholesterolemia and hyperlipidemia are present in up to 85% of patients with PBC. In early-stage disease, there is a marked elevation in high-density lipoprotein (HDL) rather than low-density lipoprotein (LDL), but this ratio is reversed with histologic disease progression. Total serum cholesterol levels tend to be markedly elevated early in the disease and may fall to low levels once end-stage liver disease has developed. There is no clear correlation between xanthelasma formation and serum cholesterol levels.56 Dietary fat restriction and cosmetic surgery to eliminate xanthomas are ineffective. A reduction in serum cholesterol and LDL levels with improvement in xanthelasma formation is associated with ursodeoxycholic acid therapy.57 Statin-based therapy is effective for dyslipidemia in PBC, yet no large experience has been reported to date and there does not currently appear to be a strong justification for its use. Two published investigations have independently concluded there is no increased risk of death from cardiovascular disease in PBC patients with severe hypercholesterolemia compared to the general population.56,58

Metabolic bone disease Metabolic bone disease in PBC is related to osteopenia rather than osteomalacia (defective bone mineralization). While a number of chronic liver diseases have recently been associated with osteopenia, the greater involvement in PBC is likely associated with cholestasis and the predilection of PBC for females who are independently at risk for metabolic bone disease. Potential etiologies include defective osteoblast activity in premenopausal women, increased osteoclast activity in pre- and postmenopausal women, polymorphisms of vitamin D metabolism which predispose to bone disease, and cigarette smoking which reduces serum vitamin D levels.59 Approximately one-third of patients with PBC have osteopenia and 11% have osteoporosis defined by a Z score 16.0

72

Data from Nevens et al.

patients who had bled had a higher variceal pressure than the patients who have not bled, even though the HVPG in the two subgroups was similar.15 The frequency of bleeding from large varices is 50–53% as compared to 5–18% with small varices.5,16 The presence of red color signs seen during endoscopy, as red weal marks (longitudinal red streaks on the varices), cherry red spots (discrete cherrycolored flat spots on the varices), and hematocystic spots (raised discrete red spots on varices resembling blisters) and the severity of cirrhosis predict the probability of variceal bleeding fairly reliably (Table 39.3).5 The probability of bleeding from varices in a patient with Child’s class C who has large-sized varices in the presence of red color signs is nearly 76% within the first year of diagnosis. On the other hand, the probability of bleeding from the varices in a patient in Child’s class A, with small varices and no red color signs, is less than 10%. Spontaneous cessation of bleeding occurs in around 50% of the patients. However, the patients with Child’s class C cirrhosis and who are actively bleeding on endoscopy are unlikely to have a spontaneous cessation of bleeding. After the index bleeding episode, the risk of rebleeding is high within the first 6 weeks.10,17 Over 50% of such rebleeding episodes occur within 3–4 days from the time of admission for the bleeding.10,18,19 The risk factors for early rebleeding are severe initial bleeding as defined by a hemoglobin 50

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Feldstein et al.

597

Devascularization surgery Surgical devascularization of the lower esophagus and stomach is an alternative method to control variceal bleeding which does not increase the risk of encephalopathy. These procedures have been used extensively in Japan and favorable results have been reported from other parts of Asia and Europe as well.65 Surgical variceal ligation with esophageal transection is an effective means of controlling acute variceal bleeding, but bleeding frequently recurs as additional varices develop. The Sugiura operation involves a more extensive procedure consisting of transthoracic paraesophageal devascularization, esophageal transection, splenectomy, esophagogastric devascularization, pyloroplasty, and vagotomy, and is associated with an improved long-term control of bleeding.65 However, the experience with the rest of the world is less favorable, with increased rebleeding and mortality. This procedure is performed when surgery is required in a patient with extensive thrombosis of the splanchnic bed precluding a portal decompressive procedure.

PRIMARY PROPHYLAXIS OF VARICEAL BLEEDING Nonselective ␤-adrenergic receptor antagonists (propranolol and nadolol) and nitrates are the mainstay of therapy in the prevention of a first variceal bleeding episode. The role of EVL as a modality for the primary prophylaxis is very promising, but needs further confirmation.

Pharmacologic therapy A large number of studies have examined the utility of nonselective ␤-adrenergic receptor antagonists for the primary prophylaxis of variceal hemorrhage. Seven trials have used propranolol while two used nadolol (Fig. 39.3).41,66 A meta-analysis of nine randomized, controlled trials concluded that the use of nonselective ␤-adrenergic receptor antagonists decreases the risk of

Coleman Conn PROVA Pascal IMPPB Ideo Andreani Lebrec Strauss 0

20

40 Bleeds (%)

60

80

Clinical trials of the effects of nonselective ␤-adrenergic Fig. 39.3 receptor antagonists with controls in the primary prophylaxis of variceal bleeding.

•

initial hemorrhage in patients with cirrhosis and gastroesophageal varices.41 These trials included a total of 996 patients (489 treated and 507 controls) with four studies focused on those with large varices. Five studies included varices of any size with a portal pressure gradient >10–12 mmHg. Only two trials had a double-blinded design. A decreased risk of variceal bleeding was observed in seven trials, and was statistically significant in four of these trials. The risk of bleeding was reported to increase in only one of these nine clinical trials, which was only published as an abstract. The odds ratio for death was decreased (less than 1.0) in seven of the nine trials, and reached statistical significance in one trial.67 These data have been corroborated by two recent meta-analyses.68,69 These meta-analyses confirm that nonselective ␤-blockers reduce the incidence of initial variceal bleeding by 45% and decrease the bleeding related mortality by 50%. Also, propanolol is the most cost-effective therapy for primary prophylaxis of variceal bleeding in cirrhotic patients who have esophageal varices regardless of their Child’s class and the risks of bleeding.70 As most of the studies conducted have been in the patients with medium to large varices, these results cannot be extrapolated for using these agents in small varices. Various randomized, controlled trials have evaluated the role of nitrates for primary prophylaxis of variceal hemorrhage.34,71–76 These studies suggest that the potential for a beneficial or detrimental effect of nitrates depends on the stage of liver disease and the extension of portal collaterals. Thus, in the early stages of cirrhosis, it would be desirable to target nitrates to the liver microvasculature, while in a later stage, nitrates could be deleterious by aggravating the hyperdynamic syndrome through the expansion of the vascular bed. While ISMN monotherapy is as effective as nadolol in preventing variceal hemorrhage,75 it was associated with a higher mortality, especially in those over 51 years of age. A combination of ISMN and nadolol has been shown to be superior to nadolol alone (12% versus 29% bleeding) for the primary prophylaxis of variceal bleeding.71 The mortality was similar across the study groups. The current role of nitrates is restricted to combination therapy along with a nonselective betablocker in selected individuals with high-risk varices who have relatively preserved liver functions.

Primary Prophylaxis of Variceal Bleeding

prosthetic H-grafts have also been used as alternative surgical approaches to the side-to-side shunt.61 Mesocaval shunt is an interposition shunt performed by creating an anastomosis between the superior mesenteric vein and the inferior vena cava. This shunt avoids the hepatic hilum and preserves the portal vein, which may be important in potential liver transplantation candidates. (2) Partial portosystemic shunts, e.g., a small-diameter portacaval H-graft, are created in an attempt to lower the portal pressure below the threshold for bleeding and, at the same time, maintain some portal flow. Decreasing the diameter of the portacaval H-graft from 16 mm or 20 mm to 8 mm maintains portal perfusion in most patients and reduces the frequency of encephalopathy.61 (3) The selective shunts selectively decompress variceal flow, while preserving portal blood flow. The distal splenorenal shunt (DSRS) was designed to avoid the high rate of encephalopathy seen with total shunts.62–64 It involves separation of the splanchnic circulation in to a relatively portal hypertensive venous circulation which maintains antegrade flow into the liver and a decompressed variceal compartment where blood flow is diverted away from varices via the short gastric veins and splenic veins into the left renal vein. While the literature uniformly support their efficacy in controlling hemorrhage, the data related to encephalopathy are less consistent.41

Variceal Hemorrhage

598

Endoscopic sclerotherapy The role of endoscopic sclerotherapy (EST) as a modality for primary prophylaxis of variceal bleeding has been evaluated in several clinical trials and subjected to meta-analysis. Sclerotherapy trials were highly heterogeneous as regards to the treatment effects on both bleeding (pooled odds ratio, 0.6; CI, 0.49–0.74) and mortality (pooled odds ratio, 0.76; CI, 0.61–0.94).77,78 There was also heterogeneity in the rate of bleeding in the untreated groups. Favorable results of sclerotherapy were obtained in trials with high bleeding rates among controls and several of these trials had a low quality score.79 A large prospective study had to be terminated due to a significantly higher mortality in the EST group as compared to controls.80 EST should therefore not be used for primary prophylaxis of variceal hemorrhage. Primary prophylaxis of variceal bleeding with ␤-blockers is also more costeffective than EST.70

Endoscopic variceal band ligation Esophageal varices are obliterated more rapidly with EVL compared to EST. Also, EVL is associated with fewer complications.81 EVL has been reported to be superior to no therapy in the prevention of the index variceal bleed and also has a survival benefit.82–84 While a single study has found EVL to be superior to propranolol for primary prophylaxis,84 other studies have failed to confirm this.85 Moreover, the bleeding rates associated with the propranolol group were higher than those reported with placebo in another study published by the same group in the same time period. Currently, the ␤-blocker therapy remains the first-line modality of primary prophylaxis, and EVL should be used in the patients with contraindications or side effects to these medications.

Shunts Several studies evaluated the role of shunt surgery for primary prophylaxis in the 1960s to 1970s. Even though the rate of bleeding was very low, this modality of primary prophylaxis of variceal bleeding was abandoned due to the high rates of hepatic encephalopathy. TIPS is not indicated for primary prophylaxis because there are no data or a priori reasons to support this concept.

Summary It is recommended that all patients with cirrhosis undergo screening endoscopy.22 Those with no varices should have repeat endoscopy performed at 2–3 year intervals while those with small varices should have endoscopy repeated in a year. Those with normal liver function (Child’s class A) and medium to large varices or those with advanced liver failure and varices of any size should be considered for primary prophylaxis with a nonselective beta-blocker. The dose should be titrated to achieve a resting heart rate of about 55–60 beats/min. Ideally, HVPG measurements should be done 4–8 weeks after initiation of therapy to identify nonresponders (HVPG >12 mmHg or a nonsustained drop in HVPG by 25%). Such individuals, along with those who are intolerant of therapy, may be considered for EVL. Nitrates may be used in combination with a nonselective beta-blocker in selected cases of young cirrhotics with well-preserved liver function,

particularly if they are hemodynamic nonresponders to betablockade alone.

MANAGEMENT OF ACUTE VARICEAL BLEEDING According to the Baveno II consensus conference,86 an acute variceal bleeding episode is clinically significant when there is: blood transfusion requirement of ␤2 units, and a systolic pressure 100/min, at the time of hospital admission for the bleed. The goals of management include hemodynamic resuscitation, prevention and treatment of complications, and control of bleeding.

Resuscitation Hemodynamic resuscitation should be started immediately after ensuring a protected airway and estimation of blood loss. After the initial assessment of blood loss, the next step is volume replacement with crystalloids and blood products. Care should be taken to replace the lost blood by packed cells to avoid overtransfusion, as it can lead to rebound increase of portal pressure and precipitate early rebleeding.87 The hematocrit should be maintained around the low 30% range. Replacement of clotting factors and platelets, when 90%) of death related to the shunt surgery. In a subgroup of patients with severe active variceal bleeding who were considered to be at a high risk of dying after shunt surgery,109 TIPS was effective in achieving hemostasis in all the patients with a 6-week mortality of 50%. Also, TIPS is very effective in controlling gastric variceal bleeding.110

Summary Figure 39.5 shows an algorithm for the management of an acute variceal bleeding. After starting the initial resuscitative measures, vasoactive therapy with terlipressin, somatostatin, or octreotide should be started immediately. The bleeding varices are treated with EVL, or EST if EVL is not available. Failure to control bleeding with these measures is an indication for TIPS or surgery.

•

Algorithm for management of acute Fig. 39.5 variceal bleeding.

Active variceal bleeding

Supportive measures (antibiotics, lactulose etc.)

Hemodynamic resuscitation

Administer vasopressors immediately Intravenous Terlipressin/ Octreotide/ Somatostatin

Emergency EVL or EST

Bleeding stopped

Bleeding continues

Secondary prophylaxis

Early rebleeding

EVL or EST

Balloon tamponade ± vasopressors Octreotide/ Somatostatin/ Terlipressin

Child-Pugh class

A

B or C

EVL vs. β-blockers vs. shunt surgery

EVL OLT evaluation

TIPS/shunt surgery

601

SECONDARY PROPHYLAXIS OF VARICEAL BLEEDING All patients who survive an index bleed are at a very high risk for rebleeding, therefore necessitating secondary prophylactic therapy. The various options for a secondary prophylaxis are discussed below.

Pharmacologic therapy Nonselective ␤-blockers are the most studied pharmacologic agents for the secondary prophylaxis of a variceal bleeding. The role of nonselective ␤-blockers was assessed in eleven clinical trials, wherein 428 patients received ␤-blockers, and 400 received placebo.21,111,112 While seven trials showed improved rebleeding rates with ␤-blockers, four studies could not demonstrate such an effect (Fig. 39.6).21,112 Overall, there was a 40% decreased risk of bleeding and a 20% decreased risk of death.68,113 Poor prognostic indicators associated with rebleeding in patients receiving propranolol are the presence of hepatocellular carcinoma, poor patient compliance, lack of persistent decrease in pulse, and continued alcohol use.114 Acute hemodynamic changes after the initiation of propranolol did not predict long-term outcome.115 However, a sustained decline in the portal pressure for 1 month after initiation of therapy has been shown to decrease the risk of rebleeding. EST has been compared to ␤-blocker therapy in various clinical trials.41,116–118 The data are difficult to summarize given the heterogeneity among trials. Overall, EST is somewhat superior to ␤-blockers for prevention of rebleeding, but does not confer a survival advantage.41 The combination of ISMN and nadolol was superior to EST as well as EVL with respect to the incidence of

rebleeding, but the mortality rate among the two groups was not significantly different.116 The combination of pharmacologic therapy (nadolol or propranolol) and EST has been compared to EST alone in many clinical trials. In a meta-analysis, 10 clinical trials comparing the two treatment options showed that the combination is better than EST alone. However, when an outlier trial in the EST alone group showing exceedingly high rebleeding rate (75%) was excluded, there was no difference in the rebleeding rates between the two groups, and the mortality rate was similar (Fig. 39.7).41 The combination of EST and propranolol was found to be superior to propranolol alone in decreasing the rebleeding rate and risk of death.117 A recent randomized trial comparing the combination of EVL, sucralfate, and nadolol versus EVL alone showed that the combination is better than EVL alone in preventing a rebleeding (23% versus 47% ).118 The preliminary results of a controlled trial comparing TIPS with EST and ␤-blockers showed lower rebleed rates in the TIPS subgroup.

Endoscopic therapy The role of EST in the secondary prophylaxis of variceal bleeding has been extensively evaluated. Compared to placebo, EST decreases both the rebleeding risk (from 70% to 40–50%), and risk of death (from 50–75% to 30–60%).112,119–121 EVL has been shown to be superior to EST for the prevention of rebleeding and has fewer complications (see Fig. 39.7). Also, the number of sessions required to achieve variceal obliteration were less with EVL as compared to EST.41 However, the recurrence of varices was higher in the patients who received EVL rather than EST. Patients with paraesophageal varices larger than 5 mm in diameter are more likely to develop recurrent varices.122,123 Combined EVL and EST, when compared to EST alone, showed similar efficacy (80% versus 85%) in achieving variceal obliteration. However, the complication rate (3% versus 20%), and rebleeding rate (3% versus 16%) was lower with the combination therapy. However, several other clinical trials have demonstrated a higher incidence of complications in the combination group,124 without reducing the number of sessions required to eradicate varices. Recently,

EST vs beat blockers

Beta blockers

100

EST + beta blocker vs EST 50

EST + beta blockers vs beta blockers

EVL vs EST 0 0

25

50 Control

75

100

Fig. 39.6 Clinical trials of nonselective ␤-blockers in the secondary prophylaxis of variceal bleeding.

•

0.1

1

•

10

Clinical trials comparing EVL alone, EST alone, and EST plus Fig. 39.7 pharmacologic therapy in the secondary prophylaxis of variceal bleeding.

Secondary Prophylaxis of Variceal Bleeding

Balloon tamponade is often used as a temporary way to control bleeding and stabilize the patient before TIPS is performed. If bleeding occurs more than 48 hours after the initial episode, a secondlook endoscopy with another attempt to control the bleeding with EVL or EST may be done. However, it is imperative not to delay institution of definitive second-line treatment in order to control bleeding before life-threatening complications set in.

argon plasma coagulation of the esophageal mucosa has been used to reduce the risk of recurrent varices; its role in routine practice remains to be defined. EVL is therefore the preferred endoscopic intervention for secondary prophylaxis.

Transjugular intrahepatic portosystemic shunts Transjugular intrahepatic portosystemic shunts (TIPS) is more effective than the endoscopic therapy for prevention of recurrent variceal bleeding with a cumulative risk of bleeding at 1 year being 8–18%.56,125,126 A total of 12 randomized clinical trials have been published comparing TIPS with endoscopic treatment with or without ␤-blockers (Fig. 39.8). While TIPS was associated with better long-term control of bleeding, there was no survival benefit with TIPS. The risk of encephalopathy was significantly higher in patients with TIPS as new or worsened encephalopathy occurred in 25–33% of the patients after TIPS.52 Advanced age, liver failure, shunt diameter, and a history of encephalopathy before TIPS were the risk factors for worsening of encephalopathy post-TIPS.52 The role of TIPS as a first-line modality for the secondary prophylaxis of variceal bleeding has been offset by the lack of survival benefit and high morbidity. TIPS is used as a salvage therapy in the patients with bleeding refractory to endoscopic therapy.45 A single clinical trial found better long-term control of bleeding with small-diameter H surgical grafts compared to TIPS.127 The results of this trial are not easily generalizable because of the high failure rates associated with TIPS.

Shunt surgery Surgical shunt is an excellent option to prevent recurrent variceal bleeding in patients who have failed on endoscopic or pharmacologic therapies, particularly when hepatic synthetic capacity is well preserved. There are four published trials comparing DSRS (307 patients) with EST,62,108,128 and three trials comparing central portal-caval shunts.103 Shunt surgery when compared to the EST significantly reduced the incidence of rebleeding (OR, 0.18; 95% CI, 0.12–0.28), but failed to show a survival benefit and significantly increased the incidence of hepatic encephalopathy (OR,

2.11; 95% CI, 1.1–4.0). Recurrent bleeding after shunt occurs in 10–20% of the patients, the highest risk being in the first month after surgery.62 Devascularization procedures are usually considered in the patients with contraindications to shunts as splanchnic vascular thrombosis and should preferably be performed by the experienced surgeons. The choice of surgical procedure should be individualized and must take into account the severity of the liver disease and the local expertise in the procedure.

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•

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first bleeding and reducing the mortality rate associated with gastrointestinal bleeding in patients with cirrhosis, regardless of severity. 69. Cheng JW, Zhu L, Gu MJ, et al. Meta-analysis of propranolol effects on gastrointestinal hemorrhage in cirrhotic patients. World J Gastroenterol 2003; 9(8):1836–1839. 70. Teran JC, Imperiale TF, Mullen KD. Primary prophylaxis of variceal bleeding in cirrhosis: a cost-effectiveness analysis. Gastroenterology 1997; 112(2):473–482. 71. Merkel C, Marin R, Sacerdoti D, et al. Long-term results of a clinical trial of nadolol with or without isosorbide mononitrate for primary prophylaxis of variceal bleeding in cirrhosis. Hepatology 2000; 31(2):324–329. 72. Merkel C, Marin R, Enzo E, et al. Randomised trial of nadolol alone or with isosorbide mononitrate for primary prophylaxis of variceal bleeding in cirrhosis. Gruppo-Triveneto per L’ipertensione portale (GTIP). Lancet 1996; 348(9043):1677–1681. 73. Garcia-Pagan JC, Feu F, Navasa M, et al. Long-term haemodynamic effects of isosorbide-5-mononitrate in patients with cirrhosis and portal hypertension. J Hepatol 1990; 11(2):189–195. 74. Garcia-Pagan JC, Navasa M, Bosch J, et al. Enhancement of portal pressure reduction by the association of isosorbide-5-mononitrate to propranolol administration in patients with cirrhosis. Hepatology 1990; 11(2):230–238. 75. Angelico M, Carli L, Piat C, et al. Effects of isosorbide-5-mononitrate compared with propranolol on first bleeding and long-term survival in cirrhosis. Gastroenterology 1997; 113(5):1632–1639. 76. Angelico M, Carli L, Piat C, et al. Isosorbide-5-mononitrate versus propranolol in the prevention of first bleeding in cirrhosis. Gastroenterology 1993; 104(5):1460–1465. 77. Witzel L, Wolbergs E, Merki H. Prophylactic endoscopic sclerotherapy of oesophageal varices. A prospective controlled study. Lancet 1985; 1(8432):773–775. 78. Piai G, Cipolletta L, Claar M, et al. Prophylactic sclerotherapy of high-risk esophageal varices: results of a multicentric prospective controlled trial. Hepatology 1988; 8(6):1495–1500. 79. Pagliaro L, D’Amico G, Sorensen TI, et al. Prevention of first bleeding in cirrhosis. A meta-analysis of randomized trials of nonsurgical treatment. Ann Intern Med 1992; 117(1):59–70. 80. The Veterans Affairs Cooperative Variceal Sclerotherapy Group. Prophylactic sclerotherapy for esophageal varices in men with alcoholic liver disease: A randomized single-blind, multicenter clinical trial. N Engl J Med 1991; 324:1779. 81. Stiegmann GV, Goff JS, Michaletz-Onody PA, et al. Endoscopic sclerotherapy as compared with endoscopic ligation for bleeding esophageal varices. N Engl J Med 1992; 326(23):1527–1532. 82. Lay CS, Tsai YT, Teg CY, et al. Endoscopic variceal ligation in prophylaxis of first variceal bleeding in cirrhotic patients with high-risk esophageal varices. Hepatology 1997; 25(6): 1346–1350. 83. Lo GH, Lai KH, Cheng JS, et al. Prophylactic banding ligation of high-risk esophageal varices in patients with cirrhosis: a prospective, randomized trial. J Hepatol 1999; 31(3):451–456. 84. Sarin SK, Lamba GS, Kumar M, et al. Comparison of endoscopic ligation and propranolol for the primary prevention of variceal bleeding. N Engl J Med 1999; 340(13):988–993. 85. Lui HF, Stanley AJ, Forrest EH, et al. Primary prophylaxis of variceal hemorrhage: a randomized controlled trial comparing band ligation, propranolol, and isosorbide mononitrate. Gastroenterology 2002; 123(3):735–744. 86. de Franchis R. Developing consensus in portal hypertension. J Hepatol 1996; 25(3):390–394.

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88. Goulis J, Armonis A, Patch D, et al. Bacterial infection is independently associated with failure to control bleeding in cirrhotic patients with gastrointestinal hemorrhage. Hepatology 1998; 27(5):1207–1212. 89. Walker S, Stiehl A, Raedsch R, et al. Terlipressin in bleeding esophageal varices: a placebo-controlled, double-blind study. Hepatology 1986; 6(1):112–115. 90. Freeman JG, Cobden I, Record CO. Placebo-controlled trial of terlipressin (glypressin) in the management of acute variceal bleeding. J Clin Gastroenterol 1989; 11(1):58–60. 91. Silvain C, Carpentier S, Sautereau D, et al. Terlipressin plus transdermal nitroglycerin vs. octreotide in the control of acute bleeding from esophageal varices: a multicenter randomized trial. Hepatology 1993; 18(1):61–65. 92. Dagradi AE. The natural history of esophageal varices in patients with alcoholic liver cirrhosis. An endoscopic and clinical study. Am J Gastroenterol 1972; 57(6):520–540. 93. Planas R, Quer JC, Boix J, et al. A prospective randomized trial comparing somatostatin and sclerotherapy in the treatment of acute variceal bleeding. Hepatology 1994; 20(2):370–375. 94. Escorsell A, Bordas JM, del Arbol LR, et al. Randomized controlled trial of sclerotherapy versus somatostatin infusion in the prevention of early rebleeding following acute variceal hemorrhage in patients with cirrhosis. Variceal Bleeding Study Group. J Hepatol 1998; 29(5):779–788. Continuous somatostatin infusion is as effective as sclerotherapy in preventing early variceal rebleeding and maintaining low mortality after the initial variceal bleed. Somatostatin has a lower complication rate than sclerotherapy. 95. Avgerinos A, Armonis A, Raptis S. Somatostatin or octreotide versus endoscopic sclerotherapy in acute variceal haemorrhage: a meta-analysis study. J Hepatol 1995; 22(2):247–248. 96. Jenkins SA, Shields R, Davies M, et al. A multicentre randomised trial comparing octreotide and injection sclerotherapy in the management and outcome of acute variceal haemorrhage. Gut 1997; 41(4):526–533. 97. Sung JJ, Chung SC, Yung MY, et al. Prospective randomised study of effect of octreotide on rebleeding from oesophageal varices after endoscopic ligation. Lancet 1995; 346(8991–8992):1666–1669. 98. Besson I, Ingrand P, Person B, et al. Sclerotherapy with or without octreotide for acute variceal bleeding. N Engl J Med 1995; 333(9): 555–560. The combination of sclerotherapy and octreotide is more effective than sclerotherapy alone in controlling acute variceal bleeding, but there is no difference between the overall mortality rates associated with the two approaches to treatment. 99. Primignani M, Andreoni B, Carpinelli L, et al. Sclerotherapy plus octreotide versus sclerotherapy alone in the prevention of early rebleeding from esophageal varices: a randomized, double-blind, placebo-controlled, multicenter trial. New Italian Endoscopic Club. Hepatology 1995; 21(5):1322–1327. 100. D’Amico G, Pietrosi G, Tarantino I, et al. Emergency sclerotherapy versus vasoactive drugs for variceal bleeding in cirrhosis: a Cochrane meta-analysis. Gastroenterology 2003; 124(5):1277–1291. 101. Teres J, Baroni R, Bordas JM, et al. Randomized trial of portacaval shunt, stapling transection and endoscopic sclerotherapy in uncontrolled variceal bleeding. J Hepatol 1987; 4(2):159–167. 102. Burroughs AK, Hamilton G, Phillips A, et al. A comparison of sclerotherapy with staple transection of the esophagus for the

emergency control of bleeding from esophageal varices. N Engl J Med 1989; 321(13):857–862. 103. Cello JP, Grendell JH, Crass RA, et al. Endoscopic sclerotherapy versus portacaval shunt in patient with severe cirrhosis and acute variceal hemorrhage. Long-term follow-up. N Engl J Med 1987; 316(1):11–15. 104. Huang YH, Yeh HZ, Chen GH, et al. Endoscopic treatment of bleeding gastric varices by N-butyl-2-cyanoacrylate (histoacryl) injection: long-term efficacy and safety. Gastrointest Endosc 2000; 52(2):160–167. 105. Vargas L, Ovalle L, Estay R, et al. [Esophagogastric varix hemorrhage. Experience with cyanoacrylate and polidocanol in 68 patients with active hemorrhage]. Rev Med Chil 1999; 127(6):685–692. 106. Lo GH, Lai KH, Cheng JS, et al. A prospective, randomized trial of sclerotherapy versus ligation in the management of bleeding esophageal varices. Hepatology 1995; 22(2):466–471. 107. Lo GH, Lai KH, Cheng JS, et al. Emergency banding ligation versus sclerotherapy for the control of active bleeding from esophageal varices. Hepatology 1997; 25(5):1101–1104. 108. Henderson JM, Kutner MH, Millikan WJ Jr, et al. Endoscopic variceal sclerosis compared with distal splenorenal shunt to prevent recurrent variceal bleeding in cirrhosis. A prospective, randomized trial. Ann Intern Med 1990; 112(4):262–269. 109. Sanyal AJ, Freedman AM, Luketic VA, et al. Transjugular intrahepatic portosystemic shunts for patients with active variceal hemorrhage unresponsive to sclerotherapy. Gastroenterology 1996; 111(1):138–146. 110. Chau TN, Patch D, Chan YW, et al. ‘Salvage’ transjugular intrahepatic portosystemic shunts: gastric fundal compared with esophageal variceal bleeding. Gastroenterology 1998; 114(5):981–987. 111. Lebrec D, Poynard T, Bernuau J, et al. A randomized controlled study of propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a final report. Hepatology 1984; 4(3):355–358. 112. Rossi V, Cales P, Burtin P, et al. Prevention of recurrent variceal bleeding in alcoholic cirrhotic patients: prospective controlled trial of propranolol and sclerotherapy. J Hepatol 1991; 12(3):283–289. 113. Hayes PC, Davis JM, Lewis JA, et al. Meta-analysis of value of propranolol in prevention of variceal haemorrhage. Lancet 1990; 336(8708):153–156. 114. Poynard T, Lebrec D, Hillon P, et al. Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a prospective study of factors associated with rebleeding. Hepatology 1987; 7(3):447–451. 115. Valla D, Jiron MI, Poynard T, et al. Failure of haemodynamic measurements to predict recurrent gastrointestinal bleeding in cirrhotic patients receiving propranolol. J Hepatol 1987; 5(2):144–148. 116. Villanueva C, Balanzo J, Novella MT, et al. Nadolol plus isosorbide mononitrate compared with sclerotherapy for the prevention of variceal rebleeding. N Engl J Med 1996; 334(25):1624–1629. 117. Ink O, Martin T, Poynard T, et al. Does elective sclerotherapy improve the efficacy of long-term propranolol for prevention of recurrent bleeding in patients with severe cirrhosis? A prospective multicenter, randomized trial. Hepatology 1992; 16(4):912–919. 118. Lo GH, Lai KH, Cheng JS, et al. Endoscopic variceal ligation plus nadolol and sucralfate compared with ligation alone for the prevention of variceal rebleeding: a prospective, randomized trial. Hepatology 2000; 32(3):461–465. 119. Westaby D, Macdougall BR, Williams R. Improved survival following injection sclerotherapy for esophageal varices: final analysis of a controlled trial. Hepatology 1985; 5(5):827–830.

References

87. Kravetz D, Sikuler E, Groszmann RJ. Splanchnic and systemic hemodynamics in portal hypertensive rats during hemorrhage and blood volume restitution. Gastroenterology 1986; 90(5 Pt 1):1232–1240.

Variceal Hemorrhage

606 120. The Copenhagen Esophageal Varices Sclerotherapy Project. Sclerotherapy after first variceal hemorrhage in cirrhosis. N Engl J Med 1984; 311:1594. 121. Terblanche J, Bornman PC, Kahn D, et al. Failure of repeated injection sclerotherapy to improve long-term survival after oesophageal variceal bleeding. A five-year prospective controlled clinical trial. Lancet 1983; 2(8363):1328–1332. 122. Lo GH, Lai KH, Cheng JS, et al. Prevalence of paraesophageal varices and gastric varices in patients achieving variceal obliteration by banding ligation and by injection sclerotherapy. Gastrointest Endosc 1999; 49(4 Pt 1):428–436. 123. Leung VK, Sung JJ, Ahuja AT, et al. Large paraesophageal varices on endosonography predict recurrence of esophageal varices and rebleeding. Gastroenterology 1997; 112(6):1811–1816. 124. Saeed ZA, Stiegmann GV, Ramirez FC, et al. Endoscopic variceal ligation is superior to combined ligation and sclerotherapy for esophageal varices: a multicenter prospective randomized trial. Hepatology 1997; 25(1):71–74.

125. Sanyal AJ, Freedman AM, Luketic VA, et al. Transjugular intrahepatic portosystemic shunts compared with endoscopic sclerotherapy for the prevention of recurrent variceal hemorrhage. A randomized, controlled trial. Ann Intern Med 1997; 126(11):849–857. 126. Rossle M, Deibert P, Haag K, et al. Randomised trial of transjugularintrahepatic-portosystemic shunt versus endoscopy plus propranolol for prevention of variceal rebleeding. Lancet 1997; 349(9058): 1043–1049. 127. Rosemurgy AS, Goode SE, Zwiebel BR, et al. A prospective trial of transjugular intrahepatic portasystemic stent shunts versus smalldiameter prosthetic H-graft portacaval shunts in the treatment of bleeding varices. Ann Surg 1996; 224(3):378–384. 128. Teres J, Bordas JM, Bravo D, et al. Sclerotherapy vs. distal splenorenal shunt in the elective treatment of variceal hemorrhage: a randomized controlled trial. Hepatology 1987; 7(3):430–436.

SECTION SIX MANAGEMENT OF HEPATIC DISORDERS

40

CHAPTER FORTY

Ascites and spontaneous bacterial peritonitis Andrés Cárdenas, Pere Ginés Gibert and Juan Rodés

INTRODUCTION Ascites is the accumulation of free fluid in the peritoneal cavity. This entity was first described by the ancient Egyptians and Greeks; however it was Erasitratus of Cappadoccia, circa 300 BC,1 that first described hardness of the liver as a risk factor for ascites formation. A celebrated figure with ascites and cirrhosis was Ludwig van Beethoven who was treated with serial large-volume paracentesis and died of liver failure in the early nineteenth century.2 In the natural history of cirrhosis, patients may develop significant complications of renal function manifested by impaired sodium and solute-free water excretion, and renal vasoconstriction. These are responsible for fluid accumulation in the form of ascites, dilutional hyponatremia, and hepatorenal syndrome, respectively. Ascites is the most common complication of cirrhosis resulting in poor quality of life, increased risk for infections, renal failure, and mortality. Nearly 60% of patients with compensated cirrhosis develop ascites within 10 years of the disease.3 The development of ascites in cirrhosis is a poor prognostic feature and it has been estimated that half of these patients will die within 2 years without liver transplantation.4 Thus, the onset of ascites in a cirrhotic patient is an indication to consider liver transplantation. Dilutional hyponatremia and hepatorenal syndrome are events that occur later and carry a very poor prognosis. Patients with cirrhosis and ascites are at risk of developing infections, particularly infection of the ascitic fluid, which is known as spontaneous bacterial peritonitis (SBP). This chapter will focus on the evaluation, diagnostic approach, and management of ascites, dilutional hyponatremia, and spontaneous bacterial peritonitis. The evaluation and management of hepatorenal syndrome is discussed in Chapter 42.

PATHOPHYSIOLOGY OF ASCITES Most patients with advanced cirrhosis have impaired ability to maintain extracellular fluid volume within normal limits. This results in increased total extracellular fluid volume and subsequent accumulation of fluid in the peritoneal and/or pleural cavities and interstitial tissue.5–9 The main factor responsible for this increase in extracellular fluid volume is an abnormal increase in renal sodium reabsorption.6 Although the exact pathogenesis of abnormal fluid regulation in cirrhosis is not completely known, a large body of evidence indicates that it is secondary to arterial

splanchnic vasodilation with a subsequent decrease in effective arterial blood volume (the volume sensed by arterial and cardiopulmonary receptors).5–9 The accumulation of fluid and the abnormalities in renal function are the consequence of the homeostatic activation of vasoconstrictor and antinatriuretic factors triggered to compensate for the relative arterial underfilling (Fig. 40.1). A detailed review of the pathogenesis of ascites may be found elsewhere.6–9

DIAGNOSIS AND EVALUATION OF PATIENTS WITH CIRRHOSIS AND ASCITES In most cases, ascites develops insidiously over the course of weeks to months. The main symptoms are an increase in abdominal girth often accompanied by lower extremity edema. In patients with a large amount of ascites, respiratory function and physical activity may be impaired. Dyspnea in these patients may occur as a consequence of increasing abdominal distention and/or accompanying pleural effusions. Other common manifestations of patients with ascites include dull abdominal pain, anorexia, malaise, weakness, malnutrition, jaundice, and spider nevi or telangiectasias. Increased intra-abdominal pressure may favor the development of abdominal hernias in patients with cirrhosis and long-standing ascites.10 Umbilical hernias increase in size if ascites is not treated and occasionally cause complications such as strangulation or rupture. Inguinal hernias can also be problematic in patients with ascites.10 The current classification of ascites divides patients in three groups.8 In grade 1 ascites, fluid is detected only by ultrasound; in grade 2, ascites is moderate with symmetrical distention of the abdomen; and in grade 3, ascites is large or tense with marked abdominal distention.8 Besides a complete physical examination, evaluation of cirrhotic patients with ascites should include standard electrolyte, renal, hematology, coagulation (prothombin time or INR), liver tests (aminotransferases, bilirubin, albumin, total protein, alkaline phosphatase, serum alpha-fetoprotein) and an abdominal ultrasonography to rule out hepatocellular carcinoma and evaluate patency of portal venous system.9 In addition, an upper gastrointestinal endoscopy to assess the presence and characteristics of esophageal and gastric varices or portal hypertensive gastropathy should be performed since these may require prophylaxis to reduce the risk of hemorrhage (Table 40.1). In patients without previously documented liver disease, the

Ascites and Spontaneous Bacterial Peritonitis

608

•

Cirrhosis Portal hypertension Splanchnic arterial vasodilation Decreased total systemic vascular resistance Arterial underfilling Decreased effective arterial blood volume

The pathogenesis of ascites Fig. 40.1 formation, dilutional hyponatremia, and hepatorenal syndrome in patients with cirrhosis and ascites.The neurohormonal systems are represented by the renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system (SNS), and arginine vasopressin (AVP). The neurohumoral effects of these systems on the systemic circulation and renal function in cirrhosis with ascites are responsible for sodium and water retention as well as hepatorenal syndrome.

Stimulation of neurohormonal systems RAAS/SNS

AVP

RAAS/SNS

Sodium retention

Solute-free water retention

Renal vasoconstriction

Increased renal tubular reabsorption of sodium

Increased reabsorption of water in distal renal tubules

Reduced systemic or local vasodilators and/or increased local vasoconstrictors

Ascites and edema formation

Dilutional hyponatremia

Hepatorenal syndrome

Table 40.1 Evaluation of patients with cirrhosis and ascites General evaluation Complete history and physical examination Arterial blood pressure, heart rate, and pulse oxymetry Standard hematology, coagulation, liver tests, and alphafetoprotein Abdominal ultrasonography and Doppler flow (including the kidneys) Upper gastrointestinal endoscopy Liver biopsy (selected cases) Evaluation of ascitic fluid Total protein and albumin measurement Cell count Culture in blood culture bottles Evaluation of renal function* 24-h urine sodium Diuresis after water load (5% dextrose i.v., 20 mL/kg)** Serum electrolytes, serum blood urea nitrogen, and serum creatinine Urine sediment and protein excretion Evaluation of circulatory function* Arterial pressure Plasma renin activity and plasma noradrenaline concentration*** * Renal and circulatory function should be assessed with the patient maintained on a low-sodium diet without diuretic therapy for at least 5 days. ** May provide important information when an accurate estimate of prognosis is required. *** In clinical research setting.

diagnosis of cirrhosis should be confirmed either histologically or by a combination of clinical (cutaneous stigmata), ultrasonographic (diffuse parenchymal heterogeneity, nodular liver edge, or signs of portal hypertension), and endoscopic findings (presence of gastroesophageal varices). When indicated, percutaneous liver biopsy should be performed preferably after the resolution of ascites inasmuch as the presence of intra-abdominal fluid may increase the risk of complications. In patients with significant coagulation disturbances, liver biopsy may be performed through a transjugular approach. Renal and circulatory function should be carefully evaluated in patients with cirrhosis and ascites because of its key importance in the assessment of prognosis and design of therapy (see later).11–14 Evaluation of renal function should be performed in conditions of low sodium intake (approximately 80 mEq/day) and at least 4 days after diuretic withdrawal.9 Parameters to be measured include 24-hour urine volume and sodium excretion, serum electrolytes, and serum creatinine. A strong prognostic marker in cirrhotic patients with ascites is the ability to handle water by means of a water load test. In this test a patient receives 20 mL/kg of intravenous 5% dextrose and following this the renal excretion of water is measured. Impaired ability to excrete the water load (urine volume of 1.2 mg/dL,

and intense sodium retention (urine sodium less than 10 meq/ day) (Table 40.2).4,12 However, the easiest way to identify patients in need of liver transplantation is to recognize those with severe renal functional abnormalities such as refractory ascites or hepatorenal syndrome. Interestingly, in patients with ascites, parameters of renal function and systemic hemodynamics are better predictors of prognosis than liver tests, such as albumin, bilirubin, and prothrombin time.

Sodium restriction Because the amount of exogenous fluid retained as ascites or edema depends on the balance between sodium intake and excretion, a reduction in sodium intake helps achieve negative sodium balance. The response of patients to sodium restriction may be predicted by measuring baseline (i.e., without diuretics) urinary sodium excretion.24 Patients with marked sodium retention (urine sodium excretion less than 10 mEq/day) will have a markedly positive sodium balance even under conditions of sodium restriction of 80 mEq/day. The daily gain of sodium in these patients will range between 70 and 80 mEq/day, which is equivalent to an increase of approximately 500 mL/day of extracellular fluid (average increase in body weight of 500 g/day). In these patients, ingestion of greater amounts of sodium with the diet will proportionally increase the gain in extracellular fluid and

Table 40.2 Prognostic factors in cirrhotic patients with ascites Parameter

Median survival (mo)

Urine sodium (mEq/day) *10 8 3–8 1.5 mg/dL) who are treated with spironolactone. Hypokalemia

may occur only in patients treated with loop diuretics alone. Painful gynecomastia is a common complication of chronic spironolactone therapy. However, in most cases pain is mild and does not require discontinuation of the drug. In selected cases, tamoxifen (20 mg p.o. b.i.d.) may be useful to decrease pain, but clinical experience is limited.27 Finally, muscle cramps, sometimes severe, are frequent in patients treated with diuretics and may require a reduction in diuretic dosage. Quinidine (quinidine sulfate, 400 mg/day),28 intravenous albumin administration (25 g/week),29 or oral zinc have been shown to reduce the frequency and intensity of muscle cramps in some cirrhotic patients with ascites treated with diuretics.

Therapeutic paracentesis Therapeutic paracentesis is the treatment of choice in the management of grade 3 ascites.8,9,30 Complete removal of ascites in one tap in combination with intravenous albumin (6–8 g per liter tapped) has been shown to be quick, effective, and associated with a lower number of complications than conventional diuretic therapy.30 After a therapeutic tap, a postparacentesis circulatory dysfunction may develop; this is a circulatory derangement with marked activation of the renin-angiotensin system that occurs 24–48 hours after the procedure.31 This disorder is clinically silent, not spontaneously reversible, and associated with hyponatremia, renal impairment, decreased survival, and may be prevented with the administration of plasma expanders.32 When less than 5 L of ascites are removed, artificial plasma expanders and albumin are equally effective. However, when more than 5 L is removed, albumin is the plasma expander of choice (Fig. 40.2).33 Albumin is administered at a dose of 6–8 grams per liter of ascites removed. It is recommended that 50% of the total amount is given immediately after the procedure and 50% 2–4 h later. The recommended doses of dextran 70 and polygeline are 8 g and 150 mL per liter of ascites removed, respectively. Patients with a known history of cirrhosis and without any complications of ascites or paracentesis can be managed as outpatients. However, patients in

60 Albumin Dextran-70 or Polygeline

Patients (%)

Ascites and Spontaneous Bacterial Peritonitis

610

p10 mmol/L to a serum sodium of 60 cm with PN-related complications

> 120 cm stasis, overgrowth

Transplantation

Tapering

variety of recirculating loops and pouches, as well as retrograde intestinal pacing. Those with experience with these procedures conclude that these procedures are highly inconsistent, fraught with complications, and of limited long-term efficacy. Hence, it is not recommended that such procedures be used on a regular basis.27 In contrast, procedures designed to increase functional absorptive capacity of the bowel can be quite successful in the appropriately selected individual with dilated bowel. These procedures include relieving mechanical obstruction from intra-abdominal adhesions or strictures with proximal dilatation of the small bowel. To minimize loss of residual bowel, adhesiolysis should be done to minimize iatrogenic enterotomies, and strictures should be preferentially dealt with by stricturoplasty rather than enterectomy. In those SBS patients with dilated bowel without stricture or other mechanical obstruction, one may perform a tapering enteroplasty with or without lengthening of the bowel. This includes the well-known procedure first described by Bianchi in 1980.33 The Bianchi procedure consists of dissecting along the mesenteric border of the small intestine to reveal the blood vessels, which independently supply the two halves of the bowel along its longitudinal axis. The bowel is then divided between these vessels

60–90 cm PN-dependent

Tapering with lengthening (STEP or Bianchi procedure)

along its longitudinal axis so as to create two tubes of equal lengths. These tubes are subsequently anastomosed end to end in an isoperistaltic fashion. The result is an intestinal segment that is twice as long as but half the diameter of the original segment (Fig. 55.4A). More recently, the serial transverse enteroplasty (STEP) procedure has been used. This involves serial application of a linear stapler from opposite directions, which divides the bowel from the mesenteric and antimesenteric borders. The net result is increase in length and reduction in diameter of the bowel, similar to the Bianchi procedure (Fig. 55.4B). Although the actual surface area of the intestine is not increased with either procedure (at least acutely), the function of the bowel improves and thus absorptive capacity increases significantly. Surgical procedures that improve function of the remnant bowel account for more than half of the specialized surgical treatments for SBS patients and have a reported success rate of 90% in the hands of experienced surgeons.27 There is little to offer patients who have failed to achieve nutritional autonomy with standard management and specialized surgical treatments (if indicated) other than intestinal transplantation. However, intestinal transplantation carries high morbidity and mortality despite significant progress in this procedure as discussed below. Consequently, many have attempted to identify

Specialized Care

•

Fig. 55.3 Algorithm for surgical treatment in SBS.TPN, total parenteral nutrition. (Reprinted from Thompson JS et al, Annals of Surgery, 1995; 222:600–607. © 1995, reprinted with permission of Lippincott,Williams & Wilkins.)

Approach to the Patient with Short-bowel Syndrome

780 A N=

70 cm c colon

>70 cm c colon

150 cm w/o colon

29

8

12

Off 38%

Off 63%

Off 33%

Reduced 50%

Reduced 55% Reduced 37% N/C 7% B

x jejunal-ileal length (cm) Range

28 (0–68)

122 (75–183)

No change 17% 99 (46–150)

•

PN status 1 year following treatment for 49 PN-dependent Fig. 55.5 patients with = 70 cm of small bowel continuity with some colon (n=29), for those >70 cm small bowel in continuity with colon (n=8), and those with =150 cm small bowel and no colon (n=12). ‘Off’ indicates no PN, ‘Reduced’ indicates less than what was originally given, and ‘No ChangeNC’ indicates similar volume and calories to that which was originally administered.The mean jejunal-ileal length and the range are also provided). (Reprinted from Byrne TA et al,Transplant Proceedings, 2002; 34:887–890. © 2002 with permission from Elsevier.)

•

(A) Bianchi and (B) STEP procedure to taper and lengthen Fig. 55.4 dilated small bowel in SBS patients.

growth factors and nutrients, which may enhance intestinal adaptation through specialized medical and nutritional regimens without surgical intervention. The largest clinical experience is with growth hormone and glutamine. Exogenous administration of growth hormone (GH) has been shown in experimental animal models to increase colonic mass, enhance sodium and water absorption in the small and large intestine, increase amino acid transport by enterocytes, and promote mucosal hyperplasia after extensive small bowel resection. Glutamine (GLN), a conditionally essential amino acid in catabolic states, serves as a primary fuel for both enterocytes and colonocytes, accelerates mucosal hyperplasia, and enhances sodium and water absorption following massive enterectomy in animals. Based on the above experimental evidence, a specialized treatment plan using a combination of GH and GLN with strict adherence to an SBS-appropriate diet was developed.34 Use of this therapy in a diverse group of nearly 400 SBS patients over the past decade has demonstrated significant efficacy in patients previously thought to have no chance of gaining nutritional autonomy. Subsets of this group have been reported on over the years.8,14,25 This includes a group of patients with an average of 28 cm of jejunum-ileum anastomosed to colon in whom 38% became TPN independent, and an additional 55% had significant reductions in their TPN utilization (Fig. 55.5). This group of patients is traditionally thought of as the most difficult to treat and least likely to become TPN independent.4 At least two other groups have found positive effects from using combined GH and

GLN in SBS patients as well.35,36 This therapy is not without controversy, however. Data from a group of eight patients did not show a benefit from such therapy.37 Of note, seven of the eight patients in this series had Crohn’s disease and six of the eight had no colon. SBS patients with no colon and diseased remnant bowel (whether active or inactive disease) have significant limitations on their ability to adapt, which may explain why no benefit was observed in this small study. In contrast, a more recent prospective, randomized, double-blind, placebo-controlled clinical study in 41 patients further supports use of this therapy in the appropriately selected and motivated patient in whom standard management techniques have failed or are likely to fail.38 Patients receiving growth hormone and glutamine had a dramatic statistically significant response (Table 55.2). This approach is relatively safe therapy with minimal complications in experienced hands, and long-term efficacy has been achieved. Hence, such therapy should be considered before committing patients to intestinal transplantation or life-long TPN.

INTESTINAL TRANSPLANTATION Intestinal transplantation is a potential alternative for those SBS patients who have failed all standard and specialized treatments. While life saving for some, it carries a very high morbidity and mortality. Hence, intestinal transplantation should be reserved for those who (1) are not likely to become TPN independent despite maximal standard and specialized treatment, and (2) have potentially life-threatening complications of TPN dependence. One way to predict the likelihood of achieving nutritional autonomy without intestinal transplantation is based on the ratio of jejunal-ileal length to body weight, which was developed based on clinical studies in patients with the shortest segments of bowel. Those with a small bowel/body weight ratio of greater than 0.5 have a 75% chance of TPN independence. Those with a ratio of

781

Dietary modification with supplemental GLN (n = 9)

Dietary modification with rhGH (n = 16)

Dietary modification with rhGH and supplemental GLN

Decrease in PN volume (liters)

3.8 ± 0.8

5.8 ± 1.0*

7.7 ± 0.8**

Decrease in PN calories (kcal)

2661 ± 439

4323 ± 464*

5745 ± 519**

Decrease in PN frequency (days)

2.0 ± 0.3

3.0 ± 0.5*

4.2 ± 0.4**

Data reported as mean ± SEM. * p60).125 In another case-control study of 156 CD patients and 282 UC patients, the odds ratio of a vertebral fracture was 1.72 and hip fracture 1.59. The disease severity predicted the risk of a fracture even after adjusting for steroid use.126 In addition, only 13% of IBD patients who had had a fracture were on any kind of antifracture treatment. More than 50% of patients on long-term steroid therapy develop osteoporosis, irrespective of the underlying disease. Up to 20% of bone mass can be lost per year with chronic steroid use. The effect is dosage-dependent and patients on 10 mg/day of prednisone have a significantly lower bone density than those on 0–5 mg/day.127 In addition to prednisone, one study showed that budesonide may also suppress the pituitary-adrenal axis and thus carries a potential risk of causing osteoporosis. Osteonecrosis is characterized by death of osteocytes and adipocytes and eventual bone collapse. The pain is aggravated by motion and swelling of the joints. It affects the hips more often than knees and shoulders and in one series, 4.3% of patients developed osteonecrosis within a 6-month period of steroid use.

Diagnosis is made by bone scan or MRI, and treatment consists of pain control, core decompression, and arthroplasty. The other extraintestinal manifestations are detailed in Table 56.6.

TREATMENT RECOMMENDATIONS The complete medical treatment recommendations are outlined in Table 56.3. For mild to moderate inflammatory Crohn’s disease, 5-ASA agents are the first choice followed by antibiotics and then budesonide. In moderate to severe disease, patients will usually need either prednisone or infliximab to induce a remission. Methotrexate is generally reserved for use in 6-MP/AZA refractory patients. In severe to fulminant disease, most often intravenous steroids, infliximab, or TPN are indicated. Although antibiotics and 6-MP/AZA can be used for perianal fistulas, infliximab is indicated in severe perianal fistulizing disease. Although 5-ASA agents may be marginally effective in maintaining remission, the only two agents consistently proven to maintain remission are 6-MP/AZA and infliximab. For the pregnant Crohn’s patient, most medical therapy is safe and patients should continue it throughout pregnancy to maintain remission. Indications for surgery are detailed in Table 56.5.

SUMMARY Crohn’s disease is an idiopathic granulomatous disease that can affect the entire gastrointestinal tract. The etiology is thought to be an immune-medicated intestinal inflammation with a genetic predisposition. The differential diagnosis is broad but there are certain key features such as noncaseating granulomas, transmural inflammation, cobblestoning, fistulization, and recurrence after surgery that make the diagnosis apparent. There are multiple extraintestinal manifestations, the most important of which are metabolic bone disease, arthritis, skin, eye, and hepatobiliary disorders. Chronic and extensive colitis can lead to colon cancer and patients should undergo colonoscopic surveillance after 8–10 years of disease. While traditional therapy is directed at blocking more general components of the inflammatory cascade, newer therapies are targeted against specific cytokines. The future of Crohn’s disease therapy is in pharmacogenomics; the determination by genetic analysis of the correct medication for the correct disease phenotype. The main goal for the future treatment of Crohn’s disease

Table 56.6 Extraintestinal manifestations Category

Clinical course

Treatment

Rheumatologic disorders (5%–20%)128 Peripheral arthritis Asymmetric/migratory Parallels bowel activity

Reduce bowel inflammation

Sacroiliitis

Symmetric/spine and hip joints Independent of bowel activity

Steroids/injections/methotrexate/anti-TNF

Ankylosing spondylitis

Gradual fusion of spine Independent of bowel activity

Azulfadine/methotrexate/anti-TNF

Dermatologic disorders (10%–20%)128 Erythema nodosum Hot, red, tender, nodules/extremities Parallels bowel activity


797

Category

Clinical course

Treatment

Pyoderma gangrenosum

Ulcerating, necrotic lesions Extremities, trunk, face, stoma Independent of bowel activity

Antibiotics/steroids/cyclosporine/infliximab/ dapsone/azathioprine/intralesional steroids/ thalidomide/NOT debridement or colectomy

Pyoderma vegetans

Intertriginous areas Parallels bowel activity

Evanescent; resolves without progression

Pyostomatitis vegetans

Mucous membranes Parallels bowel activity

Evanescent; resolves without progression

Metastatic Crohn’s disease

Crohn’s disease of the skin Parallels bowel activity


Sweet’s syndrome

Neutrophilic dermatosis Parallels bowel activity


Aphthous stomatitis

Oral ulcerations Parallels bowel activity

Reduce bowel inflammation/topical rx

Ocular pain, photophobia, blurred vision, headache Independent of bowel activity

Topical or systemic steroids

Mild ocular burning Parallels bowel activity

Topical corticosteriods

Ocular disorders (1%–11%)129 Uveitis

Episcleritis

Hepatobiliary disorders (10%–35%)128 Fatty liver Secondary to chronic illness, malnutrition, steroid rx

Improve nutrition/reduce steroids

Cholelithiasis

Patients with ileitis or ileal resection Malabsorption of bile acids, depletion of bile salt pool, secretion of lithogenic bile


Primary sclerosing cholangitis (PSC)

Intrahepatic and extrahepatic Inflammation and fibrosis leading to biliary cirrhosis and hepatic failure; 7%–10% cholangiocarcinoma

ERCP/high dose ursodiol lowers risk of colonic neoplasia

Genitourinary disorders (4%–23%)128 Calculi Calcium oxalate: following small bowel resection (colon intact) Uric acid: large ileostomy outputs

Hydration

Ureteral obstruction

Varies from minimal periureteral fibrosis to complete obstructive uropathy

Treatment varies

Deep vein thrombosis/pulmonary embolus/cerebrovascular accidents/ arterial emboli Correlates with classic risk factors for thrombosis

Anticoagulation/thrombolysis

Cardiopulmonary complications

Myocarditis/pleuropericarditis/ endocarditis/airway disease/ interstitial lung disease/necrobiotic parenchymal nodules/serositis

Treatment varies

Amyloidosis

Reactive to CD; diarrhea/constipation/ renal failure

Treatment varies

Pancreatitis

Secondary to duodenal fistulas, ampullary CD, gallstones, PSC, medications (6-MP/AZA/5-ASA), autoimmune, primary CD of the pancreas

Treatment varies

Other130 Thromboembolic disease (Clinical studies 1.3%–6.4%; postmortem 39%)

Hydration/decrease diarrhea

Summary

Table 56.6 Extraintestinal manifestations—cont’d

Crohn’s Disease

798 will be to give the correct medication at disease initiation and thereby prevent the sometimes devastating complications. By knowing from the start which subsets of patients will respond to medicines such as 6-MP/AZA, infliximab, or a yet undiscovered novel medication, we may be able to alter the natural history of Crohn’s disease itself.

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121. Armenti V, Ahlswede K, Ahlswede B, et al. National transplantation pregnancy registry outcomes of 154 pregnancies in cyclosporinetreated female kidney transplant recipients. Transplantation 1994; 57:502–505. 122. Katz A, Antoni C, Keenan GF, et al. Outcome of pregnancy in women receiving infliximab for treatment of Crohn’s disease or rheumatoid arthritis. Am J Gastroenterol 2004; 99(12):2385–2392. 123. Yazdanpanah Y, Klein O, Gambiez L, et al. Impact of surgery on quality of life in Crohn’s disease. Am J Gastroenterol 1997; 92(10):1897–1900. 124. Thirlby R, Fenster F, Lonborg R. Effect of surgery on health-related quality of life in patients with inflammatory bowel disease. Arch Surg 1998; 133:826–832. 125. Bernstein CN, Blanchard JF, Leslie W, et al. The incidence of fracture among patients with inflammatory bowel disease: A population-based cohort study. Ann Intern Med 2000; 133(10):795–799. 126. Van Staa TP, Cooper C, Brusse LS, et al. Inflammatory bowel disease and the risk of fracture. Am J Gastroenterol 2003; 128:1591–1597. 127. Bernstein CN, Lewis WD. Review article: osteoporosis and inflammatory bowel disease. Aliment Parmacol Ther 2004; 19(9):941–952. 128. Isaacs KL. Extraintestinal manifestations. Advanced therapy of inflammatory bowel disease. Hanauer SB, Bayless T, eds. Hamilton: BC Decker; 2001:267–270. 129. Mintz R, Feller ER, Bahr RL, et al. Ocular manifestations of inflammatory bowel disease. Inflamm Bowel Dis 2004; 10(2):135–139. 130. Hoffman RM, Kruis W. Rare extraintestinal manifestations of inflammatory bowel disease. Inflamm Bowel Dis 2004; 10(2):140–147.

References

A randomized double-blind placebo-controlled trial. Gastroenterology 2001; 120:1330–1338.

SECTION SEVEN MANAGEMENT OF INTESTINAL DISORDERS

CHAPTER FIFTY-SEVEN

57

Ulcerative colitis Lawrence J. Saubermann and Francis A. Farraye

INTRODUCTION Medical therapies for ulcerative colitis (UC) have not changed dramatically in recent years, a striking contrast to the development of new biologic therapies and new strategies for treating Crohn’s disease (see Ch. 56). The reasons for this phenomenon are numerous and are due predominately to the current lack of understanding of the pathophysiology of UC. In comparison, Crohn’s disease has had an evolutionary increase of new information about the disease process as genetic loci and their role in immunologic dysregulation are being defined.1,2 Despite this deficit in our understanding of the initiating and perpetuating mediators of UC, there have been significant advances in how gastroenterologists treat patients with this disorder using currently available medications.3 New and potentially more potent biologic therapies are being investigated for their use in the treatment of UC.4–6 Along with the appropriate use of available treatments, these new treatments may reduce the significant morbidity and health burden of ulcerative colitis.

DIAGNOSIS OF ULCERATIVE COLITIS There are no clearly distinguishing features to UC, and it is a diagnosis that must be made clinically after reviewing the patient’s history, physical examination, laboratory, radiologic, endoscopic, and pathologic findings. UC is a chronic disease characterized by recurrent episodes of superficial and continuous mucosal colonic inflammation, involving the rectum and extending proximally. As a result, the typical symptoms are the passage of blood and/ or mucus per rectum, bloody diarrhea, tenesmus, and in some cases fever. Occasionally, crampy abdominal pain that is relieved with the passage of flatus or bowel movements are also present. Deep visceral pain, nausea, and/or vomiting are more suggestive of Crohn’s disease. A number of extraintestinal manifestations involving the skin, eyes, joints, and other organ systems may also be present.7 Obtaining a history of environmental and genetic factors can also assist in the diagnosis of UC.8,9 Travel history and a good medication history are particularly important in evaluating for other causes of acute and chronic diarrhea. Since UC has a familial and an as yet undefined genetic component, a patient’s family history can also assist in the differential diagnosis. Another important aspect to the patient’s history involves tobacco use.10 Often, patients relate the onset of their colitis to smoking cessa-

tion, and a number of studies have confirmed a correlation between either nonsmoking or cessation of smoking and the onset of UC.11,12 Prior appendectomy may also confer some protection and lower the risk of developing UC, but does not exclude it as a diagnosis.13,14 Psychosocial stressors could modulate the disease process and also affect relapse rates.15 Unlike Crohn’s disease, which involves the small intestine, weight loss is not usually as pronounced, and is generally related to a decrease in nutritional intake in an effort to reduce bowel frequency. On abdominal exam, left lower quadrant tenderness may be present, or if pancolitis is present, the tenderness may extend across the mid-epigastric region to the right side of the abdomen. Frank blood is commonly seen on rectal examination. The presence of anal fistulae or large external ‘hemorrhoids’ suggests Crohn’s disease rather than UC. Peritoneal signs, such as rebound and/or guarding, would imply worsening transmural inflammation in the setting of fulminant ulcerative colitis. An examination for extraintestinal manifestations may assist in the diagnosis, but are not specific to UC, and may be observed in Crohn’s disease or bacterial-associated colitis. These include arthritic, ocular, hepatic, dermatologic, and hematologic disorders.7 Laboratory findings commonly include leukocytosis and anemia. The anemia may be normocytic if acute, or microcytic if chronic and related to iron deficiency. Electrolyte disturbances are often present and consistent with chronic diarrhea, such as hypokalemia. Serum protein and albumin levels may be decreased due to the chronic inflammation and protein loss. The presence of increased acute-phase reactants is non-specific and include elevation of the erythrocyte sedimentation rate and C-reactive protein. Serum perinuclear anticytoplasmic antibodies (pANCA) levels tend to be elevated in the setting of UC, as compared to increased antiSaccharomyces antibodies (ASCA) levels in Crohn’s disease, but these tests currently lack sufficient sensitivity to be used as the sole basis for diagnosis.16,17 UC patients who are pANCA positive do appear to have a clinically worse course in terms of their response to treatment and the development of pouchitis following colectomy and ileoanal anastomosis.18 Elevated liver enzymes in a cholestatic pattern may indicate the presence of primary sclerosing cholangitis, which is present in approximately 3–5% of individuals with UC. Conversely, patients with primary sclerosing cholangitis have a 70–80% chance of having UC. Initial plain radiographs in the ill patient are useful to exclude free air in the peritoneal cavity, assess for areas of inflammation in the colon, and assist in ruling out intestinal obstruction. On

Ulcerative Colitis

804 occasion, a loss of haustral folds in the setting of chronic colitis can be seen on abdominal radiographs, though this feature is more easily observed on barium enema. Examination of the sacroiliac joints and intervertebral disc regions can be seen on plain radiographs to enable an assessment for extraintestinal articular manifestations, e.g., sacroiliitis or ankylosing spondylitis. More commonly, computerized tomography (CT) is performed during the initial evaluation in the patient with moderate to severe symptoms. CT will generally demonstrate bowel wall thickening in a distribution consistent with colitis; however, it cannot distinguish colitis that is caused by other etiologies. CT can assist in suggesting Crohn’s disease is more likely than UC if pericolonic fat ‘stranding’, or an abdominal abscess/mass, or small bowel thickening are present. Endoscopic evaluation is useful to ascertain the location and degree of activity (Fig. 57.1) and to obtain biopsies for histopathologic analysis. Because UC predominantly involves the rectum and extends proximally, a flexible sigmoidoscopy is all that is usually required in the acute setting. A full colonoscopic evaluation can be performed when the disease is less active to assess for pancolitis, as this will impact future surveillance for colorectal cancer, and possibly indicate a more difficult management case. The histologic analysis of mucosal biopsies demonstrates evidence of chronic inflammation and injury, including branching of the colonic crypts, crypt dropout, and infiltration of the mucosa with plasma cells as well as a large number of lymphocytes (Fig. 57.2). Crypt abscesses are also present, usually in more active disease states, but are not specific. Histology also helps eliminate other possible causes of colitis that must be considered in the differential diagnosis, such as ischemic colitis, infectious colitis, and microscopic colitis.

MEDICATIONS USED TO TREAT ULCERATIVE COLITIS Sulfasalazine Sulfasalazine (Azulfidine®) was the first orally administered treatment for UC and has been in clinical use for over 60 years. It is used for the treatment of mild to moderate UC for both the induction and maintenance of remission. However, its therapeutic dosage range is limited due to a significant adverse effect profile at higher doses. Better-tolerated forms of its active

•

Fig. 57.2 Ulcerative colitis histology. Mucosal biopsy demonstrating crypt abscess, crypt branching, and infiltration of the lamina propria with lymphocytes and plasma cells.

ingredient 5-aminosalicyclic acid (5-ASA) have been developed and are replacing sulfasalazine as an initial therapy for mild to moderate UC. Sulfasalazine is a conjugate of 5-ASA linked to a sulfapyridine moiety through an azo-bond that makes the medication poorly absorbed in the upper intestinal tract. In the colon, enteric bacteria cleave the azo-bond, and the 5-ASA portion exerts its local antiinflammatory effects. The precise mechanism of 5-ASA in reducing colonic inflammation is not clear, but appears to involve intracellular inflammatory mediators such as NF␬B or PPAR␥ within the colonic epithelial cells and/or within infiltrating immune cells. The initial recommended dosage of sulfasalazine in active UC is 3–4 g/day in divided doses, starting at 500 mg twice daily and increasing to the target dose over 1 week. After the induction of remission, the dose is reduced to approximately 2 g/day for maintaining remission. Both enteric coated and nonenteric coated forms are available, and peak serum levels are reached in approximately 12 hours with a half-life of about 7–8 hours.19 Sulfasalazine is poorly absorbed and possesses limited bioavailability, and what is absorbed is acetylated or hydroxylated in the liver and then conjugated to glucuronic acid for biliary excretion.19 Acetylation of the medication appears to affect the side effect profile, as it has been shown that those individuals who are slow acetylators generally have more adverse side effects in comparison to rapid acetylators.20–22 The plasma sulfapyridine concentration is much higher in the slow acetylators and is associated with side effects.23–25 Sulfasalazine is approved for use in both adults and children greater than 2 years of age, for both active disease and

•

Fig. 57.1 (A) Endoscopic image of mild UC. (B) Endoscopic image of moderate to severe UC.

A

B

805 In summary, sulfasalazine remains an important medication for the treatment of mild to moderate ulcerative colitis and is significantly less costly than the other 5-ASA formulations. Simply reducing the dose of the medication can usually treat many of the nonallergic side effects, such as headaches and abdominal discomfort. However, because of its significant adverse side effect profile, this agent is being replaced by newer nonsulfa-based 5ASA medications (e.g., mesalamine).

Aminosalicylates (5-ASA compounds) Mesalamine (5-ASA) has become the medication of choice for the treatment of mild to moderate UC.28 Mesalamine is available in a variety of preparations, including oral, enema, and suppository forms. This class of agents is well-tolerated, allowing dose escalations not possible in most patients receiving sulfasalazine. There are several 5-ASA preparations available that differ in their delivery mechanism. Asacol® (Procter and Gamble) is coated with Eudragit S and is designed to release 5-ASA at a pH of 7.0 in the terminal ileum and cecum. Pentasa® (Shire) is composed of 5-ASA incorporated into a semipermeable membrane that releases 5-ASA throughout the small and large intestine. Colazal® (Salix) is composed of 5-ASA linked to an inert carrier by an azobond, while Dipentum® (Celltech) is composed of two 5-ASA molecules linked by an azo-bond. After bacterial cleavage of the azo-bond of Colazal and Dipetum, 5-ASA is released in the colon. Asacol is commonly prescribed at a dose of 2.4 g (two 400 mg tablets three times per day),29 while Pentasa is given at a dose of 1 g four times a day.30 The dose for Colazal is 6.75 g (three 750 mg tablets three times a day) while Dipentum is given at 500 mg twice daily. (See Table 57.1 for a description of the various 5-ASA preparations.) Although generally well tolerated, some side effects have been observed with mesalamine. Mesalamine must be prescribed carefully in the setting of renal impairment as it has been reported to cause interstitial nephritis and/or worsen pre-existing renal insufficiency. It is also contraindicated for those with allergic reactions to salicylates. Rare cases of rash, hepatitis,

Table 57.1. Aminosalicylate preparations Brand name

Tablet form

Usual adult dose

Dosing interval

Aminosalicylates (5-ASA) Oral Asacol® Mesalamine

400 mg

2.4–4.8 g q.d.

b.i.d.–q.i.d.

Azulfidine®

Sulfasalazine

500 mg

3.0–6.0 g q.d.

b.i.d.–q.i.d.

Colazal

Balsalazide disodium

750 mg

6.75 g q.d.

t.i.d.

Dipentum®

Olsalazine sodium

250 mg

2.0 g q.d.

b.i.d.

Pentasa

Mesalamine

250/500 mg

4.0 g q.d.

q.i.d.

Suppository Canasa®

Mesalamine

500/1000 mg

1.0–1.5 g q.d.

q.d–t.i.d.

Suspension Rowasa®

Mesalamine

4 g in 60 mL

4.0 g q.d.

q.d–b.i.d.

®

®

Generic name

t.i.d., three times a day; b.i.d., two times a day; q.i.d., four times a day; q.d., once a day.

Medications Used to Treat Ulcerative Colitis

maintenance of remission. Sulfasalazine and the 5-ASA compounds are less effective than corticosteroids for the treatment of active disease. The initial response to sulfasalazine in UC is usually observed within 3–4 weeks of beginning the medication, and will result in clinical improvement or remission in approximately 40–80% of patients with mild to moderate disease.26 It is contraindicated in those individuals with hypersensitivity to the medication, urinary obstruction (due to poor urinary excretion of acetylated sulfapyridine), and porphyria. Reduced dosages should be given for patients with renal and hepatic impairment. In patients with hypersensitivity reactions to the medication, desensitization strategies have been effective. The side effect profile for sulfasalazine is significant and almost always related to the sulfapyridine component. These side effects include hematologic changes, such as leukopenia (rarely agranulocytosis), thrombocytopenia, hemolytic or aplastic anemia. Megaloblastic anemia due to folate deficiency is also well described, and all individuals on sulfasalazine should take a folic acid supplement daily. Neurologic effects include headache and less commonly a peripheral neuropathy. Rarely, pancreatitis or hepatotoxicity as a result of a hypersensitivity reaction occurs. Pulmonary infiltrates may develop and are usually associated with a peripheral blood eosinophilia. Male infertility is a common side effect of the medication, and is a result of oligospermia. After stopping the medication, this effect is reversible within 3 months.27 Dermatologic effects are primarily a pruritic skin rash, with rare cases of erythema multiforme (Stevens-Johnson syndrome). The most concerning reaction with administration of sulfasalazine is a hypersensitivity reaction to the sulfapyridine component. This usually manifests within the first 1–3 weeks of therapy, but may be delayed. Typically, patients present with hepatomegaly, increased liver enzymes, rash, fever, lymphadenopathy, leukocytosis, and eosinophilia, which may progress to liver failure. As a result of these potential toxic and severe adverse effects of sulfasalazine, monitoring of patients should include baseline and periodic complete blood counts, liver function tests, and electrolytes with renal assessment.

Ulcerative Colitis

806 thrombocytopenia, leukopenia, anemia, pericarditis and pleuritis with pericardial and pleural effusions have also been noted. Gastrointestinal complaints occur less often than sulfasalazine, and include nausea, vomiting, dyspepsia, constipation, and rarely, pancreatitis. In contrast to sulfasalazine, however, there does not appear to be any significant effects on sperm counts in men taking mesalamine. Currently, there are insufficient data to determine whether the new forms of 5-ASA are superior to sulfasalazine in terms of their efficacy,31–33 and all forms of 5-ASA appear better than placebo in meta-analyses.26,34–37 In a recent Cochrane review, it was concluded that the newer 5-ASA preparations were superior to placebo in their ability to induce remission and tended toward a therapeutic benefit over sulfasalazine. However, a clinical advantage to using the newer 5-ASA preparations in place of sulfasalazine appeared unlikely given the higher cost of the newer 5-ASA agents.32 During maintenance therapy, while the newer 5-ASA preparations were superior to placebo, they were statistically inferior to sulfasalazine therapy.31 Eighty percent of patients who are unable to tolerate sulfasalazine are able to tolerate mesalamine. Enema administration is very effective in the setting of distal colitis.38,39 Studies have shown that combination therapy with both oral and rectal administration is better than oral or rectal therapy alone at similar concentrations.40

Corticosteroids In the setting of moderate to severe UC unresponsive to 5-ASAs, corticosteroids can induce remission, but have no role in maintenance therapy.41 They do not prevent relapses, and a significant percentage of patients are likely to become ‘steroid dependent’ if they are unresponsive to traditional maintenance regimens. These patients will commonly relapse upon tapering of the steroid preparation. In this setting, the significant side effect profile of chronic steroid use becomes a major issue. Intravenous corticosteroids are generally administered to the hospitalized patient once other causes for colitis have been excluded. There does not appear to be any significant differences in terms of efficacy among the parenteral preparations used.42 Oral corticosteroids are useful in the patient with moderate colitis, and remission rates of approximately 70% are commonly achieved.43 Oral agents can also be used to transition patients after induction of remission with parenteral corticosteroids for outpatient management. Prednisone and prednisolone are commonly used preparations, with a typical daily dose of 40–60 mg of prednisone or its equivalent. The use of higher doses of corticosteroids does not appear to confer any benefit to patients with mild to moderate disease that are unresponsive to 5-ASA therapy. Topical corticosteroid preparations (enemas and foams) are available for the treatment of distal ulcerative colitis but are less effective than topical 5-ASA formulations.44 Steroid-related side effects are significant and can result in serious consequences. They include hypertension, hyperglycemia, osteonecrosis, osteopenia, mood disorders, hypertrichosis, epidermal thinning, and change in adipose distribution. Given the lack of data to suggest that maintenance regimens with corticosteroids are effective in UC, the early addition of an immunomodulator is recommended (discussed below). It is also recommended that calcium supplementation and the use of bisphosphonates be

considered due to the risk of osteopenia while taking corticosteroids for prolonged periods of time.45 In a population-based study from the Mayo Clinic, of 185 UC patients diagnosed between 1970 and 1993, 34% needed steroids at some time during the course of their illness. Immediate outcomes (30 days) for UC patients treated with steroids were complete remission in 54%, partial remission in 30%, and no response in 16%. At 1 year, 22% of the patients were steroid dependent, 29% underwent colectomy, and the remaining 49% were off steroids.46 Therefore, although steroids are very effective in inducing remission in patients with UC, they should be avoided for maintenance therapy.

IMMUNOMODULATORS Azathioprine and 6-mercaptopurine Used as immunosuppressive agents in the setting of solid organ transplantation, azathioprine or 6-mercaptopurine (6-MP) are the most commonly used immunomodulators in the treatment of both Crohn’s disease and UC. These medications are primarily used in UC patients with moderately to severely active disease for maintenance of remission and also for their steroid-sparing effect. There are limited data regarding the induction of remission in UC with either agent.47,48 Their exact mechanisms of action are not known, but these agents do affect DNA and RNA synthesis, and a recent report has suggested a possible role in causing T-cell apoptosis.49 Although responses can occur as early as 8 weeks, it may take up to several months for patients to respond to azathioprine or 6-MP. Given this latency period, these agents are generally initiated early in the treatment of moderately active UC. A trial in patients with steroid-treated Crohn’s disease using an initial intravenous loading dose of azathioprine did not decrease the time to response.50 More commonly, oral azathioprine is given in the setting of other immunosuppressive agents, such as steroids or cyclosporine, during a moderate or severe episode of colitis, while tapering these other agents.51 Azathioprine bioavailability is about 50%, and it is converted rapidly to 6-mercaptopurine (6-MP) in the bloodstream and then into several additional metabolites, of which 6-thioguanine (6-TG) is the therapeutically active metabolite. The metabolism of azathioprine and 6-MP is controlled by thiopurine methyltransferase (TPMT), and those individuals with a genetic decrease in levels of TPMT are prone to toxicity. Approximately 11% of individuals are heterozygous for TPMT mutations, and they have a 50% reduction in their ability to metabolize the medication. About 1 in 300 individuals are homozygous and at risk for severe toxicity. Genetic testing is available for this enzyme and can be performed prior to the initiation of therapy. Regardless of whether TPMT genotype or activity is measured, the patient’s complete blood count should be monitored for leukopenia. Monitoring will identify those individuals with genetic deficiencies in TPMT within the first few weeks, at which time the dose can be adjusted accordingly. 6-TG was considered as a potential alternative immunomodulator, but long-term treatment results in nodular hyperplasia and fibrosis in the liver, thereby precluding its use.52 Azathioprine is generally initiated at a dose of 0.5–1 mg/kg/ day in divided doses, and if tolerated, increased to 2.0–2.5 mg/

807 this drug interaction results from the inhibition of TPMT by mesalamine and sulfasalazine.57 As noted, azathioprine is primarily used as a maintenance therapy and as a means for reducing steroid dependency. Azathioprine has been demonstrated to be effective at maintenance of disease remission in 80–90% of patients over two years.58 In addition, it has enabled the discontinuation of corticosteroids in steroid-dependent subjects.59 In one study, with steroid-dependent active UC, the 1-year relapse rate was 31% on azathioprine as compared to 61% on placebo.60 In another study in which intravenous cyclosporine was started for severe steroid refractory UC, 10 of 12 subjects responded to azathioprine; only one patient experienced a relapse, while no patient required colectomy by 16 months.61 Two other studies have confirmed the observation that the addition of azathioprine after induction with intravenous cyclosporine results in a reduction in relapse and the need for colectomy.62,63 Furthermore, in a double-blind, placebo-controlled study of 44 subjects with active UC, significant reductions in steroid use were again seen in the azathioprine-treated group.64 The duration of maintenance therapy with azathioprine or 6-MP in patients with UC is unknown. In summary, azathioprine or 6-MP has become the current medication of choice for long-term maintenance for moderate to severe UC, especially in the steroid-dependent patient. The role of these two agents in the induction of remission is less clear. The use of these drugs requires close monitoring for toxicity, including frequent laboratory measurements, and regular office visits. Table 57.2 summarizes the typical doses of the immunomodulators.

Cyclosporine In severe cases of ulcerative colitis in the hospitalized patient unresponsive to intravenous corticosteroids, parenteral cyclosporine can be used as a potent and rapidly acting immunosuppressive medication. Cyclosporine has a significant side effect profile and toxicity that limits its long-term use in patients with UC. Consequently, it is reserved for patients with severe colitis

Table 57.2 Corticosteroid and immunomodulator preparations Brand name

Generic name

Tablet form

Usual adult dose

Corticosteroids Prednisolone

40–60 mg p.o. q.d

Prednisone

40–60 mg p.o. q.d

Methylprednisolone

40–60 mg i.v. q.d

Hydrocortisone

300 mg i.v. q.d

Immunomodulators Imuran®

Azathioprine

50 mg

2.0–2.5 mg/kg q.d.

Purinethol®

6-mercaptupurine

50 mg

1.0–1.5 mg/kg q.d.

Cyclosporine Neoral®

Cyclosporine

b.i.d., two times a day; q.d., once a day; i.v., intravenous.

2.0–4.0 mg/kg i.v. continuous over 24 h 25 mg, 100 mg

Twice the i.v. dose given b.i.d.

Immunomodulators

kg/day. Initial doses of 6-MP are 50 mg/day, and the standard dose is 1.0–1.5 mg/kg daily. As noted above, an alternative approach is to start at the target dose after assessment of the TPMT genotype or enzyme activity.53,54 Dosing needs to be adjusted in the setting of renal insufficiency. The side effects of azathioprine are usually bone marrow suppression. Leukopenia and or thrombocytopenia are dose dependent and reversible. Because this side effect can occur late in the course of treatment, laboratory values need to be followed on a weekly basis initially and then periodically thereafter. Rare red-cell aplasia has also been reported, which may present late in the course of therapy. Gastrointestinal side effects are common in patients taking azathioprine and most commonly include nausea, vomiting, and dyspepsia, all of which may be transient. Some patients who are intolerant to azathioprine due to nausea or headaches can tolerate 6-MP. Pancreatitis is a well-documented adverse effect that occurs in about 3–5% of individuals, and the medication must be discontinued in this setting. Hepatotoxicity is also associated with the use of azathioprine, usually in the form of cholestatic liver disease in the setting of a hypersensitivity reaction. This hypersensitivity reaction is rare and presents as fevers, chills, leukocytosis, renal impairment, and hepatotoxicity, usually within the first few weeks of treatment. Monitoring of liver enzymes is thus recommended during the first few weeks of therapy and then regularly thereafter. Although significant concern had been raised regarding the potential for an increased risk of malignancy with azathioprine use, retrospective reviews have not detected a significant increase in the number of cancers in those taking azathioprine.55,56 Azathioprine and 6-MP are both contraindicated in patients on allopurinol. Allopurinol inhibits xanthine oxidase, which metabolizes 6-MP to an inactive metabolite; coadministration can result in severe pancytopenia. In addition, clinicians should be aware of an interaction between 5-ASA preparations and azathioprine or 6-MP. In a study of patients with Crohn’s disease receiving azathioprine or 6-MP, the addition of mesalamine or sulfasalazine resulted in an increase in whole blood 6-TG concentrations and a high frequency of mild leukopenia. It is felt that

Ulcerative Colitis

808 refractory to steroids who would otherwise undergo a colectomy.65 The starting dose originally described in the randomized controlled trials was 4 mg/kg/day,65 although recent data have suggested that 2 mg/kg/day has similar efficacy with less toxicity.66 UC clinical trials have indicated a clear benefit of cyclosporine in severe, steroid-refractory disease. In the original randomized, controlled study of cyclosporine versus placebo in hospitalized UC patients unresponsive to intravenous steroids, the response rate was 82% at a mean of 7 days.65 Cyclosporine is bound to lipoproteins in the blood and has a half-life of approximately 8 hours. It is distributed throughout the fatty tissues and is excreted primarily through the biliary system along with its metabolites. Its mechanism of action is unclear, but the drug appears to inhibit second-messenger molecules in T cells, such as cyclophilin and calmodulin, which leads to a downregulation of inflammatory molecules and leukocyte function. Patients on intravenous cyclosporine can be changed to an oral preparation; however, due to decreased oral bioavailability, higher doses (typically twice the intravenous dose) are used. High-fat meals may interfere with absorption. Following cyclosporine levels does not appear to be related to efficacy in treatment and are obtained primarily to help avoid toxicity and to evaluate the bioavailability of the medication. As indicated above, cyclosporine has a number of significant side effects. Nephrotoxicity is commonly observed (up to approximately 25% of individuals) and may occur either early or late. This effect is dose-related and is usually reversible, but irreversible renal toxicity may occur. Oliguria is a common presentation along with a rise in serum creatinine. Patients must be monitored closely for hyperkalemia and hypomagnesemia. Hypertension is another significant and common side effect of cyclosporine use, occurring in up to 50% of individuals, and its use is contraindicated in the setting of uncontrolled hypertension. The onset is typically early and may be associated with the development of headaches. Blood pressure monitoring should be performed at baseline and then every other week initially, followed by monitoring every month thereafter. This effect is also reversible, but can be managed by antihypertensive medications if necessary. Rare cases of hemolytic uremic syndrome, hepatotoxicity in the form of hyperbilirubinemia and seizures have been described. Tremors may be observed while on cyclosporine. Another common side effect is hypercholesterolemia, with hypertriglyceridemia rarely observed. Other issues that have been noted with cyclosporine use include gingival hyperplasia and an increased risk of opportunistic infection, specifically Pneumocystis carinii pneumonia. Prophylaxis against P. carinii is recommended in the setting of cyclosporine use when administered with azathioprine/6MP and corticosteroids.

NEW THERAPIES/OTHER MEDICATIONS A large number of new biologic therapies are being considered for UC. Although none has been approved at this time for UC, active investigation is underway with a number of potential antiinflammatory agents. The antitumor necrosis factor-␣ (TNF-␣) treatments, including mouse-human chimeric (infliximab) and fully humanized antibodies (CDP571), have been used in patients with UC, with mixed results to date. The majority of these studies have been open-label in small numbers of subjects.67 In one randomized, placebo-controlled study involving infliximab, no benefit was detected at 6 weeks in moderately severe and steroid-resistant

UC.68 Two recent large multicenter randomized, placebocontrolled studies found that infliximab at doses of 5–10 mg/kg were effective in treating ulcerative colitis refractory to at least one standard therapy including 5-ASA, corticosteroids, or immunosuppressants (Supplement to Gastroenterology 2005, 128: A-104, A-105). In the Active Ulcerative Colitis One (ACT 1) trial, clinical response rates at 30 weeks were 52.1% and 50.8% for the 5 mg/kg and 10 mg/kg infliximab groups compared with 29.8% of the placebo. Remission rates were 33.9%, 36.9% and 15.7% respectively. Similar responses were seen in another large multicenter trial (ACT 2). Another antibody blocking strategy for the treatment of UC involves reducing leukocyte adhesion. The ␣4 integrin is critical for the recognition and migration of leukocytes through the intestinal endothelium. Two different forms of an antibody that block either the ␣4 integrin or ␣4␤7 pair of integrins on the surface of leukocytes and prevent their adhesion/migration are being investigated. Initially, 10 subjects were tested with an anti-␣4 infusion, and a clinically significant response was noted in 50% of subjects by 2 weeks.69 However, recent larger studies have been suspended due to the development of progressive multifocal leukoencephalopathy (PML) in several subjects. Similarly, leukopheresis columns are being tested to remove circulating leukocytes that may be involved in the disease process. Some benefits have been described in reducing steroid dependence over time; however, this approach is still considered experimental.70,71 Large randomized, controlled trials are ongoing. Another targeted antibody-based therapy involves antibodies directed against the interleukin-2 receptor alpha-chain (CD25). To date, this approach has been demonstrated to be beneficial in a small clinical trial.72 Other biologic treatments include the use of small molecules, such as the ten amino acid antiinflammatory molecule known as RDP58.73,74 This amino acid molecule inhibits proinflammatory substances like TNF-␣ and interferon-gamma at a local, intracellular point, rather than in a systemic fashion.74 Transdermal nicotine has been considered a possible treatment for UC. The rationale for its use has been the observation that many UC subjects experience their initial episode within weeks to months after the cessation of smoking.12 In some trials, transdermal nicotine has been shown to be an additional effective therapy to induction regimens.75–78 However, the side effects are significant, and nicotine must be used cautiously in nonsmoking individuals or in those who may return to smoking and become nicotine dependent.75 This mode of therapy is not effective for use as a maintenance therapy.79 Antibiotics have also been used as additive therapy to induce remission in UC. A double-blind, randomized trial of ciprofloxacin reported a beneficial effect in steroid or aminosalicylate-treated individuals.80 However, when given alone, it did not appear to be effective.81 In another trial, metronidazole and tobramycin had no effect on the clinical course of UC.82 Intramuscular methotrexate has been demonstrated to be effective in treating Crohn’s disease (see Ch. 56). However, in UC when administered orally at doses of 12.5 or 15 mg, no benefit from methotrexate has been demonstrated in the treatment of patients with UC.83,84 The unfractionated form of heparin has also been examined in UC and was initially believed to be beneficial; however, further studies have found it to be ineffective as a monotherapeutic agent.85,86

809

MEDICAL TREATMENT STRATEGIES The goals of treating UC are the control of symptoms and the induction and maintenance of clinical remission, while limiting medication-induced side effects. The choice of medical therapy in patients with UC is based on the extent and severity of disease, which can be modified by patient preference and their response to previous therapeutic trials. Traditionally, therapies have been applied using a tiered approach, with increasing efficacy and toxicity at higher levels. Oral and topical therapies are initiated in patients with mild to moderate disease, followed by immunomodulator treatment in patients with moderate to severe disease. As discussed above, there has been a strategic shift in practice in the treatment of UC, primarily to an increase in the use of immunomodulation earlier in the course of the disease to prevent recurrent exacerbations, limit steroid toxicity, and reduce disease morbidity.

Proctitis Patients with ulcerative proctitis typically present with hematochezia and mucus both with and without bowel movements, tenesmus, and a lack of systemic signs or symptoms. Due to its distal location, topical therapies are very effective,35 and they cover the affected region well.88 Patient preference usually determine the form of treatment to be used. Topical 5-ASA (mesalamine) enemas, suppositories, or foam (not available in United States) are the first-line therapy for induction and maintenance of remission, with reported remission rates

of approximately 75%.89 Doses are generally 500–1000 mg/day for the suppositories and 4 g for the 5-ASA enemas. Nightly enemas or twice daily enemas are often used, but patient preference often dictates the use of 5-ASA suppositories.90–92 Corticosteroids are available in enema, foam, and suppositories as well.93,94 Topical corticosteroids can also be used, and while some studies have demonstrated effectiveness equal to topical mesalamine therapies, meta-analyses have indicated a greater derived benefit with mesalamine therapy.44,93–95 Topical corticosteroids may be useful in those individuals intolerant to mesalamine or in more severe cases of distal colitis.39,96 Oral 5-ASA medications are generally less efficacious than topical 5-ASA therapies for proctitis.97 The use of topically administered mesalamine formulations has been demonstrated to be effective for maintenance of remission for proctitis (Fig. 57.3).98

Left-sided colitis Left-sided colitis includes proctosigmoiditis or colitis extending to the splenic flexure. The treatment of left-sided colitis includes both topical and oral forms of 5-ASA, as well as topical corticosteroids. Induction of remission: Similar to proctitis, the initial induction regimen involves the use of sulfasalazine or 5-ASA-containing compounds.39,99 Doses range 2–4 g in daily divided doses for 5-ASA and 4 g for sulfasalazine.100 Topical therapy is commonly used, but oral therapy tends to be preferred by most patients. Enemas effectively treat the more proximal disease-affected areas than suppositories or foam.35,88 The combination of topical and oral 5-ASA forms is superior to either one alone, possibly a result of either improved compliance, a higher total 5-ASA dose, or a more directed form of localized therapy.40,101–103 In patients unable to attain remission with high-dose oral and topical 5-ASA, corticosteroid enemas may be initiated in an attempt to avoid systemic steroids.96,104–106 However, in the patient with ongoing symptoms in the absence of systemic toxicity, such

Assess disease activity:

Mild

Moderate

Severe

5-ASA suppository b.i.d. or cortisone foam q.h.s./b.i.d.

5-ASA suppository b.i.d. or cortisone foam q.h.s./b.i.d. ± oral 5-ASA

5-ASA suppository b.i.d. or cortisone foam q.h.s./b.i.d. + oral 5-ASA

No response: Prednisone 40–60 mg q.d.

Response: Taper and discontinue steroids Maintain on oral/topical 5-ASA therapy or cortisone foam/oral 5-ASA Fig. 57.3

No response: Add AZA/6–MP then taper and discontinue steroids

• A suggested approach to the management of ulcerative proctitis.

No response: Prednisone 40–60 mg q.d.

Response: Taper and discontinue steroids Add AZA/6–MP

No response: Consider surgery Consider experimental protocol

Medical Treatment Strategies

A recent study compared the efficacy of the probiotic preparation Escherichia coli Nissle 1917 with mesalazine in maintaining remission in patients with UC. The rate of relapse was similar in both groups at 12 months (36.4% in the probiotic group and 33.9% in the mesalazine group).87

Ulcerative Colitis

810 as fever, weight loss, or severe abdominal pain, oral corticosteroids should be considered. Typically, they should be prescribed once or twice daily. If symptoms of progression and toxicity are present, hospitalization and the use of intravenous corticosteroids may be necessary (see below in the next section on pancolitis). Maintenance regimen: After achieving remission, patients are often gradually tapered off their topical 5-ASA formulations in favor of the easier to tolerate oral 5-ASA formulations. In general, the dose of sulfasalazine is often reduced from 4 g to 2 g daily for maintenance to prevent dose-related toxicity. Dose reductions are generally not necessary for the newer mesalamine-based therapies, and the dose of mesalamine typically used to induce remission is now commonly prescribed as the maintenance dose. In more severe cases of left-sided UC, where the use of oral and topical mesalamine has been maximized, azathioprine or 6-MP can be added in an attempt to induce and maintain a lasting remission. This approach has not been investigated extensively in patients with left-sided colitis; however, its benefit can be inferred from its efficacy in patients with pancolitis. Serial monitoring of complete blood counts and liver enzymes is required at initiation and throughout the course of treatment. Oral folic acid should be administered because of indirect evidence that it may help prevent the development of dysplasia and neoplasia in chronic UC (Fig. 57.4).107,108

Pancolitis Disease extending from the rectum proximal to the splenic flexure is defined as pancolitis or extensive colitis. It is important to assess

the disease extent by endoscopy and biopsy in all patients with UC, as individuals who initially present with extensive colitis more commonly require colectomy or develop complications. Induction regimen: The disease activity determines the form of induction therapy. For mild cases, therapy with sulfasalazine or mesalamine is generally initiated. As in distal colitis, topical therapy is useful as an adjunct to oral therapy. The response rate using this regimen approaches 70–80%, and over 50% of patients will achieve a lasting remission. Sulfasalazine or 5-ASA doses should be maximized to induce remission and to avoid the use of corticosteroids. In more moderate cases, or when patients are not responding rapidly to maximal 5-ASA treatments, the addition of oral corticosteroids is warranted. Typically, in the outpatient setting, doses are initiated at 40–60 mg/day of prednisone, either in single or twice daily doses.109 After the patient has achieved remission, steroid doses can be tapered. Although data comparing various steroid tapering strategies are not available, in general, a decrease of 5–10 mg/week is used until a daily dose of 20 mg is achieved, at which time the daily dose is decreased in 5 mg increments per week. Those patients who appear to require corticosteroids early in the course of their disease and relapse as the steroid dose is tapered are candidates for immunomodulator treatment with azathioprine or 6-MP. Owing to their delayed onset of action, these medications should be considered early in the course of the illness. In severe cases of UC or in those patients not responding to oral corticosteroids, hospitalization may be required. Stool studies should be obtained for enteric pathogens including C. difficile and

Assess disease activity and extent:

Mild

Moderate

Severe

5-ASA enema b.i.d./q.h.s. or Hydrocortisone enema b.i.d./q.h.s. + oral 5-ASA

5-ASA enema b.i.d./q.h.s. or Hydrocortisone enema b.i.d./q.h.s. + oral 5-ASA

Oral steroids (if no response to maximal oral and topical 5-ASA)

No response: Add PO steroids Continue oral and topical 5-ASA agents

No response: Add AZA/6-MP

Response: Taper and discontinue steroids Maintain 5-ASA. Consider AZA/6-MP for maintenance

Response: Taper and discontinue steroids Maintain induction dose 5-ASA ± topical agents

Response: Taper and discontinue oral steroids. Maintain with AZA/6-MP ± oral 5-ASA

No response: IV cyclosporine

Response: Switch to oral cyclosporine + TMP/SX. Maintain with AZA/ 6-MP. Taper and discontinue steroids

No response: Surgery

No response: Consider experimental protocol Consider surgery

Fig. 57.4

No response: IV steroids

• A suggested approach to the management of left-sided ulcerative colitis.

811 is possible for patients to experience an exacerbation of their disease. Patients should be evaluated for other possible causes of colitis, including infections such as Clostridium difficile, enteric pathogens, or cytomegalovirus. Repeat endoscopy can determine if the disease recurrence is localized to the distal colon and rectum, or is more extensive. If localized, topical therapy may be initiated or the dose increased. Efforts should be made to maximize the 5-ASA dose during the steroid taper to reduce disease relapse. Currently, maintenance with azathioprine or 6-MP is the treatment of choice for corticosteroid-dependent patients.51,58 The once or twice a day dosing regimen increases compliance. For example, in one study of 35 patients, the combination of azathioprine and sulfasalazine was significantly better than sulfasalazine and placebo in maintaining remission.115 There are risks associated with the use of these medications, including a slightly increased risk of infection, and individuals must decide with their physician’s assistance whether the possible benefits outweigh the risks of therapy. Close monitoring of the blood counts for the development of leukopenia is required, particularly in those with genetic mutations in the TPMT gene, who may achieve toxic blood levels and have bone marrow suppression or severe leukopenia. Most patients with severe pancolitis who respond to intravenous steroids can be changed to oral preparations and will probably require use of azathioprine or 6-MP to maintain remission. Many of these patients are initiated on the azathioprine or 6-MP during their acute hospitalization. This approach facilitates their transition off oral steroids within 2–3 months as the azathioprine/ 6-MP is beginning to achieve its efficacy.51 Those individuals who required intravenous cyclosporine to achieve remission can be changed to oral cyclosporine using twice the intravenous dose.116 However, due to its significant toxicity, oral cyclosporine should be considered a ‘bridge therapy,’ and azathioprine or 6-MP should be initiated concurrently with the eventual goal of discontinuing the cyclosporine at a later date.61,62 Patients on cyclosporine are at risk for Pneumocystis carinii pneumonia and, as stated above, should receive prophylaxis with sulfamethoxazole/trimethoprim three times per week. Patients should be re-evaluated during the first week after discharge from the hospital and should then be seen every 2 weeks during the first few months while adjusting medications (Fig. 57.5).

Fulminant colitis Fulminant or toxic colitis is a medical and surgical emergency. Surgery should not be delayed, and expedited assessments by the emergency room physician, gastroenterologist, and surgeon are required. These patients have severe colitis with significant anemia, fever, abdominal tenderness, and abdominal distention. Very close monitoring is required, and patients may or may not have concomitant colonic dilation.117 The presence of colonic dilation on an abdominal radiograph raises the possibility of toxic megacolon, which may also be associated with cytomegalovirus or C. difficile infection. The use of antidiarrheal medications, hypokalemia, and other electrolyte disturbances can predispose patients to the development of toxic megacolon. Moreover, the use of corticosteroids may mask symptoms and signs of megacolon, and toxic megacolon should also be considered in those patients whose bowel movements suddenly decrease in the setting of increased abdominal distention.

Medical Treatment Strategies

a limited flexible sigmoidoscopy performed to exclude superimposed cytomegalovirus or other infections. These patients often have weight loss, anemia, fever, abdominal pain, and nocturnal and frequent bowel movements (>10/day). Intravenous steroids should be initiated after an initial evaluation to exclude any contraindication to their use. The starting dose is typically 300 mg/day of hydrocortisone, 32–48 mg of methylprednisolone, or 40–60 mg of prednisone, in divided doses or by continuous infusion. There are no data to suggest that continuous or divided dosing confers any benefit over the other, nor are there data to suggest that higher doses of steroids provide any additional benefit. Steroid enemas or foam may also be added topically to treat tenesmus. In these severe cases, 5-ASA therapy adds little or no benefit and can thus be initially deferred and started once patients begin to show evidence of improvement or at the time of hospital discharge. Surgical consultation should be obtained in all patients admitted with a severe attack of UC. Hospitalized patients are often fasted in an attempt to reduce the frequency of bowel movements. However, as the small intestinal mucosa is not involved in UC, oral feeding is recommended whenever possible.110 A low-residue diet may be preferred, but inflammation causes a catabolic state, and caloric supplementation is frequently required. If a patient reports significant nausea, vomiting, or worsening of abdominal pain associated with eating, parenteral nutrition may be considered. While most patients respond to intravenous corticosteroid administration within the first week, approximately 20–30% of patients are unresponsive. Steroid-refractory individuals are unlikely to improve in response to continued steroid administration.111 Therefore, after 5–7 days of intensive therapy with intravenous corticosteroids, options include proceeding with colectomy or adding intravenous cyclosporine. Response rates for intravenous cyclosporine of 70–80% have been reported in steroidrefractory patients after 1 week of therapy.65,112,113 The traditional starting dose is 4 mg/kg/day administered by continuous infusion, although recent data suggest that 2 mg/kg/day may be as effective while reducing side effects.66 Blood levels are monitored to maintain levels between 200 and 400 ng/ml, despite the fact that these levels do not correlate with a clinical response. Patients must be made aware of risks and benefits prior to initiating therapy, and must be carefully monitored for electrolyte disturbances, cholesterol levels, renal dysfunction, and hypertension. Hypertension can be treated by the concomitant use of calcium channel blockers. Patients are likely to respond during the first 5–7 days, and those who do not respond at 7 days are unlikely to attain remission. Under such circumstances, total proctocolectomy should be recommended. Trials of other immunosuppressive medications, such as methotrexate or mycophenolate mofetil, have either demonstrated no effect or are considered experimental at this time.83,114 Maintenance regimen: Individuals with mild pancolitis who respond to aminosalicylates are maintained on the dose used to achieve remission,29 except in those patients responding to induction doses of sulfasalazine. In such cases, the dose can be tapered from 4 to 2 g/day if the patient experiences side effects.40,102 For 5-ASA compounds, long-term monitoring is required, including periodic testing of renal function, blood counts, and liver enzymes. In more moderate pancolitis cases, in which oral corticosteroids are required to achieve remission, it may be more difficult to maintain remission. During the tapering of the steroid dose, it

Ulcerative Colitis

812 Assess overall disease severity:

Mild < 4 BMs, ± bleeding Normal ESR No toxicity

Moderate 4–6 BMs Bleeding, elevated ESR Minimal toxicity

Severe >6 BMs Anemia, tachycardia elevated ESR, fever

Fulminant: Toxic megacolon severe anemia, abdominal tenderness pneumatosis, perforation

Oral 5-ASA ± 5-ASA enema

Oral 5-ASA ± oral steroids ± 5-ASA enema

Admit to hospital i.v. steroids for one week trial

Admit to hospital Consider 24–48 h course of medical therapy or surgery

Response: Taper and discontinue steroids Maintain with 5-ASA

No response: Add AZA/6MP Consider i.v. steroids

Response: Taper and discontinue steroids Maintain with AZA/6-MP

Fig. 57.5

Response: Taper and discontinue oral steroids. Begin oral 5-ASA Begin AZA/6-MP

No response: i.v. steroids followed by i.v. cyclosporine (if no response to one week of steroids)

No response: i.v. cyclosporine

Response: Switch to oral cyclosporine + TMP/SX. Maintain with AZA/6-MP Taper and discontinue steroids

No response: Surgery Consider experimental protocol

• A suggested approach to the management of pan ulcerative colitis.

Radiographs may show distention (>6 cm) and/or bowel wall edema (‘thumbprinting’) in fulminant colitis, and in some cases, pneumatosis may be present. Computerized tomographic scanning is more sensitive than plain X-ray films for identifying free air, pneumatosis, or edema. The medical aspect to the management of toxic megacolon requires the recognition of the severity of the illness and supportive care. A short trial of intravenous corticosteroids can be administered in some cases, and complete bowel rest with nothing given orally is mandatory. Antibiotics are empirically used as transmural extension is assumed, and the risk of bacterial septicemia and/or bacterial peritonitis is high. Clearly, intensive care monitoring, and administration of crystalloid, colloid, or blood products are given as needed. Emergency surgery is necessary in those individuals with evidence of perforation, as well as in those who fail to improve rapidly or who deteriorate clinically. Morbidity is greater in those patients who develop colonic perforation; thus, close monitoring with serial radiographs, laboratory testing, and physical examinations should help guide the decision to initiate surgical therapy.

Pregnancy/fertility issues Infertility in UC is primarily due to male oligospermia that occurs with the use of sulfasalazine. Oligospermia will resolve within 3 months after discontinuing sulfasalazine in favor of a newer 5-ASA agent. Women with UC have normal fertility unless they have undergone proctocolectomy and ileal pouch-anal anastomosis (IPAA).118 Pregnancy in the setting of UC has been studied extensively (see Ch. 10), and both the impact of inflammatory bowel disease on pregnancy and the effect of the pregnancy on inflammatory bowel disease have been evaluated. In more active disease states,

there is a significant increase in the number of spontaneous abortions, premature and low-birth weight infants. The effect of pregnancy on UC disease activity itself does not appear to be significant, with both exacerbations and remissions noted that might be related to the natural history of the disease. Therefore, the goal of medical therapy is to maintain remission or reduce the level of disease activity, before and during the pregnancy.119 The safety of medications used to treat UC during pregnancy has been extensively studied. A recent review of 207 conceptions at an inflammatory bowel disease (IBD) referral center reported no significant effects in patients taking any of the commonly used IBD medications.120 Most of these drugs are well tolerated during pregnancy, including the 5-ASA compounds and corticosteroids. A prospective evaluation and a case-report study of mesalamine use in UC indicated no significant increase in reported congenital abnormalities.121,122 Another review of 5-ASA use within a Scandinavian birth registry likewise found no increased risk of congenital malformations.123 The immunosuppressive medications azathioprine and 6-MP have been categorized as unsafe during pregnancy. However, recent data have found no increased risk to the fetus. Rather, the greater risk appears to be associated with an increase in disease activity during pregnancy.124,125 Although cyclosporine appears safe to use, it is generally used only during active disease and patients should be changed to another immunomodulator agent once remission has been achieved. If required to assist in diagnosis and management, sigmoidoscopy can be performed safely in the pregnant patient. Occasionally, surgery is also required to treat fulminant colitis, and should not be avoided if clinically necessary for the safety of the mother. In those patients with an ileal pouch-anal anastomosis, fertility is decreased and the timing of surgery and plans for a family need to be considered.126

813

SURGERY The most common indications for colectomy are medically intractable disease, complications of colitis, including dysplasia or cancer, and side effects of medical therapy. In the case of the critically ill toxic colitis patient, urgent surgery is required. Otherwise, a short trial of intravenous corticosteroids is warranted to try to prevent the need for emergency surgery, but lack of improvement during the initial 24–72 hours is generally indicative of a poor prognosis and the need for surgery. Toxic megacolon also requires surgery in most cases and can be viewed as a complication of the extensive disease process. In the acute setting, proctocolectomy or subtotal colectomy is performed with an end-ileostomy. At a later time, an ileal pouchanal anastomosis (IPAA) can be performed in appropriate candidates. The IPAA operation is more technically demanding than a total proctocolectomy and ileostomy, and both immediate and long-term complications are associated with this procedure. Nonetheless, this operation achieves the highest patient satisfaction rate, as it allows for construction of an ileal reservoir for stool and defecation through an intact anal sphincter. A major indication for total proctocolectomy is the association of UC with colonic neoplasia. The prevalence of colonic adenocarcinoma in subjects with UC increases at a rate of about 1% per year after 8–10 years of disease. Thus, 30 years after the onset of UC, the risk of developing cancer is approximately 20%. Risk factors for an increased risk of colonic neoplasia include the extent and duration of disease, concomitant primary sclerosing cholangitis, a family history of colorectal cancer, and as the severity of disease.127,128 In patients with pancolitis, annual

surveillance colonoscopy is recommended after the seventh year of disease, with random biopsies taken at 10 cm intervals, as well as biopsies of any abnormal-appearing mucosa. Indications for proctocolectomy include either flat high-grade or low-grade dysplasia confirmed by an expert pathologist. Recent data support the conservative treatment of polypoid dysplastic lesions that are completely removed and without associated flat dysplasia elsewhere in the colon.129 Because of the increased risk of colon cancer development in patients with long-standing disease, some individuals may opt for elective surgery given a clear understanding of the risk/benefit ratio. Colectomy represents a ‘cure’ for UC, and for many individuals a reduction in the use of medication and an improvement in quality of life provide the rationale to consider this option. Nonetheless, because of problems associated with IPAA, every effort must be extended to maximize medical therapy before proceeding with surgery.

Pouchitis As many as 25% of UC patients will require a colectomy during the course of their illness, and the majority of those having surgery will undergo an IPAA procedure rather than an ileostomy. Inflammation of the pouch (pouchitis) is a well-recognized complication after IPAA.130 In a large series from the Mayo Clinic, 40% of patients had a single episode of pouchitis, while 15% and 5% experienced intermittent episodes and chronic pouchitis, respectively.131 Symptoms of pouchitis include increased stool frequency, pelvic and abdominal pain, rectal bleeding, tenesmus, fecal incontinence, and fever. Symptoms alone should not be used to make a diagnosis of pouchitis.132 The differential diagnosis of pouchitis includes the irritable pouch, ‘cuffitis,’ Crohn’s disease, and anatomical problems with the pouch, including strictures. The evaluation of the symptomatic pouch requires endoscopy, including assessment of the prepouch ileum, and biopsy.133

Pouchoscopy Rule-out other causes for symptoms e.g. Crohn’s disease, infection, irritable pouch, cuffitis, stricture

Metronidazole (20 mg/kg/day) or Ciprofloxacin (1000 mg/day) for 7–10 days

Response: Monitor for recurrence

Asymptomatic

No response: Trial of another antibiotic

Recurrence Repeat course of antibiotics Consider trial of probiotics to prevent relapse

No response: Trial of other therapies (probiotics, steroid enemas, oral budesonide immunomodulators, experimental protocol)

Response: Monitor for recurrence

Fig. 57.6

• A suggested approach to the management of pouchitis.

No response: Consider surgery

Surgery

In conclusion, both planning for and the management of pregnancy in UC should be a coordinated exercise among the patient, the obstetrician, and the gastroenterologist.

Ulcerative Colitis

814 The treatment of pouchitis involves the use of antibiotics. Metronidazole (20 mg/kg/day) and ciprofloxacin (1000 mg/day) are both effective, with the latter showing benefit over the former in one clinical trial.134 Other treatments have included budesonide enemas135 and probiotics, either to prevent relapses in patients with chronic pouchitis136 or to prevent the first episode of pouchitis in patients after IPAA (Fig. 57.6).137

SUMMARY The medical management of ulcerative colitis has not changed significantly in recent years. The biggest advance has been the development of the new generation aminosalicylates that allow for increased dosing with fewer side effects compared with sulfasalazine. There has also been a shift towards the earlier use of immunomodulators as maintenance therapy. Improvements in surgical techniques have led to this option being exercised more frequently in clinically indicated settings. Overall, the management of patients with ulcerative colitis requires an understanding of the disease process as well as a ‘team’ effort consisting of experienced gastroenterologists, nutritionists, radiologists, surgeons, and pathologists. Treatment algorithms must consider the extent of colonic involvement (Figs 57.3, 57.4, 57.5). It is anticipated that new biologic agents will be added to the treatment armamentarium during the next several years as scientists continue to unravel the pathobiology of this disorder.

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CHAPTER FIFTY-EIGHT

58

Intestinal obstruction Sareh Parangi and Richard Hodin

MECHANICAL OBSTRUCTION OF THE INTESTINE Introduction Definitions: Intestinal obstruction is one of the most common disorders seen by both gastroenterologists and surgeons, and a thorough knowledge of this disorder is important for virtually all physicians. This chapter will review the definition of mechanical obstruction of the intestine, the clinical presentations, the proper evaluation of the patient, and the therapeutic considerations. Obstruction of the intestine occurs when there is impairment in the normal flow of luminal contents due to an extrinsic or intrinsic encroachment on the intestinal lumen. A complete obstruction is present if there is no passage of intestinal contents beyond the point of obstruction, whereas a partial obstruction means some passage of intraluminal contents is occurring distal to the obstruction. An obstruction is described as a simple obstruction if only one point of obstruction is seen, whereas in a closed-loop obstruction two sites of luminal obstruction exist. Strangulated obstruction occurs when the blood flow to the intestine is compromised causing ischemic necrosis of the gut. This is often seen with closed-loop obstructions but can also be present with simple complete obstructions, especially as a late event. Intestinal pseudo-obstruction is used to describe a functional obstruction with no mechanical or anatomic cause, such as Ogilvie’s syndrome in which colonic pseudo-obstruction is present. Adynamic ileus refers to impaired passage of luminal contents due to disordered or absent motility. Both pseudo-obstruction and ileus can mimic a mechanical obstruction. Adynamic ileus usually leads to distended loops of small and large bowel, but vascular compromise of the intestine almost never occurs. The key to the management of patients with small intestinal obstruction is early diagnosis so that proper therapy can be instituted. Identification of those patients with strangulation is of critical importance since prompt surgical correction is needed in order to minimize morbidity and mortality. Numerous clinical and radiological criteria can be helpful in distinguishing simple from strangulating obstruction, but this differentiation remains a challenge to even the most experienced clinicians (Fig 58.1). Etiology: Hippocrates describes the entity of small bowel obstruction and early treatment included observation, reduction of hernias when applicable, narcotics for pain, and even the use of mercury or lead ingestion to ‘open’ areas of occluded small

intestine. Praxagoras in 350 BC performed the first operative intervention for a small bowel obstruction by creating an enterocutaneous fistula to relieve the obstruction.1 In 1912, Hartwell and Hoguet first described the aggressive use of normal saline administration to prolong the life of animals with mechanical obstruction, and to this day fluid resuscitation remains a cornerstone of treatment in every patient with intestinal obstruction.2 Common causes of intestinal obstruction include adhesive bands, hernias, malignant neoplasms (most commonly colonic or ovarian), inflammatory bowel disease, ischemic strictures, diverticulitis, radiation-related strictures, intussusception, gallstones, bezoars, as well as foreign bodies. Small intestinal obstruction has a variety of etiologies that differ markedly as a function of age (Table 58.1). For example, in the neonate, congenital anomalies such as atresia, malrotation of the midgut with volvulus, duodenal atresia, and imperforate anus are common causes of obstruction, whereas infants are more likely to have strangulated hernias or intussusception. Over 90% of pediatric intussusceptions are idiopathic with no lead-point cause and most present before the first year of age. Males are more likely to be affected. Meconium ileus also accounts for over 30% of all neonatal small bowel obstructions and can be seen in 7–25% of neonates with cystic fibrosis In contrast, small intestinal obstruction in adults is primarily due to either adhesive bands or groin hernias, whereas large bowel obstruction occurs in the settings of diverticulitis, cancer, or volvulus. Although strangulated hernias were the most common cause of small bowel obstruction in the past, more recent series indicate that adhesive bands are now far more likely to be the etiology. In 1900, Gibson reviewed the reports of 1000 patients with intestinal obstruction and found that 35% were on the basis of strangulated hernias, whereas only about 19% were caused by bands.3 Similarly, Vick reviewed 6892 patients from Great Britain with acute obstruction between 1925 and 1930 and found that approximately 50% were due to strangulated hernias, whereas adhesions accounted for only 7% of the cases.4 The increase in elective inguinal hernia repairs coupled with an increase in the number of laparotomies performed in recent decades likely account for a change in etiology of obstruction over time. In 1955, Wangensteen reviewed 1252 cases of obstruction and found only 10% to be due to hernias, compared with 37% due to adhesions.5 Certain surgical procedures appear more likely to cause a future obstruction due to an adhesive band or matted intestine. Prior colorectal procedures account for one-third of all

Intestinal Obstruction

820

Obtain clinical history: Nature of pain Last flatus/bowel movement Onset of abdominal distention Nausia or vomiting Fever/chill History of previous abdominal operations, IBD, malignancy, radiation, or gallstones

Physical examination: Vital signs, hydration status/ fever/shock Abdominal examination Peritonitis, involuntary guarding, level of distention Note scars/hernias/ascites

Obtain laboratory testing: WBC Electrolytes Consider liver function tests, arterial blood gas

Radiologic testing: Plain radiographs of abdomen/CXR CT scanning with contrast Free air/pneumatosis/portal venous air Degree of small bowel dilation/air fluid levels Presence of colonic air or colonic dilation Transition point/hernias/tumors/ abscess/inflammation Consider enteroclysis/angiography

Fig. 58.1

Initiate resuscitation Fluids/nasogastric decompression/NPO Monitor urine output

Q. Does patient need urgent operation? Shock/involuntary guarding/peritonitis Yes Free air/portal venous air/pneumatosis Massive intestinal distention Severe leukocytosis or acidosis

Operative intervention Preoperative antibiotics Surgical exploration Intestinal resection if needed

No Differentiate between clinical scenarios: SBO vs Ileus SBO vs colonic obstruction Simple SBO vs strangulating SBO Trial of non-operative management Continued hydration, NG suctioning, monitoring urine output Repeated physical examination

Obstruction resolves with non-operative management

Suspected strangulated or closed loop obstruction Obstruction does not resolve and requires operative management Obstruction resolves with non-operative management BUT there is no explanation for obstruction Consider work up with CT scan or SBFT looking for structural lesion causing obstruction prior to surgery

• Algorithm for evaluating the patient with bowel obstruction.

patients who later present with small bowel obstruction.6 In fact, the risk of an adhesion related small bowel obstruction appears to be around 10% within 1 year of colorectal surgery, and can increase to approximately 30% at 10 years.7 Other previous operations that are the causative agent of future obstructions are: gynecologic procedures (22%), appendectomy (14%), and hernia repair (10%).8 Cholecystectomy and foregut surgery appear to be

responsible only for a minority of subsequent small bowel obstructions. Positive trauma laparotomies, especially those from penetrating injuries or those with gross spillage of intestinal contents, also appear to be at high risk for future intestinal obstruction. Of patients diagnosed with an initial presentation of adhesion-related bowel obstruction, 5% present within the first month of the operation, 23% between the first month and the

Table 58.1 Common causes of mechanical bowel obstruction as a function of age Neonate

Infant

Young adult

Middle age/elderly

Atresia

Inguinal hernia

Adhesions

Adhesions

Midgut volvulus

Intussusception

Groin hernia

Groin hernia

Meconium ileus

Meckel’s diverticulum

Imperforate anus

Colon cancer Diverticulitis Sigmoid volvulus

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Clinical history and presentation The diagnosis of intestinal obstruction is usually made on clinical grounds with the symptoms of crampy abdominal pain, decreased or absent flatus and stool, nausea and/or vomiting, and signs of abdominal distention on exam. A thorough history should be taken, including the onset and the duration of the current episode of abdominal pain, the last known time flatus and/or stool was passed, when vomiting started, when abdominal distention was noted, the presence of fever or chills, and whether the patient has had similar episodes in the past. The past history should be noted for previous abdominal operations, previous obstructive episodes, inflammatory bowel disease, known gallstone or diverticular disease, known hernias, previous abdominal malignancies, or a history of abdominal irradiation. A history of recent travel or ingestion of a foreign body should be also sought. A prior history of small bowel obstruction is particularly important since

patients with mechanical small bowel obstruction due to adhesions often will experience recurrences of the problem. The pain described in 85–90% of patients is vague, colicky, and poorly localized; and is due to visceral distention of the intestine as it contracts against a mechanical obstruction. Partial obstructions can lead to intermittent crampy pain, especially soon after meals, but with complete obstruction the crampy pain tends to be more severe. Nausea and vomiting are common features of small bowel obstruction. Reflex vomiting is common and in cases of early or distal obstructions the volume of the vomitus will be quite small, since it takes some time for intestinal contents to back up to the stomach. The vomitus often contains occult blood and appears as ‘coffee grounds’ in color, probably due to distention of the stomach with resultant mucosal hemorrhage. Evaluation of such patients for gastrointestinal bleeding will not be fruitful and will delay the diagnosis and treatment of the true problem of the mechanical obstruction. The level of the obstruction is often suggested based upon the pattern of the pain, since proximal small bowel obstruction usually causes more frequent cramps, perhaps every 3–5 minutes, whereas more distal small bowel and large bowel obstructions cause less severe cramps with longer durations between episodes. Constant pain, especially if localized, or a history of fever, chills, rigors, or worsening mental status often suggests ischemia and infarction, and patients with these findings in their history should be taken for urgent laparotomy to avoid the mortality that can be as high as 30%.

Physical examination The patient will often display signs of dehydration with dry mouth and loss of skin turgor. Vomitus can be malodorous and feculent, especially after a few hours of a complete obstruction given overgrowth of both anaerobic and Gram-negative bacteria.11 The waves of abdominal pain, or colic, can actually be witnessed at the bedside and provide the strongest possible indication of a mechanically obstructed intestine. Occasionally, audible bowels sounds, or borborygmi, are present as a result of strong intestinal muscular contractions. Bowel sounds can be hyperactive during the initial phases of the obstruction, whereas later on the bowel becomes more dilated and bowel sounds can be diminished or even absent. Inspection of the abdomen will usually reveal distention, although the magnitude of distention will be greater with more distal and/or long-standing obstructions. Patients with large bowel obstruction will be especially distended on physical examination due to the large capacity of the colon, whereas proximal jejunal obstruction is generally associated with minimal distention. The presence of surgical scars should be noted, indicating the possibility of intra-abdominal adhesions as the etiology. The abdomen should be carefully and gently palpated from the costal margins to the groins. Any ascites or hepatomegaly should be noted since these can be signs of a malignancy. An abdominal wall hernia might also be evident as the site of the obstruction and common sites of herniation, such as the inguinal and femoral canals, and umbilicus should be palpated carefully since even moderate obesity coupled with distention can make the examination difficult. When hernia contents are soft and easily reducible in the obstructed patient, it is likely that an etiology other than the hernia exists. Any pre-existing hernia will tend to protrude in a patient who develops a bowel obstruction (Fig. 58.2). Tenderness, erythema, or induration in the abdominal wall at the site of a hernia usually indicates ischemia in an incarcerated loop of

Mechanical Obstruction of the Intestine

first year, and approximately 11–12% between the first and fifth year, 11% between the fifth and tenth years, and 12% between the tenth and twentieth year. Fourteen percent of patients present with a bowel obstruction more than 20 years after the initial abdominal operation. The etiology for obstruction also differs geographically, such that large and even small bowel volvulus is relatively common in certain African countries, and less developed countries generally have higher incidences of strangulated hernias.9 Pathophysiology of obstruction: In the setting of obstruction, the normal absorptive mechanisms of the small bowel are deranged, such that excess fluid losses occur. Initially, there is vomitus, bowel wall edema, and transudative loss into the peritoneal cavity, but during the late stages of obstruction, venous pressure increases with resultant hemorrhage into the lumen, worsening the problem with hypovolemia. Both small bowel and colonic obstruction result in marked changes in motility, with increased contractions in segments proximal to the obstruction, and decreased motility in segments distal to the obstruction.10 Swallowed gas and increased intraluminal fluid contents due to both decreased absorptive capacity of the intestine and increased secretion result in increased intraluminal pressure. Increased intraluminal pressure in late complete obstruction or closed-loop obstructions can lead to ischemic necrosis of the mucosa due to its high metabolic needs. Ischemia of the intestine initially leads to a loss in the protective barrier function of the mucosa, but over time there can be necrosis of all layers of the intestinal wall with resultant perforation. In some cases there is a direct compromise to the circulation of the segment of intestine, such as with compression of vessels through a tight hernial ring. The normal relatively sterile environment of the proximal small intestine is altered under obstructed conditions such that bacterial overgrowth occurs, most notably involving the anaerobes such as Bacteroides.11 The feculant vomiting seen in cases of longstanding distal small bowel obstruction is due to this bacterial overgrowth and is virtually pathognomonic for a high-grade or complete distal mechanical small bowel obstruction. The importance of bacterial overgrowth in the morbidity and mortality of intestinal obstruction has been demonstrated in experimental animals, e.g., germ-free dogs survive intestinal strangulation better than controls.12 As such, antibiotics may be of benefit in the setting of strangulation, although there is probably no role for antibiotics in patients with simple mechanical bowel obstruction.

822 Intestinal Obstruction

•

Fig. 58.2 A distended abdomen is seen in this patient with small bowel obstruction. Patients should be examined carefully to look for incarcerated hernias.An incarcerated umbilical hernia is seen with characteristic changes in skin color (black arrow). A subxiphoid hernia is also more prominent (black arrowhead), given the massive abdominal distention.

bowel but can also denote active inflammatory bowel disease. Although mild, diffuse tenderness is a common feature in patients with distention from a mechanical obstruction, involuntary guarding or other signs of peritoneal irritation are unusual and suggest the possibility of ischemia or infarction of the bowel, perhaps even with perforation. Rectal examination is important in order to detect mass lesions and to check for the presence of stool that is usually absent in cases of mechanical bowel obstruction, especially of long-standing nature. It is important to remember that while the majority of patients are able to provide a thorough history that will aid in establishing a rapid diagnosis, some patients are unable to provide a good history, especially elderly patients who present in a delayed fashion with significant dehydration, tachycardia, oliguria, azotemia, hemoconcentration, increased abdominal compartment pressures, and even shock. The use of repeated physical examinations are essential to detect any changes such as fever, hypotension, or peritoneal signs, findings that should alert the physician to the need for rapid intervention.

late in the course of the obstruction.13 In partial obstructions or early complete obstructions blood testing is usually normal. Routine blood counts will reveal an elevated hematocrit indicative of intravascular volume depletion. Leukocytosis is sometimes present, but is often the result of hemoconcentration and an acute stress response, rather than actual underlying infection. A markedly elevated white blood cell count (>18 000) should raise the suspicion for strangulation; however, it must be kept in mind that one-third of patients with strangulated small bowel obstructions have white blood cell counts between 10 000 and 14 000. The blood chemistries may reveal elevated blood urea nitrogen and creatinine, indicating hypovolemia with prerenal azotemia. In cases of suspected strangulation and vascular compromise, arterial blood gas measurements are used to evaluate for acidosis. Hyperkalemia can also be a sign of bowel necrosis. Mild elevations in serum levels of pancreatic enzymes such as amylase can be a sign of intestinal perforation or pancreatitis, although these may also be seen with simple obstructions.

Laboratory tests

Radiologic evaluation

Laboratory tests are not very helpful in the diagnosis and/or management of patients with bowel obstruction, with most abnormalities being neither sensitive nor specific and often developing

In bowel obstruction radiologic imaging is used for several purposes: to confirm the diagnosis, to help distinguish between simple and strangulating obstructions, to differentiate the various

823

A

will allow delineation of both air-fluid levels and free air against the liver. Small bowel loops can be distinguished from colonic loops as the markings of the valvulae conniventes stretch across the entire lumen of the small bowel. Twenty-one percent of patients with suspected small bowel obstruction are in fact obstructed. Overall, the sensitivity and specificity of plain X-rays of the abdomen in obstruction is approximately 65% and 57%, respectively (Fig. 58.3A).14 Of those patients with non-specific abdominal radiographs, 9% have high-grade obstruction (Fig. 58.4A).15,16 Small bowel obstruction will lead to dilation of the

B

C

Dilated loops of small bowel

Collapsed loops of small bowel

•

Fig. 58.3 Radiologic imaging in a patient with small bowel obstruction in the distal ileum due to an adhesion. (A) Plain radiographs demonstrate distended loops of small intestine, and no air in the colon. (B) Reformatted coronal CT images reveal distended loops of small bowel in the right abdomen (black arrows) with bowel wall edema, and mesenteric swirling and edema (white arrow). (C) Standard axial CT images reveal distended loops of small bowel in the right abdomen and collapsed loops of small bowel with no contrast in the left abdomen.

A

B Proximal obstruction

Massive gastric distention

•

Radiologic imaging in a patient with proximal small bowel obstruction and massive gastric distention due to a postoperative adhesion. Fig. 58.4 (A) Plain radiographs can be deceivingly non-specific in proximal obstruction, revealing only a few air-fluid levels in the right upper quadrant (white arrows). (B) Reformatted coronal CT images show a very proximal obstruction (black arrow) with massive gastric distention (white arrow), and edema of the small bowel mesentery.


causes of obstruction, to differentiate small and large bowel obstruction, to estimate the degree of obstruction, and to help exclude paralytic ileus. An upright chest radiograph might show free air under the diaphragm, pneumonia, or demonstrate compromised cardiopulmonary status. Plain radiography of the abdomen continues to be used since it is readily available, quick, and is quite sensitive for high-grade or complete obstructions, particularly in cases of a distal obstruction. Supine and upright radiographs should be obtained, but if an upright cannot be obtained then a left lateral decubitus film with the right side up


824 small bowel with air-fluid levels and a stepladder appearance on an upright film. Although differential air-fluid levels, i.e., air-fluid levels at different heights in the same loop of bowel, have been considered an important finding suggestive of a mechanical obstruction, Harlow et al.17 found this sign to be very insensitive, since it was present in only 52% of patients with proven mechanical obstruction. In addition, 29% of patients with adynamic ileus had this finding on plain radiographs. In small bowel obstruction of long-standing nature, perhaps greater than 24 hours, all of the air and stool from the colon will have been evacuated and this will be evident on plain abdominal films. However, if the obstruction is in its early phase, or if it is only partial, then some air and stool will be present within the colon, making distinction between an early complete and a partial small bowel obstruction very difficult. In adynamic ileus there are dilated loops of small bowel as well as colon, with overall less dilation of the small intestine compared to the colon. Sentinel loops of moderately dilated small bowel with impaired motility can be seen adjacent to areas of acute inflammation such as is seen in acute pancreatitis. In cases of acute colonic obstruction (especially with a competent ileocecal valve which does not allow any backward decompression into the distal ileum) the entire colon up to point of obstruction may be massively dilated with haustrae seen as incomplete indentations in the colonic wall. The dilation is often worse in the cecum due to Laplace’s law that dictates that the wall tension will be greatest in the area with the largest radius. In advanced cases of strangulation, edematous small bowel can take on a thumbprinted appearance, and air may be seen in the wall of the intestine, portal venous system, or free in the abdominal cavity. Any of these findings on a plain upright X-ray almost always indicates the need for urgent operation. Abdominal CT scans with intravenous contrast are employed increasingly to evaluate patients with suspected bowel obstruction in whom the plain radiograph alone does not provide a full answer. The CT scan can provide useful information, clearly identifying the dilated proximal and collapsed distal bowel, a feature that is aided by the administration of an oral contrast agent.18 CT scan of the abdomen usually enables one to confirm the diagnosis of bowel obstruction, often demonstrates its cause, and helps differentiate between small and large bowel obstruction. This modality may be especially helpful in identifying closed-loop obstruction before the onset of strangulation.19 Bowel obstruction is considered to be present when distended loops of bowel are seen proximal to collapsed loops. When a point of transition from dilated to normal bowel caliber is seen without apparent cause, adhesions are the presumed cause (see Fig. 58.3). Frager et al.20 compared standard clinical evaluation, including plain radiographs, with CT scans in 90 cases of suspected small bowel obstruction. The correct diagnosis of complete obstruction was made in only 46% of patients by clinical, plain radiographic findings, whereas CT scan was found to be 100% sensitive in these cases (see Fig. 58.4). CT scan was also superior in cases of partial small bowel obstruction. However, false-positive CT scans were obtained in six cases, suggesting that the CT scan criteria for small bowel obstruction may have been too broad. Based upon these and other series in the literature,15,16 CT scan has replaced the contrast small bowel follow-through in many centers as the primary radiologic tool in cases of suspected mechanical small bowel obstruction. In general, CT scans appear to be better at distinguishing closed-loop obstructions and strangulation and appear to be helpful in

demonstrating causative agents such as hernias, tumors, abscesses, and inflammatory diseases (Fig. 58.5). There are similar advantages of CT scan in cases of large bowel obstruction, where tumor masses and pericolic inflammatory changes can be identified. Angiography may be helpful in cases of suspected mesenteric ischemia, especially if the findings on CT angiography are inconclusive or if a therapeutic angiographic intervention is planned. Enteroclysis is performed by instilling a dilute barium contrast material directly past the pylorus using a small tube and allows for enhanced visualization of the lumen of the obstructed bowel. The frequent intermittent fluoroscopic monitoring during an enteroclysis study along with the volume challenge instilled into the small bowel can be helpful in delineating the cause and location of small bowel obstruction preoperatively, especially in those with low-grade or intermittent obstructions. This modality may also be helpful in ruling out obstruction if the results of other radiologic studies are indeterminate. The drawbacks of enteroclysis include the inability to obtain subsequent CT imaging due to the retained barium, the risk of inspissation and impaction of barium, the operator dependent nature of the procedure, and the inability to examine structures outside the lumen of the bowel. To overcome some of the limitations associated with enteroclysis, CT enteroclysis is now being employed in some centers. This examination involves the infusion of water-soluble contrast material through a nasointestinal tube followed by CT imaging after moderate distention of the small intestine. Interpretation of the CT images allows for a higher reliability given the presence of volume-challenged intestine displayed with cross-sectional imaging. In addition, CT enteroclysis images may be easier to interpret because of the ability to demonstrate bowel loops that may have been superimposed on conventional imaging.21 Abdominal ultrasound has been previously touted as a useful test in patients with suspected small bowel obstruction. Ultrasound can detect fluid-filled, dilated small bowel proximal to collapsed bowel and also the presence of peristaltic activity. Ko et al.22 compared ultrasound with plain radiographs retrospectively in 54 patients with surgically proven obstruction and found that ultrasound was diagnostic in 89% of the cases, compared with 71% by plain X-rays. These authors also found ultrasound to be more accurate than plain films in determining the level and cause of the obstruction. Ogata et al.23 studied 50 patients with suspected bowel obstruction and found ultrasound to be highly accurate with a sensitivity of 88% and a specificity of 96%. Plain radiographs were very sensitive in this study (96%), but the specificity was only 65%. Ultrasonic evaluation is extremely operator dependent, limiting its value to those who have expertise readily available.

Therapy All the clinical decision-making skills of the experienced surgeon must come into play in order to make the correct therapeutic decisions when evaluating the patient with bowel obstruction (see Fig. 58.1). Decisions fall into broad categories: (1) determining the extent of fluid resuscitation, initiating nasogastric decompression, and monitoring urinary flow rates; (2) differentiating between the clinical scenarios of adynamic ileus, small bowel, and colonic obstruction based on the clinical and radiologic data; (3) differentiating simple from strangulating obstructions; (4) determining which patients will need an urgent operation after

825

Femoral Hernia

C

•

B Obturator hernia

Fig. 58.5 CT imaging often delineates the cause for mechanical obstructions. (A) Axial CT images reveal a femoral hernia with a loop of incarcerated small intestine (white arrow). Note the femoral hernia is medial to the femoral vessels (white arrowhead). (B) Obturator hernias are very difficult to distinguish on physical examination; in this standard axial CT image herniated small bowel is seen deep to the femoral vessels in the obturator canal (arrow). (C) Reformatted coronal CT images help confirm that small bowel is protruding through the obturator canal into the obturator fossa (arrows).

Coronal CT images of Obturator hernia

fluid and electrolyte resuscitation; and (5) determining which patients can be safely managed with nonoperative treatment and repeat examinations.

Fluid resuscitation and intestinal decompression Fluid resuscitation and correction of acid base and electrolyte imbalances are among the most important interventions done for both patients with obstruction and ileus, and treatment should not be delayed by radiologic imaging. A balanced salt solution or lactated ringers can be used, with potassium supplementation as needed to correct deficits. Adequate fluid replacement will often correct any acid base imbalances and use of intravenous bicarbonate is rarely needed. Continued fluid losses caused by vomiting and nasogastric suctioning should be taken into account. Urinary catheterization will allow close monitoring of urine output as a measure of the adequacy of the fluid replacement. Occasionally, a Swan-Ganz catheter is needed for close monitoring, especially in those with congestive heart failure, marginal pulmonary status, or renal failure. A nasogastric tube should be used to decompress the stomach in most patients with adynamic ileus and all patients with

obstruction, and the patient should not be fed solids or liquids by mouth. This decompression allows for reduced gastric distention, lessens the nausea and vomiting, increases patient comfort, and may reduce the risk of aspiration. The use of long intestinal tubes such as the Cantor or Miller-Abbott tubes is rarely indicated and it is fairly clear from the literature that they add little to the decompression provided by standard nasogastric suctioning.24,25

Differentiating adynamic ileus from bowel obstruction In adynamic ileus, there is usually gas present in both the small bowel and colon, usually with most of the gas seen in the colon. Patients with adynamic ileus usually appear less ill, may be less tender on physical exam, and radiologic studies show gas in the colon as well as the small bowel. The underlying cause of the adynamic ileus is often obvious (recent operation, narcotic use, pain, electrolyte imbalances) but can sometimes be difficult to elucidate. Treatment of the underlying cause for the ileus usually leads to its resolution as both colonic and small bowel motor function returns to normal. Early partial small obstructions can be quite difficult to differentiate from adynamic ileus, and the overall clinical picture and repeated physical examinations and


A


826 radiologic evaluations are often necessary to differentiate between these two entities. In partial small bowel obstructions operative treatment is rarely indicated prior to a trial of nonoperative management. If the patient continues to pass flatus and no worrisome signs develop on repeat examinations, most patients will respond to nonoperative treatment and exploratory laparotomy can be avoided. It is important to note that when patients with no known etiology for a mechanical obstruction (i.e., they have had no previous abdominal operations and have no hernias) present with partial or complete obstructions, these patients need to be explored if no cause for their obstruction is found, since they could have a small bowel tumor or other intra-abdominal malignancy which can be difficult to diagnose with current technology. Colonic pseudoobstruction (Ogilvie’s syndrome) will result in isolated and often massive colonic dilatation. As in adynamic ileus, the treatment is directed to management of the underlying cause with correction of electrolyte imbalances, mobilization, and withdrawal of drugs such as psychiatric medications and opioids. Both the rapidity of the gaseous distention and the ultimate size of the colon must be taken into consideration in order to avoid a colonic perforation that can be devastating. A cecal diameter of greater than 12 cm, especially if rapidly expanding, should be treated aggressively with colonoscopic deflation and placement of a decompressing catheter or with surgical intervention via an ileostomy or cecostomy.26 Intravenous administration of the cholinergic agonist neostigmine has been used successfully to aid in colonic decompression in cases of colonic pseudo-obstruction. Cardiac monitoring is necessary when neostigmine is used and in some patients the medication is contraindicated.27

Differentiating small from large bowel obstruction Among the most important distinctions in the patient with a mechanical bowel obstruction is whether the site is within the small or large intestine. This difference is usually evident on plain radiographs, since the characteristic features of dilated colon will not be present in patients with small bowel obstruction. The differentiation between small and large bowel obstruction is critical in regard to both underlying etiologies (see Table 58.1) and clinical management. Regardless of the cause, if nonoperative treatment fails, surgical exploration in a patient with mechanical small bowel obstruction will usually allow for adequate and complete treatment, without the need for stoma formation or subsequent surgical intervention. In the case of colonic obstruction, the timing and nature of the surgical intervention can be more complex, and in some cases stoma creation may be needed.

Differentiating simple from strangulating obstruction The most important issue to be addressed in patients with mechanical small bowel obstruction is whether or not strangulation exists. Series which have compared mortality figures for simple versus strangulating obstruction have clearly demonstrated the importance of early recognition and treatment, since mortality for strangulated cases is generally 2–10 times higher than that for simple obstruction.9 In those patients with strangulating groin hernias, the signs on physical exam are usually clear and include a firm, tender mass, perhaps with overlying erythema of the skin. In such situations, prompt surgical repair usually with bowel resection is mandatory. However, in those patients with obstruction on the basis of intra-abdominal pathology, the

identification of strangulation may be extremely difficult. One of the most common mechanisms for strangulating small bowel obstruction is the closed loop which is usually due to adhesions and results in a twisting of a segment of intestine. The closed loop is a segment of small bowel occluded at two points along its course by a single constrictive lesion, often occluding both the small bowel and the mesentery. Patients with closed-loop obstruction usually have severe pain early, and the fluid-filled loops of bowel are often not seen on plain abdominal radiographs. It is with this particular group of patients that the experienced clinician is called upon to make a rapid and accurate diagnosis so that surgical intervention might prevent the sequelae of infarction and perforation with resultant peritonitis. The differentiation between simple and strangulating obstruction has been the subject of numerous studies designed to identify one or more key signs or symptoms that could reliably predict the presence of strangulation. Silen et al.28 reviewed the case histories of 480 patients with mechanical small bowel obstruction due to causes other than external hernias or mesenteric vascular occlusion. Unfortunately, these authors were not able to easily differentiate simple from strangulating obstruction. For example, although it has been generally taught that those patients with strangulation will have continuous pain, whereas a simple obstruction would cause an intermittent or colicky pain, this was not found to be the case in this series. Similar results were reported by Zollinger and Kinsey29 who found that constant pain was present in 18% of patients with simple obstruction, and 20% of those with strangulation. So, too, tenderness to palpation is present in most (≈85%) patients with strangulation, but is also present in a majority (≈75%) of patients with simple obstructions.28 A similar overlap has been documented in regard to other signs such as fever, leukocytosis, and the presence of a mass. Based upon these studies, as well as the anecdotal experience of numerous surgeons, it has generally been accepted that only short periods of observation (2.5 cm) and therefore can enter the intestinal tract only by a process of ulceration and fistulization. The most common site of entry is a cholecystoduodenal fistula, although stones may also erode into the stomach, jejunum, ileum, colon, or through the distal common bile duct into the duodenum. The gallstone will cause obstruction in the distal ileum or rarely at other areas of intestinal narrowing. The presentation will be that of acute, perhaps recurrent, attacks of small bowel obstruction, and would be suggested by the concurrent radiologic features of intestinal obstruction along with air in the biliary tree. Surgical treatment mandates removal of the stone via enterotomy, or resection in cases where the stone has become severely impacted in the wall of the bowel. Whether or not to perform a cholecystectomy at the time of relief of the obstruction remains controversial,65 but as long as the gallbladder is emptied of all stones, the chances of recurrent intestinal obstruction are extremely low.9 Kasahara

Special Forms of Intestinal Obstruction

Table 58.2 Etiologies of intestinal strictures


830 et al. reviewed 112 cases of gallstone ileus and found a significant mortality (19%) in patients treated with a one-stage procedure (enterotomy plus cholecystectomy), whereas there was no mortality in those treated with enterolithotomy alone, leading these authors to recommend the latter procedure in most patients.66 In contrast, Clavien et al. reviewed a series of 33 patients and concluded that a one-stage procedure was safe and effective in most patients.67 Therefore, if the general condition of the patient is good and anatomical factors are favorable, a one-stage procedure can be recommended. In addition to gallstones, other intraluminal foreign bodies can rarely cause small bowel obstruction, including various bezoars, worms, and swallowed objects.68–71

Intussusception Intussusception occurs when an entire advancing proximal segment of bowel, usually including part of its mesentery (intussuscipiens) invaginates into a more distal receiving segment of bowel (intussusceptum). Intussusception is the most common cause of childhood obstruction. However, intussusception in young adults and adults is rare, accounting for less than 5% of obstructions. Adult intussusception is usually due to an intrinsic bowel lesion such as a small bowel tumor (primary or metastatic), submucosal lipoma, Meckel’s diverticulum, or parasite that usually initiates the process. In addition, intussusception is now being more frequently described at sites of jejuno-jejunal anastomoses such as after a Roux-en-Y gastric bypass.72 The presenting clinical picture of an adult with intussusception is generally the same as those with other reasons for obstruction; however, episodes of pain and obstruction may be quite intermittent and sometimes more chronic. Radiologic studies aid in the diagnosis, and sometimes a barium enema is helpful, especially in the setting of intussusception where a large bowel tumor is the causative agent. CT findings can be quite classic and include the target sign, a sausage-shaped mass with alternating layers of low and high attenuation which represents the intussuscepted mesentery.73 In a small number of patients with melanoma, small bowel obstruction with intussusception caused by a metastatic lesion in the small bowel is the first manifestation of disease (Fig. 58.7). Treatment involves surgical exploration and reduction of small bowel intussusceptions with resection of any suspicious lesions or segments of bowel. Large bowel intussusceptions should not be reduced, given a high chance of malignancy, and resection should be performed. Rarely, an enterotomy with resection of a small polyp may be prudent, especially in the setting of Peutz-Jeghers syndrome where multiple polyps may be present throughout the entire small bowel.9

A

B

•

Volvulus Volvulus, or twisting of the intestine, most often occurs in the small bowel, cecum, or sigmoid colon and in the Western hemisphere accounts for approximately 5% of the cases of adult obstruction. A loop of bowel with a disproportionately long mesentery is most at risk for torsion. Often the torsed segment of intestine rapidly becomes a closed-loop obstruction with occlusion of its blood supply. The sigmoid is involved in 7–8% of the cases and the cecum in 10%. Volvulus of the small intestine occurs much more often in newborns and can be associated with congenital anomalies.74 Volvulus of the stomach can be due to congenital or acquired diaphragmatic defects or large paraesophageal hernias. Most patients present with colicky, intermittent abdominal pain and a grossly distended abdomen, sometimes asymmetric in nature. Radiologic studies are very helpful and often help confirm clinical suspicion. In sigmoid volvulus, a tremendously distended sigmoid loop is seen with a ‘bent innertube sign,’ and a barium enema will often reveal the sigmoid twist at the base of the mesocolon, above which lies the dilated loop of obstructed sigmoid colon. Treatment of sigmoid volvulus includes attempts at nonoperative reduction with barium enema, or passage of a soft tube past the obstructing point with the aid of sigmoidoscopy. These treatments often result in prompt and dramatic reductions in the size of the distended abdomen. Successful nonoperative reduction allows optimization of cardiopulmonary comorbidity in a high-risk group of patients and converts an emergent to an elective procedure and minimizes operative morbidity as a result.75 Surgical intervention is recommended if nonoperative reduction methods are unsuccessful, and elective resection of the sigmoid is performed, given the risks of recurrence of the volvulus. Small bowel volvulus remains a difficult and elusive clinical diagnosis even with the aid of CT imaging; immediate operation is mandatory given the risk of ischemia. Radiologic studies in cecal volvulus will often reveal evidence of small bowel obstruction with great distention of the cecum, which can sometimes be in the left upper quadrant. Distended loops of small bowel can sometimes be seen to the right of the distended cecum. Treatment is usually operative and includes reduction of the twist, and cecopexy or resection of the right colon. Laparoscopy is being considered more often in the setting of uncomplicated cecal volvulus.76

Early postoperative obstruction In the early postoperative period (within 3–4 weeks) following laparotomy for any reason, small bowel obstruction occurs in

C

Fig. 58.7 Metastatic melanoma presenting as intussusception of the small bowel. (A) CT imaging in a patient with abdominal pain reveals classic findings of intussusception with a sausage-shaped mass (white arrow) and alternating layers of low and high attenuation representing the intussuscepted mesentery. (B) At operation, multiple points of intussusception are found (white arrowhead). (C) Each intussusception lead point was a small bowel tumor comprised of metastatic melanoma (black arrow).

831

PREVENTION Attempts to prevent small bowel obstruction have been focused on reducing adhesions, since this is the most common underlying etiology. It is thought that adhesion formation can be reduced by avoiding excessive tissue ischemia, trauma, and manipulation. Since fibrin deposition is one of the initiating events in adhesion formation, various anticoagulants, e.g., heparin and dextran, or

thrombolytic agents, e.g., streptokinase and urokinase, have been used, but with minimal success. Several synthetic agents have been developed which may reduce the incidence of adhesions. Becker et al.80 reported a prospective, randomized study using a bioresorbable membrane (Seprafilm adhesion barrier, modified sodium hyaluronic acid and carboxymethylcellulose; Genzyme) placed anterior to all bowel loops in patients undergoing colectomy/ ileoanal pouch procedures with diverting loop ileostomies. At the time of ileostomy closure (8–12 weeks), laparoscopy was used to assess the degree of adhesion formation and showed that 51% of the patients treated with the membrane were free of adhesions, compared to only 5% of control patients. More recently, Beck et al.81 used Seprafilm in over 1700 patients undergoing abdominal and pelvic surgery in a prospective, randomized, multicenter study with no increase in rates of intra-abdominal abscess, pulmonary embolism or foreign body reaction. However, of note, in those patients in whom an intestinal anastomosis was wrapped with Seprafilm, a higher rate of anastomotic leak, fistula, peritonitis, abscess, and sepsis was seen. Whether or not using such treatments will lower the incidence of chronic adhesions and subsequent small bowel obstruction will need to be determined by further studies. Other chemical and biologic agents (such as Adcon-P) are being rapidly developed and studied for the purpose of reducing postoperative adhesions.82,83 A decrease in the incidence of adhesive small bowel obstruction is hopefully anticipated as more and more laparoscopic operations replace formal laparotomies, since it is well recognized that laparoscopy leads to minimal adhesion formation. In patients who are to receive postoperative radiotherapy, e.g., following resection of ovarian or rectal cancers, radiation-induced small bowel strictures may be prevented by placement of a pelvic ‘sling’ at the time of initial laparotomy, thereby restraining the small intestine in the upper abdomen and out of the radiation field.84

SUMMARY Intestinal obstruction is one of the most common disorders seen by both gastroenterologists and surgeons, and a thorough knowledge of this disorder is important for virtually all physicians. The key to the management of patients with small intestinal obstruction is early diagnosis so that proper therapy can be instituted. All the clinical decision-making skills of the experienced surgeon will come into play in order to make the correct therapeutic decisions when evaluating the patient with bowel obstruction. Decisions fall into broad categories: (1) determining the extent of fluid resuscitation, initiating nasogastric decompression, and monitoring urinary flow rates; (2) differentiating between the clinical scenarios of adynamic ileus, small bowel, and colonic obstruction based on the clinical and radiologic data; (3) differentiating simple from strangulating obstructions; (4) determining which patients will need an urgent operation after fluid and electrolyte resuscitation; and (5) determining which patients can be safely managed with nonoperative treatment and repeat examinations. Identification of those patients with strangulation is of critical importance since prompt surgical correction is needed in order to minimize morbidity and mortality. Numerous clinical and radiological criteria can be helpful in distinguishing simple from strangulating obstruction, but this differentiation remains a challenge to even the most experienced clinicians.

Summary

approximately 1–5% of patients. The differentiation between obstruction and adynamic ileus can usually be made on clinical grounds, since an ileus rarely persists for more than 5 or 6 days. Clearly, many patients thought to have a ‘prolonged ileus’ really have some degree of mechanical small intestinal obstruction.77 The diagnosis of early postoperative obstruction can be made in those patients who initially experience return of bowel function, only subsequently to develop nausea, vomiting, and abdominal distention. Plain radiographs may distinguish adynamic ileus from obstruction, since a predominance of small bowel gaseous distention would not be seen in most cases of ileus. Frager et al. examined 36 patients with CAT scans and reported 100% sensitivity and specificity in distinguishing mechanical small bowel obstruction from paralytic ileus.78 It should be noted that the distinction between ileus and mechanical obstruction in the early postoperative period is rarely of clinical consequence, since the treatment will usually be identical, that being nonoperative.77 This is the case because in early postoperative obstruction the chances of nonoperative resolution appears to be higher and the incidence of strangulation lower than in other clinical settings. Soft, filmy, and broad-based adhesions form early after laparotomy, occasionally leading to some degree of luminal obstruction, a situation that will resolve as the adhesions undergo their natural course of dissolution and reformation. The fact that the adhesions contain little scar tissue probably explains why the incidence of strangulation is so rare in the early postoperative setting. Many clinicians have suggested a relatively long trial of nonoperative therapy, perhaps 3–4 weeks, before considering surgical intervention. Clearly, there are some patients who have more severe forms of obstruction, e.g., twisting of the mesentery or internal herniations, who will require prompt surgical correction, even in the early postoperative period. In patients with early postoperative obstruction after laparoscopic surgery special consideration must also be given to etiologies other than adhesions or internal hernias as causes of any prolonged ileus or early postoperative small bowel obstruction. Trocar site herniation, trocar insertion injuries to organs, or inadvertent intestinal injury should be strongly considered. In fact, some patients undergoing laparoscopic surgery who go on to have a postoperative complication such as small bowel injury can have very different presenting signs and symptoms, perhaps due to different immune and cytokine responses in those undergoing laparoscopic surgery.79 Physicians taking care of the patient after laparoscopic surgery must be especially vigilant given the relatively subtle and potentially delayed physical exam findings which may accompany intra-abdominal processes such as internal herniation, or missed small bowel injury. Patients with early postoperative obstruction after laparoscopic surgery should be carefully examined and consideration should be given to an earlier return to the operating room if warranted, which can often be accomplished laparoscopically.


832

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This important paper reviews and provides illustrations of a relatively rare but new kind of internal hernia, becoming increasingly frequent due to the large increase in the number of laparoscopic gastric bypasses.

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References

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59

CHAPTER FIFTY-NINE

Chronic intestinal pseudo-obstruction Juan-R. Malagelada

INTRODUCTION

Core clinical manifestations

Chronic intestinal pseudo-obstruction (CIP) is a relatively rare condition, conceptually simple to grasp but difficult to manage in practice. The clinical picture of pseudo-obstruction develops when there is protracted failure of intestinal peristalsis to overcome the normal resistance to flow. Consequently, CIP mimics the effects of a chronic, partial obstruction of the bowel, but without mechanical impediment.1,2 CIP can result from either reversible or irreversible dysfunction of the gut smooth muscle and/or its neurohormonal regulatory systems.3 When the dysfunction is caused by diseases restricted to the smooth muscle or enteric nerves, the condition is classified as primary CIP. This classification includes some CIP forms that are genetic hereditary or nonhereditary conditions.4–6 When the dysfunction is part of a systemic condition, it is classified as secondary. Myopathic pseudo-obstruction refers to CIP caused by enteric smooth muscle degeneration, which may eventually become replaced by collagen, whereas neuropathic pseudoobstruction refers to CIP caused by neural enteric or extra-enteric disorders.7,8 Enteric neuropathies in turn may be divided into degenerative (noninflammatory) and inflammatory forms. The latter may be amenable to specific therapy. CIP was initially a diagnosis restricted to small bowel motor dysfunction. Presently, CIP connotes a broader diagnostic label, encompassing the entire gastrointestinal tract.9 Furthermore, it is well recognized that even in primary CIP other visceral systems, particularly the vesicourinary, may be affected, probably because their neuromuscular tissue structure and neural control are similar to that of the gastrointestinal tract.

Core clinical manifestations correspond to chronic (conventionally defined as longer than 3 months) intestinal obstruction-like symptoms. Chronic intestinal pseudo-obstruction may present abruptly, mimicking the clinical picture of acute mechanical small bowel obstruction, or as repeated subocclusive crisis characterized by colicky-type abdominal pain and abdominal distention. Unfortunately, these symptoms are rather non-specific. Patients may describe other types of pain: pressure-like, painful bloating, and sometimes focal pain. Abdominal distention may refer to the sensation of distention (bloating), to visible distention, or to both. Audible borborygmi may or may not be presented. Unlike complete mechanical obstruction where flatus is virtually absent, patients with CIP may describe either excessive flatulence (albeit usually stating that it brings minor, if any relief to their abdominal symptoms) or no gas expulsion at all. Nausea and vomiting (exceptionally feculent) may be very prominent manifestations in some patients. Disturbances in bowel habit are common but unpredictable. Some patients suffer from diarrhea, others from constipation, and some manifest alternating diarrhea and constipation resembling a severe irritable bowel syndrome. The signs observed on physical examination are also varied and mostly non-specific and include abdominal distention, borborygmi, and high-pitch bowel sounds. In uncomplicated CIP there should be no signs of peritoneal irritation.

CLINICAL FEATURES

Chronic intestinal pseudo-obstruction, as a neuromuscular disorder, may involve any segment of gut and even other organs with comparable tissue structure. Alternatively, focal or regional involvement predominates in some patients and determines peculiarities of the clinical presentation.10 Thus, some patients with esophageal dysmotility may complain mostly of reflux-like or achalasia-like symptoms. In other patients a picture akin to gastroparesis dominates the clinical presentation. These are patients who complain of nausea, vomiting, and other manifestations of delayed gastric emptying. It should be noted, however, that such a gastroparetic picture is as likely to result pathogenetically from altered small bowel motility as from gastric dysmotility, or from a combination of both.11 Colonic atony and dilatation may be particularly prominent in some patients with CIP, which

Chronic intestinal pseudo-obstruction is characterized by a stereotyped clinical picture that defines the syndrome. In addition, there may be associated manifestations that depend on the involvement of different regions or organs, the etiology, and related conditions or complications. Knowledge of the various clinical facets of CIP is a prerequisite for effective management. To facilitate the description of the clinical picture of CIP, it will be arbitrarily divided into three parts: 1. Core clinical manifestations; 2. Clinical peculiarities associated with the involvement of different regions; and 3. Complications.

Clinical peculiarities associated with specific regional involvement

Chronic Intestinal Pseudo-Obstruction

836 has led to some confusion with Ogilvie’s syndrome.12 However, the latter denomination should probably be reserved for patients with acute or subacute colonic distention in the context of toxic, neoplastic, or systemic diseases. Patients with megacolon and other forms of colonic neuromuscular contractile failure associated with protracted constipation, as the exclusive or predominant clinical manifestation, should probably also be excluded from CIP classification. However, it is true that some CIP patients present initially as colonic inertia, and only years later (sometimes after colectomy) does it become apparent that the small bowel is also affected. Anorectal dysfunction is a relatively common feature of CIP and, even without distal complaints, manometric studies may disclose abnormalities. Extraintestinal manifestations should be actively investigated in patients with CIP. Urinary tract involvement is particularly common in myopathic CIP and it tends to manifest clinically by recurrent infections and altered micturition.13 In secondary CIP, drugs, systemic disease, and neurologic disorders may produce accompanying manifestations that should be looked for, since they can help establish the specific etiology of secondary CIP (see below).

Clinical manifestations of complications In severe CIP, malnutrition and specific deficits may be part of the clinical picture. This situation should be anticipated in patients who tolerate intake poorly, vomit frequently, and suffer from secondary diarrhea and malabsorption. In fact, the latter manifestations are often due to bacterial overgrowth in the small bowel. Specific deficiencies in electrolytes, vitamins, minerals, and metals may produce the corresponding clinical manifestations. However, more commonly, deficits are not clinically obvious and should be actively sought by an appropriate battery of blood and urine tests.14

RELEVANT TESTS USED IN THE DIAGNOSIS OF CHRONIC INTESTINAL PSEUDO-OBSTRUCTION Step 1: Abdominal imaging A critical step in the diagnosis of CIP is to exclude mechanical obstruction or another specific intestinal lesion responsible for the clinical syndrome, which may be challenging for two main reasons: (1) a ‘hidden’ lesion causing partial bowel obstruction may be difficult to identify in a distended bowel partially filled with fluid and organic detritus, and (2) conversely, in many patients with CIP presenting with potentially obstructing lesions (commonly, kinks and adhesions from prior abdominal surgeries), it may be difficult to ascertain whether there is partial mechanical obstruction (with secondary proximal neuromuscular dysfunction) or whether the observed postsurgical sequelae in fact represent epiphenomena without pathologic significance. Abdominal imaging should, therefore, be performed initially in the evaluation of a patient with suspected chronic intestinal pseudo-obstruction. Note, however, that in ill patients certain urgent measures such as decompressing the abdomen and reestablishing fluid and electrolyte balance and nutritional support (see later) may need to be implemented immediately, even prior to diagnostic studies. Note also that imaging procedures are most informative when performed after thorough bowel decompression

obtained either by prolonged fasting and/or via aspiration by nasogastric or nasoenteric tube.

Endoscopy The main value of endoscopy is the identification of mucosal lesions (e.g., Crohn’s ulcers and focal amyloid ‘pimples’) that might otherwise be missed by radiology. Endoscopy is, therefore, a reasonable first step in most patients. The upper intestine should be examined as far distally from the pylorus as possible, and ordinarily should be complemented by colonoscopy and ileoscopy.

Plain abdominal radiology Plain abdominal radiology may not reliably distinguish between intestinal mechanical obstruction and pseudo-obstruction. However, it is useful to establish the presence of air-filled and dilated loops of bowel and, later, to follow up response to therapy.

Abdominal CT scan An abdominal CT scan should be obtained early in the diagnostic process. It provides information regarding the magnitude of intestinal dilation, thickness of the intestinal walls and, sometimes crucially, a change in the caliber of the intestinal lumen that may indicate an area of mechanical obstruction. The CT scan may also detect masses or extraintestinal and/or retroperitoneal pathology causing the obstruction.

Gastrointestinal transit with barium contrast Gastrointestinal transit with barium contrast may help to localize the precise location and magnitude of an occlusive lesion. It may be indicated when the acute crisis has been resolved and signs of peritonitis and ileus are absent. In general, barium contrast should be avoided when there is a possibility of colonic mechanical obstruction or severe inertia, to preclude barium solidification and impaction in the colon.

Enteroclysis Enteroclysis consists of the administration of barium suspension directly into the small bowel via nasoenteric tube. It is a timehonored procedure that in our hands retains good value in the management of CIP. If enteroclysis shows free flow of barium into the terminal ileum and colon, it is unlikely that a significant midsmall bowel obstructing lesion has been missed.

Step 2: Physiological assessment of intestinal function Physiological assessment is the logical next step when a mechanical obstructing lesion or other significant intraabdominal pathology has been reasonably excluded by the imaging procedures in the first step.

Measurement of gut transit In theory, measurement of small bowel transit speed should be a rewarding diagnostic approach to a condition such as CIP that represents a gut propulsive disturbance. In practice, however, measurements of transit are not that useful and are rarely indicated. Indirect methods such as the lactulose hydrogen breath test, which assesses the time-span from mouth to cecum, may be hampered by technical pitfalls, including spurious early hydrogen peaks caused by small bowel bacterial overgrowth. Direct transit

837

Gastrointestinal manometry Direct measurement of gut contractile activity should, in principle, never be undertaken without: (1) having first decompressed the stomach and small bowel; and (2) without performing the pertinent imaging procedures described above to exclude mechanical obstruction. Failure to take these two preliminary steps may result in erroneous interpretation of the contractile patterns registered manometrically. With this important proviso, it is also true that gastrointestinal manometry may occasionally provide indication of an unsuspected obstruction when it shows postprandial intense minute rhythm activity and/or a characteristic pattern of high amplitude, near simultaneous phasic contractions that may be associated with mechanical impediment (Fig. 59.1). In the absence of mechanical obstruction, gastrointestinal manometry is currently the most sensitive and specific test for the diagnosis of CIP.17–19 Gastrointestinal manometry is performed by

means of an orointestinal tube fitted with perfused pressure ports or electronic sensors that record the phasic pressure waves produced by contractile activity of the stomach, duodenum, and jejunum, both fasting and postprandially. It should be performed after overnight fast. Any medication that may interfere directly or indirectly with intestinal motility (prokinetic agents, calcium channel blockers, opiates, antidepressants, and any other drugs that may interfere with gut neuromuscular activity) should be withdrawn well prior to the test procedure. A test meal is ingested after an initial 3-hour fasting recording interval to evaluate the postprandial motor pattern. The small bowel manometric recording may be used to diagnose pseudo-obstruction when the following alterations are observed: 1. Myopathic pattern: The typical recording would show well-coordinated contractile activity, with presence of the interdigestive motor complex in the fasting period and a postprandial pattern following ingestion of a meal, but with phasic pressure waves of decreased amplitude (>20 mmHg) due to weaker contractions by the musculature of the digestive tract (Fig. 59.2). 2. Neuropathic pattern: The typical recording would show contractile activity of normal amplitude, but with irregular patterns since, although the muscle remains unaffected, neurohormonal control of activity is disturbed. Of course, mixed or non-specific manometric patterns do occur. For instance, when a neurogenic or myogenic disorder is severe and has progressed, contractile failure may develop and little pressure activity may be visible in the manometric tracing. Some have claimed that a normal gastrointestinal manometry excludes CIP,20 but we have seen some symptomatic CIP cases with normal manometry in adults who presented evidence of enteric neuropathy on morphologic study of full-thickness biopsy of the small bowel, who later developed unequivocal manometric abnormalities.

Duodenal cap 1

2 Descending duodenum Distal duodenum Proximal jejunum 1 2 3 4

5 min

50 mmHg

Vomiting

•

Fig. 59.1 The manometric pattern that may be observed in some patients with subacute mechanical obstruction of the small bowel. Note the simultaneous, high-amplitude, and repetitive pressure waves detected in the duodenum and jejunum.The patients vomited at the beginning of the recording and a normally progressing interdigestive migrating motor complex-like front developed as a commonly observed postemetic event.Note that absence of this ‘mechanical obstruction pattern’ does not exclude such a possibility, which should be investigated by the appropriate imaging tests. (Reprinted from Manometric Diagnosis of Gastrointestinal Motility Disorders 1986: p.85. © 1986 with permission from Thieme, New York.)

Relevant Tests used in the Diagnosis of Chronic Intestinal Pseudo-Obstruction

measurements, mostly based on radioscintigraphy, are more accurate since they allow visualization and quantification of whole gut transit of an externally monitored radiolabeled marker(s). However, patients with radiologic evidence of stasis (dilated loops of small bowel, pooling of barium) do not need further documentation of delayed transit. Moreover, in those patients without gross luminal disturbance apparent on contrast studies, changes in transit speed may be difficult to interpret. On the other hand, in CIP patients in whom colonic stasis predominates, as opposed to small bowel stasis, transit measurements may be of greater practical value by documenting either pancolonic or segmental colonic propulsive defects. Colonic transit can be measured either with radiopaque markers15,16 or with ‘gammagraphic’ techniques, a variation of the whole gut transit method encapsulating the gamma-emitting label in an entericcoated cover to release it in the distal small bowel/cecal area.


838 Normal

Visceral myopathy

Antroduodenal 1

2 50 mmHg

3

4 5 Descending duodenum Distal duodenum

Proximal jejunum 5 min

•

Typical manometric pattern in a patient with CIP caused by a visceral myopathy (panel on right). Note the normally progressing Fig. 59.2 interdigestive migrating motor complex albeit with a much lower amplitude of phasic pressure waves than in the normal example shown on the left panel. In the advanced stages, very often these vestiges of normal motor activity disappear. (Reprinted from Manometric Diagnosis of Gastrointestinal Motility Disorders 1986: p.85. © 1986 with permission from Thieme, New York.)

Esophageal, colonic and anorectal manometry Manometry is normally used to characterize the extent of the gut motor disturbance; however, it is rarely used for definitive diagnosis because contractile and/or reflex abnormalities are non-specific. It may be symptom-guided. Esophageal manometry may be useful in cases with dysphagia and/or chest pain, while colonic and/or anorectal manometry may be particularly useful in cases with prominent defecatory disturbance.21

Laparoscopy and laparotomy In patients in whom it is not possible to exclude conclusively the presence of a mechanical subocclusive lesion by conventional testing, it may be necessary to resort to exploratory laparoscopy or laparotomy with direct examination of the abdominal cavity and intestinal loops. Surgical examination should always be conducted by an experienced surgeon and in a specialized center.22 Furthermore, if no evidence of mechanical obstruction or other significant pathology is apparent at surgery, a fullthickness biopsy of the small intestine should be obtained to examine the myenteric plexus and muscle layers to ascertain the existence of a primary motor disorder. Because many centers lack sufficient experience and/or tools to perform the complex tissue analysis required, referral of the patient to a specialized center for exploratory laparotomy and biopsy is advisable.

Tissue morphology Full-thickness specimens of the small intestine should be appropriately fixed, processed in sections cut perpendicular to the mucosa, and stained with hematoxylin and eosin, with Mason’s trichrome, and processed for various specific techniques, as outlined below. Smooth muscle should be differentiated from fibrosis (and quantified) and smooth muscle cells carefully observed for morphological anomalies. Identification of enteric neuropathies requires a combination of light microscopy,

immunohistochemistry, electromicroscopy, and molecular biology techniques, and it is best performed at specialized centers. It includes assessment of neuronal loss and neuronal degenerative features, assessment of neurochemically distinct subclasses of enteric neurons and assessment of neurotropic factors and related receptors. In inflammatory forms of enteric neuropathies, the immune infiltrate may be characterized by identifying putative messengers involved in lymphocyte recruitment (chemokines) and immune-mediated neuronal damage (cytokines). A normal appearance of smooth muscle and neural tissues does not exclude CIP because some neuromuscular dysfunctions do not evidence into histopathological abnormalities. Furthermore, not all molecular disease mechanisms have been characterized. Positive findings do, however, make such diagnosis of CIP much more tenable.23,24

Evaluation of the extension of the disease Once the diagnosis of small bowel disorder has been established by the above tests, the digestive and extradigestive extent of the condition should be investigated, first, to determine whether other tissues and systems are affected, and second, to help establish the etiology of the gut anormality.

Digestive This is to be performed, if not obtained yet, during the initial diagnostic evaluation. 1. Esophagus, by esophageal manometry; 2. Stomach, by gastric emptying test; and 3. Colon, via colonic transit time, colonic manometry and/or anorectal manometry.

Extradigestive 1. Urinary system: It may be affected in both myopathic and neuropathic pseudo-obstruction. In advanced cases,

839

Diagnosis of complications Complications in CIP arise from: 1. Associated extraintestinal neuromuscular dysfunction: This category chiefly refers to urinary tract abnormalities (ureteral and/or renal collector system dilatation, bladder dysfunction). The urological abnormalities may be clinically silent or manifested by either micturition problems or recurrent urinary tract infections. 2. Associated autonomic dysfunction: This complex disorder may produce orthostatic hypotension, accommodative ocular disturbances, or sweating abnormalities (see also secondary CIP). 3. Complications of bowel dilatation and stasis: This category includes hydroelectrolytic disturbances, aspiration pneumonia (from vomiting), small bowel bacterial overgrowth, and malnutrition.

Etiologic diagnosis in secondary chronic intestinal pseudo-obstruction There are many conditions causing or associated with CIP (see elsewhere), and it is therefore important to follow an efficient strategy to reach the correct diagnosis. The diagnostic process may be divided into three steps: priority tests, second-line tests, and ‘exceptional’ tests. Priority tests: These include a battery of easily available and relatively inexpensive blood and urine analyses. Check for blood electrolytes (chloride, sodium, potassium, calcium), thyroid hormones (T3, T4, TSH), renal function (blood urea nitrogen, creatinine), metabolism (glucose, glycosylated hemoglobin), collagen-vascular disease (antinuclear antibodies, urinary albumin, urinary sediment), dysproteinemias (protein electrophoresis). One should check initially for occult neoplasia (chiefly small cell carcinoma of the lung) by chest X-ray and antineuroenteric antibodies. Second line tests: Second-line tests should be performed next, if the initial screening has yielded no apparent cause of CIP. Three types of second-line tests should be considered: 1. Brain imaging to check for intracranial disease (tumor, ischemic lesion, hydrocephalus): CT or MRI. 2. Imaging tests to check for occult malignancy in the thorax (negative chest X-ray) and abdomen, specially retroperitoneal or mesenteric: Usually CT scan of chest and abdomen, abdominal ultrasound, or MRI, depending on the clinical situation. 3. Small bowel/rectal biopsy to check for the possibility of amyloidosis, celiac disease, Whipple’s disease, and

lymphoma, and to search for cytomegalovirus or other viral inclusions. These disorders may sometimes produce a clinical picture similar to CIP. Exceptional tests: Exceptional tests are directed towards identifying conditions that are either rare or infrequently associated with CIP. Such conditions include abdominal vascular disease (arteriography, dynamic CT scan), rare metabolic disorders such as porphyria, heavy metal intoxication, and other even more esoteric conditions. Adds expense; think carefully before ordering.

GOALS OF THERAPY AND WELL-BEING With the exception of some secondary forms, CIP is a chronic incurable condition. Therefore, the primary goals of therapy should be to alleviate troublesome symptoms, restore well-being, and avoid incapacitation (Table 59.1).25 In clinical practice, patients with CIP present with a wide spectrum of clinical severity. Some CIP patients have relatively mild symptoms: abdominal discomfort, distention, and alterations in bowel movement pattern. These mild CIP cases are able to carry on with normal nutrition and activities, and their illness resembles that of nonserious conditions such as irritable bowel syndrome or functional dyspepsia. It is even conceivable that all of these conditions share a common pathophysiology, although this possibility remains to be proven. At the other end of the spectrum are patients with very severe CIP afflicted by protracted vomiting, with a distended abdomen containing dilated loops of bowel and unable to tolerate any oral intake. Psychological support is a key measure for chronically ill patients with CIP. In particular, patients with moderate and severe forms are often frustrated and depressed over their inability to conduct normal lives. They cannot eat what they want, they experience pain and other uncomfortable symptoms, and their physical and social activities may be significantly curtailed. Knowledge about incurability further discourages patients. Under these somewhat gloomy circumstances, many forms of psychological support are indicated. Physicians responsible for the primary care of the patients should be available and compassionate. Nursing and nutritionist assistance may help build up confidence. Psychotherapist assistance on a regular basis may facilitate coping. There is also an important role for psychopharmacological agents, particularly the newer isomeric serotonin reuptake inhibitor antidepressants with minimal anticholinergic side effects. In some patients with CIP, the condition may be aggravated (or rarely caused solely by) various drugs that interfere pharmacologically with normal contractile and propulsive gut activity. The most common culprits are opiates, tricyclic antidepressants,

Table 59.1 Principles of management of chronic intestinal pseudo-obstruction Establish a clinical diagnosis Exclude mechanical obstruction Differentiate between idiopathic and secondary forms Perform a physiologic assessment Outline a therapeutic plan

Goals of Therapy and Well-Being

appropriate imaging techniques may show a dilated pyelocalyceal system and bladder. In the early stages, the involvement may only be detectable by a urodynamic study. 2. Cardiovascular system: It tends to be affected primarily, but not exclusively, in neuropathic pseudo-obstruction. Alterations in cardiac rhythm, orthostatic hypotension, or syncopal symptoms may occur. Abnormalities are investigated via cardiac electrical studies and the tilt table test for autonomic blood pressure regulation. 3. Autonomous nervous system and central nervous system: Investigated via CT scan or brain MRI, cutaneous impedance test, variation in heart rate during deep inspiration or Valsalva maneuver.


840 and anticholinergics. The possibility that drugs are responsible for a flare-up of the CIP syndrome should always be considered and evaluated by drug withdrawal, if feasible. Prevention and treatment of complications is another important facet of pharmacological therapy.

MANAGEMENT OF CHRONIC INTESTINAL PSEUDO-OBSTRUCTION IN THE ACUTE PHASE Management of CIP may be somewhat arbitrarily, but conveniently, divided between acute exacerbations and maintenance between successive crises. In the acute phase (Table 59.2), standard management guidelines are: 1. Nothing by mouth; 2. Nasogastric or nasoenteric suction to decompress the digestive tract. The latter (via endoscopically guided enteric tube) may be required if there is significant upper intestinal stasis; 3. Parenteral hydration and electrolyte replacement matched to the volume aspirated. In addition, total parenteral nutrition should be considered if oral intolerance persists over 1 week; and 4. Pharmacological treatment of the motor dysfunction.26,27 In the acute setting, drugs that may be administered parenterally should be used: a. Metoclopramide: A dopamine D2-receptor antagonist and 5-HT4-receptor agonist with a weaker 5-HT3receptor antagonist action at high doses. It increases the frequency and amplitude of antral contractions, improves antro-pyloric coordination and alleviates nausea and vomiting via central antiemetic action. It has potential side effects at the central nervous system level that restrict its use. It may be administered at doses of 10 mg every 8 hours by slow infusion (since boluses may induce acute anxiety). b. Erythromycin: Macrolide antibiotics act as motilin agonists. When given intravenously, they are excellent gastric prokinetic agents, inducing a powerful burst of activity that begins in the proximal stomach and

extends aborally into the small bowel, resembling phase III of the interdigestive motor complex. Erythromycin is preferentially used as an acute treatment for gastroparesis at 200 mg doses, administered as rapid intravenous infusion every 6–8 hours. When administered orally, its prokinetic effect may be diminished, and some authors caution against its use, as disbacteriosis and resistances may potentially develop. However, other reports suggest that it may be useful.28 In general, we suggest that it should be replaced by another prokinetic after a maximum treatment period of 10 days. c. Octreotide: A somatostatin analogue, it acts mainly on the small intestine, inducing activity that resembles phase III of the interdigestive motor complex, hence improving intestinal propulsion and decreasing bacterial overgrowth.29 The recommended dose is 50 micrograms administered subcutaneously as a single night dose. It may slow down gastric emptying, and therefore, if the patient has gastroparetic symptoms, it should be combined with a prokinetic agent. d. Neostigmine: Reversible inhibitor of acetylcholinesterase, it may be administered intravenously. Indicated for acute colonic pseudo-obstruction or Ogilvie’s syndrome,30 but it may be tried in small bowel stasis, although its usefulness tends to be limited to point treatment of gas distention. Administered intravenously in a single dose of 0.5–2.5 mg, it may be repeated after several hours if necessary. The alternative (or complement) to neostigmine is colonoscopic decompression, which has a success rate of 75–90% and a relapse rate of 15% in Ogilvie’s syndrome. In severe cases, the above measures may not produce sufficient improvement for patients to maintain their nutritional status without aggravation of their abdominal symptoms. In that case, the application of venting catheters via laparoscopic surgery (gastric and/or jejunal) should be considered to maintain the intestine decompressed and, eventually, to permit nutrient intake and/or to serve as a direct route for enteral nutrition.

MAINTENANCE MANAGEMENT Table 59.2 Therapeutic plan in chronic intestinal pseudo-obstruction Treat the cause (rarely possible) Supporting measures Diet modification Decompression/drainage Correct nutritional, metabolic imbalances Avoid narcotic dependence Psychological support Pharmacologic treatment Prokinetics Antiemetics Visceral hypoalgesic agents Antibiotics Surgical approach Exceptional Focal (resection, plication, bypass)

Diet and lifestyle During intercrisis periods, the objective is to maintain an adequate nutritional status, while inducing minimal or no abdominal discomfort. The following recommendations should be applied: 1. An oral diet should be administered to the extent tolerated by the patient, with additional formula nutritional supplements to attain the required daily caloric intake. 2. If a significant gastroparesis component exists, adequate nutrition may only be attainable by means of infused enteral nutrition via a gastrostomy or jejunostomy catheter (preferably with its tip located distally to the ligament of Treitz). 3. Home parenteral nutrition (TPN) should be implemented only if the patient does not tolerate oral or enteral feedings. TPN should preferably be administered sporadically, several days a week, to supplement any oral intake that the patient might accept. Shortcomings include growth retardation in children, and complicating hepatobiliary infections and metabolic events.

841

Disease-specific treatment During maintenance periods, the following drugs should be considered: 1. Orally-administered prokinetics: These should be used when a gastroparesis component exists, possibly as an extension of the initial treatment with intravenous erythromycin. a. Metoclopramide (see above for pharmacological properties): 10 mg orally before meals. Higher doses may be given; however, the risk of dystonic reactions increases. b. Domperidone: This agent, not available in the US, is a D2 dopamine receptor antagonist that crosses poorly the blood–brain barrier. Therefore, it acts primarily on gastric peripheral D2 receptors diminishing proximal gastric relaxation and facilitating gastric emptying. It also acts on the area postrema (partially outside the blood–brain barrier), which confers some antiemetic action. It is given orally at a dose of 10 mg before meals. Side effects are uncommon. c. Cisapride: This drug is an agonist of gastrointestinal 5-HT4 receptors, facilitating the release of acetylcholine and improving gastric and intestinal contractility. It is administered in 5–20 mg doses before meals and at bedtime. A major potential side effect is cardiac arrhythmia manifested as syncope, which precipitated its withdrawal for use in the US. Risk factors include advanced age, prior cardiac pathologies, and coadministration with drugs that use the same metabolic pathway (antiarrhythmics, ketokonazole, erythromycin). Severe dispensing restrictions apply in many countries, including the US. d. Tegaserod: This agent is a selective partial 5-HT4 agonist that promotes propulsive peristaltic activity in the small and large bowel, accelerating bowel transit, which also possesses some antinociceptive properties. It may be useful in patients with predominant constipation, bloating, and abdominal pain. Standard doses are 6 mg orally twice daily or 12 mg as a single morning dose, but higher doses may be tried in a stepup fashion. It does not act at central nervous system levels and significant side effects appear to be rare. e. Sildenafil: This drug, used for male erectile dysfunction, is an orally active phosphodiesterase type 5 inhibitor that has been shown to promote gastric emptying in diabetic gastroparesis, at 50 mg dose.32 2. Octreotide (see above for pharmacological properties): It may be administered for an indefinite period at the previously described dosage (50 ␮g subcutaneously at bedtime); it helps improve motor activity of the small intestine and control bacterial overgrowth. In patients with severe abdominal pain, it may also be administered as a visceral analgesic at doses of 100–200 ␮g every 8 or 12 hours subcutaneously. However, at such higher doses, it may also aggravate gastroparesis and malabsorption.

3. Antibiotics: In patients with bacterial overgrowth (see special section below). 4. Laxatives: In cases with associated constipation: a. Fiber supplement and bulk-forming agents (unless massive small bowel stasis); b. Osmotic laxatives: magnesium salts and polyethyleneglycol-based preparations; c. Stool lubricants and softeners; d. Conventional contact or irritant laxatives. It is probably best to avoid fermentable sugars, such as lactilol and lactulose. When colonic inertia predominates, high doses or the stronger laxatives may be required. e. Misoprostol, a prostaglandin derivative with antiulcer properties that stimulates propulsive activity in the small bowel and colon, and decreases fluid reabsorption. The usual dose is 400–1200 ␮g daily and is best administered during the interprandial periods. f. Colchicine, the well-known antigout agent may be occasionally useful with resistant constipation. Given in setup doses from 1 to 6 mg orally, it may induce diarrhea.

Management of complications In CIP, bacterial hypercolonization of the mid and upper gut is a major cause of malabsorption and diarrhea. When bacterial overgrowth is considered to be clinically significant, as with associated malabsorption, investigation and subsequent therapy are indicated. The initial test for the evaluation of small bowel bacterial overgrowth in CIP is the hydrogen breath test, preferably with glucose. If the test is abnormal, a 1–2-week course of antibiotic treatment should be prescribed. The following antibiotics may be administered orally: doxycycline, metronidazole, ciprofloxacin, and amoxicillinclavunalate. After antibiotics, patients may be monitored clinically and by repeat glucose breath test. If treatment is ineffective and bacterial overgrowth is still suspected, a different antibiotic therapy should be tried. If the patient’s condition still does not improve, it should probably be concluded that his or her diarrhea is unrelated to the bacterial overgrowth. If the initial glucose breath test is normal, but the clinical presentation is very suggestive of bacterial overgrowth, antibiotic treatment can be given empirically. However, chances for success under such circumstances are less likely. In many patients, antibiotic therapy needs to be reapplied at intervals because of recurrent reinfection of the small bowel, usually 5–10 days monthly with alternating antibiotics.

Mechanical and surgical approaches to palliation Palliation via special intraluminal catheters and surgical procedures should be contemplated in selected cases. The usefulness of nasogastric or nasojejunal suction in patients with symptomatic luminal pooling in the upper and mid gut has been discussed above. Sometimes, gastric aspiration will suffice, but often it is necessary to intubate the small bowel to achieve successful intestinal decompression. In such cases, endoscopic decompression may allow rapid and effective decompression of a dilated stomach and/or small bowel. However, unless endoscopic decompression is followed by other sustaining therapeutic measures, the benefit may be short lived. Sustaining measures may be pharmacological and/or placement of permanent decompression catheters (see below). In contrast, endoscopic decompression may offer longer-lasting results

Maintenance Management

Repeated vomiting and stasis may damage the esophagogastric mucosa. Therefore, adjuvant treatment with a proton pump inhibitor may be appropriate, even though there is some evidence that these agents mildly slow gastric emptying. Opioid-induced aggravation of CIP may be alleviated by using Alvimopan, a novel peripheral opioid antagonist.31


842 in acute or subacute dilation of the colon that has not fully responded to neostigmine. Decompression via colonoscopy is most successful and long lasting with aspiration proximal to the hepatic flexure. Whether to leave a decompressing rectal tube in place is debatable, but some data suggest anal retention may be a factor in large bowel gas pooling. Endoscopic colonic decompression, as a relieving maneuver, sometimes may need to be performed repeatedly, occasionally accompanied by percutaneous endoscopic colostomy.33 Nasogastric or intestinal aspiration may be maintained safely for several days, or even weeks provided nutritional requirements are well covered by parenteral routes. However, some patients with CIP become chronically dependent on gastric and/or intestinal ‘venting’ to prevent accumulation of air and secretions.34 This long-term objective is best achieved by surgically placing a gastrostomy or jejunostomy catheter, or sometimes both (a venting gastrostomy and a venting/feeding jejunostomy). The gastrostomy may be performed endoscopically, but jejunostomy usually requires a laparotomy with insertion of silicon or polyurethane

tubes into a jejunal loop close to the duodenal-jejunal angle using a subserosal tunnel method. Parenteral nutrition at home should be considered an absolutely last resort because of its inherent morbidity and mortality over extended periods of time. Circumstances that may require diagnostic laparotomy with suspected CIP is discussed above. Therapeutic surgery has a role limited in the palliation of pseudo-obstruction, although in wellselected cases it may be quite helpful.35 On the other hand, the illadvised use of surgery may even worsen patients, particularly if repeat ‘blank’ laparotomies (including lysis of adhesions) are performed. The recommended surgical procedures are diverse but focus specifically on the elimination of stagnant segments via entero-enteric anastomosis, plication, or partial resection. In addition, volvulus may develop in children with pseudo-obstruction and may require surgical correction. In general, the experience with intestinal diversion without resection has been disappointing, at least in pediatric patients. The only exception may be plication and reconstruction of dilated bowel segments in some forms of

Patient with suspected chronic intestinal pseudo-obstruction (CIP)

Plain abdominal X-ray (during crisis)

Both small and large bowel dilated

Paralytic ileus

No

No

Yes

Non-dilated loops or only small bowel dilatation

Exclusively dilated colon

Exclude mechanical occlusion

Rule out structural pathology?

Abdominal CT normal Consider colonic inertia or Ogilvie’s syndrome

Yes Specific causal treatment

Digestive tract imaging Colonoscopy and/or barium enema if no colonic obstruction Perform small bowel series with barium

No

Tests normal?

Yes

Patient with probable CIP

Yes

Either myopathic or neuropathic CIP

Perform gastrointestinal manometry

Minute rhythm pattern?

No

Conclusive myopathic or neuropathic pattern?

Yes

No Normal manometric pattern?

No

Follow up with repeated clinical and manometric evaluation at 3–6 months

Conclusive myopathic or neuropathic pattern? No

Yes Probable functional disorder

Fig. 59.3

Yes

Still normal manometric pattern?

No

If severe clinical picture consider laparoscopy with transmural intestinal biopsy

• Algorithm detailing the main sequential steps indicated in the evaluation of a patient with suspected chronic intestinal pseudo-obstruction.

843

SUMMARY

clinically significant, as with associated malabsorption, investigation and subsequent therapy are indicated. Palliation via special intraluminal catheters and surgical procedures should be contemplated in selected cases. Figure 59.3 provides an overview of the evaluation of patients with chronic intestinal pseudo-obstruction.

REFERENCES 1. Christensen J, Dent J, Malagelada J-R, et al. Pseudo-obstruction. Gastroenterol Internat 1990; 3:107–119. A consensus document on what constitutes pseudo-obstruction. 2. Dudley HAF, Sinclair ISR, McLaren IF, et al. Intestinal pseudoobstruction. J R Coll Surg Edinb 1958; 3:206–217. 3. Di Lorenzo C. Pseudo-obstruction: current approaches. Gastroenterology 1999; 116:980–987. Excellent review with emphasis on pediatric CIP. 4. Mueller LA, Camilleri M, Emslie-Smith AM. Mitochondrial neurogastrointestinal encephalomyopathy: manometric and diagnostic features. Gastroenterology 1999; 116:959–963. A description of the MNGIE syndrome with documentation of intestinal dysmotility by enteric manometry. 5. Bracci F, Iacobelli BD, Papadatou B, et al. Role of electrogastrography in detecting motility disorders in children affected by chronic intestinal pseudo-obstruction and Crohn’s disease. Eur J Pediatr Surg 2003; 13(1):31–34. 6. Pingault V, Girard M, Bondurand N, et al. SOX10 mutations in chronic intestinal pseudo-obstruction suggest a complex physiopathological mechanism. Hum Genet 2002; 111(2):198–206. Epub 2002; Jul 06. 7. Debinski HS, Kamm MA, Talbot IC, et al. DNA viruses in the pathogenesis of sporadic chronic idiopathic intestinal pseudoobstruction. Gut 1997; 41(1):100–106. Evidence linking a viral etiology to cases of sporadic CIP. 8. Jain D, Moussa K, Tandon M, et al. Role of interstitial cells of Cajal in motility disorders of the bowel. Am J Gastroenterol 2003; 98(3):618–624. 9. Lyford G, Foxx-Orenstein A. Chronic intestinal pseudoobstruction. Curr Treat Options Gastroenterol 2004; 7(4):317–325. A good updated review on CIP by a group with ample experience.

Chronic intestinal pseudo-obstruction (CIP) is a relatively rare condition, conceptually simple to grasp but difficult to manage in practice. CIP is characterized by a stereotypical clinical picture that defines the syndrome. In addition, there may be associated manifestations that depend on the involvement of different regions or organs, the etiology, and related conditions and complications. Knowledge of the various clinical facets of CIP is a prerequisite for effective management. To establish the diagnosis of chronic intestinal pseudo-obstruction, it is essential to exclude conclusively mechanical obstruction along the gastrointestinal tract, chiefly in the small bowel. In patients in whom it is not possible to exclude conclusively the presence of a mechanical subocclusive lesion by conventional test, it may be necessary to resort to exploratory laparoscopy or laparotomy with direct examination of the abdominal cavity and intestinal loops. Management of CIP may be somewhat arbitrarily, but conveniently, divided between acute exacerbations and maintenance between successive crises. Prokinetic drugs and laxatives constitute the mainstay of maintenance therapy. When bacterial overgrowth is considered to be

10. Smith DS, Williams CS, Ferris CD. Diagnosis and treatment of chronic gastroparesis and chronic intestinal pseudo-obstruction. Gastroenterol Clin North Am 2003; 32(2):619–658. 11. Stanghellini V, Camilleri M, Malagelada J-R. Chronic idiopathic intestinal pseudo-obstruction: clinical and intestinal manometric findings. Gut 1987; 28:5–12. 12. Delgado-Aros S, Camilleri M. Pseudo-obstruction in the critically ill. Best Pract Res Clin Gastroenterol 2003; 17(3):427–444. 13. Lapointe SP, Rivet C, Goulet O, et al. Urological manifestations associated with chronic intestinal pseudo-obstructions in children. J Urol 2002; 168(4 Pt 2):1768–1770. 14. Nightingale JM. The medical management of intestinal failure: methods to reduce the severity. Proc Nutr Soc 2003; 62(3):703–710. 15. Sloots CE, Felt-Bersma RJ. Effect of bowel cleansing on colonic transit in constipation due to slow transit or evacuation disorder. Neurogastroenterol Motil 2002; 14:55–61. 16. Fort JM. Azpiroz F, Casellas F, et al. Bowel habit after cholecystectomy: physiological changes and clinical implications. Gastroenterologist 1996; III: 617–622.

References

focal myopathic CIP, especially megaduodenum.36,37 As a rule, such palliative surgical procedures are more appropriate in myogenic than neurogenic CIP. Major obstructive symptoms causing unbearable distress may require segmental resections; these may need to be very extensive and thus require a commitment to enteral or parental feeding. Transplantation may be regarded as the only definitive cure for many forms of CIP. Candidates are patients with end-stage CIP who require total parenteral nutrition to survive. Outcomes of transplantation are still relatively uncertain.38–40 Surgical palliation is far less effective when it attempts to correct a widespread intestinal motor dysfunction, even if symptoms appear to arise from a circumscribed area. However, severe abdominal bloating or impending obstruction may be considerably alleviated by strategically placed venting stomas. Colectomy is justified in severe colonic dysfunction, although not infrequently the small bowel involvement becomes apparent afterwards. For this reason, we advise to always evaluate gastric and especially small bowel motor function by appropriate manometric and other tests prior to attempting a colonic resection in a patient with colonic inertia who does not manifest clinical evidence of upper and mid gut disfunction. In particular, it is important to estimate prior to surgery the load of nutrients that the small bowel (or specific areas of the small bowel) is able to accept. This estimation may be accomplished by placing a nasojejunal tube and infusing via a peristaltic pump a semi-elemental formula solution, preferably isosmolar, beginning at low rates (0.25 mL/min) and gradually increasing it to rates of 2 mL/min. In general, an intake of 30 kcal/kg of ideal weight/day is an adequate goal. Since CIP patients tend to be in a stress situation, a 1.5 g/kg/day of proteins should be included. If the patient tolerates such load of enteric feedings without symptoms, the small bowel has sufficient preserved capability to sustain normal nutrition. Nevertheless, there is no guarantee that overt small bowel pseudo-obstruction will not develop over time. Implantation of gastric and intestinal pacemakers aimed at coordinating motility remains, despite considerable technical advances, an investigational approach. Gastric pacing has met, however, with some success in alleviating symptoms in patients with gastroparesis.


844 17. Malagelada J-R, Camilleri M, Stanghellini V. Manometric diagnosis of gastrointestinal motility disorders. New York: Thieme-Stratton; 1986. The original description of human gastrointestinal manometry and its clinical applicability. It contains numerous tracing of actual cases. Useful to learn how to read manometric tracings in the stomach and small bowel.

28. Emmanuel AV, Shand AG, Kamm MA. Erythromycin for the treatment of chronic intestinal pseudo-obstruction: description of six cases with a positive response. Aliment Pharmacol Ther 2004; 19(6):687–694. 29. Soudah HC, Hasler WL, Owyang C. Effect of octreotide on intestinal motility and bacterial overgrowth in scleroderma. N Engl J Med 1991; 325:1461–1467.

18. Camilleri M, Parkman H, Quigley EMM, et al. Measurement of gastroduodenal motility in the GI laboratory. Gastroenterology 1998; 115:747–762.

30. Ponce RJ, Saunders MD, Kimmey MB. Neostigmine for the treatment of acute colonic pseudo-obstruction. N Engl J Med 1999; 341:137–141.

19. Fell JME, Smith VV, Milla PJ. Infantile chronic idiopathic intestinal pseudo-obstruction: the role of small intestinal manometry as a diagnostic tool and prognostic indicator. Gut 1996; 39: 306–311.

31. Schmidt WK. Alvimopan* (ADL 8-2698) is a novel peripheral opioid antagonist. Am J Surg 2001; 182(5A Suppl):27S–38S.

The role of intestinal manometry in the differentiation of myopathic or neuropathic CIP in the first 2 years of life. 20. Cucchiara S, Borrelli O, Salvia G, et al. A normal gastrointestinal motility excludes chronic intestinal pseudoobstruction in children. Dig Dis Sci 2000; 45(2):258–264. 21. Pensabene L, Youssef NN, Griffiths JM, et al. Colonic manometry in children with defecatory disorders: role in diagnosis and management. Am J Gastroenterol 2003; 98(5):1052–1057. 22. Murr MM, Sarr MG, Camilleri M. The surgeon’s role in the treatment of chronic intestinal pseudoobstruction. Am J Gastroenterol 1995; 90:2147–2151. Important review helping to define the uses of surgery in the management of CIP. 23. Streutker CJ, Huizinga JD, Campbell F, et al. Loss of CD117 (c-kit)and CD34-positive ICC and associated CD34-positive fibroblasts defines a subpopulation of chronic intestinal pseudo-obstruction. Am J Surg Pathol 2003; 27(2):228–235. 24. Fava M, Borghini S, Cinti R, et al. HOX11L1: a promoter study to evaluate possible expression defects in intestinal motility disorders. Int J Mol Med 2002; 10(1):101–106. 25. Schwankovsky L, Mousa H, Rowhani A, et al. Quality of life outcomes in congenital chronic intestinal pseudo-obstruction. Dig Dis Sci 2002; 47(9):1965–1968. 26. Malagelada JR, Distrutti E. Management of gastrointestinal motility disorders. A practical guide to drug selection and appropriate ancillary measures. Drugs 1996; 52:494–506. 27. Pandolfino JE, Howden CW, Kahrilas PJ. Motility-modifying agents and management of disorders of gastrointestinal motility. Gastroenterology 2000; 118:S32–S47.

32. Bianco A, Pitocco D, Valenza V, et al. Effect of sildenafil on diabetic gastropathy. Diabetes Care 2002; 25:1888–1889. 33. Thompson AR, Pearson T, Ellul J, et al. Percutaneous endoscopic colostomy in patients with chronic intestinal pseudo-obstruction. Gastrointest Endosc 2004; 59(1):113–115. 34. Pitt HA, Mann LL, Berquist WE, et al. Chronic intestinal pseudoobstruction. Management with total parenteral nutrition and a venting enterostomy. Arch Surg 1985; 120:614–618. It describes the placement and maintenance of intraluminal catheters for intestinal decompression in CIP. 35. Shibata C, Naito H, Funayama Y, et al. Surgical treatment of chronic intestinal pseudo-obstruction: report of three cases. Surg Today 2003; 33(1):58–61. 36. Mansell PI, Tattersall RB, Balsitis M. Megaduodenum due to hollow visceral myopathy successfully managed by duodenoplasty and feeding jejunostomy. Gut 1991; 32:334–337. 37. Loire J, Gouillat C, Partensky C. Megaduodenum in chronic intestinal pseudo-obstruction: management by duodenectomyduodenoplasty. Gastroenterol Clin Biol 2000; 24(1):21–25. 38. Nishida S, Levi D, Kato T, et al. Ninety-five cases of intestinal transplantation at the University of Miami. J Gastrointest Surg 2002; 6(2):233–239. A large series of intestinal transplantation at a specialized US medical center: outcomes, pitfalls, hopes. 39. Iyer K, Kaufman S, Sudan D, et al. Long-term results of intestinal transplantation for pseudo-obstruction in children. J Pediatr Surg 2001; 36(1):174–177. 40. Mousa H, Hyman PE, Cocjin J, et al. Long-term outcome of congenital intestinal pseudoobstruction. Dig Dis Sci 2002; 47(10):2298–2305.


60

CHAPTER SIXTY

Hirschsprung’s disease Peter J. Milla

INTRODUCTION

Genetics

History, epidemiology, and presentation

Hirschsprung’s disease can be sporadic or familial, has a complex genetic pattern, and appears to be polygenic or multifactorial.21–23 A higher incidence of familial involvement has been reported in females and in patients with long segment disease.8,24,25 Two major cell signaling systems required for development and maintenance of the enteric nervous system are involved, the RET/GDNF (glial-cell line derived neurotrophic factor26–31) and the endothelin systems,32,33 but mutations in transcription factors known to be important for neuronal development, such as SOX 10,34 SIPl and, more recently, PMX2B,35 as-yet undefined genes, may be required for the HSCR phenotype. HSCR may also be associated with Waardenburg syndrome, Smith-Lemli-Opitz syndrome, Down syndrome and multiple endocrine neoplasia syndrome type 2A (MEN 2A).36 The latter association ties up with the RET abnormalities encountered in Hirschsprung’s disease as well as in MEN 2A. The former suggests that there may be a relevant locus on the X chromosome resulting in the Hirschsprung phenotype. The RET gene, which maps to chromosome IOqll.227,29,30 and codes for a cell surface tyrosine kinase receptor, is the major gene involved in human HSCR, and mutations of this gene occur in approximately 50% of familial and sporadic cases of HSCR.36 As part of the RET-GDNF-GFRal signaling system, RET promotes the survival of neurons, mitosis of progenitor cells, and differentiation of neurons. Ret-1– knockout mice have aganglionosis of the small and large intestines and there is an association with renal agenesis. The RET receptor tyrosine kinase consists of an intracellular tyrosine kinase, a transmembrane domain, and an extracellular domain in neurons and neuronal precursor cells. Mutations affecting the intracellular domain affect signaling functions, whereas those affecting the extracellular domain affect ligand binding.37,38 Multiple mutations resulting in loss of function have been identified that are associated with HSCR, but where they cause a gain of function they are associated with the development of other conditions such as familial medullary thyroid carcinoma (FMTC), multiple endocrine neoplasia (MEN) 2A, and MEN 2E. Around 5% of patients with HSCR will have an associated MEN 2A or FMTC.38 Glial-derived neurotrophic factor (GDNF) is a ligand for the RET receptor and requires the co-receptor GFRal for effective signaling.26,28 It acts on early ENS precursor cells to stimulate

Congenital aganglionosis or Hirschsprung’s disease (HSCR) was first described by Harald Hirschsprung in 1887.1 It occurs in about 1 in 4500 live births, and results in a distal aganglionic segment of bowel of variable length. There is a male predominance of 3.8:1. In about 75% of patients the abnormal segment is restricted to the rectosigmoid colon. In a small minority (about 8%) the condition may be more widespread, involving the whole colon (total colonic aganglionosis) or even the entire gastrointestinal tract.2–8 In about 7% of those with the short-segment disease there is a familial tendency, increasing to about 21% in patients with total colonic aganglionosis. Most patients present in the first few days of life, 95% failing to pass meconium in the first 24 hours of life. Five percent may present later with constipation and 30% with symptoms of an enterocolitis. Fewer than 1% are not diagnosed until adult life.8–13 Presentation varies with the age of the patient and the extent of disease. In the newborn period, bilious emesis, abdominal distention, and failure to pass meconium or abnormal stool frequency are common. Complete intestinal obstruction may occur, and perforation of the cecum or the appendix occurs in 3–5%. If diagnosis is not established in the newborn period, infants may present with constipation. This most often occurs in breast-fed infants.14 It may be followed by acute obstruction, frequent episodes of fecal impaction, or the development of acute life-threatening enterocolitis. Enterocolitis develops in 15–50% of cases, may be the initial feature of HSCR in up to 12% of patients and is the main cause of death, the mortality reaching 20–50%.7,15–17 From infancy until adulthood, mild to severe constipation may be the only symptom of HSCR.16–20 Because clinical features do not allow complete differentiation between these problems, the diagnosis of HSCR must always be considered in any child, adolescent, adult with severe intractable constipation11,18,20 or in any child or infant with a history of onset from birth or very shortly thereafter. Where the diagnosis is established in adult life (mean age 26 years, range 11–73), most have had symptoms since childhood and frequently only evacuate their bowel with enemas. Occasionally chronic colitis and pseudopolyps have been reported.11,12

Hirschsprung’s Disease

846 differentiation, and in in vitro studies can attract migrating ENS cells.28 Heterozygosity of GDNF may contribute to the severity of the HSCR phenotype, but is not responsible for it. Although not described in humans, the gdnf–/– knockout mouse has a similar phenotype to the ret–/– mouse. Other members of the GDNF family have now been identified (neurturin, artemin, persephin), but mutations in their genes have not been demonstrated to result in HSCR.

Endothelin signaling system The endothelin (ET) system in the developing embryo may regulate interactions between gut neural crest and mesenchyme cells. The endothelin family consists of ET-1, ET-2, ET-3, and VIP, but it is ET-3 that is important in ENS development via its interaction with the endothelin receptor-B (ETRB). This has been demonstrated in mouse knockout models. The lethal spotted mouse mutant (Is/Is) has distal colonic aganglionosis secondary to a mutation in the Et-3 gene, and colonic aganglionosis is found to a greater extent in the piebald lethal mouse, which lacks the ETRB gene. ET-3 mutations are associated with approximately 5% of human HSCR cases, with mutations of ETB accounting for 5–7% of cases. Mutations of the ET-3 and ETRB genes have been described in the Shah-Waardenburg syndrome, which is characterized by enteric aganglionosis, skin and hair pigmentation defects, and sensorineural hearing loss.39 As well as ET-3 and ETRB abnormalities, mutations in the endothelin converting enzyme-l can lead to the presentation of aganglionosis, albeit with associated autonomic, craniofacial, and cardiac abnormalities.39 Mutations of other signaling systems, including the hedgehog signaling system, may have a role in congenital enteric aganglionosis but, given the widespread role of these systems in embryonic development, it is unlikely that enteric aganglionosis would present without many other complex abnormalities. In familial cases, in all families so far studied RET has always been involved, but mutations in at least two other genes are required for expression of the phenotype.40 Routine screening for RET or other mutations is not yet practical and, due to incomplete understanding of the complex genetic nature of the condition, is not yet clinically indicated.

PATHOGENESIS Developmental basis The loss of innervation of the distal segment of bowel is due to failure of colonization of the bowel by neural crest cells in early embryonic development from 4 to 10 weeks of gestation.37 Recent advances in understanding the developmental neurobiology of the enteric nervous system shows that the intrinsic innervation of the gut is developed from neural crest cells from the vagal and sacral neural crest which migrate into and colonize the bowel in a mainly cranio-caudal direction. Within the primitive gut the precursor cells proliferate and differentiate into the multitude of different neurons and glial cells required for the enteric nervous system. This process requires the correct sequence of events coded for by many different genes to occur in both the precursor cells and the environment into which they are moving if a functional nervous system is to develop. Study of animal models and of humans with HSCR has shown that aganglionosis may

result from defects of either the neural crest cells themselves (RET or ETRB) or abnormality of the mesenchymal environment (GDNF or ET-3) into which they are migrating.

Pathophysiology The aganglionosis in HSCR results in a lack of intrinsic enteric inhibitory nerves, with loss of inhibition of the enteric musculature due to absence of intrinsic nitrergic and peptidergic neurons. This results in a contracted segment of gut with loss of the rectoanal sphincteric reflex. The proximal normal ganglionic bowel is dilated, tapering to the narrowed distal aganglionic bowel.41

DIAGNOSIS The diagnosis needs to be based on the pathologic demonstration of aganglionosis before definitive surgery is undertaken.5 Because obtaining biopsy specimens involves a degree of risk, and because expert histopathology may not be available, other less invasive techniques such as barium enema and anorectal manometry have been used to select patients who require a biopsy.

Barium enema The barium enema, although not diagnostic, can be suggestive and supportive.5 A single-contrast enema is used, and the colon is not prepared. In infants with HSCR, a transition zone from the distal nondilated colon is usually easily detected.13 However, the absence of a transition zone does not exclude the diagnosis,10 as it may be absent in 20–30% of patients.42 In patients with total colonic aganglionosis, the entire colon may appear normal. Barium enema is less helpful in the newborn because a visible transition zone is often not present.

Anorectal manometry In normal individuals, distention of the rectum causes relaxation of the internal anal sphincter (IAS). This effect is absent in patients with HSCR.43 After the newborn period, manometry has been shown to accurately diagnose Hirschsprung’s disease in 90–100% of patients, with a specificity of 97% and sensitivity of 79%.44 In newborns and premature infants the diagnostic accuracy of manometry is lower (from 90% to 70%)43,44 because it is more difficult to perform, and inaccurate results are more common,43 with both false-positive and false-negative tests.44

Rectal biopsy Confirming the absence of ganglion cells in the abnormal segment of colon is critical to the diagnosis of HSCR.45,46 Suction rectal biopsy, which produces a specimen of mucosa and submucosa, is commonly used and allows assessment of the submucous plexus. Accuracy is excellent if the specimen is adequate and if a trained pathologist is available. When ganglion cells are present, the diagnosis of HSCR is excluded even if only one ganglion cell is seen. Inadequate suction rectal biopsies, however, may fail to reveal ganglion cells in up to 39% of patients without HSCR,45,46 almost always because no submucosa is included in the biopsy. The use of immunohistochemical stains for acetylcholinesterase in combination with hematoxylin and eosin staining can increase

847

TREATMENT Initial management Definitive treatment of HSCR at the present time is surgical.13–17,49 However, initial medical management to stabilize the patient before surgery is important. Correction of dehydration and electrolyte imbalance, antibiotic therapy for Clostridia difficile if enterocolitis is present, and colonic decompression with the use of physiological saline rectal washouts and rectal tubes50 until the time of surgery may be necessary.

Short segment disease Definitive surgery The principle of definitive surgery is to relieve the distal obstruction by resection of the aganglionic segment, followed by a ‘pullthrough’ of ganglionic bowel down to the anus.5 Traditional surgical treatments consist of either a two- or three-stage operation (an initial colostomy, followed later by a definitive ‘pullthrough’ and/or subsequent closure of the stoma).51 Usually, the

Swenson

•

Duhamel/Martin

pull-through is performed at the age of 9–12 months or when the child weighs 8–10 kg.2 Three ‘pullthrough’ operations have stood the test of time: Swenson pull-through (rectosigmoidectomy), Duhamel pullthrough (retrorectal transanal pull-through), and Soave pullthrough (endorectal pullthrough) (Fig. 60.1).52 The Swenson pull-through procedure was the first definitive operation to be developed for this disease. It involves resection of the aganglionic segment and anastomosis of the normal ganglionic proximal bowel to a 1–2-cm rectal cuff (see Fig. 60.1).7,53 It requires a combined abdominoperineal approach, is probably the most difficult technically, and requires extensive pelvic dissection, so injury to the sacral innervation of the bladder and ejaculatory mechanisms may occur. In an effort to avoid the extensive pelvic dissection, other surgical alternatives have been proposed. In the Duhamel pull-through, the aganglionic rectum is left in place, and normal ganglionic bowel is brought down behind the rectum and through an incision in the posterior rectal wall at the level of the internal anal sphincter.54 The pelvic dissection is thus limited to the retrorectal space.54 The original Duhamel procedure used anastomosis of the ganglionated proximal bowel to the closed native rectum at the anal verge. Dilatation of the rectum by fecal retention in the blind loop resulted in the addition of a proximal suture anastomosis of the anterior native rectum to the pulled through colon,52 thus creating a rectum of expanded size with an anterior aganglionic wall and a posterior ganglionic wall. The third alternative is the endorectal pull-through originally described by Soave.52 In this procedure the mucosal lining of the rectum is removed by submucosal dissection to the anus and the normally innervated colon is passed through the rectal muscular tube for anastomosis within 1 cm of the anal verge (see Fig. 60.1).52,55 The modified Soave procedure is relatively easy to perform, and the procedure obviates the need for any pelvic dissection. The incidence of complications is probably determined more by the skill of the individual surgeon and the underlying factors determining the presence of the aganglionosis than the type of operation performed. The outcome of short segment HSCR shows

Soave/Boley

Fig. 60.1 The three major operative procedures for Hirschsprung’s disease.The unshaded portion of the rectum is aganglionic, and the shaded pullthrough bowel contains ganglion cells. (Modified from Philippart AI. Hirschsprung’s disease. In: Aschcraft KW, Holder TM, eds. Pediatric surgery. 2nd edn. Philadelphia:WB Saunders; 1993:358–371.)

Treatment

the accuracy of diagnosis to a sensitivity of 97–100% with a specificity of 100%. A marked increase in acetylcholinesterase activity is seen in the lamina propria and muscularis mucosae of patients with HSCR.46,47 For cases in which suction biopsy has produced equivocal results or is inadequate, it may be necessary to obtain a fullthickness specimen of the rectal wall, which requires a surgical procedure under general anesthesia.48 Such biopsies allow the evaluation of both the myenteric plexus and submucosal plexus, and some use this procedure to confirm every diagnosis before definitive surgical correction. However, if an experienced pathologist is available and the suction biopsy specimen shows a lack of ganglion cells with abnormal acetylcholinesterase staining, no further diagnostic steps are necessary before definitive surgery is undertaken. Rectal biopsy is the gold standard and the diagnostic method of choice.


848 disrupted anastomoses (11%) and enterocolitis (16%) to be commoner after Swenson pull-throughs than after Duhamel (2% and 6%, respectively) or Soave (6% and 2%, respectively) operations, but for anal stenosis and incontinence to be much the same (3–5%) whatever operation was done.2,55

Long-term outcome There are few descriptions of the long-term outcome of treatment of HSCR. Undoubtedly, the outcome for total colonic and total intestinal aganglionosis, both morbidity and mortality, is quite different than that for short segment disease and will be considered separately. For short segment HSCR long-term survival is excellent, although sudden death from enterocolitis may occur years after successful surgical reconstruction.16 Many studies, however, show a higher than anticipated incidence of problems, particularly persistent obstruction, fecal incontinence, or enterocolitis.5,56–58 Several large studies have shown that between 50% and 75% of patients considered that their pattern of defecation was normal, and about 20% had a degree of fecal incontinence (6% severe) which improved with age. Recurrent enterocolitis occurs in 2–30%, 6% after operation for the first time. Growth overall was comparable to the normal population. Delayed development occurred in 8–10% and behavioral problems in3%. The functional results were largely determined by the length of the aganglionic segment beyond the rectosigmoid and the degree of neurologic impairment. However, the outcome was less favorable for those who underwent a Swenson pull-through compared to a Soave or Duhamel operation. The increased incidence of abdominal distention, micturition, and sexual dysfunction, together with the anal stenosis and disrupted anastomoses that occur early after operation, has led to the Swenson pull-through being much less popular today. Surgical advances in the last 10 years have been the demonstration that a primary pull-through operation may be as effective as a staged procedure in the newborn period,17,51,59,60 and that short-term outcome are the same.51 Recent reports have also described the surgical treatment of Hirschsprung’s disease by laparoscopic surgery,60,61 either in neonates or in older children. The procedure entails performing the pull-through laparoscopically and the rectal dissection and anastomosis transrectally. The results in small studies are comparable to those of open methods, and the techniques appear to be safe and effective.60,61 However, long-term studies of either of these techniques are not yet available.

Postoperative problems Enterocolitis Enterocolitis remains the major cause of both morbidity and mortality in HSCR with Hirschsprung’s disease.5,9,16,62 It occurs after surgical treatment in 2–33% of patients14 and is associated with mortality ranging from 0% to 30%.3,13–15,63 It appears to occur more commonly after Swenson than after Duhamel or Soave pull-through operations. It commonly presents with abdominal distention in 83%, explosive diarrhea in 69%, vomiting in 51%, fever in 34%, lethargy in 27%, rectal bleeding in 5%, and colonic perforation in 2.5%. Chronic diarrhea (longer than 2 weeks) was present in 54% and delayed growth in 44%. The occurrence of explosive diarrhea in any patient with Hirschsprung’s disease should suggest the diagnosis, even in the absence of systemic

symptoms.15,16,62 The presence of postoperative enterocolitis needs to be recognized promptly, as a child can initially have mild symptoms followed by a rapidly fulminating course that may lead to death. The diagnosis is aided by abdominal X-ray showing an intestinal cutoff sign and at least two air-fluid levels.13,63 Endoscopic examination will show colitis and the presence of pseudomembranes if Clostridia is present. A barium enema is rarely indicated.15,62 The pathogenesis continues to be poorly understood.64 Fecal stasis and bacterial overgrowth seem important. Associations between enterocolitis and the presence of Clostridium difficile have been reported although recent reports indicate that in up to two-thirds of patients, toxin determination for C. difficile or stool cultures for other pathogens are negative.15 Other organisms that have been associated with enterocolitis include rotavirus, retrovirus, Pseudomonas, or Escherichia coli. If the enterocolitis is secondary to C. difficile,16 the clinical findings may be more fulminant, with rapid progression, shock and prostration, and eventually death.16 The treatment of choice includes fluid and electrolyte support, antibiotics, and the use of transrectal decompression either by tube or by sphincter dilatation, or rectal washout.5,15,16,62 Antibiotics against C. difficile and bowel flora should be started empirically as soon as the appropriate cultures are obtained.16,62 However, it is necessary to remain alert for the occurrence of idiopathic forms of inflammatory bowel disorder in the setting of HSCR.

Fecal incontinence Fecal incontinence occurs much more commonly than is generally thought. In one long-term study designed specifically to evaluate the extent of incontinence,57 it was found to be present in 80% of patients. In 53%, fecal incontinence was significant with constant leaking, and in 27% the incontinence was less severe. Contrary to other reports, the incontinence did not diminish with increasing age. The mean age of the patients was 10.1±3.6 years, and the age at definitive surgery, sex of the child, the extent of aganglionosis, the type of surgery, and early or late postoperative complications did not influence the presence or absence of postoperative incontinence. Children with soiling were more likely to have loose stools, a history of anal dilatation, and emotional disturbances. The pathophysiology of the incontinence is not well understood. Different manometric abnormalities have been described. In one study, 10% of patients were not able to squeeze voluntarily, and impaired rectal sensation was most commonly present after the Duhamel or Swenson pull-through (50%). The presence of the rectoanal inhibitory reflex has been variable and does not correlate with outcome,49,65,66 indicating that other factors must influence continence in these patients. Careful evaluation is necessary in order to differentiate between fecal incontinence due to overflow and encopresis or to abnormalities in colonic or anorectal function. Physical examination, colonic transit studies, abdominal radiographs, and colonic and anorectal manometry will allow such differentiation. Treatment of fecal incontinence is complex. If related to constipation, laxatives and aperients may be helpful. Other treatments have included enemas, bowel management tubes,67 or more recently, antegrade colonic enemas.68 On the other hand, if the fecal incontinence is not related to constipation but to anorectal dysfunction, enemas to maintain an empty rectosigmoid together

849

Obstruction Recurrent obstruction is one of the most common and difficult to manage postoperative symptoms occurring in HSCR.3 Obstructive symptoms may be related either to an anatomic problem, usually anal stenosis, or to functional disorder.17,49,56,58 Anal stenosis can usually be managed with dilatation,8 although a secondary surgical procedure may be necessary, most commonly after a Swenson pull-through. Stenosis in the pulled-through bowel has also been described, both probably secondary to ischemic damage. Most patients with obstructive symptoms do not have stenosis. In one study in which 107 patients were monitored for at least 4 years, 15% had recurrent episodes of gaseous distention and symptoms suggestive of persisting obstruction in the absence of an anatomically defined lesion. Such symptoms may be as a consequence of a retained aganglionic segment after an inadequate initial operation.56 The exact incidence of this complication is difficult to establish. The aganglionosis may also be acquired or secondary after a successful initial operation. Such occurrence is rare but has been well documented.49,63 This complication has been reported after any of the different corrective procedures, and whilst it may be related to a hypoxic insult49,63 we now know that aganglionosis may occur following various forms of lymphocytic ganglionitis,70 which are progressive, and if this is the case, then the original diagnosis of HSCR was incorrect. Further investigation to demonstrate circulating enteric neuronal antibodies of the anti-Hu variety should be undertaken in both children and adults, and treatment of the underlying autoimmune disorder with immunosuppressive drugs commenced. In adults a search for an associated small round cell carcinoma of the lung must also be undertaken.70 If aganglionosis is suspected, a barium enema may show a transition zone, and four-quadrant rectal suction biopsy at different levels will be necessary to confirm the aganglionosis, or as a consequence of associated neuronal pathology including intestinal neuronal dysplasia. Some authors have suggested that intestinal neuronal dysplasia (IND) type B in children with HSCR may be associated with the presence of obstructive symptoms.48,49,54 This type of IND is characterized by malformations of the parasympathetic submucous plexus and can be found in a proportion of patients which varies between 1% and 25% in different studies of children with HSCR.71 Anorectal manometry is not useful in the diagnosis of IND,72 so diagnosis depends upon a full-thickness rectal biopsy.48 The value of suction rectal biopsy for the diagnosis of IND is controversial, and recent studies have raised questions about its usefulness and accuracy.48 The significance of IND as a clinicopathologic entity apart from associated with HSCR is somewhat questionable.48,72 Whereas some authors suggest that IND may be associated with obstructive symptoms, others believe that its presence may not be significant.48,71,72 Hanimann and coworkers71 reported that in 47 cases 11 (23%) had associated IND and that after a mean follow-up of 5 years, no differences in symptoms were seen in patients with IND and those without it. Cord-Udy et al.48 reported that the histologic criteria of IND were

not helpful in predicting clinical outcome and suggested that the finding of IND should not influence clinical management. It is clear, however, that some symptomatic children with HSCR may have motility abnormalities related to neuronal dysplasia in the residual colon. Therefore, in children with HSCR who have undergone definitive surgery and who have obstructive symptoms, it may be necessary to obtain a full-thickness rectal biopsy specimen to exclude the presence of IND. In such children, management should be conservative unless symptoms are severe and clearly associated with the abnormal segment, when surgical resection may be necessary.73 Functional obstruction may also be as a consequence of the inflammation associated with enterocolitis. Although the inflammatory process is primarily present in the lamina propria of the mucosa, the neuromusculature as in other inflammatory bowel disorders may become involved.74 Persistent IAS dysfunction is another possible cause of obstructive symptoms. This dysfunction is sometimes referred as to ‘internal sphincter achalasia,’75 and is related to specific abnormalities in IAS innervation.41 Because current surgical treatment preserves the IAS, a distinct sphincteric abnormality may explain some of the frequently observed long-term obstructive symptoms.41,58 It is possible that high IAS tone produces a functional outflow obstruction that with time leads to colonic dilatation and less efficient peristalsis to expel stool.49,67 Because of sphincteric abnormalities, some authors have suggested that an internal sphincter myotomy or partial myectomy should be performed in patients with postoperative obstructive symptoms that have not responded to medical management.76–78 Partial myectomy has been shown to significantly decrease IAS pressure.78 Even though the initial experience suggested a poor response after partial myectomy,53 recent reports have shown it to be useful in the treatment of these children.77,78 Sphincter-dividing procedures are not always effective and are sometimes associated with fecal incontinence. With the extensive use of botox in children with skeletal muscle problems and in the treatment of internal sphincteric achalasia,75 it has been suggested that it could be used to produce a ‘medical’ myectomy to allow evaluation of a reduction in sphincter pressure without permanent sphincter destruction.79 Further studies are required to evaluate the role of this potential modality of treatment. If an anatomic problem such as a stricture or anal stenosis is present, it should be corrected. If aganglionosis is present, the segment should be removed and definitive surgery carried out. If the patient has IND, laxatives, aperients, and prokinetic agents are indicated.49 If the colonic transit study and anorectal manometry indicate that the obstruction is at the level of the internal sphincter, a partial myectomy or myotomy may be considered.49 If the symptoms do not improve and there is evidence of colonic distention and malfunction, further surgery needs to be considered. Such surgery may involve performing a new pull-through operation, though redo procedures have a higher incidence of complications. A flowchart of these factors in the pathogenesis of obstruction is shown in Fig. 60.2 in the form of a treatment algorithm. It may also be necessary at times to create a colostomy or ileostomy if obstructive symptoms or recurrent enterocolitis persists. In more recent years, antegrade colonic enemas have been developed as a method of treating constipation and fecal incontinence of various causes, including Hirschsprung’s disease.80

Treatment

with dietary manipulation and biofeedback therapy are indicated.56 Where it is associated with excessive propulsive rectosigmoid contractile activity, anticholinergic drugs such as propantheline may help.69 Where incontinence is very severe and results in serious degradation of quality of life, consideration should be given to reverting to a stoma.


850

•

Anatomic problem?

Functional problem?

Physical examination Barium enema Colonoscopy

Barium enema Colonic transit Rectal biopsy Anorectal manometry Other motility studies

Anal stenosis

Fig. 60.2 Algorithm for the evaluation and treatment of patients with obstructive symptoms.

Stricture Aganglionosis

Outlet

Neuronal

Surgery

Problems

Dilatation Dysmotility Surgery Hypertonic sphincter

Prokinetic Rectal tube for decompression Antibiotics

Intestinal dysplasia

Myectomy Surgery Segmental ACE resection

Revision

Ileostomy

The antegrade colonic enema procedure produces a continent conduit from the skin to the cecum that can be catheterized for self-administration of enemas.80 This technique can be accomplished either surgically with the use of an appendiceal stump or percutaneously with the insertion of a cecostomy tube under local anesthesia.80 The procedure tends to be more successful in patients with defects in extrinsic innervation such as spina bifida, but in short-term studies, antegrade colonic enemas have been shown to be effective in children with Hirschsprung’s disease in whom a permanent colostomy was being considered for the treatment of refractory constipation or incontinence. There are as yet no long-term follow-up data and the decision as to which course to follow is often determined by patient preference. Success is the product of the patient’s motivation to carry out the care required after either of these procedures.

Total colonic and total intestinal Hirschsprung’s disease Definitive surgery In total colonic and total intestinal HSCR, complications are more frequent and more severe than in patients with shorter segment disease.49,81–83 The mortality rate is higher and may be as high as 47%.8,81–83 Improvements in medical management of complications, particularly in parenteral and enteral nutrition, as well as in surgical techniques, have decreased such high mortality rates and allowed the survival of those with total intestinal HSCR. Surgical therapy initially includes an ileostomy, followed at a later stage by an endorectal pull-through along with total colectomy or a long side-to-side anastomosis with the aganglionic distal end of the rectum.81–83 In total intestinal HSCR a high jejunostomy and

Colostomy

gastrostomy are the preferred surgical treatments, followed by long-term home parenteral nutrition and, where and when necessary, intestinal transplantation.

Postoperative problems and long-term outcome Fecal incontinence occurs in the majority in the early postoperative period, and failure to thrive, malnutrition, and disturbances in electrolyte balance, lipid metabolism, and vitamin B12 absorption have all been described.81 A common problem is that of recurrent obstructive episodes which lead to intestinal dilatation, diarrhea, and postoperative enterocolitis.81–83 Almost certainly, these episodes are as a result of dysmotility of the apparently normally innervated gut. A number of studies have shown that abnormal motility occurs in the upper gastrointestinal tract well above the aganglionic segment.84 In such patients, intermittent antibiotics and irrigation via a rectal tube are required chronically for decompression. If it is clear that the patient has a functional obstruction at the level of the sphincter, a partial myectomy may be indicated. This operation should be performed only in patients who have been fully evaluated, inasmuch as fecal incontinence may result after the procedure. In those with severe and recurrent symptoms, it may be necessary to return to a decompression stoma as in patients with intestinal pseudoobstruction. With aggressive follow-up and nutritional support, as well as treatment of obstructive episodes, most patients who survive will eventually attain normal growth and the ability to feed enterally. Long-term follow-up (12–23 years) has, however, shown that although survivors develop normally and are socially and professionally integrated, fecal incontinence remains a significant problem. All had accelerated passage of stool, but one study has shown that 75% were incontinent at 5 years, 50% at

851 3. Puri P. Hirschsprung’s disease: Clinical and experimental observations. World J Surg 1993; 17:374–384. 4. Hoehner JC, Wester T, Pahlman S, et al. Alterations in neurotrophin and neurotrophin receptor localization in Hirschsprung’s disease. Pediatr Surg 1996; 31:1524–1529.

FUTURE DIRECTIONS

5. Reding R, Goyet V, Gosseye S, et al. Hirschsprung’s disease: A 20 year experience. Pediatr Surg 1997; 32:1221–1225.

The first operative technique for Hirschsprung’s disease was described in 1948 by Swenson. While this was widely billed as curative treatment, in reality this, and surgical techniques since that time, have only relieved the obstruction caused by the aganglionic segment of colon. Despite this, progress in surgical techniques and diagnostic methods has allowed the successful survival of the majority of affected children. In spite of this, treatment is inadequate in a significant proportion of children and better treatment modalities are required. Postoperative problems continue to occur, and diagnosis continues to be made late. Effort in the short term needs to be directed to better understanding of the associated enterocolitis, with the lessons learned from other idiopathic inflammatory bowel disorders applied to HSCR. Dysmotility of the ganglionic gut may underlie many postoperative obstructive episodes, yet there are still few systematic studies of these episodes. The principal diagnostic modalities are well understood but are only patchily available in most countries, leading to unnecessary delays in diagnosis and treatment. The availability of long-term home parenteral nutrition has enabled the survival of children with total intestinal aganglionosis. In the short term, the emergence of intestinal transplantation from the realms of experimental treatment will allow these children a better quality of life. Recent research has produced a better understanding of the genetic factors involved and of the developmental neurobiology of the enteric nervous system so that it is now possible to contemplate neuronal replenishment of the aganglionic gut.85 In the medium to long term, it can be foreseen that autologous neuronal transplantation could replace surgery as the treatment of choice for some forms of HSCR. Undoubtedly, these further refinements will lead to better and more timely treatment of those affected with HSCR.

6. Bealer JF, Natuzzi ES, Buscher C, et al. Nitric oxide synthase is deficient in the aganglionic colon of patients with Hirschsprung’s disease. Pediatrics 1994; 93:647–651.

AUTHOR’S RECOMMENDATIONS An approach to the child with obstructive symptoms To establish the cause of the obstruction, simple tests are required. The treatment depends upon accurately delineating the etiology. In general, while evaluation of the patient is in progress, close attention to rectal decompression and treatment of symptoms suggestive of enterocolitis are necessary. Specific therapy should be based on the results of the evaluation, which is presented in the form of an algorithm in Figure 60.2.

REFERENCES 1. Hirschsprung H. Stuhltragheit Neugeborener infolge von Dilatation und Hypertrophie des Colons. Jarb Kinderheilkd 1887; 27:1–9. Original clinical description of HSCR still valid today. 2. Kleinhaus S, Boley SJ, Sheran M, et al. Hirschsprung’s disease. A survey of the members of the surgical section of the American Academy of Pediatrics. J Pediatr Surg 1979; 14:588–597.

7. Swenson 0. Early history of the therapy of Hirschsprung’s disease: Facts and personal observations over 50 years. J Pediatr Surg 1996; 31:1003–1008. 8. Swenson 0, Sherman P, Fisher IN. Diagnosis of congenital megacolon: an analysis of 501 patients. J Pediatr Surg 1973; 8:587–594. Largest cohort of patients but diagnostic tools have advanced. 9. Qualman SJ, Pysher T, Schauer G. Hirschsprung disease: Differential diagnosis and sequelae. Perspect Pediatr Pathol 1997; 20:111–126. 10. Hung WT, Chiang TP, Tsai YW, et al. Adult Hirschsprung’s disease. Pediatr Surg 1989; 24:363–366. 11. Bassotti G, Mortara G, Lazzaroni M, et al. Adult Hirschsprung’s disease mimicking Crohn’s disease. Hepatogastroenterology 1995; 42:100–102. 12. Wang TY, Lin TC, Hsu H; Hirschsprung’s disease manifested with obstructive colitis in adult: A case report. Chin Med (Taipei) 1996; 58:444–447. 13. Barness PR, Lennard-Jones JE, Hawley PR, et al. Hirschsprung’s disease and idiopathic megacolon in adults and adolescents. Gut 1986; 27:534–541. 14. Rudolph C, Benaroch L. Hirschsprung disease. Pediatr Rev 1995; 16:5–11. 15. Elhalaby EA, Coran AG, Blane CE, et al. Enterocolitis associated with Hirschsprung’s disease: A clinical-radiological characterization based on 168 patients. Pediatr Surg 1995; 30:76–83. 16. Marry TL, Matlak ME, Hendrickson M, et al. Unexpected death from enterocolitis after surgery for Hirschsprung’s disease. Pediatrics 1995; 96:118–121. Enterocolitis remains the major cause of mortality. 17. Teitelbaum MD. Hirschsprung’s disease in children. Curr Opin Pediatr 1995; 7:316–322. 18. Nurko SS. Constipation. In: Walker-Smith J, Hamilton D, Walker AW, eds. Practical pediatric gastroenterology. Hamilton, Ontario: BC Decker; 1996:95–106. 19. Nurko SS, Garcia-Aranda A, Guerrero VY, et al. Treatment of intractable constipation in children: Experience with cisapride. J Pediatr Gastroenterol Nutr 1996; 22:38–44. 20. Todd I. Adult Hirschsprung’s disease. Br J Surg 1977; 64:311–312. References 21–44 refer to the genetic revolution in HSCR, mice, men, and experimental studies. 21. Passarge E. The genetics of Hirschsprung’s disease. N Engl J Med 1967; 276:138–143. 22. Pingault V, Puliti A, Prehu M, et al. Human homology and candidate genes for the dominant megacolon locus, a mouse model of Hirschsprung disease. Genomics 1997; 39:86–89. 23. Eng C. The RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschsprung’s disease. N Engl J Med 1996; 335:943–951.

References

10 years and 25% at 15 years after definitive surgery in this group of patients with HSCR.83 Enterocolitis occurred even long after initial repair, so these patients need to be followed closely for many years.


852 24. Many TL, Seo T, Matalak ME, et al. Gastrointestinal function after surgical correction of Hirschsprung’s disease: Long-term follow-up in 135 patients.J Pediatr Surg 1995; 30:655–658.

44. Low PS, Quak SH, Prabhakaran K, et al. Accuracy of anorectal manometry in the diagnosis of Hirschsprung’s disease. J Pediatr Gastroenterol Nutr 1989; 9:342–346.

25. Heij HA, de Vries X, Bremer I, et al; Long term anorectal function after Duhamel operation for Hirschsprung disease. Pediatr Surg 1995; 30:430–432.

45. Hanani M, Udassin R, Ariel I, et al. A simple and rapid method for staining the enteric ganglia: Application for Hirschsprung disease. J Pediatr Surg 1993; 28:939–941.

26. Trupp M, Arinas E, Fainzibla M, et al. Peripheral expression and biological activities of GDNF, a new neurotropic factor for avian and mammalian peripheral neurons. Nature 1996; 381:789–793.

46. Lake BD, Puri P, Nixon HH, et al. Hirschsprung’s disease an appraisal of histochemically demonstrated acetylcholinesterase activity in suction rectal biopsies, an aid to diagnosis. Arch Pathol Lab Med 1978; 102:244–247.

27. Schuchardt A, D’Agati V, Larsson-Blomberg L, et al. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor ret. Nature 1994; 367:380–383.

Suction rectal biopsy with acetylcholinesterase staining is the gold standard for the diagnosis of HSCR.

28. Sanchez MP, Selos Santiago I, Frezen J, et al. Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature 1996; 382:70–73.

47. Schofield DE, Devine W, Yunis EJ. Acetylcholinesterase-stained suction rectal biopsies in the diagnosis of Hirschsprung’s disease. J Pediatr Gastroenterol Nutr 1990; 11:221–228.

29. Edery P, Lyonnet S, Mulligan LM, et al. Mutation of the ret proto oncogene in Hirschsprung’s disease. Nature 1994; 367:378–380.

48. Cord-Udy CL, Smith VV, Ahmed S, et al. An evaluation of the role of suction rectal biopsy in the diagnosis of intestinal neuronal dysplasia. J Pediatr Gastroenterol Nutr 1997; 24:1–6.

30. Lyonnet S, Bellono A, Pelet A, et al. A gene for Hirschsprung’s disease maps to the proximal long arm of chromosome 10. Nat Genet 1993; 4:346–350. 31. Moore MW, Klein RD, Farinas I, et al. Renal and neuronal abnormalities in mice lacking GDNF. Nature 1996; 382:76–79. 32. Hosoda K, Hammer RE, Richardson JA, et al. Targeted and natural piebald lethal mutations of endothelin B receptor gene produce megacolon associated with spotted coat colour in mice. Cell 1994; 79:1267–1276. 33. Payette RF, Tennyson VM, Pomeranz HD, et al. Accumulation of components of basal laminae: association with the failure of neural crest cells to colonise the presumptive aganglionic bowel of LS/LS mutant mice. Dev Biol 1988; 125:341–360. 34. Kapur RP, Yost C, Palmiter RD. A transgenic model for studying the development of the enteric nervous system in normal and aganglionic mice. Development 1992; 116:167–175. 35. Benailly HK, Lapierre JM, Laudier B, et al. PMX2B, a new candidate gene for Hirschsprung’s disease. Clin Genet 2003; 64:204–209. 36. Angrist M, Bolk S, Thiel B. et al. Mutation analysis of the RET receptor tyrosine kinase in Hirschsprung disease. Hum Mol Genet 1995; 4:821–830.

49. Moore SW, Millar AJ, Cywes S. Long term clinical, manometric, and histologic evaluation of obstructive symptoms in the postoperative Hirschsprung’s patient. J Pediatr Surg 1994; 29:106–111. 50. Marty TL, Seo T, Sullivan JJ, et al. Rectal irrigations for the prevention of postoperative enterocolitis in Hirschsprung’s disease. J Pediatr Surg 1995; 30:652–654. 51. Pierro A, Fasoli L, Kiely EM, et al. Staged pull-through for rectosigmoid Hirschsprung’s disease is not safer than primary pull-through. J Pediatr Surg 1997; 32:505–509. 52. Philippart AI. Hirschsprung’s disease. In: Ashcraft KW, Holder TM, eds. Pediatric surgery. Philadelphia: WB Saunders; 1993:358–371. 53. Swenson 0, Sherman JO, Fisher JH. The treatment and postoperative complications of congenital megacolon: A 25 year follow up. Ann Surg 1975; 182:266–272. 54. Klein MD, Philippart AI. Hirschsprung’s disease: Three decades’ experience at a single institution. J Pediatr Surg 1993; 10:1291–1294. 55. Tariq GM, Brereton RJ, Wright VM. Complications of endorectal pull-through for Hirschsprung’s disease. J Pediatr Surg 1991; 26:1202–1208.

37. Newgreen D, Young HM. Enteric nervous system: development and developmental disturbances – Part 1. Pediatr Dev Patho1 2002; 5:224–247.

56. Nurko SS. Complications after gastrointestinal surgery: A medical perspective. In: Walker WA, Durie PR, Hamilton JR, et al. eds. Pediatric gastrointestinal disease. Pathophysiology, diagnosis, management. 2nd edn. St Louis: Mosby; 1996:2067–2094.

38. Mulligan LM, Eng C, Healey CS, et al. Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet 1994; 6:70–74.

57. Catto-Smith AG, Coffey CM, Nolan T, et al. Fecal incontinence after the surgical treatment of Hirschsprung’s disease. J Pediatr 1995; 127:954–957.

39. Edery P, Attie T, Amiel J, et al. Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah Waardenburg syndrome). Nat Genet 1996; 12:442–444.

58. Moore SW, Albertyn R, Cywes S. Clinical outcome and long-term quality of life after surgical correction of Hirschsprung’s disease. J Pediatr Surg 1996; 31:1496–1502.

40. Bolk S, Pelet A, Hofstra R, et al. A human model for multigenic inheritance: phenotypic expression in Hirschsprung’s disease requires both RET gene and a new 9q31 locus. Proc Natl Acad Sci USA 2000; 97:268–273.

59. Cilley RE, Starter MB, Hirschl RB, et al. Definitive treatment of Hirschsprung’s disease in the newborn with a one-stage procedure. Surgery 1994; 115:551–556.

Evidence that HSCR is a multigenic disorder. 41. Bealer JF, Natuzzi ES, Flake AW, et al. Effect of nitric oxide on the colonic smooth muscle of patients with Hirschsprung’s disease J Pediatr Surg 1994; 29:1025–1029. 42. Taxman TL, Yulish BS, Rothstein FC; How useful is the barium enema in the diagnosis of infantile Hirschsprung’s disease? Am J Dis Child 1986; 140:881–884. 43. Lopez-Alonso M, Ribas J, Hernandez J, et al. Efficiency of the anorectal manometry for the diagnosis of Hirschsprung’s disease in the newborn period. Eur J Pediatr Surg 1993; 5:160–163

60. Georgeson KE, Fuenfer MM, Hardin WH. Primary laparoscopic pull-through for Hirschsprung’s disease in infants and children. J Pediatr Surg 1996; 30:1017. 61. Rothenberg S, Chang JH. Laparoscopic pull-through procedures using the harmonic scalpel in infants and children with Hirschsprung’s disease. J Pediatr Surg 1997; 32:894–896. Advances in surgical technique but improvement in outcome controversial. 62. Blane CE, Elhalaby E, Coran AG. Enterocolitis following endorectal pull-through procedure in children with Hirschsprung’s disease. Pediatr Radiol 1994; 24:164–166.

853

64. Aslam A, Spicer RD, Corfield AP. Children with Hirschsprung’s disease have an abnormal colonic mucus defensive barrier independent of the bowel innervation status. J Pediatr Surg 1997; 32:1206–1210. 65. Mishalany HG, Wooley MM. Postoperative functional and manometric evaluation of patients with Hirschsprung’s disease. J Pediatr Surg 1987; 22:443–446. 66. Nagasaki A. Anorectal manometry after Ikeda Z-shaped anastomosis in Hirschsprung’s disease. Prog Pediatr Surg 1989; 21:59–66. 67. Blair GK, Djonlic K, Fraser GC, et al. The bowel management tube: An effective means for controlling fecal incontinence. Pediatr Surg 1992; 27:1269–1272. 68. Dick AC, McCallion WA, Brown S, et al. Antegrade colonic enemas. Br J Surg 1996; 83:642–643. 69. Di Lorenzo C, Solzi GF, Flores AF, et al. Colonic motility after surgery for Hirschsprung’s disease. Am J Gastroenterol 2000; 95:1759–1764. 70. Smith VV, Gregson N, Foggensteiner L, et al. Acquired intestinal aganglionosis and circulating autoantibodies without neoplasia or other neural involvement. Gastroenterology 1997; 112:1366–1371. 71. Hanimann B, Inderbitzin D, Briner J, et al. Clinical relevance of Hirschsprung-associated neuronal intestinal dysplasia. Eur J Pediatr Surg 1992; 2:147–149. 72. Koletzko S, Ballauff A, Hadziselimovic F, et al. Is histological diagnosis of neuronal intestinal dysplasia related to clinical and manometric findings in constipated children? Results of a pilot study. J Pediatr Gastroenterol Nutr 1993; 17:59–65. Intestinal neuronal dysplasia in perspective; read in conjunction with reference 48. 73. Ryan DP. Neuronal intestinal dysplasia. Semin Pediatr Surg 1995; 4:18–25. 74. Collins SM. The immunomodulation of enteric neuromuscular function: implications for motility and inflammatory disorders. Gastroenterology 1996; 111:1683–1699.

75. Langer JB, Birnbaum E. Preliminary experience with intrasphincteric botulinum toxin for persistent constipation after pull-through for Hirschsprung’s disease. J Pediatr Surg 1997; 32:1059–1062. 76. Kobayashi H, Hirakawa H, Puri P. Abnormal internal anal sphincter innervation in patients with Hirschsprung’s disease and allied disorders. J Pediatr Surg 1996; 31:794–799. 77. Blair GK, Murphy JJ, Fraser GC. Internal sphincterotomy in postpull-through Hirschsprung’s disease. J Pediatr Surg 1996; 31:843–845. 78. Bannani SA, Forootan H. Role of anorectal myectomy after failed endorectal pull-through in Hirschsprung’s disease. J Pediatr Surg 1994; 29:1307–1309. 79. Nurko S. Botulinum toxin for achalasia: Are we witnessing the birth of a new era? J Pediatr Gastroenterol Nutr 1997; 24:447–449. 80. Shandling B, Chait PG, Richards HF. Percutaneous cecostomy: A new technique in the management of fecal incontinence. J Pediatr Surg 1996; 31:534–537. 81. Hengster P, Pernthaler H, Gassner I, et al. Twenty-three years of follow-up in patients with total colonic aganglionosis. Klin Padiatr 1996; 208:3–7. 82. Endo M, Watanabe K, Fuchimoto Y, et al. Long-term results of surgical treatment in infants with total colonic aganglionosis. J Pediatr Surg 1994; 29:1310–1314. 83. Tsuji H, Spitz L, Kiely EM, et al. Management and long-term followup of infants with total colonic aganglionosis. J Pediatr Surg 1999; 34:158–161. Outcome of total colonic aganglionosis is worse than short-segment HSCR. Management is a real challenge. 84. Miele E, Tozzi A, Staiano A, et al. Persistence of abnormal gastrointestinal motility after operation for Hirschsprung’s disease. Am J Gastroenterol 2000; 95:1226–1230. 85. Bondurand N, Natarajan D, Thapur N, et al. Neuron and glia generating progenitors of the mammalian enteric nervous system isolated from foetal and post-natal gut cultures. Development 2003; 130:6387–6400. Perhaps the beginning of the development of alternative forms of treatment.

References

63. Moore SW, Neveling U, Kaschula RO. Acquired aganglionosis following surgery for Hirschsprung’s disease: A report of five cases during a 33 year experience with pull-through procedures. Histopathology 1993; 22:163–168.


61

CHAPTER SIXTY-ONE

Diverticular disease of the colon Bradley R. Davis and Jeffrey B. Matthews

INTRODUCTION Diverticular disease of the colon was rarely described before the twentieth century, and it was not until 1899 that Graser first correlated the pathological changes with the clinical signs and symptoms.1,2 Today the diagnosis is extremely common, affecting about 10% of the population over the age of 45 and 65% of those over 80.3 Its emergence as a significant clinical and pathological disorder (diverticulitis) has been attributed to the dramatic reduction in the fiber content of Western diets,4 and although it remains considerably less common in Asia and Africa, studies of immigrant populations suggest that westernization of diets is associated with an increased frequency of diverticulosis within about 10 years.5 Some prospective data suggests an inverse relationship, independent of dietary fiber intake, between physical activity and the development of symptomatic diverticular disease in men, although the basis for this is unclear.6 Although diverticula develop in many people, clinical complications occur in only a small percentage. These complications usually, but not always, develop after age 40, and are usually related to perforation and inflammation or to bleeding. It is estimated that symptomatic diverticulitis will develop in 20% of patients with diverticula,7 accounting for approximately 455 000 admissions at an annual cost of US$1.9 billion.8 Most colonic diverticula are pseudodiverticula and represent mucosal and submucosal herniation through the muscle layers of the colon at areas of intrinsic weakness, where the nutrient arteries enter adjacent to the teniae.1 The diverticula may be single but are usually multiple and can vary in size up to 2 cm. The sigmoid colon is involved in 95% of cases, although 35% of patients also have more proximal disease. Diverticula are distinctly unusual below the pelvic peritoneal reflection. Rightsided diverticulosis is rare in Western countries but is the predominant pattern in Asian populations.9–11 This condition is distinct from solitary cecal diverticulum, although both tend to affect younger patients. True diverticula are quite uncommon in the colon but when present are usually single and right sided. A true diverticulum that appears on the antimesenteric border of the sigmoid colon (giant sigmoid diverticulum) may reach enormous size and be visible on plain abdominal films.12 The cause of diverticular herniation in the colon is complex and continues to be elucidated. The underlying mechanism is an aberrant balance between intraluminal pressure, elasticity, and tensile strength of the involved colonic segment. Stiffening of the longitudinal muscle layers as a result of excessive deposition of

elastin, occurs normally with aging.13 As the colon attempts to contract against this increased resistance, hypertrophy occurs, with resultant luminal narrowing, a process referred to as myochosis coli. Isolated colonic segments are therefore exposed to excessive intraluminal pressure, which is thought to lead to mucosal herniation. Pressures are higher in patients with symptomatic disease than in those with asymptomatic diverticulosis.14 Measurements of intraluminal pressure also indicate exaggerated responses to food intake and pharmacologic stimulation which may be due in part to segmental abnormalities in cholinergic activity.15 Indigestible cereal fiber increases the wet weight and diameter of stool and decreases intraluminal pressure, supporting the notion that dietary fiber and diverticular disease are inversely related.16

CLINICAL SPECTRUM Diverticulosis and uncomplicated diverticulitis The clinical manifestations of diverticular disease are myriad, ranging from asymptomatic diverticulosis to life-threatening free perforation. Some patients with diverticulosis describe recurring episodes of lower abdominal cramping in the absence of clear-cut evidence of inflammation; so-called painful diverticulosis has been ascribed to intermittent functional obstruction associated with the hypersegmentation, although the relationship to the presence of diverticula is unclear. When the lumen of a diverticulum is occluded by a fecalith, inflammatory changes develop, initially in the lymphoid tissue at the apex of a diverticulum but soon spreading to the visceral peritoneum and pericolic fat.2 The necrotizing inflammatory process occurs without gross perforation and leakage of luminal contents. With further diverticular distention, subsequent vascular ischemia leads to microperforation, which usually results in uncomplicated diverticulitis. This is the most common clinical manifestation of diverticular disease, resulting in localized peritonitis and abdominal pain.

Complicated diverticular disease Complications of diverticulitis have been well described, and a classification scheme has been proposed by Hinchey and colleagues in an effort to stratify diagnosis and treatment (Table 61.1).l7 Most often, a perforation is walled off by surrounding structures and a localized abscess develops. Direct extension and perforation into an adjacent hollow viscous results in fistula formation.

Diverticular Disease of the Colon

856

Investigation

Table 61.1 Staging of perforative complications of diverticular disease A.

Fistula formation

B.

Inflammation and perforation

Stage I

Sigmoid obstruction, intracolonic or mesenteric abscess

Stage II

Localized pericolic abscess

Stage III

Generalized septic (purulent) peritonitis

Stage IV

Generalized fecal peritonitis

Intestinal obstruction may develop in some instances, either because of compromise of the large bowel lumen by the severe changes within the colonic wall or as a result of kinking of small bowel loops caught up in the inflammatory mass. A free perforation of a diverticulum or peridiverticular abscess may result in generalized peritonitis. Diverticular hemorrhage is discussed later in the chapter.

EVALUATION OF THE PATIENT WITH ACUTE DIVERTICULITIS Clinical features Abdominal pain, usually in the left lower quadrant, and fever are the usual initial symptoms of acute diverticulitis (Table 61.2). Nausea and vomiting are uncommon without associated intestinal obstruction. Diarrhea is reported about as frequently as constipation. Urinary function may also be altered if the inflammatory mass abuts the bladder wall. Dysuria, urgency, and urinary frequency may be present, and if fistulization has occurred, the patient may note pneumaturia or foul-smelling urine suggestive of infection with fecal organisms. Examination typically reveals tenderness with some signs of peritoneal inflammation. A tender, fixed mass is often palpable. If the inflammatory mass is confined to the pelvis, the abdominal findings may be minimal. Patients who are more seriously ill will display signs of severe localized or generalized peritonitis associated with symptoms of systemic sepsis. A necrotizing infection may extend extraperitoneally and present by extension into the abdominal wall. Leukocytosis is not invariable. Urinalysis may reveal hematuria, pyuria, or a polymicrobial infection.

The diagnosis of acute diverticulitis is often made on clinical grounds with sufficient certainty to direct initial therapy. In practice, however, most patients undergo radiologic or endoscopic investigation (Table 61.3). Useful initial studies include a complete blood count, urinalysis, and abdominal flat and upright X-rays. If the clinical picture is clear, it has been suggested that no other tests are needed to make the diagnosis. However, by relying on clinical parameters alone, the diagnosis may be incorrect in up to one-third of patients. Sigmoidoscopy may exclude rectal pathology or distal colitis, but within the first few days of assessment most clinicians are reluctant to choose sigmoidoscopy for fear of disrupting a contained perforation. Contrast enema in the acute setting is also controversial. Because of the risk of perforation, minimal pressure should be used and water-soluble contrast should be chosen. The radiologic characteristics of acute diverticulitis on water-soluble contrast enema include: (1) diverticulosis with or without spasm; (2) marked sigmoid irregularity with long luminal strictures or obstruction; and (3) extraluminal extravasation of contrast. These changes are not pathognomonic of diverticular inflammation. The advantages of contrast enema are its low cost and the ability to identify mucosal lesions. Its most important role is in the nonacute setting. Arguably, the most important diagnostic modality in acute diverticulitis is computed tomography (CT).18,19 It is noninvasive, safe, and can detect complications of diverticular disease. Bowel wall thickening, mesenteric streaking, and pericolic phlegmonous changes in association with diverticulosis indicate the presence of acute diverticulitis (Fig. 61.1). Complicated diverticulitis may be recognized by identifying associated abscesses, fistulas, or intra-abdominal or pelvic free fluid or air. The ability of CT to stratify patients for inpatient versus outpatient management of acute diverticulitis is not established but is of interest.20–22 Abdominal ultrasound is useful if local expertise in this modality is available.23 Laparoscopy as a diagnostic modality may be useful, but is rarely necessary.24

Differential diagnosis A number of entities must be considered in the differential diagnosis (Table 61.4). Both diverticular disease and colonic malignancy tend to affect an older population and may coexist in the same individual.25,26 It may be difficult to distinguish between these possibilities on initial evaluation; however, initial manage-

Table 61.2 Clinical manifestations of acute diverticulitis Symptoms

Signs

Laboratory findings

Pain, usually LLQ

Fever

Leukocytosis

Fever, chills

Abdominal tenderness

Hematuria

Malaise

Abdominal mass

Pyuria

Anorexia, nausea

Abdominal distention

Polymicrobial UTI

Diarrhea or obstipation

Pelvic or rectal irritation

Urinary frequency

Local peritoneal irritation Psoas sign

857

Examination

Major diagnostic findings

Disadvantages

Plain abdominal radiography

Soft tissue density Air-fluid levels

Non-specific

Upright chest radiography

Free intraperitoneal air

False-negative results

Contrast enema

Presence of diverticula Luminal narrowing or spasm Extravasation of contrast Fistulous tract

Perforation Barium peritonitis (water-soluble contrast is preferable)

Colonoscopy/sigmoidoscopy

Presence of diverticula Luminal narrowing or spasm

Risk of perforation

Abdominal and pelvic CT

Presence of diverticula Mural thickening Mesenteric streaking Free intra-abdominal fluid or air Pericolic abscess Air within the urinary bladder

Expense

Abdominal ultrasound

Thickened colonic segment Pericolic abscess Free intra-abdominal fluid

Operator dependent

ment is similar, and one need not go to great lengths to do so. After resolution of the acute situation, a concerted effort must be made to exclude the diagnosis of carcinoma. Crohn’s colitis may be manifested as abdominal pain, fever, a tender abdominal mass, and leukocytosis. On occasion it may be surprisingly difficult even on histopathologic examination of a resected specimen to distinguish short segmental Crohn’s disease from diverticulitis.27 Ischemic colitis may closely mimic diverticulitis. Diverticulitis may simulate urinary tract infection as well as pelvic inflammatory disease.28 Confusion between diverticulitis and appendicitis may occur in a number of circumstances, such as when the sigmoid colon or appendix crosses the midline or when the diverticulitis is right sided.

Recognition of complications A large peridiverticular abscess is suggested by the presence of a tender mass on palpation of the abdomen, digital examination of the rectum, or pelvic examination in a patient with high, spiking fever. Confirmation is by CT scan (Fig. 61.2A). The most common fistula associated with diverticulitis is colovesical. Typically, such fistulas involve the posterior wall of the bladder. In females, the uterus and broad ligaments protect the bladder, and fistulization

is less common than in males. The diagnosis may be supported by cystoscopy or by barium enema, but CT appears to be the most useful investigation,29 since air within the bladder is generally considered pathognomonic (Fig. 61.3).30 Colovaginal fistula, as a complication of diverticulitis, is mostly described in the setting of previous hysterectomy.31 A colocutaneous fistula may occur after therapeutic drainage or as a result of spontaneous rupture of a paracolic abscess through the abdominal wall. Rarely, a necrotizing infection may extend into the anterior thigh or through the pelvic floor and simulate fistula in ano.32,33 Coloenteric fistulae are usually asymptomatic but may cause diarrhea as a result of bacterial overgrowth or diversion of small bowel contents into the colon. Intestinal obstruction is most commonly partial and may be due to blockage of either the colon or the small intestine. Obstructive symptoms may dominate the clinical findings. Free perforation of an inflamed diverticulum or peridiverticular abscess results in generalized peritonitis. This catastrophic event is characterized by the sudden onset of severe abdominal pain associated with sepsis. Although free perforation of the colon may be the initial manifestation of diverticular disease, particularly in elderly patients, it may also occur while a patient is under medical

Table 61.4 Differential diagnosis of acute diverticulitis

•

Fig. 61.1 Acute diverticulitis depicted by contrast computed tomography. Mesenteric thickening and streaking are evident, along with luminal narrowing (large arrow). A small amount of extraluminal gas is also noted (small arrow) and indicates a contained (Hinchey BI) mesenteric abscess.

Acute appendicitis Perforated colon carcinoma Inflammatory bowel disease (Crohn’s disease and ulcerative colitis) Pelvic inflammatory disease Ischemic colitis Infectious colitis Foreign body perforation Urinary tract infection or nephrolithiasis

Evaluation of the Patient with Acute Diverticulitis

Table 61.3 Diagnostic investigation in acute diverticulitis


858

•

Fig. 61.2 (A) A contained pelvic abscess (Hinchey B) associated with diverticulitis. Abscess measures 4 cm (arrow). (B) A percutaneous catheter has been placed in the abscess (arrow).

A

B

•

Fig. 61.3 Colovesical fistula as seen on CT scan of the pelvis. Note the thickening of the bladder wall, the presence of oral contrast, and air within the bladder (arrow).

greater amounts are required to achieve the same effect because of their higher content of water. In patients with asymptomatic diverticulosis the addition of dietary fiber, while routinely recommended, has not been shown to reduce the incidence of diverticulitis and the approach to these patients should be individualized.

Bulk additives

TREATMENT OF UNCOMPLICATED DIVERTICULOSIS

As an alternative or in addition to increased dietary fiber intake, a variety of hydrophilic colloid bulk preparations have been introduced into the market, including products based on methylcellulose and ispaghula husk. These substances absorb 25–40 times their weight in water and thereby increase stool volume with the same net effect as dietary fiber. There is no evidence that one preparation is superior to another in terms of reduction in intraluminal pressure or increase in stool volume.38

Dietary modification

Antispasmodics and analgesics

In patients with abdominal pain associated with colonic diverticulosis in the absence of signs of acute diverticulitis, enhanced intake of dietary fiber may be of benefit,34–36 although the efficacy of this practice remains to be convincingly demonstrated.37 Fiber intake facilitates the passage of softer, bulkier stools, with a resultant decrease in colonic hypersegmentation and intraluminal pressure. Patients should be educated on ways of increasing the bulk in their diet (Table 61.5), and instructed that alleviation of their symptoms may take several months. Unprocessed wholewheat bran, 10–25 g/day, added to juice, soup, or other liquids is the recommended amount. Often, patients will note bloating and discomfort for several weeks after initiation of this regimen. More palatable approaches include increased intake of high-fiber breakfast cereals or whole-wheat bread. Although fruits and vegetables may also contribute to total dietary fiber intake, substantially

Agents that affect colonic motility, including musculotropic drugs and anticholinergics, have not been proven to be effective for socalled painful diverticulosis and cannot be recommended. Many opiates raise intraluminal pressure in the sigmoid colon and may predispose to perforation. Although meperidine in usual doses does not appear to share this property, in general the use of such compounds is to be avoided. Like dietary modification, the use of prophylactic antispasmodics has not been demonstrated to reduce the incidence of diverticulitis.

treatment for acute diverticulitis, in which case rupture of a peridiverticular abscess is the usual etiology.

Table 61.5 Potential sources of increased dietary bulk Bulk source

Amount

Unprocessed miller’s bran

10–25 g daily with water or juice

High-fiber cereal

One bowl daily

Whole-wheat bread

Five slices daily

Bulk preparations

One tbsp or one tablet once or twice daily

Fruits and vegetables

Several generous portions daily

TREATMENT OF UNCOMPLICATED ACUTE DIVERTICULITIS Medical therapy In the majority of patients the initial treatment of acute diverticulitis consists of antibiotics and some degree of dietary restriction. Most patients, about 85%, recover completely with medical therapy.39 Diverticulitis will eventually recur in about one-third, often within the first year after the initial episode; the role of surgery in these patients is discussed later. Unless the symptoms are quite mild, patients should forego oral intake until it becomes certain that urgent surgical or radiologic intervention will not be necessary. Although many advocate complete bowel rest for all patients, such practice is probably unnecessarily restrictive, and clear liquids may be allowed for selected individuals provided that no significant nausea or abdominal distention is present. Nasogastric suction is reserved for patients in whom associated small

859

Outpatient management Selected patients with uncomplicated diverticulitis may be managed in the outpatient setting, provided that they do not demonstrate potentially worrisome markers for advanced disease such as high fever, shaking chills, signs of local peritonitis, or symptoms of intestinal obstruction.41 Patients must be able to take fluids and tolerate an oral antibiotic regimen. The approach to antibiotic therapy does not change with outpatient management, with many practitioners opting for monotherapy (ciprofloxacin, amoxicillin/clavulanate), others preferring a combination approach (ciprofloxacin and metronidazole).40 Detailed instructions for follow-up must be provided, and the physician must be convinced that the patient and family are reliable. Patients are instructed to return if pain or fever fails to resolve quickly or

if fluids are not tolerated. Arrangements for subsequent outpatient investigation to confirm the diagnosis should be made.

TREATMENT OF ACUTE DIVERTICULITIS COMPLICATED BY ABSCESS Abscess formation as a complication of diverticulitis may occur in as many as 16% of patients.43 Clinical suspicion may be raised at the initial evaluation or when a patient fails to respond adequately to initial medical management. Hospitalization is mandatory, with complete bowel rest and intravenous fluid administration. Radiologic investigation by CT or ultrasound should be carried out to confirm the presence of a localized abscess. Usually such abscesses are within the leaves of the colonic mesentery, but occasionally a pelvic abscess may form as a result of dependent pooling of a macroscopic perforation.

Percutaneous radiologic catheter drainage Depending on their location and size, such abscesses may be amenable to percutaneous, radiologically guided catheter drainage. A number of reports attest to the safety and success of this approach,44–46 although the precise indications remain to be clearly defined. The goal of percutaneous drainage is to gain control of the infection such that later surgery may be performed as a one-stage procedure (see below) without colostomy under more elective circumstances.41 It is possible that successful percutaneous management of peridiverticular abscess obviates the absolute need for subsequent surgery in certain patients, but this issue is controversial. It is probably unnecessary to drain small abscesses 200 mL/day) generally fare poorer than low-output fistulas.69 A coloenteric fistula should be treated by en bloc resection of the affected segments of small bowel along with the involved colon. Again, primary anastomosis without colostomy is performed.

TREATMENT OF DIVERTICULITIS COMPLICATED BY OBSTRUCTION Small bowel obstruction associated with acute diverticulitis is managed by intravenous fluids, correction of electrolyte abnormalities, and nasogastric suction. If surgery is undertaken, resection of the adherent small intestinal segment may be required, if it cannot be readily separated from the inflammatory mass. Large bowel obstruction resulting from sigmoid luminal narrowing presents a more difficult management situation. Even if the obstruction is only partial, preoperative bowel preparation may be impossible. Of greater concern, however, are patients with complete colonic obstruction, in whom the risk of cecal perforation may be substantial. The traditional approach to this situation consists of proximal decompression via cecostomy tube placement or transverse loop colostomy, followed by elective resection of the sigmoid mass. However, current trends favor initial resuscitation followed by expeditious resection of the obstructing mass, either as a Hartmann procedure,41 as subtotal colectomy, or even with primary anastomosis after on-table colonic luminal lavage.59,70,71 The specific decision depends on the condition of the patient, the technical ease with which resection can be performed, and the surgeon’s preference. The obstruction is not infrequently found to be due to carcinoma rather than diverticulitis.72

TREATMENT OF DIVERTICULITIS COMPLICATED BY FREE PERFORATION Free perforation of a diverticulum or peridiverticular abscess is a surgical emergency. Mortality for this condition approaches 35% in many series, depending on the degree of fecal contamination, the delay before surgery, and the extent of associated comorbid disease. In addition to intravenous fluids and broad-spectrum antibiotics, pressor support may be needed, and invasive cardiovascular monitoring to guide resuscitation may be appropriate. Hartmann resection is the most commonly used procedure and is considered the most conservative approach, with mortality rates ranging from about 10% to 20% depending on the patient mix.50,73–76 It is reasonable, if anatomic circumstances permit, to bring out the distal end as a mucous fistula to avoid the risk of leakage from the rectal stump in the setting of substantial intraperitoneal soilage. Lavage and drainage of the peritoneal cavity plus transverse loop colostomy, with the diseased segment left in situ, has been advocated for the desperately ill patient,77 and one small randomized trial comparing this approach with Hartmann resection supports this view.78 However, many studies suggest either no difference or a higher mortality rate with this approach when compared with resectional procedures.79–83 Resection is associated with fewer procedures per patient, fewer total hospital days, and fewer infectious complications.39,82 Immunocompromised patients with diverticulitis, including transplant patients,84,85 patients with advanced renal failure,86 patients receiving corticosteroid therapy,87 or patients with acquired immunodeficiency syndrome, are particularly prone to free perforation, and mortality is often in excess of 30%.86,88 Recognition of diverticulitis before perforation in these individuals is often difficult because the usual signs and symptoms are frequently masked.

ELECTIVE TREATMENT OF RECURRENT EPISODES OF ACUTE DIVERTICULITIS Risk of recurrence After successful medical management of acute diverticulitis, the risk of further episodes ranges from 7% to 45% depending on the length of follow-up.89–91 About 50% of recurrences requiring hospital admission will develop in the first year after the initial attack; 90% will develop within 5 years.92,93 A number of reports suggest that institution of a high-fiber diet may reduce the risk of recurrence, although the data supporting this concept are largely uncontrolled.94,95 Patients should be encouraged to begin a diet high in bulk and cereal fiber as soon as possible after resumption of normal oral intake. There is no evidence that avoidance of ‘blockage foods’ such as popcorn, nuts, and so forth will reduce the chance of recurrence, although this advice is often given to patients.

Indications for elective surgery Indications for surgery in patients with diverticulosis and the operations recommended are shown in Tables 61.6 and 61.7. With each recurrence of acute uncomplicated diverticulitis, patients become less likely to respond to medical therapy, with success decreasing from 70–85% after the first attack to only 6%

863

After a second well-documented episode of uncomplicated diverticulitis Failure of resolution of otherwise uncomplicated diverticulitis After a first episode of acute diverticulitis complicated by abscess Diverticular disease associated with colovesical fistula Continued partial obstruction associated with diverticulitis Inability to exclude carcinoma

after the third. Furthermore, after a second episode of diverticulitis, most patients will have persistent symptoms, and as many as 50% will experience complications. This observation underlies the basis for the recommendation that patients with more than two episodes of uncomplicated acute diverticulitis be considered for elective surgery. Patients with acute complicated diverticulitis should be considered for interval sigmoid resection even if complete resolution of the attack can be accomplished by antibiotics combined, when indicated, with percutaneous catheter drainage; recurrent complications developed in about 85% of such patients in one series as opposed to only 3% of those initially managed by resection.96 Resection is also indicated for patients with colovesical fistula, and many recommend surgery for those with urinary symptoms even in the absence of a documented fistula. Surgery is also usually considered in the face of continued partial obstruction of the colon, particularly when the possibility of carcinoma cannot be excluded. Acute diverticulitis in young patients (particularly those less than 40 years) is relatively uncommon and evidence that it is particularly aggressive is largely anecdotal.97–99 Most of these cases occur in men, with obesity as a common comorbidity.100,101 While proponents of early elective resection in this population cite the high incidence (up to 66%) of surgical intervention required at the initial episode as an indication of its aggressive behavior, this has not been encountered by all groups. Surgery in these patients is often undertaken for erroneous preoperative diagnoses,102 and in fact it may be more common for surgery to be required for an elderly rather than a young patient on the first admission.97,103 Elective surgery for young patients after their first

attack of acute diverticulitis, therefore, should only be recommended after careful consideration of the patient and the severity of the initial disease because as yet the natural history has not been clearly elucidated.102,104

Results of elective surgery for diverticular disease Resection is not generally indicated for patients with abdominal pain associated with uncomplicated diverticular disease; the experience of Rennie and associates would suggest that at least 85% will experience persistent symptoms105 as compared with only 6% after elective resection for patients with objective evidence of diverticulitis.106 Mortality after elective surgery should be near zero although, for reasons that are not entirely clear, resection for diverticulitis carries a greater morbidity rate than do similar resections for other diagnoses (e.g., cancer).107 Higher anastomotic leak rates after operations for diverticulitis may be due to the tendency for high intraluminal pressure to develop in patients with diverticular disease, particularly after pharmacologic stimuli such as those associated with reversal of neuromuscular blockade; additionally, leak rates may reflect the presence of infection and technical difficulty in identifying proximal segments that are completely free of diverticula.

Minimally invasive surgery for diverticulitis Recently, minimally invasive techniques of colonic resection have been used for elective treatment of diverticulitis with low morbidity. The cost of laparoscopic procedures and the operative times are greater than those of conventional surgery, but laparoscopy may lead to a shorter hospital stay with similar morbidity.108,109 In addition, the use of laparoscopy may ultimately reduce the incidence of postoperative bowel obstruction and hernia formation, due to reduction in adhesion formation and smaller wounds. Further investigation is necessary to define these benefits. As the laparoscopic experience continues to grow, its application in the treatment of diverticular disease will expand to include both complicated and uncomplicated disease.110–113

Recurrence after prior resection Diverticulitis recurs after resection in as many as 4–12% of patients.114 The incidence of recurrence is thought to be related in part to the adequacy of distal resection; results after limited

Table 61.7 Choice of operation for diverticular disease Indication

First choice

Alternative

Elective

Resection, primary anastomosis

Fistula (Hinchey A)

Resection, primary anastomosis, drainage of fistulized organ (i.e., Foley catheter)

Resection, primary anastomosis, repair of fistulized organ

Abscess (Hinchey BI and BII)

Resection, primary anastomosis

Resection, primary anastomosis, proximal diversion

Obstruction

Resection, on-table lavage, primary anastomosis

Hartmann procedure

Perforation (Hinchey BIII)

Hartmann procedure

Resection, primary anastomosis, proximal diversion

Perforation (Hinchey BIV)

Hartmann procedure

Lavage, drainage or suture repair, proximal diversion

Elective Treatment of Recurrent Episodes of Acute Diverticulitis

Table 61.6 Indications for elective surgery for diverticular disease


864 sigmoid resection are worse than results after resections that have been extended to the proximal portion of the rectum (at or below the pelvic peritoneal reflection).54 It is important to remember that patients with recurrences may in fact have had unrecognized Crohn’s disease rather than acute diverticulitis at the time of the original operation.69,115

TREATMENT OF CECAL OR RIGHTSIDED DIVERTICULITIS Cecal diverticula may be congenital or acquired, true diverticula or pseudodiverticula. The incidence of right-sided diverticulitis appears to be higher in Asian populations, where right-sided disease is more common than sigmoid diverticulosis.9,10,116 Cecal diverticulitis is often mistaken for appendicitis or perforated cecal carcinoma. Acute cecal diverticulitis is usually manifested without a periumbilical pain prodrome, the symptoms are often of several days’ rather than hours’ duration, and patients tend to be older than patients with appendicitis.117 Nevertheless, the diagnosis is only occasionally made preoperatively, and at surgery a substantial inflammatory mass is often present. It may be difficult to distinguish between acute cecal diverticulitis and carcinoma at the time of laparotomy, and if so, a right colectomy is indicated. If no evidence of abscess formation is found and cecal carcinoma can be excluded, appendectomy followed by postoperative antibiotics usually suffices.10,118 Simple diverticulectomy (in cases of a congenital solitary cecal diverticulum) is occasionally possible.119 An asymptomatic cecal diverticulum found incidentally at surgery may simply be invaginated.

EVALUATION AND TREATMENT OF DIVERTICULAR HEMORRHAGE Clinical features While the exact incidence of diverticular hemorrhage is uncertain, it is estimated to account for 40% of lower gastrointestinal bleeding.120,121 The diagnostic and treatment challenge rests in differentiating diverticular sources of bleeding from other causes such as colitis, vascular ectasias, and neoplasia. While most patients with diverticular bleeding will have a self-limited course, massive hemorrhage does occur in fewer than 5% of patients.122

Medical management A nasogastric tube should be placed to eliminate the chance that the bleeding is due to an upper source, although endoscopy is frequently required to exclude this possibility with certainty. After fluid resuscitation and stabilization, anoscopy and/or rigid sigmoidoscopy should be performed to exclude a hemorrhoidal or low rectal source. Bleeding stops spontaneously in at least 75% of patients,123 while a number of options for localization and control are available in those patients that continue to bleed. This is covered in detail in Chapter 65, and includes angiography, colonoscopy, and radionuclide scans.124–126 Angiography, when positive, can also be used to control diverticular hemorrhage through the selective infusion of vasopressin or through superselective catheter embolization. Vasopressin, an endogenous peptide hormone that causes arterial vasoconstriction in super-physiologic doses, was first described in the treat-

ment of gastrointestinal hemorrhage in 1968.127 Through selective infusion of vasopressin into the inferior mesenteric artery, diverticular bleeding can be clinically controlled in as many as 90% of patients.128 While selective infusion limits its systemic effects, the complications associated with vasopressin infusion include colonic ischemia, myocardial ischemia and infarction, bradycardia, and hypertension which can be partly ameliorated by the concomitant use of intravenous nitroglycerin. The rebleeding rate has been reported as high as 43%128 and overall complication rate as high as 41%.129 These series are mostly older and do not take into account modern angiographic techniques and the systemic use of nitroglycerin. While vasopressin therapy has remained relatively unchanged, the use of embolization techniques has evolved significantly since its first description for the treatment of lower gastrointestinal hemorrhage in 1974.130 The unacceptably high occurrence of bowel ischemia and infarction limited its use until the advent of superselective embolization in the early 1990s, a technique that places procoagulant or barrier material selectively into or beyond the marginal artery. This procedure has gained wider acceptance in the past decade and now boasts equivalent or better clinical response rates compared to vasopressin with a significantly lower incidence of complications (15%) and rebleeding (19%). The incidence of colonic ischemia requiring colectomy is negligible (1–5%).130 The choice between vasopressin or superselective embolization largely depends on local expertise and the patient’s overall condition, but it appears that superselective embolization has superseded vasopressin in the medical treatment of lower gastrointestinal hemorrhage.

Surgery for diverticular hemorrhage Surgery is rarely required in patients whose diverticular hemorrhage ceases spontaneously or through medical intervention, in as much as recurrent episodes are infrequent.131 Elective surgery may be considered for patients with recurrent hemorrhage, with the threshold for surgery lower in patients whose bleeding site has been localized, allowing for a segmental resection. The outcome for surgery in this setting is excellent.132 In rare instances, diverticular hemorrhage is so massive that medical stabilization is impossible and emergent surgery must be undertaken to avoid exsanguination. Surgery is also indicated for continued hemorrhage despite medical attempts at control. The loss of four units of blood during the first 24 hours is predictive of at lease a 50% chance of requiring emergency surgery.133 Preoperative identification of the bleeding site is invaluable so that a limited colectomy may be performed. If such identification proves impossible, intraoperative colonoscopy with the patient in lithotomy position may localize the source,134 otherwise a subtotal colectomy with an ileorectal anastomosis should be performed. Although the mortality approaches 10% in this setting, the results are more favorable than a blind segmental resection, which is associated with a much higher risk of rebleeding (42% versus 0%) and subsequent complication.135–137

SUMMARY Colonic diverticulosis has become a ubiquitous problem in Western society due in large part to the paucity of dietary fiber ingested in this part of the world. The sigmoid colon is most

865

Abscess >2 cm

Percutaneous drainage Yes

Fistulae formation

Admit 1. i.v. antibiotics 2. i.v. resuscitation 3. Bowel rest 4. Careful observation

Elective segmental resection in 8–12 weeks with primary anastomosis (fistula closure or abscess cavity resection)

Septic/fecal peritonitis

Admit 1. i.v. antibiotics 2. i.v. resuscitation

Emergent colectomy: Hartmann procedure with or without rectal exteriorization

Complicated

Acute diverticulus

Uncomplicated

No

Admit 1. i.v. antibiotics 2. i.v. resuscitation 3. Bowel rest 4. Careful observation

Consider CT See to complicated No Resolves

Patient: 1. Reliable 2. Mild signs and symptoms 3. Able to tolerate p.o.

Fig. 61.5

Yes

Yes

Consider outpatient management. 1. p.o. antibiotics 2. Dietary modification 3. Close follow-up

Discharge/follow-up Dietary modification 1. Fiber supplementation 2. Bulk additive

• Flowchart depicting the management of patients with acute diverticulitis.

frequently affected but any portion of the colon can be involved. As the population ages, an increasing number of patients will be diagnosed with diverticulitis and diverticular bleeding. Acute diverticulitis can often be treated medically with antibiotics and a short period of bowel rest (Fig. 61.5). Repeat episodes are common and current recommendations call for elective colonic resection after two confirmed episodes of uncomplicated diverticulitis. This approach can be individualized on the basis of the severity of the episodes and the general health of the patient. In a subset of patients, complications of their disease will necessitate a more aggressive approach. In patients with free perforation and peritonitis, a Hartmann’s procedure is usually required, although stable patients without fecal soilage may be considered for an anastomosis after an on-table colonic lavage. The advances in interventional radiology have allowed many patients with abscess formation to undergo drainage followed by elective one-stage operative resection. Fistulas are managed by resection of the diseased colonic segment and repair of the adjacent organ. Diverticular bleeding is managed by a localizing study followed by selective angiographic ablation of the offending vessel or operative resection.

REFERENCES 1. Fleischner F, Ming S-C, Henken E. Revised concepts on diverticular disease of the colon. I. Diverticulosis: Emphasis on tissue derangement and its relation to the irritable colon syndrome. Radiology 1964; 83:859–871. This paper notes the radiographic appearance of sacculations of the colon and symptomatic diverticular disease. 2. Fleischner F, Ming S-C. Revised concepts on diverticular disease of the colon: II. So-called diverticulitis: Diverticular sigmoiditis and perisigmoiditis; diverticular abscess, fistula, and frank peritonitis. Radiology 1965; 84:599–609. 3. Painter NS, Burkitt D. Diverticular disease of the colon, a 20th century problem. Clin Gastroenterol 1975; 4:3–21. This paper outlines the research conducted by Burkitt in subSaharan Africa and demonstrates the relationship of diverticulosis and the consumption of dietary fiber. He noted a relationship between the consumption of a diet high in fiber content and the paucity of diverticular disease. It should be noted that the people living in this region did not routinely reach the sixth decade of life. 4. Painter N, Burkitt D. Diverticular disease of the colon: A deficiency disease of Western civilization. Br Med J 1971; 1:450–454.

References

No

Urgent colectomy: 1. Primary anastomosis with on table lavage (Hinchey BI and BII 2. Hartmann procedure (Hinchey BIII)


866 5. Ohi G, Minowa K, Oyama T, et al. Changes in dietary fiber intake among Japanese in the 20th century: A relationship to the prevalence of diverticular disease. Am J Clin Nutr 1983; 38:115–121. The authors highlight the history of dietary fiber consumption in Japan during the 20th century, noting a ‘westernization’ trend reflected in a significant decrease in rice consumption. Concomitantly, they report an increase in symptomatic diverticular disease in this same population. 6. Aldoori WH, Giovannucci EL, Rimm EB, et al. Prospective study of physical activity and the risk of symptomatic diverticular disease in men. Gut 1995; 36:276–282. 7. Ozick LA, Salazar CO, Donelson SS. Pathogenesis, diagnosis, and treatment of diverticular disease of the colon. Gastroenterologist 1994; 2(4):299–310. This review article from the gastroenterology division at Columbia University, College of Physicians and Surgeons, reports on the pathogenesis and treatment of diverticulitis and diverticular bleeding. 8. Everhart JA, et al. The burden of gastrointestinal disease. May 2001. Online. Available: http://www.gastro.org/clinicalRes/ burdenreport.html 9. Lo CY, Chu KW. Acute diverticulitis of the right colon. Am J Surg 1996; 171:244–246. 10. Harada RN, Whelan IJ Jr. Surgical management of cecal diverticulitis. Am J Surg 1993; 166:666–671. 11. Wong SK, Ho YH, Leong AP, et al. Clinical behavior of complicated right-sided and left-sided diverticulosis. Dis Colon Rectum 1997; 40:344–348. 12. Roger T, Rommens J, Bailly J, et al. Giant colonic diverticulum: Presentation of one case and review of the literature. Abdom Imaging 1996; 21:530–533. 13. Morson B. The muscle abnormality in diverticular disease of the sigmoid colon. Br J Radiol 1963; 36:385–392. 14. Cortesini C, Pantalone D. Usefulness of colonic motility study in identifying patients at risk for complicated diverticular disease. Dis Colon Rectum 1991; 34:339–342. 15. Golder M, Burleigh DE, Belai A, et al. Smooth muscle cholinergic denervation hypersensitivity in diverticular disease. Lancet 2003; 361:1945–1951. This article establishes a putative etiology for disturbances in cholinergic smooth muscle activity in the colon as an important effector mechanism in the pathogenesis of diverticulosis. 16. Gear JS, Ware A, Fursdon P, et al. Symptomless diverticular disease and intake of dietary fiber. Lancet 1979; 1:511–514. 17. Hinchey E, Schaal P, Richards G. Treatment of perforated diverticular disease of the colon. Adv Surg 1978; 12:85–109. In this article Hinchey describes the treatment of perforated diverticulum, discussing the pathogenesis of fecal peritonitis and the tailored approach to the management of these patients based on the amount of peritoneal contamination. His classification schema is still routinely used to describe the extent of peritoneal soilage. 18. Cho KC, Morehouse HT, Alterman DD, et al. Sigmoid diverticulitis: Diagnostic role of CT – comparison with barium enema studies. Radiology 1990; 176:111–115. The authors prospectively review the results of computed tomography and barium enema examinations of the colon in the diagnosis of diverticulitis. CT was superior not only in the diagnosis of diverticulitis but in confirming alternative pathology when diverticulitis was not found. 19. Birnbaum BA, Balthazar EJ. CT of appendicitis and diverticulitis. Radiol Clin North Am 1994; 32:885–898.

20. Ambrosetti P, Robert J, Witzig JA, et al. Prognostic factors from computed tomography in acute left colonic diverticulitis. Br J Surg 1992; 79:117–119. 21. Ambrosetti P, Grossholz M, Becker C, et al. Computed tomography in acute left colonic diverticulitis. Br J Surg 1997; 84:532–534. 22. Hachigian MP, Honickman S, Eisenstat TE, et al. Computed tomography in the initial management of acute left-sided diverticulitis (published erratum appears in Dis Colon Rectum 1993; 36(2):193). Dis Colon Rectum 1992; 35:1123–1129. 23. Zielke A, Hasse C, Nies C, et al. Prospective evaluation of ultrasonography in acute colonic diverticulitis. Br J Surg 1997; 84:385–388. 24. O’Sullivan GC, Murphy D, O’Brien MG, et al. Laparoscopic management of generalized peritonitis due to perforated colonic diverticula. Am J Surg 1996; 171:432–434. 25. Stefansson T, Ekbom A, Sparen P, et al. Increased risk of left-sided colon cancer in patients with diverticular disease. Gut 1993; 34:499–502. 26. Kajiwara H, Umemura S, Mukai M, et al. Adenocarcinoma arising within a colonic diverticulum (Letter). Pathol Int 1996; 46:538–539. 27. Shepherd NA. Pathological mimics of chronic inflammatory bowel disease. J Clin Pathol 1991; 44:726–733. 28. Naliboff JA, Longmire-Cook SJ. Diverticulitis mimicking a tuboovarian abscess. Report of a case in a young woman. J Reprod Med 1996; 41:921–923. 29. Jarrett TW, Vaughan ED Jr. Accuracy of computerized tomography in the diagnosis of colovesical fistula secondary to diverticular disease. J Urol 1995; 153:44–46. 30. Sarr M, Fishman E, Goldman S, et al. Enterovesical fistula. Surg Gynecol Obstet 1987; 164:41–48. 31. Grissom R, Snyder T. Colovaginal fistula secondary to diverticular disease. Dis Colon Rectum 1991; 34:1043–1049. 32. Parks A, Gordon P. Fistula-in-ano: Perineal fistula of intraabdominal or intrapelvic origin simulating fistula-in-ano. Report of seven cases. Dis Colon Rectum 1976; 19:500–506. 33. Rothenbuehler JM, Oertli D, Harder F. Extraperitoneal manifestation of perforated diverticulitis. Dig Dis Sci 1993; 38:1985–1988. 34. Spiller GA, Freeman HJ. Recent advances in dietary fiber and colorectal diseases. Am J Clin Nutr 1981; 34:1145–1152. 35. Brodribb AJ. Treatment of symptomatic diverticular disease with a high-fibre diet. Lancet 1977; 1:664–666. 36. Talbot JM. Role of dietary fiber in diverticular disease and colon cancer. Fed Proc 1981; 40:2337–2342. 37. Ornstein MH, Littlewood ER, Baird IM, et al. Are fibre supplements really necessary in diverticular disease of the colon? A controlled clinical trial. Br Med J 1981; 282:1353–1356. 38. Eastwood MA, Smith AN, Brydon WG, et al. Comparison of bran, ispaghula, and lactulose on colon function in diverticular disease. Gut 1978; 19:1144–1147. 39. Sarin S, Boulos PB. Evaluation of current surgical management of acute inflammatory diverticular disease. Ann R Coll Surg Engl 1991; 73:278–282. 40. Schechter S, Mulvey J, Eisenstat TE. Management of uncomplicated acute diverticulitis: results of a survey. Dis Colon Rectum 1999; 42(4):470–475; discussion 475–476. 41. Wong WD, Wexner SD, Lowry A, et al. Practice parameters for sigmoid diverticulitis. The Standards Task Force American Society of Colon and Rectal Surgeons. Dis Colon Rectum 2000; 43(3):290–297.

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42. Detry R, James J, Kartheuser A, et al. Acute localized diverticulitis: optimum management requires accurate staging. Int J Colorectal Dis 1992; 7:38–42. 43. Bahadursingh AM, Virgo KS, Kaminski DL, et al. Spectrum of disease and outcome of complicated diverticular disease. Am J Surg 2003; 186(6):696–701. 44. Stabile BE, Puccio E, van Sonnenberg E, et al. Preoperative percutaneous drainage of diverticular abscesses. Am J Surg 1990; 159:99–104. The authors report their experience with 19 patients treated with percutaneous drainage of large paracolic abscesses over a 17-month period.They state that preoperative percutaneous catheter drainage obviates the need for colostomy and multiple-stage surgery in approximately three-fourths of patients with large diverticular abscesses. 45. Montgomery RS, Wilson SE. Intraabdominal abscesses: Image guided diagnosis and therapy. Clin Infect Dis 1996; 23:28–36. 46. Greco R, Kamath C, Nosher J. Percutaneous drainage of peridiverticular abscess followed by primary sigmoidectomy. Dis Colon Rectum 1982; 25:53–55. 47. Ambrosetti P, Robert J, Witzig JA, et al. Incidence, outcome, and proposed management of isolated abscesses complicating acute left-sided colonic diverticulitis. A prospective study of 140 patients. Dis Colon Rectum 1992; 35:1072–1076.

58. Schilling MK, Maurer CA, Kollmar O, et al. Primary vs. secondary anastomosis after sigmoid colon resection for perforated diverticulitis (Hinchey Stage III and IV): a prospective outcome and cost analysis. Dis Colon Rectum 2001; 44(5):699–703. 59. Lee EC, Murray JJ, Coller JA, et al, Intraoperative colonic lavage in non-elective surgery for diverticular disease. Dis Colon Rectum 1997; 40:669–674. The authors describe the technique used in intraoperative colonic lavage and detail their excellent results in the surgical management of acute diverticulitis. 60. Bell G, Panton O. Hartmann resection for perforated sigmoid diverticulitis. A retrospective study of the Vancouver General Hospital. Dis Colon Rectum 1984; 27:253–256. 61. Eisenstat T, Rubin R, Salvati E. Surgical management of diverticulitis. The role of the Hartmann procedure. Dis Colon Rectum 1983; 26:429–432. 62. Belmonte C, Klas JV, Perez JJ, et al. The Hartmann procedure. First choice or last resort in diverticular disease? Arch Surg 1996; 131:612–617. 63. Wedell J, Banzhaf G, Chaoui R, et al. Surgical management of complicated colonic diverticulitis. Br J Surg 1997; 84:380–383. 64. Cirocco WC, Priolo SR, Golub RW. Spontaneous ureterocolic fistula: a rare complication of colonic diverticular disease. Am Surg 1994; 60(11):832–835. 65. Hain JM, Sherick DG, Cleary RK. Salpingocolonic fistula secondary to diverticulitis. Am Surg 1996; 62(12):984–986.

48. Hamy A, Paineau J. Percutaneous drainage of perisigmoid abscesses of diverticular origin. Ann Chir 2001; 126(2):133–137.

66. Papagiannopoulos K, Gialvalis D, Dodo I, et al. Empyema resulting from a true colopleural fistula complicating a perforated sigmoid diverticulum. Ann Thorac Surg 2004; 77(1):324–326.

49. Piardi T, Ferrari Bravo A, Giampaoli F, et al. Deferred elective colonic resection in complicated acute diverticulitis. Chir Ital 2003; 55(2):153–160.

67. Woods R, Lavery I, Fazio V, et al. Internal fistulas in diverticular disease. Dis Colon Rectum 1988; 31:591–596.

50. Classen J, Bonardi R, O’Mara C, et al. Surgical treatment of acute diverticulitis by staged procedures. Ann Surg 1976; 184:582–586. 51. Wedell J, Banzhaf G, Chaoui R, et al. Surgical management of complicated colonic diverticulitis. Br J Surg 1997; 84(3):380–383. 52. Rodkey G, Welch C. Changing patterns in the surgical treatment of diverticular disease. Ann Surg 1984; 200:466–478. 53. Hackford A, Schoetz DJ, Coller J, et al. Surgical management of complicated diverticulitis. The Lahey Clinic experience, 1967 to 1982. Dis Colon Rectum 1985; 28:317–321. This report from the Lahey Clinic reviews the results of 142 patients with complicated diverticulitis treated surgically.Those patients who were able to tolerate a one stage procedure suffered the lowest mortality and morbidity (1% and 13% respectively). 54. Benn PL, Wolff BG, Ilstrup DM. Level of anastomosis and recurrent diverticulitis. Am J Surg 1986; 151:269–271. This article from the Mayo Clinic highlights the importance of resecting the entire sigmoid colon down to the rectum distally. The proximal margin does not need to be free of all diverticulum, but be of normal caliber and compliance.

68. Bahadursingh AM, Longo WE. Colovaginal fistulas. Etiology and management. J Reprod Med 2003; 48(7):489–495. 69. Fazio V, Church J, Jagelman D, et al. Colocutaneous fistula complicating diverticulitis. Dis Colon Rectum 1987; 30:89–94. 70. Stewart J, Diament R, Brennan T. Management of obstructing lesions of the left colon by resection, on-table lavage, and primary anastomosis. Surgery 1993; 114:502–505. 71. Allen-Mersh TG. Should primary anastomosis and on-table colonic lavage be standard treatment for left colon emergencies? Ann R Coll Surg Eng 1993; 175:195–198. 72. Jackson B. The diagnosis of colonic obstruction. Dis Colon Rectum 1982; 25:603–609. 73. Khan AL, Ah-See AK, Crofts TJ, et al. Surgical management of the septic complications of diverticular disease. Ann R Coll Surg Engl 1995; 77:16–20. 74. Pain J, Cahill J. Surgical options for left-sided large bowel emergencies. Ann R Coll Surg Engl 1991; 73:394–397. 75. Nahrwold D, Demuth W. Diverticulitis with perforation into the peritoneal cavity. Ann Surg 1997; 185:80–83.

55. Moreaux J, Vons C. Elective resection for diverticular disease of the sigmoid colon. Br J Surg 1990; 77:1036–1038.

76. Berry A, Turner W, Mortensen N, et al. Emergency surgery for complicated diverticular disease: A five-year review. Dis Colon Rectum 1989; 32:849–854.

56. Alanis A, Papanicolaou G, Tadros R, et al. Primary resection and anastomosis for treatment of acute diverticulitis. Dis Colon Rectum 1989; 32:933–939.

77. Peoples JB, Vilk DR, Maguire JP, et al. Reassessment of primary resection of the perforated segment for severe colonic diverticulitis. Am J Surg 1990; 159:291–294.

57. Regenet N, Pessaux P, Hennekinne S, et al. Primary anastomosis after intraoperative colonic lavage vs. Hartmann’s procedure in generalized peritonitis complicating diverticular disease of the colon. Int J Colorectal Dis 2003; 18(6):503–507.

78. Kronborg O. Treatment of perforated sigmoid diverticulitis: A prospective randomized trial. Br J Surg 1993; 80:505–507.

References

The practice parameters published by the American Society of Colon and Rectal Surgeons reviews the pathogenesis and treatment of both complicated and uncomplicated diverticulitis. Updated frequently, they can be found at http://www.fascrs.org


868 79. Corder AP, Williams JD. Optimal operative treatment in acute septic complications of diverticular disease. Ann R Coll Surg Engl 1990; 72:82–86. 80. Krukowski ZH, Matheson NA. Emergency surgery for diverticular disease complicated by generalized and faecal peritonitis: A review. Br J Surg 1984; 71:921–927. 81. Greif J, Fried G, McSherry C. Surgical treatment of perforated diverticulitis of the sigmoid colon. Dis Colon Rectum 1980; 23:484–487. 82. Finlay I, Carter D. A comparison of emergency resection and staged management in perforated diverticular disease. Dis Colon Rectum 1987; 30:929–933.

103. Morgan RO, Kaiser M, Koshy J, et al. Incidence and treatment of diverticular disease of the colon among the elderly (Abstract). American Health Services Research Federal Health Services Research Annu Meet Abstr Book 1995; 12:118. 104. Vignati PV, Welch JP, Cohen JL. Long-term management of diverticulitis in young patients. Dis Colon Rectum 1995; 38:627–629. 105. Rennie JA, Charnock MC, Wellwood JM, et al. Results of resection for diverticular disease and its complications. Proc R Sac Med 1975; 68:575. 106. Breen R, Corman M, Robertson W, et al. Are we really operating on diverticulitis? Dis Colon Rectum 1986; 29:174–176.

83. Nagorney D, Adson M, Pemberton J. Sigmoid diverticulitis with perforation and generalized peritonitis. Dis Colon Rectum 1985; 28:71–75.

107. Bokey E, Chapuis P, Pheils M. Elective resection for diverticular disease and carcinoma. Comparison of postoperative morbidity and mortality. Dis Colon Rectum 1981; 24:181–182.

84. Carson S, Krom R, Uchida K, et al. Colon perforation after kidney transplantation. Ann Surg 1978; 188:109–113.

108. Plasencia G, Jacobs M, Verdeja JC, et al. Laparoscopic-assisted sigmoid colectomy and low anterior resection. Dis Colon Rectum 1994; 37:829–833.

85. Lao A, Bach D. Colonic complications in renal transplant patients. Dis Colon Rectum 1988; 31:130–133. 86. Starnes HJ, Lazarus J, Vineyard G. Surgery for diverticulitis in renal failure. Dis Colon Rectum 1985; 28:827–831.

109. Bruce CJ, Coller JA, Murray JJ, et al. Laparoscopic resection for diverticular disease. Dis Colon Rectum 1996; 39(Suppl10):1–6.

87. Arsura EL. Corticosteroid-association perforation of colonic diverticula. Arch Intern Med 1990; 150:1337–1338.

110. Schlachta CM, Mamazza J, Gregoire R, et al. Could laparoscopic colon and rectal surgery become the standard of care? A review and experience with 750 procedures. Can J Surg 2003; 46(6):432–440.

88. Tyau ES, Prystowsky JB, Joehl RJ, et al. Acute diverticulitis. A complicated problem in the immunocompromised patient. Arch Surg 1991; 126:855–859.

111. Guller U, Jain N, Hervey S, et al. Laparoscopic vs. open colectomy: outcomes comparison based on large nationwide databases. Arch Surg 2003; 138(11):1179–1186.

89. Elliott TB, Yego S, Irvin TT. Five-year audit of the acute complications of diverticular disease. Br J Surg 1997; 84:535–539.

112. Senagore AJ, Madbouly KM, Fazio VW, et al. Advantages of laparoscopic colectomy in older patients. Arch Surg 2003; 138(3):252–256.

90. Munson KD, Hensien MA, Jacob LN, et al. Diverticulitis. A comprehensive follow-up. Dis Colon Rectum 1996; 39:318–322. 91. Sarin S, Boulos PB. Long-term outcome of patients presenting with acute complications of diverticular disease. Ann R Coll Surg Engl 1994; 76:117–120. 92. Parks T. Natural history of diverticular disease of the colon. Clin Gastroenterol 1975; 4:53–69. 93. Colcock B. Diverticular disease. Proven surgical management. Clin Gastroenterol 1975; 4:99–119. 94. Hyland JM, Taylor I. Does a high-fibre diet prevent the complications of diverticular disease? Br J Surg 1980; 67:77–79. 95. Leahy AL, Ellis RM, Quill DS, et al. High-fibre diet in symptomatic diverticular disease of the colon. Ann R CoIl Surg Engl 1985; 67:173–174. 96. Farmakis N, Tudor RG, Keighley MR. The 5-year natural history of complicated diverticular disease. Br J Surg 1994; 81:733–735. 97. Ambrosetti P, Robert JH, Witzig JA, et al. Acute left colonic diverticulitis in young patients. J Am Coll Surg 1994; 179:156–160. 98. Anderson DN, Driver CP, Davidson AI, et al. Diverticular disease in patients under 50 years of age. J R Coll Surg Edinb 1997; 42:102–104. 99. Ouriel K, Schwartz SI. Diverticular disease in the young patient. Surg Gynecol Obstet 1983; 156:1–5. 100. Konvolinka CW. Acute diverticulitis under age forty. Am J Surg 1994; 167:562–565. 101. Schauer PR, Ramos R, Ghiatas AA, et al. Virulent diverticular disease in young obese men. Am J Surg 1992; 164:443–448. 102. Spivak H, Weinrauch S, Harvey JC, et al. Acute colonic diverticulitis in the young. Dis Colon Rectum 1997; 40:570–574.

113. Sher ME, Agachan F, Bortul M, et al. Laparoscopic surgery for diverticulitis. Surg Endosc 1997; 11:264–267. 114. Wolff BG, Ready RL, MacCarty RL, et al. Influence of sigmoid resection on progression of diverticular disease of the colon. Dis Colon Rectum 1984; 27:645–647. 115. Tchirkow G, Lavery I, Fazio V. Crohn’s disease in the elderly. Dis Colon Rectum 1983; 26:177–181. 116. Chia J, Wilde C, Ngoi S, et al. Trends of diverticular disease of the large bowel in a newly developed country. Dis Colon Rectum 1991; 34:498–501. 117. Graham S, Ballantyne G. Cecal diverticulitis. A review of the American experience. Dis Colon Rectum 1987; 30:821–826. 118. Ngoi SS, Chia J, Goh MY, et al. Surgical management of right colon diverticulitis. Dis Colon Rectum 1992; 35:799–802. 119. Markham N, Li A. Diverticulitis of the right colon – experience from Hong Kong. Gut 1992; 33:547–549. 120. Puera DA, Lanza FL, Gostout CJ, et al. The American College of Gastroenterology bleeding registry: preliminary findings. Am J Gastroentorol 1997; 92: 924–928. 121. Longstretch GF. Epidemiology and outcome of patients hospitalized with acute lower gastrointestinal hemorrhage: a population-based study. Am J Gastroenterol 1997; 92: 419–424. 122. McGuire JJ Jr, Haynes BW Jr. Massive hemorrhage for diverticulosis of the colon: guidelines for therapy based on bleeding patterns observed in fifty cases. Am Surg 1972; 175:847–855. 123. McGuire HH Jr. Bleeding colonic diverticula. A reappraisal of the natural history and management. Ann Surg 1994; 220:653–656. 124. Browder W, Cerise E, Litwin M. Impact of emergency angiography in massive lower gastrointestinal hemorrhage. Ann Surg 1986; 204:530–536.

869 132. Ferands PA, Taylor I. Management of acute lower gastrointestinal bleeding in a surgical unit over a four-year period. J Soc Med 1987; 80:79–82.

126. Foutch PG. Diverticular bleeding: Are nonsteroidal antiinflammatory drugs risk factors for hemorrhage and can colonoscopy predict outcome for patients? Am J Gastroenterol 1995; 90:1779–1784.

133. Wright AK, Pellicia O, Higgins EF, et al. Controlled semi-elective, segmental resection for massive colonic hemorrhage. Am J Surg 1980; 139:535–538.

127. Nusbaum M, Baum S, Kuroda K, et al. Control of portal hypertension by selective mesenteric arterial drug infusion. Arch Surg 1968; 97:1005–1014. 128. Darcy M. Treatment of lower gastrointestinal bleeding: Vasopressin infusion versus embolization. J Vasc Interv Radiol 2003; 14(5):535–543. 129. DeBarros J, Rosas L, Cohen J, et al. The changing paradigm for the treatment of colonic hemorrhage: superselective angiographic embolization. Dis Colon Rectum 2002; 45(6):802–808. 130. Bookstein JJ, Cholsta EM, Foley D, et al. Transcatheter hemostasis of gastrointestinal bleeding using modified autogenous clot. Radiology 1974; 113:277–285. 131. Parkes BM, Obeid FN, Sorensen VJ, et al. The management of massive lower gastrointestinal bleeding. Am Surg 1993; 59(10):676–678.

134. Bowden TA Jr, Hooks VH 3rd, Mansberger AR Jr. Intraoperative gastrointestinal endoscopy in the management of occult gastrointestinal bleeding. South Med J 1979; 72(12):1532–1534. 135. Anand AC, Patnaik PK, Bhalla VP, et al. Massive lower intestinal bleeding – a decade of experience. Trop Gastroenterol 2001; 22(3):131-134. 136. Renzulli P, Maurer CA, Netzer P, et al. Subtotal colectomy with primary ileorectostomy is effective for unlocalized, diverticular hemorrhage. Langenbecks Arch Surg 2002; 387(2):67–71. 137. Foutch PG, Zimmerman K. Diverticular bleeding and the pigmented protuberance (sentinel clot): Clinical implications, histopathological correlation, and results of endoscopic intervention. Am J Gastroenterol 1996; 91:2589–2593.

References

125. Sharma R, Gorbien MJ. Angiodysplasia and lower gastrointestinal tract bleeding in elderly patients. Arch Intern Med 1995; 155:807–812.


CHAPTER SIXTY-TWO

62

Vascular insufficiency Daniel S. Mishkin, Patricia L. Kozuch and Lawrence J. Brandt

INTRODUCTION Intestinal ischemia refers to the process whereby blood flow to the bowel is decreased with cellular injury consequent to diminished supply of oxygen and nutrients.1 A vascular emergency of the gastrointestinal tract usually results from a disturbance in the arterial blood supply or venous drainage of the bowel with consequential severe ischemic injury. Severe ischemia manifests as gangrene and perforation or less commonly as stricture formation with intestinal obstruction. Vascular emergencies much more commonly involve the colon than the small intestine, and arterial ischemia is more common than ischemia from venous occlusion.2 Vascular insufficiency encompasses a broad spectrum of disease manifestations and severity. The differences may depend on the etiology, speed of onset and duration of the ischemic event, location and length of intestine affected, as well as the specific vasculature involved and its degree of collateral flow. With such a range of possible permutations and combinations it is important to differentiate the etiology if possible and the extent of the injury to better direct therapy. Most cases of colon ischemia resolve spontaneously without sequelae, whereas most small bowel ischemia demands medical/surgical intervention and has serious sequelae or a poor outcome. Therefore, early recognition, diagnosis, and therapy are essential in the management of such patients.

Epidemiology Acute mesenteric ischemia (AMI) is an uncommon occurrence, accounting for approximately 0.1% of hospital admissions.1 A rising incidence in the past quarter century has been attributed to a heightened awareness of gastrointestinal ischemic disease as well as to an increase in the number of people at risk for AMI because of population aging and advances in the treatment of cardiovascular diseases, thereby allowing patients to survive what previously were fatal conditions. The overall mortality rate of AMI remains high at 71%; however, survival rates are significantly improved when AMI is diagnosed and treated in an expeditious manner (under 24 hours), especially when mesenteric angiography and splanchnic vasodilators are used early in the management of disease.3 The most common cause of AMI is superior mesenteric artery emboli (SMAE), accounting for approximately 50% of the cases, with nonocclusive mesenteric ischemia (NOMI) following at 25%. Superior mesenteric artery thrombosis (SMAT, 10%), mesenteric venous thrombosis (MVT, 10%), and focal segmental

ischemia (FSI, 5%) are responsible for the remainder of cases. Colon ischemia (CI) is a frequent disorder of the large bowel in older persons and is the most common form of intestinal ischemic injury. It is estimated to account for 1/100 colonoscopies, 1/700 office visits, and 1/2000 admissions to a tertiary care center. A recent study using medical claims data from a large healthcare organization in the US calculated a crude incidence rate of 7.2 cases per 100 000 person-years of observation in the general population.4

Anatomy of the splanchnic circulation Intestinal ischemia can be classified as acute or chronic and of venous or arterial origin. In acute forms, intestinal viability is threatened, whereas in the chronic forms, blood flow is inadequate to support the functional demands of the intestine. Understanding the anatomy of splanchnic circulations is important to help understand the different types of vascular insults. The celiac axis (CA), superior mesenteric artery (SMA), and inferior mesenteric artery (IMA) supply almost all of the blood flow to the digestive tract. There is marked variability of vascular anatomy among individuals, but typical patterns have emerged from anatomic dissections and abdominal angiography.5 The CA arises from the anterior aorta and gives rise to three major branches: (1) the left gastric artery, (2) the common hepatic artery, and its gastroduodenal, right gastroepiploic, and superior pancreaticoduodenal arterial branches, and (3) the splenic artery with its pancreatic and left gastroepiploic arterial branches. The CA and its branches supply the stomach, duodenum, pancreas, and the liver. The SMA has its origin from the anterior aorta near the neck of the pancreas. It gives rise to four major vessels: (1) the inferior pancreaticoduodenal, (2) middle colic, (3) right colic, and (4) ileocolic arteries, as well as to a series of jejunal and ileal branches, all of which supply their named portions of intestine. These intestinal branches typically form a series of arcades, and from the terminal arcade, numerous straight vessels arise that enter the intestinal wall. These end arteries make the intestine more vulnerable to ischemic insults because of the lack of collateral pathways. The IMA arises 3–4 cm above the aortic bifurcation close to the inferior border of the duodenum. It branches into the left colic artery and multiple sigmoid branches and terminates as the superior rectal artery. The IMA and its branches supply the large intestine from the distal transverse colon to the proximal rectum. The distal rectum is supplied by branches of the internal iliac (hypogastric) artery.

Vascular Insufficiency

872 Abundant collateral circulation to the stomach, duodenum, and rectum accounts for the paucity of ischemic events in these organs. The major anastomosis between the CA and the SMA is formed from the superior pancreaticoduodenal branch of the CA and the inferior pancreaticoduodenal branch of the SMA. These vessels constitute the pancreaticoduodenal arcade and provide blood to the duodenum and the pancreas. The splenic flexure and sigmoid colon have limited anastomoses, and ischemic damage is more common in these locations. There are three potential paths of communication between the SMA and IMA: (1) the marginal artery of Drummond, which is closest to and parallel with the wall of the intestine; (2) the central anastomotic artery, a larger and more centrally placed vessel; and (3) the arc of Riolan, an artery in the base of the mesentery. On angiography, the ‘meandering artery’ represents a dilated central artery or arc of Riolan and may be diagnostic of an occluded SMA or IMA. It is critical to determine the direction of flow in any meandering artery prior to resection of the IMA, e.g., during aortic aneurysm surgery, lest the IMA be the main vessel supplying blood to the small bowel because of an occluded SMA.

oxygen radicals and polymorphonuclear cells are thought to be integral. Such injuries lead to a wide spectrum of microscopic and gross pathologic findings. At one extreme, the milder lesions of nontransmural ischemic injury (mucosal necrosis, submucosal edema, hemorrhage, and ulceration) usually are seen with a more indolent course and ultimately heal. At the other end of this continuum is transmural necrosis (infarction), gangrene, and perforation, findings usually associated with a profound clinical outcome. Lesions of intermediate severity may progress to transmural necrosis or result in fibrosis with stricture formation.11

PATHOGENESIS OF INJURY

ACUTE MESENTERIC ISCHEMIA

In addition to the protection offered by collateral blood supply, the bowel has several other mechanisms to prevent ischemic injury. Intestinal blood flow must be reduced by at least 50% from the normal fasting level before oxygen delivery to the intestine becomes compromised.6 A rich network of intramural submucosal vessels helps protect segments of bowel from ischemia even when SMA blood flow is severely reduced.7 Further, redistribution of intramural blood supply occurs with ischemia, favoring preservation of the mucosa.8 It has been demonstrated that the bowel can endure a 75% reduction in its blood supply for up to 12 hours without significant injury.9 Two mechanisms may account for this observation: first, under normal physiologic conditions, only 20% of the mesenteric capillaries are open and utilizing oxygen at any one time;10 second, when oxygen delivery is decreased, the bowel adapts by increasing oxygen extraction. When the aforementioned parameters are exceeded, however, these compensatory mechanisms are overwhelmed and no longer protective. Blood flow to the intestine is regulated by the sympathetic nervous system, humoral factors including angiotensin II and vasopressin, and local factors such as prostaglandins and leukotrienes.7 The sympathetic nervous system, mainly via ␣-adrenergic receptors, is of primary importance in maintaining resting splanchnic arteriolar tone. When a major intestinal artery is obstructed, a reduction in pressure in the distal arterial bed below systemic pressure triggers the opening of collaterals. After several hours, however, the distal arteries begin to constrict, resulting in an increased arterial pressure, which consequently decreases collateral flow. Vasoconstriction initially is reversible, but may become irreversible after a prolonged period, even if the event initiating ischemia has been identified and corrected.1 So-called nonocclusive mesenteric ischemia (NOMI) from vasoconstriction may be seen clinically as a result of diminished cardiac output or accompany local vascular obstruction such as emboli. Both hypoxia and reperfusion are important etiologic factors in ischemic injury, with the latter playing a greater role when periods of ischemia are short. As the ischemia period lengthens, the hypoxia becomes more detrimental than reperfusion. Reperfusion injury is likely multifactorial, but

Disease spectrum and clinical presentation

GOALS OF MANAGEMENT The cardiologists and neurologists have helped further our understanding of the importance of correcting perfusion to critical organs. Limiting hypoxia and, if possible, reperfusion injury are two fundamental aspects also important in patients with vascular insufficiency of the gastrointestinal tract. In this chapter we will address the various forms of intestinal ischemia and their specific management.

Acute mesenteric ischemia (AMI) results from sudden, inadequate blood flow to the gastrointestinal tract. Regardless of the cause of the ischemic insult, the end results are similar – a spectrum of bowel injury that ranges from transient alteration of bowel function to transmural gangrene. Clinical manifestations vary with the extent of ischemic injury and, to a lesser degree, with its cause. It is important to define the cause, as treatment varies accordingly (Table 62.1).

Clinical aspects Early identification of AMI requires a high index of suspicion, especially in patients older than 50 years who have long-standing congestive heart failure, cardiac arrhythmias, recent myocardial infarction, or hypotension. NOMI increasingly has become recognized after cardiac surgery12 and in hemodialysis patients.13 Hypercoagulable states, underlying vasculitides, and intra-abdominal malignancy also have been linked to the development of AMI, particularly acute MVT. Not only are disease entities important as

Table 62.1 Causes and approximate incidences of acute mesenteric ischemia Cause

Incidence (%)

SMA embolus (SMAE)

50

Nonocclusive mesenteric ischemia (NOMI)

25

SMA thrombosis (SMAT)

10

Mesenteric venous thrombosis (MVT)

10

Focal segmental ischemia

5

(Reprinted from Brandt LJ et al in Feldman M et al ed. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, Philadelphia: W.B. Saunders; 2002, 2321–2340. © 2002, with permission from Elsevier.)

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Diagnostic evaluation While laboratory tests often are abnormal in patients with AMI, they are neither sufficiently sensitive nor specific to diagnose AMI early enough to improve prognosis. This holds true for serum levels of inorganic phosphate and standard enzyme determinations such as creatinine kinase, lactate dehydrogenase, aspartate transferase and alkaline phosphatase (including the intestinal isoenzyme). More specific enzymes including diamine oxidase, and hexosaminidase also lack sufficient sensitivity and specificity to diagnose AMI.16 More recently, glutathione S-transferase (a family of cytosolic enzymes widely distributed in the intestine)17 and intestinal fatty acid binding protein (accounting for 2% of intestinal protein and located at the tips of mucosal villi) have been shown to be promising markers for intestinal ischemia in adults and in neonates with necrotizing enterocolitis.18,19 Metabolic acidosis is neither sensitive nor specific enough to be used as an aid in diagnosing AMI early, but is common in the presence of intestinal gangrene. Leukocytosis is a common finding in AMI, with an elevated white blood cell count over 15 000/mL seen in more than 75% of patients. Thus, a normal WBC cannot reliably exclude AMI, but neither can an elevated one be used to make the diagnosis, given its lack of specificity.

Radiology Although poorly sensitive and non-specific, plain films of the abdomen are commonly obtained in evaluating patients with suspected AMI; in most medical centers today, CT scanning has replaced plain film use. There are three relatively specific findings of mesenteric ischemia which are better depicted on CT scans compared with plain films:20 (1) abnormal gas in the bowel wall or portal system; (2) acute embolic infarction of other intra-abdominal organs; and (3) thrombi in the mesenteric vessels. Early in the course of AMI, abdominal films usually are normal. In late-stage AMI, one may observe an ileus, ‘thumbprinting,’ formless loops of small bowel, and more rarely portal or mesenteric venous gas.21 The primary purpose of plain films or CT scans remains to exclude other causes of abdominal pain that might mandate a therapeutic approach

different from that for AMI. Neither a normal abdominal plain film nor a normal CT scan excludes the diagnosis of AMI. Doppler ultrasound can visualize stenoses or occlusions in the CA or SMA. However, its sensitivity for diagnosing AMI is limited by four significant factors: first, only the proximal portions of the main splanchnic vessels can be studied; second, vessel occlusions or stenoses identified by this technique are not diagnostic of intestinal ischemia, given that complete occlusions in two or even all three vessels can be seen in asymptomatic patients; third, blood flow through the SMA is highly variable, which makes interpretation of this test difficult; and fourth, NOMI, which accounts for approximately 25% of AMI, cannot be diagnosed by Doppler ultrasound.1 In patients with AMI, the sensitivity of abdominal CT depends on the underlying cause and severity of ischemia. The spectrum of CT signs for ischemia include bowel lumen dilatation, segmental wall thickening and abnormal bowel wall enhancement, arterial or venous occlusions, and intramural, portal venous, intraperitoneal and retroperitoneal gas.22 A significant limitation is that the more specific signs of ischemia, such as pneumatosis with portal vein gas, are late manifestations.23 In one study, the finding of either arterial or venous thrombosis, intramural gas, portal venous gas, focal lack of bowel wall enhancement, or liver or splenic infarcts had a sensitivity and specificity of 64% and 92%, respectively.24 In another study, the sensitivity of CT for the diagnosis of mesenteric venous thrombosis was approximately 90%.25 More recently, CT angiography (CTA) has been shown to be very promising in the diagnosis of AMI. In one study, 62 patients with a clinical suspicion of AMI were evaluatedwith CTAs for findings suggesting emboli or thrombi in the CA, SMA, or IMA.26 A finding of any one of pneumatosis intestinalis, venous gas, SMA occlusion, CA and IMA occlusion with distal SMA disease or arterial embolism was 100% specific but only 73% sensitive. The finding of bowel wall thickening in addition to focal lack of bowel wall enhancement, solid organ infarction, or venous thrombosis was 50% sensitive and 94% specific. Independently, the added angiographic findings were believed to alter the course in 19% of patients by making the diagnosis of AMI when CT alone did not. A relatively low mortality rate of 42% in studied patients with documented AMI was observed, paralleling results of older studies that also showed lower mortalities when mesenteric angiography was used diagnostically. While these data are very encouraging, it may fall short of standard angiography in terms of diagnosing NOMI as well as by its inability to allow treatment with intra-arterial vasodilators. MR angiography (MRA) is another of the newer imaging modalities used to diagnose AMI. MRA provides detailed anatomic information regarding sites of obstruction but at this time, MRA lacks sufficient resolution to diagnose NOMI secondary to low-flow states or to identify distal embolic disease.27 Delayed phase imaging also permits evaluation of the mesenteric veins. In the future, measuring the absolute value of oxygen saturation between the SMV blood relative to that of the inferior vena cava may be used.28 Selective mesenteric angiography has long been the gold standard for diagnosis of AMI, a standard now being challenged by proponents of CTA and MRA. In a review of mesenteric angiography for the diagnosis of AMI, sensitivities in five of six studies have ranged 90–100%; specificity was reported in two of these studies to be 100%.3 Not only can a diagnosis of AMI and its etiology be established confidently by conventional angiography, but a vascular ‘roadmap’ in occlusive disease can be obtained that can aid in

Acute Mesenteric Ischemia

possible precipitants for ischemia, but certain illegal drugs, such as cocaine, and various therapeutic agents, e.g., phenylephrine, amphetamines, triptans, vasopressin, and sodium polystyrene in sorbitol (kayexalate), also have been implicated.14 The overwhelming majority of patients with AMI experience abdominal pain during the ischemic episode: an acute onset is usually observed with SMAE as opposed to a more insidious presentation with NOMI. The classic teaching of ‘pain out of proportion to findings on physical exam’ often is observed in the early stages of AMI, when the abdomen is soft and even nontender. Distention and severe tenderness with rebound and guarding develop as a consequence of bowel infarction. The rapidity with which these findings develop is a function of the severity of the ischemic injury. A small proportion of patients with NOMI do not experience pain, and distention is more common in this group. Patients with SMAE may note forceful bowel evacuation. Occult bleeding is seen in three-fourths of patients with AMI; gross bleeding is rare in patients with AMI and usually indicates right colon involvement. Mental status change in elderly patients is seen in up to 30% of cases.15 Other late signs and symptoms of intestinal ischemia include nausea, vomiting, hematemesis, fever, obstruction, back pain, and shock.


874 planning revascularization procedures. Moreover, the angiographic catheter can be used to administer intra-arterial vasodilators such as papaverine. The excellent sensitivity and therapeutic potential of angiography combine to effect a significantly improved mortality rate with reported ranges of 18–53%.3 Preoperative angiography is, therefore, a valuable tool, although it should never significantly delay what may be life-saving surgery. Disadvantages of traditional angiography are its limited availability and potential renal toxicity as well as its expense and time constraints.

Other diagnostic tests Laparoscopy may be used as a diagnostic test for mesenteric ischemia with two caveats: first, intraperitoneal pressure exceeding 20 mmHg decreases SMA blood flow;29 and second, mucosal injury may exist and be unappreciated in the absence of serosal evidence of ischemia.16 The latter is explained by the mucosal-to-serosal shunting of blood flow that occurs with increased intestinal intraluminal or intraperitoneal pressures. Upper endoscopy to evaluate for mesenteric ischemia is limited by the reach of the instrument; colonoscopy, however, has become routine in the diagnosis of CI. Although the risk of performing colonoscopy in patients with CI is small, overinflation of the colon, with consequent increase of intraluminal pressure decreases total colon blood flow and renders the colon susceptible to ischemic injury. A decrease in colon blood flow becomes significant with pressure of 30 mmHg or greater and can be decreased significantly by the use of carbon dioxide as the insufflating agent.30 Intravenous fluorescein has been used both during endoscopy and intraoperatively to define areas of ischemia; the underperfused ischemic areas of bowel demonstrate proportionally less fluorescence than does the bowel with normal blood flow.16 Radioisotope studies, laser Doppler flowmetry, reflectance spectrophotometry, and superconducting quantum interference devices (SQUID) are other experimental modalities that have been studied in the diagnosis of intestinal ischemia although not yet been applied clinically.31

Therapeutic options Our approach to the diagnosis and management of AMI is based on several observations. First, if the diagnosis is not made before intestinal infarction, the mortality rate is 70–90%. Second, the diagnosis of both the occlusive and nonocclusive forms of AMI can be made in most patients by angiography. Third, vasoconstriction, which may persist even after the cause of the ischemia is corrected, is the basis of NOMI and a contributing factor in the other forms of AMI. Finally, the vasoconstriction can be relieved by vasodilators infused into the SMA. The cornerstones of our approach, therefore, are the earlier and more liberal use of angiography and the incorporation of intra-arterial papaverine in the treatment of both occlusive AMI and NOMI. All patients with suspected AMI should undergo volume resuscitation and treatment with broad-spectrum antibiotics as well as correction of any potential contributing causes of AMI such as arrhythmias or congestive heart failure. Bacterial translocation has been shown to occur during AMI owing to loss of mucosal integrity.32 Experimental studies have shown reduction in the severity and extent of bowel damage with peri-ischemic event fluid resuscitation and antibiotic treatment, covering both Gramnegative and anaerobic organisms.33

Occlusive acute mesenteric ischemia: SMAE and SMAT Superior mesenteric artery emboli (SMAE) generally arise from ventricular or left atrial thrombi, often in the setting of atrial fibrillation. Many patients have a history of peripheral arterial emboli, and synchronous emboli are seen in 20% of patients. Typically, SMAE are found at points of normal anatomic narrowing, frequently just distal to the origin of a major vascular branch. They are classified as ‘major’ emboli when found proximal to the origin of the ileocolic artery and ‘minor’ if distal to this point or in one of the distal branches of the SMA. Angiographically, SMAE are characterized by rounded filling defects that result in occlusions to flow; evidence of atherosclerotic disease is seen to a lesser extent with emboli than with thrombosis. Superior mesenteric artery thrombosis (SMAT) is found most commonly in areas of severe atherosclerotic disease, usually at the origin of the SMA. Twenty percent to 50% of patients with SMAT report postprandial pain compatible with CMI. Coronary artery disease, stroke, and peripheral artery disease are frequent comorbidities. Angiography typically demonstrates an occlusion 1–2 cm distal to the origin of the SMA. Sometimes it can be difficult to differentiate an acute thrombosis from one that is chronic and incidental: the finding of collateral vessels that provide good filling of the SMA argues against an acute thrombosis, and other etiologies for the patient’s symptoms should be sought. Alternatively, if collateral vessels cannot be appreciated or adequate collateral filling of the SMA is not seen, then the thrombosis must be considered to be acute and appropriate treatment begun. Treatment of occlusive AMI is highly dependent upon the presence or absence of peritoneal signs: when such signs are present, a patient must undergo an exploratory laparotomy. Surgical interventions include resection of necrotic bowel with thromboembolectomy, patch angioplasty, endarterectomy and bypass procedures, depending on individual vascular anatomy and cause of the occlusion, e.g., embolus or thrombus.34 ‘Second-look’ operations are recommended in an attempt to minimize the amount of bowel that needs to be resected if there is questionable bowel viability during the first surgery. The time in between the index surgery and the secondlook procedure is used to maximize bowel survival, e.g., antibiotics, fluid replacement, and correction of adverse comorbidities. Percutaneous transluminal angioplasty also has been successful in one case report of a patient with SMAT and peritoneal signs,35 but generally is not advocated, given the significant risk of re-thrombosis.

Thrombolytics In patients without peritonitis, thrombolytics have been used alone successfully to treat SMA emboli and, to a lesser extent, thrombi. The pertinent literature, however, consists of only case reports and small case series; agents that have been used include streptokinase, urokinase, and tissue plasminogen activator (tPA). To date, there have been no randomized controlled trials comparing any of these agents to each other or to other treatments.

Pharmacology of thrombolytics Plasmin, a key element in the body’s endogenous fibrinolytic system, is a protease that dissolves thrombi by breaking down fibrin and other proteins of the clotting cascade including fibrinogen and coagulation factors V and VIII.36 Plasminogen is converted to plasmin by the cleavage of a single arginyl-valyl bond, also known as the

875

Vasodilators In addition to its therapeutic role in NOMI, both canine and human studies have shown vasodilator therapy to be beneficial for AMI secondary to SMAE or SMAT because splanchnic vasoconstriction

accompanies acute embolic and thrombotic mesenteric disease. Vasodilators, however, rarely are used alone in these situations unless patients are judged to be poor operative candidates. It has been demonstrated that mesenteric vasoconstriction may develop and persist for hours, causing irreversible ‘nonocclusive’ ischemia, even after what was believed to be a successful surgery or thrombolytic therapy for SMAE or SMAT. In a classic study by Boley and colleagues, dogs with iatrogenic SMAE were treated with intra-arterial saline (n=3), intra-arterial papaverine (n=5), intra-arterial streptokinase (n=5) or both papaverine and streptokinase (n=5).40 Post-treatment angiograms and pathologic examination revealed that although the group treated with streptokinase had the most vigorous response in terms of embolus lysis, the group treated with papaverine had less vasoconstriction, better bowel perfusion, and less bowel necrosis than any of the other three groups. Interestingly, the vasodilator effects of papaverine and the thrombolytic effects of streptokinase were attenuated in the group treated with both agents. Clinically, Boley et al. demonstrated a mortality rate of 54% (compared with 70–80% mortality in traditionally managed patients) when an aggressive approach utilizing early angiography and papaverine was taken in the management of patients with suspected AMI.41 Because of these successful experimental and clinical outcomes, papaverine is used frequently both pre- and postoperatively to reduce the splanchnic vasoconstriction that typifies NOMI and accompanies SMAE, SMAT, and even acute MVT. To date, however, no randomized controlled studies have been conducted to confirm the efficacy of this approach. Studies in which embolectomy was performed early in the clinical course without the use of papaverine have had equally successful outcomes; it has been postulated that vasoconstriction had not yet developed in these patients.

Pharmacology of papaverine Papaverine is a nonselective vasodilator derived from the poppy plant (genus Papaver); it inhibits phosphodiesterase, resulting in increased levels of intracellular cyclic AMP, the net effect of which is smooth muscle cell relaxation.42 In its use as a vasodilator for AMI, papaverine is administered as a bolus dose of 60 mg directly into the SMA, followed by a constant infusion of 30–60 mg/h. Priscoline, an alpha-receptor antagonist, sometimes is administered prior to papaverine to assess mesenteric responsiveness to vasodilation. Few systemic side effects from papaverine occur owing to its high first-pass metabolism (70–90%) and its short half-life of 0.5–2 hours. Some patients with liver disease may exhibit a drop in blood pressure with this dose of papaverine, but the most common cause of hypotension during the papaverine infusion is catheter dislodgment. Patients who have a sudden drop in blood pressure should immediately have the papaverine replaced with a saline or glucose solution and promptly undergo plain film imaging of the abdomen to confirm the catheter’s location. Complete AV block is a contraindication to papaverine treatment as large doses may depress AV conduction and result in cardiac arrhythmias. Proponents of vasodilator therapy recommend that preoperative intra-arterial papaverine be started during the index angiography if possible, and continued for 12–24 hours postoperatively if no second-look surgery is planned, and through the second procedure if one is planned. In either case, angiography should be done before removal of the catheter to confirm that vasospasm does not persist. Complications from repeated angiographic studies include acute tubular necrosis and local hematomas.

Acute Mesenteric Ischemia

Arg560-Val561 ‘activator bond.’37 Endogenous tissue plasminogen activator (tPA) and urokinase serve as plasminogen activators: t-PA converts predominantly fibrin-bound plasminogen to plasmin; urokinase, produced by human kidney cells, helps keep hollow organs such as the ureter, free from thrombi. Fibrinolysis is regulated primarily by inhibitors of both plasmin and plasminogen; however, when thrombolytics are used, these inhibitory controls become overwhelmed, and thus hemorrhage is a feared side effect. Because of its fibrin specificity, tPA is theoretically safer in terms of hemorrhagic risk, but this advantage has not been borne out clinically. Contraindications to thrombolytic therapy relate primarily to increased risk of bleeding, including recent surgery, trauma, severe hypertension, active bleeding or hemorrhagic disorder, previous CVA or active intracranial process, pregnancy or puerperium, aortic dissection, and acute pericarditis.38 The largest case series of thrombolytic therapy for AMI evaluated 10 patients who presented with acute abdominal pain of 5–18 hours duration; all had angiographically proven SMAE, two with major and eight with minor emboli.39 No patients had peritoneal signs and all had normal abdominal plain films. Urokinase (200 000 units) was infused directly into the embolus, followed by infusion of urokinase at 100 000 U/h into the SMA proximal to the embolus until angiographic resolution of the embolus; infusion times ranged between 8 and 32 hours. All patients also were given systemic heparin at 1000 U/h, which was continued for 4 days after urokinase treatment and was followed by warfarin indefinitely, if fibrinolysis was successful. Response to treatment was assessed by repeated clinical assessment and angiography 4–6 h after beginning treatment and thereafter at regular intervals as appropriate, depending on clinical and radiologic results. Resolution of the occlusion was defined by normal angiography or the presence of only tiny nonobstructing emboli with normal blood flow. Follow-up angiography showed successful lysis of emboli in 90% of patients, and resolution of abdominal pain within 1 hour of infusion in 70% of patients. One of these seven patients underwent exploratory laparotomy because of equivocal physical examination findings and was found to have normal bowel. All three patients who continued to have abdominal pain or developed peritoneal signs underwent surgery with bowel resection. One death in this group was believed to be secondary to cardiac insufficiency and was without demonstrable abdominal pathology. The authors of this study believed resolution of abdominal pain within 1 hour to be the most significant factor in predicting the success of fibrinolysis. They cautiously pointed out that, in contrast to classic dogma, duration of symptoms prior to diagnosis and treatment did not predict outcome. No complications occurred from urokinase therapy, and no patient suffered from recurrent embolism or postischemic stenoses in follow-up over an average period of 11 months. Many questions with regard to fibrinolysis remain to be studied including optimal agent and dose, method of delivery (pulsespray, intra-embolic, rapidity of infusions), length of treatment, whether treatment should vary depending on emboli location or duration of symptoms, role of adjunctive anticoagulation and its optimal duration, criteria to help define need for surgery and the best means of routine postlytic evaluation.


876

Nonocclusive mesenteric ischemia Nonocclusive mesenteric ischemia (NOMI) results from vasoconstriction that initially serves as a protective mechanism in the setting of a cardiovascular event such as acute myocardial infarction with shock, arrhythmias, congestive heart failure, hypovolemia associated with burns, pancreatitis, hemorrhage, and sepsis; cirrhosis and renal failure/dialysis also are risk factors. Splanchnic vasoconstrictors such as alpha adrenergic agents and digitalis also have been linked to NOMI.43 The incidence of NOMI has decreased significantly in recent years, likely owing to improved monitoring capabilities of hemodynamic parameters in the intensive care setting as well as the widespread use of vasodilating agents in the management of congestive heart failure and myocardial infarction.44 Vasoconstriction which initially is reversible may become irreversible if it is not corrected quickly, even after correction of the precipitating cause. Angiographically, four signs help to reliably diagnose NOMI: narrowing at the origins of SMA branches, alternating dilation and narrowing in the intestinal branches (the ‘stringof-sausages’ sign), spasm of the vascular arcades, and impaired filling of intramural vessels.45 An algorithm for management of NOMI proposed by Boley et al. over 25 years ago is still the treatment regimen with the best survival rates. As soon as angiographic diagnosis is established, intra-arterial (SMA) papaverine is initiated with a bolus of 60 mg and then infused at a dose of 30–60 mg/h. If peritoneal signs remain absent or remit within 20–30 minutes after papaverine infusion has begun, then papaverine is continued and repeat angiography is performed in 24 hours to document absence of or improvement in vasospasm. Papaverine infusion may be stopped at this point or continued if vasospasm persists; optimally an angiogram is repeated daily during infusion. If peritoneal signs are newly noted or persist longer than 20–30 minutes after papaverine is started, then exploratory laparotomy is mandated with resection of bowel as needed. Second-look procedures are done if bowel viability is in question. Papaverine is continued intraoperatively and postoperatively for 24 hours or until the time of the second-look operation.43

Focal segmental ischemia Focal segmental ischemia (FSI) is generally not a life-threatening condition as only short segments of bowel are involved and adequate collateral blood flow generally limits transmural necrosis. The etiology of FSI is varied and includes atheromatous emboli, strangulated hernias, immune complex disorders and vasculitis, blunt abdominal trauma, segmental thrombosis, radiation therapy, and oral contraceptives. Limited necrosis may present as acute enteritis, chronic enteritis (often resembling Crohn’s disease), or a stricture. The most common presentation is chronic small bowel obstruction with intermittent abdominal pain, distention, and vomiting. Bacterial overgrowth and protein-losing enteropathy also can occur. Definitive treatment of FSI is resection of the involved bowel.1

Mesenteric venous thrombosis Mesenteric venous thrombosis (MVT) may have an acute, subacute, or chronic presentation. Patients with MVT are typically younger than those with other types of mesenteric ischemia. MVT is associated with a myriad of hypercoagulable states, including protein

C, protein S or antithrombin III deficiencies, factor V Leiden mutation, anticardiolipin antibodies, malignancy, estrogens and pregnancy, intra-abdominal inflammation and sepsis, postoperative states, and trauma. MVT secondary to cirrhosis or neoplasm tends to start at the site of obstruction and propagate peripherally, while the centripetal propagation is observed in hypercoagulable states. If collateral blood flow does not permit venous drainage around the obstructed vessel, the bowel will become congested, edematous, cyanotic, and thickened with intramural hemorrhage. Serosanguinous peritoneal fluid heralds early hemorrhagic infarction. Coincidental arterial vasoconstriction may occur and also causes bowel infarction. Acute MVT presents with abdominal pain in more than 90% of patients and, as with acute arterial ischemia, the pain initially is out of proportion to the physical findings. The mean duration of pain before admission is 5–14 days but may be more than 1 month in as many as 25% of individuals.46 Other symptoms, including nausea and vomiting, occur in more than 50%. Lower gastrointestinal bleeding, bloody diarrhea, or hematemesis occurs in 15% and indicates bowel infarction. Fecal occult blood is found in more than half the instances during the course of MVT. Initial physical findings vary at different stages and with different degrees of ischemic injury, but guarding and rebound tenderness develop as bowel infarction evolves. Subacute MVT describes the condition in patients who have abdominal pain for weeks to months but no intestinal infarction. Subacute MVT can be due either to extension of thrombosis at a rate rapid enough to cause pain but slow enough to permit collaterals to develop, thereby preventing infarction, or to acute thrombosis of venous drainage sufficient to permit recovery from ischemic injury. The diagnosis usually is made on imaging studies ordered to diagnose other conditions. Non-specific abdominal pain usually is the only symptom of subacute MVT, and findings of physical examination and laboratory tests are normal. Some patients who present with subacute MVT ultimately develop intestinal infarction; this blurs the distinction between the acute and subacute forms of MVT. At autopsy, coexistent new and old thromboses have been found in nearly half of patients.

Diagnosis Standard CT is the current diagnostic test of choice for MVT. Evaluations of the colon are of little value since the colon is rarely involved. Characteristic findings on small bowel series include marked thickening of the bowel wall due to congestion and edema with separation of loops and ‘thumbprinting.’ Selective mesenteric arteriography can establish a definitive diagnosis before bowel infarction, can differentiate venous thrombosis from arterial forms of ischemia, and can provide access for vasodilator therapy if indicated. Angiographic findings of MVT include thrombus in the SMV with partial or complete occlusion, failure to visualize the SMV or portal vein, slow or absent filling of the mesenteric veins, arterial spasm, failure of the arterial arcades to empty, reflux of contrast medium into the artery, and prolonged blush in the involved segment.47 Ultrasonography, CT, and magnetic resonance imaging (MRI) all have been used to demonstrate thrombi in the SMV and the portal vein.48–50 CT can diagnose MVT in more than 90% of patients and is the diagnostic study of choice. Specific findings include thickening and enhancement of the bowel wall, enlargement of

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Therapeutic options Most patients with acute MVT are initially believed to have an arterial form of AMI. Treatment of MVT generally involves surgery, anticoagulation, or both. Surgical intervention includes resection of necrotic bowel, thrombectomy or both; thrombolytics have been used successfully in case reports. In symptomatic individuals, treatment is determined by the presence or absence of peritoneal signs; signs of peritonitis mandate laparotomy and resection of infarcted bowel. If long segments of questionably viable bowel are found and arterial spasm is present, papaverine is infused and if arterial spasm is relieved and the SMV or portal vein is visualized, thrombectomy and a second-look operation may be attempted to determine whether resection should be performed, using similar guidelines as for arterial causes of AMI. Following surgery, heparin should be administered. A comparison of patients who were treated surgically with those who were treated medically suggested that nonoperative management is a reasonable option provided the diagnosis on CT is certain and there is no transmural necrosis or perforation.51 Current recommendations for continued anticoagulation are based on whether an underlying hypercoagulable state is discovered, in which case lifelong coumadin is advocated. If no underlying thrombotic state is found, then anticoagulation is generally recommended for 3–6 months, although this is an arbitrary duration not yet supported by evidence-based data.1 The diagnosis and management of intestinal ischemia are summarized in Figure 62.1.

CHRONIC MESENTERIC VENOUS THROMBOSIS Disease spectrum and clinical presentation Chronic MVT is seen in patients who are asymptomatic at the time of thrombosis but who may develop gastrointestinal bleeding from varices.52 Most patients bleed from gastroesophageal varices secondary to thrombosis of the portal or splenic vein, and they have physical findings of portal hypertension. Findings are absent if only the SMV is involved. Laboratory studies may show secondary hypersplenism with pancytopenia or thrombocytopenia.

Diagnostic evaluation Chronic MVT can be asymptomatic; however, it may manifest as gastrointestinal bleeding, in which case the diagnostic evaluation

is directed towards determining the cause of the bleeding. Endoscopy and appropriate imaging studies should identify the cause and site of bleeding and the extent of thrombosis. While other tests may be used, the most common imaging modality is the CT scan to identify the vascular abnormalities. Papaverine-enhanced selective SMA angiography may further delineate the anatomy, but is more invasive than the other tests currently available.

Therapeutic options Treatment of chronic MVT is aimed at controlling bleeding, usually from esophageal varices. Sclerotherapy, portosystemic shunts, devascularization procedures, and bowel resection all have a place in treating selected patients. No treatment is indicated for patients with asymptomatic chronic MVT.1

COLON ISCHEMIA Colon ischemia (CI) is a frequent disorder of the large bowel in older persons and is the most common form of intestinal ischemic injury.53 It comprises a spectrum of clinical manifestations from mild to severe forms (Table 62.2). The initial presentation usually is the same among these types and does not necessarily predict the course of disease, with the exception of ischemia that involves the ascending colon simultaneously with the small intestine. This latter pattern usually is caused by SMAE or NOMI, may have associated shock, and carries a mortality rate of more than 50%.54,55 In a recent retrospective review of 53 cases of ischemic colitis, it was concluded that CI usually runs a benign course; however, peripheral vascular disease and right colon involvement have been reported to be associated with severe outcomes.56

Incidence The incidence of CI is underestimated, because many patients suffer only mild or transient damage and do not seek medical attention. Also, CI is frequently misdiagnosed and confused with other disorders, notably inflammatory bowel disease. It is estimated to be seen in 1/700 office visits and in the authors’ teritiary care hospital accounts for 1/100 colonoscopies and 1/2000 admissions. A recent study using medical claims data from a large healthcare organization in the US calculated a crude incidence rate of 7.2 cases per 100 000 person-years of observation in the general population, in contrast to 42.8 cases per 100 000 person-years for IBS patients. After adjustment for age, sex, and calendar year, the incidence of colon ischemia in people with IBS was 3.4 times higher than in persons without.4 CI has no sex predilection, and more than 90% of patients with CI of noniatrogenic causes are older than 60 years. CI affecting young persons has been documented in case reports or series of a few patients and has been due to vasculitis, coagulation disorders, illicit use of cocaine, and iatrogenic causes, including a wide variety of medications such as estrogens and progesterones and sodium polystyrene in sorbitol (Kayexalate).14

Pathophysiology and etiology Colon ischemia can result from alterations in the systemic circulation, or anatomic or functional changes in the local mesenteric vasculature (Table 62.3). The colon is relatively vulnerable to hypoperfusion since it has a lower blood flow per gram of tissue

Colon Ischemia

the SMV, a central lucency in the lumen of the vein (representing a thrombus), a sharply defined vein wall with a rim of increased density, and dilated collateral vessels in a thickened mesentery. The diagnosis of MVT usually is made at laparotomy, where its hallmarks are serosanguinous peritoneal fluid, dark red to blueblack edematous bowel, thickening of the mesentery, good arterial pulsations in the involved segment, and thrombi in cut mesenteric veins. At this stage, some degree of intestinal infarction invariably has occurred. When persons suspected to have AMI exhibit features suggesting MVT, contrast-enhanced CT is performed before SMA angiography. A history of deep vein thrombosis or a family history of an inherited coagulation defect prompts CT as the first imaging study.


878 dration, cardiac failure, sepsis, or hemorrhage may lead to CI, usually within the distribution of the SMA, by compromising flow volume and triggering reflex mesenteric vasoconstriction.

than does the rest of the gastrointestinal tract and, in contrast to the small bowel, its physiologic action of defecation is associated with a decrease in blood flow. The colon vasculature also is more sensitive to autonomic stimulation. In addition, the microvasculature plexus of the colon is less developed and is embedded in a relatively thick wall as compared to the small bowel. In most cases, no specific cause for CI is identified, and such episodes are viewed as localized nonocclusive ischemia, perhaps secondary to small vessel disease. Abnormalities on angiography rarely correlate with clinical manifestations of disease, but age-related abnormalities in the splanchnic vessels, including narrowing of small vessels, tortuosity of the long colic arteries, and fibromuscular dysplasia of the superior rectal artery, may be identified. Once again, vasospasm appears to be another important mechanism of ischemic injury, as the splanchnic vessels respond vigorously to vasoactive substances.57 Thus, hypotension from dehy-

Pathology The morphologic changes of the colon after an ischemic insult vary with the duration and severity of the injury. The mildest changes include mucosal and submucosal hemorrhage and edema with or without partial mucosal necrosis. Subsequently, these hemorrhages are resorbed or the overlying mucosa is sloughed, thereby evacuating the hemorrhage and creating an ulcer at the site. More severe injury results in more extensive damage, and the submucosa becomes edematous and contains abundant granulation and fibrous tissue. A variable inflammatory component, hemosiderin-laden macrophages, and preferential

Laparotomy A

Yes Resuscitate the patient and correct any predisposing or precipitating factors

History of DVT or familial No Peritoneal hypercoagulable state findings No

Plain film

Yes

Other cause

Dynamic CT scan

Major arterial occlusion nonembolic

Mesenteric venous thrombosis

No persistent peritoneal findings

Persistent peritoneal findings



Heparin with or without thrombolytic agents

Laparotomy

Anglographic evidence of collaterals

No anglographic evidence of collaterals

Short ischemic segment

Extensive ischemic involvement

Good filling of SMA

SMA filling is absent or poor

Resect

Nonviable

Observe

Continuous papaverine infusion, if possible

Heparin

Resect

Coumarin Long-term parenteral nutrition

Viable

Close

Main vein open or reconstituted

Main vein occluded

Heparin, papaverine

Thrombectomy, heparin, papaverine

Second-look ± resection Thrombolytic agents

Fig. 62.1

• Algorithm for the diagnosis (A) and treatment

Laparotomy, arterial reconstruction, and/or resection Second-look operation when appropriate

879

Clinical presentation Colon ischemia usually presents with sudden, crampy, mild, left lower abdominal pain, an urgent desire to defecate, and passage within 24 hours of bright red or maroon blood mixed with the stool. CI can account for approximately 20% of patients who present with lower gastrointestinal bleeding.60 The pain that accompanies CI usually is not as severe and is felt more in the left lower abdomen when compared with that of AMI. Bleeding usually is not sufficient to require transfusion. Mild to moderate abdominal tenderness usually is present over the involved segment of bowel. The splenic flexure, descending colon, and sigmoid most commonly are affected (Fig. 62.2). Certain causes tend to affect particular segments of colon: systemic low-flow states, the right colon; local

Normal findings B Abdominal angiogram

Minor arterial occlusion or embolus

Major embolus




Continuous papaverine infusion


Observe

Laparotomy and local resection

Selected cases: contraindication to surgery good perfusion of the distal mesenteric vascular bed after bolus of a vasodilator

Repeat angiogram Stop the infusion and remove the catheter Angiogram normal

Observe

Thrombolytic agents or heparin

•





Observe

Laparotomy

Splanchnic vasoconstriction (no occlusion)



Continuous Continuous papaverine Continuous infusion postoperatively papaverine infusion papaverine infusion Embolectomy and/or resection

Observe

Laparotomy with or without resection

Continuous papaverine infusion postoperatively

Repeat angiogram

Continuous papaverine infusion postoperatively

Repeat angiogram

Thrombolytic agents

Repeat angiogram and possibly a second-look operation

Repeat angiogram and possibly a second-look operation

cont’d (B) of intestinal ischemia. (From American Gastroenterological Association Medical Position Statement: guidelines on intestinal Fig. 62.1 ischemia. Gastroenterology. 2000; 118:951–3.)

Colon Ischemia

injury of the superficial epithelium with relative sparing of the lower crypts is suggestive of ischemic damage.58 Other findings include pseudomembranes, cryptitis, and crypt abscesses, but these are not prominent, and can overlap with the histopathologic findings associated with IBD.59 Histologic abnormalities in ischemic colitis are segmental. Occasionally, the inflammatory response and granulation tissue are so abundant as to produce a heaping-up of the mucosa and submucosa that resembles a stricture, constricting or polypoid neoplasm, or a submucosal tumor. With more severe and prolonged ischemia, the muscularis propria is damaged and replaced by fibrous tissue, thus forming a stricture. In the most severe forms of ischemic damage, there is transmural infarction of all layers of the colon, with gangrene and perforation.


880 Table 62.2 Types and approximate incidence of colon ischemia Type

Incidence (%)

Reversible colopathy

30–40

Transient colitis

15–20

Chronic ulcerating ischemic colitis

20–25

Stricture

10–15

Gangrene

15–20

Fulminant universal colitis

2–3 wk

Consider repeat BE or colonoscopy after 1–2 wk

Laparotomy Segmental colitis

Symptomatic Resection of involved bowel

Normal

Asymptomatic

Recurrent fever or sepsis Stricture formation

Observe

Treat as IBD?

883

CHRONIC MESENTERIC ISCHEMIA Disease spectrum and clinical presentation Chronic mesenteric ischemia (CMI) is uncommon, accounting for less than 5% of all intestinal ischemic diseases; it almost always is caused by mesenteric atherosclerosis. Abdominal pain is caused by ischemia in the small intestine as blood is ‘stolen’ from this organ to meet the increased demand for gastric blood flow as food enters the stomach.69 Patients classically complain of abdominal cramping discomfort that occurs within 30 minutes after eating, gradually increases in severity, and then slowly resolves over 1–3 hours. Although minimal at first, abdominal pain progressively increases and the association of pain with meals leads to fear of eating (sitophobia) with resultant weight loss. Nausea, bloating, episodic diarrhea, and malabsorption or constipation may occur, but it is the weight loss and relation of the abdominal pain to the meals that characterize this syndrome. Early in the course of disease, if patients do not eat, they remain pain free; pain occurs only after eating or during a meal. Later, pain may become continuous, and this portends intestinal infarction. Physical findings are usually limited, but patients with advanced disease may appear cachectic. Many patients have evidence of cardiac, cerebral, or peripheral vascular disease. The abdomen typically remains soft and nontender even during painful episodes, although significant distention may be appreciated. An abdominal bruit is common but non-specific.

Diagnostic evaluation The diagnosis of CMI is supported by the demonstration of highgrade stenoses in multiple mesenteric vessels, in patients with unexplained chronic abdominal pain, weight loss, and food aversion.70 A high clinical index of suspicion is crucial to making the diagnosis, due to the vague nature of the complaints and the lack of a specific diagnostic test. Plain radiographs of the abdomen usually are normal, although vascular calcifications may be present. Endoscopic inspection of the GI tract usually reveals it to be normal, and random biopsies of the upper tract may show only non-specific abnormalities. Barium studies are normal or show non-specific evidence of either malabsorption or a motility disturbance. A number of tests have been proposed to establish the presence of CMI, including duplex ultrasonography and MR angiography, but none has proven sufficiently sensitive and specific to be diagnostic. Mesenteric duplex ultrasonography has been advocated as a reasonably accurate screening modality for the detection of highgrade CA and SMA stenoses.71 Elevated ‘peak systolic velocity’ in the SMA and CA as determined by duplex ultrasonography indicates

significant stenosis of >50%;72,73 this, however, does not establish the diagnosis of CMI.74,75 Postprandial duplex ultrasonography does not significantly improve upon this yield.76 The current gold standard test is dependent on the arteriographic demonstration of an occlusive process of the splanchnic vessels, and, to a great measure, the exclusion of other gastrointestinal disorders. Angiography should show occlusion of two or more splanchnic arteries to allow the diagnosis of CMI; however, such occlusions, even of all three vessels, do not by themselves make the diagnosis of CMI, because they may be present with no corresponding clinical symptoms. In most patients with CMI, at least two of the three splanchnic vessels are either completely obstructed or severely stenosed. In a large review of patients with CMI,70 91% had occlusion of at least two vessels and 55% had involvement of all three; 7% and 2% had isolated occlusion of the SMA and CA, respectively. Magnetic resonance angiography (MRA) appears to provide highly accurate images of the arterial and venous mesenteric vasculature.77,78 In addition, cine phase-contrast MRA may be able to detect significant abnormalities in mesenteric blood flow.79,80 Contrastenhanced MRA has demonstrated excellent sensitivity and specificity for the detection of major splanchnic vessel stenoses and occlusions, although sensitivity is attenuated for smaller peripheral vessels and specificity may be lower for IMA stenosis.27 Again, the findings of splanchnic artery occlusions alone are insufficient to diagnose CMI; to this end, functional MRA also has been studied. The normal increase in postprandial SMV flow compared to its fasting state has been shown to be less in patients with CMI compared with controls.79,80 The usefulness of these techniques, especially functional MRA, is currently limited by the need for significant expertise in the use of this highly specialized equipment. At present, MRA should be considered experimental as a diagnostic tool for CMI. Another modality, balloon tonometry, uses an intraluminal catheter apparatus to indirectly measure the intestinal intramural pH (pHI) in the jejunum after a test meal. A decrease in pHI reflects a decrease in oxygen delivery to the gut and results from a shift to anaerobic metabolism with subsequent cellular acidosis; such a decrease in pHI correlates with abdominal pain and may be a good marker of tissue ischemia. Grum et al. used a canine model to show that pHI dropped precipitously when blood flow (oxygen delivery) was decreased below 60% of baseline.81 Tonometry has been applied to predict multiple organ failure and death in the intensive care unit setting,82 to help diagnose CMI83,84 and to assess for CI after abdominal aortic surgery.85

Therapeutic options The mainstay of treatment for CMI is surgical bypass, although percutaneous angioplasty and stenting procedures also have been studied. Therapeutic outcomes may be difficult to assess as success has been defined in different ways, including graft patency, relief of symptoms, and long-term survival. As reviewed in one recent article, means of 85% for long-term pain relief, 86% for graft patency, and 7% for mortality rate were found for surgical revascularization.86 Presently, only retrospective reviews of percutaneous angioplasty and stenting are available and are hampered not only by their inherent suboptimal study design but also by lack of homogeneity in terms of patient population, procedural technique, postprocedural assessment, and length of follow-up. Additionally, it may be difficult to compare surgery with percutaneous procedures

Chronic Mesenteric Ischemia

and after cross-clamping the aorta has been used successfully to predict which patients will develop CI after aneurysmectomy.68 Because postoperative CI is serious and difficult to diagnose early, colonoscopy should be performed within 2 to 3 days after surgery for a ruptured abdominal aortic aneurysm or in patients with a prolonged cross-clamping time, a patent IMA on preoperative aortography, nonpulsatile flow in the hypogastric arteries during surgery, or postoperative diarrhea. If CI is identified, oral feeding and liquids are stopped and antibiotic therapy is begun; clinical deterioration requires reoperation. At surgery, all ischemic colon must be resected.


884 as usually more vessels are bypassed in surgery than are treated percutaneously; further, only high-grade stenoses and not partly occluded vessels are treated percutaneously. Although initial success rates for percutaneous angioplasty and stenting are reported to range between 63% and 100%,87 long-term efficacy is generally less than that for surgery; one recent study reported that patients treated with percutaneous angioplasty and stenting developed recurrent symptoms at a rate of 28% at 1 year and 34% at 3 years.86 More recently, a study looking at patients treated with only angioplasty plus stenting found success rates equivalent to those of surgery at 15 months (83% symptomatic relief, 94% stent patency, 10% complication rate).87 However, restenosis and recurrent symptoms occur in one-third to one-half of patients within the first year, making the limited durability of the procedure its greatest limitation. Although experience is limited, a number of reports have described placement of an expandable metal stent to help prevent reocclusion.88,89 More data are likely needed before definitive conclusions can be reached.

FUTURE DIRECTIONS The significant morbidity and high mortality of ischemic injury will only be reduced by early diagnosis and treatment. In the future, diagnosis is certain to depend even more on technologically sophisticated imaging studies. At present, therapy consists of intra-arterial vasodilators, thrombolytics, and judicious surgery. The future directions of therapy may include the use of agents to: 1. re-establish blood flow early in the course of disease, e.g., glucagon, angiotensin converting enzyme inhibitor; 2. inhibit platelet aggregation, e.g., iloprost (a synthetic derivative of prostacyclin); 3. vasodilate selectively, e.g., ovine corticotropin releasing factor, sauvagine, and urotensin I; 4. prevent reperfusion injury by inhibiting free radicals, e.g., superoxide dismutase, allopurinol, melatonin, caffeic acid phenethyl ester, ethyl pyruvate; 5. prevent reperfusion injury by inhibiting neutrophil recruitment and adhesion, e.g., antibodies against intercellular adhesion molecule-1, heparin-binding epidermal growth factor, hepatocyte growth factor; and 6. improving mucosal viability, e.g., glycine, glucagonlike peptide-2a, IL-11.

SUMMARY Intestinal ischemia refers to the process whereby blood flow to the bowel is decreased and cellular injury occurs consequent to diminished supply of oxygen and nutrients. Gastrointestinal ischemia may result from a disturbance in the arterial blood supply or venous drainage of the bowel. Both hypoxia and reperfusion are important etiologic factors in this process. Regardless of its cause, the end results of ischemia are similar – a spectrum of bowel injury that ranges from transient alteration of bowel function to transmural gangrene. The most common cause of AMI is SMAE, followed by NOMI, SMAT, MVT, and FSI. Early on, AMI is characterized by severe abdominal pain, yet a paucity of physical findings. All patients with suspected AMI should undergo correction of underlying cardiovascular conditions and treatment with broadspectrum antibiotics. An aggressive approach utilizing early angiography and papaverine in combination with surgery can

significantly reduce mortality of AMI. Papaverine is used frequently to reduce the splanchnic vasoconstriction that typifies NOMI and accompanies SMAE, SMAT, and even acute MVT. CI is a frequent disorder of the large bowel in older persons. Its incidence is underestimated, because most patients suffer only mild, transient damage and do not seek medical attention. Generally, symptoms of CI resolve quickly. Irreversible damage from CI, e.g., gangrene and perforation, segmental ulcerating colitis, or stricture, or universal colitis, is uncommon. CMI typically is caused by mesenteric atherosclerosis. Patients classically complain of abdominal pain after eating and weight loss. A high clinical index of suspicion is crucial to making the diagnosis, due to the vague nature of the complaints and the lack of a specific diagnostic test. The current gold standard test is dependent on the arteriographic demonstration of an occlusive process of the splanchnic vessels, and the exclusion of other gastrointestinal disorders. Angiography should show occlusion of two or more splanchnic arteries to allow the diagnosis of CMI. The mainstay of treatment for CMI is revascularizing the stenotic vessels either by surgical bypass or percutaneous angioplasty with or without stenting procedures.

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72. Harward TR, Smith S, Seeger JM. Detection of celiac axis and superior mesenteric artery occlusive disease with use of abdominal duplex scanning. J Vasc Surg 1993; 17:738–745. 73. Moneta GL, Lee RW, Yeager RA, et al. Mesenteric duplex scanning: A blinded prospective study. J Vasc Surg 1993; 17:79–84. 74. Moneta GL, Yeager RA, Dalman R, et al. Duplex ultrasound criteria for diagnosis of splanchnic artery stenosis or occlusion. J Vasc Surg 1991; 14:511–518. 75. Bowersox JC, Zwolak RM, Walsh DB, et al. Duplex ultrasonography in the diagnosis of celiac and mesenteric artery occlusive disease. J Vasc Surg 1991; 14:780–786. 76. Gentile AT, Moneta GL, Lee RW, et al. Usefulness of fasting and postprandial duplex ultrasound examinations for predicting highgrade superior mesenteric artery stenosis. Am J Surg 1995; 169:476–479. 77. Holland G, Dougherty L, Carpenter J, et al. Breath-hold ultrafast three-dimensional gadolinium-enhanced MR angiography of the aorta and the renal and other visceral abdominal arteries. AJR Am J Roentgenol 1996; 166:971–981. 78. Shirkhoda A, Konez O, Shetty AN, et al. Mesenteric circulation: Three-dimensional MR angiography with a gadolinium-enhanced multiecho gradient-echo technique. Radiology 1997; 202:257–261. 79. Burkart DJ, Johnson CD, Reading CC, et al. MR measurements of mesenteric venous flow: Prospective evaluation in healthy volunteers and patients with suspected chronic mesenteric ischemia. Radiology 1995; 194:801–806. 80. Li KC, Hopkins KL, Dalman RL, et al. Simultaneous measurement of flow in the superior mesenteric vein and artery with cine phasecontrast MR imaging: Value in diagnosis of chronic mesenteric ischemia. Work in progress. Radiology 1995; 194:327–330. 81. Grum C, Fiddian-Green RG, Pittenger GL, et al. Adequacy of tissue oxygenation in intact dog intestine. J Appl Physiol 1984; 56:1065–1069. 82. Taylor DE. Revving the motor of multiple organ dysfunction syndrome: Gut dysfunction in ARDS and multiorgan failure. Respir Care Clin N Am 1998; 4:611–631. 83. Boley SJ, Brandt LJ, Veith FJ, et al. A new provocative test for chronic mesenteric ischemia. Am J Gastroenterol 1991; 86:888–891. 84. Kolkman JJ, Groeneveld AB. Occlusive and non-occlusive gastrointestinal ischaemia: A clinical review with special emphasis on the diagnostic value of tonometry. Scand J Gastroenterol Suppl 1998; 225:3–12. 85. Bjorck M, Hedberg B. Early detection of major complications after abdominal aortic surgery: predictive value of sigmoid colon and gastric intramucosal pH monitoring. Br J Surg 1994; 81:25–30. 86. Kasirajan K, O’Hara PJ, Gray BH, et al. Chronic mesenteric ischemia: Open surgery versus percutaneous angioplasty and stenting. J Vasc Surg 2001; 33:63–71. Comparison of the difference between percutaneous angioplasty and stenting versus open surgery with regards to early and late complications. 87. Sharafuddin MJ, Olson CH, Sun S, et al. Endovascular treatment of celiac and mesenteric arteries stenosis: Applications and results. J Vasc Surg 2003; 38:692–698. 88. Yamakado K, Takeda K, Nomura Y, et al. Relief of mesenteric ischemia by Z-stent placement into the superior mesenteric artery compressed by the false lumen of an aortic dissection. Cardiovasc Intervent Radiol 1998; 21:66–68. 89. Waybill PN, Enea NA. Use of a Palmaz stent deployed in the superior mesenteric artery for chronic mesenteric ischemia. J Vasc Interv Radiol 1997; 8:1069–1071.


CHAPTER SIXTY-THREE

63

Neoplastic diseases of the small and large bowel Paul C. Schroy III

INTRODUCTION Intestinal tumors, particularly those arising in the large bowel, constitute a commonly encountered management challenge to both primary care providers and GI specialists alike. Not surprisingly, appropriate treatment strategies are contingent on a number of factors, including tumor type, site of origin, extent of disease, and natural history. This chapter will focus initially on management issues related to epithelial tumors of the large bowel, i.e., adenomatous polyps and adenocarcinoma, which are by far the most common, clinically significant GI neoplasms. The management of epithelial tumors of the small bowel will be discussed next since treatment options are generally similar to those applied to epithelial tumors of the large bowel. The remainder of the chapter will discuss the management of intestinal lymphomas, carcinoid tumors, and miscellaneous stromal tumors.

COLORECTAL CANCER AND POLYPS Epidemiology Adenocarcinoma of the large intestine, commonly referred as colorectal cancer, is by far the most common malignant tumor of the large intestine. Worldwide incidence and mortality rates of colorectal cancer vary considerably.1 With the notable exception of Japan, industrialized countries are at greatest risk. High rates are found in North America, Australia, New Zealand, and Western Europe, while lower rates are found in Eastern Europe, most South American countries, Asia, and Africa. In the United States, colorectal cancer currently ranks as the fourth most commonly diagnosed malignancy and second leading cause of cancer-related death among males and females. In 2004 alone, there were approximately 146 940 new cases and 56 730 deaths.2 Incidence rates have declined slightly over the past two decades, but remain in excess of 40 cases per 100 000 population.2 Declines in incidence have been more dramatic for whites than blacks and for distal cancers compared to proximal cancers.3 Both cancers of the colon and rectum demonstrate a slight male predominance.2 An American’s lifetime risk of developing colorectal cancer is nearly 6%.2 Age is an important determinant of risk. Although extremely uncommon in individuals below the age 35 (except with rare predisposing genetic syndromes), the incidence of colorectal cancer increases steadily with age,

beginning around age 40 with an approximate doubling with each successive decade thereafter to around age 80.1 High-risk groups have been identified and include those with a personal or family history of colorectal cancer or adenomatous polyps, various genetic polyposis and nonpolyposis syndromes, and longstanding inflammatory bowel disease (Table 63.1). Overall 5-year survival rates have improved significantly in recent years, but racial disparities persist. Between 1992 and 1999, overall 5-year survival rates were in excess of 60% for whites but only 53% for blacks.2 Differences in cancer stage at diagnosis, therapy, or comorbidities rather than tumor biology may account for this discrepancy.4

Adenoma–carcinoma sequence Virtually all colorectal cancers arise from pre-existing adenomas through a process referred to as the ‘adenoma–carcinoma sequence.’ Only a fraction of adenomas evolve into cancers, however, given the disproportionate prevalence of adenomas relative to lifetime individual risk of colorectal cancer. The conversion rate for adenomas to cancer has been estimated to be on the order of 2.5 polyps per 1000 (0.25%) per year.5 Cross-sectional studies have identified increased polyp size (>1 cm), villous histology, high-grade dysplasia, and older age (>60 years) as important clinicopathologic determinants of malignant transformation.6 These determinants alone, however, do not accurately identify all adenomas at risk, since high-grade dysplasia and cancer can be found, albeit rarely, in small tubular adenomas in individuals under the age of 60.7 Consequently, recent interest has focused on potential molecular determinants of risk, since it is now firmly established that the adenoma–carcinoma sequence is a complex multistage process involving an accumulation of genetic alterations of specific oncogenes, tumor suppressor genes, and/or DNA mismatch repair genes.8–11 Another clinically important concept with respect to the adenoma–carcinoma sequence relates to ‘polyp dwell time,’ i.e., the amount of time it takes for a benign adenoma to transform into an invasive cancer. Although direct observational evidence is lacking, extrapolation of existing data suggest that it takes an average of about 10 years for an adenoma, particularly if 50 years) is the only risk factor are considered to be of ‘average risk,’ whereas those with other risk factors, such as a positive family history or inflammatory bowel disease, are considered to be at ‘increased risk’ (see Table 63.1). Ascertainment of risk is fundamental to appropriate clinical decision-making and provides a framework by which to discuss current recommendations for colorectal cancer screening and surveillance.

Screening guidelines for average-risk individuals Fecal occult blood testing, sigmoidoscopy, double-contrast barium enema, and colonoscopy have been advocated by most authoritative groups as appropriate screening tests for ‘average-risk’ individuals, beginning at age 50.33–36 The different tests vary with respect to effectiveness, strength of supporting evidence, risk of complications, complexity and cost (Table 63.3). The digital rectal

examination has not been shown to be an effective screening test for colorectal cancer and hence is not included in these guidelines. Moreover, the common practice of using the digital rectal examination as a means of obtaining a stool sample for fecal occult blood testing should be discouraged, because of concerns about test performance. Several studies have suggested that performing fecal occult blood testing at the time of a digital rectal examination does not increase false-positivity rates and therefore may be useful in noncompliant patients.37–39 Each of these studies concluded that a diagnostic colonoscopy should be performed for all positive tests, regardless of the method of stool collection. Because of concerns about sensitivity, however, conventional homebased testing on spontaneously passed stools is recommended for those testing negative by digital rectal examination. Annual Fecal Occult Blood Testing (FOBT): It has long been recognized that occult bleeding is an early sign of colorectal cancer. The most commonly performed tests to detect occult bleeding exploit the fact that hemoglobin possesses peroxidase activity, which can be easily detected at the bedside by the addition of a hydrogen peroxide reagent to a guaiac-impregnated slide (e.g., Hemoccult II, Hemoccult II Sensa). These guaiac-based tests are not specific for blood; peroxidase- and pseudoperoxidasecontaining foods such as red meat and certain vegetables will also produce a positive test. Three separate randomized controlled trials have demonstrated that FOBT followed by diagnostic colonoscopy significantly reduces colorectal cancer mortality by 15–18% if performed biannually and 33% if performed annually.23–25,27 FOBT also reduces the incidence of colorectal cancer.28 The major limitations of FOBT relate to test sensitivity and specificity. Although randomized controlled trials reported programmatic sensitivities of 72–78% for nonhydrated slides and 88–92% after hydration,23,25 point sensitivity for nonhydrated slides may be

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