GREGORY G. GINSBERG, MD UNIVERSITY OF PENNSYLVANIA PHILADELPHIA, PENNSYLVANIA
NUZHAT A. AHMAD, MD UNIVERSITY OF PENNSYLVANIA PHILADELPHIA, PENNSYLVANIA
An innovative information, education, and management company 6900 Grove Road • Thorofare, NJ 08086
Copyright © 2006 by SLACK Incorporated
ISBN 10: 1-55642-694-1 ISBN 13: 9781556426940
All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without written permission from the publisher, except for brief quotations embodied in critical articles and reviews. The procedures and practices described in this book should be implemented in a manner consistent with the professional standards set for the circumstances that apply in each specific situation. Every effort has been made to confirm the accuracy of the information presented and to correctly relate generally accepted practices. The authors, editor, and publisher cannot accept responsibility for errors or exclusions or for the outcome of the material presented herein. There is no expressed or implied warranty of this book or information imparted by it. Care has been taken to ensure that drug selection and dosages are in accordance with currently accepted/recommended practice. Due to continuing research, changes in government policy and regulations, and various effects of drug reactions and interactions, it is recommended that the reader carefully review all materials and literature provided for each drug, especially those that are new or not frequently used. Any review or mention of specific companies or products is not intended as an endorsement by the author or publisher. Library of Congress Cataloging-in-Publication Data The clinician’s guide to pancreaticobiliary disorders / edited by Gregory Ginsberg, Nuzhat Ahmad. p. ; cm. Includes bibliographical references and index. ISBN 1-55642-694-1 (alk. paper) 1. Pancreas--Diseases. 2. Biliary tract--Diseases. [DNLM: 1. Biliary Tract Diseases. 2. Pancreatic Diseases. WI 700 C64117 2006] I. Ginsberg, Gregory G. II. Ahmad, Nuzhat. RC587.C55 2006 616.3’6--dc22 2005022427 Printed in the United States of America. Published by:
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DEDICATION I dedicate this book to my mother Geraldine McDonnell Ginsberg, always a lady, who schooled me in humor and humility. In her personal struggle with chronic illness she exemplified strong will, perseverance, and grace. G.G.G. Dedicated to Professor Abdus Salam: Pakistani Nobel Laureate in Physics 1979— for leading by example. N.A.A.
CONTENTS Dedication ................................................................................................................v Acknowledgements ....................................................................................................ix About the Editors .....................................................................................................xi Contributing Authors ............................................................................................ xiii Preface .................................................................................................................... xv Chapter 1:
Development and Function of the Pancreas, Bile Duct, and Gallbladder .................................................................................1 Binita M. Kamath, MBBChir; Raman R. Sreedharan, MD; Petar Mamula, MD
Chapter 2:
Gallstones and Gallbladder Disorders .............................................21 Ann Marie Joyce, MD; William B. Long, MD
Chapter 3:
Choledocholithiasis ..........................................................................47 Eric Goldberg, MD; Peter Darwin, MD
Chapter 4:
Bile Duct Injuries ...........................................................................69 Janak N. Shah, MD
Chapter 5:
Ampullary Disorders ......................................................................91 William B. Silverman, MD, FACG
Chapter 6:
Cholangiocarcinoma ......................................................................103 Patrick R. Pfau, MD
Chapter 7:
Infections of the Biliary System ....................................................121 Faten N. Aberra, MD, MSCE
Chapter 8:
Acute Pancreatitis .........................................................................147 John Horwhat, MD; Paul Jowell, MD
Chapter 9:
Chronic Pancreatitis .....................................................................179 Tyler Stevens, MD; Darwin L. Conwell, MD
Chapter 10: Pancreatic Ductal Complications .................................................217 Ali Fazel, MD Chapter 11: Solid Pancreatic Tumor..................................................................239 Shyam Varadarajulu, MD; Mohamad A. Eloubeidi, MD, MHS, FACP, FACG Color Atlas Chapter 12: Pancreatic Cystic Lesions ...............................................................257 David G. Forcione, MD; Brenna C. Bounds, MD
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Chapter 13: Surgical Approaches to Pancreatic Cancer.................................... 287 Giorgos C. Karakousis, MD; Francis R. Spitz, MD Chapter 14: Biliary Tract Surgery .................................................................... 297 Rachel Rapaport Kelz, MD, MSCE; Jon B. Morris, MD Chapter 15: Imaging of the Pancreatobiliary System Using Endoscopic Ultrasound.................................................................. 311 Nuzhat A. Ahmad, MD Chapter 16: Magnetic Resonance Imaging/Magnetic Resonance ....................327 Cholangiopancreatography of the Pancreatobiliary System Wendy C. Hsu, MD; Evan S. Siegelman, MD Chapter 17
Pancreaticobiliary Diseases: The Role of the Interventional Radiologist ...................................................................................353 Richard Shlansky-Goldberg, MD; Aalpen Patel, MD
Index.....................................................................................................................367
ACKNOWLEDGMENTS For their support and inspiration we wish to acknowledge our parents and teachers, our respective spouses and kids, colleagues and students, and most certainly our patients. We are grateful to the contributing authors for their time and dedication devoted to developing a text that will benefit countless clinicians and patients.
ABOUT
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EDITORS
Gregory G. Ginsberg, MD is Professor of Medicine at the University of Pennsylvania School of Medicine, Gastroenterology Division, and Executive Director of Endoscopic Services at the University of Pennsylvania Health Systems. A graduate of Lafayette College, Easton, PA and Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, he completed Internal Medicine and Gastroenterology training at Georgetown University Medical Center, Washington, DC. Dr. Ginsberg’s clinical practice and research have focused on the development of new techniques and the evaluation of new technologies as they apply to endoluminal management disorders of the digestive system. Outside of his professional activity, he finds fulfillment with his wife, Jane, and four daughters, Jenny, Kathleen, Elizabeth, and Meg. Nuzhat A. Ahmad, MD is an Assistant Professor of Medicine at the University of Pennsylvania School of Medicine, Gastroenterology Division, and Associate Director of Endoscopic Services at the University of Pennsylvania Health Systems. She is also the chief of Gastroenterology at the Philadelphia VA Medical Center.
CONTRIBUTING AUTHORS Faten Aberra, MD, MSCE Instructor of Medicine Division of Gastroenterology Hospital of the University of Pennsylvania Philadelphia, PA Brenna Casey Bounds, MD Instructor in Medicine Harvard Medical School Director of Endoscopic Training Massachusetts General Hospital Boston, MA Darwin L. Conwell, MD Department of Gastroenterology and Hepatology The Cleveland Clinic Foundation Cleveland, OH Peter Darwin, MD Associate Professor of Medicine Director of Gastrointestinal Endoscopy University of Maryland Medical School Baltimore, MD Mohamad A. Eloubeidi, MD, MHS, FACP, FACG Associate Professor of Medicine and Pathology Director, Endoscopic Ultrasound Program Co-Director, Pancreatico-biliary Center University of Alabama at Birmingham Birmingham, AL Ali Fazel, MD Assistant Professor of Medicine Co-Director, Center for Endoscopic Ultrasound Division of Gastroenterology, Hepatology and Nutrition Department of Medicine University of Florida Gainesville, FL
David G. Forcione, MD Assistant Physician Gastrointestinal Unit Massachusetts General Hospital Instructor of Medicine Harvard Medical School Boston, MA Eric Goldberg, MD Assistant Professor of Medicine University of Maryland Medical School Baltimore, MD John Horwhat, MD Duke University Durham, NC Wendy C. Hsu, MD Hospital of the University of Pennsylvania Philadelphia, PA Paul Jowell, MD Associate Professor of Medicine Division of Gastroenterology Duke University Medical Center Durham, NC Ann Marie Joyce, MD Instructor of Medicine Hospital of the University of Pennsylvania Philadelphia, PA Binita M. Kamath, MBBChir Division of GI & Nutrition The Children's Hospital of Philadelphia Philadelphia, PA Giorgos C. Karakousis, MD Resident in General Surgery Department of Surgery Hospital of the University of Pennsylvania Philadelphia, PA
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William B. Long, MD Associate Professor of Medicine Hospital of the University of Pennsylvania Philadelphia, PA Petar Mamula, MD Division of GI & Nutrition The Children's Hospital of Philadelphia Philadelphia, PA Jon B. Morris, MD Associate Professor of Surgery Program Director for General Surgery Division of GI Surgery Department of Surgery Hospital of the University of Pennsylvania Philadelphia, PA
Richard Shlansky-Goldberg, MD Department of Radiology Division of Interventional Radiology Hospital of the University of Pennsylvania Philadelphia, PA Evan S. Siegelman, MD Associate Professor of Radiology Department of Diagnostic Radiology Hospital of the University of Pennsylvania Philadelphia, PA William B. Silverman, MD, FACG Professor of Medicine Division of GI/Hepatology Department of Internal Medicine University of Iowa Hospitals & Clinics Iowa City, IA
Aalpen Patel, MD Department of Radiology Division of Interventional Radiology Hospital of the University of Pennsylvania Philadelphia, PA
Tyler Stevens, MD Department of Gastroenterology and Hepatology The Cleveland Clinic Foundation Cleveland, OH
Patrick R. Pfau, MD Assistant Professor of Medicine Director of Gastrointestinal Endoscopy University of Wisconsin Medical School Madison, WI
Francis Spitz, MD Assistant Professor of Surgery Department of Surgery Hospital of the University of Pennsylvania Philadelphia, PA
Rachel Rapaport Kelz, MD, MSCE Assistant Professor of Clinical Surgery Hospital of the University of Pennsylvania Philadelphia, PA
Raman R. Sreedharan, MD Division of GI & Nutrition AI DuPont Hospital for Children Wilmington, DE
Janak N. Shah, MD Director of Therapeutic Endoscopy San Francisco Veterans Medical Center Assistant Clinical Professor of Medicine University of California San Francisco, CA
Shyam Varadarajulu, MD Assistant Professor of Medicine Division of Gastroenterology-Hepatology University of Alabama at Birmingham School of Medicine Birmingham, AL
PREFACE This book was developed as part of the popular Clinician’s Guide series and focuses on the understanding, diagnosis, and management of disorders of the pancreas and biliary systems. Chapters are clear and concise and written in a uniform manner. The multidisciplinary effort provides a broad and complete treatment of the topic. Images, artwork, graphics, and tables provide a visually appealing complement to the robust text. We think clinicians will find this to be a ready and reliable resource when encountering patients with pancreaticobiliary disorders.
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Development and Function of the Pancreas, Bile Duct, and Gallbladder Binita M. Kamath, MBBChir; Raman R. Sreedharan, MD; Petar Mamula, MD
Introduction DEVELOPMENT AND FUNCTION OF THE PANCREAS The pancreas makes its appearance in the fetal embryo as early as the 4th week of gestation. The development of pancreas starts as a dorsal and a ventral outpouching from the endodermal lining of the primitive duodenum (Figure 1-1). The dorsal anlage appears earlier than the ventral anlage and eventually forms the neck, body, tail, and superior part of the head of the pancreas. The ventral anlage appears more caudally and is closely related to the bile duct and hepatic diverticulum and develops into the inferior part of the head and uncinate process of the pancreas. The two parts of the pancreas are brought into apposition by the partial rotation of the duodenum by 7 weeks of gestation, and they eventually fuse together. Each part of the primitive pancreas has an axial duct—the dorsal duct (duct of Santorini) arising directly from the duodenal wall and the ventral duct (duct of Wirsung) arising from the common bile duct. At the time of the fusion of the dorsal and ventral parts of the pancreas, the ducts fuse at the junction of the head and body of the pancreas to form the main pancreatic duct. In the majority of individuals, the ventral duct (duct of Wirsung) becomes the main excretory duct and opens into the major papilla along with the common bile duct. The proximal part of the dorsal duct (duct of Santorini) becomes the accessory duct and is patent in 70% of individuals. A wide variety of anatomic variations exist in relation to the fusion and openings of the dorsal and ventral ducts. Both exocrine and endocrine cells originate from a common pluripotent progenitor under the influence of multiple transcription factors1. Distinct pathways like Hedgehog, Notch, and TGF-ß signaling promote or restrict cell differentiation and morphogenesis. Disruptions in these pathways may lead to development of various congenital anomalies (Table 1-1).
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Figure 1-1. Embryology of the pancreas, liver, and biliary tree. (Reprinted from Moore K, et al. The Developing Human, 1982, with permission from Elsevier.)
Table 1-1
CONGENITAL ANOMALIES OF THE PANCREAS Pancreas divisum Pancreas annulare Heterotopic pancreas Aplasia Hypoplasia Dysplasia Ductal anomalies
The pancreas has an exocrine and an endocrine function. The exocrine function consists of production of various digestive enzymes such as lipase, amylase, proteases, and nuclease by acinar cells. The endocrine function unit are islets of Langerhans composed of four different types of cells: a type secreting glucagon, d type secreting somatostatin, PP cells secreting pancreatic polypeptide, and ß secreting insulin.
DEVELOPMENT OF THE BILIARY TRACT AND THE GALLBLADDER The liver primordium appears as a thickening of the ventral midline endoderm (the hepatic plate) by day 22 of development (see Figure 1-1). The cells in the hepatic plate proliferate to form the hepatic diverticulum that projects into the septum transversum. The proliferating endodermal cells of the hepatic diverticulum invade the septum
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Figure 1-2. Morphogenesis of the intrahepatic ducts in mouse. At embryonic (E) day
15.5 the biliary precursor cells form a single-layered ring called ductal plate, which over the next two days becomes bilayered with focal dilations between the layers. These dilations give rise to the bile ducts, while the rest of the ductal plate regresses. (Adapted from Lemaigre F. Development of the biliary tract. Mechanisms of development. 2003;120:8187, with permission from Elsevier.)
transversum, forming cords of hepatoblasts. These hepatoblasts give rise to the intraand extrahepatic biliary system as well as the parenchymal elements of the liver. The intrahepatic bile ducts develop primarily by a process of differentiation from the hepatocytes at the margins of the portal tracts. This differentiation results in the formation of the so-called ductal plate, a single layer or sleeve of cells surrounding a portal vein 2 (Figure 1-2). The ductal plate becomes a double layer of cells around 7 weeks of gestation. Through a process termed as remodeling, tubular structures form between the two cell layers of the ductal plate. These developing bile ductules express cytokeratins consistent with differentiated biliary epithelium. After completion of remodeling, the nontubular elements of the ductal plate involute, leaving only the centrally located, highly differentiated interlobular duct. Maturation of the intrahepatic biliary tree progresses from the hilum of the liver outwards to the periphery beginning at approximately 11 weeks gestational age and continues for several months after birth. The physiologic and biochemical factors governing the differentiation and remodeling of the ductal plate are essentially unknown at present, though the role of ductal-vascular interactions is increasingly being recognized. The extrahepatic bile ducts and gallbladder develop from the caudal portion or pars cystica of the hepatic diverticulum before the 4th week of gestation. The pars cystica originates from the anterior side of the duodenum but assumes the definitive position of the common bile duct following rotation of the duodenum. The cystic portion of the hepatic diverticulum is initially hollow but the lumen is obliterated by proliferation of epithelial cells. The early gallbladder and extrahepatic biliary tree therefore consist of solid cords of epithelial cells in the 5th week of gestation. Subsequent vacuolization results in the formation of a lumen in the common bile duct by week 6 and this is fol-
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lowed by canalization of the hepatic ducts. Finally, a definitive lumen develops in the cystic duct and the gallbladder by recanalization during the 7th week. The epithelium of the extrahepatic biliary system is continuous with the duodenum at one end and the primitive hepatic cords at the other. The gallbladder is patent by the 3rd month of gestation and its wall contains muscle fibers. Bile secretion starts at the beginning of the 4th month of gestation and thereafter the biliary system constantly contains bile, which is secreted into the gut lumen. The interlobular ducts formed from the differentiation and remodeling of the ductal plate are joined by intrahepatic extensions of the extrahepatic ducts, to complete the bile duct system.
Congenital Abnormalities of the Pancreas PANCREAS DIVISUM Pancreas divisum is the most common congenital anomaly of the pancreas. The incidence has been reported to be between 5% and 11% of the population3. Pancreas divisum arises as a result of the incomplete fusion of the dorsal and ventral ductal structures. This leads to persistence of two drainage systems. The ventral duct (duct of Wirsung) drains only the head of the pancreas through the major papilla. The dorsal duct (duct of Santorini) drains the body and tail of the pancreas through a smaller minor papilla, which is positioned proximal to the major papilla. The minor papilla through which the major portion of the pancreas drains could be too small for proper drainage and can lead to a functional stenosis.
Clinical Manifestations and Evaluation Pancreas divisum may cause recurrent abdominal pain. Additionally, the stenosis of the minor papilla has been implicated as a cause for recurrent pancreatitis. Computed tomography (CT) scan of the abdomen may suggest the diagnosis, but the confirmation of the diagnosis is made by endoscopic retrograde cholangiopancreatography (ERCP) (Figure 1-3). Recently the noninvasive magnetic resonance cholangiopancreatography (MRCP) is being increasingly used.
Management Endoscopic therapies include papillotomy of the minor papilla with or without sphincterotomy of the major ampulla, ductal balloon dilatation, and pancreatic dorsal duct stent placement. Surgical therapy includes minor papilla sphincterotomy and sphincteroplasty.
ANNULAR PANCREAS This is the second most common anomaly of the pancreas, and occurs when a band of pancreatic tissue encircles the second part of the duodenum. There are several theories that have been put forward to explain the anomalous development:
1. Fixation of the tip of the ventral anlage resulting in failure of rotation. 2. Hypertrophy of the dorsal and ventral anlage resulting in a constriction around the duodenum.
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Figure 1-3. Pancreas divisum.
Contrast injection following cannulation of the ampulla of Vater demonstrates a small pancreatic duct of Wirsung. (Reprinted from M. Al Samman. Pancreas Divisum. eMedicine.com, Inc., 2004. Used with permission.)
3. Baldwin’s theory, which describes the persistence of the left ventral bud that normally atrophies during development.
Clinical Manifestations and Evaluation Symptoms depend on the severity of the constriction and most patients are asymptomatic. In severe cases, polyhydramnios is noted during pregnancy followed by feeding difficulty, vomiting, and abdominal distension during the neonatal period. In less severe cases, the manifestations are less dramatic and present at an older age or even adulthood with nausea, post-prandial fullness, vomiting, weight loss, and even gastrointestinal bleeding. In mild cases, there are no symptoms and the diagnosis is made as an incidental finding. In severe cases of constriction presenting in the neonatal period, the abdominal x-ray shows the classic “double bubble sign” (Figure 1-4) suggesting duodenal obstruction. In older children and adults, the upper intestinal contrast study findings of annular filling defect in the duodenum, prestenotic dilatation, and reverse peristalsis in the proximal segment are suggestive of annular pancreas. CT scan of the abdomen, MRCP, and ERCP are other useful investigative modalities. The diagnosis is confirmed at laparotomy.
Management Management is surgical. Surgical division of the pancreatic ring is associated with complications and hence avoided. Bypass surgery is the surgery of choice, whereas duodenostomy is done for isolated stenosis in children. Other extensive bypass surgeries may be performed depending on the anatomy.
HETEROTOPIC PANCREAS This anomaly, also called pancreatic rest, ectopic pancreas, accessory pancreas, or aberrant pancreas, is defined as pancreatic tissue lacking anatomic and vascular
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Figure 1-4. Pancreas
annulare. Abdominal x-ray showing classic “double bubble” sign indicating duodenal obstruction seen in duodenal atresia and annular pancreas. (Used with permission from eMedicine.com, Inc., 2004.)
continuity with the main body of the pancreas. The incidence is up to 15% in autopsy specimens. Approximately 70% of heterotopic pancreas is located in the upper gastrointestinal tract. Other sites include gallbladder, liver, omentum, colon, appendix, Meckel’s diverticulum, intestinal duplication cysts, and extra intestinal sites such as bronchopulmonary sequestration and umbilicus. Histologically, both ductal and acinar tissues are recognized in the tissue.
Clinical Manifestations and Evaluation Symptoms if present include epigastric pain, gastrointestinal bleeding, abdominal distension, nausea, vomiting, and dyspepsia. Complications include mucosal ulcers with gastrointestinal bleeding, intussusceptions, intestinal obstruction, cholecystitis, jejunal atresia, and carcinoma arising from the aberrant tissue. This anomaly is usually found as incidental finding during endoscopy and it appears as discrete submucosal yellow nodules of sizes varying from 2 mm to 4 cm with a central umbilication (Figure 1-5). Biopsy of the nodule can confirm the diagnosis histologically.
Management Incidentally diagnosed heterotopic pancreases ideally do not require any intervention. Endoscopic ultrasound is an effective tool in accurate characterization. If the diagnosis is in doubt, surgical excision is considered, as it is both diagnostic and curative. In the event of complications, surgical excision is the procedure of choice.
PANCREATIC AGENESIS, HYPOPLASIA, AND DYSPLASIA Complete agenesis of the pancreas is incompatible with life and is rare. Partial agenesis is usually due to the abnormal development of the dorsal anlage, and the size and shape of the pancreas vary. In hypoplasia, the size and shape of the gland is
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Figure 1-5. Heterotopic
pancreas. Endoscopic picture of heterotopic pancreas tissue in the antrum of the stomach.
normal but there is fatty tissue replacing the normal epithelial cells and reduced ductal differentiation. In dysplasia, there is abundant fibromuscular tissue with disorganized ductal and parenchymal tissues.
Clinical Manifestations and Evaluation Symptoms are variable and depend on the degree of involvement of the exocrine and endocrine functions. Manifestations include failure to thrive, malabsorption, and insulin-dependent diabetes. Studies including ERCP, MRCP, angiography, and abdominal and endoscopic ultrasound may be helpful. Also, cholycystokinin-secretin stimulation tests may be performed to assess the degree of pancreatic exocrine function. Definitive diagnosis is made during laparotomy or at autopsy.
Management The therapy is mainly supportive with insulin and pancreatic enzyme replacement.
Congenital Abnormalities of the Biliary Tract CONGENITAL ABNORMALITIES OF THE INTRAHEPATIC BILIARY DUCTS Intrahepatic bile duct anomalies encompass a wide range of disorders (Table 1-2). A full discussion of intrahepatic biliary pathology is beyond the scope of this chapter and will be discussed elsewhere. Clinically important conditions have been included briefly.
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Table 1-2
CONGENITAL ANOMALIES OF THE BILIARY TRACT Intrahepatic Bile Duct Anomalies Cystic disorders Solitary cysts Polycistic conditions (ARPKD/CHF, ADPKD, Caroli disease) Bile duct paucity Syndromic-Alagille syndrome Nonsyndromic
Extrahepatic Bile Duct Anomalies Biliary atresia* Agenesis Choledochal cyst Bile duct stenosis Accessory ducts Positional anomalies Duplication Spontaneous perforation Bronchobiliary fistula ADPKD = autosomal dominant polycystic kidney disease, ARPKD/CHF = autosomal recessive polycystic kidney disease/congenital hepatic fibrosis *Biliary atresia is not a true congenital anomaly; see text for further details.
Cystic Disorders Cystic conditions affecting the intrahepatic tree may be solitary or polycystic. The distinction between communicating and noncommunicating cysts is clinically significant, as duct cysts communicating with the biliary tree have a greater likelihood of causing clinical disease. Communicating duct cysts can be associated with cholangitis, stone formation, and (relatively uncommonly) neoplasia. Noncommunicating duct cysts are usually asymptomatic, and may present as an abdominal mass or biliary obstruction. Solitary Cysts
Definition Solitary cysts are noncommunicating developmental cysts, which are lined by simple cuboidal or biliary-type epithelium and are not associated with cysts in other organs. The surrounding hepatic parenchyma displays secondary atrophy, portal fibrosis, and bile duct proliferation.
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Clinical Manifestations and Evaluation Solitary cysts are usually asymptomatic and are identified incidentally on ultrasonography. If symptomatic, most commonly they present as an upper abdominal mass. Rupture, torsion, or hemorrhage of a solitary hepatic cyst may occur. Management Management is surgical excision, if necessary.
Polycystic Conditions Polycystic liver conditions are often associated with cystic disorders of the kidney. Renal tubular development parallels biliary development during gestation. The hallmark hepatic histopathological finding in polycystic liver disease is ductal plate malformation. Autosomal Recessive Polycystic Kidney Disease/Congenital Hepatic Fibrosis
Definition Congenital hepatic fibrosis (CHF) is characterized by ductal plate malformation, communicating cysts, and hepatic fibrosis resulting in portal hypertension and an increased risk of ascending cholangitis. Typically, CHF is associated with autosomal recessive polycystic kidney disease (ARPKD) and these are best considered a single disorder with a wide spectrum of manifestations. Etiopathogenesis Mutations in the polycystic kidney and hepatic disease 1 gene (PKHD1) on chromosome 6p21.1-p12 have recently been identified as the molecular cause of ARPKD/CHF. Clinical Manifestations and Evaluation The clinical manifestations of ARPKD/CHF vary in large part according to the age at first presentation. In newborn patients with ARPKD, the renal lesions are diffuse and prominent clinically, whereas in patients who exhibit the clinical picture of CHF, the renal lesions are often not as evident in early life and are minor. Therefore, renal disease predominates in neonates and infants, whereas the hepatic-related disease predominates in older children and adults. In older patients who present with the hepatic manifestations of CHF, the most significant abnormality is portal hypertension and esophageal varices. Clinically, hematemesis or melena is the presenting sign in 30% to 70% of patients. Palpable kidneys are often noted at initial evaluation and renal dysfunction is present in approximately 20% of patients. A liver biopsy is diagnostic, showing classic ductal plate malformation. Dilatation of the intrahepatic ducts is common in this condition, as is an increased risk for cholangitis. Cholangitis may be occult, acute, or chronic in nature, and contributes significantly to both the morbidity and mortality of congenital hepatic fibrosis. Management There is no therapy for the underlying developmental anomaly in ARPKD/CHF. For portal hypertension, portosystemic shunting has been the treatment of choice, as there is a low incidence of postoperative encephalopathy. Ursodeoxycholic acid therapy and prophylactic antibiotic administration may have a role in selected patients. In
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Figure
1-6. Caroli's disease. Ultrasound of the liver in a neonate with Caroli's disease demonstrating multiple dilated intrahepatic bile ducts.
those patients with chronic cholangitis and/or progressive hepatic dysfunction, liver transplantation may prove to be the optimal therapy. Caroli’s Syndrome and Caroli’s Disease
Definition Caroli’s syndrome describes congenital dilatation of the intrahepatic biliary tree in association with ductal plate malformation. Caroli’s disease, a much rarer condition, involves intrahepatic biliary dilatation only and these cysts are therefore noncommunicating. Both conditions are associated with ARPKD. Etiopathogenesis Caroli’s syndrome results from a derangement of bile duct differentiation including small and large ducts, and could actually be part of the spectrum of ARPKD/CHF. In contrast, Caroli’s disease appears to arise from an arrest in remodeling of the ductal plate at the larger intrahepatic ducts only (and hence there is no associated ductal plate malformation and CHF). Clinical Manifestations and Evaluation Caroli’s syndrome manifests as CHF with portal hypertension and cholangitis. In both Caroli’s syndrome and disease, ductal cyst formation predisposes to bile stasis, lithiasis, and infection. Abdominal CT, ultrasonography (Figure 1-6), and cholangiograms demonstrate irregular cystic dilatation of the large, proximal intrahepatic biliary tree. Cholangiocarcinoma is also a potential complication of these disorders. Management Caroli’s syndrome is managed as CHF. Caroli’s disease requires antibiotics for infection and partial hepatectomy may also be effective if the lesion is discrete. Many patients can be managed with hepatico-jejunostomy. Percutaneous transhepatic cholangiography may be used adjunctively to clear remnant and recurrent stone disease. Autosomal Dominant Polycystic Kidney Disease
Definition Autosomal dominant polycystic kidney disease (ADPKD) is characterized by renal and hepatic cysts (polycystic liver disease), often in association with other visceral anomalies such as intracranial and aortic aneurysms, mitral valve prolapse, pancreatic cysts, and colonic diverticula. ADPKD is rarely associated with CHF.
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Etiopathogenesis ADPKD results from mutations in one of at least three distinct genetic loci, termed PKD1, PKD2, and PKD3. Clinical Manifestations and Evaluation ADPKD is usually symptomatic after age 40, however, it can be anatomically identified even in fetal life. It is important to recognize for its genetic implications, although the functional significance of the finding is not apparent until beyond childhood. The hepatic lesions are primarily duct cysts, which are readily demonstrated ultrasonographically. Cysts increase in size from childhood until 40 to 50 years of age. Commonly, the cysts in this condition are dilated ductal elements, which are not demonstrated to communicate with the distal biliary tree. However, they may manifest clinically with abdominal pain, infection and abscess formation, cyst rupture, bleeding, and biliary obstruction. The renal lesion consists of cysts that appear to arise from multiple areas along the nephron and increase in size with age, resulting in end-stage renal disease in 50% of patients. Cysts may also be found in other organs, including spleen, pancreas, thyroid, ovary, endometrium, seminal vesicles, and epididymis. Arterial aneurysms are present in 15% of cases. Management The renal disease in ADPKD requires careful management. In many cases, the polycystic liver disease does not require treatment. Infection necessitates antibiotics in combination with percutaneous drainage. Surgical fenestration can be helpful for relief of symptoms or biliary compression.
Bile Duct Paucity Decrease in ductal number (paucity) is one of the most significant abnormalities of the intralobular bile ducts in children. Bile duct paucity can occur in association with other features, as in Alagille syndrome (see below) or in isolation—nonsyndromic bile duct paucity. A full discussion of these disorders is beyond the scope of this chapter. Syndromic Bile Duct Paucity—Alagille Syndrome
Definition Alagille syndrome (AGS) is an autosomal dominant multisystem developmental disorder characterized by bile duct paucity, occurring in association with cardiac, musculoskeletal, ocular, facial, renal, pancreatic, and vascular abnormalities. AGS has a frequency of at least 1 in 80,000. Etiopathogenesis The disease gene in AGS has been identified as Jagged1 (JAG1) on chromosome 20p12, which encodes a ligand in the evolutionarily conserved Notch signaling pathway. Clinical Manifestations and Evaluation AGS is characterized by a wide variability in its clinical spectrum, even within individual pedigrees. The diagnosis is made when bile duct paucity on liver histology is accompanied by the major extrahepatic findings of the syndrome: chronic cholestasis, characteristic facies, cardiac murmur (typically due to peripheral pulmonary stenosis), vertebral anomalies (typically butterfly vertebrae), and posterior embryotoxon in the eye.
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Cholestasis is manifest by pruritus and elevations in serum bile acid concentrations. This pruritus is among the most severe in any chronic liver disease. The presence of severe cholestasis results in the formation of xanthomas, characteristically on the extensor surfaces of the fingers, the palmar creases, nape of the neck, and around inguinal trauma sites. Progression to cirrhosis and hepatic failure is recognized in approximately 20% of AGS patients. Management Infants with intrahepatic cholestasis may have significant fat malabsorption and fat-soluble vitamin deficiency. Antihistamines may give some relief for the pruritus, and care should be taken to keep the skin hydrated with emollients. Cholestyramine, ursodeoxycholic acid, and rifampin may improve pruritus, and biliary diversion is emerging as a useful tool for refractory cases. The outcome of syndromic bile duct paucity is highly variable and is most directly related to the severity of the hepatic and cardiac lesions, with mortality predominantly attributable to these two organs. Transplantation does appear to have a higher risk for patients with AGS, due in part to the severity of cardiopulmonary disease.
CONGENITAL ABNORMALITIES OF THE EXTRAHEPATIC BILIARY DUCTS Extrahepatic Biliary Atresia The inclusion of extrahepatic biliary atresia (BA) in this chapter is somewhat controversial as the etiology of this condition is not yet clear and it does not appear to be a true congenital abnormality. However, as it is an early onset disease of the biliary system and the number one cause for pediatric liver transplantation in the United States, it certainly warrants discussion and is therefore included. Definition
BA is a progressive, idiopathic, necroinflammatory process resulting in obliteration of the lumen of the extrahepatic biliary tree within the first 3 months of life. BA occurs with an estimated frequency of 1 in 10 to 15,000 live births, resulting in between 250 and 400 new cases each year in the United States. Etiopathogenesis
BA may represent the final common pathway of several different etiologies but at least two major forms exist: postnatal or nonsyndromic form and the fetal or syndromic form. The pathogenesis of BA remains a mystery and the hypotheses and supporting evidence are beyond the scope of this discussion. Most of the theories and research focus on a viral infection or toxin exposure, developmental defect, genetic predisposition, vascular etiology, and an immune or autoimmune phenomenon4. Clinical Manifestations and Evaluation
Postnatal BA accounts for the majority of cases. These infants appear typically healthy at birth and then present with the characteristic features of jaundice due to conjugated hyperbilirubinemia, pale stools, dark urine, and hepatomegaly within the first 3 months of life. Splenomegaly will be found in most patients. Approximately 15% to 20% of infants have syndromic BA and have associated anomalies including defects of laterality (situs inversus, bilateral bilobed lungs, abdominal situs inversus, intestinal malrotation, anomalies of the portal vein and hepatic artery, polysplenia, and asplenia) and cardiac and renal defects.
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Figure 1-7. Biliary atresia. Intraoperative cholangiogram demonstrating contrast in the gallbladder (arrow) of a 2-monthold girl with biliary atresia with no filling of the intra- or extrahepatic biliary tree.
Rapid diagnosis of BA is necessary to optimize the response to surgery. No single biochemical test is specifically diagnostic of BA, though an elevated GGT suggests a biliary cause. Abdominal ultrasound may identify choledochal cysts or other causes of extrahepatic obstruction. 99mTc-labeled diisopropyl iminodiacetic acid scintigraphy (DISIDA) evaluation of hepatic uptake and biliary excretion into the duodenum may be helpful in indirectly assessing the patency of the biliary system. A liver biopsy (percutaneous or open) will help distinguish obstructive from nonobstructive causes of cholestasis. Histologically, in biliary obstruction there is expansion of the portal spaces with proliferation of bile ductules with bile stasis and plugging. A biopsy suggestive of obstruction mandates surgical exploration and an intraoperative cholangiogram (Figure 1-7), which is the definitive test. Management
If not corrected, BA is uniformly fatal within the first 2 years of life. If a cholangiogram is consistent with BA, a surgical hepatoporto-enterostomy or Kasai procedure is attempted. The two most important indicators in determining the surgical outcome are age at the operation and the surgeon’s experience. Success with biliary drainage is more likely if surgery takes place before 8 weeks of age. However, BA is a progressive condition and despite surgery at an appropriate time, two-thirds of children still require liver transplantation. Biliary atresia is now the most common indication for liver transplantation in infants and children, and although the presence of situs ambiguus may require technical adjustments, associated anomalies do not preclude transplantation.
Choledochal Cyst Definition
Choledochal cysts are segmental dilatations of the biliary tree. They most commonly involve the extrahepatic tree and are therefore considered in this section;
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Figure 1-8. Choledochal cyst classification
(From Todani et al. Congenital bile duct cysts: classification, operative procedures, and review of thirty-seven cases including cancer arising from choledochal cyst. Am J Surg. 1977;134:266, with permission from Excerpta Medica.)
Figure
1-9. Choledochocoele (arrow) endoscopic retrograde cholangiopancreatography image in a 16-year-old girl.
however, they may also involve the intrahepatic system. A classification system is illustrated in Figure 1-8. Five types are recognized: • Type I: Diffuse enlargement of the common bile duct with three subtypes:
a) spherical, b) segmental, and c) cylindrical • Type II: Common bile duct (CBD) diverticulum • Type III: Cystic dilatation of the intraduodenal portion of the CBD choled-
ochocoele (Figure 1-9) • Type IV: Multiple intra- and extrahepatic bile duct cysts • Type V: Multiple intrahepatic bile duct cysts. Cystic dilation of the CBD may become very large. Most commonly there is dilation of the common duct itself (type I) or, rarely, dilation in a diverticulum of the common duct wall (type II). Of cases presenting in childhood, over 90% have been reported as type I and 75% of the remainder as type II. The dilated region is usually sharply demarcated, and the common duct below the cystic area may appear narrowed. Single or multiple intrahepatic cysts are classified as type V cysts and appear to be rare. This category overlaps and blends into Caroli's disease, a condition characterized by intrahepatic dilation of major ducts.
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Figure 1-10. Choledo-
chal cyst. Magnetic resonance cholangiopancreatogram image of a choledochal cyst in a 14-year-old girl.
Choledochal cysts usually are nonsyndromic (ie, usually not associated with primary malformations of other organ systems), but they may occur in association with other anomalies of the hepatopancreatobiliary duct system, including gallbladder agenesis, double gallbladder, and pancreas divisum. Clinical Manifestations and Evaluation
Choledochal cysts may remain asymptomatic throughout childhood, but they may be found in young infants or in adults with histories of symptoms since childhood. Presenting symptoms include biliary colic, jaundice, and a palpable abdominal mass in the right upper quadrant. This classic clinical triad is only seen in approximately 25% of patients. Occasionally patients present with symptoms of acute pancreatitis. Preoperative diagnosis may be difficult, but ultrasound is especially helpful in diagnosing a choledochal cyst in an infant. Hepatobiliary scintigraphy, endoscopic retrograde cholangiography, and MRCP (Figure 1-10) may also be very useful. Management
Once significant symptoms occur, surgery is usually necessary for the choledochal cyst (Figure 1-11). Complications include malignancy, rupture, calculi, and, rarely, portal hypertension and/or hemorrhage. Cholangiocarcinoma develops in 4% to 8% of patients, often after 20 years of age. Despite few abnormalities in liver function, affected patients may have mild to severe degrees of hepatic fibrosis. Because of the occasional association with other anomalies of the biliary tract, as precise an anatomic evaluation as possible must be performed prior to surgery. Response to surgery is usually very good if done early. If excision of the cyst is not possible, a choledochocystojejunostomy may be performed.
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Figure 1-11. Choledo-
chal cyst. Intraoperative image of choledochal cyst in a 14-year-old girl. For full-color version, see page CA I of the Color Atlas.
Other Extrahepatic Biliary Duct Anomalies Definition
Accessory ducts, positional alterations, duplications, and stenosis. It has been stated that the extrahepatic biliary tree has more anomalies than any other area of the body (see Table 1-2). Clinical Manifestations and Evaluation
Many anatomic variations are asymptomatic and found incidentally at surgery, radiography, or autopsy. Anomalies and variants include accessory ducts (extranumerary ducts usually arising from the right lobe of the liver and entering one of the normal extrahepatic ducts); cholecystohepatic ducts or sinuses of Luschka (abnormal duct elements which arise in the liver, pass through the gallbladder wall, and enter one of the normal extrahepatic ducts); duplication or partial division by a septum of the common duct; ectopic orifice of the common duct (in the stomach or proximal duodenum); and numerous variations in the configuration of the hepatic ducts and common duct. Anomalies of potential pathologic significance include the cystic duct draining into the left side of the main duct or directly into the duodenum (short choledochus syndrome); aberrant hepatic duct with dorsocaudal branch draining into the common duct; agenesis of the common duct; intrahepatic junction of the hepatic ducts; and congenital bronchobiliary fistula (usually between the right main stem bronchus and the bile duct system within the left lobe of the liver). An isolated stricture or stenosis of the extrahepatic biliary tree usually occurs secondary to surgery or trauma. However, occasionally these may be congenital and occur most commonly at the bifurcation of the hepatic ducts. Common duct stenosis, localized atresia, and duplication have also all been reported in association with duodenal atresia. Spontaneous perforation of the bile ducts is a rare condition that occurs in the first few months of life. The most common site of perforation is the point at which the cys-
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tic and common hepatic ducts join to form the common duct. The etiology is unclear, but may be caused by an intrinsic weakness at a specific point due to a developmental defect. Spontaneous perforation of the bile ducts may result in a bile leak into the peritoneal cavity with subsequent sterile bile peritonitis and pseudocyst formation. Management
These minor anomalies and variations become significant at surgery. Accidental severing of an anomalous duct may result in postoperative leakage leading to peritonitis. Ligation of an unrecognized duct may be symptomatic if the area of liver that is drained is large enough. In performing cholecystectomy on patients with an anomalous right hepatic duct that empties into the cystic duct, care must be taken to ligate the cystic duct between the gallbladder and the junction with the anomalous duct in order to maintain adequate drainage of the anomalous duct. Unrecognized anomalous ducts may also cause recurrence of symptoms after cholecystectomy.
Congenital Abnormalities of the Gallbladder AGENESIS OF THE GALLBLADDER Definition Congenital absence of the gallbladder.
Clinical Manifestations and Evaluation Agenesis of the gallbladder may be discovered incidentally at autopsy or at surgery for unrelated indications. Absence of the gallbladder may also be found as part of a broader pattern of malformation in children with multiple congenital anomalies (imperforate anus, bicuspid aortic valves, cerebral aneurysms, and in association with extrahepatic biliary atresia). The incidence of gallbladder agenesis has been estimated at 1 in 10,000 among the general population. When symptomatic, the majority has right upper quadrant abdominal pain, whilst others present with symptoms suggestive of acute or chronic cholecystitis. The diagnosis may be difficult to make radiographically as oral cholecystograms or ultrasonography often show false-positive diagnoses of apparently diseased, contracted, and scarred gallbladders, suggesting cholecystitis.
Management After surgical exploration, over 90% of symptomatic patients with gallbladder agenesis are greatly improved or symptom free. This is true both for patients who are found to have associated stones and for those without stones. The reason for improvement in patients without stones is not known. One speculation is that improvement may be the result of lysis of periportal and right upper quadrant adhesions during the exploration. Patients whose symptoms recur postoperatively may be treated with oral smooth muscle relaxants and analgesics, a conservative regimen that has proven successful in most patients with biliary dyskinesia. More extensive evaluation and treatment is only necessary for the few patients who fail to respond.
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Table 1-3
CONGENITAL ANOMALIES OF THE GALLBLADDER Agenesis (syndromic and nonsyndromic) Hypoplasia Diverticulum Duplication and mutiple gallbladders Heterotopic tissue in gallbladder Mobile and interposed gallbladder Positional alterations Septation defects
STRUCTURAL VARIATIONS OF THE GALLBLADDER Definition Numerous variations in gallbladder structure and position have been described.
Clinical Manifestations and Evaluation Anatomic variations (Table 1-3) include: • Multiple gallbladders (see below). • Septation of the gallbladder (see below). • Gallbladder diverticulum. • Ectopic position of the gallbladder (left sided, free floating, retrodisplaced,
retroperitoneal, transverse, intrahepatic, suprahepatic, supradiaphragmatic, in the falciform ligament, in the mesocolon, in the abdominal wall). • Unusually mobile gallbladder and “interposed gallbladder” (anomalous insertion of both hepatic ducts into the gallbladder with the cystic duct draining into the duodenum). • Gallbladder hypoplasia or “microgallbladder” is usually seen in cystic fibrosis. The gallbladder may have a septum dividing the cavity into two parts (septate gallbladder). These parts may be partially or completely separated, leading to a bilobed gallbladder with a single cystic duct (“vesica divisa”). Some authors think of these malformations as duplications, whereas others make a distinction between these and “true” duplications. Cases of multiseptate gallbladder are rare and not considered part of the spectrum of gallbladder duplication but are more clearly due to defects in recanalization. Occasionally, two separate gallbladders, each with its own cystic duct, may develop (“vesica duplex”). Controversy exists over whether these anomalies predispose to stone formation. The cystic ducts may join to form a single, Y-shaped cystic duct; the two
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cystic ducts may remain separate and both empty into the common duct, or one of the cystic ducts may connect elsewhere, such as into an hepatic duct. Occasionally the second or “accessory” gallbladder may be found in another site such as under the left lobe of the liver, imbedded within the liver, or within the gastrohepatic ligament. Multiple gallbladders may be missed by routine radiographic diagnostic studies, especially if one is nonvisualized because of disease. Symptomatic duplication is usually reported in adults and only rarely in childhood. There are probably several different pathogenetic mechanisms involved in the various forms of gallbladder duplication. These include the development of more than one pars cystica primordium at two different sites in the developing common duct, splitting of the pars cystica during the 5th and 6th weeks of development, growth of diverticula from the cystic duct or from intrahepatic ducts, or aberrant canalization after the solid stage of development. There is some suggestion that biliary anomalies may predispose to lithiasis. This seems to be a relatively uncommon complication considering the frequency of biliary tract structural variation. Lithiasis may be related to duct damage from regurgitation of pancreatic secretions (as in anomalous pancreaticobiliary duct union); or mechanical obstruction to gallbladder emptying caused by torsion of the cystic duct in cases of malpositioning (as has been suggested to account for the high incidence of stones in intrahepatic gallbladders). Malposition of the gallbladder may also lead to torsion and gangrene. Gallbladder diverticulum has been associated with malignant transformation.
Management Evaluation and treatment as usual are recommended for symptoms of cholecystitis. Patients with symptomatic multiple gallbladders generally benefit from removal of all of these cystic structures. Most symptomatic gallbladder anomalies require surgery.
HETEROTOPIC TISSUE IN THE GALLBLADDER Definition Ectopic tissue of foregut origin located within the gallbladder mucosa.
Clinical Manifestations and Evaluation Numerous heterotopic tissues have been identified in the gallbladder, though gastric is the most common. Pancreatic, hepatic, thyroid, and adrenal have also been reported. Although extremely rare, these reported cases usually present with clinical symptoms such as abdominal pain and the heterotopic tissue is identified in surgical resections. Lithiasis often coexists. It has also been suggested that heterotopic tissue may promote carcinogenesis of the gallbladder and metaplastic areas surrounding the heterotopic tissue has been reported. Of note, heterotopic gastric tissue has been reported in the biliary tree as well, and as a cause of symptoms such as hemobilia.
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Management Management is surgery, if symptomatic.
References 1. Kim SK, Hebrok M. Intercellular signals regulating pancreas development and function. Genes Dev 2001;15:111-27. 2. Crawford JM. Development of the intrahepatic biliary tree. Semin Liver Dis. 2002;22:213-26. 3. Lerner A, Branski D, Lebenthal E. Pancreatic diseases in children. Pediatr Clin North Am 1996;43:125-56. 4. Sokol RJ, Mack C. Etiopathogenesis of biliary atresia. Semin Liver Dis. 2001;21:51724.
Suggested Reading Adam E, Morgan R. The pancreas. In: Grainger & Allison’s Diagnostic Radiology: A Textbook of Medical Imaging. 4th ed. New York: Churchill Livingstone, Inc.; 2001:1343-1345. Alonzo-Lej F, Revor WB, Pessagno DJ. Congenital choledochal cyst with a report of 2, and an analysis of 94 cases. Surg Gynecol Obstet Internat Abst Surg. 1959;108:130. Benya E. Pancreas and biliary system: Imaging of developmental anomalies and disease unique to children. Radiol Clin North Am. 2002;40(6):1355-1362. Desmet V. Congenital diseases of intrahepatic bile ducts: variations on the theme “ductal plate malformation”. Hepatology. 1992;16(4):1069-1083. Haber BA, Russo P. Biliary atresia. Gastroenterol Clin North Am. 2003;32(3):891913. Emerick KM, Rand EB. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology. 1999;29:822-829. Kamath BM, Russo P, Piccoli DA. Heritable disorders of bile ducts. Gastroenterol Clin North Am. 2003;32(3):857-875. Matsumoto Y, Uchida K, Nakase A, Honjo I. Clinicopathologic classification of congenital cystic dilatation of the common bile duct. Am J Surg. 1977;134(5):569574. Schweizer P, Schweizer M. Pancreaticobiliary long common channel syndrome and congenital anomalous dilatation of the choledochal duct—study of 46 patients. Eur J Ped Surg. 1993;3(1):15-21. Whitcomb D. Hereditary and childhood disorders of the pancreas, including cystic fibrosis. In: Feldman. Slesinger & Fordtran’s Gastrointestinal and Liver Disease. 7th ed. Philadelphia, Pa: Elsevier; 2002:881-884. Witzleben CL, Piccoli DA: Disorders of the biliary tract: extrahepatic bile ducts. In: Walker WA, Durie PR, Hamilton JR, Walker-Smith JA, Watkins JB, eds. Pediatric Gastrointestinal Disease. Ontario, Canada: B.C. Decker; 2000:915-927.
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Gallstones and Gallbladder Disorders Ann Marie Joyce, MD; William B. Long, MD
Gallbladder Anatomy and Physiology The gallbladder lies under the right lobe of the liver with its superior adventitia fused with the liver capsule and its inferior portion covered by visceral peritoneum. Inferiorly, it is adjacent to the duodenum and the transverse colon, permitting gallstones to infrequently form fistulae into these organs. The cystic duct connects the gallbladder to the extrahepatic bile duct. Anomalies of the extrahepatic ducts including aberrant ducts that drain individual segments of the liver into the gallbladder, cystic duct, or extrahepatic duct can present challenges to surgeons, endoscopists, or radiologists. Duplication and agenesis of the gallbladder are rare anomalies. The cystic artery supplying the gallbladder is an end artery, and the gallbladder is, therefore, susceptible to ischemic injury. About half of bile secreted overnight enters the gallbladder via the cystic duct. In the gallbladder, formation of micelles from bile salt monomers and absorption of electrolytes and water allow great concentration of bile without increase in osmolality. Contraction of the gallbladder and relaxation of the sphincter of Oddi during meals provides bile for the digestive process. Cholecystokinin is the most important hormonal stimulus of gallbladder contraction, but cholinergic nervous stimuli also provoke contraction. Intravenous infusion of cholecystokinin normally leads to greater than 40% emptying of the gallbladder.
Gallstone Pathophysiology Human gallstones are classified into cholesterol, black, brown, and rare other types. Cholesterol stones are the most common stone type in Western countries and are composed primarily of cholesterol, but even “pure” cholesterol gallstones usually have a bilirubin pigment center and many cholesterol stones have concentric layers pigmented by bilirubin, alternating with purer cholesterol layers. Bilirubin is the predominant constituent of black and brown stones that are referred to as “pigment”
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stones. Cholesterol and black stones form nearly exclusively in the gallbladder and brown stones form mainly in the bile ducts. Cholesterol and black stones may pass from the gallbladder into the bile duct. Three factors are believed to be involved in the formation of cholesterol stones:
1. Supersaturation of bile with cholesterol 2. Stasis of bile in the gallbladder 3. Nucleation factors that accelerate cholesterol precipitation from bile. Supersaturation with cholesterol is essential, but may not be sufficient for stone formation. Cholesterol in bile is solubilized by bile salts and phospholipids (mainly lecithin). Supersaturation usually involves excess secretion of cholesterol, but may also reflect decreased bile salt or phospholipid secretion. Cholesterol is secreted with lecithin by the hepatocyte canaliculus in the form of vesicles. Bile salts are secreted by a different canalicular pathway and form pure bile salt micelles. Bile salt micelles interact in the bile ducts and gallbladder with vesicles to form mixed micelles composed of bile salts, cholesterol, and lecithin. The proportion of vesicles and mixed micelles depends on overall bile salt-lecithin ratio, types of bile salts, and total biliary cholesterol. In the gallbladder, crystals of cholesterol may precipitate from cholesterol rich vesicles if adequate bile salt and lecithin are not available. Electron microscopy has demonstrated round vesicles clustered on the surface of growing cholesterol crystals. Individuals without gallstones have bile intermittently supersaturated with cholesterol and such bile may form crystals in the laboratory after incubation for several days. Bile from patients with cholesterol stones (which has similar bile salt, cholesterol and phospholipid concentration as bile of non-stone individuals) forms crystals in only a few days; this accelerated crystalization implies pronucleating or, perhaps, antinucleating factors in bile of stone patients. Retarded gallbladder emptying may provide time needed for supersaturated bile to form crystals and stones, especially if net pronucleating activity is present. Although gallstones may form quite rapidly in certain circumstances (such as patients receiving parenteral feeding or on crash diets), cholesterol stones usually grow slowly and asymptomatically. An imaginative study published in 1986 employed the varying proportion of carbon isotopes in the atmosphere and biosphere since nuclear bomb testing in the 1950s to determine the age of gallstones removed at cholecystectomy in 15 patients.1 Gallstones in these patients grew 1 to 4 mm per year (mean, 2.6 mm per year) and none of the 11 symptomatic patients had symptoms until at least 2 years (mean, 8 years) after stone formation began. Stones in the patients without symptoms had been present for at least 10 years before cholecystectomy. Gracie and Ransohoff 2 also reported delayed onset of symptoms in asymptomatic gallstone patients followed prospectively. Among 123 such patients, only 18 developed severe biliary pain over 24 years. As shown in Table 2-1, multiple conditions are associated with increased risk of cholesterol gallstone formation. From a pathophysiologic standpoint, it is probably inaccurate to regard cholesterol or pigment stone disease as a single disease. Increased cholesterol secretion, decreased bile salt secretion or both have been reported in patients with cholesterol gallstones. Conditions of increased risk may also reflect alterations of gallbladder motility or nucleation factors.
Gallstones and Gallbladder Disorders Table 2-1
INCREASED RISK OF GALLSTONE FORMATION Cholesterol Stones Female gender Increasing age Obesity Rapid weight loss Prolonged fasting TPN Western diet Lack of exercise Pregnancy and multiparity Race (eg, certain Native American groups) Family history Apo E genotype Disease of terminal ileum (eg, Crohn's disease) Diabetes Cerebrotendinous xanthomatosis Vagotomy Medications Estrogen and progesterone Octreotide Clofibrate Gilbert’s syndrome?
Pigment Stones Increasing age Hemolytic anemia Prosthetic cardiac valve Cirrhosis Gilbert’s syndrome? Juxta-papillary diverticulum Biliary parasites Foreign matter in bile ducts Choledochocysts, Caroli’s disease
Other Types of Stones or Sludge Ceftriaxone
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Cholesterol Stone Formation CHOLESTEROL SUPERSATURATION The ratio of cholesterol to phospholipid and bile salt in hepatic bile increases at low bile salt flow rates, which occur overnight or with more prolonged fasting. During fasting, most of the bile salt pool is sequestered in the gallbladder and even individuals without stones may have hepatic bile supersaturated with cholesterol, whereas bile in the gallbladder is rich in bile salts and may remain unsaturated with cholesterol. Cholesterol stone formation requires supersaturation of bile in the gallbladder. Such supersaturation with cholesterol may occur because of increased cholesterol secretion or decreased bile salt secretion. Supersaturation caused by increased cholesterol secretion appears to be the major cause of cholesterol lithiasis associated with obesity, rapid weight loss, and estrogen therapy. Native Americans with cholesterol gallstones have bile salt pools that are reduced by up to 50% and reduced bile salt secretion.3 Reduction in bile salt pool has been noted before onset of stones and may be an intrinsic defect. Cholesterol synthesis is also increased in these groups, perhaps driven by reduced bile salt pool and need for precursor cholesterol in bile salt synthesis. Increased fecal bile salt loss has been identified. The combination of high synthetic rate of bile salts, reduced bile salt pool, and increased fecal loss suggests that increased intestinal loss of bile salts may be an underlying defect in cholesterol gallstone disease. Supersaturation produced by reduced bile salt secretion has also been found in patients with ileal resection or disease in whom enterohepatic circulation of bile salts is reduced and in cerebrotendinous xanthomatosis in which bile salt synthesis is reduced. Normal gallbladder mucosa absorbs some cholesterol, reducing cholesterol saturation in the gallbladder. Gallbladder mucosa of patients with cholesterol stones, however, loses this capacity to absorb cholesterol.4 Abnormal function of the gallbladder mucosa may be a pathogenic cofactor for gallstone formation.
GALLBLADDER HYPOMOTILITY Gallbladder hypomotility provides opportunity for crystallization, aggregation of crystals, and growth to macroscopic stones from supersaturated bile. Gallbladder hypomotility may be determined in patients and controls by ultrasound or nuclear medicine studies of fasting volume, ejection volume, and contracted volume. Although there is great overlap of values, asymptomatic cholesterol gallstone patients, in general, have greater fasting and postprandial gallbladder volume and decreased percent gallbladder emptying compared to gallstone-free individuals.5 Greater fasting volume and decreased percent emptying of the gallbladder persist 1 year after dissolution of stones by oral ursodeoxycholic acid therapy, suggesting that altered gallbladder function is not necessarily caused by the stones, but may be an underlying disorder. On the other hand, studies in animal gallstone models reveal that supersaturated bile induces defects in contractility of gallbladder muscle, implying that motility defects may be a result of an abnormality in bile. Gallbladder muscle from patients with cholesterol stones has increased membrane cholesterol/phospholipid ratio and decreased membrane fluidity resulting in impaired muscle contractility.6 These abnormalities are corrected by removing the excess cholesterol from the plasma membranes.
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Impaired gallbladder emptying and increased incidence of gallstones occur in the latter part of pregnancy, in individuals treated with oral contraceptives or somatostatin, following spinal cord injury, with diabetes mellitus, after vagotomy, and in patients receiving long-term parenteral nutrition. These associations suggest that alteration of gallbladder motility contributes to gallstone formation. In none of these situations, however, is gallbladder hypomotility likely to be the only factor leading to stone formation. For instance, patients with severe spinal cord injury have a threefold increase in risk of gallstones, but these patients may have disorders of gastric, duodenal, and colonic motility; dietary changes; muscle atrophy; and weight loss, in addition to decreased gallbladder motility.
NUCLEATING FACTORS Several studies indicate that a nucleating factor, or less likely absence of an antinucleating factor, is important in initiating crystal and stone formation. Individuals free of gallstones may intermittently have supersaturated with cholesterol without crystal formation and, in vitro, such bile usually takes 2 to 3 weeks to form crystals. In contrast, gallbladder bile of cholesterol stone patients forms crystals in vitro in a few days.7 Patients with pigment stones have nucleation time (time required to form crystals) similar to that of individuals with no stones. Seeding with crystals of supersaturated bile from nonstone individuals initiates rapid crystal formation, suggesting that antinucleating factors are not present. Many investigations suggest that gallbladder mucin is a major nucleating factor. Mucin is found in human gallstones, and in animal models increased secretion of gallbladder mucin occurs as early as 18 hours after beginning a lithogenic diet and precedes crystal formation. Cholesterol crystals also first appear in the mucus layer. In vitro studies demonstrate that nucleation time is inversely proportional to the concentration of added mucin. In part, the action of mucin to accelerate crystal formation may result from its ability to bind cholesterol and concentrate it.8 Cholesterol concentration is 3 to 4 times higher in the mucous gel covering the gallbladder mucosa than in luminal bile. The complexity of understanding the pathogenesis of gallstone disease is emphasized by a study of 20 patients with cholesterol gallstones showing a 50% prolongation of colonic transit time compared with stone-free controls. Colon transit time correlated with serum chenodeoxycholic acid (a secondary bile acid produced in the colon) that has been previously found to stimulate secretion of biliary cholesterol and increase mucus glycoprotein content of bile. Other than mucin, some biliary proteins, including IgM and IgG, have been reported to accelerate cholesterol nucleation. One study found that biliary IgA was a potent inhibitor of cholesterol crystallization in model bile. Another study 9 questioned the importance of mucin, immunoglobulin, and other proteins for cholesterol precipitation from gallbladder bile. Analysis of bile from 52 patients with cholesterol stones and 40 patients without stones found that only cholesterol saturation, and not protein or mucin concentration, correlated with in vitro cholesterol crystal formation.
AGE, SEX, AND R ACE Age, sex, and genetic factors (including race) appear to play major roles in gallstone formation. Prospective ultrasound studies of more than 14,000 random US civilians
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performed between 1988 and 1994 estimated that 6.3 million men and 14.2 million women aged 20 to 74 years have gallstones10. The difference in gallstone prevalence between men and women was much greater in the younger individuals. At age 20 to 29 years, 1% of men and 4% of women had stones, but in 60- to 74-year-old individuals, prevalence of gallstones was 17% for men and 16% for women. The increased risk of gallstone formation in women compared to men occurs before age 60, suggesting that estrogen secretion may be involved. Multiparity also increases risk of gallstones. During pregnancy cholesterol secretion in bile and gallbladder volume and stasis increase; these events may underlie the increased development of gallstones. Race plays an important role in incidence of gallstones. The ultrasound study mentioned above confirmed earlier studies that black men and women have a lower prevalence of gallstones than whites. The highest overall prevalence in this study was in Mexican American women, of whom 27% had stones, compared to 17% in nonHispanic white and 14% in black women. Other studies have identified an unusually high prevalence in women of the Pima tribe of Arizona, among whom more than 70% of adult women have gallstone disease. A high rate in other indigenous American groups in Alaska, New Mexico, Chile, and Bolivia with very different diets, environments, and cultures argues for a genetically determined predisposition to stone formation among indigenous Americans.11 Although no gene that predisposes to stone formation has been identified in Native Americans, it has been speculated that nutritional deprivation among the first persons to cross the Bering land bridge from Asia 10,000 to 20,000 years ago may have selected a gene that promoted storage of nutrients. Under conditions of plenty, such a “thrifty” gene might now result in stone formation. Even though obesity is common in some Native American populations, the high prevalence of gallstones among young nonobese Pimas and Chileans supports a genetic, in addition to nutritional or environmental, factor. In Native Americans, as in other populations, female sex, increasing age, high percent body fat, multiparity, and low serum HDL cholesterol have been identified as independent risk factors for gallstone formation. Biliary cholesterol hypersecretion has been reported in Pima Indians and in normal weight Chileans and may be under genetic control. The hypothesis that cholesterol gallstone formation has genetic influences is also supported by findings that some families have an increased frequency of gallstones, that gallstones are more frequent in first-degree relatives of gallstone patients, and that cholesterol supersaturation and gallstone formation is increased in monozygotic compared with dizygotic twins. Comparing 171 first-degree relatives of patients with gallstones with 200 matched controls in Israel, gallstones were found in 21% of the first-degree relatives and only 9% of the control group. As multiple factors appear to increase the risk of cholesterol gallstone formation, there are likely to be multiple genetic factors involved. A peculiar form of cholesterol gallstone disease associated with mutation in the MDR3 gene that regulates the phosphotidylcholine translocator across the canalicular membrane of the hepatocyte has been described in six patients12 . These patients had cholesterol crystals in bile, high bile cholesterol/phospholipid ratio, cholestasis, recurrence of symptoms after cholecystectomy, and prevention of recurrence by ursodeoxycholic acid therapy. Genetic factors have been identified in inbred mice that form cholesterol gallstones. One gene is associated with gallbladder hypomotility and prolonged intestinal transit. Another gene is associated with low plasma HDL and increased biliary cholesterol. A murine genetic gallstone “map” has been described and may provide clues in the quest for genes that predispose to human gallstone formation13.
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OBESITY AND WEIGHT LOSS Obesity is a major risk factor for cholesterol gallstones14. This association is most evident in women. Overweight women with a BMI of 30 kg/m 2 or more have at least double the risk for cholesterol stones as women of lesser weight. With more severe obesity, the risk is as high as seven times that of women with BMI less than 24 kg/m 2 . Studies of obesity in men suggest a similar but less severe association with cholesterol stones. Dieting with rapid weight loss over several weeks leads to development of stones in 12% of individuals. Greater weight loss increases the risk. Thirty-eight percent of 111 obese patients treated with gastric bypass formed stones after surgery and a third of these became symptomatic. Cholesterol saturation has been found to increase in most, but not all, patients with rapid weight loss. Obese subjects risk gallstone development both by being obese and by experiencing periods of rapid weight loss. Truncal obesity in men was correlated with increased stone formation in one study. With weight stabilization after weight loss, biliary cholesterol secretion and saturation decreases. Obesity is associated with excessive hepatic secretion of cholesterol and this is the suspected reason for increased incidence of cholesterol stones. Most, but not all, studies report normal gallbladder contractility in obese compared to lean individuals. In vitro, accelerated cholesterol crystal formation has not been found in bile of obese patients without stones.
LACK OF EXERCISE Lack of exercise increases the risk of gallstone formation in both men and women. About 60,000 women in the Nurses Health Study prospectively reported their physical activity and whether they had undergone cholecystectomy during 10 years.15 Cholecystectomy was used as an indicator of symptomatic cholelithiasis (other smaller studies have indicated that exercise is associated with a reduced prevalence of gallstones). Relative risk of cholecystectomy among women with the highest quintile of physical activity was 0.69 compared to the risk in the lowest quintile. The beneficial effect of exercise was seen even when the data were controlled for obesity and recent weight loss. A similar protective effect of physical activity has been found among men in prospective studies. The protective effect of exercise may involve several metabolic pathways other than its effect on controlling weight. Exercise increases high-density lipoprotein, improves glucose tolerance, and reduces colonic transit time; each of these effects has been associated with reduced risk of gallstones.
MEDICATION Certain medications dispose to gallstone formation. Men and women taking estrogen have increased incidence of gallstones and cholecystectomy, perhaps caused by the observed increased secretion of biliary cholesterol. Clofibrate is also associated with increased biliary cholesterol and gallstones. Octreotide decreases gallbladder contractility and use for months is associated with gallstone formation. The cephalosporin ceftriaxone is excreted in bile, and biliary sludge or stones formed by precipitated drug have been reported in 43% of children receiving high doses; sludge may dissolve when the medication is discontinued.
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GILBERT’S SYNDROME Bile in most individuals contains only trace amounts of unconjugated bilirubin. Limited studies, however, reveal that individuals with Gilbert’s syndrome may have increased, although small, amounts of unconjugated bilirubin in bile. Patients with hemolytic anemia, thalessemia, spherocytosis, and sickle cell disease have a significant increase in gallbladder stones if they also have Gilbert’s syndrome; the type of stones in patients with both hemolysis and Gilbert’s syndrome has not been reported. We recently studied 52 patients with common duct stones removed after endoscopic sphincterotomy and found that 23% were homozygous for the Gilbert’s gene; this frequency of Gilbert’s syndrome is increased (p4 mm), a distended gallbladder, and Murphy’s sign. Murphy’s sign is defined as tenderness in the right upper quadrant with palpation. This sign has a positive predictive value of 90%32 . Cholescintigraphy, also known as hepatobiliary iminodiacetic acid (HIDA) scan, is another imaging test of the gallbladder. The tracer is taken up by the liver, secreted in the bile, and then flows through the common bile duct into duodenum. In patients with patent cystic duct, the tracer should be taken up by the gallbladder as well as enter the small bowel. If there is nonvisualization of the gallbladder but high clinical suspicion, morphine sulfate can be administered. The morphine contracts the sphincter of Oddi, increasing the pressure in the common bile duct facilitating filling the gallbladder. This test is not accurate in patients that are fasting, on TPN, or critically ill. Some studies have shown that HIDA has a greater sensitivity and specificity when compared with ultrasound. The two tests together are additive33. In our institution, the HIDA scan is reserved for those patients with high clinical suspicion for acute cholecystitis and a normal ultrasound.
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CT scan and MRI may also be used to evaluate cholecystitis. An advantage of these tests is that the remainder of the abdomen can be evaluated.
TREATMENT Once the diagnosis of acute cholecystitis is made, the patient is admitted to the hospital. Conservative management should include basic measures such as fasting, fluid and electrolyte resuscitation, and pain medications. If the patient is vomiting, a nasogastric tube is placed. Antibiotics covering gram-negative rods and anaerobes should be started if there are signs of sepsis or failure to improve after 12 to 24 hours. Organisms are rarely aspirated from the gallbladder. The organisms that have been involved with acute cholecystitis include Escherichia coli, Klebsiella, Streptococcus faecalis, Clostridium welchi, Proteus, and Enterobacter. Laparoscopic cholecystectomy is currently the standard treatment for acute cholecystitis. The first cholecystectomy was done in 1882 by Langenbuch. Laparoscopic cholecystectomy has become more common since its introduction in the late 1980s. General anesthesia is administered to an appropriate surgical candidate undergoing a laparoscopic cholecystectomy. A trocar is placed into the umbilicus and pneumoperitoneum induced with a nonflammable gas. A telescope is then placed through the umbilicus. Three additional trocars are placed (subxiphoid, right midclavicular line, and anterior axillary line). The gallbladder is retracted away from the liver. The cystic artery and duct are identified and dissected. Clips are placed on each. The gallbladder is dissected from the liver and delivered intact through the umbilical incision. An intraoperative cholangiogram can be performed during a laparoscopic cholecystectomy to evaluate the anatomy of the biliary tree and to detect choledocholithiasis. A prospective study of 514 patients undergoing laparoscopic cholecystectomy showed that routine cholangiography was not needed 34. Preoperative endoscopic retrograde cholangiopancreatography (ERCP) is performed in patients with a high suspicion for choledocholithiasis. These patients usually have jaundice, dilated common bile duct, visualized common bile duct stones on imaging study, or cholangitis. An urgent ERCP is recommended in gallstone pancreatitis in a patient presenting with cholangitis and pancreatitis. A preoperative ERCP is sometimes advocated for patients who have had a Billroth II gastrectomy; if the ERCP is not successful and a stone is identified at surgery then a common duct exploration will be performed. ERCP is not recommended in patients who do not have evidence of choledocholithiasis or to define the biliary anatomy for the surgeon. The mortality related to laparoscopic cholecystectomy is 0 to 0.07% 35,36 .The conversion rate to open, which has decreased with more experience, is 2.2% to 5.2%35,37. There are intraoperative complications and postoperative complications. At the time of surgery, there can be bleeding from transection of the superior epigastric artery or its branches, or from the trocar site. Intraperitoneal bile spillage occurs in 30% of cases38-40. There can also be a thermal injury. Postoperatively, patients can develop abdominal pain related to a bile leak from a misplaced clip or bile duct injury. Bile leakage may be treated with ERCP and stent placement allowing bile to preferentially flow into the duodenum. In cases of bile duct transection, surgery may be required. The timing of cholecystectomy for the treatment of acute cholecystitis is controversial. In a recent meta-analysis by Papi et al36, a total of 12 studies were reviewed to determine the appropriate timing of surgery. In this review, early operation, defined
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Figure 2-1. Mirizzi’s
syndrome: Stone in the cystic duct causes extrinsic compression of the main bile duct. (Thanks to Dr. Francis J. Scholz, Lahey Clinic, Burlington, Mass.)
as surgery within 72 hours of admission, did not carry a higher risk of mortality and morbidity compared to delayed operation. About 20% of patients required emergent surgery because of perforation or recurrent symptoms in the delayed group. In critically ill patients at high risk for surgery, percutaneous cholecystostomy and drainage may be performed. This is commonly done using local anesthetic and ultrasound guidance, is technically successful in 98% to 100%, and is effective in 75% to 90%41,42 . Mortality, which may be due to underlying disease, is 20% 42 . Most of these patients will undergo a cholecystectomy when they become medically stable.
Mirizzi’s Syndrome Mirizzi’s syndrome was first described in 1948 as an extrinsic compression of extrahepatic bile duct by an impacted stone in the cystic duct or gallbladder neck causing jaundice. It is rather uncommon—seen in 1% of patients undergoing cholecystectomy. Patients usually present with biliary colic, jaundice, and fever. Abdominal ultrasound can reveal evidence of biliary obstruction. In 1982, McSherry et al43 classified Mirizzi’s syndrome into two types, which is important in terms of surgical management. In type I, there is extrinsic compression of the common hepatic duct. In type II, the calculus erodes through the septum between the cystic and common bile duct leading to a cholecystocholedochal fistula. ERCP can demonstrate the extrinsic compression (Figure 2-1) and a stent can be placed for decompression prior to cholecystectomy.
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In patients with type I, a partial cholecystectomy is effective because of the significant degree of inflammation involving the common bile duct44. A complete cholecystectomy in these patients may lead to a major common bile duct injury. The approach to a patient with type II depends on the size of the fistula. Small fistulas can be treated with partial cholecystectomy and cholecystocholedochoduodenostomy, whereas a larger fistula is better served with a Roux-en-Y hepaticojejunostomy45. Patients with suspected Mirizzi’s syndrome may have associated malignancy as frequently as 27% of cases46.
Biliary-Enteric Fistula Fistulas can occur between the biliary tree and the bowel, skin, blood vessels, or lungs. Fistulas most commonly occur in acute or chronic cholecystitis. Cholecystoenteric fistula occurs when a stone erodes through the gallbladder to the duodenum, stomach, colon, or jejunum. About 75% are cholecystoduodenal fistula47. This occurs in cholecystitis and cholelithiasis. Patients may be asymptomatic and noted to have pneumobilia on a plain abdominal film. In asymptomatic patients, surgery is not needed. If the fistula is symptomatic or discovered intraoperatively, a cholecystectomy with closure of the duodenal defect should be performed. The next most common fistula is a cholecystocolic fistula. Patients usually have a history of biliary colic and present with acute onset of worsening abdominal pain, fever, chills, and possibly steatorrhea. The acute change in abdominal pain is related to the colonic flora being introduced into the biliary tract. The bile is released directly into the colon, which bypasses the usual absorption in ileum, resulting in steatorrhea. A fistula can be demonstrated on a barium enema. A cholecystectomy should be performed. A choledochoduodenal fistula may be caused by perforation of common duct stone or rarely by duodenal peptic ulcer disease and hepatobiliary neoplasms. Patients may complain of several years of peptic ulcer disease. The fistula can be demonstrated with UGI, EGD, or ERCP. Treatment is based on the causative disease. A parapapillary fistula is a subgroup of choledochoduodenal fistula. This occurs in the setting of choledocholithiasis, papillary carcinoma, or postpapillotomy. Treatment is through ERCP. Thoracobiliary and bronchobiliary fistulas are extremely rare but associated with significant morbidity. They are caused by thoracoabdominal trauma, malignancies, liver abscess, parasitic liver disease (eg, echinococcosis, amoebic disease), choledocholithiasis, postoperative biliary stenosis, or rare congenital disorder. These fistulas typically develop from cholangitis that eventually forms an abscess. This abscess ruptures toward the pleural space with progression into the bronchial tree. Patients present with bilitysis (bile pigments in sputum) and have evidence of bronchiolitis. They usually have right upper quadrant pain, pleuritic chest pain, fever, chills, and leukocytosis. Surgery is recommended in congenital cases and acquired cases may respond to stenting. Cholecutaneous fistula rarely occurs because of the early recognition of cholangitis. It occurs more commonly in females in the 5th to 7th decade of life. The opening is in the right upper quadrant or via the falciform ligament at the umbilicus. This fistula is demonstrated through a sonogram or ERCP. Treatment is a cholecystectomy with repair of the fistulous tract.
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Figure 2-2. Gallstone ileus caused by a huge stone having perforated into the colon, obstructing the narrower sigmoid colon. (Thanks to Dr. Jorge Obando, Lahey Clinic, Burlington, Mass.)
Gallstone Ileus Gallstone ileus is a mechanical gallstone obstruction of the bowel that usually occurs in the elderly. A 2- to 2.5-cm gallstone erodes through the gallbladder into the duodenum and becomes lodged within the small bowel usually at the level of the ileocecal valve. Less commonly, a large stone may perforate into the colon and obstruct distally (Figure 2-2). The stone(s) may also become lodged in the duodenum (known as Bouveret’s syndrome48) or at a colonic stricture. The patient presents with typical symptoms of bowel obstruction, ie, abdominal distension, abdominal pain, and vomiting. Occasionally “tumbling obstruction” occurs as the stone intermittently obstructs in progressively narrower small bowel. The diagnosis can be difficult to make and therefore may be delayed. Rigler et al49 described some plain film findings: pneumobilia, bowel obstruction, and visualized stones. These findings can also be seen on a CT scan of the abdomen (see Figure 2-2). On a plain film, air within the gallbladder and duodenum can be noted and is known as Balthazar’s sign50,51. An abdominal ultrasound can sometimes localize the stone within the intestine and document a diseased gallbladder. The treatment depends on the presentation and the comorbidity of the patient. The procedure can be done in a one-step or two-step approach. The one-step is enterotomy with removal of stone including cholecystectomy. The two-step is to remove the stone and then remove the gallbladder at a later date. The mortality is up to 20%52 .
Emphysematous Cholecystitis Emphysematous cholecystitis, reported by May and Strong in 1971, is a form of cholecystitis that results from thrombosis or occlusion of cystic artery with ischemic necrosis of the gallbladder wall53. Gas forming organisms, such as Clostridia, infect
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Figure 2-3. Emphysematous cholecystitis: Gas seen within wall of gallbladder. (Thanks to Dr. Francis J. Scholz, Lahey Clinic, Burlington, Mass.).
the gallbladder wall. Emphysematous cholecystitis more commonly occurs in diabetic, elderly men and may occur in severe acalculous cholecystitis. Clinical presentation is similar to that of severe acute cholecystitis. Air is seen in the right upper quadrant on ultrasound, plain abdominal film, and CT scan (Figure 2-3). Patients should be started on broad-spectrum antibiotics. Early cholecystectomy is required because of the high risk of perforation. Conversion to open cholecystectomy ranges from 40% to 50% in earlier studies54,55. The complication rate is 21% to 27%55,56.
Acute Acalculous Cholecystitis DIAGNOSIS The diagnosis of acute acalculous cholecystitis can be difficult to make because of the lack of specific findings and complexity of affected patients. It is an important diagnosis to make because of its high mortality. Acute acalculous cholecystitis should be suspected in critically ill patients with unexplained fever and hyperamylasemia. A patient with acute acalculous cholecystitis may also have a similar presentation to a patient with calculous cholecystitis. An abdominal ultrasound is a valuable test that can be done at the bedside. Gallbladder wall thickening (>4 mm), presence of pericholecystic fluid, and Murphy’s sign can be seen. The sensitivity ranges from 67% to 92% and specificity is greater than 90%57. A CT scan of abdomen can identify some of the changes in the gallbladder described above and it can also detect other intra-abdominal pathology. CT scan has a very sensitivity and specificity of 100%57. A HIDA scan may not be particularly useful in these patients because of their fasting state. The concentrated, viscous bile within the gallbladder in fasting patients may impede filling of the gallbladder. The administration of morphine sulfate can help reduce the false positive rate58. In acalculous cholecystitis, there can be no cystic duct obstruction so a HIDA scan can have a high false negative rate.
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TREATMENT Early recognition is the most important aspect of treatment given the rapid progression of disease. There is a much higher complication rate and mortality rate associated with acalculous cholecystitis compared with calculous cholecystitis. Broadspectrum antibiotics are used to cover both gram negative and anaerobic organisms. It is also important to correct the hemodynamic instability of the patient. If the patient’s condition allows, the best treatment is laparoscopic cholecystectomy. A less invasive approach would be a percutaneous cholecystostomy tube that can usually be placed at the bedside. A nasobiliary tube placed directly into the gallbladder at the time of ERCP can help decompress the inflamed gallbladder. This method was shown to be effective in a small study of 20 patients59.
Acalculous Biliary Pain Acalculous biliary pain can be difficult to diagnose. Patients usually present with biliary colic but no gallstones are detected. If there is a high clinical suspicion, a HIDA scan is performed. Delayed gallbladder emptying, as defined as an ejection fraction of less than 35%, can represent acalculous biliary pain. Caulfield et al reviewed multiple studies that demonstrate that symptomatic patients with an ejection fraction of less than 50% have a 97% improvement or complete resolution of symptoms after a cholecystectomy60. The resected gallbladder usually shows evidence of chronic cholecystitis 61.
Gallbladder Polyps DIAGNOSIS The majority of polyps are found incidentally on abdominal ultrasound as nonmobile filling defects (Figure 2-4). These polyps range from a few millimeters to 2 cm in size and can be single or multiple. Adenomas and adenomyomas of the gallbladder have malignant potential. The majority of gallbladder polyps are cholesterol based and have no malignant potential but can become quite large. With imaging modalities it can be difficult to determine the type of polyp, and therefore its malignant potential. Symptomatic polyps or polyps greater than 1.5 cm usually require surgery because of high malignant potential. Endoscopic ultrasound (EUS) can be used to further define polyps. In a study comparing polyps less than 20 mm using transabdominal ultrasound and endoscopic ultrasound, EUS faired better in determining cancer. Sensitivity of EUS is 91.7% compared with 54.2% for abdominal ultrasound62 . Size, number, shape, and echogenecity of the polyp have been studied and can be used to determine the risk of developing cancer. Polyps less than 10 mm have a 0 to 5% chance, polyps ranging from 10 to 15 mm a 11% to 13% chance, and polyps greater than 15 mm have about 46% to 70% chance of being malignant. Solitary polyps and sessile polyps have a higher risk of being malignant. With ultrasound evaluation, polyps that are isoechoic with the liver parenchyma have a tendency to be a cancer63.
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Figure 2-4. Large gallbladder polyp
seen on ultrasound. (Thanks to Dr. Francis J. Scholz, Lahey Clinic, Burlington, Mass.)
TREATMENT The introduction of laparoscopic cholecystectomy has made the decision to operate easier. It is generally recommended that patients that have gallbladder polyps and are symptomatic or patients with polyps that are greater than 15 mm should have surgery.
Gallbladder Cancer DIAGNOSIS Abdominal pain is a common presentation of gallbladder carcinoma. The pain is usually similar to that of biliary colic or acute cholecystitis. Some patients have nausea, weight loss, or anorexia. Jaundice occurs in less than 50% of patients. Patients may also present with ascites, palpable mass in right upper quadrant, and hepatomegaly. Laboratory investigations are usually not helpful because they are nonspecific. The liver profile can reflect biliary obstruction with elevated alkaline phosphatase and bilirubin. Some tumor markers, CEA, AFP, and human choriogonadotropic hormone may be elevated. The tumor markers are more helpful to follow progress of the disease. There is no ideal imaging modality to diagnose gallbladder cancer. A transabdominal ultrasound is a common modality to investigate biliary colic, right upper quadrant pain, and gallbladder pathology. Most patients will have gallstones 64. CT is useful to evaluate local spread of disease and to detect liver metastases. The introduction of endoscopic ultrasound has improved the staging of gallbladder cancer. Endoscopic ultrasound can further investigate the wall of the gallbladder. A study by Azuma et al62 showed that EUS correctly diagnosed gallbladder cancer (86.5%) compared with abdominal ultrasound (51.7%). Larger studies are needed to determine the usefulness of EUS in gallbladder cancer. A small study of six patients underwent fine needle aspiration of a gallbladder mass and lymphadenopathy65. The technique proved to be possible and safe. Aspiration of the gallbladder and lymphadenopathy may be able to improve the accuracy of EUS.
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Chapter 2
CT scan and MRI can also help diagnose gallbladder cancer and determine the presence of gallbladder disease. CT scan of the abdomen can also identify a mass within or replacing the gallbladder. It is particularly useful for staging of the disease because it can detect liver involvement or significant lymphadenopathy. Angiography can detect tumor vessels in gallbladder wall and encasement of other vessels, such as portal vein. It is the most specific and reliable tool to stage gallbladder cancer66. Cholangiogram during the time of an ERCP can be helpful to relieve the obstruction but can also be diagnostic. The cholangiogram can reveal a stricture at the common hepatic duct. There may be failure to fill the gallbladder.
TREATMENT Gallbladder cancer is detected in about 1% of gallbladder surgeries 67. The extent of surgery depends on the general health of the patient along with the extent of the tumor. About 70% of patients are unresectable at the time of diagnosis. In carcinoma in situ or a T1 tumor, cholecystectomy is appropriate. This is the typical presentation with incidental carcinoma and reoperation does not have to occur. If cancer is detected perioperatively, then an open extended cholecystectomy is usually performed. This includes a hepatic resection as well as lymph node dissection. This aggressive surgery can improve survival68. If the pancreas or duodenum are involved, a hepatopancreatoduodenectomy may be performed. In many cases, palliative therapy is the only option because of the delayed presentation and overall poor prognosis. Biliary stenting with metal stents can relieve biliary obstruction. Radiation or celiac ganglion nerve block may be considered for pain relief. Roux-en-Y choledochojejunostomy can help to relieve obstruction. Chemotherapy has a poor response. About 10% to 20% response rate is seen with mitomycin and 5-FU69. There is no improvement in survival with radiation.
SURVIVAL The 5-year survival rate is less than 5% in most cases because of late presentation. If the cancer is found incidentally, survival significantly improves. For stage I tumors, the 5-year survival is 60%. For patients with stage II, the 5-year survival rate is 24% but this can improve close to 60% if these patients undergo an extended cholecystectomy. For stage III and stage IV, the 5-year survival rate is 9% and 1%, respectively 70,71.
Porcelain Gallbladder Porcelain gallbladder is a gallbladder with calcification of the wall. It may present with right upper pain or be asymptomatic. The diagnosis can be made with a plain film of the abdomen, a right upper quadrant ultrasound, or a CT scan of the abdomen (Figure 2-5). The significance of porcelain gallbladder is its association with gallbladder adenocarcinoma. About 20% of gallbladders with calcification will contain a malignancy 72,73. The resection of a calcified gallbladder is usually done through an open approach, but in cases with a patent cystic duct and uncalcified gallbladder neck, laparoscopic cholecystectomy has been successful74.
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Figure 2-5. Porcelain gallbladder: Plain film demonstrating the calcified gallbladder. (Thanks to Dr. Francis J. Scholz, Lahey Clinic, Burlington, Mass.)
Summary Gallstones are very common in the population, but the majority are asymptomatic. If a stone becomes dislodged, then problems can occur, which include cholecystitis, cholangitis, fistula formation, or Mirizzi's syndrome. In certain situations, the gallbladder can become inflamed in the absence of stones. The main modality of treatment for gallbladder disease is a cholecystectomy. In the future, emphasis should be placed on the prevention of gallstone disease and improvement of the medical management of gallstones.
References 1. Mok HYI, Druffel ERM, Rampone WM. Dating gallstones from atmospheric radiocarbon produced by nuclear bomb explosions. N Engl J Med. 1986;314:1075-1077. 2. Gracie WA, Ransohoff DF. The natural history of silent gallstones: The innocent gallstone is not a myth. N Engl J Med. 1982;307:798-800. 3. Grundy SM, Metzger AL, Adler RD. Mechanisms of lithogenic bile formation in American Indian women with cholesterol gallstones. J Clin Invest. 1972;51:30263043.
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4. Corradini AG, Elisei W, Giovannelli L, et al. Impaired human gallbladder lipid absorption in cholesterol gallstone disease and its effect on cholesterol solubility in bile. Gastroenterology. 2000;118:912-920. 5. Jazrawi RP, Pazzi P, Petroni ML, et al. Postprandial gallbladder motor function: Refilling and turnover of bile in health and in cholelithiasis. Gastroenterology. 1995;109:582-591. 6. Chen Q, Amaral J, Biancani P, Behar J. Excess membrane cholesterol alters human gallbladder muscle contractility and membrane fluidity. Gastroenterology. 1999;116:678-685. 7. LaMont JT, Carey MC. Cholesterol gallstone formation, 2: pathobiology and pathomechanics. Prog Liver Disease. 1992;10:165-191. 8. Nunes DP, Afdhal NH, Offner GD. A recombinant bovine gallbladder mucin polypeptide binds biliary lipids and accelerates cholesterol crystal appearance time. Gastroenterology. 1999;116:936-942. 9. Miquel JF, Nunez L, Amigo L, et al. Cholesterol saturation, not proteins or cholecystitis, is critical for crystal formation in human gallbladder bile. Gastroenterology. 1998;114:1016-1023. 10. Everhart JE, Khare M, Hill M, Maurer KR. Prevalence and ethnic differences in gallbladder disease in the United States. Gastroenterology. 1999;117:632-639. 11. Miquel JF, Covarrubias C, Villaroel L, et al. Genetic epidemiology of cholesterol cholelithiasis among Chilean Hispanics, Amerindians, and Maoris. Gastroenterology. 1998;115:937-946. 12. Rosmorduc O, Hermelin B, Poupon R. MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis. Gastroenterology. 2001;120:1459-1467. 13. Lammert F, Carey MC, Paigen B. Chromosomal organization of candidate genes involved in cholesterol gallstone formation: A murine gallstone map. Gastroenterology. 2001;120:221-238. 14. Everhart J. Contributions of obesity and weight loss to gallstone disease. Ann Intern Med. 1993;119:1029-1035. 15. Leitzman MF, Rimm EB, Willett WC, et al. Recreational physical activity and risk of cholecystectomy in women. N Engl J Med. 1999;341:777-84. 16. Beilstein MC, Ahmad NA, Ginsberg GG, et al. Gilbert’s syndrome and choledocholithiasis. Gastroenterology. 2004;126:A232. 17. Lee SP, Nichols JF. Nature and composition of biliary sludge. Gastroenterology. 1986; 90:677-686. 18. Ostrow JD. The etiology of pigment gallstones. Hepatology. 1984;4:215S-222S. 19. Brink MA, Slors JFS, Keulemans YCA, et al. Enterohepatic cycling of bilirubin: A putative mechanism for pigment gallstone formation in ileal Crohn’s disease. Gastroenterology. 1999;116:1420-1427. 20. Cariati A, Cetta F. Rokitansky-Aschoff sinuses of the gallbladder are associated with black pigment gallstone formation: a scanning electron microscopy study. Ultrastructural Pathology. 2003;27:265-270. 21. Akiyoshi T, Nakayama F. Bile acid composition in brown pigment stones. Dig Dis Sci. 1990;35:27-32. 22. Xiao ZL, Biancani BP, Carey MC, Behar J. Hydrophilic but not hydrophobic bile acids prevent gallbladder muscle dysfunction in acute cholecystitis. Hepatology. 2003; 37:1442-1450.
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23. Ryu JK, Ryu KH, Kim KH. Clinical features of acute acalculous cholecystitis. J Clin Gastroenterol. 2003;36:166-169. 24. Amaral J, Xiao Z, Chen Q, Yu P, Biancani P, Behar J. Gallbladder muscle dysfunction in patients with chronic acalculous disease. Gastroenterology. 2001;120:506-511. 25. Sessa F, Furlan D, Genasetti A, Billo P, Feltri M, Capella C. Microsatellite instability and p53 expression in gallbladder carcinomas. Diagn Mol Pathol. 2003; 12:96-102. 26. Senior JR, Johnson MF, DeTurck DM, et al. In vivo kinetics of radiolucent gallstone dissolution by oral dihydroxy bile acids. Gastroenterology. 1990;99:243. 27. Roda E, Festi D, Lezoche E, et al. Strategies in the treatment of biliary stones. Gastroenterol Int. 2000;13:7. 28. May GR, Sutherland LR, Shaffer EA. Efficacy of bile acid therapy for gallstone dissolution: A meta-analysis of randomized trials. Aliment Pharmacol Ther. 1993;7:139. 29. Tomida S, Abei M, Yamaguchi T, et al. Long-term ursodeoxycholic acid therapy is associated with reduced risk of biliary pain and acute cholecystitis in patients with gallbladder stones: A cohort analysis. Hepatology. 1999;30:6. 30. Schoenfield LJ, Berci G, Carnovale RL, et al. The effect of ursodiol on the efficacy and safety of extracorporeal shock-wave lithotripsy of gallbladder stones. The Dornier National Biliary Lithotripsy Study. N Engl J Med. 1990;323:1239. 31. Sackmann M, Pauletzki J, Sauerbruch T, et al. The Munich Gallbladder Lithotripsy Study: Results of the first 5 years with 711 patients. Ann Intern Med. 1991;114:290. 32. Ralls PW, Colletti PM, Lapin SA, et al. Real-time sonography in suspected acute cholecystitis. Radiology. 1985;155:767. 33. Kalimi R, Gecelter G, Caplin D, et al. Diagnosis of acute cholecystitis: Sensitivity of sonography, cholescintigraphy, and combined sonography-cholescintigraphy. J Am Coll Surg. 2001;193:609-613. 34. Clair DG, Carr-Locke DL, Becker JM, et al. Routine cholangiography is not warranted during laparoscopic cholecystectomy. Arch Surg. 1993;128:551-554. 35. MacFadyen BV Jr , Vecchio R, Ricardo AE, Mathis CR. Bile duct injury after laparoscopic cholecystectomy. The United States experience. Surg Endosc. 1998;12:315-321. 36. Papi C, Catarci M, D’Ambrosio L, et al. Timing of cholecystectomy for acute calculous cholecystitis: A meta-analysis. Am J Gastroenterol. 2004;99:147-155. 37. Bingener-Casey J, Richards ML, Strodel WE, et al. Reasons for conversion from laparoscopic to open cholecystectomy: a 10-year review. J Gastrointest Surg. 2002;6:800-805. 38. Assaff Y, Matter I, Sabo E, et al. Laparoscopic cholecystectomy for acute cholecystitis and the consequences of gallbladder perforation, bile spillage, and “loss” of stones. Eur J Surg. 1998;164:425-431. 39. Kimura T, Goto H, Takeuchi Y, et al. Intraabdominal contamination after gallbladder perforation during laparoscopic cholecystectomy and its complications. Surg Endosc. 1996;10:888-891. 40. Soper NJ, Dunnegan DL. Does intraoperative gallbladder perforation influence the early outcome of laparoscopic cholecystectomy? Surg Laparosc Endosc. 1991;1:156161. 41. Spira RM, Nissan A, Zamir O, et al. Percutaneous transhepatic cholecystostomy and delayed laparoscopic cholecystectomy in critically ill patients with acute calculous cholecystitis. Am J Surg. 2002;183:62-66.
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42. Byrne M, Suhocki P, Mitchell R, et al. Percutaneous cholecystostomy in patients with acute cholecystitis: experience of 45 patients at a US referral center. J Am Coll Surg. 2003;197:206-211. 43. McSherry CK, Ferstenberg H, Virshup M. The Mirizzi’s syndrome: Suggested classification and surgical therapy. Surg Gastroenterol. 1982;1:219-225. 44. Cottier DJ, McKay C, Anderson JR. Subtotal cholecystectomy. Br J Surg. 1991;78:13261328. 45. Karademir S, Astarcioglu H, Sokmen S, et al. Mirizzi’s syndrome: Diagnostic and surgical considerations in 25 patients. J Hepatobiliary Pancreat Surg. 2000;7:72-77. 46. Redaelli CA, Buchler MW, Schilling MK, et al. High coincidence of Mirizzi’s syndrome and gallbladder carcinoma. Surgery. 1997;121:58-63. 47. Morrissey K, McSherry C. Internal biliary fistula and gallstone ileus. In: Surgery of the Liver and Biliary Tree. Philadelphia: Churchill-Livingstone; 1994:909-922. 48. Bouveret L. Sténose du pylore adhérent à la vésicule. Rev Méd (Paris). 1896;16:1-16. 49. Rigler L, Borman C, Noble J. Gallstone obstruction: pathogenesis and roentgen manifestations. JAMA. 1941;117:1753-1759. 50. Balthazar EJ, Schechter LS. Gallstone ileus. The importance of contrast examinations in the roentgenographic diagnosis. AJR Am J Roentgenol. 1975;125:374-379. 51. Balthazar EJ, Schechter LS. Air in gallbladder: a frequent finding in gallstone ileus. AJR Am J Roentgenol. 1978;131:219-222. 52. Svartholm E, Andren-Sandberg A, Evander A, et al. Diagnosis and treatment of the gallstone ileus. Report of 83 cases. Acta Chir Scand. 1982;148:435-438. 53. May RE, Strong R. Acute emphysematous cholecystitis. Br J Surg. 1975;58:453458. 54. Eldar S, Sabo E, Nash E, et al. Laparoscopic cholecystectomy for the various types of gallbladder inflammation: a prospective trial. Surg Laparosc Endosc. 1998;8:200207. 55. Eldar S, Sabo E, Nash E, et al. Laparoscopic vs open cholecystectomy for acute cholecystitis. Surg Laparosc Endosc. 1997;7:407-414. 56. Eldar S, Sabo E, Nash E, et al. Laparoscopic cholecystectomy for acute cholecystitis: prospective trial. World J Surg. 1997;21:540-554. 57. Mirvis SE, Vainright JR, Nelson AW, et al. The diagnosis of acute acalculous cholecystitis: A comparison of sonography, scintigraphy, and CT. AJR Am J Roentgenol. 1986;147:1171. 58. Flancbaum L, Choban PS, Sinha R, Jonasson O. Morphine cholescintigraphy in the evaluation of hospitalized patients with suspected acute cholecystitis. Ann Surg. 1994;220:25. 59. Brugge WR, Friedman LS: A new endoscopic procedure provides insight into an old disease: Acute acalculous cholecystitis. Gastroenterology. 1994;106:1718. 60. Canfield AJ, Hetz SP, Schriver JP, et al. Biliary duskiness: A study of more than 200 patients and review of the literature. J Gastrointestinal Surg. 1998;2:443-448. 61. Poynter MT, Saba AK, Evans RA, et al. Chronic acalculous biliary disease: cholecystokinin cholescintigraphy is useful in formulating treatment strategy and predicting success after cholecystectomy. Am Surg. 2002;68(4):382-4. 62. Azuma T, Yoshikawa T, Araida T, et al. Differential diagnosis of polypoid lesions of the gallbladder by endoscopic ultrasonography. Am J Surg. 2001;181:65-70. 63. Sugiyama M, Atomi Y, Kuroda A, et al. Large cholesterol polyps of the gallbladder: Diagnosis by means of US and endoscopic US. Radiology. 1995;196:493-7.
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64. Khan ZR, Neugut AI, Ahsan H, Chabot JA. Risk factors for biliary tract cancers. Am J Gastroenterol. 1999;94:149-152. 65. Jacobson BC, Pitman MB, Brugge WR. EUS-guided FNA for the diagnosis of gallbladder masses. Gastrointest Endosc. 2003;57(2):251-254. 66. Rosch J, Grollman JH, Jr, Steckel RJ. Arteriography in the diagnosis of gallbladder disease. Radiology. 1969;92(7):1485-1491. 67. Wanebo HJ, Vezeridis MP. Carcinoma of the gallbladder. J Surg Oncol. 1993;3(Suppl):134-139. 68. Taner CB, Nagorney DM, Donohue JH. Surgical treatment of gallbladder cancer. J Gastrointest Surg. 2004;8:83-89. 69. Falkson G, MacIntyre JM, Moertel CG. Eastern Cooperative Oncology Group experience with chemotherapy for inoperable gallbladder and bile duct cancer. Cancer. 1984;54:965-969. 70. American Joint Committee on Cancer. Manual of Staging of Cancer. 4th ed. Philadelphia: Lippincott-Raven; 1992. 71. Chijiiwa K, Tanaka M. Carcinoma of the gallbladder: An appraisal of surgical resection. Surgery. 1994;115:751-756. 72. Ashur H, Siegal B, Oland Y, et al. Calcified gallbladder (porcelain gallbladder). Arch Surg. 1978;113:594-596. 73. Shimizu M, Miura J, Tanaka T, et al. Porcelain gallbladder. Relation between its type by ultrasound and incidence of cancer. J Clin Gastroenterol. 1989;11:471-6. 74. Kuroki T, Tajima Y, Matsuzaki S. Pre- and intraoperative evaluation of biliary system for successful laparoscopic cholecystectomy in porcelain gallbladder patients. Hepatogastroenterology. 2002;49:621-624.
chapter
3
Choledocholithiasis Eric Goldberg, MD; Peter Darwin, MD
Epidemiology of Choledocholithiasis Gallstone disease is extremely prevalent in the United States. More than 6 million men and 14 million women aged 20 to 74 have gallbladder disease, and 8.7 million Americans have undergone cholecystectomy1. The annual cost of this common digestive ailment exceeds 6 billion dollars per year 2. Choledocholithiasis, defined as the presence of gallstones in the common bile duct, is seen in up to 15% of patients with gallbladder stones2 . The majority of patients with choledocholithiasis have secondary stones, which are stones that have originated within the gallbladder. Primary common bile duct stones are rare in the United States but are seen commonly in patients of Asian descent. Because the majority of stones originate within the gallbladder, the pathogenesis of choledocholithiasis is similar to the pathogenesis of cholelithiasis (Chapter 2) and is covered only to a limited extent here.
Pathogenesis of Cholesterol Stones The major constituents of bile are cholesterol, bile acids, phospholipids, and bilirubin. Cholesterol is hydrophobic and is therefore insoluble in water. However, bile acids are able to solubulize cholesterol through the formation of mixed micelles3. Phospholipids are also able to solubulize cholesterol through the formation of vesicles4. The initial step in cholesterol gallstone formation is the production of lithogenic bile (Figure 3-1). Lithogenic bile occurs when bile becomes supersaturated with cholesterol. Although production of lithogenic bile via cholesterol supersaturation is the precipitating event in cholesterol gallstone formation, additional pathogenic mechanisms must be present for stones to develop. Nucleation is the process by which cholesterol in supersaturated bile aggregates to form solid crystals. Cholesterol crystals form from aggregation of vesicular cholesterol5. The higher the proportion of cholesterol to phospholipid within vesicles, the more readily nucleation occurs 6. The gallbladder
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Chapter 3
Estrogen Replacement Therapy
Obesity
Cholesterol Supersaturation
Pregnancy
Gallstones
Progesterone
Oral Contraception
Nucleation
Gallbladder Hypomotility
Ceftriaxone
TPN
Octreotide
Figure 3-1. Pathogenesis mechanisms involved in cholesterol gallstone formation. milieu is also important in the pathogenesis of cholesterol gallstones. Concentration of bile within the gallbladder increases cholesterol to phospholipid ratios within cholesterol vesicles. This enhances the nucleation process within the gallbladder when compared to the biliary and hepatic ducts7. This may help explain why secondary bile duct stones are much more common than primary bile duct stones. Gallbladder stasis plays a crucial role in the formation of gallstones by allowing crystals to aggregate into larger stones.
Pathogenesis of Pigmented Stones Black pigmented stones result from increased excretion of bilirubin and may be seen in patients with chronic hemolytic diseases, vascular prostheses, and cirrhosis. The major component of black pigmented stones is bilirubin, but they also contain varying amounts of calcium salts, glycoproteins, and mucin8. Bilirubin is also the major constituent of brown pigmented stones. Brown pigmented stones are strongly associated with bile chronically infected by bacteria. Bacteria, such as Eschericha coli, use the enzyme B-glucuronidase to hydrolyze conjugated bilirubin into insoluble bilirubin salts. Similar to cholesterol stones, gallbladder function contributes to pigmented stone formation. Gallbladder hypomotility, precipitation of insoluble calcium salts, and secretion of mucin and glycoproteins all contribute to lithogenesis.
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49
Secondary Bile Duct Stones Choledocholithiasis is found in 8% to 18% of all patients with symptomatic gallstones2 . In the Western hemisphere, most common bile duct stones are secondary stones and composed primarily of cholesterol9. Two facts strongly support the theory that most stones in the common bile duct originate in the gallbladder. First, stones that are recovered from the gallbladder are similar in composition to stones recovered from the common bile duct in patients undergoing cholecystectomy and common bile duct exploration. Second, more than 80% of patients who have common bile duct stones also have concomitant gallbladder stones10.
Primary Bile Duct Stones Although most stones that form in the gallbladder are composed predominantly of cholesterol, primary bile duct stones are typically pigmented. Factors that lead to their formation include biliary stasis, biliary infection, and the presence of periampullary diverticula. The role of infection in the pathogenesis of primary common bile duct stones has been investigated through cultures of stones recovered from the common bile duct. In one investigation, 100% of brown pigmented stones and 74% of cholesterol stones recovered from the common bile duct were culture positive11. Gram-negative enteric organisms were among the most frequently cultured organisms. Periampullary diverticula may predispose patients to the formation of primary duct stones. In one study, 88% of patients with periampullary diverticula had recurrent common bile duct stones following cholecystectomy compared with 32% of patients without periampullary diverticula12 . One potential explanation is that colonization of the periampullary diverticulum by bacteria leads to chronic biliary infection. Some reports suggest that a low cystic duct insertion may also predispose patients to developing primary bile duct stones13.
Hepatolithiasis (Intrahepatic Duct Stones) Hepatolithiasis refers to stones that occur proximal to the common hepatic duct. The prevalence of hepatolithiasis is much higher in Southeast Asia than the Western hemisphere. In the Swedish population, a necropsy study showed a prevalence of .6%14. In Southeast Asia, the overall prevalence is 10%15. Parasitic infection of the biliary tree by Clonorchis sinensis and Ascaris species may play a role in the pathogenesis of hepatolithiasis16. However, not all patients with hepatolithiasis have evidence of biliary parasitic infestation, and not all patients with infection develop intrahepatic stones. Therefore, other pathogenic mechanisms such as diet, biliary stasis, and genetics are likely involved.
Microlithiasis and Biliary Sludge Biliary sludge, also known as microlithiasis, is a viscous suspension of biliary fluid containing crystals and small stones. The pathogenesis, etiology, clinical presentation, complications, and management of sludge in the common bile duct is nearly identical to that of true choledocholithiasis. Therefore, biliary sludge in the common bile duct should be considered as a form of choledocholithiasis.
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Chapter 3
Risk Factors for Choledocholithiasis In the United States, most common bile duct stones are cholesterol stones that originate from the gallbladder. Therefore, the risk factors for choledocholithiasis mirror the risk factors for cholelithiasis (see Chapter 2). Specific risk factors for increased likelihood of choledocolithiasis include concurrence of juxta-ampullary diverticulum, dilated common bile duct, and history of choledocolithiasis.
Clinical Manifestations Choledocholithiasis may come to clinical attention in a variety of ways. First, it may present with symptoms such as biliary colic and jaundice. Second, it may present with complications including acute pancreatitis, ascending cholangitis, and secondary biliary cirrhosis. Third, patients with choledocholithiasis may have incidentally discovered abnormalities on laboratory or imaging studies. Finally, some patients with choledocholithiasis remain asymptomatic and never present to their clinician. Although the natural history of cholelithiasis has been well established, the natural history of choledocholithiasis is less clear. Older studies suggest that more than 50% of patients with asymptomatic choledocholithiasis will develop symptoms or complications over a 13-year period 23. In a recent review of patients with choledocholithiasis discovered at the time of laparoscopic cholecystectomy, 35% of patients spontaneously passed their common bile duct stones without significant complications by 6 weeks24.
BILIARY PAIN The pain caused by choledocholithiasis is nearly indistinguishable from classic biliary pain caused by stones intermittently obstructing the cystic duct. Biliary pain is often erroneously named “biliary colic” but it is not colicky. It is a constant pain that may last for hours. Biliary pain is typically felt in the right upper quadrant or epigastrium, and may radiate to the right shoulder or interscapular area. It is often associated with nausea and vomiting. Biliary pain in the setting of choledocholithiasis is secondary to the sudden obstruction of the common bile duct, resulting in increased luminal pressure and distention of the common bile duct. Although malignant biliary obstruction results in similar ductal distention, the gradual onset of the obstruction renders it less likely to produce pain.
JAUNDICE When common bile duct stones partially or completely obstruct the flow of bile, jaundice ensues. Cystic duct obstruction typically does not cause jaundice (exception in Mirizzi syndrome—see below). Therefore, when a patient with cholelithiasis presents with biliary colic and jaundice, there should be strong clinical suspicion of a concomitant bile duct stone.
ASCENDING CHOLANGITIS Bile in healthy subjects is sterile. However, in patients with choledocholithiasis, bacterial colonization of common duct calculi occurs. In one review, bacteria were
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found in the bile of 58% of patients with common bile duct stones25. Translocation of enteric organisms across the sphincter of Oddi into stagnant bile is the major mechanism of bacterial entry into the biliary system. Ascending cholangitis is a potentially life-threatening bacterial infection of the biliary tree. Charcot’s triad of fever, biliary pain, and jaundice signifies the presence of ascending cholangitis. However, this triad is present in only one half of patients with ascending cholangitis. When sepsis ensues, patients may develop hypotension and altered mental status. These findings together with Charcot’s triad are referred to as Reynold’s pentad. Most commonly, the bacteria causing cholangitis are enteric in origin including Escherichia coli, Klebsiella species, and Enterococcus species. Anaerobic bacteria such as Bacteroides species have also been implicated.
SECONDARY BILIARY CIRRHOSIS Prolonged extrahepatic biliary obstruction from choledocholithiasis can result in the development of cirrhosis. The duration and extent of the obstruction are the major factors determining the likelihood of developing secondary biliary cirrhosis. On average, secondary biliary cirrhosis develops after the common bile duct has been obstructed for more than 5 years26.
GALLSTONE PANCREATITIS Gallstones are the most common cause of acute pancreatitis in the United States. Acute pancreatitis results when gallstones temporarily obstruct the Ampulla of Vater either by impaction or passage through the ampulla. The exact mechanism by which gallstones cause pancreatitis remains unclear. Reflux of bile into the pancreatic duct may contribute, in addition to mechanical ampullary obstruction from stones or edema 27. Analysis of medical records of 2,583 patients with gallstones from Rochester, Minnesota demonstrates that 3% of patients with cholelithiasis develop acute gallstone pancreatitis. For patients with cholelithiasis, the relative risk of acute pancreatitis was 12 to 25 times in women and 14 to 35 times in men. After cholecystectomy, the relative risk of pancreatitis decreased in both genders to less than two times28. Although the incidence of gallstone pancreatitis in patients with choledocholithiasis has not been thoroughly analyzed, it is likely much higher than seen with simple cholelithiasis alone. Smaller stones (10 mm in diameter).
MAGNETIC RESONANCE CHOLANGIOPANCREATOGRAPHY Magnetic resonance cholangiopancreatography (MRCP) is a noninvasive modality designed specifically to image the biliary and pancreatic ducts (Figure 3-2). MRCP uses a T2 weighted sequence allowing visualization of static fluid in the ducts. The risks and complications are negligible when compared with invasive imaging modalities such as endoscopic retrograde cholangiopancreatography (ERCP). There is extensive literature with MRCP for the diagnosis of common bile duct stones. The sensitivity and specificity for choledocholithiasis are reported to be well over 90%36. Small stones, impacted distal stones, and sludge may be missed. As this test has a significantly higher sensitivity than both ultrasound and CT, it should be considered when there is a low to intermediate clinical suspicion for a common duct stone. Patients with a high clinical suspicion for a common bile duct stone should proceed directly to ERCP, as a therapeutic intervention will likely be required.
HEPATOBILIARY IMINODIACETIC ACID (HIDA) CHOLESCINTIGRAPHY Technetium-HIDA is primarily used to exclude cystic duct obstruction in patients with suspected acute cholecystitis. However, findings on HIDA scanning may also suggest the presence of choledocholithiasis. These include absent or delayed bowel visualization and prominent bile ducts. Occasionally, HIDA scanning may show abnormalities suggestive of choledocholithiasis in patients with normal ultrasound studies37. Because other noninvasive imaging studies, such as MRCP, have superior sensitivity to HIDA scanning, HIDA scanning has a limited role in the routine diagnosis of choledocholithiasis.
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Figure 3-3. Endoscopic
retrograde cholangiogram showing multiple filling defects within a moderately dilated common bile duct.
PERCUTANEOUS TRANSHEPATIC CHOLANGIOGRAPHY Percutaneous transhepatic cholangiography (PTC) is an invasive imaging technique in which contrast is injected into a catheter that has been percutaneously inserted into a dilated intrahepatic duct. A percutaneous cholangiogram has both diagnostic and therapeutic applications. However, management of choledocholithiasis by means of PTC requires time to have the percutaneous tract dilated and matured. Therefore, multiple sessions are required. The ability for single-step intervention by ERCP has limited PTC in most centers to those patients with altered surgical anatomy or a failed endoscopic approach. Local expertise dictates the role for interventional radiology in the diagnosis and management of common bile duct stones.
ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY ERCP is the gold standard test for the diagnosis of choledocholithiasis to which all other imaging modalities are compared (Figure 3-3). The sensitivity and specificity of ERCP for choledocholithiasis exceed 90%. Although the diagnostic and therapeutic applications of ERCP are well documented, the indications for this test as a diagnostic modality are evolving. The sensitivity and specificity of MRCP and endoscopic ultrasonography (EUS) for the diagnosis of CBD stones are comparable to that of ERCP, without the risk for major complications, notably acute pancreatitis. With the widespread availability of MRCP and EUS, the need for diagnostic ERCP to exclude a common bile duct stone has decreased. For patients with a high clinical suspicion of choledocholithiasis, ERCP should clearly be the first line test because therapeutic interventions are likely to be required in this group of patients.
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ENDOSCOPIC ULTRASONOGRAPHY EUS allows the ultrasound transducer to be positioned in the duodenum for optimum visualization of the bile duct. The specificity of EUS has been shown to be superior to both ultrasound and CT for the diagnosis of choledocholithiasis38. Preliminary studies have also shown the diagnostic accuracy of EUS to be superior to MRCP and even ERCP in the evaluation of common bile duct stones35,39. EUS is currently being evaluated for the diagnosis of common bile duct stones in patients with a low to intermediate clinical suspicion of a stone. These situations include exclusion of common duct stones prior to laproscopic cholecystectomy or in patients who have recovered from gallstone pancreatitis. Because EUS offers a highly accurate test with few complications and avoids the need for fluoroscopy, its role is also being evaluated in pregnant patients. However, EUS does require sedation and has no therapeutic capability. The limited availability outside academic centers makes general recommendations difficult. The ideal setting for this modality is EUS coupled with same-setting therapeutic ERCP if common duct stones are seen.
INTRAOPERATIVE CHOLANGIOGRAPHY Intraoperative cholangiography (IOC) may be performed during cholecystectomy to exclude CBD stones40. If CBD stones are discovered, surgical removal should be considered. Alternatively, the patient can be referred for ERCP post cholecystectomy. For patients with a low to intermediate clinical suspicion of common duct stones, IOC is a cost-effective diagnostic technique with little added risk.
Endoscopic Management of Choledocholithiasis SPHINCTEROTOMY Since the advent of endoscopic sphincterotomy in the 1970s, the management of common bile duct stones has transitioned from surgical to predominantly endoscopic treatments. Endoscopic sphincterotomy is performed by cutting both the superficial and deep muscles of the sphincter of Oddi. The primary purpose of endoscopic sphincterotomy is to remove the barrier impeding the passage of stones from the common bile duct into the duodenum. In addition, sphincterotomy expands the orifice to the bile duct large enough to accommodate a variety of devices used by the endoscopist for the extraction of stones. Endoscopic sphincterotomy is performed with a sphincterotome. Sphincterotomes can be categorized into three types: pull-type sphincterotomes, push-type sphincterotomes, and needle-knife sphincterotomes. Pull-type sphincterotomes are by far the most commonly used. In cases where cannulation is difficult, a needle-knife sphincterotome is sometimes used. Push-type sphincterotomes are rarely used today. Pull-type sphincterotomes have a cutting wire attached to the distal tip of the instrument. This wire can be tightened to “bow” the distal tip of the sphincterotome. During sphincterotomy, current is applied through the cutting wire from an electrosurgical cautery generator.
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Figure
3-4. Endoscopic sphincterotomy performed via the standard pull technique. For full-color version, see page CA II of the Color Atlas.
The first step when performing standard pull-type sphincterotomy is cannulation of the bile duct. Next, a guidewire is passed through the lumen of the sphincterotome into the biliary tree. Then, the sphincterotome is withdrawn from the bile duct until the distal one-third of the cutting wire is in the papillary orifice. The sphincterotome is then bowed so that the cutting wire is in contact with the roof of the papilla. Finally, electrocautery current is applied though the wire, until the papilla and sphincter of Oddi have been adequately incised (Figure 3-4). The orientation of the incision should be longitudinal to the direction of the intraduodenal portion of the bile duct. The length of sphincterotomy should be determined based on numerous factors including size of the stone(s) to be removed, size of the papilla, and diameter of the bile duct. In general, larger stones require a larger sphincterotomy. Although a larger sphincterotomy facilitates stone extraction, this must be balanced against the risk of duodenal perforation and post-sphincterotomy bleeding which increases with increasing size of sphincterotomy. When performed by physicians experienced with ERCP, the success of endoscopic sphincterotomy exceeds 95%. Needle-knife sphincterotomes are used primarily to access sphincterotomy in cases in which cannulation of the bile duct is not possible with standard sphincterotomes or catheters. The needle-knife sphincterotome is a catheter that has a short cutting wire extending from its tip. Similar to the pull-type sphincterotome, electrocautery current can be applied through the wire for cutting purposes. However, unlike the pull-type sphincterotomy, which is usually performed over a guidewire, the needle knife is used freehand similar to a scalpel. The papilla is unroofed using the needle knife until access to the bile duct can be achieved. Once the bile duct is successfully cannulated, completion of the sphincterotomy is usually performed using standard pull type sphincterotomes. Needle-knife sphincterotomy used in difficult CBD cannulation is commonly referred to as “precut” sphincterotomy or preferably “access” sphincterotomy.
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Table 3-1
COMPLICATIONS OF ENDOSCOPIC SPHINCTEROTOMY Early • • • •
Pancreatitis Hemorrhage Perforation Cholangitis
Late • • • •
Recurrent stone formation Sphincter stenosis Cholecystitis Cholangitis
Complications of endoscopic sphincterotomy are classified as either early (within 30 days) or late (Tables 3-1 and 3-2). Early complications occur in less than 10% of sphincterotomies and include pancreatitis, perforation, and hemorrhage41. Late complications occur in nearly 25% of patients and include recurrent common bile duct stones, papillary stenosis, cholangitis, and cholecystitis.
BILIARY SPHINCTER DILATION Although endoscopic sphincterotomy is the primary technique used to open the biliary sphincter to facilitate stone extraction, there are certain situations where endoscopic sphincterotomy is either unsafe or may not be feasible. Examples of this situation include: patients with coagulopathy; markedly distorted ampullary anatomy from periampullary diverticula; patients with Billroth II anatomy; and patients who may not be able to receive blood transfusions should post-sphincterotomy bleeding occur, such as Jehovah’s witnesses. In these situations, endoscopic balloon dilation of the papillary orifice is a reasonable alternative to endoscopic sphincterotomy. Endoscopic balloon dilation of the papilla is performed by placing a dilating balloon across the biliary sphincter and into the bile duct. The balloon is then inflated to a maximum diameter of 8 to 10 mm. Most studies addressing endoscopic balloon dilation of the papilla have used 8 mm balloons. The dilation creates a papillary orifice that allows the extraction of most stones less than 10 mm in size. Stones larger than 10 mm can also be removed through the dilated papillary orifice, but may require additional techniques such as lithotripsy. There are a few advantages to performing endoscopic balloon dilation of the papilla compared to endoscopic sphincterotomy. First, the risk of significant bleeding is much lower with balloon dilation. Second, sphincter of Oddi function is preserved following the procedure. However, the clinical significance of sphincter preservation remains unclear as long-term follow-up studies in patients who have undergone
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Table 3-2
MANAGEMENT OF THE EARLY COMPLICATIONS OF ENDOSCOPIC SPHINCTEROTOMY Complication
Incidence
Pancreatitis Hemorrhage
5% to 30% 1% to 2%
Perforation
0.1% to 0.5%
Cholangitis
1% to 5%
Treatment NPO, IV Fluids, Pain Control Endoscopic (epinephrine, hemoclip, balloon tamponade) or Angiographic Embolization or Surgery Conservative (NPO, Antibiotics, Nasobiliary tubes, biliary endoprosthesis) or Surgery Antibiotics
sphincterotomy have not shown a high incidence of adverse consequences. The major disadvantage to endoscopic balloon dilation of the papilla is a high rate of post-ERCP pancreatitis42 . Most therapeutic endoscopists perform endoscopic balloon dilation only when endoscopic sphincterotomy is unsafe or not possible.
STONE EXTRACTION Following sphincterotomy or balloon dilation of the papilla, most stones smaller than 1 cm can be extracted with either extraction balloons or baskets (Figure 3-5). In cases where multiple common bile duct stones are present, the most distal stones should be removed first.
Extraction Balloons Extraction balloons have an inflatable balloon on their distal tip. The technique for stone extraction involves inserting the distal tip of the balloon catheter into the bile duct and above the level of the stone. Then, the balloon is inflated and pulled down the bile duct and through the papillary orifice. Multiple different balloon sizes are available and should be tailored to the size of the bile duct and stone to be removed.
Extraction Baskets Multiple different types of extraction baskets are available. Choice of a particular type of basket depends on the size and shape of the stone to be removed. The technique of basket extraction involves insertion of the basket into the bile duct to the level of the stone. The stone is then captured within the basket and extracted through the papilla. One potential risk of basket extraction is that the basket can itself become impacted at the level of the ampulla. This situation occurs when the basket captures
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Figure 3-5. Four choles-
terol gallstones removed from the common bile duct using an extraction balloon. For full-color version, see page CA II of the Color Atlas.
a stone that is too large to be removed through the papilla. Although this situation is rare in expert hands, it potentially requires surgical removal. Therefore, baskets should not be used to extract stones that are larger than the sphincterotomy.
LITHOTRIPSY Mechanical Lithotripsy Mechanical lithotripsy was initially used by urologists for the management of ureteral stones, and later employed by biliary endoscopists for the crushing and removal of large or difficult CBD stones. The basic technique involves insertion of a lithotripsy compatible basket into the bile duct. Once the stone is captured within the basket, the basket is compressed, which crushes the stone. When standard retrieval methods fail, mechanical lithotripsy should be the next maneuver attempted, as it is technically easy to perform and safe. It should be considered as first line therapy if the stone to be extracted is too large relative to the duct or sphincterotomy size, or in the presence of a distal biliary stricture. The initial lithotriptors were extremely cumbersome to use and stiff, making cannulation challenging. There are several flexible basket lithotriptors now available that make cannulation easier compared to the initial models. They can be used for simple basket extraction or converted to mechanical lithotriptors when needed. Once a stone is secured in the basket, extraction should be attempted with gentle pressure. If extraction is difficult, a metal lithotripsy sheath is fed over the basket and a screw type handle tightened to crush the stone within the sheath. The Trapezoid basket (Boston Scientific, Natick, Mass) allows both cannulation over a wire and lithotripsy with a single step device (Figure 3-6). It is essential when removing large or difficult stones to be certain the basket is lithotriptor compatible should the basket get impacted in the ampulla.
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Figure 3-6. Endo-
scopic retrograde cholangiography. A trapezoid basket is being used to crush a stone.
There are several series looking at success using mechanical lithotripsy. Complete stone clearance has been reported from 88% to 98% 43. Often, multiple sessions with short-term stenting are required to achieve complete clearance.
EXTRACORPOREAL SHOCK WAVE LITHOTRIPSY ESWL uses shock waves generated external to the body to fragment calculi. There is extensive urologic experience with ESWL, and the equipment has evolved from fixed units requiring water submersion to the smaller, mobile devices currently available. ESWL has been used successfully for both pancreatic and biliary tract stones. Localization of biliary stones is performed under either ultrasound or fluoroscopic guidance. Stone localization is aided by the presence of a biliary endoprosthesis. Indwelling nasobiliary or percutaneous catheters allow for “on the spot” cholangiography and flushing of the crushed stone fragments. Alternatively, ERCP may be performed immediately after ESWL to perform extraction of large residual fragments. Technically, ESWL is a straight forward and safe method for the fragmentation of large stones. In our institution, ESWL is performed if mechanical lithotripsy fails and surgical extraction is not planned. Several series have demonstrated stone clearance rates of up to 90%.44 Several sessions of ESWL may be required to achieve adequate fragmentation. Side effects and complications are generally not severe and include hematuria, hemobilia, and hyperamylasemia.
ELECTROHYDRAULIC LITHOTRIPSY Electrohydraulic shock waves were first used to fragment bladder stones in the 1950s. A “spark-gap” device conducts a high voltage electric discharge that creates a mechanical shock wave. Some of the initial work in the biliary tree was performed
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using a dog model45. Because the shock wave can also injure normal tissue, electrohydraulic lithotripsy (EHL) should be applied either with a balloon-guided catheter or under direct visualization. Direct vision of the stone to be fragmented is accomplished using a “Mother-Baby” system where a small choledochoscope is introduced through the therapeutic channel of a duodenoscope. The choledocoscope is then passed into the biliary tree to localize the stone. Once the stone is localized, an EHL fiber is passed through the working channel of the choledochoscope, and the tip of the EHL fiber is applied as close as possible to the surface of the stone. Because EHL requires a liquid medium to generate sufficient shock waves to fragment the stone, saline is continuously irrigated into the bile duct. Intraductal saline irrigation also facilitates the clearance of stone debris generated from lithotripsy. Direct comparison of ESWL and intracorporeal electrohydraulic lithotripsy has yielded similar results, with clearance of difficult stones in greater than 70% of cases46. As with other forms of nonmechanical lithotripsy, the technique is often limited to specialized centers.
Laser Lithotripsy Laser lithotripsy uses athermic shock waves to fragment stones. Laser lithotripsy systems currently used in clinical practice include cumarin and rhodamine 6G dye lasers, frequency doubled double pulse-pulse neodymium:YAG, and holmium:YAG lasers. Initial laser lithotripsy required cholangioscopy and direct stone visualization to prevent injury to normal tissue. Newer “smart laser” systems with stone recognition ability limit the potential for tissue trauma and allow treatment with less than ideal visualization. The systems fire only if catheter tip and stone are in direct contact. “Blind” fragmentation of CBD stones using an optical stone tissue detection system has proven to be of benefit in large or difficult stones. In a series of stones not amenable to standard therapy, 87% ultimately achieved complete stone clearance47. A randomized comparison favored intracorporeal laser lithotripsy over ESWL for difficult bile duct stones48. Because it is technically challenging, laser lithotripsy is generally limited to specialized tertiary care centers.
BILIARY STENTING FOR CHOLEDOCHOLITHIASIS Endoscopic removal of common bile duct stones is successful in greater than 90% of cases. In situations where endoscopic removal of common bile duct stones is unsuccessful, long-term management is dependent on the age and general health status of the patient. For young and otherwise healthy patients, surgical common bile duct exploration and stone removal should strongly be considered to help avoid long-term complications of choledocholithiasis such as secondary biliary cirrhosis. In elderly patients with multiple comorbidities, biliary stenting with 10 French plastic stents is a viable temporary and long-term option for managing choledocholithiasis. Biliary endoprostheses provide adequate decompression of the biliary tree and prevent stone impaction at the level of the ampulla. Bile is able to flow both through the stent and around the stent to maintain biliary drainage. Plastic biliary endoprostheses generally remain patent for approximately 3 months duration. After 3 months, occlusion of endoprostheses is common because of stone debris and bacterial biofilm, which obstruct the lumen of the stent. Even in the circumstance of stent occlusion, bile drainage around the stent may be sufficient to prevent symptoms of biliary obstruction in patients with
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choledocholithiasis. Another benefit of biliary stenting is that the stent itself may help break up large stones, making future endoscopic attempts at stone removal more successful. Stone fragmentation occurs as a result of friction generated against the stone by the stent, which rubs against the stone during intestinal peristalsis. In one review of 23 elderly patients with large common bile duct stones who were treated with biliary endoprostheses, 87% remained completely asymptomatic after a mean follow-up of 23 months49. The major long-term complications of biliary endoprostheses for management of choledocholithiasis is recurrent biliary obstruction and cholangitis. This can usually be treated medically with antibiotics and stent exchange. When performing plastic biliary stent insertion for choledocholithiasis, a few management techniques are important to consider. First, a sphincterotomy should be performed prior to stent placement. This will facilitate bile drainage around the stent should stent occlusion occur. Second, 10 French stents have longer patency rates than 7 French stents and are preferred. Third, for patients with markedly dilated bile ducts, there is a concern for stent migration with straight plastic stents. Double pigtail stents may have an advantage in this circumstance, as their position in the bile duct is more secure. Finally, repeat ERCP with an attempt at stone extraction should be considered within a few months of initial stent placement. If multiple attempts at stone removal are unsuccessful, long-term biliary stenting is usually sufficient to prevent biliary complications. Patients managed with long-term biliary endoprosthesis should be followed closely by their physician. If the patient develops symptoms of biliary obstruction or laboratory abnormalities consistent with biliary obstruction, replacement of the stent should be performed.
PERCUTANEOUS TRANSHEPATIC CHOLANGIOGRAPHIC MANAGEMENT CHOLEDOCHOLITHIASIS
OF
Once a percutaneous tract to the biliary system has been obtained, dilated, and matured, therapeutic interventions can be performed. Mechanical lithotripsy using basket devices have been used as has laser or electrohydraulic lithotripsy through a percutaneously inserted choledochoscope. Percutaneous expulsion of bile duct calculi into the duodenum by dilating the papilla with a balloon catheter has been used both from a T-tube tract and transhepatically. Technical success has been reported in over 90% of cases50.
MANAGEMENT OF CHOLEDOCHOLITHIASIS DISCOVERED DURING INTRAOPERATIVE CHOLANGIOGRAPHY The optimum strategy for the treatment of stones found by intraoperative cholangiogram has not been determined. Numerous options are available. First, the stone can be removed via open or laparoscopic common bile duct exploration51. Second, attempts can be made to extract the stone through the cystic duct. Third, post cholecystectomy ERCP with stone extraction is a viable option in centers with an experienced therapeutic endoscopist. Finally, as previously noted, a significant percentage of small stones may pass spontaneously and it may be reasonable to simply observe the patient.
Choledocholithiasis
NONINVASIVE MANAGEMENT DISSOLUTION THERAPY
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CHOLEDOCHOLITHIASIS: STONE
Methyl-tert-butyl ether (MTBE) and mono-octanoin are both effective agents for the dissolution of cholesterol stones. Several series have evaluated their use in refractory CBD stones. The solvents are infused by either nasobiliary catheters or a T-tube for a mean of 7 days52 . In one trial, complete stone clearance could be achieved in 49%53. Multiple complications have been reported including death from cholangitis during the infusion. With the advent of other methods for the treatment of refractory stones, chemical dissolution has fallen from favor. Experience with oral dissolution for CBD stones is limited. Several reports suggest that chenodeoxycholic acid (CDCA) or ursodeoxycholic acid (UDCA) may be effective. A controlled study showed improvement compared to placebo in patients with retained CBD stones54. Treatment of nonextractable CBD stones has been attempted with combination of UDCA and endoprosthesis. In a study of 22 patients with “defiant” stones, 10 were treated with a combination of UDCA and stent placement, and 12 were treated with stent placement alone55. It appeared that UDCA facilitated the later extraction of these difficult stones. Although it is difficult to make firm recommendations based on this nonrandomized study, UDCA may be beneficial in patients with difficult to treat stones, especially if future extraction attempts are intended.
THE ROLE OF CHOLECYSTECTOMY CHOLEDOCHOLITHIASIS
IN
THE
MANAGEMENT
OF
Cholecystectomy is an integral part of the management of patients with choledocholithiasis, as patients with choledocholithiasis are susceptible to other complications of gallstone disease such as cholecystitis. The value of cholecystectomy was demonstrated in a trial of 120 patients who underwent endoscopic sphincterotomy for choledocholithiasis who were then randomized to either a “wait and see” group or cholecystectomy group. Of the patients in the “wait and see group”, 47% had recurrent biliary symptoms within 2 years compared to 2% of patients in the cholecystectomy group. Furthermore, patients who developed recurrent biliary symptoms in the “wait and see” group more often required conversion from laparoscopic cholecystectomy to open cholecystectomy compared to patients who initially underwent cholecystectomy56. For patients who are poor operative candidates, it is acceptable to perform endoscopic sphincterotomy and stone extraction, and then follow the patient’s clinical course to determine whether the benefits of future cholecystectomy outweigh the operative risks.
Rare Presentations of Gallstone Disease MIRIZZI'S SYNDROME Stones in the gallbladder or cystic duct typically do not cause jaundice, because the flow of bile from the hepatic ducts, through the common bile duct, and into the duodenum is unimpeded. Jaundice associated with gallstone disease is usually caused by migration of stones into the common bile duct. However, Mirizzi's syndrome is an
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exception to this rule. Mirizzi's syndrome is caused by obstruction of the common hepatic duct from external compression by either a stone impacted in the cystic duct or by severe inflammation around the cystic duct. Mirizzi's syndrome is covered in more detail in Chapter 2.
HEPATOLITHIASIS Hepatolithiasis is a condition characterized by the formation of primary pigmented stones within the intrahepatic bile ducts. It is rare in the United States, but common in patients from Southeast Asia. An increasing incidence is now being encountered in the United States because of immigration of patients from Southeast Asia. Other names for this disorder include Oriental cholangiohepatitis and recurrent pyogenic cholangitis. Although the cause of this disorder is poorly understood, bacterial infection and possibly parasitic infection of the biliary tree is believed to be important in the pathogenesis. Patients with hepatolithiasis develop numerous intrahepatic bile duct stones, intrahepatic biliary strictures, and areas of biliary dilation. Although the entire biliary tree can be affected, the left hepatic duct and its branches are more commonly involved. Affected patients often present with recurrent episodes of cholangitis characterized by fever, jaundice, and right upper quadrant pain. Diagnosis may be suggested by CT scan or ultrasound which shows intrahepatic stones and biliary dilation. Cholangiography can also be used to make the diagnosis. An important consideration is that ERCP may underestimate disease extent because of its inability to visualize segments proximal to a biliary stricture. MRCP is an extremely helpful complementary imaging technique to better define involvement of the entire biliary tree. Management of patients with hepatolithiasis usually requires collaboration between gastroenterologists, surgeons, and interventional radiologists. In patients who present acutely with signs and symptoms of biliary obstruction and infection, ERCP may be performed. However, clearance of stone burden and achievement of biliary decompression can be difficult even in the hands of experienced therapeutic endoscopists, because of the presence of multiple biliary strictures. For patients who cannot have their biliary tree entirely cleared by ERCP, strong consideration should be given to percutaneous transhepatic cholangiography or surgery. Surgical options include stone removal, biliary bypass via a hepaticoenterostomy, and hepatic resection. Although not commonly performed in the United States, percutaneous transhepatic choledochoscopy with stone extraction is a frequently used procedure in Asian countries to manage patients with hepatolithiasis. Even in patients who have complete clearance of stones from their biliary system, recurrence is common. Therefore, patients with hepatolithiasis should undergo periodic surveillance for recurrent stone disease with either ultrasonography or MRCP. In patients in whom recurrent stone disease occurs, strong consideration should be made to clear the stones before symptoms ensue. In addition to cholangitis, complications of hepatolithiasis include secondary biliary cirrhosis and cholangiocarcinoma.
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Conclusions Because of the high prevalence of gallbladder disease in the United States, secondary choledocholithiasis with cholesterol stones is frequently encountered. Over the past few decades, great strides have been made in the diagnosis and management of choledocholithiasis. Diagnosis of choledocholithiasis has markedly improved with newer noninvasive imaging techniques such as MRCP and EUS. The therapy of choledocholithiasis has evolved from invasive open common bile duct explorations to endoscopic methods of stone extraction. Large, difficult to remove stones can now be managed with lithotripsy techniques, such as mechanical lithotripsy, electrohydraulic lithotripsy, and ESWL. As endoscopic equipment continues to evolve, further improvements in the diagnosis and management of choledocholithiasis can be expected. In the future, smaller endoscopes that can be inserted directly into the bile duct will allow direct visualization of stones and may preclude the need for fluoroscopy. Newer, easier to use extraction devices will allow even the most difficult stones to be managed in nontertiary care settings. For the rare patient who has stones that can not be endoscopically extracted, stents with improved long-term patency rates may prevent the need for surgery and further endoscopic procedures. Ongoing research will likely result in improvements in the rate of post-ERCP complications, such as pancreatitis. In addition, pharmacological prevention of stone recurrence can be expected in the future.
References 1. Everhart JE, Khare M, Hill M, Maurer KR. Prevalence and ethnic differences in gallbladder disease in the United States. Gastroenterology. 1999;117:632-639. 2. Ko C, Lee S. Epidemiology and natural history of common bile duct stones and prediction of disease. Gastrointest Endosc. 2002;56:S165-S170. 3. Admirand WH, Small DM. The physico-chemical basis of cholesterol gallstone formation in man. J Clin Invest. 1968;47:1043-1052. 4. Somjen GJ, Gilat T. Contribution of vesicular and micellar carriers to cholesterol transport in human bile. J Lipid Res. 1985;26:699. 5. Halpern Z, Dudley MA, Kibe A, et al. Rapid vesicle formation and aggregation in human biles. A time-lapse video-enhanced contrast microscopy study. Gastroenterology. 1986;90:875. 6. Halpern Z, Dudley MA, Lynn MP, et al. Vesicle aggregation in model systems of bile: relation to crystal nucleation and lipid composition of the vesicular phase. J Lip Res. 1986;27:295. 7. Lee S, Ko S. Gallstones. In Yamada E, ed. Textbook of Gastroenterology. 4th ed. Philadelphia: Lippincott, Williams & Wilkins; 2003: 2258-2263. 8. Leuschner U, Guldutuna S, Hellstem A. Etiology, pathogenesis and therapy of pigment gallstones. Dig Dis. 1991;9:282. 9. Whiting MJ, Watts JM. Chemical Composition of common bile duct stones. Br J Surg. 1986;73:229. 10. Madden JL. Common duct stones: Their origin and surgical management. Surg Clin North Am. 1973;53:1095. 11. Tabata M, Nakayama F. Bacteria and gallstones. Etiological significance. Dig Dis Sci. 1981;26:218-224.
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12. Kennedy RH, Thompson MH. Are duodenal diverticula associated with choledocholithiasis? Gut. 1988;29:1003. 13. Bornman PC, Kottler RE, Terblanche J, et al. Does low entry of the cystic duct predispose to stones in the common bile duct? Br Med J. 1988;297:31. 14. Lindstrom CG. Frequency of gallstone disease in a well-defined Swedish population. A prospective necropsy study in Malmo. Scand J Gastroenterol. 1977;12:341. 15. Nakayama F, Soloway RD, Nakama T, et al. Hepatolithiasis in East Asia. Retrospective study. Dig Dis Sci. 1986;31:21. 16. Chen HH, Zhang WH, Wang SS. Twenty-two year experience with the diagnosis and treatment of intrahepatic calculi. Surg Gynecol Obstet. 1984:159:519. 17. Barbara L, Sama C, Morselli-Labate AM, et al. A ten year incidence of gallstone disease: The Sirmione study. J Hepatol. 1993;18(Suppl 1):S43. 18. DenBesten L, Doty JE. Pathogenesis and management of choledocholithiasis. Surg Clin N Am. 1981;61:893. 19. Marighini A, Ciambra M, Bacceliere P, et al. Biliary sludge and gallstones in pregnancy: Incidence, risk factors and natural history. Ann Intern Med. 1993;199:116-20. 20. Sampliner RE, Bennett PH, Comers LJ, et al. Gallbladder disease in Pima Indians. Demonstration of high prevalence and early onset by cholecystography. N Engl J Med. 1970;283:1358. 21. Sarin SK, Negi VS, Dewan R, et al. High familial prevalence of gallstones in the first degree relatives of gallstone patients. Hepatology. 1995;22:138. 22. Khanuja B, Cheah Y-C, Nishina PM, et al. Lith1, a major gene affecting cholesterol gallstone formation among inbred strains of mice. Proc Natl Acad Sci USA. 1995;92:7729-7733. 23. Millbourn E. Klinische studien uber die choledocholithiasis. Acta Chirurg Scand. 1941;86 (Supp 65) as quoted in Yamada. 24. Collins C, Maguire D, Ireland A, et al. A prospective study of common bile duct calculi in patients undergoing laparoscopic cholecystectomy: Natural history of choledocholithiasis revisited. Ann Surg. 2004;239:28-33. 25. Csendas A, Beccera M, Burdiles P. Bacteriological studies of bile from the gallbladder in patients with carcinoma of the gallbladder, cholelithiasis, common bile duct stones and no gallstones disease. Eur J Surg. 1994;160:363-367. 26. Scobie BA. Hepatic cirrhosis secondary to obstruction of the biliary system. Am J Dig Dis. 1965;10:135-46. 27. Lerch MM, Saluja A, Runzi M, et al. Pancreatic duct obstruction triggers acute pancreatitis in the opossum. Gastroenterology. 1993;104:853-861. 28. Moreau JA, Zinsmeister AR, Melton LJ, DiMagno EP. Gallstone pancreatitis and the effect of cholecystectomy. Mayo Clin Proc. 1988;63:466-473. 29. Lee SP, Nicholls JF, Park HZ. Biliary sludge as a cause of acute pancreatitis. N Engl J Med. 1992;326:589-593. 30. Ros E, Navarro S, Bru C, et al. Occult microlithiasis in “idiopathic” acute pancreatitis: Prevention of relapses by cholecystectomy or ursodeoxycholic acid therapy. Gastroenterology. 1991;101:1701-1709. 31. Cooperberg PL, Gibney RG. Imaging of the gallbladder. Radiology. 1987;163:605613. 32. Einstein DM, Lapin SA, Ralls PW, Halls JM. The insensitivity of sonography in the detection of choledocholithiasis. AJR Am J Roentgenol. 1984;142:725-728.
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33. Mitchell S, Clark RA. A comparison of CT and sonography in choledocholithiasis. AJR Am J Roentgenol. 1984;142:79. 34. Soto JO, Alvarez O, Munera F, et al. Diagnosing bile duct stones: Comparison on unenhanced helical CT, CT cholangiography and MR cholangiography. AJR Am J Roentgenol. 2000;175:1127-1134. 35. Palazzo L, O’Toole. EUS in common bile duct stones. Gastrointest Endo. 2002;56: S49-57. 36. MacEneaney P, Mitchell M, McDermott R. Update on magnetic resonance cholangiopancreatography. Gastronterol Clin North Am. 2002;31:731-746. 37. Colletti PM, Ralls PW, Lapin SA, et al. Hepatobiliary imaging in choledocholithiasis. Clin Nucl Med. 1986;11:482-486. 38. Sugiyama M, Atomi Y. EUS for the diagnosis of choledocholithiasis. Gastrointest Endosc. 1997;45:143-6. 39. De Ledinghen V, Lecesne R, Raymond J, et al. Diagnosis of choledocholithiasis: EUS or MRCP. Gastro Endo. 1999;49:26-31. 40. Flowers JL, Zucker K, Graham S. Laproscopic cholangiography. Ann Surg. 1992;211:230. 41. Cotton PB, Geenen JE, Sherman S, et al. Endoscopic sphincterotomy for stones by experts is safe, even in younger patients with normal ducts. Ann Surg. 1998; 227:201204. 42. DiSario JA, Freeman ML, Bjorkrnan DJ, et al. Endoscopic balloon dilation compared to sphincterotomy (EDES) for extraction of bile duct stones: Preliminary results [abstract]. Gastrointest Endosc. 1997;45:AB129. 43. Hintz R, Adler A, Veltzke. Outcome of mechanical lithotripsy of bile duct stones in an unselected series of 704 patients. Hepatogastroenterology. 1996;43:473-476. 44. Lomanto D, Fiocca F, Nardovino M, et al. ESWL experience in the therapy of difficult bile duct stones. Dig Dis Sci. 1996;41:2397-2403. 45. Sievert C, Silvas E. Evaluation of electrohydraulic lithotripsy as a means of gallstone fragementaion in the canine model. Gastrointest Endosc. 1987;32:233-235. 46. Adamek H, Maier M, Jokobs R, et al. Management of retained bile duct stones: A prospective open trial comparing extracorporeal and intracorporeal lithotripsy. Gastrointest Endosc. 1996;44:40-47. 47. Hochberger J, Bayer J, May A, et al. Laser lithotripsy of difficult bile duct stones: Results in 60 patients using a rhodamine 6G dye laser with optical stone tissue detection system. Gut. 1998;43:823-890. 48. Neuhaus H, Zillinger C, Born P, et al. Randomized study of intracorporeal laser lithotripsy verses extracorporial shock-wave lithotripsy for difficult bile duct stones. Gastrointest Endosc. 1998;47:27-34. 49. Van Steenbergen W, Pelemans W, Fevery J. Endoscopic biliary endoprosthesis in elderly patients with large bile duct stones: Long-term follow-up. J Am Geriatr Soc. 1992;40:57-60. 50. Garcia-Garcia L, Lanciego C. Percutaneous treatment of bile duct stones: Sphincteroplasty and occlusion balloon for the clearance of bile duct calculi. AJR Am J Roentgenol. 2004;182:663-670. 51. Ebner S, Rechner J, Beller S, et al. Laproscopic management of common bile duct stones. Surg Endosc. 2004;18:762-765. 52. Diaz D, Bories P, Ampeles M, et al. Methyl-tert-butyl ether in the endoscopic treatment of common bile duct radiolucent stones in elderly patients with nasobiliary tube. Dig Dis Sci. 1992;37:79-100.
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53. Stock S, Carson G, Lavelle M, et al. Treatment of common bile duct stones using mono-octanoin. Br J Surg. 1992;79:653-654. 54. Salvioli G, Salati R, Lugli R, et al. Medical treatment of biliary duct stones: Effect of ursodeoxycholic acid administration. Gut. 1983;24:609-14. 55. Johnson G, Geenen J, Venu R, et al. Treatment of nonextractable common bile duct stones with combination of ursodeoxycholic acid and endoprosthesis. Gastro Endo. 1993;39:528-531. 56. Boerma D, Rauws EA, Keulemans YC, et al. Wait and see policy or laparoscopic cholecystectomy after endoscopic sphincterotomy for bile duct stones: A randomized trial. Lancet. 2002;360:761-5.
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4
Bile Duct Injuries Janak N. Shah, MD
Introduction Bile duct injuries may be attributed to a variety of mechanisms, but most are caused iatrogenically, as complications of surgical procedures. Injuries to the bile ducts are a considerable cause of morbidity in afflicted patients. In earlier years, therapy frequently was operative. However, since the early 1990s, minimally invasive procedures have emerged as a replacement to surgery, and are now used as the first-line treatment for many bile duct injuries. This chapter will review bile duct injuries and their treatment, with specific emphasis on the endoscopic therapy of bile duct injuries. Special issues of biliary injuries as related to laparoscopic cholecystectomy and liver transplantation will be emphasized.
Etiology Most biliary injuries are iatrogenic in nature, occurring as complications of surgery, such as laparoscopic cholecystectomy, liver transplantation, and other hepatobiliary operations1,2 . Nonoperative hepatobiliary procedures, such as those used in the ablation of hepatic tumors, are increasingly used in the modern era, and may also lead to iatrogenic damage to the bile ducts. Common causes of biliary injuries are listed in Table 4-1.
LAPAROSCOPIC CHOLECYSTECTOMY AND BILE DUCT INJURIES Laparoscopic cholecystectomy was introduced in the late 1980s, and has since essentially replaced open cholecystectomy for the treatment of symptomatic gallbladder stones3. Given the lack of tactile feedback and three-dimensional visualization during laparoscopic cholecystectomy, there has been increased concern for iatrogenic injury using the laparoscopic approach. Although overall morbidity and mortality rates for open versus laparoscopic cholecystectomies appear similar, injuries to the bile ducts occur more frequently following the laparoscopic approach4.
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Table 4-1
ETIOLOGIES OF BILE DUCT INJURIES Postsurgical Cholecystectomy (laparoscopic or open) Liver transplantation Hepatobiliary surgery (eg, hepatic resection)
Other Iatrogenic Tumor ablation therapies: radiofrequency ablation, cryoablation, chemoembolization Liver biopsy Transjugular intrahepatic portosystemic shunt (TIPS procedure) External beam radiotherapy
Noniatrogenic Penetrating trauma (eg, stab wound, gun shot wound) Blunt trauma (eg, motor vehicle accident)
Potential factors that predispose to the risk of injury during laparoscopic cholecystectomy include anatomical variations of the biliary system (eg, accessory duct of Luschka, absent or short cystic ducts), acute or chronic inflammation of the gallbladder, maneuvers used to control hemorrhage intraoperatively (eg, electrocautery, laser), and improper surgical technique4. Aberrant right hepatic ducts are found in 8% of patients undergoing cholecystectomy and in 17% of patients with complications following cholecystectomy, and seem to be important predisposing factors for bile duct injuries5,6. Numerous large series from the United States and worldwide reveal that biliary tract injuries complicate laparoscopic cholecystectomy in 0.5% to 0.8% of cases7-11. Types of injuries following surgery include bile leaks and fistulas, biliary strictures, and complete or partial bile duct transection4. Leaks are the most common biliary complication, and mostly arise from the cystic duct stump or accessory ducts of Luschka4,7,8. Complete transection of the bile duct comprises less than 2% of overall bile duct injuries following laparoscopic cholecystectomy, but may represent a much higher proportion at tertiary referral centers 4. As might be expected, increased surgical experience appears to decrease the rates of biliary complications3,9,10. The routine use of intraoperative cholangiography may lower complication rates11,12 .
LIVER TRANSPLANTATION AND BILE DUCT INJURIES Cadaveric orthotopic liver transplantation (OLT) is now routinely used in the management of patients with end stage liver disease who are appropriate candidates for such therapy. Since the late 1990s, over 4,000 liver transplants have been performed
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in the United States annually13. Although overall graft survival and patient outcomes have improved since the advent of OLT, biliary injuries following transplantation remain a common problem, and occur in 6% to 34% of OLT recipients14-17. The most common types of biliary complications following OLT include bile leaks and strictures. Bile leaks complicate liver transplantation in 8% to 26% of cases15-18. The use of surgically placed biliary drainage tubes (T-tubes) during bile duct reconstruction may be associated with an increase rate of this complication. Several studies reveal an over two- to threefold higher rate of bile leaks in patients receiving duct-to-duct anastomoses with T-tubes compared to those without T-tubes15,19,20. Bile leaks usually occur either at the T-tube insertion site (majority), or at the biliary anastomosis. Whereas T-tube associated leaks are due to the physical defect at the biliary insertion site, anastomotic leaks are often the result of local ischemia and necrosis21. Most bile leaks are diagnosed within 3 months of surgery, and those located at the T-tube site are usually temporally related to the manipulation or removal of the catheter16. Although it may be difficult to predict which patients will develop bile leaks after T-tube removal, duct mural irregularities on final T-tube cholangiograms (prior to removal) have been associated with the development of bile leaks22 . Biliary strictures occur in 3% to 16% of OLT recipients, and represent the second most common type of biliary injury following transplantation14,15,17-19,23. In contrast to bile leaks, they are often encountered later in the post-transplant period16. Biliary strictures may be classified by their location, either as anastomotic or nonanastomotic. Nonanastomotic strictures involve the biliary tree of the donor graft, are attributed to ischemia from graft preservation injury or hepatic artery thrombosis, and are also referred to as ischemic type biliary strictures24,25. Anastomotic strictures are attributed to a combination of surgical technique, fibrotic healing, and local tissue ischemia 26. Although bile leaks are more common in the setting of T-tubes, the opposite effect is seen for biliary strictures, and therefore T-tube use is favored at some centers. Numerous studies, including two randomized trials, demonstrate higher rates of biliary strictures in OLT patients receiving duct-to-duct anastomoses without T-tubes as compared to those with T-tubes (10% to 20% versus 2% to 8%)19,20,27,28. A direct anastomosis between the bile duct and intestine (choledochojejunostomy) also seems to be associated with an increased risk of anastomotic strictures16,25. A less common biliary complication after OLT is the development of primary bile duct stones, sludge, and casts. Stones and/or sludge occur in 2% to 13% of OLT recipients, and are usually diagnosed later in the post-transplant period (4 to 18 months post-OLT) 29-31. An underlying biliary stricture is encountered in over two-thirds of patients with bile duct stones31. Biliary casts are more diffuse lithogenic formations (“cast-like” appearance) that arise in the donor biliary tree. Biliary cast syndrome appears to be independently associated with both hepatic ischemia and biliary strictures, and is seen in up to 6% of OLT recipients, usually within 1 year of transplantation32 . Living donor liver transplantation (LDLT) is being increasingly performed in the Unites States,33 and raises specific issues related to biliary injuries after transplantation. The two main types of biliary complications of LDLT are the same as those of cadaveric OLT, but the incidence of bile leaks and strictures may be greater. Leaks are found in 10% to 40%, and strictures are encountered in about 20% of LDLT recipients34-36. There are limited data directly comparing biliary injuries following
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cadaveric OLT and LDLT. The available data are conflicting, as one study from Asia demonstrated similar biliary complication rates (6%) for LDLT and OLT, whereas a US study revealed a three- to fourfold higher rate of both bile leaks and strictures in LDLT recipients36,37. However, an increased rate of biliary complications in LDLT patients seems highly plausible, as biliary reconstructions may involve multiple and smaller diameter duct-to-duct anastomoses36,38. An additional type of injury unique to LDLT is the formation of leaks at the cut surface of the split liver graft38. With the rise in LDLT being performed worldwide, bile duct injuries involving donors are also being increasingly recognized. Bile leaks occur in 2.5% to 6% of donors, and biliary strictures occur in about 1% 33,39,40. As might be expected, the risk of biliary injuries in donors is higher at transplant centers performing fewer LDLT procedures33. Also, the risk appears greater when utilizing right hepatectomy grafts, likely due to the creation of a sharper angle at the porta hepatis between the native common bile duct and left hepatic duct 39,40.
OTHER CAUSES OF BILE DUCT INJURIES Nonoperative medical procedures may also lead to bile duct injuries. Large studies demonstrate that bile leaks and biliary strictures complicate 0.2% to 2% of cases following the minimally invasive treatment of hepatic tumors using techniques such as radiofrequency ablation, laser thermotherapy, and transarterial chemoembolization41-43. Although it may be difficult to predict which patients will develop injury after tumor ablation treatment, results from one recent investigation suggest that the incidence of bile duct injury following transarterial chemoembolization may be increased in noncirrhotic livers, during therapy of tumors of nonhepatocellular origin, and with highly selective embolization of distal arterial branches44. Other tumor ablation techniques, such as hepatic cryoablation and external beam radiation therapy, may also give rise to bile leaks and biliary strictures, respectively45-48. Iatrogenic bile duct injury may occur during other minimally invasive procedures such as transjugular intrahepatic portosystemic shunts (TIPS) and liver biopsy. During placement of TIPS, inadvertent fistulous connections between hepatic veins and the biliary system may be created49,50. Liver biopsies are associated with bile leaks and biliovascular fistulas in fewer than 1% of cases51,52 . Noniatrogenic causes of biliary injuries are usually due to trauma, and include complications of gun shot wounds as well as blunt wounds53. Specific types of injury consist of bile leaks (most common), biliovascular fistulas, and strictures. As most published information on biliary complications secondary to trauma is based on case reports and case series, the true incidence is difficult to determine54,55.
Clinical Presentation and Diagnosis BILIOVASCULAR FISTULAE Biliary injuries that result in fistulous connections between bile ducts and vascular structures are rare, two-thirds of which are caused iatrogenically 56. Patients with bilioarterial fistulas usually present with signs and symptoms of upper GI hemorrhage due to hemobilia. Persistent clots in the biliary tree may also lead to signs and symptoms of biliary obstruction. Endoscopy may reveal blood exiting the papilla, but the diag-
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nosis is usually confirmed at angiography 56. Patients with fistulas between the biliary and hepatic venous systems may present with hemobilia, jaundice (due to bilemia or obstruction from intraductal clot), or biliary sepsis 49,50,56. Contrast opacification of the biliary system during endoscopic retrograde cholangiopancreatography (ERCP) will demonstrate the presence of a fistulous tract between the biliary and hepatic venous system50. The common clinical features and diagnostic methods for various types of biliary injuries are summarized in Table 4-2.
BILE LEAKS Bile leaks result from defects in the bile duct wall, and should be suspected in patients with history of hepatobiliary surgery or abdominal trauma who present with abdominal pain, fever, peritoneal signs, or new onset ascites1,13. Iatrogenic bile leaks tend to present early in the postoperative period, and may be recognized in association with T-tube manipulations13,18. Mild elevations of serum liver tests and white blood cell counts may be present57,58. Leaks that freely communicate with the peritoneal cavity may result in diffuse abdominal pain from bile peritonitis. Those that connect to more localized collections (bilomas) may produce focal areas of tenderness. Although abdominal pain and tenderness are common presenting features, these may be absent in corticosteroid use13. Direct cholangiography is considered the reference standard to establish the diagnosis of a bile leak59. The presence and anatomic location of leaks are easily visualized at percutaneous transhepatic cholangiography (PTC) or endoscopic retrograde cholangiopancreatography (ERCP). Moreover, therapeutic measures can be undertaken immediately (see section on Management). When leaks are suspected in postcholecystectomy and post-OLT patients, specific attention should be paid to the cystic duct stump (Figure 4-1), and biliary anastomosis and/or T-tube site, respectively4,18. Hepatobiliary scintigraphy is also highly accurate in detecting bile leaks (>85%), and is a useful noninvasive modality to establish the diagnosis58-60. Due to the excellent performance characteristics of nuclear scintigraphy for detection of biliary complications, some advocate that ERCP is unnecessary if the hepatobiliary scan is normal61. However, cholangiography remains the benchmark for establishing the diagnosis, and should be performed when there is high suspicion despite negative hepatobiliary scinitigraphy. Other noninvasive imaging techniques such as CT and MRI may demonstrate intraperitoneal fluid collections and thereby suggest bile leaks in patients with the appropriate clinical history. However, the presence of a bile leak cannot be definitively diagnosed using standard CT or MRI. In small case series, MR cholangiopancreatography (MRCP) has suggested the presence of leaks that were later confirmed at ERCP62 , but MRCP is not a conventional method for detecting leaks. CT cholangiography, which involves thin section spiral CT scanning after the administration of an intravenous cholangiographic agent, may become an effective means of identifying bile leaks, but has not been studied in large series 63,64.
BILIARY STRICTURES Biliary strictures should be suspected in patients with history of biliary tract surgery who present with jaundice, signs and/or symptoms of cholangitis, or abnormal serum liver tests of a cholestatic pattern18,65. In comparison to leaks, strictures are
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Table 4-2
BILE DUCT INJURIES: CLINICAL PRESENTATION AND DIAGNOSTIC METHODS Biliary Injury
Clinical Presentation
Primary Diagnostic Test
Bile leak
Abdominal pain/tenderness Fever New onset ascites (on exam or imaging) Bilious output from surgical drains Recent manipulation of T-tube Mild elevation serum liver tests Elevated WBC count
ERCP / PTC or Hepatobiliary scintigraphy
Biliary Stricture
Jaundice Cholangitis Elevated liver tests (cholestatic pattern) Dilated biliary ducts (Ultrasound/CT/MRI) Abnormal liver biopsy
ERCP / PTC or MRCP
Bilioarterial fistula
Upper GI hemorrhage Angiography (hemobilia): hypotension, tachycardia, shock hemetemesis, melena, hematochezia decrease hemoglobin/hematocrit Biliary obstruction (intraductal clot)
Biliovenous fistula
Jaundice/biliary obstruction ERCP (intraductal clot) Hyperbilirubinemia (bilemia) Upper GI hemorrhage (hemobilia)
`
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Figure 4-1. Balloon occlusion cholangiogram at ERCP demonstrates contrast extravasation at cystic duct stump (arrow) near surgical drain in a patient following laparoscopic cholecystectomy.
usually identified later after the inciting event, even months to years after surgery1. Occasionally, patients will present with clinical or histologic evidence of end stage liver disease years after the initial insult that caused the stricture. Abdominal ultrasound, CT, or MRI often demonstrate dilation of the intrahepatic or extrahepatic biliary tree, but these findings may be absent, especially in the post-OLT setting13. At times, a liver biopsy performed for evaluation of cholestasis may reveal histologic findings (eg, pericholangitis, bile ductular proliferation) that initiate the concern of biliary stricture or obstruction13. As for bile leaks, direct cholangiography at PTC or ERCP remains the reference standard for establishing the diagnosis of biliary strictures1,2 . Even subtle strictures can be detected, and their location precisely characterized. During cholangiography, likely sites of possible strictures (eg, biliary anastomosis in post-OLT patients) should be specifically investigated. Therapeutic measures can also be undertaken during PTC or ERCP (see Management section). Other noninvasive imaging techniques have proven useful in the diagnosis of biliary strictures. Hepatobiliary scintigraphy can detect the presence of biliary obstruction, but is less useful in this regard than for bile leaks59,60. Although the lack of radiotracer activity in the duodenum may suggest complete bile duct obstruction, hepatobiliary scans cannot discriminate the underlying cause (stricture versus biliary stone). MRCP has emerged as a valuable, noninvasive method of characterizing biliary strictures, and appears comparable to PTC and ERCP in this regard66,67. The unprocessed MR images that are reconstructed to produce the MRCP may provide additional, useful information on extraductal abnormalities 67. In complete bile duct transection or high grade strictures in which ERCP may only demonstrate the distal biliary tree, MRCP can depict the entire biliary system, both proximal and distal to the stricture 68. Although the focus of this chapter is on bile duct injuries and benign disease, one must always entertain the possibility of biliary strictures due to malignant disease. There should be a low threshold to thoroughly investigate strictures that present in patients with a clinical presentation worrisome for malignancy, or without a definite history of hepatobiliary surgery or other potential biliary injury.
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Management Although bile duct injuries are attributed to a variety of iatrogenic and noniatrogenic causes, the techniques that should be used in their treatment remain similar. A variety of endoscopic, percutaneous, and surgical methods are available. The optimal approach is highly dependent on local expertise, and is best determined under multidisciplinary discussions involving surgeons, interventional radiologists, and therapeutic endoscopists. The therapy of bile leaks, strictures, and other ductal injuries is described in this section. Specific treatment considerations related to biliary injuries following laparoscopic cholecystectomy and liver transplantation will also be addressed.
MANAGEMENT OF BILE LEAKS The treatment of bile leaks has evolved with advances in minimally invasive techniques. Although small leaks may spontaneously heal with conservative management within a day, those with persistent symptoms should undergo therapy17,22 . In earlier years, the only treatment options were surgical. In the modern era, management may consist of endoscopic, percutaneous, and surgical approaches. Available therapeutic techniques and other management aspects for bile leaks are listed in Table 4-3. Many centers that have experienced biliary endoscopists favor the endoscopic approach, as this avoids surgical morbidity and the uncomfortable presence of percutaneous catheters. Endoscopic options include endoscopic sphincterotomy, biliary stent placement, nasobiliary drain, or a combination thereof18,31,69-71. The physiologic goal of endoscopic therapy is to decrease the pressure gradient between the biliary system and duodenum70. This promotes bile flow preferentially into the small intestine bypassing the leak site, and allows the bile duct defect to heal. Endoscopic sphincterotomy alone has been used for bile leaks with high success rates (88%) in one study69. However, it is not favored as sole therapy at many centers13,18, and a direct comparison of sphincterotomy to biliary endoprosthesis in a canine model revealed significantly longer time to healing in the group treated with sphincterotomy 72 . Nasobiliary drains and plastic biliary stents effectively treat bile leaks in 80% to 100% of patients18,31,70,71,73,74. One advantage of nasobiliary drains over indwelling stents is the ability to maintain access for repeat cholangiography and assessment of leak closure. Healing is confirmed for most leaks within 1 week, and the nasobiliary tube can then be removed75. However, the presence of a nasobiliary catheter can be irritating to some patients, alterations of patient position may lead to inadvertent dislodgement from the biliary tree, and therefore many centers prefer treatment using biliary stents13,18. Additionally, one group has suggested improved success rates with biliary endoprostheses as compared to nasobiliary drains based on a small series of patients with bile leaks following laparoscopic cholecystectomy 74. Some centers advocate the use of long biliary stents that traverse the site of leak (“leak-bridging”)13,71. Theoretically, these may form an additional physical barrier at the leak site, and divert bile away from the defect. However, short biliary stents that just traverse the papilla and decrease the transpapillary pressure gradient appear to be equally effective for uncomplicated bile duct leaks (Figure 4-2) 70. Biliary stent placement does not require sphincterotomy18,31,74, and positioning attempts should be made through the intact papilla. Regardless of whether a leak-bridging or
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Table 4-3
BILE LEAKS: TREATMENT TECHNIQUES AND MANAGEMENT ASPECTS Endoscopic Biliary stent (transpapillary or leak-bridging) Nasobiliary drain Endoscopic sphincterotomy
Percutaneous Transhepatic biliary drain Biloma / abscess drainage (* adjunct therapy to other techniques)
Surgical Primary repair of defect Biliary reconstruction
Other Treatment of biliary obstruction, if present (calculi, strictures) Antibiotics for bile peritonitis
Figure 4-2A. ERCP demonstrates
contrast leak (arrow) along T-tube tract in OLT recipient. Reprinted with permission from Pfau P, et al., Endoscopic management of postoperative biliary complications in orthotopic liver transplantation. Gastrointestinal Endoscopy. 2000;52:55-63. Copyright 2000, American Society for Gastrointestinal Endoscopy.
78 Figure
Chapter 4
4-2B. Placement transpapillary stent (10F, 5cm).
of
Figure 4-2C. Interval ERCP at 4
weeks demonstrates no evidence of bile leak (stent removed immediately prior to cholangiogram).
transpapillary stent is used, a large diameter stent (10 French or higher) is optimal, as the increased diameter should improve internal bile flow. The placement of a biliary stent requires a repeat endoscopy for removal. Repeat ERCP should be performed within 4 to 8 weeks, and leak closure is seen in 84% to 100% of patients18,31,70,71. Any associated fluid collections should be percutaneously drained when infection is suspected, as adjunct therapy to the endoscopic management of leaks76,77. Broad spectrum antibiotics are usually prescribed for patients with bile peritonitis. When leaks are identified during T-tube removal, the placement of a drainage catheter adjacent to the biliary insertion site via the T-tube tract should be considered, as this technique reduced the incidence of bile peritonitis from 20% to 9% in one study 78. Areas of distal bile duct obstruction (eg, calculi, strictures) should also be addressed, as these may elevate intraductal pressures and contribute to delayed or unsuccessful healing of the leak site18,31,77. New endoscopic techniques hold promise for the treatment of bile leaks. One group has compared botulinum toxin injection into the sphincter of Oddi to endobiliary stents for the treatment of cystic duct leaks in a canine model, and found both techniques equally effective79. If results are confirmed in larger human trials, an advantage of this method over biliary stenting would be the avoidance of repeat
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endoscopy for stent removal. Another group has described a novel method using nbutyl-2-cyanoacrylate glue for the occlusion of biliary fistulas. Leaks were closed in 7 of 9 patients using cyanoacrylate glue at one ERCP procedure, and obviated the need for surgical intervention after prior failed endoscopic therapy 80. Both of these innovative techniques may expand the role of endoscopic treatment of bile leaks, but further studies will be required. For patients who have failed or are not candidates for endoscopic therapy due to inaccessibility of the bile duct (failed cannulation or surgically altered anatomy), transhepatic biliary drainage may be used for treatment of leaks with similar success rates to endoscopic therapy 81. However, percutaneous biliary access and therapy in a non-dilated biliary system may be technically challenging and requires interventional radiology expertise. Although minimally invasive therapies are highly successful in the management of bile leaks, their failure warrants surgical treatment. Patients with more complex ductal injuries or larger size leaks are more likely to require surgical management 71,77,82 . Initial palliation with endoscopic stenting, however, enables operative repair to be performed electively and perhaps at a center with more experience in such management. Common surgical options for the management of bile leaks include primary repair and biliary reconstruction (eg, choledochojejunostomy, hepaticojejunostomy)18,31,71,82-84, and are discussed elsewhere in this textbook.
MANAGEMENT OF BILIARY STRICTURES Advances in minimally invasive therapy have substantially impacted the treatment approach to biliary strictures. Progress in endoscopic and percutaneous methods has minimized the need for surgery for most strictures. Initial treatment attempts for strictures that are accessible and traversable with guidewires should be at ERCP or PTC, prior to considering operative treatment. Biliary strictures can be successfully treated endoscopically in 60% to 90% of cases14,31,65,85-87. Therapy may require several interval ERCP procedures (2 to 8 ERCPs) performed over one year or more, using repeat stricture dilations and multiple biliary stents (1 to 6 stents) 65. An algorithm for the endoscopic treatment of benign bile duct strictures is suggested in Figure 4-3. The first step is stricture dilation, performed using rigid or pneumatic dilation catheters. Subsequently, one or more polyethylene stents that traverse the stricture should be placed. The largest diameter and maximum number of stents that are possible should be deployed. The stricture dimensions and bile duct size will dictate the caliber and number of stents, as well as the initial dilation diameter. Placement of more than one stent usually requires endoscopic sphincterotomy. Repeat ERCP is suggested at 3 months, with removal of the indwelling stents and reassessment of the stricture. If the stricture is not adequately resolved, repeat dilation and stenting should be performed, with an increased number of stricture-traversing stents, if possible. This cycle should be continued at 3-month intervals until stricture resolution. Adequate treatment may be judged on cholangiographic findings, the ability to pull inflated balloon catheters through the stricture, and persistence of normal serum liver tests after removal of biliary stents (Figure 4-4). In rare instances, standard ERCP may be unsuccessful despite an accessible papilla due to failed biliary cannulation or inability to traverse the stricture. In this setting, the percutaneous transhepatic placement of a guidewire or catheter into the duode-
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Step 1: Stricture Dilation at ERCP
· ·
Balloon or rigid dilators Dilation size depends on stricture and bile duct diameters
Step 2: Biliary Stent Placement ·
Maximum number/diameter of polyethylene stents as possible across stricture
Step 3: Repeat ERCP at 3 Months ·
Remove previously placed stents Reassess stricture
·
Stricture Present · · ·
Repeat Steps 1-3 Increase dilation diameter Increase stent caliber/number Consider surgical therapy after endoscopic treatment duration greater than 18-24 months
Stricture Resolved · · ·
Clinical follow-up Follow-up serum liver tests Reevaluate for signs/symptoms suggestive of recurrent stricture
Figure 4-3. Algorithm for endoscopic management of benign bile duct strictures.
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Figure 4-4A. ERCP demonstrates anastomotic stricture in a patient 3 months after OLT. Reprinted from Rerknimitr R, et al., Biliary tract complications after orthotopic liver transplantation with choledochocholedochostomy anastomosis. Gastrointestinal Endoscopy, 55:224-31. Copyright 2002, American Society for Gastrointestinal Endoscopy.
Figure 4-4B. Balloon dilation of anastomotic stricture at ERCP.
num may allow successful subsequent ERCP for stricture therapy. This combined endoscopic and PTC technique (“rendezvous” procedure) permits endoscopic biliary access after prior failed ERCP in over 90% of patients88. The rendezvous method is favored over PTC procedures alone, as biliary stricture therapy with PTC may require long-term percutaneous access (1 year or more) and large caliber dilations of the percutaneous, transhepatic tract88. In patients with surgically altered anatomy in which the papilla is inaccessible endoscopically, percutaneous therapy should be considered. Specific instruments are similar to those used endoscopically, and include balloon dilators and biliary drains/ stents. Success rates for transhepatic stricture management are comparable to those achieved endoscopically (approximately 80%) 89,90. There may be an additional role of PTC therapy for proximal and hilar strictures, as endoscopic maneuvers are less successful for treating strictures at those locations87.
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Figure 4-4C. Radiograph after balloon
dilation and placement of 2 plastic stents that traverse the stricture (10F).
Figure 4-4D. Interval cholangiogram
demonstrates complete resolution of anastomotic stricture after successful endoscopic therapy.
Failure of nonoperative management of bile duct strictures justifies surgical therapy. ERCP or PTC failures may occur at the initial procedure when encountering a complete or nearly obstructed stricture. Inability to traverse the stenosis at initial ERCP with either guidewires or stents is reported in approximately 20% of cases 85. Minimally invasive techniques may also be ultimately unsuccessful due to stricture persistence despite treatment, or stricture recurrence. Restenosis develops in 20% of patients within 2 years of stent removal, and at least 40% of these fail repeat endoscopic therapy 85. Operative measures usually involve biliary reconstruction, and may include choledochoduodenostomy, choledochojejunostomy, and hepaticojejunostomy. For select, poor operative candidates who have failed minimally invasive therapy but have ERCP or PTC-accessible strictures, large-diameter self-expandable metallic stents may be considered91. However, metallic stent placement is permanent, and repeat biliary interventions may be required over the long-term in over 50% of
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83
patients92 . Selection for such therapy is probably best on a case-by-case basis after thorough discussions involving the patient and a multidisciplinary team. Recent technological innovations hold promise for future treatments. Bioabsorbable self-expanding biliary stents have been developed, and may provide large caliber stent therapy for benign strictures without the potential detriment of permanent metallic stents93. However, these are not yet commercially available. Advances in EUS techniques now allow for EUS-guided access to the biliary tree for therapeutic purposes, and may expand the opportunity for endoscopic therapy of previously inaccessible strictures94.
MANAGEMENT OF BILIOVASCULAR FISTULAS Fistulous tracts between the biliary and hepatic arterial system often present as hemobilia. Therapy for this type of injury is twofold, and includes angiographic embolization of the fistula and the ERCP/PTC treatment of clot related biliary obstruction, if present13,56. Surgery is indicated when embolization fails. Overall mortality for this type of fistula is 5%56. Fistulas between the biliary tree and hepatic veins may be treated with biliary stents for decompression in a similar fashion as for bile leak therapy50. Stent placement should promote bile flow in a normal direction instead of into the venous system. However, there is a theoretical risk of flow reversal that may lead to hemobilia if the biliary tree is decompressed to the point of a substantial pressure difference between the two systems50. Fistulas that arise in relation to TIPS may require shunt revision49.
SPECIAL MANAGEMENT CONSIDERATIONS WITH LAPAROSCOPIC CHOLECYSTECTOMY Major bile duct injuries following laparoscopic cholecystectomy usually affect the extrahepatic biliary system, and are often due to accidental ligation, laceration, resection, and/or misapplied clipping of the right, left, or common duct (Figure 45)4,84. Although they usually require operative repair84, dislodgement of partially impinging clips on the extrahepatic duct using balloon dilation at ERCP has been described95. Timely recognition and repair of bile duct injuries following laparoscopic cholecystectomy are extremely important as a long interval between injury and evaluation is associated with the development of liver cirrhosis96.
SPECIAL MANAGEMENT CONSIDERATIONS WITH LIVER TRANSPLANTATION The general approach to the repair of bile leaks and strictures for OLT recipients is similar to that for other patients, and is described in previous sections. However, one specific transplant issue regarding bile leaks worth recognizing is that the endoscopic treatment success is significantly poorer for anastomotic leaks compared to T-tube site leaks (43% versus 95%)18. Anastomotic breakdown is likely a reflection of local ischemia, and may be more difficult to address nonoperatively than leaks at other sites. A particular post-OLT concern with strictures is that those located in the proximal donor biliary system (nonanastomotic) may be the result of ischemia. Concurrent hepatic artery thrombosis or stenosis is found in about 50% of patients with nonanastomotic strictures, and should be investigated and treated, if present13.
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Figure 4-5A. Radiograph demonstrates
numerous surgical clips (arrow) in the region of the common hepatic duct in a patient with prior laparoscopic cholecystectomy.
Figure 4-5B. Cholangiogram reveals major bile duct injury with large volume of contrast extravasation near hilum and no opacification of intrahepatic ducts. This patient required operative repair with hepaticojejunostomy.
One unique type of biliary complication of liver transplantation is the formation of bile duct casts, and occurs in at least 6% of OLT recipients with an associated mortality of 10% 32 . Biliary casts are successfully treated in 60% using endoscopic and percutaneous methods, but operative reconstruction is required for failure of minimally invasive therapy 32 . Most liver transplant recipients are on immunosuppressive regimens. Antibiotic prophylaxis should be considered prior to ERCP or PTC treatment of biliary complications, especially in the setting of possible bile duct obstruction or stricture 97.
Future Considerations The diagnosis and treatment of bile duct injuries is evolving. Advances in noninvasive imaging will likely replace the current standard of direct cholangiography at ERCP or PTC for the diagnosis of most biliary injuries. More importantly, innova-
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tions in technology and endoscopic techniques (eg, bioabsorbable stents, EUS-guided biliary access and bilioenteric anastomoses) 93,94, should expand the role of minimally invasive therapy and allow an even greater proportion of patients with bile duct injuries to be treated nonoperatively. Physicians caring for such patients will need to keep current with new developments in a variety of fields, including noninvasive imaging, therapeutic endoscopy, interventional radiology, and surgery.
Conclusion Injuries to the bile ducts are usually caused iatrogenically, and remain an important source of morbidity for afflicted patients. The most common types of injury include biliary leaks and strictures. An increasing incidence of bile duct injuries may be anticipated given the ongoing popularity of laparoscopic cholecystectomy and the expected rise in liver transplantation. Minimally invasive techniques, such as ERCP, play a vital role in the evaluation of such injuries, and should be used as first-line treatment for the majority.
References 1. Costamagna G, Shah SK, Tringali A. Current management of post-operative complications and benign biliary strictures. Gastrointest Endosc Clinics N Am. 2003;13:635648. 2. Frattaroli FM, Reggio D, Guadalaxara A, et al. Benign biliary strictures: a review of 21 years experience. J Am Coll Surg. 1996;183:506-513. 3. The Southern Surgeons Club. A prospective analysis of 1518 laparoscopic cholecystectomies. N Engl J Med. 1991;324:1073-1078. 4. MacFadyen BV, Vecchio R, Ricardo AE, et al. Bile duct injury after laparoscopic cholecystectomy. Surg Endosc. 1998;12:315-321. 5. Kullman E, Borch K, Lindstrom E, et al. Value of routine intraoperative cholangiography in detecting aberrant bile ducts and bile duct injuries during laparoscopic cholecystectomy. Br J Surg. 1996;83:171-175. 6. Suhocki PV, Meyers WC. Injury to aberrant bile ducts during cholecystectomy: a common cause of diagnostic error and treatment delay. AJR Am J Roentgenol. 1999;172:955-959. 7. Fathy O, Zeid MA, Abdallah T, et al. Laparoscopic cholecystectomy: a report on 2000 cases. Hepatogastroenterology. 2003;50:967-971. 8. Scott TR, Zucker KA, Bailey RW. Laparoscopic cholecystectomy: a review of 12,397 patients. Surg Laparoscopy Endosc. 1992;2:191-198. 9. Regoly-Merei J, Ihasz M, Szeberin Z, et al. Biliary tract complications in laparoscopic cholecystectomy. A multicenter study of 148 biliary tract injuries in 26,440 operations. Surg Endosc. 1998;12:294-300. 10. Deziel DJ, Millikan KW, Economou SG, et al. Complications of laparoscopic cholecystectomy: a national survey of 4,292 hospitals and an analysis of 77,604 cases. Am J Surg. 1993;165:9-14. 11. Flum DR, Dellinger EP, Cheadle A, et al. Intraoperative cholangiography and the risk of common bile duct injury during cholecystectomy. JAMA. 2003;289:16391644.
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12. Flum DR, Koepsell T, Heagerty P, et al. Common bile duct injury during laparoscopic cholecystectomy and the use of intraoperative cholangiography: adverse outcome or preventable error? Arch Surg. 2001;136:1287-1292. 13. Tung BY, Kimmey MB. Biliary complications of orthotopic liver transplantation. Dig Dis. 1999;17:133-144. 14. Klein AS, Savader S, Burdick JF, et al. Reduction of morbidity and mortality from biliary complications of liver transplantation. Hepatology. 1991;14:818-823. 15. Rolles K, Dawson K, Novell R, et al. Biliary anastomosis after liver transplantation does not benefit from T tube splintage. Transplantation. 1994;57:402-404. 16. Greif F, Bronsther OL, Van Thiel DH, et al. The incidence, timing, and management of biliary tract complications after orthotopic liver transplantation. Ann Surg. 1994;219:40-45. 17. O’Connor TP, Lewis D, Jenkins RL. Biliary tract complications after liver transplantation. Arch Surg. 1995;130:312-317. 18. Pfau P, Kochman ML, Lewis JD, et al. Endoscopic management of postoperative biliary complications in orthotopic liver transplantation. Gastrointest Endosc. 2000;52:55-63. 19. Rouch DA, Emond JC, Thistlethwaite JR, et al. Choledochocholedochostomy without a T-tube or internal stent in transplantation of the liver. Surg Gynecol Obstet. 1990;170:239-244. 20. Koivusalo A, Isoniemi H, Salmela K, et al. Biliary complications in one hundred adult liver transplantations. Scand J Gastroenterol. 1996;31:506-511. 21. Sheng R, Sammon JK, Zajko AB, et al. Bile leak after hepatic transplantation: cholangiographic features, prevalence, and clinical outcome. Radiology. 1994;192:413416. 22. Shuhart MC, Kowdley KV, McVicar JP, et al. Predictors of bile leaks after T-tube removal in orthotopic liver transplant recipients. Liver Transpl Surg. 1998;4:62-70. 23. Randall HB, Wachs ME, Somberg KA, et al. The use of T-tube after orthotopic liver transplantation. Transplantation. 1996;61:258-261. 24. Sanchez-Urdazpal L, Gores GJ, Ward EM, et al. Diagnostic features and clinical outcome of ischemic-type biliary complications after liver transplantation. Hepatology. 1993;17:605-609. 25. Colonna JO, Shaked A, Gomes AS, et al. Biliary strictures complicating liver transplantation. Incidence, pathogenesis, management, and outcome. Ann Surg. 1992;216:344-350. 26. Porayko MK, Kondo M, Steers JL. Liver transplantation: late complications of the biliary tract and their management. Semin Liver Dis. 1995;15:139-155. 27. Vougas V, Rela M, Gane E, et al. A prospective randomized trial of bile duct reconstruction at liver transplantation: T-tube or no T-tube? Transpl Int. 1996;9:492495. 28. Nuno J, Vicente E, Turrion VS, et al. Biliary tract reconstruction after liver transplantation: with or without T-tube? Tranplant Proc. 1997;29:564-565. 29. Barton P, Maier A, Steininger R, et al. Biliary sludge after liver transplantation: 1. Imaging findings and efficacy of various imaging procedures. AJR Am J Roentgenol. 1995;164:859-864. 30. Somberg KA, Osorio RW, Lake JR, et al. Choledocholithiasis following orthotopic liver transplantation (OLT): clinical features, risk factors, and endoscopic management (abstract). Gastrointest Endosc. 1993;39:328.
Bile Duct Injuries
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31. Rerknimitr R, Sherman S, Fogel EL, et al. Biliary tract complications after orthotopic liver transplantation with choledochocholedochostomy anastomosis: Endoscopic findings and results of therapy. Gastrointest Endosc. 2002;55:224-31. 32. Shah JN, Haigh WG, Lee SP, et al. Biliary casts after orthotopic liver transplantation: clinical factors, treatment, and biochemical analysis. Am J Gastroenterol. 2003;98:1861-1867. 33. Brown RS, Russo MW, Lai M, et al. A survey of liver transplantation from living adult donors in the United States. N Engl J Med. 2003;348:818-825. 34. Testa G, Malago M, Valentin-Gamazo C, et al. Biliary anastomosis in living related liver transplantation using right liver lobe: techniques and complications. Liver Transpl. 2000;6:710-714. 35. Ishiko T, Egawa H, Kasahara M, et al. Duct-to-duct biliary reconstruction in living donor liver transplantation utilizing right lobe graft. Ann Surg. 2002;236:235-240. 36. Shah JN, Ahmad NA, Shetty K, et al. Biliary tract complications following living donor liver transplantation: types and endoscopic management (abstract). Gastrointest Endosc. 2003;57:AB203. 37. Park JS, Kim MH, Lee SK, et al. Efficacy of endoscopic and percutaneous treatments for biliary complications after cadaveric and living donor liver transplantation. Gastrointest Endosc. 2003;57:78-85. 38. Icoz G, Kilic M, Zeytunlu M, et al. Biliary reconstructions and complications encountered in 50 consecutive right-lobe living donor liver transplantations. Liver Transpl. 2003;9:575-80. 39. Hasegawa K, Yazumi S, Egawa H, et al. Endoscopic management of postoperative biliary complications in donors for living donor liver transplantation. Clin Gastroenterol Hepatol. 2003;1:183-188. 40. Lo CM. Complications and long-term outcome of living liver donors: a survey of 1,508 cases in five Asian centers. Transplantation. 2003;75:S12-5. 41. Rhim H, Yoon KH, Lee JM, et al. Major complications after radio-frequency thermal ablation of hepatic tumors: spectrum of imaging findings. Radiographics. 2003; 23:123-134. 42. Vogl TJ, Straub R, Eichler K, et al. Malignant liver tumors treated with MR imaging-guided laser-induced thermotherapy: experience with complications in 899 patients (2,520 lesions). Radiology. 2002;225:367-377. 43. Kim HK, Chung YH, Song BC, et al. Ischemic bile duct injury as a serious complication after transarterial chemoembolization in patients with hepatocellular carcinoma. J Clin Gastroenterol. 2001;32:423-427. 44. Yu JS, Kim KW, Jeong MG, et al. Predisposing factors of bile duct injury after transcatheter arterial chemoembolization (TACE) for hepatic malignancy. Cardiovasc Intervent Radiol. 2002;25:270-274. 45. Sarantou T, Bilchik A, Ramming KP. Complications of hepatic cryosurgery. Sem Surg Oncol. 1998;14:156-162. 46. Iannitti DA, Heniford T, Hale J, et al. Laparoscopic cryoablation of hepatic metastases. Arch Surg. 1998;133:1011-1015. 47. Nakakubo Y, Kondo S, Katoh H, et al. Biliary stricture as a possible late complication of radiation therapy. Hepatogastroenterology. 2000; 47: 1531-1532. 48. Schmets L, Delhaye M, Azar C, et al. Postradiotherapy benign biliary stricture: successful treatment by self-expandable metallic stent. Gastrointest Endosc. 1996; 43:149-152.
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49. Boyer TD. Transjugular intrahepatic portosystemic shunt: current status. Gastroenterology. 2003;124:1700-1710. 50. Mallery S, Freeman ML, Peine CJ, et al. Biliary-shunt fistula following transjugular intrahepatic portosystemic shunt placement. Gastroenterology. 1996;111:1353-1357. 51. Cohen MB, A-Kader HH, Lambers D, et al. Complications of percutaneous liver biopsy in children. Gastroenterology. 1992;102: 629-632. 52. Grant A, Neuberger J. Guidelines in the use of liver biopsy in clinical practice. Gut. 1999;45:IV1-IV11. 53. Parks RW, Chrysos E, Diamond T. Management of liver trauma. Br J Surgery. 2000;87:519-520. 54. Degiannis E, Khelif K, Leandros E, et al. Gunshot injuries of the extrahepatic biliary ducts. Eur J Surg. 2001;167:618-621. 55. Harrell DJ, Vitale GC, Larson GM. Selective role for endoscopic retrograde cholangiopancreatography in abdominal trauma. Surg Endosc. 1998;12:400-404. 56. Green MH, Duell RM, Johnson CD, et al. Haemobilia. Br J Surg. 2001;88:77386. 57. Mutignani M, Shah SK, Tringali A, et al. Endoscopic therapy for bile leaks from aberrant right hepatic ducts severed during cholecystectomy. Gastrointest Endosc. 2002;55:932-936. 58. Brooks DC, Becker JM, Connors PJ, et al. Management of bile leaks following laparoscopic cholecystectomy. Surg Endosc. 1993;7:292-295. 59. Brugge WR, Rosenberg DJ, Alavi A. Diagnosis of postoperative bile leaks. Am J Gastroenterol. 1994;89:2178-2183. 60. Brugge WR, Alavi A. Cholescintigraphy in the diagnosis of the complications of laparoscopic cholecystectomy. Semin Ultrasound CT MR. 1993;14:368-374. 61. Kurzawinski TR, Sleves L, Farouk M, et al. Prospective study of hepatobiliary scintigraphy and endoscopic cholangiography for the detection of early biliary complications after orthotopic liver transplantation. Br J Surg. 1997;84:620-623. 62. Khalid TR, Casillas VJ, Montalvo BM, et al. Using MR cholangiopancreatography to evaluate iatrogenic bile duct injury. AJR Am J Roentgenol. 2001;177:1347-1352. 63. Wicky S, Gudinchet F, Barghouth G, et al. Three-dimensional cholangio-spiral CT demonstration of a post-traumatic bile leak in a child. Eur Radiol. 1999;9:99-102. 64. Stockberger SM, Johnson MS. Spiral CT cholangiography in complex bile duct injuries after laparoscopic cholecystectomy. J Vasc Interv Radiol. 1997;8:249-252. 65. Costamagna G, Pandolfi M, Mutignani M, et al. Long-term results of endoscopic management of postoperative bile duct strictures with increasing numbers of stents. Gastrointest Endosc. 2001;54:162-168. 66. Taylor AC, Little AF, Hennessy OF, et al. Prospective assessment of magnetic resonance cholangiopancreatography for noninvasive imaging of the biliary tree. Gastrointest Endosc. 2002;55:17-22. 67. Chaudhary A, Negi SS, Puri SK, et al. Comparison of magnetic resonance cholangiography and percutaneous transhepatic cholangiography in the evaluation of bile duct strictures after cholecystectomy. Br J Surg. 2002;89:433-436. 68. Yeh TS, Jan YY, Tseng JH, et al. Value of magnetic resonance cholangiopancreatography in demonstrating major bile duct injuries following laparoscopic cholecystectomy. Br J Surg. 1999;86:181-184. 69. Llach J, Bordas JM, Elizalde JI, et al. Sphincterotomy in the treatment of biliary leakage. Hepatogastroenterology. 2002;49:1496-1498.
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70. Bjorkman DJ, Carr-Locke DL, Lichtenstein DR, et al. Postsurgical bile leaks: endoscopic obliteration of the transpapillary pressure gradient is enough. Am J Gastroenterol. 1995;90:2128-2133. 71. Morelli J, Mulcahy HE, Willner IR, et al. Endoscopic treatment of post-liver transplantation biliary leaks with stent placement across the leak site. Gastrointest Endosc. 2001;54:471-475. 72. Marks JM, Ponsky JL, Shillingstad RB, et al. Biliary stenting is more effective than sphincterotomy in the resolution of biliary leaks. Surg Endosc. 1998;12:327-330. 73. Al-Karawi MA, Sanai FM. Endoscopic management of bile duct injuries in 107 patients: experience of a Saudi referral center. Hepatogastroenterology. 2002;49:12011207. 74. Neidich R, Soper N, Edmundowicz S, et al. Endoscopic management of bile leaks after attempted laparoscopic cholecystectomy. Surg Laparosc Endosc. 1996:6:348354. 75. Sherman S, Jamidar P, Shaked A, et al. Biliary tract complications after orthotopic liver transplantation. Endoscopic approach to diagnosis and therapy. Transplantation. 1995;60:467-470. 76. Kozarek RA, Ball TJ, Patterson DJ, et al. Endoscopic treatment of biliary injury in the era of laparoscopic cholecystectomy. Gastrointest Endosc. 1994;40:10-16. 77. Ponchon T, Gallez JF, Valette PJ, et al. Endoscopic treatment of biliary tract fistulas. Gastrointest Endosc. 1989;35:490-498. 78. Goodwin SC, Bittner CA, Patel MC, et al. Technique for reduction of bile peritonitis after T-tube removal in liver transplant patients. J Vasc Interv Radiol. 1998;9:986990. 79. Brodsky JA, Marks JM, Malm JA, et al. Sphincter of Oddi injection with botulinum toxin is as effective as endobiliary stent in resolving cystic duct leaks in a canine model. Gastrointest Endosc. 2002;56:849-851. 80. Seewald S, Groth S, Sriram PVJ, et al. Endoscopic treatment of biliary leakage with n-butyl-2-cyanoacrylate. Gastrointest Endosc. 2002;56:916-919. 81. Ernst O, Sergent G, Mizrahi D, et al. Biliary leaks: treatment by means of percutaneous transhepatic biliary drainage. Radiology. 1999;211:345-348. 82. Bergman JJ, van den Brink GR, Rauws EA, et al. Treatment of bile duct lesions after laparoscopic cholecystectomy. Gut. 1996;38:141-147. 83. Thuluvath PJ, Atassi T, Lee J. An endoscopic approach to biliary complications following orthotopic liver transplantation. Liver International. 2003;23:156-162. 84. Bauer TW, Morris JB, Lowenstein A, et al. The consequences of major bile duct injury during laparoscopic cholecystectomy. J Gastrointest Surg. 1998;2:61-66. 85. Bergman JJ, Burgemeister L, Bruno MJ, et al. Long-term follow-up after biliary stent placement for postoperative bile duct stenosis. Gastrointest Endosc. 2001;54:154-161. 86. Morelli J, Mulcahy HE, Willner IR, et al. Long-term outcomes for patients with post-liver transplant anastomotic biliary strictures treated by endoscopic stent placement. Gastrointest Endosc. 2003;58:374-379. 87. Draganov P, Hoffman B, Marsh W, et al. Long-term outcome in patients with benign biliary strictures treated endoscopically with multiple stents. Gastrointest Endosc. 2002;55:680-686. 88. Verstandig AG, Goldin E, Sasson T, et al. Combined transhepatic and endoscopic procedures in the biliary system. Postgrad Med J. 1993;69:384-388.
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89. Kim JH, Lee SK, Kim MH, et al. Percutaneous transhepatic cholangioscopic treatment of patients with benign bilio-enteric anastomotic strictures. Gastrointest Endosc. 2003;58:733-738. 90. Roumilhac D, Poyet G, Sergent G, et al. Long-term results of percutaneous management for anastomotic biliary stricture after orthotopic liver transplantation. Liver Transpl. 2003;9:394-400. 91. Schmets L, Delhaye M, Azar C, et al. Postradiotherapy benign biliary stricture: successful treatment by self-expandable metallic stent. Gastrointest Endosc. 1996;43:149152. 92. Tesdal IK, Adamus R, Poeckler C, et al. Therapy for biliary stenoses and occlusions with use of three different metallic stents: single-center experience. J Vasc Interv Radiol. 1997;8:869-879. 93. Ginsberg G, Cope C, Shah JN, et al. In vivo evaluation of a new bioabsorbable selfexpanding biliary stent. Gastrointest Endosc. 2003;58:777-784. 94. Mallery S, Matlock J, Freeman ML. EUS-guided rendezvous drainage of obstructed biliary and pancreatic ducts: report of 6 cases. Gastrointest Endosc. 2004;59:100107. 95. Bauer TW, Morris JB, Lowenstein A, et al. The consequences of a major bile duct injury during laparoscopic cholecystectomy. J Gastrointest Surg. 1998;2:61-66. 96. Leggett P, Atwa H, Hamat H. Use of endoscopic retrograde cholangiopancreatography to dislodge clip impingement on the common hepatic duct. Surg Endosc. 2001;15:1490. 97. Nordin A, Halme L, Makisalo H, et al. Management and outcome of major bile duct injuries after laparoscopic cholecystectomy: from therapeutic endoscopy to liver transplantation. Liver Transpl. 2002;8:1036-1043. 98. Hirota WK, Petersen K, Baron TH, et al. Guidelines for antibiotic prophylaxis for GI endoscopy. Gastrointest Endosc. 2003;58:475-482.
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5
Ampullary Disorders William B. Silverman, MD, FACG
Introduction Ampullary disorders of the major papilla of Vater are twofold: the first being problems of the sphincter itself (sphincter of Oddi dysfunction) and the second concerning disorders of the mucosa around the major papilla (ampullary dysplasia). These will be discussed in this chapter.
Sphincter of Oddi Dysfunction Sphincter of Oddi dysfunction has been described by Geenen and colleagues1. It is thought to cause outflow obstruction of either the biliary and/or pancreatic ductal system, leading to symptoms of abdominal pain, nausea, and vomiting as well as signs (elevated hepatic enzymes, elevated amylase or lipase, dilated bile duct and/or pancreas ductal systems). It has been most often described in the post-cholecystectomy situation, hence the name “post-cholecystectomy syndrome”. The underlying pathophysiology is thought to be related to sphincter muscle dysfunction, resulting in increased sphincter muscle tone, failure of the sphincter to relax, or fibrosis either in the muscle or in the region of the muscle resulting in a fixed outlet obstruction. Causes for this problem are not known with certainty. The passage of occult biliary lithiasis may also be involved.
DIAGNOSIS Sphincter of Oddi dysfunction may be categorized as either biliary or pancreatic, depending on the patient’s symptoms and serum and radiographic imaging study abnormalities. Most investigative work has involved the biliary system. More recently, studies investigating the pancreatic portion of this disorder have been described.
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Table 5-1
CLASSIC CRITERIA FOR BILIARY SPHINCTER OF ODDI DYSFUNCTION SOD TYPE Pain
Abnormal Hepatic Enzymes on 2 Occasions
Dilated CBD
Delayed Drainage >45 min
I II III
+ + -
+ or + -
+ or + -
+ + +
SOD = sphincter of Oddi dysfunction; CBD = common bile duct
MILWAUKEE CLASSIFICATION—BILIARY Criteria used in the classic Milwaukee classification (Table 5-1) include suggestive abdominal pain that is episodic, lasting 45 minutes to several hours, and is located in the epigastrium and right upper quadrant. There may be elevated hepatic enzymes >2 times the upper limit of normal on more than one occasion, a dilated biliary ductal system, and delay in drainage of contrast from the biliary ductal system immediately after a retrograde cholangiogram. Presence of all of these factors constitutes Type I biliary sphincter of Oddi dysfunction. This is believed to be due to fibrosis at the level of the sphincter muscle, resulting in a fixed obstruction. Presence of suggestive pain plus elevated serum liver test or dilated biliary ducts or delay in contrast after retrograde cholangiogram constitutes sphincter of Oddi dysfunction Type II, believed to be a functional obstruction at the level of the muscle resulting from sphincter spasm. Presence of suggestive abdominal pain in the absence of either radiographic or serum blood test abnormalities would be consistent with Type III biliary sphincter of Oddi dysfunction. The criteria for biliary sphincter of Oddi dysfunction have been relaxed somewhat in recent years by clinical investigators. The reasons for this are mostly pragmatic. Rather than having elevated serum liver numbers on two occasions, one occasion is frequently considered satisfactory. Likewise, hepatic enzyme elevation greater than two times the upper limit of normal has been relaxed to 1½ times the upper limit of normal or simply any elevation at all would be considered adequate for the distinction between sphincter of Oddi dysfunction Type II versus Type III. Finally, the criteria of “delay in contrast after retrograde cholangiogram” has been largely abandoned. The distinction between classic and contemporary criteria for sphincter of Oddi dysfunction has been well summarized in a recent review by Petersen 2 .
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Table 5-2
CLASSIC CRITERIA FOR PANCREATIC SPHINCTER OF ODDI SOD
Pain
Abnormal Pancreas Dilated Delayed Drainage Enzymes on 2 PD >8 min Occasions
I II III
+ + +
+ + -
+ or + -
+ or + -
SOD = sphincter of Oddi dysfunction; PD = pancreas duct
PANCREATIC SPHINCTER OF ODDI DYSFUNCTION The classification is similar to that used in biliary disorders (Table 5-2). There have been fewer investigations in this area relative to biliary dyskinesia. Patients typically present with clinical pancreatitis. It is important to exclude other causes of pancreatitis, including gallstones, tumors, medications, viruses, pancreas divisum, and inherited disorders (familial pancreatitis, cystic fibrosis, celiac disease, hypertriglyceridemia, etc).
DIAGNOSTIC TESTING FOR SPHINCTER OF ODDI DYSFUNCTION Patients with pain suggestive of a pancreaticobiliary origin plus putative serum laboratory or radiographic abnormalities (dilated biliary or pancreatic ductal system in the absence of obstructing mass lesion) are often evaluated for sphincter of Oddi dysfunction. The Milwaukee criteria mentioned above are used for initial screening. Older, noninvasive provocation tests (morphine-prostigmine test) were described by Nardi and Acosta 3. Elevated serum liver numbers accompanied by typical symptoms after this test were considered diagnostic of biliary sphincter of Oddi dysfunction. Unfortunately, the test was poorly tolerated by patients and was later abandoned in favor of other tests, notably sphincter of Oddi manometry. Sphincter of Oddi manometry with ERCP is considered the current gold standard for the diagnosis of sphincter of Oddi dysfunction. Sphincter of Oddi manometry, as currently practiced, employs a triple lumen perfusion catheter placed into the lumen of the sphincter of Oddi. It is performed during the same session as ERCP, although it was customarily performed during a separate session years ago. Basal sphincter pressure, phasic sphincter pressure, frequency of contractions, duration of contractions, and the determination of antegrade/simultaneous/retrograde contractions within the perfused catheters are the classic diagnostic criteria measured. Most contemporary investigators use only basal sphincter pressure to diagnose sphincter of Oddi dysfunction. Depending on the technique used, either three or two perfusion catheter channels can be used to measure pressure. If two leads are used, the third catheter channel is used to aspirate perfused fluid, to prevent overfilling of the pancreatic ductal
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system. The aspiration technique, described by investigators in Indiana, has resulted in a statistically significant reduction in ERCP/Sphincter of Oddi manometry related pancreatitis rates compared to nonaspiration methods. Validation of sphincter of Oddi manometry in predicting clinical improvement after endoscopic sphincterotomy has been published by Geenen and colleagues in a well-designed prospective randomized control trial. Elevated basal sphincter pressure greater than 40 mm Hg, relative to duodenal pressure, was shown to be the most useful predictor of relief of symptoms after biliary sphincterotomy in patients with biliary sphincter of Oddi dysfunction Type II. Because the majority of patients with sphincter of Oddi dysfunction Type I will have elevated basal sphincter pressure on manometry, the clinical utility of performing this extra test during ERCP test for Type I patients has been questioned. Most investigators do empiric endoscopic sphincterotomy without the manometry. As noted in a recent review article, supportive data for this traditional practice are lacking. Contemporary interpretation of biliary and pancreatic sphincter of Oddi manometry involves determination of basal sphincter pressure alone. The other criteria (phasic or peaks sphincter pressures, frequency of contractions, duration of contractions, or the determination of retrograde contractions) have been largely abandoned both in clinical and research arenas. Abnormalities of these latter criteria due to physiologic phenomena such as migrating motor complex have been suggested by others. Delay in ductal drainage at the time of ERCP has been found to occur in patients without manometric criteria for sphincter of Oddi dysfunction. Given the risks inherent in ERCP/manometry, as well as the equivocal benefits to many patients, the development of a noninvasive screening test for patients with potential sphincter of Oddi would be desirable. Two tests done include provocative pancreatic or biliary ultrasound testing or provocative biliary cholescintigraphy. Correlation with the current gold standard (sphincter of Oddi manometry), however, has been disappointing. Hence, while these noninvasive provocative tests may be well tolerated, their clinical utility may be suboptimal.
DIFFERENTIAL DIAGNOSIS OF SPHINCTER OF ODDI DYSFUNCTION The symptoms and signs seen with sphincter of Oddi dysfunction are seen in other diseases as well. It is important to exclude these other entities. In the setting of sphincter of Oddi Type I, fixed obstruction due to tumor involving the ampulla of Vater, pancreatic head, or biliary ductal system needs to be excluded. Occult biliary lithiasis or microlithiasis would cause biliary or pancreatic ductal system dilation with fluctuating elevations in either biliary or pancreatic serum liver tests and would present in a similar manner as sphincter of Oddi Type II. Idiopathic pancreatitis may be due to pancreatic sphincter of Oddi dysfunction or may be a separate entity unrelated to the sphincter of Oddi dysfunction. Chronic pancreatitis, unrelated to the sphincter of Oddi, may present with abdominal pain and fluctuations in serum amylase or lipase. Whether sphincter of Oddi dysfunction occurs in the setting of chronic pancreatitis remains controversial. More controversial still is whether elevated pancreatic basal sphincter pressures in chronic pancreatitis are a cause of that entity or an epi-phenomenon resulting from it. Most frustrating is the evaluation and management of biliary and pancreatic sphincter of Oddi dysfunction Type III. In this entity, patients present with “sugges-
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tive” biliary or pancreatic symptoms. Even the most seasoned senior clinician would admit difficulty implicating a pancreaticobiliary etiology of abdominal pain, to the exclusion of all other potential etiologies, in this situation. The coexistence of gut motility disorders in this entity has been shown. Equally so, coexistence of luminal gut barostatic abnormalities has been demonstrated. Additional disease processes to exclude in the setting of abdominal pain with normal serum testing and radiographic testing include peptic ulcer disease, coronary artery disease, musculoskeletal related pain, gut ischemia, and somatization disorders. The list is long. A careful, methodical approach is key here.
TREATMENT OF SPHINCTER OF ODDI DYSFUNCTION In patients with Type I sphincter of Oddi dysfunction, after excluding ductal obstruction due to mass lesions, ERCP with biliary or pancreatic endoscopic sphincterotomy would be the treatment of choice. Addition of sphincter of Oddi manometry in this setting is not commonly done. Biliary or pancreatic sphincter of Oddi dysfunction Type II and III normally requires the addition of sphincter of Oddi manometry to ERCP to measure ductal basal sphincter pressure. Empiric sphincterotomy in the absence of confirmatory sphincter of Oddi manometry abnormality for SOD II has been suggested by some, but is to be discouraged based on a recent consensus conference conclusion. Traditionally, biliary sphincterotomy alone, which also ablates the common sphincter segment, has been the treatment of choice in treating both biliary and pancreatic SOD II and III. Pancreatic sphincterotomy was believed to be hazardous. Dual (biliary and pancreatic) sphincterotomy has been advocated when there is manometric confirmation of pancreatic sphincter hypertension. This is based on the observation that many patients with pancreatic sphincter hypertension who are treated with “biliary only” sphincterotomy will require repeat ERCP with pancreatic sphincterotomy for persistent symptoms 4. As manometry and sphincterotomy of the pancreatic duct are associated with an increased rate of ERCP related complications, these should be reserved for centers that offer expertise in these procedures. Sphincter of Oddi dysfunction Type III, with its “suggestive” pain but absence of serum or radiographic testing abnormalities, continues to remain both the most frustrating to treat and the most controversial category of sphincter of Oddi dysfunction. Whether the symptoms described by the patient are, in fact, due to abnormalities at the level of the sphincter of Oddi, or whether they are functional and related to other portions of the gut (irritable bowel syndrome variant) has been suggested. Empiric trials of medications such as anticolon tricyclic antidepressants and sphincter relaxing medicines such as nitrates and calcium channel blockers prior to consideration of ERCP with sphincter of Oddi manometry have been advocated, as the rate of complications from ERCP may exceed the benefit in this setting. Improvement in symptoms after endoscopic sphincterotomy varies widely from 30% to 80%, depending upon whether the patient has type I, II, or III SOD and whether there is biliary and/or pancreatic sphincter involvement. Interpretation of positive results is hampered by both small study sample size and a lack of standardization regarding outcomes. In general, patients with Type I SOD respond better to sphincter ablation than do Type II patients. Type III SOD patients tend to respond the least well.
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COMPLICATIONS OF TREATMENT Complications of sphincter of Oddi manometry and endoscopic treatment of patients with sphincter of Oddi dysfunction are largely related to those inherent to the ERCP procedure, rather than being unique to the manometry, and include pancreatitis (5% to 30%), perforation (40%, with median survival ranging from 9 to 30 months26. Distal extrahepatic cholangiocarcinomas are treated with pancreatoduodenectomy. Negative resection margins in distal cholangiocarcinomas are achieved in up to 40% of patients. Five-year survival rates are 20 to 30% after successful surgical resection, slightly better than that found with resected hilar tumors 4,27. The surgery performed for hilar cholangiocarcinoma is based on the extent of disease or Bismuth classification. Tumors that are below the confluence of the right and left hepatic ducts or only reach the confluence (Bismuth Types I and II, respectively) are treated with resection of the extrahepatic bile ducts with at least 5 mm diseasefree margins, a regional lymphadenectomy, and then reconnected with a Roux-en-Y hepaticojejunostomy. Treatment of Bismuth Type III cholangiocarcinomas where the tumor involves the common hepatic duct and either the right or left hepatic ductal systems are now routinely treated in tertiary care centers with hepatic lobe resection in addition to the removal of the extrahepatic bile ducts and a lymphadenectomy. More aggressive surgery with hepatic lobectomy has led to an increased percentage of patients who have negative resection margins, which in turn results in a significantly improved median survival rate, with 3-year survival as high as 70% 24,28. Resection of the caudate lobe
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in any tumor that involves the confluence is also becoming more routine and improves the rate of margin-negative resections25. Surgeons in Asia and now increasingly in the West are becoming more aggressive with Type IV hilar cholangiocarcinomas and with local vascular invasion by performing lobectomy in association with resection of the portal vein and hepatic artery. These latter methods remain controversial because of the potential increased immediate surgical morbidity and mortality but most studies demonstrate an increased number of patients who have successful complete resections and a resultant improved patient survival rate when these surgical techniques are used. Orthotopic liver transplantation has traditionally been thought to be contraindicated in the treatment of cholangiocarcinoma due to the high rate of recurrence and very poor survival rate. However, small studies have shown that selected patients with early stage locally nonresectable cholangiocarcinomas can achieve acceptable 5-year survival rates29,30. These patients are generally treated with pretransplant neoadjuvant chemotherapy and radiation. With a limited number of organs available for transplantation, patient selection is crucial prior to transplanting patients for cholangiocarcinomas. Patients who are young, have early stage disease, and possibly patients with PSC are the groups of patients with the most potential benefit found with liver transplantation.
CHEMOTHERAPY AND R ADIATION No randomized controlled studies have demonstrated a definitive survival benefit with the addition of adjuvant treatment to surgery for cholangiocarcinoma—either radiation, chemotherapy, or their combined use. However, half of all cholangiocarcinomas have lymph node metastases at the time of diagnosis and locoregional recurrence is common postsurgical resection, suggesting a potential benefit of adjuvant therapy4,31. Though results are mixed, a number of retrospective uncontrolled studies have shown a benefit with adjuvant radiation or chemoradiotherapy in incompletely resected tumors or patients with microscopic positive margins at surgery. Radiation therapy in particular is usually offered for macro- or microscopic disease after surgery in fit patients. Data and benefit of adjuvant treatment in patients with completely resected cholangiocarcinoma is even less clear. In patients with completely resected tumors, studies examining radiation and chemotherapy have failed to show a clear survival advantage32,33. Due to insufficient proof of its efficacy, adjuvant therapy in the setting of completely resected cholangiocarcinoma should be given on an individual case-to-case basis and preferably in the setting of a clinical trial. Standard external beam radiation for locally advanced cholangiocarcinoma not amenable to surgical treatment and recurrent cholangiocarcinoma has not been shown to prolong survival or improve quality of life. External radiation has been shown to play an important palliative role in localized painful metastases, bleeding from the primary tumor, and biliary decompression4,8. Benefits, including survival benefits, have been reported in a few smaller studies with conformal radiation, intraductal brachytherapy, and transcatheter irradiation in conjunction with chemotherapy and external beam radiation34,35. Further studies are needed to verify these findings. The literature in addition has not shown consistent improved survival and outcome with systemic chemotherapy for nonresectable cholangiocarcinoma. Partial responses
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have been shown with multiple different medications, with the most experience being with 5-Fluorouracil (5-FU) based treatments. Difficulty with chemotherapy is that recurrence is usually locoregional rather than distant. Also, there are no adequate radiographic markers of disease progression and recurrence in cholangiocarcinoma to document response to or failure of therapy. Five-FU based treatment strategies usually have partial responses in approximately 20% of patients. Newer agents, particularly gemcitabine alone or in combination with cisplatin have increased partial response rates to 30% to 50%, with small increases in the median time to tumor progression4,35. Consistently the most important predictor of response to chemotherapy is performance status at the time of initiation of treatment. High performance status translates into an increased chance of responding to chemotherapy and more importantly a significant improvement in quality of life with chemotherapy, which is the major goal in the treatment of nonresectable cholangiocarcinoma. Again, the need to enroll patients with advanced cholangiocarcinoma in clinical trials involving newer chemotherapeutic agents or combinations is crucial.
PALLIATION Palliation of cholangiocarcinoma primarily means decompressing the bile duct to relieve jaundice and sometimes pruritis. Modalities available are surgical bypass of the biliary tree or through placement of biliary stents via an endoscopic or percutaneous method. Comparison of surgical versus stent therapy has found no significant differences in overall survival or clinical success rates but a significantly increased procedure-related morbidity and mortality has been demonstrated with surgery 36. Thus biliary stenting is the recommended treatment for relief of jaundice in cholangiocarcinoma over surgery except in cases when stenting fails or occasionally when expected survival is thought to be for greater than 1 year. The percutaneous route for stenting is more invasive with the need for at least initial external drainage as compared to endoscopic stenting. Endoscopic placement of stents should be the primary mode of palliating cholangiocarcinoma with percutaneous stenting reserved for endoscopic failures and in cases in which on prestenting imaging it is evident that the tumor extends proximally into the liver and will not be able to be stented retrogradely via the endoscope. For distal cholangiocarcinoma, the stent type and delivery method of choice is a covered or uncovered self-expandable metal stent (SEMS) placed via the ERCP scope. Metal stents have been shown to have a high rate of relief of jaundice and have a median duration of patency at least twice that of plastic stents37. Metal stents in addition require fewer needs for reintervention and result in fewer episodes of cholangitis. More controversy exists with proximal complicated hilar tumors because of the increased difficulty in stenting these types of strictures. For hilar tumors, MRCP is recommended prior to ERCP placement of stents to guide the endoscopist in the placement of the stent (Figure 6-4). MRCP can indicate the exact location of the strictures and proximal areas of dilation to target stent placement. This allows safe stent placement into the proper lobe/segment of the liver while minimizing the chance of cholangitis38. As with distal cholangiocarcinoma, placement of SEMS (uncovered) are preferred in hilar tumors, particularly in patients who will survive 6 months or longer. SEMS decrease costs overall to the patient, and lead to fewer recurrent hospitalizations10.
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Chapter 6 Figure 6-4A. Series of cholangiograms demonstrating the placement of a self-expanding metal stent (SEMS) in a patient with an unresectable hilar cholangiocarcinoma. Preprocedure imaging showed a hilar tumor with more pronounced dilation of the right hepatic system. Using the pre-ERC imaging as a guide, a wire was placed into the right hepatic ducts.
Figure 6-4B. A catheter was then
advanced over the wire and a cholangiogram was obtained of the selected right ductal system.
Figure 6-4C. Finally, a self-expanding
metal stent was placed across the strictured hilar tumor with drainage of the right system and subsequent resolution of the patient’s jaundice.
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The necessity to drain both sides of the liver in patients with Type IV hilar tumors by stenting bilaterally is unclear. Recent data shows that unilateral stenting into the easiest segment to access will relieve jaundice in greater than 85% of patients with minimal complications39. However, a small but not insignificant number of patients will need bilateral stent placement, which can usually be accomplished with ERC and SEMS. Thus for hilar cholangiocarcinoma, palliation of jaundice is adequately achieved and maintained in most but not all cases with unilateral stenting and preferably with metallic stents to prolong patency. Photodynamic therapy (PDT) for palliation in cholangiocarcinoma is a more recent option available to aid in biliary decompression. PDT works by providing the patient with a photosensitizer, usually hematoporphyrin, that becomes concentrated in the tumor. Light is then applied via a laser probe passed through the endoscope directly within the tumor. This has been shown to aid in relief of jaundice, and in early studies, to provide a survival benefit over just biliary stenting alone40.
Conclusion Overall survival for cholangiocarcinoma remains poor, with 5-year survival occurring in just 10% of patients22 . However, tremendous strides have been made in the surgical techniques and approach to cholangiocarcinoma with more aggressive techniques, including hepatic resection. This in recent reports has increased 5-year survival to as high as 20% to 50%14,25,41,42 . Thus, future efforts in the treatment of cholangiocarcinoma should be directed at increasing the number of patients who can undergo resection and even more importantly curative resection. This begins with improving and developing better screening methods for cholangiocarcinoma, particularly for patients with primary sclerosing cholangitis. Continued and improved advancement in imaging is needed to better determine who is a potential candidate for resection prior to surgery. With regard to surgery itself, the surgical techniques more recently being employed need to be further tested, tried, and applied to better determine if more aggressive surgical techniques do lead to better outcomes. More studies need to be performed with the use of adjuvant and neoadjuvant therapy to determine if outcomes in patients with both curative and noncurative surgery can be improved. Finally, a huge percentage of patients cannot undergo surgery and life expectancy is usually less than 1 year. Improvement and studies in the palliative care of cholangiocarcinoma is crucial, with better radiochemotherapy programs and more novel treatments such as biliary PDT being investigated and put into clinical use. When progress is made in all of these areas, we can hope to finally improve outcomes in the overall treatment of cholangiocarcinoma.
References 1. Callery MR, Meyers WC. Bile duct cancer. In: Cameron JL, ed. Current Surgical Therapy. 6th ed. Baltimore, Md: Mosby; 1998: 455-461. 2. Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology. 2001;33:1353-1357. 3. Tajima Y, Kuroki T, Fukuda K, et al. An intraductal papillary component is associated with prolonged survival after hepatic resection for intrahepatic cholangiocarcinoma. Br J Surg. 2004;91: 99-104.
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4. Khan SA, Davidson BR, Goldin R, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: consensus document. Gut. 2002;51(Suppl 6):VI1-VI9. 5. Bismuth H, Castaing D. Hepatobiliary Malignancy. London: Edward Arnold; 1994. 6. Gores GJ. Cholangiocarcinoma: current concepts and insights. Hepatology. 2003;37: 961-969. 7. Burak K, Angulo P, Pasha TM, et al. Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis patients. Am J Gastroenterol. 2004;99:523526. 8. De Groen PC, Gores GJ, LaRusso NF, et al. Biliary tract cancers. N Engl J Med. 1999;341:1368-1378. 9. Sorensen HT, Friis S, Olsen JH, et al. Risk of liver and other types of cancer in patients with cirrhosis: a nationwide cohort study in Denmark. Hepatology. 1998;28:921-925. 10. Nichols JC, Gores GJ, LaRusso NF, et al. Diagnostic role of serum CA 19-9 in patients with primary sclerosing cholangitis. Mayo Clin Proc. 1993;68:874-879. 11. Ramage JK, Donaghy A, Farrant JM, et al. Serum tumor markers for the diagnosis of cholangiocarcinoma in primary sclerosing cholangitis. Gastroenterology. 1995;108:865-869. 12. Yeh TS, Jan YY, Tseng JH, et al. Malignant perihilar biliary obstruction: magnetic resonance cholangiopancreatographic findings. Am J Gastroenterol. 2000;95:432440. 13. Strasberg SM. ERCP and surgical intervention in pancreatic and biliary malignancies. Gastrointest Endosc. 2002;56(Suppl):S213-S217. 14. Su CH, Tsay SH, Wu CC, et al. Factors influencing postoperative morbidity, mortality, and survival after resection for hilar cholangiocarcinoma. Ann Surg. 1996;223:384-394. 15. Hawes RH. Diagnostic and therapeutic uses of ERCP in pancreatic and biliary tract malignancies. Gastrointest Endosc. 2002;56(Suppl):S201-S205. 16. Jailwala J, Fogel EL, Sherman S, et al. Triple-tissue sampling at ERCP in malignant biliary obstruction. Gastrointest Endosc. 2000;51:383-390. 17. Ponchon T, Gagnon P, Berger F, et al. Value of endobiliary brush cytology and biopsies for the diagnosis of malignant bile duct stenosis: results of a prospective study. Gastrointest Endosc. 1995;42:565-572. 18. Keiding S, Hansen SB, Rasmussen HH, et al. Detection of cholangiocarcinoma in primary sclerosing cholangitis by positron emission tomography. Hepatology. 1998;28:700-706. 19. Fritscher-Ravens A, Bohuslavizki KH, Broering DC, et al. FDG-PET in the diagnosis of hilar cholangiocarcinoma. Nucl Med Commun. 2001;22:1277-1285. 20. Kluge R, Schmidt F, Caca K, et al. Positron emission tomography with [(18)F]fluoro2-deoxy-D-glucosefor diagnosis and staging of bile duct cancer. Hepatology. 2001;33:1029-1035. 21. Fritscher-Ravens A, Broering DC, Knoefel WT, et al. EUS-guided fine-needle aspiration of suspected hilar cholangiocarcinoma in potentially operative patients with negative brush cytology. Am J Gastroenterol. 2004;99:45-51. 22. Eloubeidi MA, Chen VK, Jhala NC, et al. Endoscopic ultrasound-guided fine needle aspiration biopsy of suspected cholangiocarcinoma. Clin Gastroenterol Hepatol. 2004; 2:209-213.
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23. Gores GJ. Early detection and treatment of cholangiocarcinoma. Liver Transpl. 2000; 6(Suppl2):S30-S34. 24. Tsao JI, Nimura Y, Kamiya J, et al. Management of hilar cholangiocarcinoma: comparison of an American and a Japanese experience. Ann Surg. 2000;232:166-174. 25. Burke EC, Jarnagin WR, Hochwald SN, et al. Hilar cholangiocarcinoma: patterns of spread, the importance of hepatic resection for curative operation, and a presurgical clinical staging system. Ann Surg. 1998;228:385-394. 26. Shirabe K, Shimada M, Harimoto N, et al. Intrahepatic cholangiocarcinoma: its mode of spreading and therapeutic modalities. Surgery. 2002;131(1 Suppl):S159S164. 27. Nakeeb A, Pitt HA, Sohn TA, et al. Cholangiocarcinoma: a spectrum of intrahepatic, perihilar, and distal tumors. Ann Surg. 1996;224:463-475. 28. Nakeeb A, Tran KQ, Black MJ, et al. Improved survival in biliary malignancies. Surgery. 2002;132:555-563. 29. Sudan D, DeRoover A, Chinnakotla S, et al. Radiochemotherapy and transplantation allow long-term survival for nonresectable hilar cholangiocarcinoma. Am J Transplant. 2002;2:774-779. 30. De Vreede I, Steers JL, Burch PA, et al. Prolonged disease-free survival after orthotopic liver transplantation plus adjuvant chemoirradiation for cholangiocarcinoma. Liver Transpl. 2001;7:1023-1033. 31. Jarnagin WR, Ruo L, Little SA, et al. Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies. Cancer. 2003;98:1689-1700. 32. Pitt HA, Nakeeb A, Abrams RA, et al. Peri-hilar cholangiocarcinoma: postoperative radiation therapy does not improve survival. Ann Surg. 1995;221:788-798. 33. Takada T, Amano H, Yasuda H, et al. Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreatobiliary carcinoma. Cancer. 2002;95:16851695. 34. Foo ML, Gunderson LL, Bender CE, et al. External radiation therapy and transcatheter iridium in the treatment of extrahepatic bile duct carcinoma. Int J Radiat Oncol Biol Phys. 1997;39:929-935. 35. Hejna M, Pruckmayer M, Raderer M. The role of chemotherapy and radiation in the management of biliary cancer: a review of the literature. Eur J Cancer. 1998;34:977986. 36. Smith AC, Dowsett JF, Russell RC, et al. Randomized trial of endoscopic stenting versus surgical bypass in malignant low bile duct obstruction. Lancet. 1994;344:16551660. 37. Flamm CR, Mark DH, Aronson N. Evidence based assessment of ERCP approaches to managing pancreatobiliary malignancies. Gastrointest Endosc. 2002;56(Suppl): S218-S225. 38. Freeman ML, Overby C. Selective MRCP and CT-targeted drainage of malignant hilar biliary obstruction with self-expanding metal stents. Gastrointest Endosc. 2003;58:41-49. 39. DePalma GD, Galloro G, Siciliano S, et al. Unilateral versus bilateral endoscopic hepatic duct drainage in patients with malignant hilar biliary obstruction: results of a prospective, randomized, and controlled study. Gastrointest Endosc. 2001;53:547553.
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40. Ortner MA, Liebetruth J, Schreiber S, et al. Photodynamic therapy of nonresectable cholangiocarcinoma. Gastroenterology. 1998;114:536-542. 41. Miyazaki M, Ito H, Nakagawa K, et al. Aggressive surgical approaches to hilar cholangiocarcinoma: hepatic or local resection? Surgery. 1998;123:131-136. 42. Kosuge T, Yamamoto J, Shimada K, et al. Improved surgical results for hilar cholangiocarcinoma with procedures including major hepatic resection. Ann Surg. 1991;230:663-671.
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7
Infections of the Biliary System Faten N. Aberra, MD, MSCE
Introduction Infections affecting the biliary tree are as vast and include bacteria, viral, and parasitic infections. This chapter will provide information on the etiology, pathogenesis, clinical presentation, diagnostic testing, and treatment of the various infectious syndromes and organisms that affect the biliary system (Table 7-1).
Acute Cholecystitis Acute cholecystitis is inflammation of the gallbladder. There are two major types of acute cholecystitis—calculous and acalculous.
ACUTE CALCULOUS CHOLECYSTITIS Etiology and Pathophysiology In calculous cholecystitis, which makes up over 90% of cholecystitis cases, gallstones obstruct the gallbladder outlet leading to poor drainage of bile1, 2 . The blockage of bile drainage leads to increased intraluminal gallbladder pressure, gallbladder distention, and supersaturated cholesterol bile acids, triggering an inflammatory reaction leading to gallbladder wall edema1. Prostaglandin E2 and I2 have been shown to mediate the inflammatory response3. Venous and lymphatic obstruction may develop, as well as ischemia and necrosis of the gallbladder. In the early stages of cholecystitis, bile is sterile, but later in the process infection occurs. The most common organisms cultured from bile are Escherichia coli, Klebsiella, and Enterococcus 2 . Complications of acute calculous cholecystitis occur in 2% to 30% of patients and include gallbladder perforation, gallbladder gangrene, emphysematous cholecystitis, empyema, and cholecystoenteric fistulas1,2 . Factors associated with a worse prognosis include diabetes, male gender, advanced age, high temperature, and significant leukocytosis4.
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Table 7-1
ORGANISMS INVOLVED IN BILIARY DISEASE Microbial Class
Organism
Clinical Associated Syndrome
Bacteria
Escherichia coli Klebsiella pneumonia and oxytoca Enterococcus faecalis Enterobacter cloacae Proteus Streptococcus Bacteroides fragilis Clostridium perfringins Pseudomonas Staphylococcus epidermis Salmonella Coxiella burnetti Non-01 vibrio cholerae Mycobacterium avium intracellulare
Cholecystitis/cholangitis Cholecystitis/cholangitis
Virus
Cytomegalovirus
Hepatotropic viruses: A, B, C, E Reovirus 3 Rotavirus (groups A and C)
Cholecystitis/cholangitis Cholangitis# Cholangitis Cholangitis Cholangitis Cholangitis Cholangitis# Cholangitis# Acalculous cholecystitis Acalculous cholecystitis Acalculous cholecystitis AIDS related cholangiopathy
Acalculous cholecystitis/AIDS related cholangiopathy/vanishing bile duct syndrome post OLT* Cholestasis Biliary atresia^ Biliary atresia^
Fungi
Candida albicans
Acalculous cholecystitis
Parasites
Ascaris Clonorchis sinensis
Biliary obstruction, cholangitis Cholangitis/recurrent pyogenic cholangitis/cholangiocarcinoma Cholangitis/cholecystitis/ cholangiocarcinoma
Opisthorchis viverrini and felineus
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Table 7-1, continued
Microbial Class
Organism
Clinical Associated Syndrome
Parasites
Fasciola hepatica Echinococcosis granulosus and multilocularis Microsporidia Cryptosporidia Isospora belli
Biliary colic, cholangitis Obstructive jaundice, biliary colic, cholangitis; Budd-Chiari; cirrhosis AIDS-related cholangiopathy AIDS-related cholangiopathy AIDS-related cholangiopathy
# = cholangitis associated with history of biliary procedures *OLT = orthotopic liver transplantation ^ = controversial
Clinical Presentation Patients may have symptoms of upper abdominal pain or right upper quadrant pain associated with fever, nausea, or vomiting 2,5. Studies have shown that mid-epigastric pain occurs as frequently as right upper quadrant pain5. Patients may also complain of pain in the back, right scapula, or right clavicular region 2 . On physical exam, right upper quadrant pain elicited by palpation under the right costal margin when the patient inspires is called Murphy’s sign. In a systematic review of clinical predictors for acute cholecystitis, Murphy’s sign had a sensitivity of 0.65 (95% CI, 0.59-0.71), specificity 0.87 (95% CI, 0.85-0.89), and likelihood ratio positive of 2.8 (95% CI, 0.8-8.6)5. Patients may also have hyperalgesia to light palpation of the infrascapular area or right upper quadrant6. Another sign associated with acute cholecystitis is Boas’ sign, point tenderness in the region to the right of the 10th to 12th thoracic vertebrae 5,7-9. There is yet to be a study assessing the test characteristics for a combination of symptoms and signs.
Diagnostic Tests Leukocytosis (white blood cell count >10,000/mL) may be present, sensitivity 0.63 (95% CI, 0.60-0.67) and specificity 0.57 (95% CI, 0.54-0.59)5. The presence of both leukocytosis and fever based on two studies with a total of 351 patients had a surprisingly low sensitivity of 0.24 (95% CI, 0.21-0.26) and specificity of 0.85 (95% CI, 0.76-0.91)5. Leukocytosis with a left shift may also be present. Ultrasound is an excellent diagnostic test, but it is not perfect for making a diagnosis of cholecystitis with a sensitivity of 88% (95% CI, 74-100%) and specificity of 80% (95% CI, 62-98%)5. Sonographic features of acute cholecystitis are gallblad-
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der wall thickening, pericholecystic fluid, gallbladder distention, and a sonographic Murphy’s sign 2 . Radionuclide scanning has better test characteristics, with sensitivity and specificity greater than 90%, but cannot assess for other biliary or abdominal pathology10-16. A false positive radionuclide scan may occur if the patient has been in a prolonged fasting state, on total parenteral nutrition, or has hepatic impairment. Although somewhat controversial, ultrasound is usually the first diagnostic test completed due to the ease of performing the test by the operator, portability, lower cost, and additional information on abdominal pathology that may be obtained. In patients with a high clinical suspicion of acute cholecystitis and negative ultrasound findings, radionuclide scan is usually the next test completed. Other modalities for radiological diagnosis of acute cholecystitis include computed tomography (CT) and magnetic resonance imagine/magnetic resonance cholangiopancreatography (MRI/MRCP). CT has been found to be inferior to both ultrasound and radionuclide scan for diagnosing acute cholecystitis17, whereas MRI/MRCP with recent improvements and modification of technology has been shown to have excellent test characteristics that equal and even in some studies surpass ultrasound17-20. Due to cost and availability at hospitals, ultrasound is still preferred over MRI/MRCP.
Treatment Initial management of a patient diagnosed with acute calculous cholecystitis is cessation of parenteral nutrition, intravenous fluids, and analgesia. The choice of analgesia is usually a narcotic, meperidine or morphine. Meperidine was recommended in the past due to the belief that there was less spasm and lower pressures of the sphincter of Oddi compared to use with morphine. This belief was recently challenged and it was determined that the substantiation was based on case reports rather than controlled studies21. Antibiotics should be started if a patient has a high fever, tachycardia, hypotension, or there is no clinical improvement after 12 hours. Broad spectrum antibiotics are preferred and anaerobic coverage is usually added to severe cases. Curative treatment for acute calculous cholecystitis is cholecystectomy. Aside from emergent surgery, early or late (usually defined as 6 to 12 weeks) surgery has not been shown to differ in morbidity or mortality and thus early surgery is generally preferred due to decreased hospitalization costs2 . Laparascopic cholecystectomy has become the surgical approach of choice over open cholecystectomy unless there is complicated disease such as gallbladder perforation. For some patients, the risk of surgery outweighs the benefit and percutaneous cholecystostomy is a reasonable option, with a success rate of 75% to 90% reported1,2 . Percutaneous cholecystostomy can be performed at bedside in patients who cannot be moved from the intensive care unit. Once the patient has recovered, elective cholecystectomy should be performed.
ACUTE ACALCULOUS CHOLECYSTITIS Etiology and Pathophysiology In 2% to 12% of cholecystitis cases, gallstones are not found and this is termed acalculous cholecystitis2 . Acute acalculous cholecystitis usually occurs in patients who are severely ill such as septic, trauma, or burn patients2,22,23. Other risk factors for
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acute acalculous cholecystitis include immunosuppression, HIV, lymphoproliferative disorders, prolonged fasting, total parenteral nutrition, acute renal failure, vascular disease, systemic vasculitides, male gender, and extremes of age22,24,25. Perhaps the underlying mechanisms leading to acalculous cholecystitis are ischemia and gallbladder stasis.26 One study revealed that 70% of patients with acalculous cholecystitis had atherosclerotic disease27. Many nonenteric organisms can cause acalculous cholecystitis. Salmonella, Cytomegalovirus, Coxiella burnetii, non-O1 Vibrio cholerae, Ascaris, and Candida albicans are but a few of the nonenteric organisms that may cause cholecystitis along with other systemic disease25,28-38.
Clinical Presentation Patient symptoms are similar to that for acute calculous cholecystitis with the exception that abdominal pain localizing in the right upper quadrant occurs less frequently.
Diagnostic Tests The initial test is usually an ultrasound as in acute calculous cholecystitis. If the results are not conclusive, then radionuclide scan should be considered. Because many patients with acalculous cholecystitis are usually critically ill and have been fasting, radionuclide scanning is completed with a morphine injection to decrease false positive scans39,40.
Treatment Percutaneous cholecystostomy is usually preferred in critically ill patients over cholecystectomy during initial presentation, and later in their hospital course they usually do not need cholecystectomy 2 . Endoscopic biliary drainage in this setting has been assessed but has not been in favor as it offers few advantages over percutaneous drainage41,42 . Treatment is otherwise similar to acute calculous cholecystitis with the exception that acalculous cholecystitis is usually secondary to another disease and the primary disease must be treated. The morbidity and mortality from acute acalculous cholecystitis is higher than in calculous cholecystitis, with mortality usually a result of their underlying disease22 .
Bacterial Cholangitis ETIOLOGY AND PATHOPHYSIOLOGY The term cholangitis is used to describe inflammation of the bile ducts that may be due to noninfectious and infectious causes. Infections affecting the biliary tree are bacterial, viral, and parasitic infections. Patients with bacterial cholangitis often have a history of biliary disease (including prior biliary duct infection), have a median age between 50 and 60 years, and equal gender distribution43-45. Due to the protective barriers of continuous bile flow and sphincter of Oddi protection from intestinal debris, bile is usually sterile46. Biliary obstruction independently does not always lead to cholangitis. The components required for bacterial biliary infections to occur are obstruction of biliary flow and colonization of bacteria.
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Bacterial concentrations in the small bowel increase with lack of bile salts. Bile is believed to have bactericidal properties and with biliary obstruction there is less bile salt, decreased biliary IgA, and increased hypochlorhydria in the small intestine43. Bile salt has been shown in vitro to reduce bacterial migration into enterocytes and perhaps prevent endotoxin translocation43,47. Bacteria may ascend into the common bile duct, or attain access into the biliary tree through the portal vein and lymphatics43. Cholangitis usually ensues when biliary pressures are greater than 15 cm of water48. Complete obstructions are associated with bactibilia in 10% of cases, compared to 64% of partial obstructions49,50. There are numerous causes of biliary obstruction, some of which are iatrogenic. The most common cause of biliary obstruction is choledocholithiasis51. Other causes of biliary obstruction leading to bacterial infection include benign strictures (such as primary sclerosing cholangitis), malignant strictures, ampullary stenosis (benign or malignant), choledochal cysts, sump syndrome, juxtapapillary diverticulum, biliary casts in orthotopic transplant liver recipients, pancreatic tumors, pancreatitis, and parasites 43,46,52 . Juxtapapillary diverticulum may obstruct the sphincter of Oddi by debris trapped in the diverticulum blocking bile exiting the sphincter and also by leading to dysfunction of the sphincter, allowing bacteria to ascend the biliary tree53. Biliary sludge also may contribute to obstruction54. The risk is higher for cholangitis with obstruction from choledocholithiasis than from neoplastic strictures43.
MICROBIOLOGY Bacteria primarily involved in cholangitis originate from the gastrointestinal tract. The bacteria most commonly involved in acute cholangitis are Escherichia coli, Klebsiella, and Enterococcus 53. Other bacteria also isolated are Enterobacter, Proteus, and Streptococcus 55. Bacteroides fragilis is the most common anaerobic organism isolated, followed by Clostridium perfringens, found in up to 15% of appropriately cultured cases43. Aerobes are more commonly isolated but this may be due to poor techniques available in isolating anerobes43. There have also been case reports of Haemophilus influenza causing cholangitis, with many of the cases in association with alcoholism and cancer56. More than one organism is cultured from bile 30% to 87% of the time43. Twenty-one to 83% of patients are bacteremic with 33% to 84% of blood and bile isolates matching43. Iatrogenic causes include endoscopic retrograde cholangiopancreatography (ERCP), surgery, and interventional radiological procedures involving the bile ducts. When biliary stents or drains are placed, bacteria may enter the biliary system due to contamination of the device, ascent of intestinal bacteria into the biliary tree, access through the portal venous system, and migration of skin flora57. Bacteria associated with biliary prosthetics include Pseudomonas, K oxytoca, K pneumoniae, Enterobacter cloacae, S. epidermis, and Enterococcus faecalis 2,57,58.
CLINICAL PRESENTATION Unfortunately, symptoms generally occur once the infection has become systemic and can sometimes be vague. The classic symptoms of bacterial cholangitis are fever, right upper quadrant abdominal pain, and jaundice, also called Charcot’s triad. All three symptoms occur in 50% to 100% of cases2,43,59. Fever is the most common
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symptom, occurring in 95% of cases, with right upper quadrant pain in 90% and jaundice in 80%51,60. If symptoms are not identified early, then sepsis may ensue with symptoms and signs of confusion, lethargy, and hypotension. On rare occasions, symptoms of Charcot’s triad are present in the setting of altered mental status and hypotension; this is termed Reynold’s pentad 2 . Nausea and vomiting occurs in up to 50% of patients45,58. Abdominal pain may not always be located in the right upper quadrant, may not always be present, and on physical exam there may be very few abdominal findings.
DIAGNOSIS Most often the diagnosis of cholangitis can be diagnosed clinically, and laboratory and radiographic studies are supportive. Laboratory results may reveal leukocytosis, hyperbilirubinemia (88% to 100%), elevated alkaline phosphatase (78%), and mild elevations of transaminases, although transaminases of >1000 may occur if biliary pressures acutely rise2,43. Serum amylase may be elevated in up to 30% to 40% of patients without pancreatitis58,61. Several radiographic imaging modalities are useful for diagnosing biliary obstruction that may be causing cholangitis, including ultrasound, CT, radionuclide scanning, MRCP, and ERCP. A brief overview of these studies will be discussed here, but more detail will be provided in other chapters on the work-up for various causes of obstruction. Ultrasound and CT are usually the first imaging tests completed. Ultrasound is useful for diagnosing biliary obstruction by detecting biliary dilation and aiding in differentiating between cholecystitis and cholangitis. However, in early or low level obstruction, biliary dilation may not be present and may be undetected by ultrasound. Sensitivities range from 80% to 99% for detection of obstruction and the sensitivity is significantly lower for detection of stones, approximately 15% 62 . The literature is conflicting as to whether ultrasound is accurate in determining the location or level of biliary obstruction and whether CT scan is superior63-65. Spiral or helical CT scan may provide increased sensitivity over a normal CT, as will CT cholangiography. MRCP, with sensitivities of 89% to 93% and specificities of 90% to 99% for diagnosing obstruction, is superior to both ultrasound and CT and rivals ERCP in diagnosing and locating biliary obstruction62, 66-69. MRCP may be obtained when therapeutic ERCP is believed to be too high risk or unnecessary and a diagnosis has not yet been determined. ERCP and PTC are excellent tools for the diagnosis and treatment of an obstruction in patients with cholangitis who are not improving clinically on antibiotics or whom initially present as very ill. The sensitivity and specificity of ERCP for diagnosing obstruction has been reported as 89% to 98% and 89% to 100%, respectively43. Neither ERCP and PTC should be used solely for diagnostic purposes due to the risks associated with these procedures and the availability of MRCP. Cholescintigraphy may be useful in detecting mild partial biliary obstructions in patients with a subtle clinical presentation of obstruction, and mildly abnormal liver function tests with an obstructive pattern without jaundice and a normal ultrasound. Cholescintigraphy also has the advantage of differentiating between cholecystitis and biliary obstruction and possibly detecting both simultaneously62 .
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TREATMENT In patients suspected of having cholangitis, blood cultures should be obtained, and antibiotics and supportive care (volume repletion, coagulation and electrolyte parameters corrected) initiated. Antibiotics with broad spectrum coverage should be considered. The decision on the specific antibiotics chosen may be based on factors such as prior biliary procedures, age, and local microbial sensitivities. Several antibiotics have been considered good choices due to the effectiveness against the organisms commonly involved in cholangitis and include fluoroquinolones, third generation cephalosporins (cefoperazone and ceftazidime), ampicillin and gentamicin combination, pipericillin, and mezlocillin. Ciprofloxacin, as compared to netilmicin, imipenem, ceftazidime, cefoperazone, and ampicillin, has been shown to have the highest concentrations in bile during an obstruction55. Whether high antimicrobial biliary concentrations improve outcomes is still unclear 70. Another factor to take into consideration when selecting an antibiotic is that cefoperazone, ceftazidime, and netilmicin tend to not cover Enterococcus. Ampicillin has been associated with higher resistance of organisms71. Cephalosporins, ampicillin with gentamicin, and fluoroquinolones do not have anaerobic coverage, so the addition of metronidazole should be considered if treating with these antibiotics. Antimicrobial therapy should be initiated quickly, but the cornerstone of treatment is decompression of biliary obstruction. ERCP success rates for drainage have been reported as high as 90% to 100%72-78. ERCP therapeutic techniques involved in decompression include sphincterotomy, stone extraction, and stent or drain placement. In patients with gallbladder stones without common bile duct stones or other forms of obstruction, sphincterotomy has been shown to decrease the duration of cholangitis and hospital stay, but does not reduce the incidence of recurrent cholangitis. In critically ill patients, nasobiliary drains or stents may be preferred over sphincterotomy and stone extraction due to less risk of procedure-related complications such as bleeding, perforation, and pancreatitis72 . Endoscopic stents and drains are usually temporary and removed after a patient has recovered. Long-term stenting is indicated in conditions with chronic mechanical obstruction, including benign and malignant strictures. In cases of hepatolithiasis, intrasegmental cholangitis, inability to access the papilla due to prior surgery, or ERCP failure, PTC is an option43. PTC’s success rate of 90% for relief of obstruction is slightly less than that of ERCP79. As in ERCP, biliary drains can be placed by PTC. ERCP is preferred over PTC and surgery due to lower mortality rates, fewer complications, shorter hospitalization, and high success rates76,77,79,80. Surgery was the main form of treatment for cholangitis prior to the advent of endoscopic and interventional radiological procedures. Due to the high risk of mortality (as high as 50%), surgical intervention is limited to those that have failed medical therapy and nonsurgical techniques of drainage2,58. Surgical options include choledochotomy, surgical sphincteroplasty, decompression, T-tube insertion, and removal of the gallbladder if also involved58. The risk of postoperative mortality and morbidity declines if surgery is completed on an elective basis44, 58. Patients who had cholangitis due to stones will also eventually require elective cholecystectomy. A management algorithm for patients with possible acute cholecystitis or bacterial cholangitis is provided in Figure 7-1.
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Upper Abdominal Pain, Fever, Jaundice
Physical exam: assess for Murphy's sign
RUQ ultrasound
gallstones
+ ductal stones (+/gallstones)
Antibiotics and t/c elective cholecystectomy
Antibiotics, ERCP or PTC
send cbc, lfts, if febrile start antibiotics and IVF after sending blood cultures
+ sonographic signs of cholecystitis
Antibiotics, PTC for drainage
-RUQ ultrasound
t/c HIDA or MRCP
Figure 7-1. Algorithm for acute cholecystitis/cholangitis work-up.
PROGNOSIS Acute obstructive suppurative cholangitis is a quickly progressive form of cholangitis that requires emergent drainage and has a high rate of greater than 60% mortality58. Poor prognostic indicators for mortality in acute cholangitis include acute renal failure, cholangitis associated with liver abscesses or liver cirrhosis, cholangitis secondary to high malignant biliary strictures or after percutaneous transhepatic cholangiography, abnormal platelet counts, hypoalbuminemia, female gender, and age43, 81.
Parasites Several parasites invade the biliary tract and may induce inflammation, stricture formation, and/or obstruction leading to secondary bacterial cholangitis. The most common parasites infecting the biliary system are Ascaris lumbricoides, Clonorchis sinensis, Opisthorchis viverrini and felineus, Fasciola hepatica, and Echinococcus granulosus and multilocularis 46.
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Figure 7-2.
Ascaris life cycle. Obtained with permission from CDC DPD library.
ASCARIS LUMBRICOIDES Background Ascaris is the most common parasite associated with cholangitis. Ascaris is a nematode (roundworm) primarily located in the tropics and subtropics and over 1 billion people are estimated to be infected with this parasite82,83. Eggs of the worm reside in the soil and mature into larvae within 10 to 12 days (Figure 7-2). The larvae may be accidentally ingested due to contamination of food. The shell of the larvae is usually broken in the duodenum, and when larvae are in the third stage they are highly infectious. At this larval stage, they may penetrate the wall of the intestine at the level of the cecum and enter the portovenous system and lymphatics. After entering the portovenous system, they travel to numerous organs (liver, heart, and lung) by way of the pulmonary artery. Larvae that have penetrated the lungs tend to enter bronchial cavities and work themselves up the bronchial tree to the level where they may be swallowed into the gastrointestinal tract. By the time they re-enter the gastrointestinal tract, they have matured and may be at a late larval stage or young adults. The parasite further matures in the gastrointestinal tract into adulthood. At this stage, Ascaris tends to invade the biliary tree by way of the ampulla, leading commonly to obstruction (see Figure 7-2). The worms may ascend the biliary tree, making their way into the liver and may even penetrate through liver tissue, through Gibson’s capsule, and into the peritoneum. If trapped in the biliary tree, dead worms can cause a more reactive inflammatory response than live worms 84. Biliary colic, acute cholecystitis, acute cholangitis, acute pancreatitis, and hepatic abscess may develop83.
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Clinical Manifestation Symptoms of biliary infection are similar to that of bacterial cholangitis: abdominal pain, fever, and jaundice. Patients may also have hepatomegaly.
Diagnosis Supporting information for biliary Ascariasis is peripheral eosinophilia. Ultrasound usually reveals dilated ducts and may show movement of a linear structure85,86, but the diagnosis is usually made by ERCP. Pigmented stones and/or adult worms may be visualized or retrieved from the biliary tree. Dead worms and larval shells are a nidus for calcification and stone formation84. Stool studies may be negative for the parasite.
Treatment If obstruction is present, then endoscopic extraction should be done. In addition, patients should be treated with levamisole or tetramisole hydrochloride and mebendazole. Pyrantel pamoate should be added if there is a heavy parasite burden83,84. Antibiotics and supportive treatment should also be started if obstruction is present and secondary bacterial cholangitis is likely.
LIVER FLUKE CHOLANGITIS This class of trematodes (flukes) includes Opisthorchis viverrini and felineus, Clonorchis sinensis, and Fasciola hepatica. Opisthorchis and Clonorchis are primarily located in Asia (China, Hong Kong, Vietnam, and Korea) and Russia.
Clonorchis Sinensis Background
Intermediate hosts of Clonorchis are snails and fish. The fluke enters humans after they eat raw fish that are infected. The Clonorchis adult worms are approximately 15×3 mm (Figure 7-3) 87. Clonorchis can penetrate through the ampulla and ascend the biliary tree where eggs are deposited. The adult flukes reside in the medium-sized and small intrahepatic bile ducts and, occasionally, in the extrahepatic bile ducts, gallbladder, and pancreatic duct88. The flukes can cause mechanical obstruction, inflammatory reaction, adenomatous hyperplasia, and periductal fibrosis. Embryonated eggs are passed into feces and reintroduced to the intermediate hosts (Figure 7-4). Clinical Manifestation
Most patients infected with Clonorchis are asymptomatic and symptoms are usually seen with heavy worm infestation. If symptoms are present, jaundice is most common. Diagnosis
It is very unusual to have significant ductal dilation by ultrasound or CT scan89. Mild diffuse ductal dilation may be detected, especially in intrahepatic ducts, and hepatic abscesses may also be present89,90. Clonorchis can usually be diagnosed definitively by detecting eggs in the feces.
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Figure 7-3. A. Ascaris in ampulla. B. Worm
removed by dormia basket. Reprinted with permission from Al-Karawi M, Sanai FM, Yasawy MI, et al. Biliary strictures and cholangitis secondary to ascariasis: endoscopic management. Gastrointest Endosc. 1999;50:695-697. For full-color version, see page CA IV of the Color Atlas.
Figure 7-4. Clonorchis life cycle. Obtained with permission from CDC DPD image library.
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Figure 7-5. Picture of adult Clonorchis.
Reprinted with permission from Chu DW, Li JC, Lee DW, Rong ZX, Chen XW, Chan AC. Unusual presentations of hepatic clonorchiasis. Gastrointest Endosc. 2003;58:637-639.
Treatment
By the time cholangitis occurs, which is usually secondary bacterial, ductal fibrosis, strictures, and stones may have formed. Treatment is similar to that for bacterial cholangitis, primarily antibiotics and possibly ERCP, PTC, or surgery may be required based on findings. Treatment for Clonorchis is praziquantel (75 mg/kg/day in three doses for 1 day) or albendazole in a dose of 10 mg/kg for 7 days87. Prognosis
There is a close relationship of Clonorchis with recurrent pyogenic cholangitis and an increased incidence of cholangiocarcinoma.
Opisthorchis viverrini and felineus O viverrini and felineus are commonly found in Asia and Eastern Europe. It has been a major public health problem in many parts of Southeast Asia, including Thailand, Lao PDR, Vietnam, and Cambodia91. Opisthorchis usually infects dogs and cats. As in Clonorchis, snails and fish are the intermediate hosts. Humans may be infected by ingesting raw fish that contains the parasite. The life cycle is similar to Clonorchis, with Opisthorchis residing in the biliary tree (Figure 7-6). In early infection or low infectious burden, few changes in the biliary structures are found. On the other hand, patients with a large infectious burden or chronic infection have been shown to have proliferation of ductal epithelial cells, bile duct hyperplasia, and periductal fibrosis91. In heavy infections with Opisthorchis, adult flukes may be seen in the gallbladder, common bile duct, and pancreatic duct 92 . Cholelithiasis is not particularly frequent in Opisthorchiasis 93. However, biliary sludge is often seen in the gallbladder in heavy O viverrini infections94, 95. Eggs and worm fragments have been observed in gallstones and in sludge supporting the role of the parasite in initiating cholelithiasis96. Infection in humans may lead to cholangitis, obstructive jaundice, hepatomegaly, cholecystitis, and cholelithiasis. Diagnosis is usually confirmed by the presence of eggs in feces. Treatment is with praziquantel. There is an increased risk for cholangiocarcinoma in those infected with O viverrini.
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Figure 7-6.
Opisthorcis life cycle. Obtained with permission from CDC DPD image library.
Fasciola hepatica Fasciola hepatica is found in most parts of the world except for North America and usually infects sheep and cattle. The adult fluke is large, flat, brownish, and leaf-shaped and measures approximately 2.5×1 cm87. The intermediate host is aquatic plants such as watercress (Figure 7-7). Humans may become infected by accidental ingestion of contaminated watercress. The infective larvae penetrate the intestinal wall, pass into the peritoneum, migrate into the liver, and take several weeks to eventually migrate into the biliary ducts where they reside. In the acute phase of the infection, patients may have symptoms such as fever, right upper quadrant pain, and arthralgias even with light infectious burden97,98. A few weeks after the worms enter the bile canaliculi, symptoms may decline or disappear completely. In the chronic phase, patients may develop biliary colic or cholangitis97. Extrahepatobiliary disease may also develop, such as pulmonary infiltrates, pleuropericarditis, meningitis, or lymphadenopathy 97. On examination hepatomegaly may be present. Blood tests may reveal eosinophilia, and serologic tests may help in establishing the diagnosis. Ova may be recovered from bile or stool and a concentration method such as formol ether is necessary to enhance the chance of finding eggs87 (Figure 7-8). CT examination of the liver may show small nodules or tortuous linear tracks87. MRI may also be useful. Individual cases with obstruction of bile ducts and biliary cirrhosis have been reported, but they are extremely rare. Medical treatment is useful for the hepatic stage of the disease. Bithionol (30 to 50 mg/kg on alternate days for 10 to 15 doses) is the drug of choice for treating fascioliasis87. Triclabendazole may also be used. During the biliary stage, ERCP may be required to relieve obstruction99.
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Figure 77. Fasciola
hepatica life cycle. Obtained with permission from CDC DPD image library.
Figure 7-8. Fasciola hepatic egg. Obtained with permission from CDC DPD image library.
Echinococcosis E granulosus and E multilocularis belong to the family of cestodes (tapeworms) and are associated with biliary disease. E Granulosus
E granulosus is found where there are poor sanitary conditions and cattle, dogs, and humans live in close proximity. Cases have occurred in Europe, particularly near the Mediterranean and Russia, New Zealand, Australia, and parts of South America. Both E granulosus and E multilocularis have been spreading to new regions throughout the world. Canines, such as dogs, wolves, and foxes, serve as the intermediate hosts and are vectors for human infection87 (Figure 7-9). E granulosus develops in the intestine of dogs and eggs are passed into the feces. Sheep, cattle, swine, goats, camels, horses, and
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Figure 7-9.
Echinococcosis life cycle. Obtained with permission from CDC DPD image library.
humans may accidentally be infected by ingesting contaminated food. When humans ingest the eggs, the embryo passes into the gastrointestinal tract and develops. The eggs hatch into infective larva called oncospheres. The oncospheres pass through the duodenal wall and find their way to the portal and lymphatic system, going to sites such as the liver, lung, spleen, muscle, bone, kidney, and brain. The embryo grows into large two-layered cysts and may cause symptoms once larger than 10 cm. The liver is the most common site for E granulosus to inhabit, and more than 90% of the time it inhabits the liver and/or lung100. Symptoms are usually absent and primarily based on the size and location of cysts. Patients may present with jaundice, cholangitis, vague upper abdominal pain, or abdominal mass when the cysts are large. Cysts have also been shown to compress or erode into the bile ducts, portal vein, hepatic veins, and lymphatics. Patients may present with other systemic symptoms as they may infect almost any organ in the body. The diagnosis may be made by a combination of cross-sectional imaging (such as ultrasound, CT, or MRI) and serology 84,87. Serology is 80 to 100% sensitive and 88% to 96% specific for liver cyst infection but less sensitive for lung (50% to 56%) or other organ involvement (25 to 56%) 87. Antigen based assays are less sensitive than antibody based assays100. Imaging remains more sensitive than serodiagnosis, and a characteristic scan in the presence of negative serologic results should still suggest the diagnosis of Echinococcosis 87. Fine needle aspiration is not preferred for diagnosis due to the risk for cyst rupture, but it can be done safely. Cyst leak or rupture may lead to anaphylaxis and secondary seeding of larvae. The primary treatment is surgical removal of the cysts and medical treatment with benzimidole agents such as albendazole (10 mg/kg/day in divided doses or 400mg BID for 1 to 3 months) or mebendazole (40 mg/kg/day divided into three doses) pre- and postoperatively. Agents such as chlorhexidine, hydrogen peroxide, 80% alcohol, hypertonic saline, and 0.5% cetrimide may also be injected into the cyst once some fluid is removed to reduce the risk of rupture. Surgical resection of cysts
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Figure 7-10.
ERCP image of Echinococcosis involving the hepatobiliary system. Reprinted with permission from Rodriguez AN, Sanchez del Rio AL, Alguacil LV, De Dios Vega JF, Fugarolas GM. Effectiveness of endoscopic sphincterotomy in complicated hepatic hydatid disease. Gastrointest Endosc. 1998;48:593-597.
has a 2% mortality, morbidity of 23%, and recurrence rate of 10.4%101. Albendazole is preferred because it has better absorption, but is associated with side effects such as leukopenia and jaundice. If cysts are inoperable, benzimidole medication may be used but the cure rate is low (29%). A new formulation of albendazole shows promise due to higher bioavailability with cure rates as high as 80% to 90%102 . Studies show praziquantel (25 mg/kg/day) may increase the efficacy of albendazole by increasing the absorption100. Another option for inoperable cysts is the PAIR procedure (puncture, aspiration, injection, and reaspiration) and the success rate is not yet known. PAIR is contraindicated in cysts that are superficial, inaccessible, calcified, solid, or in communication with bile ducts100. If cholangitis is present, antibiotics should also be added to the treatment regimen103. E multilocularis
E multilocularis is found in western and central Europe, Russia, Turkey, Japan, Kurile Islands, China, Alaska, and northern Canada and causes alveolar cyst disease. The definitive hosts are fox that pass parasitic eggs in the feces, which may contaminate grass and wild fruits. Usually the eggs are ingested and grow within rodents, but humans may also accidentally ingest contaminated fruits and vegetables. E multilocularis is more aggressive than E granulosum. Humans may also acquire the parasite by contact with an infected fox. E multilocularis passes through the human body in a similar pattern as that of E granulosum, but E multilocularis cysts reproduce asexually by lateral budding. Invasion into tissue by this parasite has been described as a highly aggressive tumor and may be mistaken for a tumor on imaging studies. The liver is the most common organ involved (Figure 7-10). Clinical manifestations occur gradually and may include upper abdominal pain, jaundice, and hepatomegaly. Patients may also manifest symptoms related to cholangitis, portal hypertension (from secondary biliary cirrhosis or parasitic portal thrombosis), and Budd-Chiari syndrome.
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The diagnosis is usually made by serologic and imaging studies. Imaging studies may be suspicious for carcinoma or sarcoma. Surgery is the primary form of treatment. Since wide resection margins are necessary for cure, partial hepatectomy or even liver transplantation may be needed. Adjuvant albendazole therapy (up to 20 mg/kg/day) should be given preoperatively to increase the likelihood of cure by surgery and continued for 2 years postoperatively. Patients who are inoperable may be treated with benzimidazoles.
Recurrent Pyogenic Cholangitis ETIOLOGY AND PATHOPHYSIOLOGY Recurrent pyogenic cholangitis, also known as Oriental cholangiohepatitis, is a syndrome of strictures of the bile duct, hepatolithiasis, intermittent obstruction, and recurrent biliary infections. It is more commonly encountered in people in China, Southeast Asia, and the Philippines, although it is more commonly seen now in Western countries due to Asian immigration. It appears to be declining in the Eastern hemisphere due to improved economic development104. Clonorchis sinensis, Ascaris, and other endemic parasites are commonly detected in patients with this syndrome, although the exact etiology and pathogenesis are not yet fully known.
CLINICAL MANIFESTATION Symptoms are similar to acute bacterial cholangitis: fever, abdominal pain, and jaundice.
DIAGNOSIS Ultrasound, CT scan, MRCP, ERCP, and PTC are all useful in providing information to aid in the diagnosis. ERCP and PTC are not recommended for only diagnostic purposes due to higher risk of complications. Ultrasound typically reveals ductal dilation, periportal echogenicity, and common bile duct thickening manifested by a hypoechoic stripe lying internal to the echogenic line of the normal bile duct. CT is useful in visualizing proximal to the obscure ductal obstruction and providing more detailed information of hepatic lesions. MRCP was shown to be superior to cholangiography in detecting all strictures 86% versus 44%, verified surgically. Cholangiography provides detail on ductal anatomy.
TREATMENT In addition to supportive management, initiation of antibiotics and drainage of all obstructive lesions are required. Percutaneous and surgical means for drainage are required more frequently than in acute bacterial cholangitis and the technique used is determined by location of the strictures. Hepatic-jejunostomy may be required for treatment and for easier access to hepatobiliary ducts that are involved105,106. Other surgical options include surgical sphincteroplasty, choledochojejunostomy, and choledochoduodenostomy107. Choledochoduodenostomy is a more attractive surgical option because it can be done laparascopically and keeps the bile duct accessible for endoscopy107.
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AIDS-Related Cholangiopathy ETIOLOGY AND PATHOPHYSIOLOGY Abnormalities of the bile ducts in AIDS patients were first noted by Margulis et al in 1986. In 1989, Cello et al described the syndrome in more detail. The estimated prevalence may be as high as 45% in AIDS patients, although the true incidence is not known, as patients may not have cholangiography available to make the diagnosis and many are asymptomatic with the syndrome108. Male homosexuals are more likely to have the syndrome109. The etiology is not yet known but opportunistic infections such as cryptosporidium, cytomegalovirus, and microsporidium are suspected with cryptosporidiosis reported most frequently, in 20% to 62% of patients109,110. Cytomegalovirus is detected in 23% to 42% of patients and Microsporidia is detected in 10% of patients111. E bieneusi accounts for most of the Microsporidia cholangitis cases, but E intestinalis has also been reported112 . Mycobacterium avium intracellulare and Isospora belli have also been reported in AIDS-related cholangitis in 1000 mg/dL. At this point, the lipemic serum will appear milky in the tube used to collect the blood and the laboratory merely serves to confirm the high pre-test suspicion of hypertriglyceridemia that arises when viewing the specimen. Simply viewing the tube of serum, although helpful, is rarely possible, as phlebotomists or nurses usually draw the blood before the clinician sees the patient. It is helpful to read the report of serum chemistries carefully when sus-
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pecting AP, however, as it will often be reported on the result sheet that the specimen appeared lipemic. It could then be inferred that the patient has hypertriglyceridemia even before measuring the level. The serum level of triglycerides may be inaccurate in the setting of acute illness and a baseline fasting measure should be drawn after the illness has resolved if no such values are available from before the onset of illness. Acquired causes of hypertriglyceridemia are reported in Table 8-5. The final laboratory test that can be helpful in determining etiology in AP is the serum calcium level. Occasionally, a patient with AP will be found to have hypercalcemia when the serum chemistries from admission are reviewed and this metabolic derangement may be the etiology that explains AP in a minority of patients. As with triglycerides, serum calcium will be altered in the setting of acute illness and hypocalcemia will actually be more prevalent as AP progresses. The possible etiologies associated with hypercalcemic AP are diverse and listed in Table 8-6.
POST-ERCP PANCREATITIS Most of the major etiologies of AP in the United States—gallstone, alcohol, medications, hypertriglyceridemia, and hypercalcemia—may be suspected based on laboratory tests that are discussed above. As we have outlined, these etiologies will usually be evident in the early stages of the evaluation from the clinical history, laboratory evaluation, and review of medications. While not yet discussed, the unfortunate patient who presents with abdominal pain, nausea, emesis, and a threefold or greater elevation in amylase following ERCP provides the clinician with yet another etiology for AP that can be readily ascertained from the clinical history post-ERCP pancreatitis. The anticipated rate of post-ERCP pancreatitis ranges from 1% to 7% according to data reviewed by the Standards of Practice Committee of the American Society of Gastrointestinal Endoscopy18. For patients with suspected sphincter of Oddi dysfunction undergoing sphincter of Oddi manometry, the risk is up to 20% to 25%19. Unfortunately, despite years of research involving the search for a medication or technique that can reliably decrease the risk of post-ERCP pancreatitis, no such panacea has been found. Efforts in the past have included studies of lidocaine sprayed onto the papilla, nitroglycerine (sublingual and transdermal), heparin, gabexate, corticosteroids, somatostatin, octreotide, nifedipine, allopurinol, IL-10 and prophylactic stents20-36. Recently, the Duke Biliary Group presented promising data at the 2003 Digestive Diseases Week on the use of synthetic secretin37. Although certain medications such as gabexate, somatostatin, and synthetic secretin have shown real promise, the problem lies in being able to correctly select which patients to treat 38. We cannot endorse the use of any of these prophylactic medications at this time and do not use any in our endoscopy suite. At the present time, a program of universal prophylaxis cannot be justified. Additional etiologies for AP are listed in Table 8-4.
Radiological Evaluation in Acute Pancreatitis In this section, we will address the radiological evaluation of patients with AP. We will cover its role in determining etiology as well as its use in the management of pancreatitis. Transabdominal ultrasound (US) is frequently performed in the setting of AP. The main role of US in AP is for establishing a biliary etiology and when positive for biliary stones in the gallbladder or bile duct, the study is quite useful. The exam’s sensitivity
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and accuracy suffers, however, due to body habitus (obesity), overlying bowel gas, and dependency on the operator’s skill level. In one prospective study of 50 consecutive patients with AP designed to evaluate the role of US in the diagnosis and prognosis of AP and the detection of a biliary origin, the pancreas could not be visualized in six patients and in 19 only partial examination was possible39. The performance characteristics of transabdominal ultrasound for the evaluation of the gallbladder itself, however, are excellent. Advantages of US include the ability to obtain results rapidly as the test is performed; it is noninvasive, requires no sedation, and has no complications. For these reasons, as well as the fact that US is relatively inexpensive compared to CT, portable, and widely available, we recommend a screening RUQ US as the initial radiological test for patients with AP when there is clinical suspicion of a biliary etiology. It is important to note that a CT scan is not an adequate study to exclude a gallstone etiology because its sensitivity is too low for the detection of gallbladder stones. In comparison, the helical abdominal CT scan with thin section scans taken through the pancreas during the administration of IV contrast (ie, the pancreas protocol CT) has become widely used for the diagnosis and risk stratification of AP. The use of IV contrast is important for evaluating whether necrosis is present. Thin cuts are primarily used to evaluate for small lesions such as tumors and are therefore crucial during the initial CT scan. Changes indicative of AP on CT scan include glandular enlargement, inflammatory stranding in the peripancreatic fat or adjacent soft tissue, and intra- or peripancreatic fluid collections. CT has undoubtedly helped many patients by diagnosing pancreatic necrosis at an earlier time, allowing aspiration for infected necrosis, earlier use of broad-spectrum antibiotics, a more timely performance of pseudocyst drainage and determination of the need for surgical debridement of infected, devitalized tissue. Some earlier data discouraged the use of CT scan early in the course of AP, fearing that the administration of IV contrast before adequate fluid resuscitation might be associated with a poorer outcome in terms of renal insufficiency. These early fears have largely been replaced by the wealth of experience demonstrating the benefits of CT scan in detecting necrosis, fluid collections, and other possible complications of AP. In fact, the Japanese Society of Abdominal Emergency Medicine has developed an evidence-based practice guideline to help clinicians with the management of AP40. This guideline gives a recommendation grade B to the use of an enhanced CT for the assessment of degree of pancreatic necrosis and inflammation. We find that many patients who are admitted through the emergency department (ED) will have already had a CT scan as part of their initial ED evaluation. This information is useful for helping to establish the diagnosis as well as for providing a baseline should the clinical course worsen over time. In terms of predicting mild versus severe AP, one study reported that the combination of the serum albumin level plus a CT scan demonstrating extrapancreatic fluid collections had a negative predictive value of 92% to 96%, positive predictive value of 67% to 100%, and was a better indicator of severity than Ranson, Glasgow, and APACHE II41. If the patient with mild pancreatitis has not already had a CT scan performed in the ED, we do not automatically perform one following admission. Instead, we allow the patient’s clinical course to dictate whether one is indicated. One retrospective study demonstrated a longer length of stay for patients with AP who underwent CT scan than those who did not despite a comparable severity of illness42 . Although these results can be criticized
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on the basis of study design and the faults inherent to a retrospective descriptive study, they still highlight the fact that abdominal CT scan is not mandatory in all patients with AP and may even have adverse consequences with regard to hospital costs (ie, length of stay) without contributing positively to outcome. In our institution, we use worsening or uncontrollable pain, especially with fever and elevated white blood cell (WBC) or signs of developing sepsis, as indicators to pursue CT scan of the pancreas. The reasons for this are to reassess the diagnosis in terms of severity and complications and especially to evaluate for pancreatic necrosis as it is now clear that patients with necrosis require broad-spectrum antibiotics and possibly antifungals to reduce morbidity from infected necrosis43-48. Magnetic resonance imaging (MRI) of the pancreas and magnetic resonance cholangiopancreatography (MRCP) have gained increasing popularity in the evaluation of hepatobiliary and pancreatic pathology. While still not widely utilized, MRI has been shown to evaluate poorly perfused areas of the pancreas in AP and discriminate areas of perinecrotic fluid from necrosis and hemorrhage that might otherwise be interpreted simply as necrosis on CT scan49. The ability to render an MRCP following MRI can supply additional information on etiology (eg, choledocholithiasis, annular pancreas, pancreas divisum) that CT may not be able to provide50. In addition, because gadolinium is a nonionic contrast agent, MRI offers a safer imaging option for patients with renal insufficiency. Unfortunately, there are disadvantages that limit the applicability of MRI. First, smaller community hospitals are much more likely to have a CT scanner than an MRI. The exam requires a more cooperative patient than CT, as it takes longer to acquire MRI than the rapid helical CT. A patient writhing in severe pain may not be able to lie still, resulting in motion artifact that renders the exam images unusable. A number of patients are claustrophobic and will resist entering the “tube”. Additionally, implanted metallic devices such as pacemakers, artificial heart valves, artificial joints, and other prostheses may prevent the patient from being able to undergo MRI. One final imaging modality worthy of mention is endoscopic ultrasound (EUS). In contrast to transabdominal ultrasound, EUS is able to detect gallstones or sludge within the gallbladder and extrahepatic bile duct regardless of body habitus. Bowel gas is not a concern and operator skill is placed in the hands of the physician, not an ultrasound technician. EUS is able to detect additional abnormalities, such as pancreas divisum and pancreatic neoplasia, which may not be apparent with other imaging modalities. The greatest utility for EUS at this time may be in helping establish a diagnosis of chronic pancreatitis or assist with finding an etiology in recurrent acute pancreatitis51,52 . A significant limitation to the use of EUS is that it is not widely available in the community practice setting. Algorithms to establish the place of this modality in the evaluation of AP have not yet been established.
Management of Pancreatitis In this section, we will address important aspects to consider when managing patients with pancreatitis. This is not intended to be an exhaustive review of management but rather a focused review of important and practical issues.
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PREDICTING SEVERITY Once a diagnosis of AP is made, one of the most important early tasks is the risk stratification of patients into the two major clinical categories: mild or interstitial pancreatitis and severe or necrotizing pancreatitis. This division is important for several reasons. First, this initial triage allows proper utilization of hospital resources. Whether clinically mild or severe, a majority of patients with AP will report pain that is 10 on a scale of 1 to 10 and so the presenting level of pain is not a helpful guide. It is imperative, however, to gain control of pain quickly and for patients with predicted severe AP we use patient controlled analgesia (PCA) with narcotics. A majority of patients with mild pancreatitis will have pain controlled with scheduled doses of narcotics with no breakthrough and some may even be well treated with an asneeded regimen. Pain is a subjective experience, though, and some patients with mild pancreatitis are eventually placed on PCA as well. It is helpful to involve the services of an anesthesia pain service for patients with complicated pain issues. Second, while values in the thousands for serum amylase and lipase will attract more attention than numbers in the hundreds, not unlike the subjective level of pain, these objective tests are also known to have a poor correlation with severity of illness. The initial task facing the clinician at the time of admission is distinguishing mild from severe and deciding which patients can be managed on “the ward” and which are more appropriately managed in a monitored setting such as the intensive care unit (ICU). In an era where patients are often held in observation units while waiting for beds to become available for admission or initially managed on a medical ward while waiting for an ICU bed, the decisions made during these early hours can truly be “life or death” for the patient with severe AP53. Finally, because early mortality in AP is usually due to multisystem organ failure, the identification of patients with severe pancreatitis as early as possible can allow for transfer to a higher level of care when such resources are available. To help guide clinicians, various predictors of severity have been developed. Some are clinically based, some are laboratory based, some can be interpreted immediately, some can be recalculated serially, and others are not valid until 48 hours into the illness. Some scoring systems are specific for pancreatitis, whereas others are for general use in severe illness. The characteristics of these various scoring systems are provided in Table 8-7.
Clinical Scoring Systems for Predicting Severity The first scoring systems that were developed to aid the clinician in determining severity in AP were clinically based. The now venerable Ranson criteria were first presented in 1974 and remained the standard until 1981, when a modified version known as the Glasgow criteria was developed. These criteria are largely derived from blood tests and are therefore easy to obtain and interpret. Unfortunately, however, application of the Ranson criteria requires laboratory data both from admission and at 48 hours to calculate severity and expected mortality. The Glasgow criteria are measured at the 48-hour mark as well. We looked at the utility of the Ranson criteria in our own institution and found that it is uncommon for clinicians to actually measure all 11 of these criteria in patients with AP. A Ranson score of >3 did indeed correlate with severe AP, though no prediction regarding outcome or mortality could be drawn from the use of the Ranson score. These latter parameters are most important to the clinician and the reason severity scales are used in the first place. As such, we agree
Acute Pancreatitis Table 8-7
CLINICAL CRITERIA SCALES Atlanta Criteria for Severe Acute Pancreatitis Organ Failure Shock: systolic blood pressure 500 mL/24 hr And/or Local Complications Necrosis Abscess Pseudocyst Unfavorable Early Prognostic Signs ≥ 3 Ranson’s signs (see below) ≥ 8 APACHE-II points
Ranson’s Criteria for Severity of Pancreatitis At Admission Age >55 yr White blood cells >16,000/mm3 Glucose >200 mg/dL Lactate dehydrogenase >350 IU/L Aspartate aminotransferase >250 U/L During Initial 48 hr Hematocrit decrease of >10 mg/dL Blood urea nitrogen increase of >5 mg/dL Calcium 6 L Mortality when score: 130, arrhythmia, EKG changes Pulmonary = dyspnea, rales PO2 3
None 90%147. Because of the time-consuming and cumbersome nature of these tests, direct PFTs have been
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Figure 9-9. Proper placement of Dreiling gastroduodenal collection tube for direct pancreatic function testing. The tip is past the ligament of Treiz with proximal port in gastric antrum and distal port in the second portion of the duodenum.
relegated to a few tertiary centers. The recent development of endoscopic collection methods for direct PFTs holds promise in increasing accessibility of these valuable tests166,167.
Indirect Pancreatic Function Tests There are a plethora of noninvasive, indirect tests of pancreatic function that do not require passage of collection tubes. Qualitative measurement of stool fat is an inexpensive and noninvasive screen for fat malabsorption (Figure 9-10). Stool fat lacks sensitivity for early CP because 90% of glandular function must be lost to result in fat malabsorption. Stool fat is nonspecific for pancreatic insufficiency because mucosal disease and bile deficiency can produce fat malabsorption. In this situation, the D-xylose test may be helpful in differentiating mucosal disease from pancreatic insufficiency. The measurement of fecal proteases such as chymotrypsin, trypsin, and elastase-1 are likewise sensitive for the detection of moderate and advanced CP168. The bentiromide and pancreolauryl tests involve ingestion of oral substances that are selectively cleaved by pancreatic enzymes169,170. The cleaved segments of these substances are absorbed into the systemic circulation and excreted. Measurement of the urinary metabolites allows a quantification of pancreatic exocrine function. Because indirect tests only become positive in the presence of overt malabsorption, the sensitivity of these tests is higher for moderate and severe CP than for mild CP. Several studies have compared the results of the radiographic and functional gold standards (ERCP versus secretin test)171,172 . Most of these studies have shown a good correlation in moderate and advanced disease and discordance in early disease. This may suggest that in some patients, functional changes may precede structural changes and vice versa.
Therapy Once the diagnosis and staging of CP is accomplished, therapy is directed at the symptoms and complications. Although variable in character and pattern, pain is the most common symptom of CP. The management of abdominal pain from CP is challenging because of superimposed narcotic addiction. Furthermore, nonvisceral (ie, non-pancreatic) pain may be present, which may predict a poor response to therapy directed at the pancreas. Medical therapy is usually the first line of treatment for patients with pain from CP. Surgery is an option for patients who fail medical therapy or who have advanced ductal and cystic changes amenable to surgical drainage.
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Figure 9-10. A.
Endoscopic view; B. Sudan stain showing steatorrhea in a patient with pancreatic insufficiency. For full-color version, see page CA IV of the Color Atlas.
MEDICAL THERAPY There are five principle medical options available for the treatment of pancreatic pain: abstinence from alcohol, analgesics, pancreatic enzymes, visceral nerve blocks, and endoscopic therapy. Abstinence from alcohol is a critical first step in therapy. Alcohol is known to hasten the progression of exocrine and endocrine dysfunction and increase mortality173,174. A review and meta-analysis demonstrated an increased likelihood of persistent pain in those who continued to imbibe (26% versus 53%)175. Analgesic agents are the cornerstones of therapy for the treatment of painful CP. It is best to start with non-narcotic analgesics such as nonsteroidal anti-inflammatory agents, acetaminophen, and tramadol. If pain persists, these agents may be combined with low doses of mild narcotics such as codeine or propoxyphene. Potent narcotics should be avoided if possible given the potential for dependency; however, recalcitrant pain may warrant their use in select cases. Differential nerve blockade (DNB) is helpful in ruling out nonvisceral sources of pain. Patients with somatosensory pain may benefit from anticonvulsants such as gabapentin. Patients with central pain may benefit from antidepressants and psychiatric counseling. When exocrine functional loss reaches a critical threshold, malabsorption results in steatorrhea and malnutrition. The mainstay of therapy for maldigestion from pancreatic insufficiency is exogenous pancreatic enzyme supplements. These medications are safe, well-tolerated, and produce few side effects. Several enzyme products are available and each contains different amounts of lipase, protease, and amylase (Table 9-4). Enteric coated may be more effective than uncoated preparations for treatment of maldigestion, given higher potency and better delivery to the small bowel. A minimum of 30,000 IU of lipase and 10,000 IU of protease should be administered with each meal to allow adequate intraluminal digestion of fat and protein. Successful treatment with pancreatic enzymes results in improvement in maldigestion and steatorrhea. Because gastric acid denatures exogenous enzymes, a daily proton-pump inhibitor may be added for patients refractory to therapy (Figure 9-11). Progress may be monitored through assessment of symptoms or more objectively through 72-hour stool fat quantification. Studies of the effects of pancreatic enzymes on abdominal pain have yielded mixed results. The supposed mechanism of pain relief relates to the breakdown of CCK-releasing peptide (CCK-RF) by exogenous enzymes within the duodenal lumen.
Enteric-coated Micro-tablets
Enteric-coated Micro-tablets
Pancrease MT 4/10/16/20
Ultrase MT6/12/16/20
Enteric-coated Micro-spheres
Capsule Tablet Tablet
Rapid Release Cotazym Pancreatin Viokase
Delayed Release Creon 5/10/20
Form
6,000 12,000 18,000 20,000
4,000 10,000 16,000 20,000
5,000 10,000 20,000
8,000 12,000 8,000
Lipase
19,500 39,000 58,500 65,000
12,000 30,000 48,000 44,000
18,750 37,500 75,000
30,000 60,000 30,000
Protease
19,500 39,000 58,500 65,000
12,000 30,000 48,000 56,000
16,600 33,200 66,400
30,000 60,000 30,000
Amylase
Enzyme Content (USP Units)
PANCREATIC ENZYME PREPARATIONS
Preparation
Table 9-4
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Figure 9-11. Management algorithm for maldigestion in pancreatic insufficiency.
Digestion of CCK-RF attenuates serum CCK levels and pancreatic stimulation. Oral pancreatic enzymes appear to decrease pain in some patients with CP176. However, a recent meta-analysis of six randomized placebo-controlled trials did not reveal a statistically significant benefit for supplemental pancreatic enzyme therapy for pain relief (Figure 9-12)132 . A major criticism with this study was the substantial methodological variability among the included studies, most importantly the mixture of coated and uncoated preparations. Uncoated preparations are better for pain relief as they are most effectively delivered to the proximal small bowel to inhibit CCK. Although the role of exogenous enzyme supplementation for pain relief is not completely understood, they are worth trying in all patients because of their safety and minimal side effects. Endoscopic modalities of treatment of CP include duct decompression, drainage of pseudocysts, and EUS-guided celiac plexus block. Patients with large-duct CP who are ineligible for surgery and have distal pancreatic duct strictures or stones may be suitable for endoscopic duct-decompression therapy. Techniques include endoscopic pancreatic sphincterotomy, balloon dilatation of strictures, mechanical or extracorporeal sound wave lithotripsy, and placement of pancreatic duct stents (Figure 9-13). Multiple studies have suggested that endoscopic therapy is effective for pain relief. For example, a study by Cremer et al noted a significant decrease in pain in 94% of patients who underwent pancreatic duct stenting with a 12-month average duration of pain relief177. Pain relief was sustained at 3 years in 55% of the patients. Most other trials have shown a more modest treatment effect. Unfortunately, few randomized trials comparing endoscopic to surgical or medical therapy have been performed178.
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Figure 9-12. Results of meta-analysis of pancreatic enzyme therapy for pain relief in CP. Reprinted with permission from Blackwell Publishers.
The benefit of endoscopic therapy must be weighed against the immediate risk of acute pancreatitis and the long-term risk of stent-induced strictures. These procedures should only be performed in high volume centers by experienced endoscopists. Patients who fail initial medical therapy are candidates for celiac plexus blockade (CPB) (Figure 9-14). Appropriate candidates include patients with small-duct disease or patients with large duct disease who fail to respond to surgical or endoscopic duct decompression. Nerve blocks are less effective in CP compared to pancreatic cancer, but should still be considered as an option for patients with recalcitrant pain179. When CPB is effective, the duration of effect is usually 2 to 4 months and may need to be repeated. In contrast to malignant disease, corticosteroid injections are favored over alcohol injections in CP because of the risk of paraplegia with alcohol. Although CPB is usually performed under CT-guidance, EUS-guided CPB has recently emerged as an effective method. One report showed a higher rate of pain relief for EUS versus CTguided CPB180. When patients do not respond to CPB, there may be nonvisceral pain contributing to their symptoms. CPB is discussed in further detail in Chapter 15.
SURGICAL THERAPY Surgical therapy is most beneficial in patients with severe pain and large duct CP. A Roux-en-Y side-to-side pancreaticojejunostomy (Puestow procedure) to drain the entire pancreas is indicated for patients with pancreatic duct dilatation greater than 7 mm. Large pseudocysts may be surgically drained at the time of duct decompression
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Figure 9-13. Endoscopic therapy for CP. A. Stone extraction using mechanical lithotripsy; B, C. Pancreatic duct stricture, pre- and post-stent placement.
through cyst-gastrostomy, cyst-duodenostomy, or cyst-jejunostomy. Most studies have shown favorable immediate success in 80% to 90% of patients. The results are often not durable, as long-term relief is seen in only 40% to 50% of patients181. It has not been established whether duct decompression surgery preserves pancreatic exocrine and endocrine function. Patients who have small-duct disease and pain unresponsive to medical therapy may undergo resection of diseased areas of the pancreas. Resection of large portions of the pancreas may produce brittle diabetes and metabolic derangements.
Complications PSEUDOCYSTS Pseudocysts are collections of pancreatic secretions that develop as a result of inflammation. Pseudocysts are the most common cysts of the pancreas; however, they differ from other pancreatic cysts in that they lack an epithelial lining. Pseudocysts may arise in either acute or chronic pancreatitis, although the mechanisms differ182 . In acute pancreatitis, pseudocysts are thought to develop from severe inflammation and liquefaction necrosis. In CP, pseudocysts result from ductal obstruction leading to upstream dilation and cyst formation. ERCP frequently shows a communication
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Figure 9-14. Celiac plexus block for visceral pancreatic pain.
of the cyst with the pancreatic duct. Most pseudocysts develop in the body and tail of the pancreas183. The most common clinical presentation is worsening abdominal pain in known CP, or several weeks after an episode of acute pancreatitis. There is often an associated elevation in the serum amylase and lipase. The natural history may include spontaneous resolution or progressive increase in size184. Pseudocysts arising in CP rarely rupture, become infected, or hemorrhage. Treatment may be conservative for small cysts, but endoscopic drainage (transmural or transpapillary) or surgical resection is required for enlarging or symptomatic cysts (Figure 9-15).
GASTRIC OUTLET AND BILIARY OBSTRUCTION Biliary obstruction and gastric outlet obstruction are relatively infrequent complications, most commonly occurring in advanced alcoholic pancreatitis. Gastric outlet obstruction from duodenal compression occurs in approximately 5% of cases, and may arise from severe fibrosis in the head of the gland, pseudocysts, or pancreatic cancer. Patients present with increased abdominal pain, vomiting, and inability to tolerate oral intake. Diagnosis may be established with barium upper GI x-ray, endoscopy, or CT scan. Biliary obstruction occurs in 10% and presents with jaundice. Although extensive fibrosis or enlarging pseudocysts are the most common causes, the development of jaundice in CP should raise concern for pancreatic cancer. Diagnosis is based on ERCP, which characteristically reveals a long, tapered stricture. A “double duct” sign may be present in the setting of large duct CP, presenting diagnostic uncertainty as to the presence of underlying ductal cancer. Surgery is most often required for management of both of these obstructive complications.
PANCREATIC ADENOCARCINOMA CP is a known risk factor for pancreatic cancer; conversely, pancreatic cancer can cause obstructive CP. Pancreatic cancer contributes substantially to mortality of pancreatitis, developing in 4% of patients with a 20-year duration of CP173. Diagnosis of pancreatic cancer in CP is difficult. It should be suspected with the development
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Figure 9-15. A. CT scan showing pancreatic pseudocyst in a patient with CP; B. Endoscopic transmural drainage of pseudocyst.
of acute worsening in abdominal pain, weight loss, or functional decline. Imaging tests often produce uncertainty in differentiating cancer from inflammatory masses and brushings are frequently nondiagnostic. Definitive diagnosis is often reserved for pathologic examination of the surgical explant.
PANCREATIC FISTULAE AND ASCITES Both internal and external fistulas may develop as a consequence of CP, usually arising from communications of pancreatic pseudocysts with adjacent cavities or from duct disruption. Communications with the peritoneal and pleural cavities produce refractory ascites and pleural effusions. Diagnosis is based on fluid analysis, which reveals elevated amylase content. Endoscopic stent placement across the region of ductal disruption may be effective for treatment of these conditions185.
SPLENIC VEIN THROMBOSIS AND SPLENIC ARTERY PSEUDOANEURYSM Splenic vein thrombosis occurs in 45% of patients with CP, but most are asymptomatic186. When morbidity occurs, it is the result of bleeding from secondary gastric varices. Splenectomy is the preferred management for recurrent bleeding from this condition. Splenic artery pseudoaneurysm is a disastrous complication arising from pancreatic inflammation and necrosis in the vicinity of the splenic artery. Pseudoaneurysms may rupture into adjacent pseudocysts resulting in hemobilia, or into the peritoneal cavity resulting in intraperitoneal hemorrhage. The mortality associated with this complication is 40% to 60%. Splenic artery pseudoaneurysms should be repaired surgically unless limiting comorbidities exist187. Endovascular therapy may also show promise in the management of this problem188.
Prognosis A multicenter study of 2,015 patients demonstrated a mortality rate for CP 3.6fold higher than for those without pancreatitis189. The 10-year survival rate was 79%
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for CP compared to 93% for patients without pancreatitis. The prognosis of CP is strongly dependent on the presence of alcohol abuse. The life expectancy is shorter for alcohol-induced compared to nonalcohol-induced CP. Other poor prognostic indicators include smoking, increased age, and concomitant cirrhosis190. Medical or surgical therapy has not been shown to impact morality. Death is frequently related to nonpancreatic causes in most patients regardless of etiology of CP. In a study of 315 patients with CP, Layer et al found that the cause of death was related to pancreatitis or pancreatic cancer in only 15% of alcohol-related and 3% of nonalcohol-related CP106.
APPROACH TO THE DIAGNOSIS OF CHRONIC PANCREATITIS Because of the significant challenges inherent in the management of this disease, we have developed a multidisciplinary approach191. All patients referred to our pancreas clinic first undergo a complete diagnostic and staging evaluation (Figure 9-16). Imaging tests are obtained to accurately determine the morphology of disease, often consisting of a pancreatic CT scan to assess gross parenchymal abnormalities (cysts, calcifications, and cancer) and an MRCP to evaluate the main pancreatic duct. If these tests do not reveal advanced structural changes, secretin-stimulated direct PFT, ERCP, and EUS are used to diagnose early CP. Most patients are referred for psychological and chemical-dependency evaluation to uncover contributing factors to the pain syndrome. After the diagnosis has been firmly established, patients with severe pain refractory to initial conservative management are referred for a differential nerve blockade (Figure 9-17). This procedure clarifies the origin of abdominal pain and may identify patients with nonvisceral pain who are less likely to respond to aggressive medical and surgical therapy directed at the pancreas. Patients with nonvisceral pain are first given a trial of conservative therapy (non-narcotic analgesics and abstinence from alcohol). If this fails, they are referred for psychotherapy and chemical dependency treatment. If there is somatosensory pain, a trial of gabapentin is attempted. Patients with visceral pain are also given a trial of conservative medical management. Further therapy is directed based on the morphology of disease (large-duct versus small-duct). Patients with large-duct disease or large pseudocysts are referred for surgical evaluation, or for a trial of endoscopic therapy. Patients with small-duct disease are referred for a CBP trial. Minimal change disease that fails to respond to nerve blocks may be considered for resection or experimental drug trials.
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Figure 9-16. Approach to the diagnosis of CP.
Figure 9-17. Approach to the management of pain in CP.
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References 1. Sarles H. Definition and classification of pancreatitis. Pancreas. 1991;6:470-477. 2. Skyhoj Olsen T. The incidence and clinical relevance of chronic inflammation in the pancreas in autopsy material. Acta Pathol Microbiol Scand. 1978;86:361-365. 3. Andersen BN, Pedersen NT, Scheel J, et al. Incidence of alcoholic chronic pancreatitis in Copenhagen. Scand J Gastroenterol. 1982;17:247-52. 4. O’Sullivan JN, Nobrega FT, Morlock CG, et al. Acute and chronic pancreatitis in Rochester, Minnesota 1940 to 1969. Gastroenterology. 1972;62:373-379. 5. Go VLW, Everhart JE. Pancreatitis. In: Everhart JE, ed. Digestive diseases in the United States; epidemiology and impact. Washington, DC: US Government Printing Office;1994:691-712. 6. Sarles H. Pancreatitis Symposium, Marseille 1963. Basel: S. Karger, 1965. 7. Gyr K, Singer MV, Sarles H. Pancraetitis: concepts and classifications. Proceedings of the second international symposium on the classification of pancreatitis in Marseille, France, March 28-30, 1984. Amsterdam: Excerpta Medica, 1984. 8. Sarles H, Adler G, Dani R, et al. The classification of pancreatitis and definition of pancreatic disease. Digestion. 1989;43:234-236. 9. Axon ATR. Endoscopic retrograde cholangiopancreatography in chronic pancreatitis. Radiol Clin N Am. 1989;27:39-50. 10. Sarner M, Cotton PB. Classification of pancreatitis. Report of an international symposium at Cambridge. Gut. 1984;25:756-759. 11. Walsh TN, Rode J, Theis BA, et al. Minimal change chronic pancreatitis. Gut. 1992;33:1566-1571. 12. Chari ST, Singer MV. The problem of classification and staging of chronic pancreatitis. Proposals based on current knowledge of its natural history. Scand J Gastroenterol. 1994;29:949-960. 13. Schneider A, Whitcomb DC. Hereditary pancreatitis: a model for inflammatory diseases of the pancreas. Best Pract Res Clin Gastroenterol. 2002;16:347-363. 14. Wenig BM, Heffess CS. Inflammatory, infectious, and other non-neoplastic disorders of the pancreas. In: Odze RD, Goldblum JR, Crawford JM, eds. Surgical Pathology of the GI tract, liver, biliary tract, and pancreas. Philadelphia: Saunders; 2004:673-697. 15. Braganza JM. Pancreatic disease: a casualty of hepatic “detoxification”? Lancet. 1983;2:1000-1002. 16. Braganza JM, Klass HJ, Bell M, et al. Evidence of altered copper metabolism in patients with chronic pancreatitis. Clinical Sci. 1981;60:303-310. 17. Braganza JM, Wickens DG, Cawood P, et al. Lipid-peroxidation (free radical oxidation) products in bile from patients with pancreatic disease. Lancet. 1983;ii:375-8. 18. Braganza JM. Free radicals and pancreatitis. In: Rice-Evans C, Dormandy TL, eds. Free radicals: chemistry, pathology and medicine. London: Richelieu;1988:357-81. 19. Guyan PM, Uden S, Braganza JM. Heightened free radical activity in pancreatitis. Free Radical Biol Med. 1990;8:347-54. 20. Uden S, Bilton D, Nathan L, et al. Antioxidant therapy for recurrent pancreatitis: a placebo-controlled trial. Aliment Pharm Ther. 1990;4:357-371. 21. De las Heras Castano G, Garcia de la Paz A, Fernandez MD, et al. Use of antioxidants to treat pain in chronic pancreatitis. Rev Esp Enferm Dig. 2000; 92: 375-385. 22. Atten MJ, Verma A, Liu K, et al. Antioxidants up-regulate PPAR and decrease fibrosis in chronic pancreatitis. Am J Gastroenterol. 2003;98:A14.
Chronic Pancreatitis
207
23. Bordalo O, Goncalves D, Noronha M, et al. Newer concept for the pathogenesis of chronic alcoholic pancreatitis. Am J Gastroenterol. 1977;68:278-285. 24. Sarles H, JP Bernard, Johnson C. Pathogenesis and epidemiology of chronic pancreatitis. Ann Rev Med. 1989;40:453-468. 25. Sarles H. Pathogenesis of chronic pancreatitis. Gut. 1990;31:629-632. 26. Solomon N, Solomon TE, Jacobson ED, et al. Direct effects of alcohol on in vivo and in vitro exocrine pancreatic secretion and metabolism. Am J Dig Dis. 1974;19:253260. 27. Steer ML, Glazer G, Manabe T. Direct effects of ethanol on exocrine secretion from the in vitro rabbit pancreas. Dig Dis Sci. 1979;24:769-774. 28. Harada H, Takeda M, Yabe H, et al. The hexosamine concentration and output in human pure pancreatic juice in chronic pancreatitis. Gastroenterol Jpn. 1980;15:520526. 29. Estevenon JP, Sales H, Fegarella C. Lactoferrin in the duodenal juice of patients with chronic calcifying pancreatitis. Scand J Gastroenterol 1975;10:327-330. 30. Multigner L, Figarella C, Sarles H. Diagnosis of chronic pancreatitis by measurement of lactoferrin in duodenal juice. Gut. 1981;22:350-354. 31. Sarles H. Etiopathogenesis and definition of chronic pancreatitis. Dig Dis Sci. 1986;31:91-107S. 32. Clain JE, Barbezat GO, Marks IN. Exocrine pancreatic enzyme and calcium secretion in health and pancreatitis. Gut. 1981;22:355-358. 33. Sahel J, Sarles H. Modifications of pure human pancreatic juice induced by chronic alcohol consumption. Dig Dis Sci. 1979;24:897-905. 34. Renner IG, Rinderknecht H, Wisner JR: Pancreatic secretion after secretin and cholecystokin stimulation in chronic alcoholics with and without cirrhosis. Dig Dis Sci. 1983;28:1089-1093. 35. Multigner L, De Caro A, Lombardo D, et al. Pancreatic stone protein, a phosphoprotein that inhibits calcium carbonate precipitation from human pancreatic juice. Biochem Biophys Res Commun. 1983;110:6974. 36. Multigner L, Sarles H, Lobardo D, et al. Pancreatic stone protein II Implication in stone formation during the course of chronic calcifying pancreatitis. Gastroenterology. 1985;89:387-391. 37. Freedman SD, Sakamoto K, Venu RP. GP2, the homologue to the renal cast protein uromodulin, is a major component of intraductal plugs in chronic pancreatitis. J Clin Invest. 1993;92:83-90. 38. Ammann RW, Heitz Ph U, Kloppel G. Course of alcoholic chronic pancreatitis: a prospective clinico-morphological long-term study. Gastroenterology. 1996;111:224231. 39. Kloppel G, Maillet B. Chronic pancreatitis: evolution of the disease. Hepatogastroenterol. 1991;38:408-412. 40. Comfort MW, Gaubill EE, Baggenstos AM. Chronic pancreatitis: a study of 29 cases without associated disease of the biliary or gastro-intestinal tract. Gastroenterology. 1946;6:239-243. 41. Ammann RW, Muellhaupt B. Progression of alcoholic acute to chronic pancreatitis. Gut. 1994;35:552-556. 42. Ammann RW, Heitz PU, Kloppel G. The “two-hit” pathogenetic concept of chronic pancreatitis. Int J Pancreatol. 1999;25:251-252. 43. Cavallini G. Is chronic pancreatitis a primary disease of the pancreatic ducts? A new pathogenetic hypothesis. Ital J Gastroenterol. 1993;25:400-407.
208
Chapter 9
44. Kino-Ohsaki J, Nishimori I, Morita M, et al. Serum antibodies to carbonic anhydrase I and II in patients with idiopathic chronic pancreatitis and Sjogrens syndrome. Gastroenterology. 1996;110:1579-1586. 45. Puig-Divi V, Molero X, Salas A, et al. Induction of chronic pancreatic disease by trinitrobenzene sulfonic acid infusion into rat pancreatic ducts. Pancreas. 1996;13:417424. 46. Hunger RE, Mueller C, Z’Graggen K, et al. Cytotoxic cells are activated in cellular infiltrates of alcoholic chronic pancreatitis. Gastroenterology. 1997;112:1656-63. 47. Cavallini G, Frulloni L. Autoimmunity and chronic pancreatitis: a concealed relationship. J Pancreas. 2001;2:61-8. 48. Apte MV, Haber PS, Applegate TL, et al. Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut. 1998;43:128-31. 49. Bachem MG, Schneider E, Gros H, et al. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology. 1998;115:421-432. 50. Schmid-Kotsas A, Gross HJ, Menke A, et al. Lipopolysaccharide-activated macrophages stimulate the synthesis of collagen type 1 and C-fibronectin in cultured pancreatic stellate cells. Am J Path. 1999;155:1749-1758. 51. Haber P, Keogh G, Apte M, et al. Activation of pancreatic stellate cells in human and experimental pancreatic fibrosis. Am J Pathol. 1999;155:1087-1095. 52. Vogelmann R, Ruf D, Wagerner M, et al. Effects of fibrogenic mediators of the development of pancreatic fibrosis in a TGF transgenic mouse-model. Am J Physiol Gastrointest Liver Physiol 2001;280:G164-172. 53. Apte MV, Phillips PA, Fahmy RG, et al. Does alcohol directly stimulate pancreatic fibrogenesis? Studies with rat pancreatic stellate cells. Gastroenterology. 2000;118:780794. 54. Casini A, Galli A, Pignalosa P, et al. Collagen type I synthesized by pancreatic periacinar stellate cells (PSC) co-localizes with lipid peroxidation-derived aldehydes in chronic alcoholic pancreatitis. J Pathology. 2000;192:81-89. 55. Saurer L, Reber P, Schaffner T, et al. Differential expression of chemokines in normal pancreas and in chronic pancreatitis. Gastroenterology. 2000;118:356-367. 56. Norman J, Franz M, Riker A. Rapid elevation of pro-inflammatory cytokines during acute pancreatitis and their origination within the pancreas. Surg Forum. 1994;45:148-160. 57. Luttenberger T, Schmid-Kotsas A, Menke A, et al. Platelet-derived growth factor stimulates proliferation and extracellular matrix synthesis of pancreatic stellate cells: implications in pathogenesis of pancreas fibrosis. Lab Invest. 2000;80:47-55. 58. Apte MV, Haber PS, Darby SJ, et al. Pancreatic stellate cells are activated by proinflammatory cytokines: implications for pancreatic fibrogenesis. Gut. 1999;44:534541. 59. Broekelmann TJ, Limper AH, Colby TV, et al. Transforming growth factor beta one is present at sites of extracellular matrix gene expression in human pulmonary fibrosis. Proc Natl Acad Sci USA. 1991;88:6642-6646. 60. Czaja MJ, Weiner FR, Flanders KC, et al. In vitro and in vivo association of transforming growth factor beta 1 with hepatic fibrosis. J Cell Biol. 1989;108:2477-2482. 61. Okuda S, Languino LR, Ruoslahti E, et al. Elevated expression of transforming growth factor beta 1 and proteoglycan production in experimental glomerulonephritis. J Clin Invest. 1990;86:453-462. 62. Van Laethem JL, Deviere J, Resibois A, et al. Localization of transforming growth factor beta 1 and its latent binding protein in human chronic pancreatitis. Gastroenterology. 1995;108:1873-1881.
Chronic Pancreatitis
209
63. Vogelmann R, Ruf D, Wagner M, et al. Effects of fibrogenic mediators on the development of pancreatic fibrosis in a TGF-beta1 transgenic mouse model. Am J Physiol. 2001;280:G164-172. 64. Van Laethem JL Robberecht P, Resibois A, et al. Transforming growth factor beta promotes development of fibrosis after repeated courses of acute pancreatitis in mice. Gastroenterology. 1996;11:576-582. 65. Whitcomb DC. Hereditary pancreatic: new insights into acute and chronic pancreatitis. Gut. 1999;45:317-322. 66. Whitcomb DC, Schneider A. Hereditary pancreatitis: a model for inflammatory disease of the pancreas. Best Pract Res Clin Gastroenterol. 2002;16:347-363. 67. Whitcomb DC. Genetic predisposition to alcoholic chronic pancreatitis. Pancreas. 2003;27:321-6. 68. Wornig H. Incidence and prevalence of chronic pancreatitis. In: Beger HG, Büchler M, Ditschuneit H, Malfertheiner P, eds. Chronic Pancreatitis. Berlin: Springer-Verlag, 1990:8. 69. Ammann RW. Alcohol and non-alcohol induced pancreatitis: clinical aspects. In: Burns GP, Bank S, eds. Disorders of the Pancreas: Current Issues in Diagnosis and Management. New York: McGraw Hill; 1992: 253-271. 70. Durbec JP, Sarles H. Multicenter survey of the etiology of pancreatic disease: relationship between the relative risk of developing chronic pancreatitis and alcohol, protein and lipid consumption. Digestion. 1978;18:337-350. 71. Pitchumoni CS, Blasser M, Saran RM, et al. Pancreatic fibrosis in chronic alcoholics and non alcoholics without clinical pancreatitis. Am J Gastroenterol. 1984;79:382388. 72. Ammann RW. Buehler H, Bruehlmann W, et al. Acute (non-progressive) alcoholic pancreatitis: Prospective longitudinal study of 144 patients with recurrent alcoholic pancreatitis. Pancreas. 1986;1:195-203. 73. Clark E. Pancreatitis in acute and chronic alcoholism. Am J Dig Dis. 1942;9:428438. 74. Corrao G, Bagnardi V, Zambon A, et al. Exploring the dose-response relationship between alcohol consumption and the risk of several alcohol-related conditions: a meta-analysis. Addiction. 1999;94:1551-1673. 75. Gukovsky I, Lugea A, Cheng J, et al. Model of chronic alcoholic pancreatitis. Gastroenterology. 2002;122:A93. 76. Witt H, Luck W, Becker M, et al. Mutation in the SPINK 1 trypsin inhibitor gene, alcohol use, and chronic pancreatitis. JAMA. 2001;265:2711-2717. 77. Pezzilli R, Morselli-Labate AM, Mantovani V, et al. Mutations of the CFTR gene in pancreatic disease. Pancreas. 2003;27:332-335. 78. Teich N, Mossner J, Keim V. Screening for mutations of the cationic trypsinogen genere: are they of relevance in chronic alcoholic pancreatitis? Gut. 1999;44:413416. 79. Levy P, Mathurin P, Roqeplo A, et al. A multidimensional case-control study of dietary, alcohol, and tobacco habits in alcoholic men with chronic pancreatitis. Pancreas. 1995:10:231. 80. Talamini G, Bassi C, Falconi M, et al. Cigarette smoking: an independent risk factor in alcoholic pancreatitis. Pancreas. 1996;12:131-137. 81. Chowdhury P, Bone RC, Louria DB, et al. Effect of cigarette smoke on serum trypsin inhibitory capacity and antitrypsin concentration. Am Rev Respir Dis. 1982;126:177179.
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82. Bynum TE, Solomon TE, Johnson LR, et al. Inhibition of pancreatic secretion in man by cigarette smoking. Gut. 1972;13:361-365. 83. Crowley-Weber Cl, Dvorakova K, Crowley C, et al. Nicotine increases oxidative stress, activates NF-kapaB and GRP78, induces apoptosis and sensitizes cells to genotoxic/xenobiotic stresses by a multiple stress inducer, deoxycholate: relevance to colon carcinogenesis. Chem Biol Interact. 2003;145:53-66. 84. Cavallini G, Talamini G, Vaona B, et al. Effect of alcohol and smoking on pancreatic lithogenesis in the course of chronic pancratitis. Pancreas. 1994;9:42-46. 85. Owyang C. Chronic Pancreatitis. In: Yamada T, Alpers DH, Kaplowitz N, et al, eds. Textbook of Gastroenterology. 4th Ed. Philadelphia: Lippincott Williams & Wilkins, 2002: 2061-2090. 86. Reber PU, Patel AG, Toyama MT, et al. Feline model of chronic obstructive pancreatitis: effects of acute pancreatic duct decompression on blood flow and interstitial pH. Scand J Gastroenterol. 1999;34:439-444. 87. Boerma D, Straatsburg IH, Offerhaus GJ. Experimental model of obstructive chronic pancreatitis in pigs. Dig Surg 2003;20:520-526. 88. Murayama KM, Barent BL, Bruber M, et al. Characterization of a novel model of pancreatic fibrosis and acinar atrophy. J Gastrointest Surg. 1999;3:418-425. 89. Suda K, Mogaki M, Oyama T, et al. Histopathologic and immunohistochemical studies on alcoholic pancreatitis and chronic obstructive pancreatitis: special emphasis on ductal obstruction and genesis of pancreatitis. Am J Gastroenterol. 1990;85:271275. 90. Ectors N, Maillet B, Aerts R, et al. Non-alcoholic duct destructive chronic pancreatitis. Gut. 1997;41:263-268. 91. Ichimura, Kondo, Ambo, et al. Primary sclerosing cholangitis associated with autoimmune pancreatitis. Hepatogastroenterol. 2002;49:1221-1224. 92. Kulling D, Tresch S, Renner E. Triad of sclerosing cholangitis, chronic pancreatitis, and Sjogren’s syndrome: case report and review. Gastrointest Endosc. 2003;57:118120. 93. Huang C, Lichtenstein DR. Pancreatic and biliary tract disorders in inflammatory bowel disease. Gastrointest Endoscopy Clin N Am. 2002;12:535-559. 94. Okazaki K. Clinical relevance of autoimmune-related pancreatitis. Best Pract Res Clin Gastroenterol. 2002;16:365-378. 95. Okazaki K, Uchida K, Ohana M et al. Autoimmune-related pancreatitis is associated with autoantibodies and Th1/Th2-type cellular immune response. Gastroenterology. 2000;118:573-581. 96. Whitcomb DC, Gorry MC, Preston RA, et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet. 1996;14:141-145. 97. Anderson MP, Rich DP, Gregory RJ, et al. Generation of cAMP-activated chloride channels by expression of CFTR. Science. 1991;251:679-682. 98. Anguiano A, Oates RD, Amos JA, et al. Congenital bilateral absence of the vas deferens: a primarily genital form of cystic fibrosis. JAMA. 1992;267:1794-1797. 99. Truninger M, Malik N, Ammann RW, et al. Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. Am J Gastroenterol. 2001;96:2657-2662. 100. Sharer N, Schwarz M, Malone G, et al. Mutations of the cystic fibrosis gene in patients with chronic pancreatitis. N Engl J Med. 1998;339:645-652. 101. Choudari CP, Yu AC, Imperiale TF, et al. Significance of heterozygous cystic fibrosis gene mutations in idiopathic pancreatitis. Gastroenterology. 1998;114:A1818.
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102. Kristidis P, Bozaon D, Corey M, et al. Genetic determination of exocrine pancreatic function in cystic fibrosis. Am J Hum Genet. 1992;50:1178-1184. 103. Whitcomb DC. Hereditary and childhood disorders of the pancreas, including cystic fibrosis. In: Feldman M, Friedman LS, Sleisenger MH, eds. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. 7th Ed. Philadelphia: WB Saunders, 2002:881912. 104. Witt H, Luck W, Hennies HC, Classen M, Kage A, Lass U, Landt O, Becker M. Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet. 1996;14:141-145. 105. Pfutzer RH, Barmada MM, Brunskil APJ, Finch R, Hart PS, Neoptolemos J, Furey WF, Whitcomb DC. SPINK1/PSTI polypmorphisms act as disease modifiers in familial and idiopathic chronic pancreatitis. Gastroenterology. 2000;119:213-216. 106. Layer P, Yamamoto H, Kalthoff L, et al. The different courses of early and late onset idiopathic and alcoholic chronic pancreatitis. Gastroenterology. 1994;107:1481-1487. 107. Prinz RA, Aranha GV. The association of primary hyperparathyroidism and pancreatitis. Am Surg. 1985;51:325-329. 108. Carey MC, Fitzgerald O. Hyperparathyroidism associated with chronic pancreatitis in a family. Gut. 1968;9:700-703. 109. Goebell H. The role of calcium in pancreatic secretion and disease. Acta Hepato-gastroenterol. 1976:23:151-161. 110. Noel-Jorand MC, Verine HJ, Sarles H. Dose-dependent and long-lasting effects of repeated intravenous injections of calcium on canine secretin-stimulated pancreatic juice secretion. Eur J Clin Invest. 1981;11:25-31. 111. Avram MM. High prevalence of pancreatic disease in chronic renal failure. Nephron. 1977;18:68-71. 112. Vaziri N, Dure-Smith B, Miller R, et al. Pancreatic pathology in chronic dialysis patients-an autopsy study of 78 cases. Nephron. 1987;46:347-349. 113. Avram MM. High prevalence of pancreatic disease in chronic renal failure. Nephron. 1977; 18: 68-71. 114. Ammann RW, Buhler H, Tuma J, et al. Chronic and relapsing acute pancreatitis associated with chronic renal insufficiency and analgesic (phenacetin) abuse. Observations in 4 patients. Gastroenterol Clin Biol. 1981;5:509-514. 115. Forsmark CE. Chronic pancreatitis. In: Feldman M, Friedman LS, and Sleisenger MH, eds. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease. 7th Ed. Philadelphia: WB Saunders; 2002:943-69. 116. Ammann RW, Muellhaupt B: The natural history of pain in alcoholic chronic pancreatitis. Gastroenterology. 1999;116:1132-1140. 117. Ammann RW, Akovbiantz A, LargiaderF, et al. Course and outcome of chronic pancreatitis: longitudinal study of a mixed medical-surgical series of 245 patients. Gastroenterology. 1984;86:820-828. 118. Ammann RW, Muench R, Otto R, Buehler H, Freiburghaus AU, Siegenthaler W. Evolution and regression of pancreatic calcification in chronic pancreatitis: a prospective long-term study of 107 patients. Gastroenterology. 1988;95:1018-1028. 119. Girdwood AH, Marks IN, Bornman PC, Kottler RE, Cohen M. Does progressive pancreatic insufficiency limit pain in calcific pancreatitis with duct stricture or continued alcohol insult? J Clin Gastroenterol. 1981;3:241-245. 120. Miyake H, Harada H, Kunichika K, Ochi K, Kimura I. Clinical course and prognosis of chronic pancreatitis. Pancreas. 1987;2:378-385.
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121. Lankisch PG, Lohr-Happe A, Otto J, et al. Natural course in chronic pancreaittis: pain, exocrine and endocrine pancreatic insufficiency and prognosis of the disease. Digestion. 1993;54:148-155. 122. Laugier R. Dynamic endoscopic manometry of the response to secretin in patients with chronic pancreatitis. Endoscopy. 1994; 26: 222-7. 123. Madsen P, Winkler K. The intraductal pancreatic pressure in chronic obstructive pancreatitis. Scand J Gastroenterol. 1982;12:553-554. 124. Okazaki K, Yamamoto Y, Nishimori I, et al. Motility of the sphincter of oddi and pancreatic main duct pressure in patients with alcoholic, gallstone-associated, and idiopathic chronic pancreatitis. Am J Gastroenterol. 1988;83:820-825. 125. Jalleh RP, Aslam M, Williamson RCN. Pancreatic tissue and ductal pressures in chronic pancreatitis. Br J Surg. 1991;78:1235-1237 126. Fuji T, Amano H, Ohmura et al. Endoscopic pancreatic sphincterotomy: Technique and evaluation. Endoscopy. 1989;21:27-30. 127. Sherman S, Lehman GA, Hawes RH, et al. Pancreatic ductal stones: Frequency of successful endoscopic removal and improvement in symptoms. Gastrointest Endosc. 1991;37:511-517. 128. Ebbehoj N, Borly L, Bulow J, et al. Evaluation of pancreatic tissue fluid pressure and pain in chronic pancreatitis. Scand J Gastroenterol. 1990;25:462-6. 129. Karanjia ND, Singh SM, Widdison AL, et al. Pancreatic ductal and interstitial pressures in cats with chronic pancreatitis. Dig Dis Sci. 1992;37:268-273. 130. Reber HA, Karanjia ND, Alvarez C, et al. Pancreatic blood flow in cats with chronic pancreatitis. Gastroenterology. 1992;103:652-659. 131. Funokoshi A, Nakano I, Shinozaki H. High plasma cholecystokinin levels in patients with chronic pancreatitis having abdominal pain. Am J Gastroenterol. 1986;81:11741178 132. Brown A, Hughes M, Tenner S, et al. Does pancreatic enzyme supplementation reduce pain in patients with chronic pancreatitis: a meta-analysis. Am J Gastroenterol. 1997;92:2032-2035. 133. Bockman DE, Buchler M, Malfertheiner P, et al. Analysis of nerves in chronic pancreatitis. Gastroenterology. 1988:94:1459-1463. 134. Di Sebastiano P, Mola FF, Bockman DE, Friess M, Buchler MW. Chronic pancreatitis: the perspective of pain generation by neuroimmune interaction. Gut. 2003;52:907-911. 135. Chowdhury RS, Forsmark CE, Davis RH, Toskes PP, Verne GN. Prevalence of gastroparesis in patients with small duct chronic pancreatitis. Pancreas. 2003;26:235238. 136. Hoogerwerf WA, Pasricha PJ, Kalloo AN, Schuster MM> Pain: the overlooked symptom in gastroparesis. Am J Gastroenterol. 1999; 94:1029-1033. 137. Conwell DL, Vargo JJ, Zuccaro G, et al. Role of differential neuroaxial blockade in the evaluation and management of pain in chronic pancreatitis. Am J Gastroenterol. 2001;96:431-436 138. DiMagno EP, Go VL, Summerskill WH. Relations between pancreatic enzyme outputs and malabsorption in severe pancreatic insufficiency. N Eng J Med. 1973;288:813-815. 139. Twersky Y, Bank S. Nutritional deficiencies in chronic pancreatitis. Gastroenterol Clin North Am. 1989;18:543-548. 140. Malka D, Hammel P, Sauvanet A, et al. Risk factors for diabetes mellitus in chronic pancreatitis. Gastroenterology. 2000;119:1324-1332.
Chronic Pancreatitis
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141. Apte MV, Keogh GW, Wilson JS. Chronic pancreatitis: Complications and management of pain. J Clin Gastroenterol. 1998;29:225-240. 142. Clain JE, Pearson RK. Diagnosis of chronic pancreatitis: Is a gold standard necessary? Surg Clin N Am. 1999;79:829-843. 143. Remer EM, Baker ME. Imaging of chronic pancreatitis. Radiol Clin N Am. 2002;40:1229-1242. 144. Balthazar E. Pancreatitis. In: Levine M, ed. Textbook of Gastrointestinal Radiology, Volume 2. Philadelphia: WB Saunders; 2000:1767-1795. 145. Scuro LA, Cavallini G, Benini L, et al. Pancreatic calcifications in patients with chronic pancreatitis: a sign of long-lasting or severe disease? Int J Pancreatol. 1990;6:139-150. 146. Lankisch PG, Otto J, Erkelenz I, Lembcke B. Pancreatic calcifications: no indicator of severe exocrine pancreatic insufficiency. Gastroenterology. 1986;90:617-621. 147. Niederau C, Grendell JH. Diagnosis of chronic pancreatitis. Gastroenterology. 1985;88:1973-1995. 148. Axon ATR, Classen M, Cotton P, et al. Pancreatography in chronic pancreatitis. International definitions. Gut. 1984;25:1107-1112. 149. Kizu M, Newmann J, Cotton PB, et al. Histological correlation with pancreatography in necropsy specimens. Gut. 1977;18:399-400. 150. Cavallini G, Riela A, Angelini GP, et al. Limitations in the interpretation of endoscopic retrograde pancreatography findings in chronic pancreatitis. In: Malfertheiner P, Ditschuneit H, eds. Diagnostic Procedures in Pancreatic Disease. Berlin: SpringerVerlag; 1985:175-184. 151. Forsmark CE, Toskes PP. What does an abnormal pancreatogram mean? Gastrointest Endosc Clin N Am. 1995;5:105-123. 152. Semelka RC, Shhoenut JP, Kroeker MA, et al. Chronic pancreatitis: MR imaging features before and after administration of gadopentetate dimeglumine. J Magn Reson Imaging. 1993;3:79-92. 153. Zhang XM, Shi H, Parker L, et al. Suspected early or mild chronic pancreatitis: enhancement patterns on gadolinium chelate dynamic MRI. J Magn Reson Imaging. 2003;17:86-94. 154. Sica GT, Miller FH, Rodriguez G, et al. Magnetic resonance imaging in patients with pancreatitis: evaluation of signal intensity and enhancement changes. J Magn Reson Imaging. 2002;15:275-284. 155. Sica GT, Braver J, Coonehy MJ, et al. Comparison of endoscopic retrograde cholangiopancreatography with MR cholangiopancreatography in patients with pancreatitis. Radiology. 1999;210:605-610. 156. Takehara Y, Ichijo K, Tooyama N, et al. Breath-hold MR cholangiopancreatography with a long-echo-train fast spin-echo sequence and a surface coil in chronic pancreatitis. Radiology. 1994;192:73-78. 157. Matos C, Metens T, Deviere J, et al. Pancreatic duct: morphologic and functional evaluation with dynamic MR pancreatography after secretin stimulation. Radiology. 1997;203:435-441. 158. Cappeliez O, Delhaye M, Deviere J, et al. Chronic pancreatitis: evaluation of pancreatic exocrine function with MR pancreatography after secretin stimulation. Radiology. 2000;215:538-564.
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159. Sahai AV, Zimmerman M, Aabakken L, et al. Prospective assessment of the ability of endoscopic ultrasound to diangose, exclude, or establish the severity of chronic pancreatitis found by endoscopic retrograde cholangiopancreatography. Gastrointest Endosc. 1998;48:18-25. 160. Nattermann C, Goldschmidt AJ, Dancgier H. Endosonography in chronic pancreatitis-a comparison between endoscopic retrograde pancreatography and endoscopic ultrasonography. Endoscopy. 1993;25:555-564. 161. Wiersma MJ, Hawes RH, Lehman GA, et al. Prospective evaluation of endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography in patients with chronic abdominal pain of suspected pancreatic origin. Endoscopy. 1993;25:555564. 162. Forsmark CE. The diagnosis of chronic pancreatitis. Gastrointest Endosc. 2000;52:293298. 163. Sahai AV, Mishra G, Penman ID, et al. EUS to detect evidence of pancreatic disease in patients with persistent or nonspecific dyspepsia. Gastrointest Endosc. 2000;52:153159. 164. Lankisch PG. Exocrine pancreatic function tests. Gut. 1982;123:777-785 165. Toskes PP. Diagnosis of chronic pancreatitis and exocrine insufficiency. Hosp Pract. 1985;97-108. 166. Conwell DL, Zuccaro G, Vargo JJ, et al. An endoscopic pancreatic function test with synthetic porcine secretin for the evaluation of chronic abdominal pain and suspected chronic pancreatitis. Gastrointest Endosc. 2003; 57: 37-40. 167. Conwell DL, Zuccaro G, Vargo JJ, et al. An endoscopic pancreatic function test with cholecystokinin-octapeptide for the diagnosis of chronic pancreatitis. Clinical Gastroenterology Hepatology. 2003;1:189-194. 168. Ammann RW, Tagwercher E, Dashiwagi H, et al. Diagnostic value of fecal chymotrypsin and trypsin assessment for detection of pancreatic disease. Am J Dig Dis. 1968;13:123-146. 169. Lankisch PG, Schreiber A, Otto J. Pancreolauryl test: evaluation of a tubeless pancreatic function test in comparison with other indirect and direct tests for exocrine pancreatic function. Dig Dis Sci. 1983;28:490-493. 170. Toskes PP. The bentiromide test for pancreatic exocrine insufficiency. Pharmacotherapy. 1984;4:74-83. 171. Branganza JM, Hunt LP, Warwich R. Relatinoship between pancreatic exocrine function and ductal morphology in chronic pancreatitis. Gastroenterology. 1982;82:13411347. 172. Malfertheiner P, Buchler M, Stanescu A, et al. Exocrine pancreatic function in correlation to ductal and parencymal morphology in chronic pancreatitis. Hepatogastroenterology. 1986;33:110-114. 173. Lowenfels AB, Maisonneuve P, Cavillini G, et al. Pancreatitis and the risk of pancreatic cancer. N Engl J Med. 1993;328:1422-1427. 174. Gullo L, Barbara L, Labo G. Effectg of cessation of alcohol use on the course of pancreatic dysfunction in alcoholic pancreatitis. Gastroenterology. 1998;95:1063-5. 175. Strum WB, Spiro HM. Chronic pancreatitis. Ann Intern Med. 1971;74:264-71. 176. Isaksson G, Ihse I. Pain reduction by an oral pancreatic enzyme preparation in chronic pancreatitis. Dig Dis Sci. 1983;28:97-102. 177. Cremer M, Deviere J, Delhaye M, et al. Stenting in severe chronic pancreatitis: results of medium term follow up in seventy-six patients. Endoscopy. 1991;23:171-176.
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178. Dite P, Ruzicka M, Zboril V, Novotny I. A prospective, randomized trial comparing endoscopic and surgical therapy for chronic pancreatitis. Endoscopy. 2003;35:553558. 179. Leung JW, Bowen-Wright M, Aveling W, et al. Celiac plexus block for pain in pancreatic cancer and chronic pancreatitis. Br J Surg. 1983;70:730-732. 180. Gress F, Schmidt C, Sherman S, et al. A prospective randomized comparison of endoscopic ultrasound- and computed tomography-guided celiac plexus block for managing chronic pancreatitis pain. Am J Gastroenterol. 1999;94:900-905. 181. Howell JG, Johnson LW, Sehon JK, et al. Surgical management for chronic pancreatitis. Am Surg. 2001;67:487-490. 182. Crass RA, Way LW. Acute and chronic pancreatic pseudocysts are different. Am J Surg 1981;142:660. 183. Maule WF, Reber HA. Diagnosis and management of pancreatic pseudocysts, pancreatic ascites, and pancreatic fistulas. In: Go VLW, DiMagno EP, Gardner JD, Lebenthal E, Reber HA, Scheele GA (eds). The Pancreas: Biology, Pathobiology and Disease. 2nd ed. New York: Raven Press;1993:741-750. 184. Yeo CJ, Bastidas JA, Lynch-Nyham A, et al. The natural history of pancreatic pseudocysts documented by computed tomography. Surg Gynecol Obstet. 1990;170:411-416. 185. Kozarek RA. Endoscopic therapy of complete and partial pancreatic ductal disruption. Gastrointest Endosc Clin North Am. 1998;8:39-53. 186. Weber SM, Rikkers LF. Splenic vein thrombosis and gastrointestinal bleeding in chronic pancreatitis. World J Surg. 2003 ;27:1271-1274. 187. Tessier DJ, Stone WM, Fowl RJ, et al. Clinical features and management of splenic artery pseudoaneurysm: case series and cumulative review of literature. J Vasc Surg. 2003;38:969-974. 188. Brountzos EN, Vagenas K, Apostolopoulou SC, et al. Pancreatitis-associated splenic artery pseudoaneurysm: endovascular treatment with self-expandable stent-grafts. Cardiovasc Intervent Radiol. 2003;26:88-91. 189. Lowenfels AB, Maisonneuve P, Cavallini G, et al. International Pancreatitis Study Group: Prognosis of chronic pancreatitis: An international multicenter study. Am J Gastroenterol. 1994;89:1467-1471. 190. Lankisch PG. Natural course of chronic pancreatitis. Pancreatology. 2001;1:3-14. 191. Conwell DL, Zuccaro G. Pain management in chronic pancreatitis. Current Treatment Options in Gastroenterology. 1999;0:295-304.
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10
Pancreatic Ductal Complications Ali Fazel, MD
Introduction Benign and malignant pancreatic diseases produce a variety of pancreatic duct (PD) abnormalities. Potential complications of the pancreatic duct include strictures, stones, and leaks. Abnormalities found on endoscopic retrograde pancreatogram characterize pancreatic ductal complications. Strictures present as a narrowing of the PD, which most often occurs in the setting of pancreatitis or pancreatic cancer. Stones almost always occur in the setting of chronic pancreatitis and can be seen as filling defects within the opacified PD. Pancreatic duct leaks are characterized by extravasation of contrast media from the pancreatic duct and into surrounding tissues. Pancreatic duct leaks can lead to pseudocysts, fistula formation, and ascites (Table 10-1). This chapter reviews the clinical manifestations, diagnostic approach, and management strategies for these complications.
Pancreatic Duct Strictures Pancreatic duct strictures are defined by a significant narrowing of the pancreatic duct on pancreatogram. Pancreatitis and pancreatic cancer cause the vast majority of pancreatic duct strictures. The diagnostic work-up revolves around the differentiation of a benign from a malignant stricture. This vital distinction leads to the consideration of surgical pancreatic resection for malignant disease, while benign strictures can often be managed by nonsurgical means (Table 10-2).
DIAGNOSTIC EVALUATION The basic challenge is to identify and operate on patients with malignancy when they are still respectable, while trying to avoid surgery in those with benign disease. Malignant cytological findings on endoscopic brushing of a stricture definitively establish the diagnosis of malignancy. Unfortunately, brushing of malignant strictures yields positive cytological findings in less than one-half of patients. In the absence of
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Table 10-1
PANCREATIC DUCTAL COMPLICATIONS Stricture Stone Leak
Table 10-2
ETIOLOGIES OF PANCREATIC DUCT STRICTURES Neoplastic • • •
Adenocarcinoma Neuroendocrine tumors Cystic neoplasms
Pancreatitis • • •
Chronic pancreatitis Acute pancreatitis Pseudocyst
Blunt abdominal trauma Stent-induced Idiopathic
positive findings on brushings, one must fall back on alternative methods to judge the likelihood of malignancy. Parameters to be considered include clinical presentation, pancreatography findings, endoscopic ultrasound, and serum Ca 19-9 (Table 10-3).
CLINICAL PRESENTATION Individuals with pancreatic strictures often present with symptoms of acute pancreatitis, acute recurrent pancreatitis, chronic pancreatitis, or pancreatic malignancy. Abdominal pain is the primary symptom of acute pancreatitis. The pain is located in the upper abdomen and often radiates to the back. This can be associated
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Table 10-3
DIAGNOSTIC TOOLS FOR THE EVALUATION OF PANCREATIC DUCT STRICTURES Clinical presentation ERCP • Pancreatography • Cytology
Endoscopic ultrasound (EUS) with FNA Serum Ca-19-9 with nausea, vomiting, and abdominal distention. In chronic pancreatitis, the upper abdominal pain becomes chronic and is often associated with steatorrhea or diabetes mellitus. The latter manifestations result from exocrine and endocrine insufficiency of the pancreas. The cardinal manifestation of pancreatic malignancy is upper abdominal pain and weight loss. This is associated with jaundice in one-half of cases. Progressive weight loss and painless jaundice strongly suggest malignancy.
ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAM Close examination of the cholangiopancreatogram provides important clues to the cause of a pancreatic duct stricture. A single irregular stricture with proximal dilation and normal distal anatomy is suggestive of malignancy (Figure 10-1). Contiguous strictures of the pancreatic duct and common bile duct carry a positive predictive value of 85% for the presence of pancreatic cancer (Figure 10-2). This “double duct sign” indicates a high likelihood of malignancy but can also be seen in the setting of chronic pancreatitis. In chronic pancreatitis, dilation of the main pancreatic duct and abnormal side branches may be seen both proximal and distal to benign strictures. Chronic pancreatitis can also present with multiple strictures and intervening areas of ductal dilation (chain of lakes appearance) (Figure 10-3). Six percent of pancreatic malignancies develop in the setting of chronic pancreatitis. Consequently, a pancreatogram consistent with chronic pancreatitis does not entirely exclude the possibility of malignancy. The diagnosis of a benign stricture must be supported by other clinical findings as well. Faulty pancreatogram technique and anatomic variation can be mistaken for the presence of a PD stricture. Underfilling of the PD creates the appearance of ductal irregularity and narrowing. An adequate injection of contrast that fills the entire main PD and secondary side branches reverses this irregular appearance. Inadvertent injec-
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Figure 10-1. A malignant ductal stricture located in the pancreatic body. Upstream to the stricture significant dilation of the pancreatic duct and side branches is seen. Downstream to the stricture the pancreatic duct appears normal.
Figure 10-2. Contiguous strictures of the pancreatic duct and common bile duct causing proximal dilation of both ducts. A “double duct sign” indicates a high likelihood of malignancy but can also be seen in chronic pancreatitis.
tion of air into the PD can create the false appearance of a PD cutoff. Advancing the catheter into the pancreatic body and gently injecting contrast into the proximal PD resolves this false appearance. Most variants are of no clinical significance and familiarity with these possibilities helps avoid unnecessary work-up. Ventral-dorsal ductal malfusions such as pancreas
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Figure 10-3. Multiple ductal stictures are separated by intervening areas of ductal dilation (chain of lakes appearance). This appearance is consistent with advanced chronic pancreatitis.
divisum and incomplete pancreas divisum can be mistaken for occlusion or stricture of the PD. Atypical configurations of the PD most often include an ansa loop or spiral loop of the ventral duct in the pancreatic head.
ENDOSCOPIC ULTRASOUND Endoscopic ultrasound (EUS) is the most sensitive method for the detection of small pancreatic masses, particularly when they are smaller than 2 cm in size. Pancreatic malignancies appear as a relatively hypoechoic area that encompasses the pancreatic duct at the site of the stricture. Fine-needle aspiration (FNA) biopsy of these focal abnormalities can definitively confirm the presence of malignancy in 80% to 90% of cases. Unfortunately, in the setting of chronic pancreatitis, the sensitivity of FNA biopsy decreases to 50%. Although EUS has proven very useful for the overall early diagnosis of pancreatic cancer, this utility has not been well studied in the setting of patients presenting with pancreatic duct strictures.
SERUM CA 19-9 Ca 19-9 is the only tumor marker of practical utility in the evaluation of PD strictures. The positive predictive value (PPV) and negative predictive value (NPV) of this marker for the diagnosis of pancreatic cancer varies depending on the cutoff value chosen. A cutoff of 37 U/mL provides a sensitivity of 80% and NPV of 90%. A cutoff of 1000 U/mL provides a specificity of 100%. Thus a value of greater than 1000 U/mL strongly supports the diagnosis of malignancy. Milder elevations can be seen in jaundiced patients without pancreatic cancer. Ca 19-9 levels can be normal in
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early pancreatic cancers, and thus low levels of this tumor marker cannot effectively exclude the possibility of pancreatic cancer1.
MANAGEMENT OF THE CYTOLOGY NEGATIVE PANCREATIC DUCT STRICTURE The management options for a newly diagnosed cytology negative PD stricture include proceeding with a pancreatic resection on the assumption that the stricture is malignant, or treating the lesion as a benign stricture. To proceed with a blind resection, a break-even point must be reached where the benefits outweigh the risks of surgery. The mortality associated with a pancreaticoduodenectomy is approximately 5% and major morbidity occurs in another 5% to 10%. Half of the patients undergoing successful resection of their tumor will experience long-term disease-free survival. Consequently, the benefits of blind resection outweigh the risks when the ultimate likelihood of a resectable pancreatic cancer is greater than 20%. Vigilant followup is needed in cases where strictures are presumed to be benign. Periodic clinical evaluation and abdominal imaging (transabdominal ultrasound, abdominal CT, or EUS) should be performed to rule out any changes that would suggest a previously undetected malignancy. Findings of particular concern include a new or evolving pancreatic mass or progressive ductal dilation.
TREATMENT OF THE BENIGN PANCREATIC DUCT STRICTURES Given the presumed role of ductal hypertension in the genesis of symptoms in patients with PD strictures, measures to bypass or traverse the stricture to relieve the increased pressure are undertaken. These measures can be medical, endoscopic, or surgical. Therapies are primarily directed at the relief of pain and the prevention of recurrent bouts of acute pancreatitis. Asymptomatic strictures do not require treatment once the possibility of malignancy has been adequately excluded. Mildly symptomatic patients respond well to conservative therapy consisting of analgesics and/or pancreatic enzymes. When conservative therapy fails, consideration is given to endoscopic or surgical intervention.
ENDOSCOPIC THERAPY OF BENIGN STRICTURES Endoscopic therapy is appropriate in symptomatic benign PD strictures. Significant strictures can present with pain and/or pancreatitis. Pancreatic malignancy must be adequately excluded prior to embarking on a course of endoscopic therapy. Endoscopic therapy often requires multiple treatment sessions necessitating significant motivation and compliance on the part of the patient. Endoscopic therapy of benign pancreatic strictures includes pancreatic sphincterotomy, stricture dilation, and/or stenting of the PD. Often multiple treatment sessions are required over an interval of 6 to 12 months. In the presence of ductal stones or pseudocyst, stone extraction and pseudocyst drainage can facilitate the treatment of PD strictures.
Pancreatic Sphincterotomy Pancreatic sphincterotomy increases the size of the pancreatic duct orifice and facilitates the insertion of endoscopic accessories. The methods for pancreatic sphincterotomy include standard pull-type sphincterotomy and needle knife sphincterotomy. Standard pull-type pancreatic sphincterotomy requires initial
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Figure 10-4. A schematic representation of a pancreatic sphincterotomy: A. Cannulation of the bile duct is obtained with a pull-type sphincterotome; B. A biliary sphincterotomy is performed exposing the pancreaticobiliary septum covering the intramural portion of the pancreatic duct; C. Deep cannulation of the pancreatic duct is obtained and a pancreatic sphincterotomy is performed in the 12 o’clock position along the full length of the pancreaticobiliary septum.
cannulation of the bile duct with a pull-type sphincterotome. A biliary sphincterotomy exposes the pancreaticobiliary septum covering the intramural portion of the PD. The pancreatic orifice can be identified near the 3 to 6 o’clock margin of the biliary sphincterotomy. Deep cannulation of the pancreatic duct is then obtained with a pull-type sphincterotome. The pancreatic sphincterotomy is performed in the 12 o’clock position along the full length of the pancreaticobiliary septum (Figure 10-4). Occasionally, cannulation of a stenotic PD orifice necessitates the use of a taper tipped catheter for cannulation. Needle knife pancreatic sphincterotomy requires the placement of a stent into the distal PD. The PD stent serves as a guide for the direction and extent of the needle knife incision and provides prophylaxis against the development of postsphincterotomy pancreatitis. The needle knife consists of a plastic catheter with a protruding bare cutting wire that delivers electrocautery current. The needle knife cut is begun at the papillary orifice and is extended along the intramural portion of the PD by following the course of the stent. This technique often cannot be used because strictures or stones in the pancreatic head can impede initial placement of the stent. Early complications of pancreatic sphincterotomy include pancreatitis, bleeding, perforation, and pancreaticobiliary sepsis. These can occur in 10% to 13% of cases. The vast majority of early complications are related to post-ERCP pancreatitis, which can develop in 7% to 13% of pancreatic sphincterotomies. Placement of a pancreatic stent decreases the risk of pancreatitis and is effective in preventing the more severe forms of post-ERCP pancreatitis. Late complications of pancreatic sphincterotomy consist of stricture at the sphincterotomy site. This has been reported to occur in up to
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14% of cases and can be treated with repeat sphincterotomy. This significant stenosis rate has led to the use of pure cut current for pancreatic sphincterotomies.
Stricture Dilation Dilation can be performed with dilation balloons or catheters. Dilation balloons are available in 4, 6, and 8 mm diameters. The diameter of the stricture and the overall diameter of the pancreatic duct determine the size of balloons used. A guidewire must be able to traverse the stricture. The dilating device is then passed over the guidewire and through the area of narrowing. The dilating balloon is 2 cm long and is located on the distal tip of a 5 to 7 French catheter. Radio-opaque markers at the distal and proximal ends of the balloon allow accurate positioning of the balloon across the stricture site. The balloon is inflated to a predetermined pressure until there is obliteration of the balloon waist at the site of narrowing. The entire procedure is performed under fluoroscopic guidance. Tight strictures that cannot be traversed with a balloon catheter can be dilated by passing a graduated dilating catheter across the stricture. This catheter is delivered over a guidewire and ranges from 3 to 10 Fr in size. The success of graduated dilation may be limited by the amount of force that can be applied to pass the dilating catheter through the stricture.
Pancreatic Stent Placement Pancreatic stent placement maintains stricture patency after dilation. The best candidates for pancreatic duct stenting appear to be those patients with a stricture in the pancreatic head and “upstream” dilation. The technique for placing a stent in the pancreatic duct is similar to that used for placing a biliary stent. In some patients, a pancreatic sphincterotomy (with or without a biliary sphincterotomy) is performed to facilitate placement of accessories and stents. The stent is advanced over a guidewire, which must traverse the stricture, and across the stricture using a “pushing catheter” under fluoroscopic guidance. Stent diameter, which ranges from 5 to 10 French, is determined by the size of dilator used and the diameter of the pancreatic duct (Figure 10-5). In general, the stent diameter should not exceed the downstream duct diameter. Flaps located on both ends of the stent prevent stent migration. Stent length should be chosen such that one flap is located just outside the papilla and the other flap is positioned beyond the stricture. High-grade strictures may require dilation prior to placement of endoprosthesis. Reported initial outcomes of endoscopic therapy of benign PD strictures have been promising. Stent insertion is technically possible in 72% to 100% of cases. Difficulty in stent insertion occurs primarily in the setting of pancreas divisum. Subsequent to stent insertion, symptomatic relief occurs in 75% to 95% of cases. This symptomatic improvement continues after stent removal in 47% to 70%. Longer term follow-up, ranging from 1 to 2 years, has shown that long-term stricture resolution occurs in 20% to 40% of patients2-5. This success has been tempered by several concerns. Long-term resolution of strictures occurs in only 20% to 40% of patients. Stent occlusion can lead to recurrent pancreatitis and pancreatic sepsis. Finally, increasingly recognized is the potential for focal pancreatitis and even stricture formation elicited by the presence of a pancreatic stent itself. Avoidance of stent-induced complications may be reduced by shortening the stent exchange intervals and limiting the duration of overall endoscopic therapy of strictures.
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Figure 10-5. Above a balloon dilation catheter, graduated dilation catheter and a pancreatic duct stent can be seen.
SURGICAL THERAPY OF BENIGN STRICTURES Surgical therapy is indicated when medical and endoscopic interventions fail to provide adequate relief. Three types of surgical procedures can be performed: 1) ductal drainage, 2) pancreatic resection, and 3) combined drainage and resection. Pancreatic duct anatomy, the presence of concomitant biliary or duodenal stricture, the presence of pseudocysts, and significant concern for malignancy influence the type of surgical procedure performed. A pancreatic head stricture associated with a biliary or duodenal stricture, a small pancreatic duct, or significant pancreatic head enlargement would necessitate a pancreatic head resection (Whipple procedure or pancreaticoduodenectomy). A pancreatic head stricture with a diffusely dilated upstream pancreatic duct and mid-body pseudocyst could be best addressed with a side-to-side pancreaticojejunostomy (Puestow procedure). A stricture in the pancreatic body or tail and pancreatitis isolated to the distal pancreas can be treated with a distal pancreatectomy. Surgical outcomes have been favorable in the setting of chronic pancreatitis. The Puestow procedure provides initial pain relief in 65% to 80% of patients. On longterm follow-up, one-third of patients experience lasting pain relief. The more extensive Whipple procedure provides pain relief in 80% to 90%. Enthusiasm for this extensive operation is tempered by the acute and chronic morbidity associated with the procedure. There are no studies comparing medical, endoscopic, and surgical therapies for treatment of benign pancreatic duct strictures.
Pancreatic Duct Stones PATHOGENESIS Pancreatic stones develop in the setting of chronic pancreatitis in over one-half of patients. Pancreatic stones develop within the pancreatic ductal system and primarily consist of precipitated calcium carbonate crystals. Pancreatic secretions consist of water, electrolytes, and digestive enzymes. These electrolytes include supersaturated concentrations of calcium and bicarbonate. Normal pancreatic secretions contain a number of factors that inhibit calcium carbonate crystal formation and aggregation.
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The acinar cells produce and secrete a “lithostatin” protein. This protein is stored in acinar zymogen granules and upon release into the pancreatic ducts inhibits the precipitation and crystallization of calcium carbonate. Citrate also plays an antilithogenic role through the chelation of calcium. Chronic pancreatitis leads to changes in pancreatic juice flow and a decrease in antilithogenic factors such as lithostatin and citrate. Changes in these poorly understood antilithogenic factors contribute to calcium carbonate stone formation in the setting of chronic pancreatitis.
CLINICAL PRESENTATION Pancreatic stone formation can aggravate the clinical course of chronic pancreatitis, manifested as increased abdominal pain, worsening pancreatic insufficiency, pseudocyst formation, or recurrent attacks of acute pancreatitis. Stones form in the main pancreatic duct as well as primary and secondary duct side branches. The rationale for intervention is based on the premise that stones that obstruct the PD and impede drainage of pancreatic secretions lead to increased ductal and parenchymal pressure. Increased pressure impairs pancreatic blood flow and leads to ischemia and pain.
DIAGNOSTIC EVALUATION The possible presence of pancreatic stones should be sought in patients with chronic pancreatitis who have worsening or refractory symptoms. The evaluation must identify pancreatic stones and their anatomic location relative to the main PD. Stones within the main PD should be extracted to remove any impediment to the flow of pancreatic juice. In contrast, stones in PD branches generally do not require extraction as long as they do not impair the overall drainage of pancreatic secretions. The various imaging modalities available to diagnose pancreatic duct stones include noninvasive imaging methods such as radiographs, CT scan, and MRCP, and invasive methods such as ERCP and EUS.
Noninvasive Imaging Most PD stones are visible on plain abdominal radiographs as focal calcified densities within the pancreas. Although the plain radiograph identifies the presence of stones, it does not provide information about the relationship of the stone to the pancreatic duct (Figure 10-6). The most sensitive modality for the detection of pancreatic calcification is CT scan. Small stones that are not visible on plain radiographs are clearly visualized on CT scan. Occasionally, the stone can be seen to be located within the main PD, causing upstream dilation of the duct. MRCP has become the noninvasive modality of choice for detection of stones and mapping of their relationship to the PD. MRI/MRCP provides images of the PD analogous to ERCP and cross-sectional images of the parenchyma similar to CT scan. The administration of secretin during MRCP enhances delineation of the PD and its branches.
Invasive Imaging When ductal anatomy and the precise location of pancreatic stones cannot be defined by noninvasive means, the method of choice is ERCP (Figure 10-7). As MRCP imaging improves, ERCP will probably become limited to cases where endoscopic therapy is planned. ERCP allows the detection of strictures and ductal
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Figure 10-6. Pancreatic duct stones (arrows) seen as focal calcified densities within the pancreas on plain abdominal radiographs. The pancreas extends across the L-1 and L-2 vertebral bodies. tortuosity downstream from the stone. Impacted stones characteristically are immobile and impede the injection of contrast or the passage of guidewires beyond their location. On EUS examination, pancreatic stones appear as hyperechoic foci with distal shadowing. EUS also provides helpful information in regards to the location of the stone relative to the main pancreatic duct. Endosonography also helps exclude the presence of a pancreatic mass at the site of any associated ductal strictures.
CHOICE OF THERAPEUTIC MODALITIES Therapeutic options for the treatment of pancreatic stones include extracorporeal shock wave lithotripsy, endoscopic extraction, and surgery. The information obtained from pancreatic imaging dictates the therapy that can be used for optimal effect. Issues that require special attention include the stone size, number, location, and degree of impaction. The presence of PD strictures and ductal tortuosity downstream from the stones also greatly influences the possibility of endoscopic extraction (Table 10-4).
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Figure 10-7. The filling defect in the main pancreatic duct of the pancreatic head (arrow)
represents a ductal stone. The stone is not impacted and contrast freely flows beyond the stone and into the proximal pancreatic.
ENDOSCOPIC THERAPY OF PANCREATIC STONES A pancreatic sphincterotomy is usually performed to both facilitate the insertion of stone retrieval devices and for stone extraction. The need for a simultaneous biliary sphincterotomy is not necessary. Standard biliary stone retrieval devices (baskets and balloons) are the most common accessories used to remove PD stones. An extraction balloon can be advanced past nonimpacted stones. Balloon inflation and withdrawal can successfully remove smaller stones in the pancreatic head. This technique is limited by the tendency of the balloon to force stones into side branches of the PD. Alternatively, stones can be grasped and extracted using baskets. Nonimpacted stones in the pancreatic head or body are often successfully removed with this technique. Stones of larger size that cannot be extracted with a balloon or basket can be initially fragmented with mechanical lithotripsy. The use of mechanical lithotripsy is usually limited to the pancreatic head due to the relative rigidity of the mechanical lithotripter. Downstream strictures usually require dilation prior to attempting stone extraction. Guidewires, balloons, and baskets often cannot be advanced past stones impacted in
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Table 10-4
SELECTION OF THERAPEUTIC APPROACH The selection of the therapeutic approach is dictated by the stone size, number, location, impaction, and the status of downstream pancreatic duct.
ERCP extraction alone • • • •
10 mm in size Greater than 3 in number Located in pancreatic body or tail Stone impaction, downstream ductal stricture, or tortuosity
Surgery • Failed endotherapy • Presence of inflammatory mass with concern for malignancy
the PD duct lumen. When a PD stone cannot be removed on initial ERCP, extracorporeal shock wave lithotripsy (ESWL) should be performed to fragment the stone and facilitate endoscopic removal. Stone clearance has been reported in 70% to 80% of cases. In individuals whom stone clearance succeeds, immediate pain relief occurs in 80% to 100% of cases. When patients have been followed for up to 5 years, this pain relief has continued in 55% to 85% of cases 6-10. Complications of endoscopic stone extraction occur in 5% to 15% of cases and are often related to the pancreatic sphincterotomy. These complications include pancreatitis, bleeding, cholangitis, and in rare instances, perforation.
EXTRACORPOREAL SHOCK WAVE LITHOTRIPSY Since its introduction in 1987, ESWL has become a safe and accepted modality for the management of PD stones. Shockwaves are generated by electrohydraulic (Dornier, Erlangen, Germany) or electromagnetic (Siemens, Munich, Germany) generators and are focused onto the targeted stone. Accurate targeting of the stone through fluoroscopic guidance is very important for successful lithotripsy. The delivery of shockwaves causes cavitation of the dissolved gases in the fluid around the stone.
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The resultant force fragments the stone into smaller particles. Most radio-opaque calcium-containing stones will easily fragment, while radiolucent stones can be resistant. The procedure is performed under conscious sedation. ERCP is performed within 24 hours of ESWL to remove the resultant stone fragments. These fragments can then be removed with balloon or basket extraction devices or will pass spontaneously. Most patients require 1 to 3 sessions, depending on the number and size of stones present. Lithotripsy is associated with little morbidity. Successful fragmentation can be confirmed on fluoroscopy. Radiographic findings sometimes can be limited to slight mottling and heterogeneity of the stone, which can be difficult to detect. Stone fragmentation rates of over 90% have been reported. Complications include skin petechiae and gastroduodenal erosions. Significant morbidity is rare, and no mortalities have been reported in large series. Combined ESWL and endoscopic therapy leads to complete clearance of the PD in 50% to 75% of cases and partial clearance in an additional 5% to 30%. Studies have demonstrated clinical improvement, defined as complete or partial pain relief, increase in body weight, and improvement of exocrine function in 62% to 86% of cases. Surgery was necessary in only 5% to 15% of patients. Combined ESWL and endoscopic therapy has been most successful in individuals with earlier stages of chronic pancreatitis, and stones in the prepapillary location without any distal PD strictures7,11.
Pancreatic Duct Leaks Extravasation of contrast media from the PD on endoscopic retrograde pancreatogram establishes the diagnosis of PD leak (Figure 10-8). Leakage of pancreatic secretions from defects in the PD into the peripancreatic tissues and organs can lead to pseudocysts, fistula formation, pleural effusion, and ascites. The leak originates from a defect in the PD that can be a consequence of acute necrotizing pancreatitis, chronic pancreatitis, or penetrating abdominal trauma. Obstructive lesions of the distal PD such as strictures or stones can perpetuate and aggravate PD leaks by forcing pancreatic secretions through PD defect and into the peripancreatic area (Table 10-5).
PANCREATIC PSEUDOCYSTS Pancreatic duct defects that arise in the setting of acute or chronic pancreatitis often lead to the collection of pancreatic secretions and inflammatory debris in the peripancreatic area (Figure 10-9). Over a period of 4 to 6 weeks, this collection develops a fibrous capsule. This fibrous capsule does not have an epithelial lining, hence the term “pseudocyst”. Pseudocysts may complicate 7% to 15% of episodes of acute pancreatitis and 20% to 25% of chronic pancreatitis cases. Although pseudocysts can be asymptomatic, they may cause abdominal pain, nausea, or vomiting. Pseudocysts can also be complicated by infection or hemorrhage. Most asymptomatic pseudocysts resolve spontaneously and do not require therapeutic intervention. However, pseudocysts that are symptomatic, demonstrate progressive enlargement, or are infected require intervention. Increasingly, the method of choice for pseudocyst drainage is endoscopic. Often radiological or surgical drainage is performed when endoscopic drainage has failed or is not technically possible. The decision to drain a pseudocyst should be made independent of the intervention chosen.
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Figure 10-8. Extravasation of contrast media from the pancreatic duct in the mid-pancreas. Contrast can be seen leaking from an otherwise normal pancreatic duct in a patient with penetrating abdominal trauma. The contrast extravasating from the pancreatic body leaks into the peripancreatic space.
DIAGNOSTIC EVALUATION Several diagnostic issues may need to be considered before proceeding with pseudocyst drainage:
1. Has the presence of a cystic neoplasm been adequately excluded? This possibility is of greatest concern in individuals who do not have a clear history of acute or chronic pancreatitis. Diagnostic sampling of cyst fluid through EUS-FNA can help exclude a neoplastic process through cytological examination and measurement of tumor markers. Pseudocyst fluid cytology shows abundant debris and inflammatory cells. Columnar cells with intracellular mucin or significant amounts of background mucin are often seen in mucinous cystic neoplasia. Fluid CEA and amylase levels can complement the diagnostic utility of cytology. In pseudocysts amylase levels are consistently high. A high cyst fluid CEA level strongly suggests a mucinous neoplasm.
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Table 10-5
CAUSES AND CONSEQUENCES OF PANCREATIC DUCT LEAKS Causes • Acute pancreatitis • Chronic pancreatitis • Abdominal trauma
Consequences • Pseudocyst • Pancreatic fistulas • Ascites
2. Is an underlying pancreatic duct obstructive lesion contributing to the pseudocyst? Obstructive lesions such as stricture or stones are most often seen in individuals with chronic pancreatitis, and if left untreated can lead to recurrence after pseudocyst drainage. ERCP identifies these lesions and allows endoscopic therapy. Dilation and stenting of strictures can be performed and stones extracted.
ENDOSCOPIC PSEUDOCYST DRAINAGE Transmural and transpapillary approaches can be employed in the endoscopic treatment of pseudocysts. In transmural drainage, a stent is placed across a communication tract created between the pseudocyst cavity and the bowel lumen (cystogastrostomy or cystoduodenostomy). This allows drainage of the fluid collection into the gastroduodenal lumen. In transpapillary drainage, a stent is placed across the papilla into the pancreatic duct. This allows drainage of the cyst fluid through the PD and papilla. The choice of therapy depends on whether the cyst communicates with the PD or is in close apposition to the gut lumen.
Transmural Drainage Transmural drainage can be performed with a standard side viewing endoscope or a therapeutic linear array echoendoscope. Standard endoscope requires the presence of a gastroduodenal wall bulge for selection of a drainage site. The therapeutic linear array echoendoscope allows the localization and drainage of nonbulging pseudocysts through ultrasound imaging. Ultrasound imaging has the additional benefit of identifying intervening blood vessels and the distance between the gastroduodenal lumen and the pseudocyst lumen. The gastroduodenal site selected for drainage should be free of significant blood vessels to decrease the risk for bleeding. The distance between the pseudocyst cavity and the gastroduodenal lumen should be less than 1 cm. This finding further ensures adequate adherence of the enteric wall to the pseudocyst wall and lowers the possibility of perforation and intraperitoneal contamination.
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Figure 10-9. Contrast leakage can be seen extravasating from the tail of the pancreatic duct and into an adjacent pseudocyst cavity (arrow).
A 19-gauge needle is advanced into the pseudocyst cavity through the selected site in the stomach or duodenum. Many authorities advocate diathermic needle cautery to create a fistula between the gut lumen and the cyst. A 0.35-inch guidewire is advanced into the pseudocyst cavity, allowing passage of other accessories over the guidewire, across the communicating tract, and into the pseudocyst. The communicating tract is enlarged using a dilation balloon (4 to 10 mm size) that is advanced over the guidewire. One or more double pigtail stents are then placed in the tract. These stents extending from the pseudocyst cavity into the gastroduodenal lumen maintain the patency of the communicating tract and provide internal drainage of the pseudocyst fluid. Pseudocyst contents containing thick fluid and significant debris benefit from the additional placement of a 7 French nasocystic catheter. The nasocystic drain allows irrigation of the pseudocyst cavity over a period of several days with the intention of clearing the cavity of all significant debris. The technical success rate of transmural drainage ranges from 90% to 100%. Transmural drainage leads to pseudocyst resolution in 80% to 100% of cases. However, pseudocyst recurrence can occur in 10% to 15% of cases12-19.
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Bleeding, perforation, and infection can occur after pseudocyst drainage. EUS imaging is thought to reduce the risk of bleeding and perforation through more careful selection of the gastroduodenal drainage site. Due to the significant risk of complications, patients are admitted for overnight inpatient observation. Due to the infection risk, intravenous prophylactic antibiotics should be administered during the procedure and continued orally for 2 to 4 weeks. Abdominal CT scans should be performed every 8 weeks to assess for resolution of the pseudocyst cavity. Radiographic resolution of the pseudocyst allows endoscopic removal of the stents. This usually occurs after 8 to 12 weeks. If the pseudocyst cavity persists, the transmural stents should be exchanged every 8 weeks to avoid occlusion of the drainage tract.
Transpapillary Drainage When the small size or anatomic location of a pseudocyst precludes transmural drainage, transpapillary drainage provides an alternative approach. This approach requires the presence of communication between the pseudocyst cavity and the PD. Any stones or strictures encountered should be treated with extraction and dilation. Failure to treat these associated pancreatic ductal diseases may result in recurrence of the pseudocyst. Depending on the size of the pancreatic duct, a 7 to 10 French stent is placed extending from the duodenum into the PD proximal to the site of ductal leakage. If the upstream PD cannot be opacified, the stent can be advanced though the PD defect into the pseudocyst cavity. Abdominal CT scans should be performed every 8 weeks to follow resolution of the pseudocyst cavity. The PD stent is exchanged every 8 weeks until complete radiographic resolution of the pseudocyst cavity. The transpapillary approach carries a lower risk of bleeding but an increased infection rate when compared to transmural drainage. Transpapillary endoscopic drainage carries a technical success rate of 94% and a complication rate of 12%. Pseudocyst recurrence occurs in 15% of patients after endoscopic drainage. The morbidity and mortality rate of endoscopic drainage are 5% to 20% and 1% to 2%, respectively12-19. Complications of endoscopic drainage include pancreatitis and infection.
PERCUTANEOUS DRAINAGE Percutaneous drainage involves the advancement of catheters into the pseudocyst cavity under CT guidance. Percutaneous drainage is the treatment of choice for the infected pseudocyst. Endoscopic drainage can further aggravate infection and is best avoided in this setting. Infection and cutaneous fistulas are the most common complications. To avoid the development of cutaneous fistulas, external drainage should not be performed in individuals with PD strictures or defects. Percutaneous drainage carries a failure rate of 16%, recurrence rate of 7%, and a complication rate of 18%.
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SURGERY DRAINAGE Multiloculated pseudocysts, pseudocysts containing significant necrotic debris, and pseudocysts associated with complete disruption of the PD are best managed with surgery. Surgery most commonly involves either internal drainage or excision of the pseudocyst cavity. Techniques for internal drainage include cystgastrostomy, cystduodenostomy, and Roux-Y cystojejunostomy. After surgery the pseudocyst recurrence rate is 10% to 20%. The morbidity and mortality rates are 20% and 1% to 2%, respectively.
PANCREATIC ASCITES AND PLEURAL EFFUSION After a ductal disruption, pancreatic fluid can occasionally leak into the peritoneal cavity. Pancreatic fluid may also enter the peritoneal cavity via disruption of a pseudocyst. The presence of pancreatic secretions elicits an oxidative response, resulting in the collection of ascitic fluid that contains very high amylase content (usually over 100,000 U/L) and protein concentration over 3 g/dL. In addition, this process may spread in the cephalad direction into the pleural cavities as well, leading to a pleural effusion with similar characteristics. Pancreatic ascites most commonly develop in the setting of chronic pancreatitis or abdominal trauma, but can occasionally be idiopathic in nature. The clinical presentation consists of increasing abdominal girth, abdominal pain, and weight loss. A variety of therapeutic options have been reported with varying success. Conservative therapy consists of NPO status, parenteral nutrition, and octreotide, with the intention of decreasing pancreatic secretions and in turn facilitating fistula closure. When conservative therapy fails, endoscopic and surgical intervention are most often successful. Endoscopic therapy consists of pancreatic sphincterotomy with placement of a PD stent. The intention is to create a path of least resistance for pancreatic drainage into the duodenum. This preferential duodenal drainage leads to closure of the pancreatic fistula. Surgical treatment consists of a Roux-en-Y jejunal anastomosis to the fistula site or an associated pseudocyst cavity. Surgical therapy succeeds in over 80% of patients when the site of PD leak has been accurately localized on ERCP20.
Conclusion The gastroenterologist, surgeon, and radiologist all contribute significantly to the management of pancreatic ductal complications. Improvements in technology and instrumentation have led increasingly toward an endoscopic approach to treatment of these cases. The expanding role of ERCP and EUS in the evaluation and treatment of pancreatic duct strictures, stones, and pseudocysts awaits confirmation from large randomized prospective studies.
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References 1. Steinberg W. The clinical utility of the CA 19-9 tumor-associated antigen. Am J Gastroenterol. 1990;85:350-355. 2. Smits ME, Badiga SM, Rauws EA, et al. Long term results of pancreatic stents in chronic pancreatitis. Gastrointest Endosc .1995;42:461-467. 3. Binmoeller KF, Jue P, Seifert H. Endoscopic pancreatic stent drainage in chronic pancreatitis and a dominant stricture: Long term results. Endoscopy. 1995;27:638644. 4. Cremer M, Deviere J, Delhaye M, et al. Stenting in severe chronic pancreatitis: results of medium term follow-up in 76 patients. Endoscopy. 1991;23:171-176. 5. Ponchon T, Bory R, Hedelius F, et al. Endoscopic stenting for pain relief in chronic pancreatitis: results of a standardized protocol. Gastrointest Endosc. 1995;42:452456. 6. Bittencourt PL, Delhaye M, Deviere J, et al. Immediate and long-term results of pancreatic ductal drainage in severe painful chronic pancreatitis [abstract]. Gut. 1996;39: A99. 7. Delhaye M, Vandermeeren A, Baize M, et al. Extracorporal shock wave lithotripsy of pancreatic duct calculi. Gastroenterology. 1992;102:610-620. 8. Dumonceau JE, Deviere J, LeMoine O, et al. Endoscopic pancreatic drainage in chronic pancreatitis associated with ductal stones: long-term results. Gastrointest Endosc. 1996;43:547-555. 9. Sherman S, Lehman GA, Hawes RH, et al. Pancreatic ductal stones: frequency of successful endoscopic removal and improvement in symptoms. Gastrointest Endosc. 1991; 37:511-517. 10. Smits ME, Rauws EA, Tytgat GNJ, et al. Endoscopic treatment of pancreatic stones in patients with chronic pancreatitis. Gastrointest Endosc. 1996;43:556-560. 11. Adamek HE, Jakobs R, Buttman A, et al. Long term follow-up of patients with chronic pancreatitis and pancreatic stones treated with extracorporeal shock wave lithotripsy. Gut. 1999;45:402-405. 12. Barthet M, Sahel J, Bodiou-Bertel C, et al. Endoscopic transpapillary drainage of pancreatic pseudocysts. Gastrointest Endosc. 1995;42:208-213. 13. Binmoeller KF, Seifert H, Walter A. Transpapillary and transmural drainage of pancreatic pseudocysts. Gastrointest Endosc. 1995;43:219-224. 14. Cremer M, Deviere J, Engelholm L. Endoscopic management of cysts and pseudocysts in chronic pancreatitis: long-term follow-up after 7 years of experience. Gastrointest Endosc. 1989;35:1-9. 15. Grimm H, Meyer WH, Nam VC, et al. New modalities for treating chronic pancreatitis. Endoscopy. 1989;21:70-74. 16. Howell DA, Lehman GA, Baron TH, et al. Endoscopic treatment of pancreatic pseudocysts: a retrospective multicenter analysis [abstract]. Gastrointest Endosc. 1995;41:424A. 17. Howell DA, Elton E, Parsons WG. Endoscopic management of pseudocysts of the pancreas. Gastrointest Endosc Clin N Am. 1998;46:143-162. 18. Kozarek RA, Ball TJ, Patterson DJ, et al. Endoscopic transpapillary therapy for disrupted pancreatic duct and parapancreatic fluid collection. Gastroenterology. 1991; 100:1362-1370. 19. Smits ME, Rauws EAJ, Tytgat GNJ, et al. The efficacy of endoscopic treatment of pancreatic pseudocysts. Gastrointest Endosc. 1995;42:202-207.
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20. Gomez-Cerezo J, Barbado Cano A, et al. Pancreatic ascites: study of therapeutic options by analysis of case reports and case series between the years 1975 and 2000. Am J Gastroenterol. 2003;98:568-577.
Suggested Reading Forsmark CE, Toskes PP. What does an abnormal pancreatogram mean? Gastrointest Endosc Clinics N Am. 1995;5:105-123. Hunt GC, Faigel DO. Assessment of EUS for the diagnosis, staging and determining the resectability of pancreatic cancer: A review. Gastrointest Endosc. 2002;55:232. Harewood GC, Wiersema MJ. Endosonography guided fine needle aspiration biopsy in the evaluation of pancreatic masses. Am J Gastroenterol. 2002;97:1386. Jowell PS. Assessment of pancreatic duct strictures. Gastrointest Endosc Clinics N Am. 1995;5:125-143. Haber GB. Endoscopic management of pancreatic stones. Techniques in Gastrointestinal Endoscopy. 1999;1:180-185. Delhaye M, Matos C, Deviere J. Endoscopic management of chronic pancreatitis. Gastrointest Endosc Clinics N Am. 2003;13:717-742. Baron TH, Harewood GC, Morgan DE, et al. Outcome differences after the endoscopic drainage of pancreatic necrosis, acute pancreatic pseudocysts and chronic pancreatic pseudocysts. Gastrointest Endosc. 2002;56:7-17. Gomez-Cerezo J, Barbado Cano A, Suarez I, Soto A, Rios JJ, Vazquez JJ. Pancreatic ascites: study of therapeutic options by analysis of case reports and case series between the years 1975 and 2000. Am J Gastroenterol. 2003;98:568-577.
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Solid Pancreatic Tumor Shyam Varadarajulu, MD; Mohamad A. Eloubeidi, MD, MHS, FACP, FACG
Introduction Ductal adenocarcinoma of the pancreas accounts for 90% of pancreatic cancers. In the United States, pancreatic cancer kills more than 26,000 persons per year, is the fourth and the fifth most common cancer in men and women, respectively1, and has the lowest 5-year survival rate of any cancer. The national 5-year survival rate has increased from 1% to 3% in whites and from 3% to 5% in blacks in the past decade1. The dismal survival of patients with pancreatic cancer is a result of the late diagnosis and low resection rates; only 10% to 20% of patients are eligible for curative resection. According to the 1995 National Cancer Data Base Report on Pancreatic Cancer 2 , 52% of 17,490 patients with pancreatic cancer had stage IV disease at diagnosis, and the overall curative resection rate (pancreatectomy) was only 14%. The specific objectives of this chapter are to discuss the presentation, diagnosis, staging, and the role of endoscopy in the management of suspected pancreatic adenocarcinoma and the evaluation of solid pancreatic tumors. Surgical management of pancreatic cancer will be discussed elsewhere in this textbook.
Clinical Presentation The suspicion of pancreatic cancer arises because of symptoms of pain, jaundice, anorexia, early satiety, or weight loss. Some symptoms may predict tumor location3 and prognosis4. Painless jaundice is the most common presentation in patients with a potentially resectable and curable lesion (52% of patients with a resectable lesion). However, pain is the most frequent symptom, seen in 80% of all patients, and present in 80% and 85% of patients with locally unresectable and advanced cancer, respectively4. The combination of pain and jaundice is present in 50% of patients with a locally unresectable lesion3. In another study of patients who underwent curative resection, preoperative steatorrhea was associated with prolonged survival, and back pain was associated with shortened survival4. It has recently been shown that onset of
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diabetes mellitus may herald the appearance of pancreatic cancer, particularly if diabetes occurs during or beyond the sixth decade of life5. Diabetes mellitus is seen in 60% to 80% of patients with pancreatic cancer, and the majority of patients received the diagnosis within 2 years of recognition of pancreatic cancer6,7. In a recent study, 72% of patients with pancreatic cancer had diabetes (all noninsulin dependent); 56% had diabetes diagnosed concomitantly with the tumor; and 16% received the diagnosis of diabetes 2 years before the diagnosis of the cancer6. Sixty-six percent of patients with pancreatic cancer and diabetes have no family history of diabetes5.
Diagnosis and Staging TUMOR MARKERS The serum concentrations of several tumor markers have been studied in pancreatic cancer. However, none has been shown to be particularly sensitive or specific in the diagnosis of pancreatic cancer8. In a review of tumor markers, cancer-associated antigen 19-9 (CA 19-9), with a cutoff value of 70 U/mL, was found to have the greatest sensitivity (70%) and specificity (87%) for diagnosis of pancreatic cancer 9,10. In other studies, with a lower cutoff of 37 U/mL, sensitivity was somewhat higher (86%) and specificity was identical (87%)11. CA 19-9 levels may also be elevated in patients with biliary tract obstruction caused by a lesion other than cancer12 . CA 19-9 can be a useful marker to monitor response to therapy. As 60% to 80% 6,7 of patients with pancreatic cancer develop glucose intolerance within 2 years before the diagnosis of pancreatic cancer, elevated plasma concentrations of islet amyloid polypeptide (IAPP), which appears to be secreted by pancreatic beta cells, have the potential for detecting early pancreatic cancer13. Compared to normal subjects, patients with other cancers, and patients with either insulin-dependent or noninsulin-dependent diabetes mellitus, concentrations of IAPP have been shown to be elevated in patients with pancreatic cancer13. The sensitivity of this test, however, is poor and it is not widely available14.
GENETIC MARKERS Genetic markers may detect pancreatic cancer, but it is unknown whether they are of value for detection of early stage pancreatic cancer. The most common gene abnormality is a codon 12 K-ras mutation, seen in around 90% of patients with pancreatic cancer15-17. K-ras mutations have been detected in plasma, in pancreatic juice, duodenal fluid, and stool, as well as in pancreatic cancer cells obtained by percutaneous needle aspiration for cytological examination. However, K-ras mutations have also been detected in patients with chronic pancreatitis18. Mutations of the p53 tumor cell suppressor gene and reduced expression of the DCC gene are also found in 50% to 70% of pancreatic cancers19,20. Further studies are required before a definitive role for genetic markers can be established in the evaluation of patients with pancreatic cancer.
COMPUTED TOMOGRAPHY Spiral computed tomography (CT) is the primary imaging study for evaluating patients presenting with symptoms suggestive of pancreatic cancer. CT is an appropri-
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ate initial imaging test because it detects tumors in the pancreas and can be used to stage for resectability and to detect liver metastases. The sensitivity of conventional CT for the diagnosis of tumors of 15 mm 23. Percutaneous fine needle aspiration (FNA) biopsy of a pancreatic mass can be performed using CT guidance. Although sensitivity and specificity in the range of 80% to 90% and 98% to 100%, respectively, have been reported 24, the diagnostic accuracy to a large extent depends on tumor size and the expertise of the operator. Also, a theoretical concern is that percutaneous FNA biopsy of the pancreas may disseminate tumor cells within the peritoneal cavity or along the needle path in patients who are believed to be candidates for potentially curative resection. Recent advances in CT technology, including the development of spiral scanners and more recently multidetector CT (MDCT) scanners, and the development of three-dimensional (3D) imaging software have improved the ability of CT to image the pancreas and to evaluate a wide range of pancreatic pathology. In most of the published series, older dynamic scanners or single-row spiral scanners were used, and 3D imaging was not included. With the narrow collimation and faster scanning possibilities with new MDCT scanners, it is likely that the CT accuracy for detecting pancreatic tumor will improve. In a recently published study using MDCT, 27 of 28 pancreatic cancers were detected 25. This progress will continue as manufacturers introduce the next generation of scanners, which can acquire up to 32 slices per second with even faster scan times. The impact of these new scanners on diagnostic accuracy will need to be carefully evaluated.
MAGNETIC RESONANCE IMAGING Magnetic resonance imaging (MRI) is gaining popularity as an imaging tool for diagnosis. Although MRI is no more accurate than CT for the diagnosis of pancreatic cancer, it may demonstrate a definite mass in patients who have indeterminate head enlargement on CT. In a study of 16 patients with indeterminate head enlargement on spiral CT, a definitive tumor was seen with MRI in 1026. Tumors are viewed as low-signal masses against the high-signal background of normal pancreatic parenchyma. Pancreatic masses, ductal dilation, and liver metastasis can be demonstrated in exquisite detail. Additionally, MR angiography and MR venography techniques using gadolinium contrast can demonstrate vascular involvement with tumor and obviate the need for conventional angiography. As opposed to CT, MRI does not involve radiation and employs an iodine-free contrast agent with rare renal toxicity. Limitations of MRI are related to cost, availability, and clinicians’ familiarity and predilection for CT imaging. Magnetic resonance cholangiopancreatography (MRCP) can also be obtained at the time of MRI. In a recent prospective, controlled study, MRCP was found to be as sensitive as endoscopic retrograde cholangiopancreatography (ERCP) in detecting pancreatic carcinomas27. MRCP uses heavy T2-weighted images that emphasize fluid-containing structures such as ducts, cysts, and peripancreatic fluid collections. Images obtained are highly comparable to those after ERCP and readily demonstrate pancreatic ductal obstruction, ectasia, and calculi.
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Figure 11-1. Biliary stricture secondary to a pancreatic head mass as seen on cholangiogram.
ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY ERCP is most useful for patients in whom CT or ultrasound does not reveal a mass lesion within the pancreas, and in those in whom the differential diagnosis includes chronic pancreatitis. ERCP has a sensitivity and specificity of 90% to 95% for diagnosing pancreatic cancer 28. Findings suggestive of a malignant tumor include superimposable strictures or obstruction of the common bile and pancreatic ducts (the “double duct” sign), a pancreatic duct stricture in excess of 1 cm in length, pancreatic duct obstruction, and the absence of changes suggestive of chronic pancreatitis (Figure 11-1). In the experience of the authors, ERCP brushings yield a definitive diagnosis in only 30% to 40% of patients and further work-up is required if tissue acquisition is desired prior to surgical intervention or if chemotherapy or radiation therapy is contemplated.
ENDOSCOPIC ULTRASOUND Endoscopic ultrasound (EUS) staging of pancreatic and other tumors follows the TNM system (Table 11-1) of the American Joint Committee on Cancer (AJCC). In 2002, the AJCC modified the T staging system for pancreatic cancer to classify tumors invading the portal venous (superior mesenteric vein or portal vein) system as T3 (these were previously staged as T4) (Figure 11-2) and tumors invading the celiac or superior mesenteric artery as T4. Although this change is likely to result in decreased reported accuracy for EUS, it remains unclear if surgical therapy is beneficial compared to radiochemotherapy for tumors invading the portal venous system. Most literature is based on the previous AJCC staging system in which all mesenteric vascular invasions (venous or arterial) were staged T4.
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Table 11-1
TNM STAGING OF PANCREATIC CANCER BY THE AMERICAN JOINT COMMITTEE ON CANCER (AJCC) Primary Tumor (T) TX: Primary tumor cannot be assessed T0: No evidence of primary tumor Tis: Carcinoma in situ T1: Tumor limited to the pancreas, 2 cm or less in greatest dimension T2: Tumor limited to the pancreas, more than 2 cm in greatest dimension T3: Tumor extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery T4: Tumor involves the celiac axis or the superior mesenteric artery (unresectable primary tumor)
Regional Lymph Nodes (N) NX: Regional lymph nodes cannot be assessed N0: No regional lymph node metastasis N1: Regional lymph node metastasis
Distant Metastasis (M) MX: Distant metastasis cannot be assessed MO: No distant metastasis M1: Distant Metastasis
AJCC Stage Groupings Stage Stage Stage Stage Stage Stage Stage
0: Tis, N0, M0 IA: T1, N0, M0 IB: T2, N0, M0 IIA: T3, N0, M0 IIB: T1, N1, M0, T2, N1, M0, T3, N1, M0 III: T4, any N, M0 IV: Any T, any N, M1
Many large series have found EUS T stage accuracy to range from approximately 78% to 94% and nodal (N) stage accuracy between 64% and 82% 29-32 . However, lower accuracy has also been described. In a study of 89 patients in whom EUS was compared to surgical and histopathologic TNM staging 33, the overall accuracy of EUS for T and N staging were 69% and 54%, respectively. Furthermore, only 46% of
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Figure 11-2. Mass in the pancreatic head invading the superior mesenteric vein as seen using a radial echoendoscope (Olympus GF-UM 130).
tumors believed to be resectable by EUS were actually found to be resectable during laparotomy. Staging accuracy of EUS can be influenced by several factors, including the experience level of the endosonographer, imaging artifacts, and the endosonographer’s knowledge of the results of previous imaging tests. In general, T stage accuracy for EUS is highest in patients with smaller tumors, whereas helical CT is more accurate in staging larger tumors34-36. The accuracy of EUS for detecting invasion into the superior mesenteric artery and vein is lower than that for detecting portal or splenic vein invasion37,38. A recent review39 that pooled data from four studies comparing the accuracy of EUS with helical CT in the evaluation of pancreatic cancer found that EUS detected more tumors (97% versus 73%), was more accurate for determining tumor resectability (91% versus 83%), and was more sensitive for detecting vascular invasion (91% versus 64%). However, when the data were interpreted individually, two of the reports concluded that CT and EUS were approximately equivalent in detecting the primary tumors34,40, while the other two found EUS to be superior41,42 . Several features of the individual reports may account for these variable conclusions, including differences in the gold standards, variations in the specific techniques used for helical CT, and the proportion of patients with advanced disease in each study. A reasonable conclusion from these data and from clinical experience is that EUS and helical CT are complementary for staging pancreatic cancer. EUS is a more accurate modality for local T staging and for predicting vascular invasion, especially in tumors less than 3 cm, while helical CT is better for the evaluation of distant metastasis and for staging larger tumors. Similar to CT, studies comparing MRI with EUS suggest that EUS may be more sensitive for detecting small tumors, while providing complementary information regarding resectability43. Several studies have compared the accuracy of angiography and EUS for determining vascular invasion37,38,44. Although the results varied, a general conclusion is that EUS is as accurate or more accurate for determining vascular invasion, with
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Figure 11-3. Fine-needle aspiration of a pancreatic head mass using the curvilinear array echoendoscope (Olympus UC 30 P).
the exception of some tumors that invade the superior mesenteric artery. In a study of 21 patients with pancreatic cancer who underwent EUS and angiography prior to an attempt at curative resection, EUS was much more sensitive than angiography for detecting vascular invasion (86% versus 21%). The specificity and accuracy of EUS were 71% and 81%, respectively, compared with 71% and 38% for angiography43.
ENDOSCOPIC ULTRASOUND-GUIDED FINE-NEEDLE ASPIRATION EUS has an important role in guiding a biopsy needle into lesions that are too small to be identified by CT or MRI or too well encased by surrounding vascular structures to safely allow percutaneous biopsy (Figures 11-2 and 11-3)44. The impact of EUS-FNA was studied by Chang et al in a series of 44 patients 45. EUS-FNA had an accuracy rate of 95% for pancreatic lesions and 88% for lymph nodes. Three patients had enlarged celiac nodes on EUS that showed malignancy on FNA. Overall, FNA precluded surgery in 41% of patients, avoided the need for further diagnostic tests in 57%, and influenced clinical decisions in 68% of patients, thus providing substantial cost savings. Gress et al examined the role of EUS-FNA in patients with suspected pancreatic cancer after a negative CT-guided FNA or ERCP brush cytology44. In 102 patients, 57 had positive cytology on EUS-FNA and 37 had negative cytology. The examination was inconclusive in 8 patients. After a median follow-up of 24 months, all 57 patients with positive cytology on EUS-FNA had verification of the diagnosis of pancreatic cancer. Of the 45 patients with negative or inconclusive cytology on EUSFNA, 41 had no evidence of pancreatic malignancy at follow-up. One particularly important application of EUS-FNA is the detection of malignant lymph nodes. FNA has been demonstrated to increase the accuracy of lymph node staging and thereby reduce the number of unnecessary surgical explorations by identifying patients with surgically incurable disease45. Lesions located in the uncinate process of the pancreas are the most difficult to puncture. To access a mass in the uncinate process, the echoendoscope must be
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Table 11-2
INDICATIONS FOR EUS-FNA •
•
• •
To document a diagnosis of malignancy in a patient with an unresectable mass as a prerequisite for adjuvant chemotherapy or radiation therapy. To exclude other tumor types such as lymphoma, small-cell metastasis, or neuroendocrine cancer that may require a different management strategy. To determine a diagnosis in patients who are reluctant to undergo major surgery without a definitive diagnosis. To document the absence of malignancy when the pretest probability of malignancy is low.
advanced into the duodenal C-loop in the “long” position. This exerts substantial angulation and torque on the FNA needle. The needle is more difficult to advance and also causes a “bowed shape.” This altered shape can result in mistargeting. Also, lesions in the pancreatic isthmus pose a similar challenge in that the echoendoscope is usually in the “long” scope position with the tip in the gastric antrum. A transgastric approach can be more difficult than the transduodenal approach due to the laxity and redundancy of the gastric wall, as well as the capaciousness of the stomach. Lacking anchorage, the echoendoscope tends to displace during advancement of the FNA needle. A controversial issue is identifying who should undergo EUS-FNA (Table 11-2). There is general consensus that it is reasonable to obtain a tissue diagnosis in patients suspected of having pancreatic cancer who are poor surgical candidates. Histologic confirmation in such patients can be helpful in deciding on chemotherapy or radiotherapy. More controversial is the role of EUS-guided FNA in patients suspected of having pancreatic cancer who appear to be resectable on other imaging studies. One view is that a tissue diagnosis will not alter management and is therefore unnecessary. This argument is supported by the recognition that the sensitivity of EUS-guided FNA is in the range of 85% to 90%, potentially leading to false negative results in up to 15% of patients. However, an argument can be made for EUS-guided FNA in such patients when the establishment of a histologic diagnosis before surgery may alter management, as other types of malignancy involving the pancreas can mimic adenocarcinoma (eg, lymphoma). Therapy for these tumors may not include surgery. Some patients and physicians want to know definitively whether cancer is present before undergoing a surgical resection. When the FNA is negative, some patients may be willing to accept the 15% chance of missing a diagnosis of cancer rather than undergoing surgery. This is especially true when there is concurrent acute or chronic pancreatitis that may mimic a focal pancreatic cancer.
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The safety of EUS-FNA for evaluating pancreatic lesions is well established46,47. Rare complications include pancreatitis, infection, and bleeding. In a multicenter study evaluating the safety of EUS-FNA of solid pancreatic masses, 14 of 4,909 (0.29%) patients developed pancreatitis46. In another study involving EUS-FNA of pancreatic cystic lesions, 1 of 81 patients developed an infected cystadenoma after EUS-FNA47. This patient did not receive prophylactic antibiotics prior to the procedure. Current standard of care includes routine administration of antibiotics for patients undergoing FNA of pancreatic cystic lesions. Patients with solid pancreatic masses do not require antibiotics prior to EUS-FNA.
Management Appropriate treatment of patients with pancreatic cancer depends on accurate preoperative staging. With the current data, we recommend using dual-phase spiral CT as the initial test to diagnose and stage pancreatic tumors. EUS is particularly useful in patients suspected of having a small resectable tumor that was not seen on CT and in patients in whom tissue acquisition by FNA is desired for definitive diagnosis (preoperatively or for palliative chemoradiation). Laparoscopy is used in some centers for staging because small hepatic and/or peritoneal metastases can be seen that are not visualized by less invasive tests. Although laparoscopy should not be done in all patients, it is indicated if there is a high likelihood of unresectability that has not been confirmed by imaging tests48. The major drawbacks of laparoscopy are the additional time required for the procedure and the inability to determine the presence of vascular invasion. The latter requires more extensive dissection and is aided by the tactile senses available only during laparotomy. The advantage of finding unresectable disease by laparoscopy is that laparotomy and its attendant morbidity and expense are not needed. If patients require laparotomy for palliative biliary and/or gastric bypass, laparoscopy is contraindicated. The authors recommend that helical CT be performed initially to evaluate for the presence of a pancreatic mass (Figure 11-4). If metastatic disease is clearly evident, an EUS-guided biopsy can confirm the diagnosis. When the helical CT is negative for metastatic disease or an obvious mass, EUS should be performed to further evaluate the pancreas (if the clinical suspicion is high for pancreatic cancer) followed by EUS-guided FNA of any apparent mass noted. Those who are found to have T1-3, N0/1 disease generally undergo exploration (with or without chemoradiation), while those who are found to have unresectable disease (T4 or M1) should be managed palliatively. Endoscopic management is indicated mainly for controlling symptoms of unresectable pancreatic cancer such as relief of obstructive jaundice, gastric outlet obstruction, and pain. Surgical and medical management of pancreatic cancer are discussed elsewhere in this book.
JAUNDICE Palliation of jaundice in patients who are not undergoing an attempt at surgical resection is usually accomplished by placement of an expandable metal stent. Surgery is generally reserved for those in whom stent placement is not possible due to technical reasons and those in whom a surgical gastric bypass for outlet obstruction is contemplated as a combined procedure.
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CT
Unresectable mass
No mass/ Resectable mass
EUS
Tissue by EUS-FNA
FNA for diagnosis
Resectable
Unresectable
Palliation
Surgery Figure 11-4. Algorithm for management of pancreatic cancer.
EXPANDABLE METAL STENTS Endoscopically placed expandable metal stents can provide minimally invasive effective palliation of jaundice. Randomized trials have shown no difference in survival between endoscopic stent placement and surgical bypass for malignant obstructive jaundice; patients who undergo stent placement have more frequent readmissions for stent occlusion, recurrent jaundice, and cholangitis, but lower morbidity and procedure-related mortality49-52 . Although metal stents can also be placed percutaneously, at least one controlled trial that included 75 patients with malignant bile duct obstruction demonstrated that patients treated with an endoscopic stent had a higher success rate for relief of jaundice (81% versus 61%) and a significantly lower 30-day mortality rate (15% versus 33%)51. Metal stents are preferred compared to plastic stents because they are much less likely to become clogged by debris or tumor in growth53. Choice of stent is operator-dependent and typically is based on predicted likelihood of survival of the evaluated patient.
SURGERY The surgical options for achieving biliary decompression include an anastomosis between the gallbladder and jejunum (cholecystojejunostomy) or common bile duct
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and jejunum (choledochojejunostomy). Drainage is successful in returning the serum bilirubin concentration in approximately 90% of patients54. One advantage of surgical bypass is the ability to perform prophylactic or therapeutic gastrojejunostomy to avoid gastroduodenal obstruction. However, in one report, the postoperative mortality and perioperative morbidity rates were 3.1% and 22%, respectively, and the median survival was 6.5 months55.
DUODENAL OBSTRUCTION Approximately 20% of patients with pancreatic cancer will develop duodenal obstruction leading to gastric outlet obstruction56. Management can be either endoscopic by means of enteral stenting or surgical by means of palliative bypass.
Enteral Stenting Recent data suggest that enteral stenting has a similar success rate as surgical palliation (with approximately 90% of patients improving clinically) but is associated with less morbidity, procedure-related mortality, and cost57,58. Despite initial success, 15% to 40% of patients require reintervention for recurrent symptoms or biliary obstruction. In contrast, in at least one report, no patient undergoing surgical decompression (ie, gastrojejunostomy) required reintervention for obstructive symptoms59. Furthermore, some patients may not improve even after successful stent placement, because of unidentified sites of malignant obstruction, diffuse peritoneal carcinomatosis with bowel encasement, or functional gastric outlet obstruction from neural (celiac axis) tumor involvement60. Several complications can occur during or after placement of the stents. Intraprocedural complications include complications of conscious sedation, pulmonary aspiration, stent malposition, perforation, and bleeding. Late complications include distal stent migration, bleeding, and perforation, as well as fistula formation.
Surgical Palliation To avoid gastric outlet obstruction, some surgeons create a prophylactic palliative gastrojejunostomy with a biliary bypass in those who are deemed to be unresectable at exploration. The benefit of a prophylactic gastrojejunostomy was shown in a prospective randomized trial in which 87 patients with an unresectable periampullary malignancy who were believed not to be at risk for duodenal outlet obstruction were randomly assigned to receive or not receive a prophylactic gastrojejunostomy59. Although the group undergoing prophylactic surgery had a similar mean survival (8.3 months), rate of postoperative complications, and length of hospital stay, therapeutic intervention for late gastric outlet obstruction occurred significantly less often (0 versus 19%). However, the real benefit of this procedure in patients with unresectable pancreatic cancer has been questioned: delayed gastric emptying is a frequent result of prophylactic gastrojejunostomy, occurring in almost 50% of patients 61, and a substantial number of those who have the procedure for symptom control die either during or within 30 days of the procedure 62 . The authors prefer surgical palliation as an initial approach in those patients who experience symptomatic outlet obstruction but are deemed fit to undergo a major surgery. In those with comorbid illnesses, terminal disease, and poor surgical candidates, enteral stenting is the preferred method of palliation.
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Figure 11-5. Celiac plexus block being performed using the curvilinear array echoendoscope.
PAIN Pain related to pancreatic cancer is often poorly controlled. Celiac plexus neurolysis (CPN) is a chemical splanchnicectomy of the celiac plexus, which ablates the afferent nerve fibers that transmit pain from intra-abdominal viscera. EUS guidance offers the most direct access to the celiac plexus of all the CPN techniques short of surgical intervention. The celiac ganglia are located at the origin of the celiac artery, which is easily identified at endosonography (Figure 11-5). The relative proximity of the celiac ganglia to the posterior gastric wall ensures an accurate passage of the injecting needle into the ganglia, thereby minimizing the risk of complications and potentially increasing the effectiveness of the block. Bupivacaine and absolute ethanol are commonly used for performing CPN. EUS-CPN performed for the palliation of pancreatic cancer pain appears to be as safe and effective as CPN performed by other techniques. An added advantage of the EUS approach is that it can be performed during staging and biopsy of the tumor. In a pilot study, pain relief lasting for a median of 10 weeks was achieved in 88% of 25 patients undergoing EUS-CPN63. Similar results were observed in a later prospective study involving 58 patients; pain scores were significantly lower than baseline in 78% of patients 2 weeks after the procedure and were sustained for 24 weeks 64. On multivariate analysis, the benefit of EUS-CPN was independent of morphine use, chemotherapy, and radiation.
Neuroendocrine Tumors CONFRONTING ISSUES Pancreatic endocrine tumors are often small and hard to detect by radiologic techniques. Since the original description of gastrinomas in 1955 by Zollinger and
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Ellison65, multiple imaging modalities have been evaluated to localize pancreatic neuroendocrine lesions for surgical resection. Studies have shown that CT, MRI, and conventional US detect tumors in less than 50% of patients 66. Somatostatin receptor scintigraphy (SRS) is reported to have the highest sensitivity for gastrinomas but is less accurate for detecting insulinomas 67. The optimal algorithm for staging pancreatic neuroendocrine tumors is unknown. Issues important for clinical management include:
1. Is the tumor localized to the region of the pancreas (including gastrinoma triangle) or metastatic? 2. Is it unifocal or multifocal within the pancreas? 3. Is it functional or non-functional, benign or malignant?
WORK-UP To determine whether a tumor is localized or metastatic, cross-sectional imaging and SRS are likely more accurate than EUS due to their ability to image broad areas67. For imaging within the pancreas, EUS provides superior resolution and accuracy relative to CT scan. In a study of 82 patients, Anderson et al identified 100 tumors in 54 patients, emphasizing the frequency of multifocal tumors 68. EUS accurately localized the tumor in 93% of patients and had a specificity of 95%, which was higher than CT or transabdominal US. EUS was not reliable for detection of extrapancreatic tumors. Zimmer et al compared EUS to CT, SRS, US, and MRI in 40 patients with neuroendocrine tumors 69. EUS had the highest overall accuracy for both gastrinomas and insulinomas but missed 50% of extrapancreatic tumors. In one report of patients who had negative ultrasonography and CT scans, EUS detected endocrine tumors in the pancreas with high sensitivity (82%) and specificity (95%) 70. In patients with nonfunctioning neuroendocrine tumors where the risk of surgery is elevated, it would be useful to distinguish benign from malignant neuroendocrine tumors. In two studies71,72 , EUS was able to accurately distinguish malignant lesions based on the presence of an irregular inhomogeneous hypoechoic mass or on invasion and obstruction of the pancreatic duct. Tumors without these features were almost always benign.
Intraductal Endoscopic Ultrasonography Intraductal endoscopic ultrasonography (IDUS) involves the insertion of an ultrathin (2 mm) US probe directly into the pancreatic duct during ERCP. Preliminary experience suggests that it may be more accurate than standard EUS for the detection of neuroendocrine tumors. Although experience with IDUS is limited, initial data suggest that IDUS may improve the evaluation of these patients and lead to the identification of tumors arising within the pancreas that have gone unrecognized by other techniques73,74. In one study, IDUS was able to identify the presence of an islet cell tumor in seven of seven patients74. In one of these patients who had multifocal disease, IDUS accurately determined the number of tumors while EUS failed to detect all lesions. The distance from the tumors to the main pancreatic duct was accurately determined, thus aiding preoperative planning of wedge resection, which was possible in two patients. EUS can also be useful for preoperative localization of pancreatic endocrine tumors by its ability to tattoo lesions by fine-needle injection using India ink 75. This may
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shorten operative time because it obviates the need to localize the tumor by palpation and intraoperative US. This technique may have the potential to facilitate tumor resection by less invasive methods, such as laparoscopic enucleation. These data suggest that EUS serves an important role in localizing tumors within the pancreas, detecting multifocal tumors, and distinguishing benign from malignant tumors. In addition, EUS should be used with cross-sectional imaging and SRS to identify extrapancreatic tumors or metastases.
MANAGEMENT Management is based on the nature of the underlying neuroendocrine tumor. In general, patients with localized disease (sporadic lesions) should be managed by laparotomy with a curative intent. Patients with tumors that are part of a syndrome such as multiple endocrine neoplasia may be managed medically as the tumors are multifocal in these patients. The clinical course of patients with metastatic pancreatic neuroendocrine tumors is highly variable. Some patients with indolent tumors may remain symptom-free for years, even without treatment. Others have symptomatic metastatic disease, either from tumor bulk or hormonal hypersecretion, and require therapy. Several options are available for the treatment of metastatic neuroendocrine tumors including somatostatin analogs, interferon alfa, cytotoxic chemotherapy, surgical resection, hepatic artery embolization, and possibly orthotopic liver transplantation in highly selected patients.
Future Trends The efficacy of direct antitumor therapy has recently been reported in clinical trials. Therapy involves dose-dependent injection of a modified adenovirus (TNFerade) that is capable of preferentially replicating in and destroying tumor cells. In a study of 37 patients76 with locally advanced pancreatic cancer treated with TNFerade (administered by either EUS or CT-guidance) and concomitant chemoradiation, 74% achieved tumor stabilization, 11% more than 50% reduction in tumor size, and five underwent tumor resection (four had negative surgical margins). The treatment is safe and only minimal adverse events were reported. The effect of TNFerade on metastatic disease and its long-term efficacy remains unclear. This exciting trial is still underway and the final results are awaited.
References 1. Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics 1996. CA Cancer J Clin. 1996;46:5-27. 2. Niederhuber JE, Brennan MF, Menck HR. The National Cancer Data Base report on pancreatic cancer. Cancer. 1995;76:1671-167. 3. Kalser MH, Barkin J, MacIntyre JM. Pancreatic cancer. Assessment of prognosis by clinical presentation. Cancer. 1985;56:397-402. 4. Mannell A, van Heerden JA, Weiland LH, Ilstrup DM. Factors influencing survival after resection for ductal adenocarcinoma of the pancreas. Ann Surg. 1986;203:403407. 5. Gullo L, Pezzilli R, Morselli-Labate AM. Diabetes and the risk of pancreatic cancer. Italian Pancreatic Cancer Study Group. N Engl J Med. 1994;331:81-84.
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6. Permert J, Larsson J, Westermark GT, et al. Islet amyloid polypeptide in patients with pancreatic cancer and diabetes. N Engl J Med. 1994;330:313-8. 7. Schwarts SS, Zeidler A, Moossa AR, et al. A prospective study of glucose tolerance, insulin, C-peptide, and glucagon responses in patients with pancreatic carcinoma. Am J Dig Dis. 1978;23:1107-14. 8. Metzgar RS, Asch HL. Antigens of human pancreatic adenocarcinomas: their role in diagnosis and therapy. Pancreas. 1988;3:352. 9. Posner MR, Mayer RJ. The use of serologic tumor markers in gastrointestinal malignancies. Hematol Oncol Clin North Am. 1994;8:533-53. 10. Pleskow DK, Berger HJ, Gyves J, Allen E, McLean A, Podolsky DK. Evaluation of a serologic marker, CA19-9, in the diagnosis of pancreatic cancer. Ann Intern Med. 1989;110:704-9. 11. Safi F, Schlosser W, Falkenreck S, Beger HG. CA 19-9 serum course and prognosis of pancreatic cancer. Int J Pancreatol. 1996;20:155-61. 12. Albert MB, Steinberg WM, Henry JP. Elevated serum levels of tumor marker CA19-9 in acute cholangitis. Dig Dis Sci. 1988;33:1223-5. 13. Westermark P, Wilander E, Westermark GT, Johnson KH. Islet amyloid polypeptidelike immunoreactivity in the islet B cells of type 2 (non-insulin-dependent) diabetic and non-diabetic individuals. Diabetologia. 1987;30:887-92. 14. Chari ST, Klee GG, Miller LJ, Raimondo M, DiMagno EP. Islet amyloid polypeptide is not a satisfactory marker for detecting pancreatic cancer. Gastroenterology. 2001; 121(3):640-645. 15. Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M. Most carcinomas of the exocrine pancreas contain mutant c-Kras genes. Cell. 1988;53:549-54. 16. Hruban RH, van Mansfeld AD, Offerhaus GJ, et al. K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am J Pathol. 1993;143(2):545-54. 17. Lemoine NR, Jain S, Hughes CM, et al. K-ras oncogene activation in preinvasive pancreatic cancer. Gastroenterology. 1992;102:230-6. 18. Rivera JA, Rall CJ, Graeme-Cook F, et al. Analysis of K-ras oncogene mutations in chronic pancreatitis with ductal hyperplasia. Surgery. 1997;121:42-49. 19. Redston MS, Caldas C, Seymour AB, et al. p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res. 1994;54(11):3025-33. 20. Hohne MW, Halatsch ME, Dahl GF, Winel RJ. Frequent loss of expression of the potential tumor-suppressor gene DCC in ductal pancreatic adenocarcinoma. Cancer Res. 1992;52:2616-19. 21. Muller MF, Meyenberger C, Bertschinger P, Schaer R, Marincek B. Pancreatic tumors: Evaluation with endoscopic US, CT, and MR imaging. Radiology. 1994;190 (3):745-51. 22. Bluemke DA, Cameron JL, Hruban RH, et al. Potentially resectable pancreatic adenocarcinoma: Spiral CT assessment with surgical and pathologic correlation. Radiology. 1995;197:381-5. 23. Legman P, Vignaus O, Dousser B, et al. Pancreatic tumors: comparison of dual-phase helical CT and endoscopic sonography. Am J Radiol. 1998;170:1315. 24. Johnson DE, Pendurthi TK, Balshem AM, et al. Implications of fine-needle aspiration in patients with resectable pancreatic cancer. Am Surg. 1997;63:675-9.
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25. McNulty NJ, Francis IR, Platt JF, et al. A multi-detector row helical CT of the pancreas: effect of contrast-enhanced multiphasic imaging on enhancement of the pancreas, peri-pancreatic vasculature, and pancreatic adenocarcinoma. Radiology. 2001;220:97-102. 26. Semelka RC, Kelekis NL, Molina PL, Sharp TJ, Calvo B. Pancreatic masses with inconclusive findings on spiral CT: is there a role for MRI? J Magn Reson Imaging. 1996;6(4):585-8. 27. Adamek HE, Albert J, Breer H, et al. Pancreatic cancer detection with magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography: A prospective controlled study. Lancet. 2000;356:190-193. 28. Freeny PC. Radiologic diagnosis and staging of pancreatic ductal adenocarcinoma. Radiol Clin North Am. 1989;27:121-128. 29. Rosch T, Lorenz R, Braig C, et al. Endoscopic ultrasound in pancreatic tumor diagnosis. Gastrointest Endosc. 1991;37:347-352. 30. Palazzo L, Roseau G, Gayet B, et al. Endoscopic ultrasonography in the diagnosis and staging of pancreatic adenocarcinoma: results of a prospective study with comparison to ultrasonography and CT scan. Endoscopy. 1993;25:143-150. 31. Gress FG, Hawes RH, Savides TJ, et al. Role of EUS in the preoperative staging of pancreatic cancer: a large single-center experience. Gastrointest Endosc. 1999;50:786791. 32. Yasuda K, Mukai H, Nakajima M, et al. Staging of pancreatic carcinoma by endoscopic ultrasonography. Endoscopy. 1993;25:151-155. 33. Ahmad NA, Lewis JD, Ginsberg GG, et al. EUS in preoperative staging of pancreatic cancer. Gastrointest Endosc. 2000;52:463-468. 34. Legmann P, Vignaux O, Dousset B, et al. Pancreatic tumors: comparison of dual phase helical CT and endoscopic sonography. AJR Am J Roentgenol. 1998;170:13151322. 35. Yasuda K, Mukai H, Fujimoto S, et al. The diagnosis of pancreatic cancer by endoscopic ultrasonography. Gastrointest Endosc. 1988;34:1-8. 36. Nakaizumi A, Uehara H, Iishi H, et al. Endoscopic ultrasonography in diagnosis and staging of pancreatic cancer. Dig Dis Sci. 1995;40:696-700. 37. Rosch T, Dittler HJ, Strobel K, et al. Endoscopic ultrasound criteria for vascular invasion in the staging of cancer of the head of the pancreas: a blind reevaluation of videotapes. Gastrointest Endosc. 2000;52:469-477. 38. Brugge WR, Lee MJ, Kelsey PB, et al. The use of EUS to diagnose malignant portal venous system invasion by pancreatic cancer. Gastrointest Endosc. 1996;43:561-567. 39. Hunt GC, Faigel DO. Assessment of EUS for diagnosing, staging, and determining resectability of pancreatic cancer: a review. Gastrointest Endosc. 2002;55:232-237. 40. Midwinter MJ, Beveridge CJ, Wilsdon JB, et al. Correlation between spiral computed tomography, endoscopic ultrasonography and findings at operation in pancreatic and ampullary tumours. Br J Surg. 1999;86:189-193. 41. Mertz HR, Sechopoulos P, Delbeke D, et al. EUS, PET, and CT scanning for evaluation of pancreatic adenocarcinoma. Gastrointest Endosc. 2000;52:367-371. 42. Harewood GC, Wiersema MJ. Endosonography-guided fine needle aspiration biopsy in the evaluation of pancreatic masses. Am J Gastroenterol. 2002;97:1386-1391. 43. Ahmad NA, Lewis JD, Siegelman ES, et al. Role of endoscopic ultrasound and magnetic resonance imaging in the preoperative staging of pancreatic adenocarcinoma. Am J Gastroenterol. 2000;95:1926-1931.
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44. Gress F, Gottlieb K, Sherman S, et al. Endoscopic ultrasonography-guided fine-needle aspiration biopsy of suspected pancreatic cancer. Ann Intern Med. 2001;134:459464. 45. Chang KJ, Nguyen P, Erickson RA, et al. The clinical utility of endoscopic ultrasound-guided fine-needle aspiration in the diagnosis and staging of pancreatic carcinoma. Gastrointest Endosc. 1997;45:387-393. 46. Eloubeidi MA, Gress FG, Savides TJ, et al. Acute pancreatitis after EUS-guided FNA of solid pancreatic masses: A pooled analysis from EUS centers in the United States. Gastrointest Endosc. 2004;60:385-389. 47. Fickling W, Madani N, Hoffman B, et al. Endoscopic ultrasound fine-needle aspiration of cystic lesions of the pancreas: a safe procedure? [Abstract.] Gastrointest Endosc. 2002;56:150. 48. Gloor B, Todd KE, Reber HA. Diagnostic workup of patients with suspected pancreatic carcinoma: the University of California-Los Angeles approach. Cancer. 1997;79:1780-6. 49. Andersen JR, Sorensen SM, Kruse A, Rokkjaer M, Matzen P. Randomised trial of endoscopic endoprosthesis versus operative bypass in malignant obstructive jaundice. Gut. 1989;30:1132-5. 50. Smith AC, Dowsett JF, Russell RC, Hatfield AR, Cotton PB. Randomised trial of endoscopic stenting versus surgical bypass in malignant low bile duct obstruction. Lancet. 1994; 344(8938):1655-60. 51. Speer AG, Cotton PB, Russell RC, et al. Randomised trial of endoscopic versus percutaneous stent insertion in malignant obstructive jaundice. Lancet. 1987;2(8550):5762. 52. Shepherd HA, Royle G, Ross AP, et al. Endoscopic biliary endoprosthesis in the palliation of malignant obstruction of the distal common bile duct: a randomized trial. Br J Surg. 1988;75(12):1166-8. 53. Prat F, Chapat O, Ducot B, et al. A randomized trial of endoscopic drainage methods for inoperable malignant strictures of the common bile duct. Gastrointest Endosc. 1998;47(1):1-7. 54. Singh SM, Longmire WP Jr, Reber HA. Surgical palliation for pancreatic cancer. The UCLA experience. Ann Surg. 1990;212(2):132-9. 55. Sohn TA, Lillemoe KD, Cameron JL, Huang JJ, Pitt HA, Yeo CJ. Surgical palliation of unresectable periampullary adenocarcinoma in the 1990s. J Am Coll Surg. 1999; 188(6):658-66; discussion 666-9. 56. Adler D, Baron TH. Endoscopic palliation of malignant gastric outlet obstruction using expanding metal stents: experience in thirty-six patients. Am J Gastroenterol. 2002;97:72. 57. Mauro MA, Koehler RE, Baron TH. Advances in gastrointestinal intervention: the treatment of gastroduodenal and colorectal obstructions with metallic stents. Radiology. 2000;215(3):659-69. 58. Yim HB, Jacobson BC, Saltzman JR, Johannes RS. Clinical outcome of the use of enteral stents for palliation of patients with malignant upper GI obstruction. Gastrointest Endosc. 2001;53:329-32. 59. Lillemoe KD, Cameron JL, Hardacre JM, et al. Is prophylactic gastrojejunostomy indicated for unresectable periampullary cancer? A prospective randomized trial. Ann Surg. 1999;230(3):322-8. 60. Yates MR III, Morgan DE, Baron TH. Palliation of malignant gastric and small intestinal strictures with self-expandable metal stents. Endoscopy. 1998;30:266-72.
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61. Doberneck RC, Berndt GA. Delayed gastric emptying after palliative gastrojejunostomy for carcinoma of the pancreas. Arch Surg. 1987;122:827-29. 62. Weaver DW, Wiencek RG, Bouwman DL, Walt AJ. Gastrojejunostomy: is it helpful for patients with pancreatic cancer? Surgery. 1987;102(4):608-13. 63. Wiersema MJ, Wiersema LM. Endosonography-guided celiac plexus neurolysis. Gastrointest Endosc. 1996;44:656-662. 64. Gunaratnam NT, Sarma AV, Norton ID, et al. A prospective study of EUS-guided celiac plexus neurolysis for pancreatic cancer pain. Gastrointest Endosc. 2001;54:316324. 65. Zollinger RM, Ellison EH. Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas. Ann Surg. 1955;142:709-723. 66. Prinz RA. Localization of gastrinomas. Int J Pancreatol. 1996;19:79-91. 67. Jensen RT, Gibril F, Termanini B. Definition of the role of somatostatin receptor scintigraphy in gastrointestinal neuroendocrine tumor localization. Yale J Biol Med. 1997;70:481-500. 68. Anderson MA, Carpenter S, Thompson NW, et al. Endoscopic ultrasound is highly accurate and directs management in patients with neuroendocrine tumors of the pancreas. Am J Gastroenterol. 2000;95:2271-2277. 69. Zimmer T, Scherubl H, Faiss S, et al. Endoscopic ultrasonography of neuroendocrine tumors. Digestion. 2000;62(Suppl 1):45-50. 70. Rosch T, Lightdale CJ, Botet JF, et al. Localization of pancreatic endocrine tumors by endoscopic ultrasonography. N Engl J Med. 1992;326:1721-1726. 71. Sugiyama M, Abe N, Izumisato Y, et al. Differential diagnosis of benign versus malignant nonfunctioning islet cell tumors of the pancreas: the role of EUS and ERCP. Gastrointest Endosc. 2002;55:115-119. 72. Kann P, Bittinger F, Engelbach M, et al. Endosonography of insulin-secreting and clinically non-functioning neuroendocrine tumors of the pancreas: criteria of benignancy and malignancy. Eur J Med Res. 2001;6:385-390. 73. Furukawa T, Oohashi K, Yamao K, et al. Intraductal ultrasonography of the pancreas: development and clinical potential. Endoscopy. 1997;29:561-569. 74. Menzel J, Domschke W. Intraductal ultrasonography may localize islet cell tumours negative on endoscopic ultrasound. Scand J Gastroenterol. 1998;33:109-112. 75. Gress FG, Barawi M, Kim D, et al. Preoperative localization of a neuroendocrine tumor of the pancreas with EUS-guided fine needle tattooing. Gastrointest Endosc. 2002;55:594-597. 76. Chang KC, Senzer N, Chung T, et al. A novel gene transfer therapy against pancreatic cancer (TNFerade) delivered by endoscopic ultrasound (EUS) and percutaneous guided fine needle injection (FNI). Gastrointest Endosc. 2004;59: AB92.
Color Atlas
Figure 1-11. Choledochal cyst. Intraoperative image of choledochal cyst in a 14-yearold girl. Also shown on page 16.
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CA II
Figure 3-4. Endoscopic
sphincterotomy performed via the standard pull technique. Also shown on page 56.
Figure 3-5. Four choles-
terol gallstones removed from the common bile duct using an extraction balloon. Also shown on page 59.
CA III Figure
5-1.
Endoscopic snare resection of a villous adenoma of the ampulla of Vater. Here, the ampulla of Vater is visualized with a side viewing duodenoscope. Note the fungating appearance of the ampullary orifice. Also shown on page 97.
Figure 5-2. Dual
sphincterotomies of the pancreatic and biliary orifices have been performed. The pancreatic duct has been stented with a short, narrow caliber stent in preparation for snare ampullectomy. Also shown on page 98.
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Figure 7-3. A. Ascaris in ampulla. B. Worm removed by dormia basket. Reprinted with permission from Al-Karawi M, Sanai FM, Yasawy MI, et al. Biliary strictures and cholangitis secondary to ascariasis: endoscopic management. Gastrointest Endosc. 1999;50:695-697. Obtained with permission. Also shown on page 132.
Figure 9-10. Endoscopic view (A) and Sudan stain (B) showing steatorrhea in a patient with pancreatic insufficiency. Also shown on page 197.
chapter
12
Pancreatic Cystic Lesions David G. Forcione, MD; Brenna C. Bounds, MD
Introduction The advent of widely available cross-sectional imaging has given rise to an impressive, ever-expanding list of pancreatic cystic lesions including benign, inflammatory (pseudocysts), and neoplastic cysts (Table 12-1). Pseudocysts are considered the most common, accounting for approximately 75% to 80% of pancreatic cystic lesions. Benign cysts, including congenital cysts, lymphoepithelial cysts, and retention cysts, are uncommon, accounting for 5% of pancreatic cystic lesions. Although accounting for only 10% to 15% of lesions, the cystic neoplasms of the pancreas have become increasingly recognized as an important subset of pancreatic disease, with a histopathologic spectrum ranging from benign to malignant. Advances in endoscopic tissue acquisition with cytologic and biomarker evaluation have resulted in improvements in diagnosis, staging, and therapeutic strategies. In particular, cyst fluid analysis has become increasingly used to distinguish cystic lesions and provide some information on malignant potential. This chapter will focus on an overview of the clinicopathologic spectrum of cystic lesions of the pancreas, with a particular focus on clinical evaluation and management.
Pseudocysts DEFINITIONS AND EPIDEMIOLOGY A pseudocyst is an inflammatory cystic cavity that develops in the setting of pancreatitis or traumatic pancreatic injury. These cystic lesions most commonly are extrapancreatic in location. Pseudocysts are not true cysts as the lining is not epithelial but is composed of inflammatory cells and fibrinous debris. This inflammatory lining is often tightly adherent to adjacent viscera (colon, stomach). The cyst contains amylase-rich fluid, often in association with a variable amount of necrotic debris. The pseudocyst exists within a radiologic and pathologic spectrum of fluid collections
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Table 12-1
CYSTIC LESIONS OF THE PANCREAS I. Non-neoplastic Inflammatory Pseudocysts Noninflammtory Lymphoepithelial cysts Enteric duplication cysts Endometrial cysts Hydatid cysts Retention cysts Congenital cysts True (simple) cysts Autosomal dominant polycystic kidney disease Cystic fibrosis von-Hippel Lindau syndrome Acinar cell cystadenoma II. Neoplastic Common Solid pseuodopapillary tumor Serous cystic neoplasms Microcystic serous cystadenoma Macrocystic (oligocystic) serous cystadenoma Mucinous cystic neoplasms Mucinous cystadenoma Mucinous cystadenocarcinoma Intraductal papillary mucinous neoplasm Uncommon Cystic neuroendocrine tumors Acinar cell cystic neoplasm Ductal adenocarcinomas Lymphoma Leiomyosarcoma Schwannoma Malignant fibrous histiocytoma Metastatic deposits (renal cell and melanoma) Paragangliomas Dermoid cysts (cystic teratomas)
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Table 12-1, continued
Vascular tumors Lymphangioma Hemangioma Hemolymphangioma Hemangiopericytoma Hemangioblastoma Hemangiosarcoma associated with both acute (AP) and chronic pancreatitis (CP). It is important, from both a diagnostic and therapeutic perspective, to stratify peripancreatic fluid collections arising from AP, CP, or pancreatic trauma as an acute fluid collection, acute pseudocyst, chronic pseudocyst, or pancreatic abscess (Atlanta Consensus Conference classification) (Table 12-2). Approximately 30% to 60% of cases of AP are associated with acute fluid collections, typically located in the potential space of the lesser omentum (lesser sac) or the anterior pararenal space. Most often, these fluid collections develop within the lesser sac and are anatomically limited anteriorly by the stomach, inferiorly by the transverse mesocolon, laterally by the spleen, and by splenic flexure on the left and the duodenum on the right. The majority of acute fluid collections (80%) will resolve spontaneously, and the remainder will undergo organization to form pseudocysts. This translates into an estimated 5,000 to 7,000 new cases of pancreatic pseudocysts being discovered each year in the United States in the clinical setting of AP. Clinical observation has demonstrated that most acute fluid collections will organize into pseudocysts within 6 weeks, although this time course remains variable among patients.
ETIOLOGY AND PATHOGENESIS Approximately 5% to 15% of all episodes of AP will result in the formation of a pancreatic pseudocyst, with about half of these pseudocysts resolving or stabilizing spontaneously (remaining asymptomatic). In line with the epidemiology of AP, most acute pseudocysts develop in the setting of alcohol or gallstone mediated pancreatic injury. Epidemiologic studies performed in the United States have favored a much greater contribution from alcohol in this regard, with reports of 70% to 80% of pancreatic pseudocysts arising in the setting of acute or chronic alcoholic pancreatitis. In contrast, French studies have noted that gallstone pancreatitis accounts for the majority of their acute pancreatic pseudocysts (45%), whereas alcoholic pancreatitis contributed to the majority of chronic pancreatic pseudocysts (94%). Although the natural history data remain limited, it appears that pseudocysts are significantly more common among patients with CP, with an estimated incidence of 20% to 40%. Several mechanisms may account for the development of a pancreatic pseudocyst. An acute inflammatory necrosis of peripancreatic tissue, in association with leakage of pancreatic juice from an inflamed surface of the pancreas, leads to the formation of an
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Table 12-2
ATLANTA CONSENSUS CONFERENCE CLASSIFICATION OF PERIPANCREATIC FLUID COLLECTIONS Acute Fluid Collections: These fluid collections develop early in the course of acute pancreatitis in the setting of liquefaction necrosis. These collections lack a defined wall. Acute Pseudocysts: Amylase-rich fluid collections with a defined lining of inflammatory cells and fibrinous debris. Chronic Pseudocysts: Amylase-rich fluid collections with a defined lining of inflammatory cells and fibrinous debris, which develop in the setting of chronic pancreatitis (in the absence of a clear episode of acute pancreatitis). Pancreatic Abscess: A circumscribed intra-abdominal collection of pus in proximity with the pancreas arising as the consequence of acute pancreatitis, trauma, or chronic pancreatitis. amylase-rich cavity (with or without communication with the main pancreatic duct). Pancreatic parenchymal necrosis and associated main pancreatic duct disruption, with gross leakage of pancreatic juice into the surrounding peripancreatic space, results in peripancreatic tissue necrosis and cyst formation. The head of the pancreas is the most common site of main duct disruption (50%), followed by the body (30%) and tail (20%). Pseudocysts may also form in the setting of an acute exacerbation of CP. Additionally, pseudocysts may form as a result of pancreatic ductal obstruction due to stricture formation, proteinacious plugging, or intraductal calculi. Finally, disruption of the pancreatic duct in the setting of acute abdominal trauma (penetrating or blunt) may result in extravasation of pancreatic juice, local tissue necrosis, and subsequent pseudocyst formation. Trauma is the most common cause of pseudocyst formation among children.
CLINICAL FEATURES It is estimated that only 50% of all pseudocysts will result in clinical symptoms, while the remainder will either spontaneously resolve or remain clinically quiescent. Pseudocysts may present clinically in one of several ways. The most common presentation is that of abdominal pain, which may develop in the setting of adjacent visceral obstruction (biliary tree, bowel, vasculature, urinary tract) due to expansion of the cyst. Pancreatic fluid may fistulize to the pleural or peritoneal spaces with ensuing pleural effusions or ascites, respectively. True spontaneous infection of pseudocysts has been reported to occur in up to 10% of cases, and likely stems from surrounding gut flora in the acute fluid collection stage. Perhaps the most common reason for the development of an infected pseudocyst
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Figure 12-1. Pseudocyst.
is from contamination during transcutaneous or transenteric needle aspiration. The most feared complication of a pseudocyst is the development of a pseudoaneurysm, which may develop from localized, enzymatic erosion into an adjacent vascular structure. Pseudoaneurysms develop in 5% to 10% of patients with pseudocysts. The most commonly affected vessels are the splenic artery, gastroduodenal, and pancreaticoduodenal arteries. These may present with abdominal pain due to acute hemorrhage into the cyst cavity or with acute gastrointestinal bleeding due to hemorrhage into the pancreatic duct (hemosuccus pancreaticus).
DIAGNOSIS Most pseudocysts are diagnosed with transabdominal ultrasound (US) or computed tomography (CT) (Figure 12-1), either in follow-up of a known fluid collection discovered at the onset of AP (an acute fluid collection) or in evaluation of abdominal pain with or without a known previous history of pancreatitis or trauma. In one series of acute pseudocysts, 39% were located in the lesser sac (or omental bursa), 31% in the anterior pararenal space, 10% within the substance of the liver, and 20% in other sites. Pseudocysts may be intra- or extrapancreatic in location, although most clinically relevant pseudocysts are extrapancreatic. Intrapancreatic pseudocysts are most frequently located in the head of the pancreas. Pseudocysts may vary in size, ranging from 1 to 35 cm, with the mean size at 9 +/- 1 cm in one study. Cyst fluid contents may measure as high as 6000 mL. The fluid appearance is typically a turbid brown, although it may also be clear or hemorrhagic in nature. Approximately 80% to 90% of affected patients will have a single pseudocyst. Multiple pseudocysts are usually found in those patients with underlying alcoholic pancreatitis, presumably due to the diffuse nature of the pancreatic injury. Communication with the pancreatic duct is reported to range from 6% to 60% of cases, with the broad variability likely reflecting differences in imaging techniques. Although pseudocysts are the most common cystic lesions of the pancreas, it is important to consider a broad differential diagnosis in the evaluation, including both
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Table 12-3
CLUES FAVORING A PANCREATIC PSEUDOCYST IN THE EVALUATION OF A PANCREATIC CYSTIC LESION • Antecedent history of pancreatitis, abdominal trauma, or abdominal • • • • • •
surgery. Clinical or radiologic evidence of chronic pancreatitis. Communication of the cyst with the main pancreatic duct. Peripancreatic inflammatory changes on abdominal computed tomography. Extrapancreatic location of the cyst. Absence of internal septae within the cyst. Cyst fluid evaluation demonstrating a very high amylase (>10,000 U/mL), low CEA (6 cm in size is no longer an absolute. Current treatment strategies rely more on the clinical and radiologic behavior of the pseudocyst to determine the need for intervention (Table 12-4). Surgical, radiologic, and endoscopic methods have all been employed to drain pseudocysts (Table 12-5). Care must be taken to exclude a complicating pseudoaneurysm, as this will need to be angiographically embolized prior to any drainage attempts. Traditional surgical cyst-gastrostomy and cyst-enterostomy are now reserved for multiloculated pseudocysts, those without close apposition to an accessible duodenal or gastric wall, and for those that have failed nonsurgical techniques. A distal pancreatectomy (often with splenectomy) may be performed in patients with pseudocysts isolated to the tail of the pancreas. Morbidity and mortality rates are reported at 10% to 30% and 1% to 5%, respectively. Recurrence rate is approximately 10% to 15%. Radiologic (percutaneous) drainage is generally used for cystic lesions that are not amenable to endoscopic drainage due to location or in suspected infected collections. Persistence of a pancreaticocutaneous fistula may complicate percutaneous drainage, particularly if there is a ductal obstruction associated with the pseudocyst. Parenteral octreotide may be required to reduce flow rate through the drain prior to removal to minimize the chances of fistula formation. Following a mean of 42 days of catheter drainage, approximately 80% to 90% of pseudocysts will be adequately treated. The reported complication rates are 15% to 20%, including bleeding and drain track infection.
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Table 12-5
TECHNIQUES FOR PSEUDOCYST DRAINAGE Surgical • • •
Cyst-gastrostomy Cyst-enterostomy Segmental pancreas resection (distal pancreatectomy)
Radiologic •
Percutaneous catheter drainage
Endoscopic • •
Transpapillary stenting Transgastric or transduodenal drainage
There has been increasing interest in the use of endoscopic drainage techniques. These include transpapillary and transmural drainage. The former employs the use of a pancreatic stent through the papilla to bridge the main pancreatic duct disruption, which communicates with the pseudocyst. In some cases, the transpapillary stent can be placed through the pancreatic duct into the cavity of the pseudocyst. For infected pseudocysts or frank pancreatic abscesses, direct transmural drainage of the collection may be performed endoscopically. Transmural drainage of pancreatic pseudocysts can be performed with or without the aid of endoscopic ultrasound (EUS) (Figure 12-2). Lesions best suited for transmural drainage are those closely associated with the gastric or duodenal wall, causing a characteristic endoscopic bulge or those with a cyst wall >head
Intraductal papillary mucinous cystic neoplasm
68 yrs
1:2
Head >> body/tail (side branch) Body/tail =head (main duct)
Body/tail = head
Type
Histology
Fluid Characteristics
Malignant Potential
Solid pseudoneoplasms
Pseudopapillary projections
Non-mucinous debris
Low
Serous cystic neoplasms
Simple cuboida epithelial
Thin, non mucinous Low amylase Low CEA
Rare
Mucinous cystic neoplasm
Flat mucinous epithelial
Viscous, mucinous Low amylase High CEA
High
Intraductal papillary mucinous cystic neoplasm
Papillary projections of mucinous epithelium
Viscous, mucinous High amylase High CEA
Moderate
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SOLID-PSEUDOPAPILLARY NEOPLASM Solid-pseudopapillary neoplasms (SPN) of the pancreas are uncommon benign or low-grade malignant epithelial neoplasms of the pancreas with cystic features. Primarily affecting young women, solid-pseudopapillary neoplasms account for 1% to 2% of all exocrine pancreatic tumors and approximately 12% of cystic neoplasms of the pancreas. The mean age of diagnosis is 26, with a reported range of 2 to 72 years. On average, male patients tend to be older than female patients (31.4 years versus 25.5 years). In all series, there is a striking female preponderance (9-10:1). First reported by Frantz in 1959, this cystic neoplasm has been classified in the literature under multiple names, including solid-cystic tumor of the pancreas, papillarycystic tumor of the pancreas, solid and papillary epithelial neoplasm, solid and cystic acinar neoplasm, Frantz’s tumor, and pancreatic embryonic tumor. With more than 500 cases now reported in the English literature, both the World Health Organization and the Armed Forces Institute of Pathology have formally categorized this lesion as a solid-pseudopapillary neoplasm. The cell of origin for this tumor remains unknown. Some investigators have cited a possible stem cell origin given the diverse immunostaining patterns (endocrine, epithelial, and mesenchymal). Cytogenetic studies have demonstrated variable rates of loss of XX and trisomy 3. Abnormalities of the Wnt pathway (involved in beta catenin and cyclin D1) have been found in over 80% of these neoplasms. Neither the K-ras nor p53 pathways seem to play a major role in the evolution of the solid pseudopapillary neoplasm. Many patients with particularly large solid-pseudopapillary neoplasms present with abdominal pain, a palpable mass, weight loss, and/or nausea and vomiting. Most frequently, however, the tumor is discovered incidentally when the abdomen is being imaged for other reasons, including after blunt abdominal trauma. There are rare case reports of significant hemoperitoneum occurring due to capsular rupture (2% to 3% of cases). Jaundice and pancreatitis are distinctly unusual. There have been no reported cases of a solid-pseudopapillary neoplasm presenting with an endocrinopathy. The diagnosis of a SPN must be considered in the differential diagnosis of a new solid-cystic mass, particularly in a young woman. SPN are well-demarcated pancreatic tumors, with rare reports of extrapancreatic or ectopic (liver, inguinal canal, retroperitoneum) sites. They tend to be large, round tumors with a size ranging from 1 to 30 cm, with a mean size at diagnosis of approximately 9 cm. Any region of the pancreas may be affected, though with greatest frequency in the body and tail. There are rare reports of synchronous tumors in the head and tail of the pancreas. The majority of SPN are mixed solid and cystic lesions, with a minority (5.6%) demonstrating only solid features. A number of different imaging modalities have been used to evaluate this lesion. Plain abdominal films may demonstrate calcifications of the tumor pseudocapsule in up to 30% of patients. Transabdominal ultrasound and CT reveal these to be welldefined mixed solid and cystic mass lesions, particularly in the body and tail of the pancreas. They may masquerade as pseudocysts with significant internal debris. On MRI, these lesions tend to demonstrate heterogeneous high signal intensity on T2weighted images with early peripheral heterogeneous enhancement with progressive fill-in on gadolinium enhanced dynamic imaging. Angiography usually demonstrates
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Figure 12-3. EUSguided FNA.
SPNs as hypovascular tumors. As SPNs do not communicate with the pancreatic duct, ERCP is typically normal or may demonstrate displacement of the pancreatic duct due to extrinsic mass effect. There are now case reports of identification and diagnosis of SPNs of the pancreas with EUS-guided FNA (Figure 12-3). Serum CEA and CA 19-9 are normal in patients with SPNs. On gross pathologic examination, the cut surface reveals lobulated, yellow tissue and cyst formation arising out of varying degrees of hemorrhage and necrosis, particularly in the center of the lesion. There is usually a distinct fibrous capsule separating the tumor from the remainder of the pancreas. On microscopy, there is a pseudopapillary architecture with cells around a delicate microvascular network. The cells lining the cyst have eosinophillic cytoplasm, which may or may not contain PAS-positive, diastase-resistant intracytoplasmic globules. There is distinct absence of mucin or glycogen staining. These features provide for a highly characteristic cytologic appearance, allowing the pathologist to distinguish the SPN from other cystic neoplasms of the pancreas. The treatment of choice is surgical resection, including for those lesions identified incidentally. Over 85% of patients (males and females equally) will have an excellent prognosis following surgery, supporting the overall benign phenotype of these lesions. Nonetheless, these tumors are best classified as having borderline malignant potential, with an infrequent but well-documented incidence of the development of invasive or metastatic lesions. Based on large series, approximately 15% of SPNs display a malignant phenotype with development of metastatic deposits or local invasion. Reported sites of metastases include (in order of decreasing frequency): liver, peritoneum, and regional lymph nodes. Direct invasion into adjacent viscera may also be seen in rare instances. Predictors of malignant potential include the presence of perineural or vascular invasion, nuclear atypia, mitotic index, and prominence of necrobiotic rests on microscopy. Metastatic deposits are more likely to have distinct cytogenetic abnormalities including aneuploidy, unbalanced chromosome 17;13 translocations, and trisomy 3.
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Several small series have highlighted the importance of being aggressive with surgical resection in all patients, including those with evidence of local invasion, metastatic deposits, and tumor recurrences. Recurrences as far out as 8 years have been reported in patients who have undergone primary resection. Therefore, patients must be followed closely for the development of new or changing abdominal symptoms. Of interest, a number of patients have now been reported with long-term survival even with known metastatic deposits, highlighting the slow tumor doubling rate (estimated at 765 days by serial CT scans). A possible survival benefit has been suggested in some series in which children with metastatic disease at the time of initial resection are treated with adjuvant chemotherapy. As one might expect, however, there are rare reports of fatalities in the face of disease progression.
SEROUS CYSTIC NEOPLASMS Serous cystic neoplasms (serous cystadenomas and serous cystadenocarcinomas) are generally benign cystic lesions of the pancreas characterized by an epithelial lining of glycogen-containing cuboidal cells. The most common serous cystic neoplasm is the microcystic serous cystadenoma, accounting for 70% of lesions. The less common variants include the macrocystic (or oligocystic) serous cystadenoma, ill-demarcated serous cystadenoma, and the solid serous cystadenoma. Serous cystadenocarcinomas are rare cystic neoplasms, presumably reflecting the uncommon phenomenon of malignant degeneration of a serous cystadenoma. Depending on the series, serous cystic neoplasms account for 10% to 36% of all cystic neoplasms of the pancreas. Compagno and Oertel first described serous cystic neoplasms of the pancreas as a clinicopathologic identity in 1978, classifying the distinct histopathology that distinguishes serous cystic neoplasms from mucinous cystic neoplasms. There is again a female preponderance, on the order of 3-4:1, although this is less consistent in the case of the macrocystic serous cystadenoma. The mean age of patients at the time of diagnosis is 61, with an age range from 34 to 91 years. There are scattered reports of children as young as 4 years with a serous cystic neoplasm. Most lesions (75%) are located in the body or tail of the pancreas. The macrocystic variant is more commonly found in the head and body of the pancreas. There is growing knowledge regarding the pathogenesis of serous cystic neoplasms. As previously noted, patients with VHL syndrome have a high frequency of serous cystadenomas. Among these patients, there is no gender predilection and the age at diagnosis tends to be younger (mean age, 42 years). Unlike sporadic cases, VHL associated serous cystic neoplasms may involve the entire pancreas. In sporadic cases, up to 70% of patients will demonstrate loss of heterozygosity (LOH) at chromosome 3p25, the location of the VHL gene. In addition, up to 50% of patients will have LOH at chromosome 10q. The majority of patients are found to have a serous cystic neoplasm incidentally, discovered through abdominal imaging or surgery. When symptomatic (up to 50% of patients), the most common clinical presentations of serous cystic neoplasms include those resulting from mass effect on the gastrointestinal lumen (nausea, vomiting, abdominal pain, bloating) and rarely obstructive jaundice from common bile duct compression (eight reported cases in the literature). There are rare reports of serous cystic neoplasms in association with hemoperitoneum, gastrointestinal bleeding, and esophageal varices due to arterial-portal shunting.
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Figure 12-4. Oligocystic pattern.
Making a correct diagnosis of a serous cystic neoplasm is vital, as it generally allows for nonoperative, expectant management in all but symptomatic patients. A number of imaging modalities have been used to characterize these lesions. These cystic masses are typically round lesions, from 1 to 25 cm in size, with a mean size of 8 cm. Plain abdominal radiographs may reveal calcifications. The classic finding on abdominal CT is that of a microcystic mass in the body or tail of the pancreas. Thin cut CT protocols may demonstrate innumerable cystic spaces within the lesion separated by thin septae. In up to 20% of cases, a central scar containing a “starburst” calcification may be seen. Additionally, the lesion is typically intense on T1-weighted and hyperintense on T2-weighted MRI, particularly in the case of a macrocystic serous cystic neoplasm. Given the lack of communication with the main pancreatic duct, ERCP may be normal or show evidence of displacement from extrinsic compression. Angiography typically demonstrates these lesions to be hypervascular in nature. One series compared the accuracy of transabdominal ultrasound (US), abdominal CT, and MRI for the diagnosis of serous cystic neoplasms. Both US and abdominal CT fared similarly, with nearly 1/3 of cases being incorrectly diagnosed and up to 16% being nondiagnostic studies. MRI performed the best of the three with an overall accuracy of 74%. EUS classically demonstrates a single, large multicompartmental cystic mass, often with larger cysts on the periphery of the lesion, or in the case of the macrocystic serous cystadenoma, an oligocystic pattern (Figure 12-4). The septae are notably thin (2 to 4 mm). The oligocystic nature of the macrocystic serous cystic neoplasm presents particular difficulties, as it may resemble a mucinous cystic neoplasm if there are one or two compartments. A central scar with calcification is a variable finding. Mural nodules and calcifications are noticeably absent in the vast majority of these lesions. EUS-FNA may provide an additional level of diagnostic insight to the ultrasound morphologic features. EUS-FNA of the cyst is most useful to obtain a cytologic sampling of the cuboidal lining and to obtain cyst fluid for analysis of biomarkers. There are several challenges facing the endoscopist performing EUS-FNA of serous cystadenoma including the hypervascular nature of the lesion, which may result in a cytology sample overly contaminated with blood. In addition, the cystic spaces may be quite small, making adequate fluid aspiration difficult. Finally, cytologic yields may
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fail to provide a diagnosis in up to 60% of cases. The aspirated cyst fluid is typically a thin, clear, or yellow-tinged fluid with minimal viscosity (reflecting the absence of mucin). Hemorrhagic aspirates are sometimes seen due to the hypervascular nature of the lesion. The cyst fluid amylase, CEA, and CA 72-4 should all be low (CEA 15 mm, a solid mass, and diffuse pancreatic involvement all raise concern for a malignant IPMN. Considered the gold standard study, ERCP may demonstrate a patulous papillary orifice with mucin extrusion in up to 50% of patients, ductal dilation in 100%, and ductal filling defects due to mucin (Figure 12-6). In fact, filling of the pancreatic duct may be challenging due to impedance from the intraductal mucin, which may then require use of an occlusion balloon. Pancreatic juice can be sampled for cytology in addition to performing brushings of the duct. The sensitivity and specificity of these
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techniques is approximately 40% and 100%, respectively. Special techniques, including acquiring cytology following secretin stimulation, appear to enhance sensitivity. There is growing interest in using pancreatic juice mutational analysis (K-ras) and measurements of telomerase activity (present in up to 90% of malignant IPMNs) to further enhance the detection rate of malignant IPMNs. ERCP also provides a conduit for per oral pancreatoscopy and intraductal ultrasound (IDUS) with high frequency (15 to 20 MHz) probes. Per oral pancreatoscopy may show typical papillary protrusions (“fish-eggs”) and IDUS may reveal focal wall thickening and nodularity. Although some investigators have demonstrated usefulness of these techniques both in diagnosis and in preoperative staging, they are not widely available and may not be technically feasible in all cases. MRI/MRCP is increasingly seen as comparable, and perhaps superior, to ERCP in the diagnosis and staging of IPMNs. Studies have demonstrated a diagnostic accuracy of 80% to 100% and enhanced detection rate for mural nodules compared to ERCP. In addition to mural nodules, main pancreatic duct >15 mm and combined side branch and main duct involvement are features on MRI/MRCP concerning for malignancy. Although MRI/MRCP does not provide the ability for cytology acquisition as does ERCP, the ability to assess the entire ductal anatomy without accompanying procedural risk makes this an essential imaging modality for evaluating patients with IPMNs. EUS has become an essential diagnostic modality for evaluating suspected IPMNs with a sensitivity and specificity of 86% and 99% using ERCP as the gold standard. On morphologic grounds, these lesions may appear as focal or diffuse dilations of the pancreatic duct or side branches. Cysts with internal septations and mural nodules may be identified. Accompanying solid mass lesions may also be seen and are an ominous finding. EUS-guided FNA provides fluid and tissue for cytopathology (yield only about 30%) and for measurement of biomarkers (amylase and CEA). Elevated amylase and CEA are consistent in IPMNs. A cyst fluid CEA >300 ng/mL supports the diagnosis of a mucinous neoplasm such as IPMN. Values in excess of 1000 ng/ml are highly suggestive of malignant degeneration. Recent data have examined the potential of 18-FDG PET in determining benign versus malignant cystic neoplasms, including patients with an IPMN. Sensitivity and specificity for 18-FDG PET was 94%. The authors concluded that 18-FDG PET should be routinely used in combination with CT in the preoperative evaluation of patients with cystic lesions of the pancreas. The main differential diagnosis that is considered when evaluating patients with suspected IPMNs includes chronic pancreatitis, ductal adenocarcinoma of the pancreas, and a mucinous cystic neoplasm (cystadenoma or cystadenocarcinoma). Changes often seen in CP may also be features when imaging the pancreas of patients with IPMNs. One recent study of EUS features noted several findings more common in IPMN as compared to CP, including dilation of PD (89% versus 42%), cysts (45% versus 11%) and pancreas atrophy (32% versus 3%). These authors concluded that two or more parenchymal abnormalities typical of chronic pancreatitis make IPMN less likely, including hyperechoic foci and stranding, calcifications, and lobularity of the gland. Patients with ductal adenocarcinoma tend to have far greater systemic symptoms and weight loss, and on imaging have more invasive features than IPMNs. In contrast to MCNs, IPMNs are more frequently seen in the pancreatic head versus in the body and tail of the pancreas, have a male rather than female predominance, and communicate with the pancreatic duct.
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On gross pathology, IPMNs exhibit cystic dilation of the main pancreatic duct alone or in combination with side branch changes. In approximately 25% of cases, only side branch duct involvement may be seen. A minority of IPMNs are multifocal, with intervening segments of normal pancreas. In a variable number of cases, one may see solid mass lesions, often arising from cystic mural nodules. Microscopically, the mucinous epithelium is characterized by papillary projections emanating from the pancreatic duct. The cells may exhibit a gastroenteric, pancreatobiliary, or oncocytic differentiation. The significance of these varying histologic categories in regard to natural history and prognosis remains uncertain. As in the case of mucinous cystic neoplasms, IPMNs are classified according to degree of epithelial cellular atypia. The four categories include adenoma, borderline tumor, carcinoma in situ, and invasive carcinoma. As the lesion progresses, there is a loss of mucin production and nuclear polarity. Carcinoma in situ is seen in up to 60% of IPMNs, with the highest prevalence in those lesions with combined main duct and side branch involvement, and the lowest with side branch disease only. Invasive carcinoma is seen in up to 35% of cases and regional (group I) lymph nodes may be found in 20% to 30%. Our understanding of the natural history of IPMNs continues to evolve. At this time, it is believed that the majority of lesions are slow growing; some taking decades to progress. The estimated 5-year survival for all patients is 60%, which compares favorably to typical ductal adenocarcinoma of the pancreas. Although the majority of lesions are benign, the rate of malignant degeneration and factors associated with this progression remain uncertain. Studies to date have demonstrated a more favorable course for side branch IPMNs compared to mixed or main duct variants (5-year survival of 90% versus 47%). In agreement with this, several imaging surveillance studies have confirmed minimal progression in most side branch IPMNs followed by MRI/MRCP over several years. In addition, multivariate analysis has established that abnormal liver tests, concurrent alcohol use, and p53 overexpression are associated with worse outcomes, whereas gross mucus identified at endoscopy was associated with a more favorable outcome. In contrast to colorectal and gastric malignancies, high frequency microsatellite instability is not associated with a good prognosis. As noted, radiologic, endosonographic, cytologic, and biochemical markers may be used to classify the risk of invasive malignancy in any given lesion. However, these markers are neither sensitive nor specific enough to base confident clinical decisions on in all cases. These limitations in our understanding have led some investigators to advocate surgical resection in all suitable patients. Because of the potentially diffuse nature of the disease process, careful preoperative imaging evaluation is essential to help guide the nature and extent of resection. Nonetheless, most surgical resections are guided by intraoperative evaluation of surgical margins by frozen section or intraoperative pancreatoscopy in combination with an assessment of the potential for operative morbidity and mortality associated with wider resection in any individual patient. A study of 113 patients with IPMNs (40 invasive and 73 noninvasive) demonstrated a 62% and 67% recurrence rate for invasive carcinoma after partial resection and total pancreatectomy, respectively (91% recurrences within 3 years). Noninvasive carcinomas rarely recur (8% after partial) and 0% recur after total pancreatectomy (median follow-up 32 to 37 months). Overall, the 5-year survival rate in this study was 84.5% for noninvasive malignancies and 36% for invasive carcinomas.
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Noninvasive, expectant management is reasonable in patients at high risk for surgical morbidity and mortality. Additionally, patients with focal side branch variant IPMN,