Evidence-based gastroenterology and hepatology [3ed.] 9781405181938, 1405181931

Table of contents :
Cover
Copyright
Table of Contents
Contributors
1.
Introduction
PART I: GASTROINTESTINAL DISORDERS
2. Gastroesophageal reflux disease
3.
Barrett’s esophagus
4. Esophageal motility disorders: Achalasia and spastic motor disorders
5. Eosinophilic esophagitis
6. Ulcer disease and Helicobacter pylori infection: Etiology and treatment
7. Non-steroidal anti-inflammatory
drug-induced gastro-duodenal toxicity
8. Acute non-variceal
gastrointestinal hemorrhage: Treatment
9. Functional dyspepsia
10. Celiac disease: Diagnosis, treatment and prognosis
11. Crohn's disease
12. Ulcerative colitis
13. Pouchitis after restorative proctocolectomy
14. Microscopic colitis: Collagenous and lymphocytic colitis
15. Drug-induced diarrhea
16. Metabolic bone disease in gastrointestinal disorders
17. Colorectal cancer in ulcerativ colitis surveillance
18. Colorectal cancer: Population screening and surveillance
19. Prevention and treatment of traveler's diarrhea
20. Clostridium difficile associated disease: Diagnosis and treatment
21. Irritable bowel syndrome
22. Ogilvie's syndrome
23. Gallstone disease
24. Acute pancreatitis
25. Obesity management: Considerations for the gastroenterologist
PART II: LIVER DISEASE
26. Hepatitis C
27. Hepatitis B: Prognosis and treatment
28. Alcoholic liver disease
29. Non-alcoholic fatty liver disease
30. Hemochromatosis
31. Wilson's disease
32. Primary biliary cirrhosis
33. Autoimmune hepatitis
34. Primary sclerosing cholangitis
35. Non-histological assessment of liver fibrosis
36. Portal hypertensive bleeding
37. Hepatic outflow syndromes and splanchnic venous thrombosis
38. Ascites, hepatorenal syndrome and spontaneous bacterial peritonitis
39. Hepatic encephalopathy: Treatment
40. Hepatocellular carcinoma
41. Fulminant hepatic failure: Treatment
42. Liver transplantation: Prevention and treatment of rejection
43. Liver transplantation: Prevention and treatment of infection
44. Management of HCV infection and liver transplantation
45. Management of HBV infection and liver transplantation
46. Liver biopsy
47. Drug induced liver disease: Mechanisms and diagnosis
Index

Citation preview

Evidence-Based Gastroenterology and Hepatology T HI RD E DI T I ON

Evidence-Based Gastroenterology and Hepatology, Third Edition John WD McDonald, Andrew K Burroughs, Brian G Feagan and M Brian Fennerty © 2010 Blackwell Publishing Ltd. ISBN: 978-1-405-18193-8

Evidence-Based Gastroenterology and Hepatology THIRD EDITION E DITE D B Y

John WD McDonald Professor of Medicine Robarts Clinical Trials, Robarts Research Unit University of Western Ontario London, Ontario, Canada

Andrew K Burroughs Professor of Hepatology and Consultant Physician/Hepatologist The Royal Free Sheila Sherlock Liver Centre Royal Free Hospital, and University College London London, UK

Brian G Feagan Professor of Medicine Robarts Clinical Trials, Robarts Research Unit University of Western Ontario London, Ontario, Canada

M Brian Fennerty Professor of Medicine Oregon Health and Science University Division of Gastroenterology and Hepatology Portland, Oregon, USA

A John Wiley & Sons, Ltd., Publication

This edition first published 2010. © 2010, 2004, 1999 by Blackwell Publishing Ltd Blackwell Publishing was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing program has been merged with Wiley’s global Scientific, Technical and Medical business to form Wiley-Blackwell. Registered office: John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial offices: 9600 Garsington Road, Oxford, OX4 2DQ, UK The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK 111 River Street, Hoboken, NJ 07030-5774, USA For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com/wiley-blackwell The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by physicians for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. Library of Congress Cataloging-in-Publication Data Evidence-based gastroenterology and hepatology / edited by John W.D. McDonald . . . [et al.]. – 3rd ed. p. ; cm. Includes bibliographical references and index. ISBN 978-1-4051-8193-8 (alk. paper) 1. Gastroenterology–Textbooks. 2. Hepatology–Textbooks. 3. Gastrointestinal system–Diseases–Textbooks. 4. Liver–Diseases–Textbooks. 5. Evidencebased medicine–Textbooks. I. McDonald, John W.D. [DNLM: . Gastrointestinal Diseases–diagnosis. 2. Gastrointestinal Diseases–therapy. 3. Evidence-based Medicine–methods. 4. Liver Diseases– diagnosis. 5. Liver Diseases–therapy. WI 140 E928 2010] RC801.E95 2010 616.3′3–dc22 2010011010 A catalogue record for this book is available from the British Library. Set in 9.25/12pt Palatino by Toppan Best-set Premedia Limited Printed in Singapore 1

2010

Contents

Contributors, vii 1 Introduction, 1 John WD McDonald, Andrew Burroughs, Brian, G Feagan and M Brian Fennerty

Part I: Gastrointestinal disorders 2 Gastroesophageal reflux disease, 19 Naoki Chiba and M Brian Fennerty 3 Barrett’s esophagus, 62 Constantine A Soulellis, Marc Bradette, Naoki Chiba, M Brian Fennerty and Carlo A Fallone

12 Ulcerative colitis, 232 Derek P Jewell, Lloyd R Sutherland, John WD McDonald and Brian G Feagan 13 Pouchitis after restorative proctocolectomy, 248 Darrell S Pardi and William J Sandborn 14 Microscopic colitis: Collagenous and lymphocytic colitis, 257 Johan Bohr, Robert Löfberg and Curt Tysk 15 Drug-induced diarrhea, 267 Bincy P Abraham and Joseph H Sellin

4 Esophageal motility disorders: Achalasia and spastic motor disorders, 78 Jason R Roberts, Marcelo F Vela and Joel E Richter

16 Metabolic bone disease in gastrointestinal disorders, 280 Ann Cranney, Alaa Rostom, Catherine Dubé, Rachid Mohamed, Peter Tugwell, George Wells and John WD McDonald

5 Eosinophilic esophagitis, 93 Elizabeth J Elliott

17 Colorectal cancer in ulcerative colitis: Surveillance, 301 Paul Collins, Bret A Lashner and Alastair JM Watson

6 Ulcer disease and Helicobacter pylori infection: Etiology and treatment, 102 Naoki Chiba

18 Colorectal cancer: Population screening and surveillance, 311 Theodore R Levin and Linda Rabeneck

7 Non-steroidal anti-inflammatory drug-induced gastro-duodenal toxicity, 139 Alaa Rostom, Katherine Muir, Catherine Dubé, Emilie Jolicoeur, Michel Boucher, Peter Tugwell and George Wells

19 Prevention and treatment of travelers’ diarrhea, 324 Herbert L DuPont

8 Acute non-variceal gastrointestinal hemorrhage: Treatment, 165 Nicholas Church and Kelvin Palmer

21 Irritable bowel syndrome, 355 Alexander C Ford, Paul Moayyedi and Nicholas J Talley

9 Functional dyspepsia, 190 Sander Veldhuyzen van Zanten 10 Celiac disease: Diagnosis, treatment and prognosis, 200 James Gregor and Michael Sai Lai Sey 11 Crohn’s disease, 211 Brian G Feagan and John WD McDonald

20 Clostridium difficile associated disease: Diagnosis and treatment, 335 Lynne V McFarland and Christina M Surawicz

22 Ogilvie’s syndrome, 377 Michael D Saunders 23 Gallstone disease, 385 Laura VanderBeek, Calvin HL Law and Véd R Tandan 24 Acute pancreatitis, 396 Colin D Johnson and Hassan Elberm 25 Obesity management: Considerations for the gastroenterologist, 415 Leah Gramlich, Marilyn Zeman and Arya M Sharma v

Contents

Part II: Liver disease

39 Hepatic encephalopathy: Treatment, 636 Peter Ferenci and Christian Müller

26 Hepatitis C, 437 Keyur Patel, Hans L Tillmann and John G McHutchison

40 Hepatocellular carcinoma, 650 Massimo Colombo and Massimo Iavarone

27 Hepatitis B: Prognosis and treatment, 448 Piero Luigi Almasio, Calogero Cammà, Vito Di Marco and Antonio Craxì

41 Fulminant hepatic failure: Treatment, 661 James O’Beirne, Nick Murphy and Julia Wendon

28 Alcoholic liver disease, 465 Hélène Castel and Philippe Mathurin 29 Non-alcoholic fatty liver disease, 475 Christopher P Day 30 Hemochromatosis, 484 Gary P Jeffrey and Paul C Adams 31 Wilson’s disease, 493 James S Dooley and Aftab Ala 32 Primary biliary cirrhosis, 508 Gideon M Hirschfield and E Jenny Heathcote 33 Autoimmune hepatitis, 524 Michael MP Manns and Arndt Vogel 34 Primary sclerosing cholangitis, 533 Nishchay Chandra, Susan N Cullen and Roger W Chapman 35 Non-histological assessment of liver fibrosis, 554 Dominique Thabut and Marika Simon-Rudler 36 Portal hypertensive bleeding, 562 Christos Triantos, John Goulis and Andrew K Burroughs 37 Hepatic outflow syndromes and splanchnic venous thrombosis, 603 Marco Senzolo, Neeral Shah, David Patch and Stephen Caldwell 38 Ascites, hepatorenal syndrome and spontaneous bacterial peritonitis, 619 Pere Ginès, Andrés Cárdenas, Vicente Arroyo and Juan Rodés

vi

42 Liver transplantation: Prevention and treatment of rejection, 685 Maria Pleguezuelo, Giacomo Germani and Andrew K Burroughs 43 Liver transplantation: Prevention and treatment of infection, 724 Antoni Rimola and Miquel Navasa 44 Management of HCV infection and liver transplantation, 740 Brett E Fortune, Hugo R Rosen and James R Burton, Jr 45 Management of HBV infection and liver transplantation, 748 Evangelos Cholongitas and George V Papatheodoridis 46 Liver biopsy, 762 Evangelos Cholongitas, Andrew K Burroughs and Amar P Dhillon 47 Drug induced liver disease: Mechanisms and diagnosis, 771 Raúl J Andrade and M Isabel Lucena

Index, 787

The colour plate section can be found facing p. 266.

Contributors

Bincy P Abraham

Andrew K Burroughs

Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, USA

The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital and Department of Surgery, University College London, London, UK

Paul C Adams London Health Sciences Centre, London, Ontario, Canada

James R Burton, Jr University of Colorado, Denver, Colorado, USA

Aftab Ala Centre for Gastroenterology, Hepatology and Nutrition, Department of Medicine, Frimley Park Hospital NHS Foundation Trust, Surrey, UK

Stephen Caldwell

Piero Luigi Almasio

Calogero Cammà

Division of Gastroenterology, Academic Department of Internal Medicine, University of Palermo, Palermo, Italy

Division of Gastroenterology, Academic Department of Internal Medicine, University of Palermo, Palermo, Italy

Raúl J Andrade

Andrés Cárdenas

Liver Unit, Gastroenterology Service, “Virgen de la Victoria” University Hospital and School of Medicine, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Málaga, Spain

Liver Unit and GI Unit, Hospital Clínic and University of Barcelona, Institut d’Investigacions Biomèdiques August Pi-Sunyer (IDIBAPS), Ciber de Enfermedades Hepáticas y Digestivas (CIBERHED), Barcelona, Spain

Vicente Arroyo

Hélène Castel

Liver Unit and GI Unit, Hospital Clínic and University of Barcelona, Institut d’Investigacions Biomèdiques August Pi-Sunyer (IDIBAPS), Ciber de Enfermedades Hepáticas y Digestivas (CIBERHED), Barcelona, Spain

Department of Hepatology, Hôpital Claude Huriez, Lille, France

Johan Bohr

Roger W Chapman

Department of Gastroenterology, Örebro University Hospital, Örebro, Sweden

Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK

Department of Hepatology, University of Virginia, Charlottesville, Virginia, USA

Nishchay Chandra Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK

Naoki Chiba Michel Boucher HTA Development, CADTH, Ottawa, Canada

Division of Gastroenterology, McMaster University Medical Centre, Hamilton and Guelph General Hospital, Guelph, Canada

Marc Bradette

Evangelos Cholongitas

Division of Gastroenterology, Centre Hospitalier Universitaire de Québec, Québec City, Canada

The Royal Free Shiila Sherlock Liver Centre, Royal Free Hospital and Department of Surgery, University College London, London, UK

vii

Contributors

Nicholas Church

Elizabeth J Elliott

Centre for Liver and Digestive Disorders, Royal Infirmary of Edinburgh, Edinburgh, UK

Discipline of Paediatrics and Child Health, University of Sydney and The Children’s Hospital of Westminster, Sydney and Centre for Evidence-Based Paediatrics, Gastroenterology and Nutrition, Sydney, Australia

Paul Collins School of Clinical Sciences, University of Liverpool, Liverpool, UK

Carlo A Fallone Massimo Colombo Department of Medicine, First Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy

Ann Cranney Canadian Protective Medical Association and Clinical Epidemiology, Ottawa Hospital Research Institute and Faculty of Medicine, University of Ottawa, Ottawa, Canada

Division of Gastroenterology, McGill University Health Center, Montreal, Canada

Brian G Feagan Robarts Clinical Trials, Robarts Research Unit, University of Western Ontario, London, Ontario, Canada

M Brian Fennerty Oregon Health and Science University, Division of Gastroenterology and Hepatology, Portland, Oregon, USA

Antonio Craxì Division of Gastroenterology, Academic Department of Internal Medicine, University of Palermo, Palermo, Italy

Peter Ferenci Division of Gastroenterology and Hepatology, Medical University Vienna, Vienna, Austria

Susan N Cullen Buckinghamshire Hospitals NHS Trust, High Wycombe, UK

Alexander C Ford

Christopher P Day

Department of Gastroenterology, St James’s University Hospital, Leeds, UK

Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK

Brett E Fortune University of Colorado, Denver, Colorado, USA

Amar P Dhillon Histopathology Department, Royal Free Hospital, London, UK

Giacomo Germani

Vito Di Marco

The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital and Department of Surgery, University College London, London, UK

Division of Gastroenterology, Academic Department of Internal Medicine, University of Palermo, Palermo, Italy

Pere Ginès James S Dooley Centre for Hepatology, University College London Medical School (Royal Free Campus), University College London and the Royal Free Sheila Sherlock Liver Centre, Royal Free Hampstead NHS Trust, London, UK

Liver Unit and GI Unit, Hospital Clínic and University of Barcelona, Institut d’Investigacions Biomèdiques August Pi-Sunyer (IDIBAPS), Ciber de Enfermedades Hepáticas y Digestivas (CIBERHED), Barcelona, Spain

John Goulis Catherine Dubé Division of Gastroenterology, University of Calgary, Calgary, Canada

Fourth Department of Medicine, Aristotelian University of Thessaloniki, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece

Herbert L DuPont

Leah Gramlich

Center for Infectious Disease, University of Texas Health Science Center at Houston, School of Public Health and Internal Medicine Service, St. Luke’s Episcopal Hospital, Department of Medicine, Baylor College of Medicine, Houston, USA

Division of Gastroenterology, Royal Alexandra Hospital University of Alberta, Edmonton, Canada

James Gregor

Hassan Elberm

Department of Medicine, University of Western Ontario, London, Ontario, Canada

Department of Surgery, Southampton University Hospitals, Southampton, UK

E Jenny Heathcote Francis Family Liver Centre, Toronto Western Hospital, University Health Network and Department of Medicine, University of Toronto, Toronto, Canada

viii

Contributors

Gideon M Hirschfield

John G McHutchison

Francis Family Liver Centre, Toronto Western Hospital, University Health Network and Department of Medicine, University of Toronto, Toronto, Canada

Division of Gastroenterology, Duke Clinical Research Institute and Duke University Medical Center, North Carolina, USA

Michael MP Manns Massimo Iavarone Department of Medicine, First Division of Gastroenterology, Fondazione IRCCS Maggiore Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy

Department of Gastroenterology, Hepatology and Endocrinology, Medical School, Hanover, Germany

Philippe Mathurin Department of Hepatology, Hôpital Claude Huriez, Lille, France

Gary P Jeffrey Western Australia Liver Transplantation Service, Sir Charles Gairdner Hospital, Nedlands, Australia

Paul Moayyedi Gastroenterology Division, McMaster University Medical Centre, Hamilton, Canada

Derek P Jewell Experimental Medicine Division, John Radcliffe Hospital, Oxford, UK

Rachid Mohamed Division of Gastroenteology, University of Calgary, Calgary, Canada

Colin D Johnson Department of Surgery, Southampton University Hospitals, Southampton, UK

Katherine Muir

Emilie Jolicoeur

Christian Müller

Department of Gastroenterology, Montfort Hospital, Ottawa, Canada

Division of Gastroenterology and Hepatology, Medical University Vienna, Vienna, Austria

Bret A Lashner

Nicholas Murphy

Center for Inflammatory Bowel Disease, Cleveland Clinic, Cleveland, USA

Queen Elizabeth Hospital (Birmingham), Edgbaston, Birmingham, UK

Calvin HL Law

Miquel Navasa

Hepatobiliary, Pancreatic and Gastrointestinal Surgery, Department of Health Policy, Management and Evaluation, University of Toronto and Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada

Liver Unit, Institut de Malalties Digestives i Metaboliques, Hospital Clinic, IDIBAPS, CIBEREHD, Barcelona, Spain

University of Toronto, Toronto, Canada

James O’Beirne Royal Free Hospital, London, UK

Theodore R Levin The Permanente Medical Group, Inc., Walnut Creek, California, USA

Kelvin Palmer

Robert Löfberg

George V Papatheodoridis

IBD Unit, HMQ Sophia Hospital, Karolinska Institute, Stockholm, Sweden

Department of Internal Medicine, Athens University Medical School, Hippokration General Hospital, Athens, Greece

M Isabel Lucena

Darrell S Pardi

Clinical Pharmacology Service, “Virgen de la Victoria” University Hospital and School of Medicine, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Málaga, Spain

Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, USA

John WD McDonald Robarts Clinical Trials, Robarts Research Unit, University of Western Ontario, London, Ontario, Canada

Gastroenterology Unit, Western General Hospital, Edinburgh, UK

David Patch The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital and Department of Surgery, University College London, London, UK

Keyur Patel Lynne V McFarland Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Washington, USA

Division of Gastroenterology, Duke Clinical Research Institute and Duke University Medical Center, North Carolina, USA

ix

Contributors

Maria Pleguezuelo

Marco Senzolo

The Royal Free Shiila Sherlock Liver Centre, Royal Free Hospital and Department of Surgery, University College London, London, UK

Department of Surgical and Gastroenterological Sciences, University-Hospital of Padua, Padua, Italy

Marika Simon-Rudler Linda Rabeneck University of Toronto, Toronto, Canada

UPMC Service d’Hépato-Gastroentérologie, Assistance PubliqueHôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris, France

Joel E Richter Department of Medicine, Temple University School of Medicine, Philadelphia, USA

Constantine A Soulellis Division of Gastroenterology, McGill University Health Center, Montreal, Canada

Antoni Rimola Liver Unit, Institut de Malalties Digestives i Metaboliques, Hospital Clinic, IDIBAPS, CIBEREHD, Barcelona, Spain

Christina M Surawicz Department of Gastroenterology, Harborview Medical Center, Washington, USA

Jason R Roberts Division of Gastroenterology and Hepatology, Medical University of South Carolina, South Carolina, USA

Lloyd R Sutherland Department of Community Health Sciences, University of Calgary, Health Sciences Centre, Calgary, Canada

Juan Rodés Liver Unit and GI Unit, Hospital Clínic and University of Barcelona, Institut d’Investigacions Biomèdiques August Pi-Sunyer (IDIBAPS), Ciber de Enfermedades Hepáticas y Digestivas (CIBERHED), Barcelona, Spain

Hugo R Rosen

Nicholas J Talley Department of Medicine, The Mayo Clinic Jacksonville, USA

Véd R Tandan Department of Surgery, St Joseph’s Healthcare Hamilton, McMaster University, Hamilton, Ontario, Canada

University of Colorado, Denver, Colorado, USA

Dominique Thabut Alaa Rostom Forzani & MacPhail Colon Cancer Screening Centre University of Calgary, Calgary, Canada

UPMC Service d’Hépato-Gastroentérologie, Assistance PubliqueHôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Université Pierre et Marie Curie, Paris, France

Michael Sai Lai Sey

Hans L Tillmann

Department of Medicine, University of Western Ontario, London, Ontario, Canada

Division of Gastroenterology, Duke Clinical Research Institute and Duke University Medical Center, North Carolina, USA

William J Sandborn

Christos Trianto

Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, USA

Michael D Saunders

Division of Gastroenterology, Department of Internal Medicine, University Hospital, Patras, Greece and The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital and Department of Surgery, University College London, London, UK

Digestive Diseases Center, University of Washington School of Medicine, Washington, USA

Peter Tugwell

Joseph H Sellin Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, USA

Department of Epidemiology and Community Medicine, University of Ottawa and Ottawa Hospital Research Institute, Ottawa, Canada

Curt Tysk Neeral Shah Department of Hepatology, University of Virginia, Charlottesville Virginia, USA

Department of Gastroenterology, Örebro University Hospital, Örebro, Sweden

Laura VanderBeek Arya M Sharma

McMaster University, Hamilton, Ontario, Canada

Division of Endocrinology, University of Alberta, Edmonton, Canada

Sander Veldhuyzen van Zanten Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Canada

x

Contributors

Marcelo F Vela

Julia Wendon

Gastroenterology Section, Baylor College of Medicine, Houston, Texas, USA

King’s College London School of Medicine and King’s College Hospital, London, UK

Arndt Vogel

Marilyn Zeman

Department of Gastroenterology, Hepatology and Endocrinology, Medical School, Hanover, Germany

Division of Gastroenterology, Royal Alexandra Hospital University of Alberta, Edmonton, Canada

Alastair JM Watson School of Clinical Sciences, University of Liverpool, Liverpool, UK

George Wells Department of Epidemiology and Community Medicine and Cardiovascular Research Methods Centre, University of Ottawa, Ottawa, Canada

xi

1

Introduction John WD McDonald1, Andrew K Burroughs2, Brian G Feagan1 and M Brian Fennerty3 1

Robarts Clinical Trials, Robarts Research Unit, University of Western Ontario, London, Ontario, Canada The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital, and University College London, London, UK 3 Oregon Health and Science University, Division of Gastroenterology and Hepatology, Ontario Oregon, USA 2

Over the past three decades the emergence of evidencebased medicine (EBM) has had a substantial impact on clinical practice. In the first half of the twentieth century, diagnostic tests or treatments, usually based on a strong scientific rationale and experimental work in animals, were routinely introduced into clinical care without good scientific proof of efficacy in people. Some of these interventions, such as gastric freezing for the treatment of ulcers and penicillamine therapy for primary biliary cirrhosis, were ultimately shown to be ineffective and harmful [1, 2]. There is little doubt that the widespread acceptance by physicians of unproved treatments has been detrimental to the well-being of many patients. Fortunately, the need for a more critical approach to medical practice was recognized. In 1948 the first randomized controlled trial (RCT) in humans was carried out under the direction of the British Medical Research Council [3]. Epidemiologists and statisticians, notably Sir Richard Doll and Sir Bradford Hill, provided scientific leadership to the medical community, which responded with improvements in the quality of clinical research. The use of randomized allocation to control for confounding variables and to minimize bias was recognized as invaluable for conducting valid studies of treatments. The initiation of these landmark experiments defined a new era in clinical research; the RCT soon became the benchmark for the evaluation of medical and surgical interventions. Gastroenterologists played an important part in these early days. In 1955, Professor Sidney Truelove conducted the first randomized trial in the discipline of gastroenterology [4]. He and his colleagues proved that cortisone was more effective than a placebo for the treatment of ulcerative colitis. As noted in Chapter 12, this treatment has stood the test of time. The ascendancy of the RCT was accompanied by a call for greater scientific rigor in the usual practice of clinical mediEvidence-Based Gastroenterology and Hepatology, Third Edition John WD McDonald, Andrew K Burroughs, Brian G Feagan and M Brian Fennerty © 2010 Blackwell Publishing Ltd. ISBN: 978-1-405-18193-8

cine. Strong advocates of the application of epidemiological principles to patient care emerged and found a growing body of support among clinicians. As the number of randomized trials grew to the point of becoming unmanageable, it was recognized that there was a need to provide summaries of the evidence provided by these trials for the use of practitioners, who frequently lack both time and expertise to consult the primary research. Busy clinicians may consult local experts, with the tacit assumption that they will make recommendations based on evidence. Liberati and colleagues provided evidence that this approach led to inappropriate care for many women with breast cancer [5]. Subsequently, convincing evidence became available through the work of Antman et al. and of Mulrow that the conventional review article and the traditional textbook chapter are seldom comprehensive, and are frequently biased [6, 7]. More recently, Jefferson reinforced this conclusion on the basis of a survey concerning recommendations for vaccination for cholera, which appeared in editorials and review articles [8]. He pointed out that authors of editorials and reviews frequently resort to the “desk drawer” technique, pulling out evidence with which they are very familiar, but failing to assemble and review all of the evidence in a systematic way. In the UK, Archie Cochrane, as early as 1979, made a compelling case that there was a need to prepare and maintain summaries of all randomized trials [9]. Cochrane’s challenge to the medical community to use scientific methods to identify, evaluate and systematically summarize the world’s medical literature pertaining to all health care interventions is now being met. From its inception in 1993, the electronic database prepared by the volunteer members of the Cochrane Collaboration and published as the Cochrane Library has grown exponentially [10]. Systematic reviews and especially Cochrane reviews are now widely used by clinicians in the daily practice of medicine, by researchers and by the public. Accordingly, data from systematic reviews published in the Cochrane Library 1

CHAPTER 1

Introduction

are featured prominently in several chapters in Evidencebased Gastroenterology and Hepatology. Unfortunately, coverage in the Cochrane Library of topics in gastroenterology and hepatology is still far from complete. Several other clinical epidemiologists played important roles in the evolution of evidence-based medicine. Beginning in the 1970s, David Sackett encouraged practicing physicians to become familiar with the basic principles of critical appraisal. Criteria developed by Sackett and others for the evaluation of clinical studies assessing therapy, causation, prognosis and other clinical topics were widely published [11, 12]. His text, Clinical Epidemiology: a Basic Science for Clinical Medicine, co-authored by colleagues Gordon Guyatt, Brian Haynes and Peter Tugwell, introduced many physicians to the concepts of EBM [13]. In the USA, Alvin Feinstein called attention to the need for increased rigor in the design and interpretation of observational studies and explored the scientific principles of diagnostic testing [14, 15]. Among gastroenterologists, Thomas Chalmers, a strong, early advocate for the RCT [16], was responsible for introducing gastroenterologists and others to the importance of randomized trials in gastroenterology and hepatology and to the concept of systematic reviews and meta-analysis as means of summarizing data from these studies [17, 18]. Despite the opposition of some, the popularity of EBM continues to grow [19]. Although the explanations for this phenomenon are complex, one factor is that many practitioners recognize that ethical patient care should be based on the best possible evidence. For this, and other reasons, the fundamental concept behind EBM – the use of the scientific method in the practice of clinical medicine – has been widely endorsed by medical opinion leaders, patients and governments.

What is evidence-based gastroenterology and hepatology? Evidence-based gastroenterology and hepatology is the application of the most valid scientific information to the care of patients with gastrointestinal and hepatic diseases. Physicians who treat patients with digestive diseases must provide their patients with the most appropriate diagnostic tests, the most accurate prognosis and the most effective and safe therapy. To meet this high standard individual clinicians must have access to and be able to evaluate scientific evidence. Although many practitioners argue that this has always been the standard of care in clinical medicine, a great deal of evidence exists to the contrary. Wide variations in practice patterns among physicians have been documented for many treatments, despite the presence of good data from widely publicized RCTs and the promotion of practice guidelines by content experts. For example, 2

Scholefield et al. carried out a survey of British surgeons who were questioned regarding the performance of screening colonoscopy for colon cancer [20]. Although this study was done in 1998 (after publication of the results of the RCTs described in Chapter 18 which demonstrated a benefit of this practice), many of these physicians failed to make appropriate recommendations for screening patients at risk. What is the explanation for this finding? One possibility is that many clinicians rely for information on their colleagues, on local experts, or on review articles or textbook chapters that are not based on the principles of EBM. Two important points about EBM should be emphasized. First, use of the principles of EBM in the management of patients is complementary to traditional clinical skills and will never supersede the recognized virtues of careful observation, sound judgment and compassion for the patient. It is noteworthy that many good doctors have intuitively used the basic principles of EBM; hence the promotion of such well-known clinical aphorisms as “go where the money is” and “do the last test first”. Knowledge of EBM enables physicians to understand why these basic rules of clinical medicine are valid through the use of a quantitative approach to decision making. This paradigm can in no way be considered detrimental to the doctorpatient relationship. Second, although RCTs are the most valuable source of data for evaluating health care interventions, other kinds of evidence must frequently be used. In some instances, most obviously in studies of causation, it is neither possible nor ethical to conduct RCTs. Here, data from methodologically rigorous observational studies are extremely valuable. A dramatic example was the demonstration by several authors (quoted in Chapter 27) that the relative risk of hepatocellular carcinoma in chronic carriers of the hepatitis B virus is dramatically higher than in persons who are not infected. Although these data are observational, the strength of the association is such that it is exceedingly unlikely that a cause other than hepatitis B virus is responsible for the development of cancer in these people. Casecontrol studies are especially useful for studying rare diseases and for the initial development of scientific hypotheses regarding causation. The etiological role of non-steroidal anti-inflammatory drugs in the development of gastric ulcer was recognized using this methodology [21]. Finally, case series can provide compelling evidence for the adoption of a new therapy in the absence of data from RCTs, if the natural history of the disease is both well characterized and severe. An example is the identification of orthotopic liver transplantation as a dramatically effective intervention for patients with advanced liver disease. Box 1.1 shows a generally agreed approach to ranking the strength of evidence that arises from various types of studies of health care interventions, and this system is used throughout the book. This ranking of evidence has

CHAPTER 1

Bo x 1 .1 Grading of recommendations and levels of ’

evidence used in Evidence-based Gastroenterology and Hepatology Grade A Level 1a • Evidence from large randomized clinical trials (RCTs) or systematic reviews (including meta-analyses) of multiple randomized trials which collectively have at least as much data as one single well-defined trial. Level 1b • Evidence from at least one “All or none” high quality cohort study; in which all patients died/failed with conventional therapy and some survived/succeeded with the new therapy (e.g. chemotherapy for tuberculosis, meningitis, or defibrillation for ventricular fibrillation): or in which many died/failed with conventional therapy and none died/failed with the new therapy (e.g. penicillin for pneumococcal infections). Level 1c • Evidence from at least one moderate sized RCT or a meta-analysis of small trials which collectively only has a moderate number of patients. Level 1d • Evidence from at least one RCT. Grade B Level 2 • Evidence from at least one high quality study of non-randomized cohorts who did and did not receive the new therapy. Level 3 • Evidence from at least one high quality case control study. Level 4 • Evidence from at least one high quality case series. Grade C Level 5 • Opinions from experts without reference or access to any of the foregoing (for example, argument from physiology, bench research car first principles)

appeared in a number of publications; we have chosen to reproduce it from Evidence-based Cardiology, along with the system used by its editors, Yusuf et al., for making recommendations on the basis of these levels of evidence [22]. As mentioned in Box 1.1, throughout this book recommendation grades appear as A or A1a.

Clinical decision making in gastroenterology and hepatology Clinical decision making by gastroenterologists usually falls into one of the following categories:

Introduction

• Deciding whether to apply a specific diagnostic test in arriving at an explanation of a patient’s problem, or determining the status of the patient’s disease. • Offering a prognosis to a patient. • Deciding among a number of interventions available for managing a patient’s problem. In this category, the first question is “Does a given intervention do more good than harm?” The second is “Does it do more good than other effective interventions?” The third is “Is it more or less cost-effective than other interventions?” A comprehensive approach would incorporate many different types of evidence (e.g. RCTs, non-RCTs, epidemiologic studies and experimental data), and examine the architecture of the information for consistency, coherence and clarity. Occasionally, the evidence does not completely fit into neat compartments. For example, there is strong (A1a) evidence through very large randomized trials that fecal occult blood testing on an annual or semi-annual basis modestly reduces mortality from colon cancer in a population at average risk for this disease. The evidence that direct examination of the colon at intervals of five to ten years results in even greater benefit has been derived only from case control studies (B3). Physicians, patients and policy advisers should have both levels of evidence available to make informed decisions. Recommendation grades appear either within the text, for example A and A1a or within a table in the chapter. The grading system clearly is only applicable to preventative or therapeutic interventions. It is not applicable to many other types of data such as descriptive, genetic or pathophysiologic.

Application of a diagnostic test Example: A four-year-old child is experiencing diarrhea and has a positive family history of celiac disease. Should a serological test for antiendomysial antibody (EMA) be done? Chapter 10 includes an extensive treatment of this topic with a summary of studies (see Table 10.1) that included various groups of patients with a greater or lesser probability of having celiac disease (ranging from patients with gastrointestinal symptoms to patients in whom celiac disease was suspected on clinical grounds). Several studies listed in Table 10.1 and the study of Cataldo et al. [23] are relevant to this patient. When evaluating this test the reader may wish to adopt the approach of Kitching et al. for deciding on the clinical usefulness of a diagnostic test (Figure 1.1) [24]. The criteria listed in Figure 1.1 for validity of a diagnostic test were clearly met in Cataldo’s study. In Chapter 10 Gregor and Say explore the utility of the test and point out that tests with high positive likelihood ratios (LR > 10) and 3

CHAPTER 1

Introduction

•

Are the study results valid? 1 Was there an independent blind comparison (or unbiased comparison) with a reference (“gold”) standard of diagnosis? 2 Was the diagnostic test evaluated in an appropriate spectrum of patients (like those seen in the reader’s practice)? 3 Was the reference standard applied regardless of the diagnostic test result?

•

What are the results? Cataldo F, Ventura A, Lazzari R et al. Antiendomysium antibodies and celiac disease: solved and unsolved questions. An Italian multicentre study. Acta Paediatr 1995;84:1125–31. A study of IgA endomysium antibodies (EMA) in 1485 children with gastrointestinal disease (688 with celiac disease confirmed by intestinal biopsy)

Results for antiendomysial antibody (EMA) test No. of patients with biopsy proven celiac disease Present

Absent

Totals

645 a c 43 a+c 688

20 b d 777 b+d 797

665 a+b c+d 810 a+b+c+d 1485

EMA positive EMA negative

Totals

Sensitivity = a/(a + c) = 645/688 = 0·94 Specificity = d/(b + d) = 777/797 = 0·97 Likelihood ratio (positive result) = sensitivity/(1–specificity) = 0·94/(1–0·97) = 31 Likelihood ratio (negative result) = (1–sensitivity)/specificity = (1–0·94)/0·97 = 0·06 Positive predictive value = a/(a + b) = 645/665 = 0·97 Negative predictive value = d/c + d = 777/810 = 0·96 Figure 1.1 Approaches to evaluating evidence about diagnosis.

low negative likelihood ratios (LR < 0.1) are generally considered to be clinically useful. The EMA test clearly falls into this category. The authors draws attention to the fact that the probability that a specific patient actually has celiac disease (based on a positive test), or does not have it (based on a negative test), also depends on the pretest odds of the patient having the disease (see Table 1.1). If the child in question, whose pretest likelihood of celiac disease is estimated to be 8%, has a negative test it may be concluded that the child almost certainly does not have celiac disease; on the other hand, if the child has a positive test, the likelihood of him or her having celiac disease is still only 65%. As Gregor and Alidina point out, the implications of misdiagnosis must be considered carefully. In the circumstance of a positive test in the child with non-specific symptoms the physician and the child’s parents should consider whether it is now reasonable to proceed to intestinal biopsy to confirm the diagnosis, rather than recommending a gluten-free diet, presumably for life. If a search for other clinical or laboratory clues reveals that celiac disease is very likely to be the correct diagnosis, the pretest likelihood may 4

Table 1.1 The anti-endomysial antibody (EMA) test for celiac disease. Dependence of post-test likelihood of celiac disease on pretest likelihood, assuming positive LR = 31, negative LR = 0.06. Pretest likelihood of celiac disease

Post-test likelihood with a positive EMA test (%)

Post-test likelihood with a negative EMA test (%)

8% (non-specific symptoms, positive family history)

65

0.5

50% (more specific symptoms)

97

6

0.25% (population screen)

8

0.02

Data from Chapter 10.

CHAPTER 1

be as high as 50%. This would raise the post-test likelihood to 97%. The physician and parents may be comfortable accepting the diagnosis and proceed to a trial of a glutenfree diet, rather than subjecting a young child to intestinal biopsy. This is an excellent example of how a skilled clinician must integrate the principles of evidence-based medicine with traditional clinical skills and judgment.

Introduction

On the basis of this evidence it is reasonable to advise the patient that her disease does carry with it an increased risk of certain relatively uncommon cancers and that adherence to a strict gluten-free diet appears to minimize this increased risk.

Recommendations concerning therapy Offering a prognosis Example: A 50-year-old woman with recently diagnosed celiac disease. has learned at a meeting of the local celiac society that patients with celiac disease have a substantial increase in the risk of developing a number of cancers and that this cancer risk is reduced by strict adherence to a gluten-free diet. Chapter 10 describes the types of study which are relevant to determination of prognosis and discusses the strengths and weaknesses of case-control and cohort studies. Gregor and Alidina point out that certain case-control studies which reported very high mortality and malignancy rates may have been subject to selection bias (inclusion of particularly ill or refractory patients) and measurement bias (patients with abdominal symptoms being more likely to undergo investigations such as small bowel biopsy which may lead to a diagnosis of celiac disease). They refer to a British study in which a cohort of patients with celiac disease was assembled and followed for ten years. This design attempts to minimize the biases that are inherent in the case-control studies. Table 1.2 shows that the risk of certain cancers is increased compared to the risk in the general population. Table 1.3 shows that strict adherence to a gluten-free diet significantly reduced this risk and may have eliminated the excess risk for several of the identified cancers.

We have provided examples of how evidence concerning the use of diagnostic tests and prognosis can be analyzed and incorporated into clinical practice. Most chapters in this book deal more extensively with evidence concerning therapy and rely heavily on data from randomized trials and meta-analyses. Example: Should a 28-year-old woman who has had an uncomplicated resection of the terminal ileum for Crohn’s disease receive maintenance therapy with an S-aminosalicylate (ASA) product? Prior to the surgery she had had steroid-dependent disease and had failed treatment with both azathioprine and methotrexate. A search of the literature for placebo-controlled randomized trials of 5-ASA for maintenance of remission in patients with a surgically induced remission of disease would reveal several trials. The largest published trial is that of McLeod and colleagues, who randomized 163 adult patients to receive either 3 g/day of 5-ASA or a placebo following surgery [26]. The primary outcome of interest was the recurrence of active Crohn’s disease as defined by the recurrence of symptoms and the documentation of active disease either radiologically or endoscopically. At

Table 1.3 Cancer morbidity by diet group. Site of cancer

Diet groupa

No.

O

E

All sites

1 2

108 102

14 17

9.06 6.42

1.5 2.6

Mouth, pharynx,

1

108

1

0.33

3.0

esophagus

2

102

5

0.22

22.7

c

Non-Hodgkin’s

1

108

2

0.12

16.7

b

lymphoma

2

102

7

0.09

77.8

c

Remainder

1 2

108 102

11 5

8.61 6.11

1.3 0.8

Table 1.2 Cancer mortality in 210 patients with celiac disease at the end of 1985. Site of cancer

ICD8

O

E

O/E

P

All sites Mouth and pharynx Esophagus Non-Hodgkin’s lymphoma Gastrointestinal tract Remainder

140–208 141–147 150 200, 202 151–154

31 3 3 9 3 13

15.48 0.31 0.24 0.21 3.07 11.65

2.0 9.7 12.3 42.7 1.0 1.1

b a a b

NS NS

O/E

P

c

a

p < 0.01. b p < 0.001. O: observed numbers; E: expected numbers. Source: Holmes GKT et al. Gut 1989; 30: 333–338 [25]. a

Diet group 1, strict adherence to gluten-free diet; group 2, reduced gluten diet or normal diet. Source: Holmes G KT et al. Gut 1989; 30: 333–338 [25]. b p < 0–01. c p < 0.001.

5

CHAPTER 1

Introduction

• Are the results valid? 1 Was the assignment of patients to treatment really randomized (and the randomization code concealed)? 2 Were all patients who entered the study accounted for at its conclusion? 3 Were the clinical outcomes measured blindly? •

Is the therapeutic effect important? 1 Were both statistical and clinical significance considered? 2 Were all clinically important outcomes reported?

•

What are the results? McLeod RS, Wolff BG, Steinhart AH et al. Prophylactic mesalamine treatment decreases postoperative recurrence of Crohn’s disease. Gastroenterology 1995;109:404–13. Randomized controlled trial in which 163 patients with Crohn’s disease who had all visible disease resected were randomized to receive mesalamine (Pentasa) 3 g daily or a placebo for a median period of 34 months. Primary outcome was recurrent Crohn’s disease defined by recurrence of symptoms and radiographic or endoscopic documentation of recurrence.

Recurrent Crohn’s disease

5-ASA Placebo

Yes

No

27 31

60 45

Risk (%)

ARR (%)

RRR (%)

31 41

10 –

24 –

ARR, absolute risk reduction; RRR, relative risk reduction.

•

Are the results relevant to my patient? 1 Were the study patients recognizably similar to my own? 2 Is the therapeutic maneuver feasible in my practice?

Figure 1.2 Elements of a valid and useful randomized trial.

the end of the follow-up period (maximum duration 72 months, median duration 34 months), 31% of patients who received active treatment remained in remission compared with 41% of those who received a placebo (p = 0.031); 5-ASA was well tolerated. A low proportion of patients developed adverse reactions in the control and active treatment groups. One patient treated with 5-ASA developed pancreatitis that was attributed to the study drug. The results of this study can be evaluated using the guidelines described in Figure 1.2, which is modeled after the approach of Kitching et al. [24].

Are the results of this study valid? A review of the methods section of the article confirms that an appropriate method of randomization was employed (computer-generated in permutated blocks), which insured concealment of the randomization code [26]. Furthermore, inspection of the baseline characteristics of the treatment and control groups shows that they are well balanced with respect to such confounding variables as the time from 6

surgery to randomization. This information further supports the legitimacy of the randomization process. Assessment of the method of randomization is important, because non-randomized designs are especially vulnerable to the effects of bias. Studies which employ “quasirandomization” schemes such as allocation to treatment according to the day of the week or alphabetically by the patient’s surname have been shown to consistently overestimate the treatment effect identified by RCTs that employ a valid randomization scheme [27, 28]. However, it may be noted that 87 patients were randomized to 5-ASA, compared with only 76 patients in the control group. This observation raises the concern that the analysis might not have been done according to the “intent to treat” principle which specifies that patients are analyzed in the group to which they were originally assigned, irrespective of the treatment that was ultimately received. The use of this strategy reduces the possibility of bias, which might occur if investigators selectively withdrew from the analysis patients who had done poorly or experienced toxicity. For this reason, the intent to treat principle yields a conservative estimate of the true benefit of the treatment. However,

CHAPTER 1

detailed review shows that in this study the discrepancy in patient numbers occurred because five patients who were randomized to the active treatment group withdrew consent prior to receiving the study medication and were not included. Thus, it appears that the analysis was based on the intent to treat principle. Approximately 10% of patients in both treatment groups had incomplete follow-up. Methodologically rigorous studies have a very low proportion of patients for whom data are missing. This issue is important, since patients who are lost to follow-up usually have a different prognosis from those for whom complete information is available. If there is incomplete follow-up data for a substantial proportion of patients then the results are uninterpretable [29]. Turning to an assessment of the outcomes in this study, both the patients and investigators were unaware of the treatment allocation. Blinding is used to reduce bias in the interpretation of outcomes. This is especially important when a subjective outcome is evaluated [30]. In this study, objective demonstration of recurrent disease (endoscopy and/or radiology) was required in addition to the more subjective measure of the introduction of treatment for recurrent symptoms. Thus, the reader can be satisfied that the primary outcome measure was both clinically meaningful and objectively assessed. Finally, the data analysis and results should be examined. A great deal of useful information can be obtained by reviewing the assumptions that were used in the sample size calculation. In this study, which analyzes a difference in proportions, the investigators had to define four variables: the alpha (type 1) error rate, the beta (type 2) error rate, the expected proportion of patients who would be expected to relapse in the placebo group, and the minimum difference in the rate of relapse which the investigator wished to detect. In this publication these parameters are easily identified. The rate of symptomatic recurrence was estimated to be 12.5% per year and it was anticipated that treatment with 5-ASA would reduce this rate by 50% to an absolute value of 6.25% per year. In contrast to the expected 50% relative risk reduction which was anticipated, the three-year actuarial risk of recurrence was 26% in the treatment group compared to 45% in the group that received 5-ASA (p = 0.039). Therefore, the relative risk reduction ((45–26%)/45% = 42%) is slightly lower than the figure which the investigators considered to be clinically meaningful. Furthermore, the probability of a type 1 error is described as a one-tailed value of p = 0.05. This implies that one-tailed statistical testing was used to derive the p value of 0.039. The use of one-sided statistical testing raises legitimate concerns regarding the statistical inferences made in the study [31]. It is inappropriate to hypothesize that 5-ASA therapy could only be beneficial, given that the drug can cause diarrhea and colitis [32]. For these reasons, uncer-

Introduction

tainty exists regarding both the clinical and statistical interpretation of these data.

Are the results of this valid study important? To assess the importance of this result it is necessary to quantify the magnitude of the treatment effect. How the evidence is presented may influence both physicians and patients in making choices. The most basic means of expressing the magnitude of a treatment of fact is the absolute risk reduction (ARR), which is defined as the proportion of patients in the experimental group with a treatment success minus the proportion of patients with this outcome in the control group. In this instance the annual rate of relapse in the placebo-treated patients was 15% (success rate of 85%) compared with 8.7% (success rate of 91.3%) in those who received the active treatment. This yields an ARR of 6.3%. The number needed to treat (NNT), the number of patients with Crohn’s disease who would have to be treated with 3 g/day of 5-ASA to maintain remission over a year, can be calculated as the reciprocal of this number, and is 16. Alternative ways of describing effectiveness include calculating the observed relative risk reduction (RRR = 63/15) of 42%, or even stating that about 90% of patients respond to maintenance therapy, ignoring the substantial placebo effect which is evident. The evidence presented as the ARR or NNT, rather than the numbers which show the treatment in a more favorable light, may still lead the physician to recommend this form of treatment and cause the patient to choose to accept this strategy over no intervention. However, the expectations of the physician and patients are likely to be more realistic than they may be if the physician accepts and promotes in an uncritical way the information that 90% of patients who receive 5-ASA maintenance therapy will remain in remission over one year [33].

Are these results applicable to my patient? Following an assessment of the validity of the evidence using the criteria described in the preceding paragraphs, it is necessary to decide whether the conclusions of the study are relevant and important to the individual patient. An initial step is to evaluate the demographic characteristics of the patients in the RCT and compare them to those of the patient in question. If the patient for whom maintenance therapy is being considered is similar to the patients who were evaluated in the trial, it is reasonable to assume that she will experience the same benefit of therapy and is at no greater risk for the development of adverse drug 7

CHAPTER 1

Introduction

Study or subgroup Lochs 2000 Brignola 1995 Mcleod 1995 Hanauer 2004 Total (95% Cl)

5-ASA Placebo Risk ratio Events Total Events Total Weight M-H, fixed, 95% Cl 36 7 27 26

152 44 87 44 327

50 10 31 31

Risk ratio M-H, fixed, 95% Cl

166 43 76 40

38.7% 8.2% 26.8% 26.3%

0.79 (0.54, 1.14) 0.68 (0.29, 1.63) 0.76 (0.50, 1.15) 0.76 (0.57, 1.03)

325

100.0%

0.76 (0.62, 0.94)

Total events 96 122 Heterogeneity: Chi2 = 0.09, df = 3 (p = 0.99); I2 = 0% Test for overall effect: Z = 2.51 (p = 0.01)

0.1

0.2 0.5 1 2 5 10 Favors 5-ASA Favors placebo

Figure 1.3 Interventions for prevention of post-operative recurrence of Crohn’s disease. Source: Doherty G, Bennett G, Patil S, Cheifetz A, Moss AC. Interventions for prevention of post-operative recurrence of Crohn’s disease. In: Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD006873. DOI: 10.1002/14651858.CD006873.pub2.

reactions. Alternatively, this patient may have characteristics that make it unlikely that a benefit from 5-ASA will be realized. For example, if the patient had residual active Crohn’s disease it would be difficult to generalize the results of the study of McLeod et al., since the patients in this trial had resection of all visible disease prior to study entry [26]. At this point, if we accept that the results are generalizable to our patient example, the relative risks and benefits of the therapy must be weighed and the patient’s preferences should be considered. Evaluation of the data reveals that the trial was methodologically rigorous and evaluated an important outcome. However, it is doubtful whether conventional statistical significance was demonstrated. This raises the question of whether the observed differences between the treatment groups might have occurred by chance. Furthermore, the magnitude of the treatment effect is relatively small. In presenting to the patient the benefit of an annual reduction in the risk of recurrence of 6.3% it is also necessary to consider the cost and inconvenience of taking medication for an asymptomatic condition. One observation in favor of recommending the treatment is that the risk of serious toxicity with 5-ASA appears to be low. Because there is a degree of uncertainty concerning the true benefit of 5-ASA maintenance therapy based on analysis of this single RCT, it would be prudent to review additional published data. A meta-analysis of 5-ASA therapy has been published [34]. Meta-analysis, the process of combining the results of multiple RCTs using quantitative methods, is an important tool for the practitioner of EBM. Pooling the results of multiple RCTs increases statistical power and thus may resolve the contradictory results of individual studies. Combining data from RCTs statistically also increases the precision of the estimate of a treatment effect. Moreover, the greater statistical power afforded by meta-analysis may allow insight into the benefits of treatment for specific subgroups of patients. These properties 8

are particularly relevant to the case under consideration, given the previously identified concerns. The meta-analysis summarized data from 15 RCTs which evaluated the efficacy of 5-ASA maintenance therapy in 1371 patients with quiescent Crohn’s disease. Patients were randomly assigned to receive either 5-ASA or placebo for treatment periods of 4–48 months. Although 5-ASA was superior to placebo in 13 of the 15 studies, the results of only two trials were statistically significant. Separate analyses were done using data from the four trials that included patients with a surgically induced remission (see Figure 1.3) in distinction to those that evaluated patients after a medically induced remission. Sensitivity analyses assessed the response to therapy in specific subgroups of patients. The overall analysis concluded that 5-ASA has a statistically significant benefit; the risk of symptomatic relapse in patients who received 5-ASA was reduced by 6.3% (95% confidence interval −10.4% to −2.1%, 2 p = 0.0028), which corresponds to an NNT of 16. Importantly, the greatest benefit was observed in the four trials that evaluated patients following a surgical resection. In these studies there was a 13.1% reduction in the risk of a relapse (95% CI: −21.8 − −4.5%, 2 p = 0.0028), which corresponds to an NNT of 8. No statistically significant effect was demonstrable in the analysis, which was restricted to the patients with medically induced remission.

Are the results of this meta-analysis valid and reliable? Figure 1.4 provides some useful guidelines for the interpretation of overview analyses. It is important that a comprehensive search strategy be adopted since publication bias, the selective publication of studies with positive results, is an important threat to the validity of meta-analysis [35]. This criterion was met. Camma and colleagues’ review of the literature was extensive and not limited to English lan-

CHAPTER 1

Introduction

• Are the results of this overview valid and reliable? 1 Is it an overview of randomized trials of treatments? 2 Does it include a methods section that describes: (a) finding and including all the relevant trials? (b) assessing their individual validity? (c) using valid statistical methods that compare “like with like” stratified by study? 3 Were the results consistent from study to study? 4 Are the conclusions based on sufficiently large amounts of data to exclude a spurious difference (type 1 error) or missing a real difference (type II error).

• Are these applicable to your patient? Differences between subgroups should only be believed if you can say “yes” to all of the following: 1 Was it hypothesized before the study began (rather than the product of dredging the data), and has it been confirmed in other, independent studies? 2 Was it one of just a few subgroups analyses carried out in this study? 3 Is the difference both clinically (beneficial for some but useless or harmful for others) and statistically significant? 4 Does it really make biologic and clinical sense? Figure 1.4 Approaches to evaluating evidence concerning overviews. Reproduced from Yusuf S et al., eds. Evidence-based Cardiology. BMJ Books, London, 1998 [22].

guage publications. The investigators also searched review articles, primary studies and abstracts by hand. Quality scores were used to evaluate the validity of the individual studies and a sensitivity analysis was done which assessed the effect of trial quality on the result. No important change in the overall result was noted when studies of lower quality were excluded from consideration. However this type of analysis was not carried out in the analysis of the subgroups of four trials (411 patients) which evaluated 5-ASA after a surgically induced remission. One of the included studies, that of Caprilli et al., which involved 95 patients, showed a greater benefit for 5-ASA than any other trial, medical or surgical, which has been performed [36]. An important methodological deficiency of this RCT was the failure to conceal the treatment allocation from the investigators. Since these physicians were aware of the treatment assignment, and the definition of relapse used required clinical interpretation, it is possible that the 27% reduction in the risk of relapse identified is an overestimation of the true treatment effect. Accordingly, the inclusion of the results of this study in the subgroup analysis of the surgical studies may overestimate the true benefit of 5-ASA. Furthermore, Camma et al. did not include an additional trial by Lochs et al., which was only available as a preliminary report at the time the meta-analysis was done [37]. This study, which is the largest RCT to evaluate 5-ASA following surgery, assigned 318 patients to receive either 4 g of active drug or a placebo for 18 months. Although Camma and colleagues described this study as “confirming” a benefit of 5-ASA after surgery, the results are not impressive. Only a 6.9% reduction in the rate of relapse was observed in patients who received the active treatment (24.5% 5-ASA com-

pared with 31.4% placebo). This difference was not statistically significant. This example underscores the importance of updating systematic reviews as new information becomes available, which is the approach of the Cochrane Collaboration, but not of reviews in conventional publications. When the data provided by Lochs et al. were aggregated with those of the other trials, the overall estimate of benefit for 5-ASA was less (ARR 4%, NNT 25) [38]. On the basis of these data it can be concluded that 5-ASA may be an effective maintenance therapy following surgery, but the magnitude of the treatment effect is modest at best. Chapter 11 includes a meta-analysis performed as part of a Cochrane review that also supports this conclusion (see Figure 1.3).

Are these results applicable to our patient example? The meta-analysis of surgical trials by Camma et al. provides important information to the clinician who must decide whether or not to offer patients 5-ASA for maintenance therapy. The concern regarding statistical significance raised by the critique of the McLeod study has been reduced. It seems likely that the beneficial effect of 5-ASA following surgery is real. However, although the majority of the criteria outlined in Figure 1.4 have been met, the issue of clinical relevance remains. The most optimistic estimate of the size of the treatment effect, derived from the meta-analysis, is an NNT of 8. However, given the possibility of bias in the study of Caprilli et al., a more conservative estimate could be based on the data of Lochs and 9

CHAPTER 1

Introduction

colleagues from the single large randomized trial which yielded an NNT of 15, or from the revision by Sutherland of Camma’s meta-analysis that yielded an ARR of only 4%, and an NNT of 25. In presenting this information to the patient the following points should be emphasized. • The existing data suggest that 5-ASA is not effective, or at the most, very marginally effective. • The annual risk of relapse following surgery is relatively low without treatment. • 5-ASA therapy is safe. • The cost of 5-ASA therapy is approximately US$70 per month. • To derive a benefit from the treatment the medication must be taken on a regular basis. This requires the patient to take six pills each day. Patients undoubtedly will react in different ways to this information. Our patient chose not to accept this therapy.

Rationale for a book on evidence-based gastroenterology and hepatology Gastroenterologists, hepatologists and general surgeons are fortunate to have many excellent textbooks that provide a wealth of information regarding digestive diseases. Such traditional textbooks concentrate on the pathophysiology of disease and are comprehensive in their scope. Evidence-based Gastroenterology and Hepatology is not intended to replace these texts, since its focus is on clinical evidence. Excellent electronic databases are available, and many traditional publications contain relevant research evidence and important summaries and reviews to support evidence-based practice. However, Cumbers and Donald have found that physicians in clinical practice find the acquisition of data from these sources time consuming [39]. Their study revealed that even locating relevant articles required on average three days for practitioners with an on-site library and a week for those without such a facility. This book has been written for the purpose of saving valuable time for busy practitioners of gastroenterology and hepatology, and for general internists and general surgeons who deal with substantial numbers of patients with disorders ranging from gastroesophageal reflux disease to liver transplantation. It has been extensively revised since the second edition was published in 2004, in order to provide more recent evidence that serves as the basis for recommendations. For example, we present data from Cochrane reviews that summarize the strong evidence that anti-TNF agents are effective for both induction and maintenance of remission of Crohn’s disease, along with a careful consideration of the adverse effect profile of these agents. 10

The book cannot claim to be comprehensive. However, the third edition has been expanded significantly, with new chapters on eosinophilic esophagitis, travelers’ diarrhea, antibiotic- associated diarrhea, non-invasive markers for the diagnosis of fibrosis, drug-induced liver injury, liver biopsy, and hepatic outflow syndromes and splanchnic thrombosis. In addition, all chapters have been extensively revised and updated to reflect current evidence. A limitation of any textbook is the timeliness of the information that it is possible to provide in print form. New evidence accumulates rapidly in clinical medicine and it is impossible to include the most up-to-date information in a textbook because of the time required for production. To meet the needs of our readers for the most timely information the editors have endeavored to include, where possible, new evidence that became available during the editorial process. It is also planned to produce electronic updates of chapters at regular intervals. These updates will appear on the Evidence-Based Medicine Series website: http://www. evidencebasedseries.com/Summary of updated evidence in the Third Edition. These summaries highlight the most significant changes to Evidence-based Gastroenterology and Hepatology since the second edition, particularly regarding treatment recommendations in specific conditions. The full discussion of the evidence can be found in the relevant chapters.

Part I: Gastrointestinal disorders Gastroesophageal reflux disease (Chapter 2) Data support the use of empiric antisecretory therapy for patients presenting with symptoms thought to be caused by GERD, without performing confirmatory diagnostic testing. PPI are significantly better than H2-RA for healing esophagitis and relieving symptoms. There are insufficient data to support routinely using PPI doses higher than standard doses for healing esophagitis, treating symptomatic GERD or atypical symptoms of GERD, although higher doses may be effective for preventing relapse that occurs at standard doses. The most cost-effective strategies are PPI based “step-down” or PPI “on-demand” approaches. Laparoscopic fundoplication is an effective alternative to medical therapy, particularly for patients whose symptoms responded to medication.

Barrett’s esophagus (Chapter 3) Aggressive anti-reflux therapy with either high-dose PPI or surgery has not been shown to revert Barrett’s esophagus to normal squamous mucosa or reduce the risk of developing cancer. Although endoscopic ablative therapy is a reasonable option in the Barrett’s patient with high grade dysplasia or superficial adenocarcinoma, these therapies are not recommended for the Barrett’s patient without neoplasia, since continued surveillance will still be required,

CHAPTER 1

complications are frequent and the risk/benefit ratio is not established. Estimates of the cost effectiveness of surveillance of Barrett’s esophagus vary widely, and it is not possible currently to make a recommendation for population screening for Barrett’s either in the general population or in those with chronic GERD.

Introduction

therapy, with the understanding that heartburn is a predictor of response and that the majority of patients will not respond (NNT = 15). H. pylori infection is present in 30–70% of patients, and eradication may lead to long-term symptom improvement in a small proportion of these patients. There is no convincing evidence for the use of prokinetic or antidepressant medications.

Esophageal motility disorders (Chapter 4) The costs and cost effectiveness of Botulinum toxin injections and pneumatic dilation for achalasia are lower than the cost of Heller myotomy. In the longer term, pneumatic dilatation appears to be more cost-effective than Botulinum toxin injection therapy.

Eosinophilic esophagitis (Chapter 5) Conventional oral corticosteroids and swallowed inhaled fluticasone both appear to be effective for this condition. However, the adverse effects of oral steroids are more frequent and severe, and inhaled (swallowed) steroids should be used as initial treatment for uncomplicated EE.

Celiac disease (Chapter 10) Although the human recombinant anti-tissue transglutamase antibody test (tTG) has a sensitivity of 96% and a specificity of 99% for diagnosis of celiac disease in some studies, the sensitivity in other studies is considerable lower. The tTG will likely remain as an adjunct to endoscopy for the diagnosis of celiac disease, rather than a replacement. A substantial amount of evidence demonstrates a lack of toxicity of oats in newly diagnosed patients with celiac disease, and in celiac disease patients in remission.

Crohn’s disease (Chapter 11)

Functional dyspepsia (Chapter 9)

Infliximab, adalimumab and certolizumab have all been shown to be effective for induction and maintenance of remission. There is emerging evidence that early combined immunosuppression with infliximab combined with azathioprine and, if necessary, steroids is superior to conventional management with corticosteroids, followed in sequence by azathioprine and infliximab in terms of steroid-free remission and avoidance of surgery at 26 and 52 weeks. Serious adverse events are not significantly more frequent in the early combined immunosuppression group. The combination of infliximab and methotrexate, although safe, has not been shown to be more effective than infliximab alone in Crohn’s disease patients who are also receiving treatment with prednisone. Although an earlier small randomized placebo-controlled trial suggested that omega-3 fatty acids are effective for maintenance of remission in patients at a relatively high risk of relapse of Crohn’s disease, two large randomized trials that included 762 patients have now shown that this approach is not effective. Natalizumab (300 mg or 3 to 4 mg/kg) is effective for induction of clinical response and remission in patients with moderately to severely active Crohn’s disease. One patient with Crohn’s disease treated with natalizumab in combination with azathioprine developed progressive multifocal leukoencephalopathy (PML). A retrospective investigation suggests that the incidence of PML is approximately 1 case per 1000 patients.

Patients undergoing endoscopy for dyspeptic symptoms tend to be more satisfied and have improved quality of life and subsequently create significantly lower health care costs than patients initially treated empirically. The practical bottom line for use of PPIs in functional dyspepsia is that it is reasonable to give patients a trial of 4–8 weeks of

Probiotic preparations of a specific lyophilized E. coli strain, or mixtures of several bacteria, when added to conventional therapy, may increase rates of induction and enhance maintenance of remission in mild ulcerative colitis. An

Ulcer disease and Helicobacter pylori infection (Chapter 6) Half of ulcer bleeding may be attributable to NSAIDs, and patients who are also positive for H. pylori have a synergistically high risk of re-bleeding. H. pylori eradication significantly reduces ulcer re-bleeding rates. Clarithromycin resistance accounts for most treatment failures. When a clarithromycin-based eradication regimen has failed, it is not worthwhile to administer it again. More effective options include PPI/amoxicillin/metronidazole or PPI with amoxicillin and levofloxacin for ten days, as well as more conventional bismuth-based quadruple regimens.

NSAID induced gastroduodenal toxicity (Chapter 7) H. pylori contributes to an excess ulcer-risk in NSAID naive patients, whereas ulcers occurring in long-term NSAID users are probably largely caused by the NSAIDs, irrespective of H. pylori status. It is appropriate to eradicate H. pylori in NSAID naive patients prior to starting chronic ASA or NSAID therapy. However, H. pylori eradication alone appears to be insufficient for ulcer prophylaxis in chronic non-ASA NSAID users. Misoprostol prophylaxis and substitution of COX-2 inhibitors appear to reduce the risk of developing endoscopically diagnosed gastric ulcers by 80% and the risk of complicated ulcers by 50%.

Ulcerative colitis (Chapter 12)

11

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Introduction

apheretic technique that removes granulocytes from the blood of patients is ineffective. Infliximab is effective for induction of remission in severe refractory disease.

Pouchitis (Chapter 13)

may be more cost effective than CT colonography, depending on relative procedural costs.

Prevention and treatment of traveler ’s diarrhea (Chapter 19)

Small controlled trials have demonstrated the efficacy of ciprofloxacin and metronidazole for acute pouchitis, of budesonide enemas for active chronic pouchitis, and of probiotic bacteria for maintaining remission of chronic pouchitis and for prophylaxis.

This new chapter summarizes the evidence for a number of interventions for chemoprohylaxis (with Rifaximin being the recommended agent). Early evidence for the efficacy of immunoprohylaxis is also presented.

Microscopic colitis (Chapter 14)

Preventive strategies, including enhanced infection control programs and antibiotic stewardship, are effective in reducing the incidence of CDAD. Complicated cases of CDAD have increased in frequency in some outbreaks, and it is postulated that the emergent hypervirulent BI/NAP10/27 strain is responsible. Evidence still favors metronidazole for treatment of initial episodes, but vancomycin appears to be the more effective treatment for severe disease. Observational studies suggest that tapered and pulsed vancomycin regimens may be effective for recurrent disease.

Budesonide is effective for short-term treatment, but the optimal strategy for long-term management needs further study. The long-term prognosis is good, and the risk of complications including colonic cancer is low.

Drug-induced diarrhea: (Chapter 15) Faced with an aging patient population and an ever increasing population of diabetic patients physicians should be aware that cholinesterase inhibitors, increasingly used in Alzheimer ’s disease, produce diarrhea in 14% of patients and metformin produces malabsorptive diarrhea in up to 50% of patients.

Metabolic bone disease in gastrointestinal disorders (Chapter 16) Bisphosphonate therapy reduces the risk of vertebral fractures in IBD patients by 6.3%. The improvement in BMD in IBD patients taking infliximab + a bisphosphonate may be greater than that observed with a bisphosphonate alone. Chronic PPI users may not have an increase in the risk of hip fracture with PPI use if they have no other identifiable risk factor. If there is a true association (as opposed to an association with confounding variables) between PPI use and decreased bone density, the fracture risk in chronic PPI users is low. The increased risk may be clinically relevant in patients with multiple other risk factors for osteoporosis, especially in patients with long-term, high-dose therapy.

Colorectal cancer in ulcerative colitis: surveillance (Chapter 17) Chromoendoscopy with targeted biopsies may increase the yield of surveillance colonoscopy. Estimates of sensitivity and specificity are made from an increased number of large surveillance programs.

Colon cancer screening (Chapter 18) The sensitivity of fecal occult blood testing, when three stools are tested using a sensitive immunochemical technique, approaches 90%. The miss rate for significant lesions at colonoscopy may be as high as 5%. There is consistent evidence that colonoscopy is less effective for reduction in right-sided CRC than it is for left-sided CRC. Colonoscopy 12

Clostridium difficile disease (Chapter 20)

Irritable bowel syndrome (Chapter 21) Colonic investigation has a very low yield in patients presenting with symptoms that are highly suggestive of IBS in the absence of alarm features. Screening to exclude celiac disease and thyroid dysfunction appears to be of value, but a panel of blood tests, including ESR and CRP, often performed when patients with suspected IBS are first seen in the outpatient clinic, has a low yield in detecting organic disease. Data to support the role of lactose hydrogen breath testing to exclude lactose intolerance are conflicting. Soluble fibre, antispasmodics (particularly hyoscine) and peppermint oil may be of some benefit in treatment of IBS patients, although the evidence is less than convincing. Both TCADs and SSRIs are effective (NNT = 4). Probiotics may also be used as second-line interventions in individuals with particularly troublesome abdominal pain and bloating. Psychological interventions should be reserved for individuals who are unresponsive to, or intolerant of, more conventional therapies, since they are time-consuming and expensive.

Ogilvie’s syndrome (Chapter 22) Evidence is presented that polyethylene glycol may reduce the frequency of recurrent cecal dilatation in patients who had initial resolution with neostigmine or decompression. Polyethylene glycol may also prevent the development of acute pseudoobstruction in patients with multiple organ failure admitted to an ICU.

Gallstone disease (Chapter 23) The natural history of asymptomatic cholelithiasis in diabetic patients appears to be similar to that in the general population, and preventative surgery should not be recom-

CHAPTER 1

Introduction

mended routinely. Laparoscopic cholecystectomy appears to be as safe as open cholecystectomy and may provide short-term improvement in quality of life. Acute cholecystitis should be treated with early laparoscopic cholecystectomy. In patients with gallstone pancreatitis preoperative ERCP may increase overall morbidity compared with the approach of cholecystectomy with intraoperative cholangiography. Patients with acute severe gallstone pancreatitis should undergo cholecystectomy following resolution of the acute episode, but during the initial hospital stay. Patients with mild to moderate pancreatitis can be considered for early laparoscopic cholecystectomy. Three approaches to the management of common duct stones (open common bile duct exploration, ERCP and sphincterotomy, and laparoscopic common bile duct exploration) have been compared, and conflicting data may relate to variation in operator expertise. The approach to CBD stones should be individualized and based on the type of expertise available at each institution.

Genetic hemochromatosis is underdiagnosed in the general population, and overdiagnosed in patients with secondary iron overload. A mild elevation in ferritin is very common, and may be related to obesity with NAFLD, regular alcohol consumption, or inflammation. The hepatic iron index reported on histological examination has limited use with the advent of genetic testing. The C282Y homozygote is the classic genetic pattern in >90% of typical cases. With other genetic variants severe iron overload is usually seen in the setting of a concomitant risk factor (alcoholism, viral hepatitis, NAFLD). Several studies have documented reversal of fibrosis following iron depletion therapy.

Acute pancreatitis (Chapter 24)

Wilson’s disease (Chapter 31)

Several recent, well-planned RCTs provided no evidence for benefit from the early use of prophylactic antibiotics in severe pancreatitis, and it is no longer recommended.

Despite isolation of several genes, the diagnosis remains a clinical one in patients presenting with abnormal liver function. Trientene and zinc therapy have further documentation of their efficacy.

metabolic syndrome. Whilst diagnostic methodology has improved, specific therapeutic agents are not available. What has been tried so far is summarized, with an outline of future prospects.

Hemochromatosis (Chapter 30)

Obesity (Chapter 25) The risk for co-morbidities, including cardiovascular disease, type 2 diabetes, obstructive sleep apnea and certain cancers, is reduced up to 40% by bariatric surgery.

Part II: Liver disease

Primary biliary cirrhosis (Chapter 32) Updated information on the use of ursodeoxycholic acid (UDCA), particularly in early PBC, still leave this drug as the one most frequently used for this disease, but with gaps in robust evidence for its efficacy.

Hepatitis C (Chapter 26)

Autoimmune hepatitis (Chapter 33)

There are concise guidelines for treatment of naive patients, based on genotype and viral load. Re-treatment is reviewed in detail as much more evidence is available from randomized studies. In the main, relapsers are worth re-treating, but genotype 1 non-responders may not yield cost-effective benefit.

Classical autoimmune hepatitis is well recognized, but “difficult to treat” cases not responding to standard immunosuppression, and the occurrence of overlap syndromes make some cases difficult to diagnose and to treat. Good outcomes have now been obtained with budenoside, tacrolimus and mycophenalate. New diagnostic algorithms have helped distinguish true overlap syndromes from disease variants.

Hepatitis B (Chapter 27) New therapies and new evaluation of interferon have revolutionized the management of these patients. The importance of monitoring for viral resistance, and using the correct combination, or sequential use, of agents is outlined.

Primary sclerosing cholangitis (Chapter 34) It is important to exclude IgG4 associated sclerosing cholangitis in the differential diagnosis. Use of UDCA is under scrutiny, and the use of high dose UDCA is reviewed.

Alcoholic related liver disease (Chapter 28) In alcoholic hepatitis there has been a consolidation of the evidence for the use of steroids and evidence for “stopping rules”, and validation of indices of non-response. Trials of agents to help abstention are reviewed.

Non-histological assessment of fibrosis (Chapter 35) This is a new chapter, which has evaluated both serum markers and transient elastography and the comparison with liver biopsy for the assessment of fibrosis.

Non-alcoholic fatty liver disease (Chapter 29)

Portal hypertensive bleeding (Chapter 36)

This disease spectrum is far better characterized, including the association with the other factors which make up the

Evolution of combined therapies using endoscopic and pharmacological ones, has replaced single mode approaches. 13

CHAPTER 1

Introduction

The use of primary prophylaxis with non-selective betablockers has been extended to grade Child C patients with cirrhosis even if varices are small. Antibiotics are now mandatory in the treatment of acute variceal bleeding as they improve control of bleeding, and mortality over and above specific endoscopic and pharmacological methods.

year of transplantation. Hepatologists who may not be in transplant centers, but who follow up patients who have had liver transplant, need to be aware of infectious complications, their diagnosis and treatment.

Hepatic outflow syndromes and splanchnic thrombosis (Chapter 37)

This is a major clinical problem, for which only recently there has been data from randomized studies and careful prospective observational studies to give some evidencebased guidance for therapy.

This is a new chapter, updating current management of hepatic outflow obstruction with a defined algorithm and use of anticoagulation for portal venous thrombosis.

Ascites, hepatorenal syndrome and spontaneous bacterial peritonitis (Chapter 38) This is an updated review of therapy, particularly for hepatorenal syndrome, for which terlipressin and albumin improve renal function in about 30% of patients. Selection for antibiotic prophylaxis in a primary setting has expanded beyond patients with low concentrations of albumin in ascites.

Hepatic encephalopathy: treatment (Chapter 39) The diagnosis and management of minimal hepatic encephalopathy are integral to this chapter, as this is an evolving area, which does affect quality of life, ability to drive safely and so on.

Hepatocellular carcinoma (Chapter 40) Combined clinical and imaging characteristics have allowed a much better clinical staging system, which guides therapy. Indications and use of loco-regional therapy, liver resection and transplantation, as well as new agents such as sorafenib have evolved, and a rationale basis for therapy is presented.

Fulminant hepatic failure (Chapter 41) Supportive management has greatly improved over the past few years. Current best practice is reviewed by new authors, and referral and indications for liver transplantation are fully discussed. The current status of liver support devices is evaluated on the basis of the few controlled trials and observational studies.

Liver transplantation: prevention and treatment of rejection (Chapter 42) New data from randomized trials has been incorporated against a background of the method of diagnosis of rejection and long-term complications and outcomes, where these have been documented.

Liver transplantation: prevention and treatment of infection (Chapter 43) New authors have completely revised this chapter, dealing with the major cause of morbidity and mortality within one 14

Management of HCV infection and liver transplantation (Chapter 44)

Management of HBV infection and liver transplantation (Chapter 45) The new therapies for HBV infection have revolutionized the outcome for HBV infected patients who come to liver transplantation. Treatment algorithms are now simplified and the importance for monitoring for viral resistance fully outlined.

Liver biopsy (Chapter 46) This is a new chapter reviewing the evidence base for diagnosis of liver disease, and staging/grading for chronic viral hepatitis. A full review of transjugular liver biopsy is given.

Drug induced liver injury (DILI) (Chapter 47) This is a new chapter, including etiopathogenetic mechanisms and practical algorithms to reach a diagnosis for this problem, which is being seen more frequently.

References 1 Ruffin JM, Grizzle JE, Hightower NC, McHardy G, Shull H, Kirsner JB. A co-operative double blind evaluation of gastric “freezing” in the treatment of duodenal ulcer. N Engl J Med 1969; 281: 16–19. 2 Dickson ER, Fleming TR, Wiesner RH et al. Trial of penicillamine in advanced primary biliary cirrhosis. N Engl J Med 1985; 312: 1011–1015. 3 A Medical Research Council Investigation. Streptomycin treatment of pulmonary tuberculosis. BMJ 1948; ii: 770–782. 4 Truelove SC, Witts LJ. Cortisone in ulcerative colitis. Final report on a therapeutic trial. BMJ 1955: 1041–1048. 5 Liberati A, Apolone G, Nicolucci A et al. The role of attitudes, beliefs, and personal characteristics of Italian physicians in the surgical treatment of early breast cancer. Am J Public Health 1990; 81: 38–41. 6 Antman EM, Lau J, Kupelnick B, Mosteller F, Chalmers TC. A comparison of results of meta-analyses of randomized control trials and recommendations of clinical experts. Treatments for myocardial infarction. JAMA 1992; 268: 240–248. 7 Mulrow CD. The medical review article: state of the science. Ann Intern Med 1987; 106: 485–488. 8 Jefferson T. What are the benefits of editorials and nonsystematic reviews? BMJ 1999; 318: 135.

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9 Cochrane AL. Archie Cochrane in his own words. Selections arranged from his 1972 introduction to “Effectiveness and efficiency: random reflections on the health services” 1972. Control Clin Trials 1989; 10: 428–433. 10 The Cochrane Collaboration. Cochrane Library 1999: www. cochrane.org. 11 Sackett DL. Clinical epidemiology. Am J Epidemiol 1969; 89: 125–128. 12 Sackett DL. Interpretation of diagnostic data: 1. How to do it with pictures. Can Med Assoc J 1983; 129: 429–432. 13 Sackett D, Haynes RB, Tugwell P, Guyatt GH. Clinical Epidemiology: a Basic Science for Clinical Medicine, 2nd edn. Little, Brown and Company, Boston, MA, 1991. 14 Reid MC, Lachs MS, Feinstein AR. Use of methodological standards in diagnostic test research. getting better but still not good. JAMA 1995; 274: 645–651. 15 Ransohoff DF, Feinstein AR. Problems of spectrum and bias in evaluating the efficacy of diagnostic tests. N Engl J Med 1978; 299: 926–930. 16 Chalmers TC. Randomization of the first patient. Med Clin North Am 1975; 59: 1035–1038. 17 Resnick RH, Iber FL, Ishihara AM, Chalmers TC, Zimmerman H. A controlled study of the therapeutic portacaval shunt. Gastroenterology 1974; 67: 843–587. 18 Sacks HS, Berrier J, Reitman D, Ancona-Berk VA, Chalmers TC. Meta-analyses of randomized controlled trials. N Engl J Med 1987; 316: 450–455. 19 Kernick D. Lies, damned lies, and evidence-based medicine. Jabs and jibes. Lancet 1998; 351: 1824. 20 Scholefield JH, Johnson AG, Shorthouse AJ. Current surgical practice in screening for colorectal cancer based on family history criteria. Br J Surg 1998; 85: 1543–1546. 21 Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal antiinflammatory drugs. A meta-analysis. Ann Intern Med 1991; 115: 787–796. 22 Yusuf S, Cairns JA, Camm AJ, Fallen EL, Gersh BJ. Evidence-based Cardiology, 2nd edn. BMJ Books, London, 2003. 23 Cataldo F, Ventura A, Lazzari R. Anti-endomysium antibodies and celiac disease: solved and unsolved questions. An Italian multicentre study. Acta Paediatr 1995; 84: 1125–1131. 24 Kitching A, Sackett D, Yusuf S. Approaches to evaluating evidence. Evidence-based Cardiology. BMJ Books, London, 1998. 25 Holmes GKT, Prior R, Lane MR et al. Malignancy in celiac disease: effect of a gluten-free diet. Gut 1989; 30: 333–338.

Introduction

26 McLeod RS, Wolff BG, Steinhart AH et al. Prophylactic mesalamine treatment decreases postoperative recurrence of Crohn’s disease. Gastroenterology 1995; 109: 404–413. 27 Chalmers TC, Celano P, Sacks HS, Smith H Jr. Bias in treatment assignment in controlled clinical trials. N Engl J Med 1983; 309: 1358–1361. 28 Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995; 273: 408–412. 29 ICH Steering Committee. ICH Harmonised Tripartite Guideline. Statistical Principles for Clinical Trials. Section 5.3-Missing Values and Outliers. Geneva: International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1998. 30 Feagan BG, McDonald JWD, Koval JJ. Therapeutics and inflammatory bowel disease: a guide to the interpretation of randomized controlled trials. Gastroenterology 1996; 110: 275–823. 31 Koch GG. One-sided and two-sided tests and p values. J Biopharm Stat 1991; 1: 161–170. 32 Kapur KC, Williams GT, Allison MC. Mesalazine induced exacerbation of ulcerative colitis. Gut 1995; 37: 838–839. 33 Naylor CD, Chen E, Strauss B. Measured enthusiasm: does the method of reporting trial results alter perceptions of therapeutic effectiveness? Ann Intern Med 1992; 117: 916–921. 34 Camma C, Giunta M, Rosselli M, Cottone M. Mesalamine in the maintenance treatment of Crohn’s disease: a meta-analysis adjusted for confounding variables. Gastroenterology 1997; 113: 1465–1473. 35 Oxman AD, Cook DJ, Guyatt GH. User ’s guides to the medical literature. VI How to use an overview. Evidence-Based Medicine Working Group. JAMA 1994; 272: 1367–1371. 36 Caprilli R, Andreoli A, Capurso L et al. Oral mesalazine (5-aminosalicylic acid; asacol) for the prevention of postoperative recurrence of Crohn’s disease. Aliment Pharmacol Ther 1994; 8: 35–43. 37 Lochs H, Mayer M, Fleig WE et al. Prophylaxis of postoperative relapse in Crohn’s disease with mesalazine (Pentasa) in comparison to placebo. Gastroenterology 2000; 119: 264–273. 38 Sutherland LR. Mesalamine for the prevention of postoperative recurrence: is nearly there the same as being there? Gastroenterology 2000; 118: 264–273. 39 Cumbers B, Donald A. Evidence-based practice. Data day. Health Serv J 1999; 109: 30–31.

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Evidence-Based Gastroenterology and Hepatology, Third Edition John WD McDonald, Andrew K Burroughs, Brian G Feagan and M Brian Fennerty © 2010 Blackwell Publishing Ltd. ISBN: 978-1-405-18193-8

2

Gastroesophageal reflux disease Naoki Chiba1 and M Brian Fennerty2 1

Division of Gastroenterology, McMaster University Medical Centre, Hamilton and Guelph General Hospital, Guelph, Canada 2 Oregan Health and Science University, Division of Gastroenterology and Hepatology, Oregon, USA

Introduction Heartburn and or regurgitation are very common symptoms encountered in patients seen in a clinical practice. Most patients with gastroesophageal reflux disease (GERD) will have these symptoms of heartburn and/or regurgitation, but many patients with these symptoms do not have GERD. Clinical studies prior to the mid-1990s focused on management of patients with predominant heartburn based on the endoscopic findings of esophagitis, as healing of the esophageal mucosa was an easily measured objective endpoint compared to subjectively assessing a patient’s symptom response to a therapy. More recently it has become known that GERD symptom severity does not predict the presence or absence of endoscopic mucosal damage (e.g. esophagitis), and patients with GERD including those with and without esophagitis, experience decrements in quality of life (QoL) associated with their symptoms. In treating GERD patients with esophagitis and those with non-erosive reflux disease (NERD), as well as those patients with symptomatic heartburn that have not undergone endoscopy, proton pump inhibitors (PPIs) offer better healing and symptom relief than less potent acid inhibitors (e.g. histamine-2 receptor antagonists or H2blockers) or acid neutralizing agents (e.g. antacids). The available PPIs are, for the most part, equally effective as treatment for GERD symptoms and healing esophagitis, although esomeprazole more effectively heals the small minority of GERD patients with more severe grades of esophagitis (Los Angeles Grades C and D). For patients with documented erosive esophagitis and in those with NERD and/or uninvestigated heartburn that relapses quickly upon discontinuing treatment, maintenance

Evidence-Based Gastroenterology and Hepatology, Third Edition John WD McDonald, Andrew K Burroughs, Brian G Feagan and M Brian Fennerty © 2010 Blackwell Publishing Ltd. ISBN: 978-1-405-18193-8

therapy with a PPI may be appropriate. For patients with documented NERD, lower doses of PPI therapy are often adequate, and treatment can also be given on demand or prn. The PPIs are very safe and offer excellent long-term control of symptoms, although recent evidence suggests that long-term use may be associated with some adverse outcomes. Anti-reflux surgery is also an effective option for treating GERD symptoms and healing esophagitis, especially since a laparoscopic alternative has now become well established and is widely available. The choice for surgery should be based on patient preference rather than issues of efficacy or cost, as there is ample evidence that neither therapeutic approach is substantially more cost-effective than the other.

Definition of gastroesophageal reflux disease Gastroesophageal reflux (GER) is a normal physiological process that most commonly occurs during and after meals in an upright position. However, due to acid neutralization by saliva and prompt esophageal clearance of physiologic refluxate, symptoms associated with physiologic GER occur in only a minority of people. Conversely, GERD occurs when reflux is frequent or caustic enough to cause the typical symptoms of heartburn, acid regurgitation and or dysphagia or result in esophageal mucosal injury. GERD also may result in extraesophageal manifestations such as non-cardiac chest pain, asthma, cough or posterior laryngitis and hoarseness [1]. Moreover, patients will often present not only with reflux symptoms but also with epigastric pain and/or discomfort, symptoms associated with “dyspepsia” rather than GERD [1–3]. It is difficult to determine at what point GER transforms a normal physiological state into a disease state, GERD. Many patients and providers regard some degree of heartburn as normal. Moreover only a small proportion of patients with GERD actually seek medical care, as noted in Castell’s “GERD iceberg” [4]. Early literature often incorrectly used the terms hiatus hernia and gastroesophageal reflux synonymously, imply19

PA RT I

Gastrointestinal disorders

ing that the hernia was the cause of the symptoms of GERD or the root cause of GERD itself. Hiatus hernia is a common structural abnormality, whereas reflux is most often caused by functional or mechanical events. Once the hiatus hernia was dismissed as the root cause of GERD, reflux disease was considered to be present when abnormally prolonged esophageal acid exposure resulted in esophageal damage, either macroscopic (endoscopic esophagitis and/or Barrett’s esophagus) or microscopic (histological esophagitis). However, more recently, it has been recognized that symptomatic gastroesophageal reflux without obvious macroscopic or microscopic esophageal injury, otherwise known as “endoscopy negative reflux disease” (ENRD) or “non-erosive reflux disease” (NERD), is an important and large part of the spectrum of reflux disease [5]. Another term, symptomatic GERD, has been used to refer to these patients previously classified as having NERD. However, this term is also imprecise and should be applied only to patients with uninvestigated reflux-like symptoms that adversely impact their normal quality of life (QoL). It is now generally accepted that GERD is really a spectrum of diseases. Attention has been focused on the typical symptoms of heartburn and acid regurgitation that are often not accompanied by any easily identified pathological findings. Even without endoscopic esophagitis, these patients have reduced health-related QoL comparable with that experienced by patients with esophagitis [6–89]. Awareness of this fact has led some experts to erroneously equate a patient with the predominant symptom of heartburn with a confident diagnosis of GERD [10, 11]. Patients with heartburn alone have only a little better than chance probability of having GERD as defined by an abnormal ambulatory esophageal acid exposure [12]. Most patients with endoscopic esophagitis will complain of heartburn [13], and even if heartburn is not the predominant symptom, endoscopic esophagitis can be identified in up to 36% of patients with suspected GERD [14]. Thus, it is clear that the symptom of heartburn in and of itself is an insufficient criterion to diagnose GERD. Many authors continue to mix symptoms and mucosal damage in the same definition of GERD. The American College of Gastroenterology definition of GERD is, “chronic symptoms or mucosal damage produced by the abnormal reflux of gastric contents into the esophagus” [15]. Experts from the Genval Workshop further expanded this definition to include the patient-centered perspective that gastroesophageal reflux is defined by the presence of “clinically significant impairment of health-related well-being (quality of life) due to reflux-related symptoms” [11]. These are similar to the 2004 Canadian GERD Consensus Conference definition: “GERD applies to individuals with reflux of gastric contents into the esophagus causing (a) symptoms sufficient to reduce quality of life and/or (b) esophageal injury” [9]. The subsequent 2006 Montreal definition: 20

“GERD is a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications” was similar [1]. In summary, these data indicate that an encompassing, objective and validated definition of GERD is lacking and instead we are relying on imperfect measures to define this disease. Furthermore, the varied phenotypic expression of the disease(s) indicates that a single reproducible measure is unlikely to be an effective tool for the definition of GERD.

Symptoms of gastroesophageal reflux disease The typical symptoms of GERD include heartburn (usually defined as a rising retrosternal burning discomfort) and acid regurgitation [1, 9]. Many investigators suggest that the diagnosis of GERD should be based primarily on the presence of these typical symptoms, as the specificity of heartburn and acid regurgitation for GERD is approximately 89% and 95% respectively [27]. Indeed, up to 96% of patients with documented erosive esophagitis also have heartburn [13]. An early study reported that when heartburn or regurgitation occurred daily, there was a positive predictive value of 59% and 66% respectively, for the diagnosis of GERD [28]. When an abnormal pH-metry is used as the gold standard, these symptoms have demonstrated 72% sensitivity and 63% specificity for GERD [29]. Many patients also have other upper abdominal symptoms as noted previously, but according to recent concepts, these patients are probably more correctly classified as having dyspepsia rather than GERD [30]. In summary, the only validated symptom measure for GERD at this time is the word description for heartburn (e.g. a burning discomfort arising behind the breastbone towards the neck).

Epidemiology of gastroesophageal reflux disease Considering the lack of consistency of symptom based definitions and methods of diagnosis of GERD, it is difficult to determine the absolute prevalence of GERD in the general population. For instance, are we measuring the prevalence of the symptoms of heartburn or acid regurgitation, and to what degree, or are we measuring the prevalence of endoscopic esophagitis? The prevalence of GERD also varies between surveys of the general population and studies of symptomatic patients that present to the family practitioner. Heartburn is experienced by 4–7% of the general US population on a daily basis and by 34–44% of the population at least once a month (Table 2.1) [5, 20, 31–33]. Similarly high rates have been observed in New Zealand [34]. Recent data suggest that Asian patients have a lower prevalence of GERD symptoms than Western pop-

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Table 2.1 Population-based questionnaire studies of the prevalence of the symptom of heartburn. Authors

Country

Daily (%)

At least once weekly (%)

At least once a month (%)

Total at least once/month (%)

Nebel et al. (1976) [16] Thompson and Heaton (1982) [17] Gallup Organization (1988) [18] Isolauri and Laippala (1995) [19] Locke et al. (1997) [20] Wong et al. (2003) [21] Diaz-Rubio et al. (2004) [22] Cho et al. (2005) [23] Bor et al. (2005) [24] Moraes-Filho et al. (2005) [25] Yamagishi et al. (2008) [26]

USA UK USA Finland USA China Spain Korea Turkey Brazil Japan

7 4 — 9 — — — — — — —

14 10 — 15 18 2.5 9.8 2.0 10 4.6 —

15 21 — 21 — 8.9 — 4.7 — — —

36 34 44 41 42 — — — — — 20

ulations [21, 35], as well as a much lower prevalence of esophagitis [36]. In contrast, the overall prevalence of reflux esophagitis in Western countries has been estimated to be about 2% [33]. However, this figure likely underestimates the true prevalence. In a group of 27% of adults self-treating with antacids more than twice a month, objective evidence of reflux esophagitis is revealed in 84% during investigation, suggesting that esophagitis is not uncommonly found in those with symptoms of heartburn [37]. Furthermore, some have estimated that the prevalence of GERD is as high as 20% of the adult population and that esophagitis is found in 35–50% of those with GERD. If these data are correct the prevalence of esophagitis in the adult population may be as high as 7–10%. A recent systematic review by El-Serag has shown an overall increase in the prevalence of GERD over the past two decades, particularly for North America and Europe, but not Asia [38]. The incidence of GERD is estimated to be 4.5 per 100,000 with a dramatic increase in persons over the age of 40 years [39]. A Canadian study found that heartburn occurred at least once a week in 19% of persons > 60 years old, compared with 4.8% of persons < 27 years old [17]. A large American retrospective cohort study in VA patients also identified older age along with being a white male as the group associated with the most severe forms of GERD [40]. Nebel et al. in 1976 [16] studied the point prevalence and precipitating factors associated with symptomatic gastroesophageal reflux using a questionnaire in 446 hospitalized and 558 outpatients (see Table 2.1). Age, sex or hospitalization did not significantly affect prevalence. In a Finnish study of 1700 adults, only 16% of symptomatic patients reported taking medications and only 5% had sought medical care [19].

In clinical practice, the relevant population is the group of patients that present with symptomatic heartburn. In this population, it has been estimated that about 50–70% of patients have normal endoscopies and the minority of patients (30–50%) have endoscopic esophagitis [41]. However, in a recently reported Canadian study of prompt endoscopy in patients with uninvestigated dyspepsia, the overall prevalence of endoscopic esophagitis was 43%, and in those with dominant heartburn, the prevalence of esophagitis was 55% [14]. Thus in this population, NERD was seen in less than half of the patients (45%). In summary, the true population prevalence of GERD and esophagitis is unknown but appears to be approximately 10–15% and 3–7% based on current data.

Pathophysiology of gastroesophageal reflux disease GERD is primarily a motility and/or anatomical disorder of the esophagus, perturbations of which allow an abnormal amount or frequency of injurious gastric contents to reflux into the esophagus. Reflux occurs as a consequence of a defect of the normal anatomic and physiological antireflux barrier that is provided primarily by actions of the lower esophageal sphincter (LES) and crural diaphragm. The two key abnormalities are thought to be abnormal transient lower esophageal sphincter relaxations (TLESRs) [42, 43], precipitated by gastric distension in the postprandial period [44] and poor basal LES tone [42]. The result of these and other less common anatomic and physiological abnormalities is an increased intraesophageal exposure of gastric refluxate and increasing damage as the pH of refluxate falls below 4, which is optimal for pepsin activation [45, 21

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46]. A hiatus hernia may act as a reservoir for acid refluxate that can then re-reflux up the esophagus [47, 48]. GERD patients with hiatus hernia have been found to have greater esophageal acid exposure and more reflux episodes vs GERD patients without a hernia [49].

Pathophysiology in non-erosive reflux disease Further support for the concept that acid alone can be the pathophysiological basis for reflux disease comes from the observation that in patients that have typical symptoms of reflux with a normal endoscopy, 6–15% with symptomatic reflux had normal 24-hour esophageal pH-metry [50–52]. Additionally, pathological reflux on pH studies has been identified in 21–61% of endoscopy negative patients [53– 55]. A recent study identified abnormal acid reflux in 84% of patients with either erosive esophagitis or NERD, a much higher proportion than previously reported. The reason for these variable results is unknown. In contrast, 71–91% of patients with erosive esophagitis at endoscopy have pathological reflux on pH studies. Thus, abnormal intraesophageal acid exposure as measured by pH studies is more frequent but not an optimal gold standard for documenting reflux disease [53–55]. However, despite these limitations the data clearly demonstrate that the proportion of intraesophageal acid exposure increases over the spectrum from NERD to worsening grades of esophagitis and Barrett’s esophagus [56]. Another conundrum in reflux disease is the patient with an apparent suprasensitive esophagus. Of 96 patients with normal 24-hour esophageal acid exposure, 12.5% were found to have a statistically significant association between their reflux symptoms and actual reflux episodes, despite having “normal” intraesophageal acid exposure [51]. In these patients, the duration of reflux episodes was shorter and the pH of reflux episodes was often lower than in patients with typical GERD, suggesting that esophageal hypersensitivity was the cause of their symptoms. These and other data have led to the concept of an acid-sensitive esophagus. An esophageal balloon distension study provided further experimental evidence of esophageal hypersensitivity in patients with normal acid exposure times with a value for a symptom index (SI) > 50% [50]. In general, these patients had significantly lower thresholds for initial perception and discomfort from esophageal balloon distension, compared with both normal controls and patients with confirmed reflux. In contrast, Fass et al. studied patients with GERD and controls without GERD and determined that patients showed enhanced perception of acid perfusion but not of esophageal distension [57]. They concluded that chronic acid reflux by itself was not the cause of esophageal hypersensitivity to distension in patients with non-cardiac chest pain, although subsequent data from this group

22

suggest that the esophagus can be primed to be hypersensitive by repeated reflux events. Carlsson et al. [58] have also demonstrated an impaired esophageal mucosal barrier in symptomatic GERD patients by measuring the transmucosal epithelial potential difference, suggesting a role for alteration in cell barrier function as a cause for reflux symptoms in some individuals. Another study examined differences in spatiotemporal reflux characteristics between symptomatic and asymptomatic reflux episodes [59]. They used a pH sensor positioned 3, 6, 9, 12 and 15 cm above the LES and found that the duration of acid exposure was longer and the proximal extent was higher in symptomatic than in asymptomatic reflux episodes. A similar study also determined that patients with NERD compared with healthy controls, had a higher, intraesophageal proximal reflux of acid [60]. Even NERD patients with normal acid exposure time seemed to perceive proximal reflux very readily, implying that their proximal esophageal mucosa is more sensitive to short duration refluxes than that of patients with esophagitis. More recently, there is a suggestion that up to two-thirds of patients with NERD have histological evidence of esophageal injury [61]. The commonest finding is dilation of intercellular spaces irrespective of esophageal acid exposure. Basal cell hyperplasia and papillary elongation were seen more frequently in NERD patients with abnormal acid exposure. However, these findings are not found consistently enough to reliably serve as the basis for the diagnosis of GERD.

Hiatus hernia The mere presence of a hiatus hernia (HH) bears no relationship to the diagnosis of esophagitis and is frequently seen in those without esophagitis. Moreover, up to half the healthy population has a hiatus hernia [62] and only half of the patients with symptoms of heartburn and regurgitation have a hiatus hernia [63]. However, some studies have suggested that patients with a hiatus hernia have greater esophageal acid exposure and more reflux episodes [49] and more severe reflux esophagitis than patients without, suggesting that a HH does have a role in some patients with reflux disease [64, 65]. A large HH may act as a reservoir for acid that re-refluxes more readily when a swallow is initiated and in this fashion contributes to GERD [47, 48]. Other supporting evidence for the role of HH in GERD comes from a study in patients with pathologic reflux (pH < 4 for more than 5% of a 24-hour intraesophageal pH-metry study) that identified hiatus hernia in 71% of patients with mild esophagitis, compared with 39% of those without esophagitis [66]. Patients with a hiatus hernia also had higher 24-hour intraesophageal acid exposure

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compared with those without, particularly during the night. However, there were no differences in symptoms of heartburn or regurgitation, whether or not patients had a hiatus hernia or esophagitis. Another study demonstrated that the presence of hiatus hernia correlated with more severe manifestations of GERD [67]. Hiatus hernia was seen in 29% of symptomatic patients, 71% with erosive esophagitis, and 96% with long segment Barrett’s esophagus. Although transient lower esophageal sphincter relaxations (TLESRs) are thought to be a key mechanism for pathological reflux, van Herwaarden et al. [49] did not find differences in LES pressure, and the incidence of TLESRs, and the proportion of TLESRs associated with acid reflux were comparable in those with and without hiatus hernia. They felt that the excess reflux in GERD patients with hiatus hernia was caused by malfunction of the gastroesophageal barrier during low LES pressure, swallowassociated normal LES relaxations, deep inspiration and straining. In summary, the pathophysiology of GERD is varied, and the most common mechanism appears to be TLESRs but mechanical defects of the gastroesophageal junction and LES also play a role in many patients with this disorder.

Natural history of gastroesophageal reflux disease There are few data about this important topic, and existing studies are limited in that they usually include heterogeneous populations. In one such study using a Swedish population-based survey of over a thousand citizens conducted over seven years, the prevalence of GERD remained stable over time at about 17–19% [68]. In a more recent 10-year follow-up Swedish study of 197 respondents out of the original 337 subject cohort, 83% reported no change in their global symptom assessment, indicating relative stability of symptoms over time [69]. A small retrospective study published in 1991 identified patients with symptoms of GERD but with a normal endoscopy and 24-hour pH study [70]. All patients received antacids or prokinetic drugs or both for 3–6 months. Thus, this was not a study of untreated patients but a study that employed treatments now recognized to be relatively ineffective (vs true untreated controls). However, 19 of the 33 patients still had symptoms at the end of six months and of these, five (26%) developed erosive esophagitis. The remainder of the patients remained asymptomatic. There was no difference in baseline pH-metry between those that went on to develop esophagitis and those that did not. Another study reported data on patients with objectively proven GERD conservatively managed without treatment

Gastroesophageal reflux disease

over a 17–22-year follow-up [71]. The authors reported on 60 patients from an initial cohort of 87 patients. Ten of these patients ultimately had an anti-reflux procedure, but of the remaining “untreated” 50 patients, 36 (72%) were less symptomatic at follow-up. Of this group, only six became symptom “free”. The majority no longer used anti-reflux medications. Only five patients remained unchanged and nine became worse. The prevalence of erosive esophagitis fell from 40% at referral to 27% at follow-up endoscopy, and six new cases of Barrett’s metaplasia developed. At follow-up, 66% of the patients had objective evidence of GERD with esophagitis, a pathological pH study or newly recognized Barrett’s metaplasia. Neither the presence of esophagitis or of hiatal hernia, nor the severity of symptoms at baseline predicted the course of the disease at follow-up. The authors concluded that the severity of reflux symptoms declined in the long term, but pathological reflux persisted in the majority of the conservatively managed patients. For patients with mild esophagitis, the course of the disease may also be relatively benign from an oesophageal injury perspective, with only 23% progressing to more severe esophagitis, while 31% improved and 46% spontaneously healed with no further episodes. However, from an impact on quality of life GERD does not appear to be a benign disease. In one study, patients with endoscopic esophagitis diagnosed more than 10 years earlier were contacted by postal questionnaire and phone interview [71]. Of the respondents, over 70% continued to have significant symptoms of reflux, and 40–50% were still taking acid suppressive medications regularly and had reduced QoL (lower Short Form (SF)-36, physical and social function domain scores). Thus, GERD is a chronic disease with significant morbidity and it impacts negatively on QoL. Despite frequent symptoms, even severe reflux disease has little effect on life expectancy, with almost no deaths directly due to GERD reported in long-term follow-up [39, 71, 72]. However, a recent population-based study identified GERD as a strong risk factor for esophageal adenocarcinoma, but not squamous cell carcinoma [73]. In summary, the above data indicate that GERD is a chronic but not static disease; progression and regression may occur, although this is not common. Despite impacting QoL adversely, GERD has little effect on life expectancy.

Esophageal complications of gastroesophageal reflux disease Complications of GERD include bleeding (< 2%), ulceration (approximately 5%) and strictures (1.2% to 20%) [71, 74, 75]. Patients with strictures are generally older and more frequently have a hiatus hernia [74]. Barrett’s esopha-

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gus has been identified in 10–20% of GERD patients [76]. Six of 50 patients (12%) developed Barrett’s esophagus during approximately 20 years of follow-up, a crude incidence of 0.6% per year [72]. The association of Barrett’s esophagus and esophageal adenocarcinoma are covered in Chapter 3.

Effects of gastroesophageal reflux disease on quality of life (QoL) Increased attention is being paid to patient QoL assessments, as opposed to histology of the esophagus as an outcome measure of importance in patients with GERD. Indeed, as there is no single physical marker for this disease, most experts now include decrements in QoL as part of the definition of GERD [9]. Several general health status and reflux-specific QoL instruments have been developed, validated and used. Examples include: Medical Outcomes Study SF-36 [77], Psychological General wellbeing (PGWB) index [78], the Gastrointestinal Symptom Rating Scale (GSRS) [79–81], the Gastroesophageal Reflux Disease – Health Related Quality of Life (GERD-HRQL) instrument [82], ReQuest [83–85], Reflux Disease Questionnaire [86], REFLUX-QUAL (RQS) [87], the Reflux questionnaire [88] and the Quality of Life in Reflux and Dyspepsia questionnaire (QOLRAD) [89]. Because of the development and availability of QoL instruments, more recent GERD clinical studies have used validated GERDspecific instruments focusing more on assessing patient satisfaction and QoL as primary endpoints [89–96]. Despite the development of more specific health-related QoL questionnaires, a 2008 systematic review identified that existing scales were still somewhat suboptimal [97]. Patients with gastrointestinal disorders have decreased functional status and well-being [98]. Those patients with chronic gastrointestinal disorders, including GERD, and congestive heart failure have the poorest health perceptions. These perceptions are worse than those that characterize some other chronic conditions such as hypertension and arthritis [79, 99, 100]. In patients with heartburn there was a substantial impairment of all aspects of health-related QoL when measured using the GSRS, QOLRAD, SF-36 and the Hospital Anxiety and Depression (HAD) scale [98]. Other studies have shown that successful treatment of GERD results in improvement in QoL. In general, patients with reflux esophagitis are considered to have equally impaired QoL to those with non-erosive disease, but those with very severe reflux esophagitis may have even more impairment [101]. NERD patients do not have objective markers such as endoscopic esophagitis that can be used to define treatment success. Symptom reduction to a level that does not cause significant impairment of health-related QoL is therefore an appropriate outcome by which to measure a therapy. Both the PGWB and GSRS scores show 24

good discriminative ability to reflect the severity of impairments in quality of life in NERD patients [102]. Improvements in health-related QoL with treatment of NERD and of erosive esophagitis have also been documented [7, 103, 104]. There are also now scales such as the Proton pump inhibitor Acid Suppression test (PASS) [105], the Gastrooesophageal reflux disease impact scale [106] and the Reflux Disease Questionnaire (RDQ) [107] that have been developed as instruments to help guide patient care. In summary, these data demonstrate that the impact GERD has on QoL is substantial and equivalent to many other diseases considered to be severe and important.

Diagnostic tests for gastroesophageal reflux disease The diagnosis of GERD depends on the definition of “pathological” in diagnostic tests. Problems in defining GERD have been recognized for more than two decades [62]. Methods of diagnosing GERD are outlined in Table 2.2. These tests evaluate different features of GERD, and none of them measures all aspects of the disease. Tests such as barium studies, scintigraphy and ambulatory oesophageal pH studies demonstrate whether reflux is occurring; endoscopy demonstrates mucosal injury and complications of GERD; ambulatory oesophageal pH studies quantify the amount of oesophageal acid exposure, the number and duration of reflux events and allow the correlation of reflux events with recorded symptoms; oesophageal sensitivity to acid is assessed by the Bernstein test. The correct interpretation of these diagnostic tests for GERD is critically important. For example, a patient with documented endoscopic esophagitis with a negative Bernstein test should not be regarded as having a “false negative” Bernstein test, but rather an acid insensitive esophagus as measured by this test. With variable patient populations, and with differences in definitions, techniques and gold standards, it is impossible to compare sensitivity and specificity values between the various diagnostic tests for GERD [108].

Manometry and lower esophageal pressure measurement LES pressures alone are not of diagnostic value, as there is considerable variation in the normal LES pressure as well as overlap of pressures in those with and without esophagitis. Furthermore, the most common finding of an LES pressure in patients with GERD is a normal one. In a review of six studies [109], LES pressure < 10 mmHg did correlate with abnormal oesophageal acid exposure but with a sensitivity of only 58% and specificity of 84%. However, there may still be some utility in low LES pressures as a predictor

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Table 2.2 Summary of diagnostic tests in gastroesophageal reflux disease. Test

What does it measure?

Comments

Esophageal manometry

• Measures lower esophageal sphincter pressure • Low ( 50, 10 of 12 (83%) of patients with a positive SI showed improvement on omeprazole 20 mg twice daily for decreased symptom frequency, severity and consumption of antacids (P < 0.01). The SF-36, QoL parameters for bodily pain and vitality also significantly improved. In the group with a negative SI only one patient clearly improved. 29

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Thirty-three consecutive patients with symptoms of reflux, abnormal pH studies, but normal endoscopies were sequentially allocated to receive ranitidine 150 mg twice daily, omeprazole 40 mg once daily, or omeprazole 40 mg twice daily for 7–10 days [163]. On the last day of treatment an esophageal pH study was repeated, and the results were correlated with symptoms. Using a 75% reduction in symptoms as a positive test, and the pH test as the gold standard, the sensitivity of the omeprazole test using a dose of 40 mg twice daily was 83.3%, while the sensitivity with omeprazole 40 mg once daily was only 27.2%. The authors concluded that the diagnosis of GERD could be ruled out if a patient failed to respond to a short course of high dose PPI. Fass et al. [164] also used an omeprazole 60 mg daily test versus placebo in GERD positive (35/42, 83%) and GERD negative patients (17%). Twenty-eight GERD-positive and three GERD-negative patients responded to the omeprazole test, providing sensitivity of 80.0% and specificity of 57.1%. Economic analysis revealed that the omeprazole test saved US$348 per average patient evaluated, with 64% reduction in the number of upper endoscopies and a 53% reduction in the use of pH testing. Most studies have used omeprazole in the “PPI test”. However, a study using 60 mg of lansoprazole once daily versus placebo for five days found that 85% tested positive during active treatment compared with 9% with placebo [165]. The PPI test sensitivity was 85% and specificity was 73%. Esomeprazole is more potent than omeprazole and it also has been evaluated as a diagnostic tool [166]. Patients (n = 440) were randomized to receive esomeprazole 40 mg once daily, esomeprazole 20 mg twice daily or a placebo for 14 days. Endoscopy and 24-hour esophageal pH-monitoring were carried out to determine the presence of gastroesophageal reflux disease (GERD). The esomeprazole treatment test had sensitivity in confirming the diagnosis of GERD of between 79% and 86% (for the two doses of PPI) after five days, while the corresponding value for placebo was 36%. In a small, eight-week, placebo-controlled study of 36 patients with non-cardiac chest pain and abnormal esophageal 24-hour pH-metry, overall pain improvement was reported by 81% of omeprazole and 6% of placebo-treated patients [167]. Similar results were reported in another small study of 39 patients [168]. The omeprazole test correctly classified 78% of patients considered to be GERD patients by 24-hour esophageal monitoring and/or endoscopy and was positive in only 14% of patients considered not to have GERD by these criteria. Thus, a therapeutic trial may be useful in conditions other than typical GERD such as non-cardiac chest pain, an observation that is further supported by more recent studies [169, 170]. 30

A meta-analysis of studies that used a trial of acid suppression for diagnosing GERD systematically and quantifiably evaluated all published studies prior to 2004 and concluded that “successful short-term treatment with a PPI in patients suspected of having GERD does not confidently establish the diagnosis, when GERD is defined by currently accepted reference standards” [171]. In summary, these data indicate that a therapeutic trial of a PPI for 1–2 weeks may be a reasonably useful clinical tool but it is by no means a gold-standard test for the diagnosis of GERD. The advantages of this approach include simplicity, noninvasiveness, ease of prescription and consumption, tolerability, and savings in terms of direct costs and time lost by the patient, but it does not demonstrate optimal sensitivity or specificity. A positive therapeutic trial may also predict longer term therapeutic response, but data confirming this notion are limited. These studies also support the notion that a symptom-based treatment is reasonable for most patients with reflux disease without a specific diagnosis. Perhaps the greatest value of this test lies in determining that GERD is not likely to be the cause of a given patient’s symptoms (high negative predictive value) when no response to high-dose PPI is achieved.

Treatment of gastroesophageal reflux disease Symptoms of gastroesophageal reflux are common and have a significant adverse impact on QOL. The costs of disease include both drug acquisition costs and indirect costs such as testing, physician visits and time off work. Because of the difficulty in making a definitive diagnosis of GERD through diagnostic investigations, the physician must make a presumptive diagnosis and initiate a management plan. The goals of therapy are to provide adequate symptom relief, heal esophagitis and prevent complications. Since initial studies in GERD have focused on mucosal healing; healing of erosive esophagitis will be discussed first, followed by discussions on NERD, and finally on symptomatic treatments in the uninvestigated patient.

Acid suppression therapy for gastroesophageal reflux disease While transient relaxations of the LES and defective basal LES tone are thought to be the primary pathophysiological determinants of reflux, symptoms and damage arising from the esophagus are the result of acidic reflux as a consequence of these and other physiological perturbations [43]. Thus, the focus of treatment has been on acid suppression. Acid secretion and/or gastric pH can be affected by various drugs. Antimuscarinic agents are weak inhibitors

CHAPTER 2

of the parietal cell M3 cholinergic receptors, and their clinical use is limited by their anticholinergic side effects. H2receptor antagonists (H2-RAs) inhibit parietal cell histamine receptors; thus acid inhibition can be largely overcome by stimulation of gastrin and cholinergic receptors, as occurs when food is eaten [172]. Tolerance or tachyphylaxis to H2-RAs develops rapidly and reduces their efficacy with continued use over time [173]. PPIs provide the most potent acid inhibition through covalent binding to the H+, K+-ATPase (acid or proton pump) located in the secretory canaliculus of the parietal cell. Inhibiting the proton pump, which is the final common pathway of acid secretion, diminishes acid secretion to all known stimuli. Despite short serum half-lives, the PPIs have a longer duration of pharmacological action owing to the dependence of acid secretion recovery on the rate of synthesis of new proton pumps by the parietal cell. Studies of intragastric acidity have been used to assess the degree and duration of acid inhibition with anti-secretary drugs [174, 175]. These studies have confirmed that PPIs are far superior to H2-RAs in their ability to suppress food stimulated, daytime and total 24-hour acid secretion. Bell et al. [174] have shown, by meta-analysis, that the healing rate of erosive esophagitis correlated directly with the duration of gastric acid suppression over a 24-hour period. The primary determinants of healing were the duration of antisecretory treatment, the degree of acid suppression and the duration of acid suppression over the 24-hour period. There was also a highly significant correlation between the time that the pH in the esophagus was above 4 and the ability to heal erosive esophagitis. The authors concluded that if intragastric acidity could be maintained above a mean pH of 4 for 20–22 hours of the day, 90% of patients with erosive esophagitis would be healed by eight weeks. Thus, the superiority of PPIs over H2-RAs was predicted prior to the performance of clinical trials based on their pharmacologic ability to achieve more effective suppression of acid secretion.

Lifestyle modifications Although lifestyle modifications as a treatment for GERD are frequently recommended, there is little evidence that these are of benefit (Box 2.1). Changing dietary habits and lifestyle modifications are generally considered useful by physicians [176, 177]. However, when patients were asked about advice they had received from physicians, lifestyle changes were only modestly recommended [178]. If a patient is under the age of 50, and has no serious “alarm symptoms” such as unexplained weight loss, dysphagia or hematemesis, it is reasonable to start empirical therapy [9, 163] as the most cost-effective approach [179]. One study assessed patients with 24-hour esophageal pH testing and found no difference in lifestyle alteration and

Gastroesophageal reflux disease

B O X 2 . 1 Recommended lifestyle modifications in gastroesophageal reflux disease

• Avoid precipitating foods and drinks: fat [200, 201] (two studies found no effect of fat [202, 203], another found no effect of caloric density [204]), chocolate [205, 206], peppermint [207], spices [208], raw onions [209], carbonated beverages [198, 210], caffeine [4, 185, 211–213], coffee [185], orange juice and tomato drink [210, 214] • Avoid alcohol [4, 210, 215–217] • Avoid cigarette smoking [4, 186, 216–218] • Avoid large meals and gastric distension [44, 219] • Avoid lying down within 3–4 hours of a meal [220] • Aggravating factors to be avoided: posture [220], physical exertion especially running [188, 189], weightlifting and cycling [189, 193] • Raising the head of the bed may have some efficacy [220–223] • Sleeping on the left lateral position reduces reflux [195–197] • Avoid tight clothes [4] • Obesity may be a risk factor [4, 22, 216–224], weight reduction helps symptoms [225], weight reduction does not help [226, 227], Roux-en-Y gastric bypass may benefit [224] • Avoid certain drugs if possible: β-blockers, anticholinergics including certain antidepressants, theophylline, calcium antagonists, nitrates

anxiety between those with positive and negative pH profiles [180]. However, the data that white wine (vs red wine) induces reflux is reasonably robust [181, 182]. There are several mechanisms identified, including reduced LES pressure [182], disturbed esophageal clearance due to increased simultaneous contractions and failed peristalsis [183, 184]. The most recently identified mechanism is the occurrence of repeated reflux events into the esophagus when pH is still acidic from a previous reflux episode, the so-called “re-reflux” phenomenon [185]. Although caffeine itself is thought to be associated with reflux, one study has proposed that it is something in coffee other than caffeine that is responsible [186]. Smoking is also often implicated (Box 2.1) but results concerning its role are controversial. One 24-hour pH study has shown an association with smoking [186] while another has not [187]. Vigorous exercise has also been implicated as exacerbating reflux, with emphasis on running [188–193], but with evidence also for weightlifting and cycling [189, 193]. Thus, there is some rationale for “mother ’s advice” not to exercise right after eating. In one study ranitidine 300 mg, given one hour before running, reduced esophageal acid exposure [192]. While there is some evidence that elevating the head of the bed is beneficial, not all investigators agree as the effective31

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ness has been studied using esophageal acid exposure (which is improved but not normalized) and not symptoms as an outcome [194]. Lastly, the effect of posture is interesting, as more acid reflux seems to occur in the right lateral position. Thus the left lateral position is recommended for sleeping [195–197]. Meining and Classen reviewed the efficacy of lifestyle modifications as a treatment for GERD in detail and determined that for many of the recommendations, the data are conflicting, weak and, at best, equivocally supportive [198]. A recent systematic review investigating the effect of lifestyle modifications on GERD found that most were not evidence based and had little to recommend their routine use [199]. In summary, these data do not allow one to recommend lifestyle modifications as a therapy for GERD, although some of the modifications are known to positively affect health in other ways (smoking cessation, weight loss, etc.) and can be recommended on that basis alone.

Placebo response rates Because healing of moderate to severe esophagitis with placebo therapy occurs in about 28% of patients [13, 228], the use of placebo controls has been important, especially for the less effective drugs, such as H2-RAs and prokinetics. Additionally, the symptomatic placebo response rate ranges from 37–64%, further underscoring the need for placebo controls in less effective therapies for GERD [229]. For PPIs, the therapeutic gain is so large that placebo-controlled trials are less necessary, although they remain useful [13].

Antacids and alginate A small randomized placebo-controlled trial of Maalox TC at a full dose of 15 ml seven times daily for four weeks in 32 GERD patients showed no significant symptom relief [230]. Other trials have reported marginal if any benefit of antacids and alginates over placebo, and antacids do not heal esophagitis [231–233]. A1d However, a recent metaanalysis concluded that compared with the placebo response the relative benefit increase was up to 60% with alginate/antacid combinations, and 11% with antacids [229]. In an uncontrolled study of patients with grade I to III esophagitis healed with either an H2-RA or omeprazole, patients were given alginate for symptomatic maintenance treatment [234]. At six months, 76% were in remission. Those with more severe baseline esophagitis relapsed more frequently. In a randomized controlled trial, sodium alginate 10 ml four times daily was slightly more effective than cisapride 5 mg four times daily for reducing both symptoms measured on a visual analog scale (0–100) (alginate

32

29 ± 22, cisapride 35 ± 25, p = 0.01) and the number of reflux episodes in a four-week period (alginate 2 ± 2, cisapride 3±4, p = 0.001) [235]. Conservative symptomatic therapy with alginate may be useful in some patients. A1d Collings et al. [236] recently demonstrated that a calcium carbonate gum decreased heartburn and intraesophageal acidity more than chewable antacids, with effects that lasted for a couple of hours. This observation suggests that such a gum may be useful for intermittent therapy, possibly because of an effect on salivation. In summary, there are sufficient data supporting a recommendation for antacids as a short-term treatment for symptomatic heartburn; alginate/antacid combinations appear to be superior to antacid use alone.

Prokinetic drugs In a randomized, placebo-controlled trial, metoclopramide and domperidone did not improve esophageal motility, duration of acid exposure or esophageal clearance, although both agents significantly increased LES pressure [237]. Cisapride is the only prokinetic drug that increases both esophageal clearance and enhances LES tone [238, 239]. However, one study provided evidence that cisapride increased acid reflux in comparison with omeprazole and famotidine [240]. Placebo-controlled trials show marginal benefit for cisapride in healing esophagitis and improving symptoms [239, 241–243]. A1d For mild grades of esophagitis, cisapride has been demonstrated to be as effective as H2-RA for healing and symptom relief with comparable tolerability [243–248]. However, this drug requires prolonged use for up to 12 weeks before clinical benefit is seen [242, 243, 245, 247, 249–251]. In one randomized trial in patients with milder GERD, omeprazole 10 or 20 mg daily was significantly more effective than cisapride 10 mg four times daily for relief of heartburn, regurgitation and epigastric pain [104]. This and other studies suggest that for symptomatic GERD, the degree of acid suppression is a more important determinant of symptom relief than prokinetic activity. A1d In healing grades I and II esophagitis, adding cisapride to omeprazole did not significantly increase efficacy over omeprazole alone [252]. In another study of healing grades II and III esophagitis, cisapride 20 mg twice daily added to pantoprazole 40 mg once daily did not improve healing over pantoprazole alone [253]. Thus, these two studies provide strong evidence that the addition of cisapride does not add any clinical benefit to treating with PPIs alone. A1d Cisapride has demonstrated only modest benefit for maintenance therapy for mild esophagitis [251, 252, 254, 255]. However, in patients with more severe erosive esophagitis initially healed with antisecretory therapy, cis-

CHAPTER 2

apride was not effective for maintenance treatment [243, 245, 256, 257] and was not more effective than placebo [258]. A1d The recent Cochrane meta-analysis concluded that there was a paucity of evidence on prokinetic therapy, with no substantive evidence that it is superior to placebo [259]. Cisapride has also been associated with the development of serious cardiac arrhythmias including torsades de pointes, when used with other drugs that inhibit cytochrome P450 3A4. These include fluconazole, itraconazole, ketoconazole, erythromycin, clarithromycin, ritonavir, indinavir, nefazodone, tricyclic antidepressants and certain tetracyclic antidepressants, certain antipsychotics, astemizole, terfenadine, and class IA and III anti-arrhythmics [260]. Thus, cisapride is not recommended for the treatment of GERD because its potential for producing significant adverse events is greater than that for other more effective agents, and in many countries the drug has now been withdrawn. In summary, there are insufficient data to recommend the use of cisapride in the treatment of GERD.

Sucralfate in gastroesophageal reflux disease For grade I–III GERD, there have been four small, randomized trials of sucralfate 1 g four times daily compared with standard dose H2-RA, none of which demonstrated any significant differences with respect to symptom resolution and healing [261–264]. However, none of these studies showed very large benefits from either intervention, with low rates of heartburn relief (34–62%) and healing (31–64%). Combining sucralfate and cimetidine was not better than monotherapy with either drug [265, 266]. The meta-analysis of randomized trials for grade II–IV esophagitis performed by Chiba et al. yielded a pooled value for healing of 39.2% for sucralfate compared with 28% for placebo [13]. However, the 95% CI was wide (3.6 to 74.8%). A1c In a six-month study of grade I–II GERD, sucralfate was more effective than placebo for preventing relapse (sucralfate 31%, placebo 65%; ARR 34%, NNT 3, p < 0.001) [267]. A1d

It is interesting that sucralfate, which does not lower acid output, reduce esophageal acid exposure or improve esophageal transit time [268] has any efficacy given our understanding of the pathophysiology of this condition. The adverse effect of constipation, the need for four times daily dosing and the modest observed benefit make sucralfate a less than optimal GERD treatment choice for most patients. In summary, there are insufficient data to support a recommendation for the use of sucralfate in the treatment of GERD.

Gastroesophageal reflux disease

H2-receptor antagonists H2-RAs are not optimally effective in the treatment of GERD but still maintain a role in symptomatic therapy and are discussed here somewhat briefly.

Intermittent/on-demand therapy for heartburn relief Acid suppressive therapy with H2-RAs has been the mainstay of treatment for acid-related disorders and in many countries these agents are available for over-the-counter (OTC) use [269]. This availability permits intermittent, on demand use by the patient. A blinded crossover trial of famotidine 5, 10 and 20 mg versus placebo showed that all famotidine doses were more effective than placebo for the prevention of meal-induced heartburn and other dyspeptic symptoms [270]. This study established that heartburn severity peaked 1–2 hours after a meal. Thus, a small dose of H2-RA taken before eating is useful to reduce GERD symptoms induced by meals. A unique formulation of a readily dissolving famotidine wafer (20 mg) was compared with standard dose (150 mg) ranitidine [271]. With both treatments, about half the patients had some symptom relief within three hours. A similar randomized trial found trivial but statistically significant differences between ranitidine and famotidine for time to adequate symptom relief (ranitidine 15 minutes, famotidine 18.5 minutes, p = 0.005) and for the proportion of patients with symptom relief at one hour (ranitidine 92%, famotidine 84%; p = 0.02) [272]. A recent meta-analysis of OTC medications determined from ten trials, yielded a relative benefit increase of up to 41% with H2-RAs compared to placebo [229]. Thus, for mild reflux symptoms, use of H2-RA on an as needed basis remains a useful therapy for GERD.

High dose H2-receptor antagonists While standard doses of H2-RAs heal more severe, grade II to IV esophagitis in about 52% of patients [13], higher doses of H2-RA (150–300 mg four times daily) are more effective, healing 74–80% of patients in 12 weeks, under conditions in which the healing rate with placebo is 40–58% [273, 274]. Silver et al. [275] compared regimens of ranitidine 300 mg twice daily and 150 mg four times daily for treatment of erosive esophagitis. At 12 weeks, the healing proportion observed for the four times daily regimen was 77% and for the twice daily regimen, 66% (absolute risk reduction (ARR) 11%, number needed to treat (NNT) 9). Ranitidine 150 mg four times daily was superior to standard dose (150 mg twice daily) ranitidine or cimetidine (800 mg twice daily) in patients with erosive esophagitis [276]. In another randomized trial in patients with erosive esophagitis [277], with ranitidine 150 mg twice daily the proportion of patients

33

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healed was 54% at eight weeks compared with 75% with 300 mg four times daily (ARR 21%, NNT 5). A1d Famotidine is pharmacologically more potent than ranitidine and a large dose of 40 mg twice daily was superior to standard dose 20 mg twice daily or ranitidine 150 mg twice daily in patients with erosive or worse esophagitis [278]. A1d These data suggest that standard dose H2-RAs can be effective in GERD symptom relief, but higher doses are necessary for healing and maintenance of healing of esophagitis. More complete data on oesophagitis healing with H2-RAs is found in the recently updated Cochrane Review [259], where there was a statistically significant benefit of H2-RAs compared to placebo. In summary, these data indicate that H2-RAs have a limited but measurable effect in treating GERD, and symptoms respond better than healing to treatment.

Erosive gastroesophageal reflux disease Meta-analysis of healing and symptom relief with proton-pump inhibitors and H2-receptor antagonists An early meta-analysis of randomized trials of patients with more severe esophagitis (grade II in 61.8%, grade III in 31.7% and grade IV in 6.5%) established the clinical efficacy of PPIs [13]. Subsequent published studies support the conclusions derived from this meta-analysis [259, 279– 295]. A1d

In the meta-analysis [13], the rate of healing, expressed as “percent healed per week”, was significantly superior with PPI therapy compared with H2-RA, particularly early in the course of treatment (weekly healing rate in first two weeks: PPI 32%, H2-RA 15%). The rate of healing slowed with increasing duration of treatment as fewer patients remained unhealed, but PPI remained superior to H2-RA. The overall healing proportions during 12 weeks, using pooled results irrespective of dose and duration were: PPI 84% (95% CI: 79 to 88), H2-RA 52% (95% CI: 47 to 57), sucralfate 39% (95% CI: 4 to 75) and placebo 28% (95% CI: 19 to 37). These data were used to plot rate of healing against time on a “healing time curve” (Figure 2.2). By the end of the second week, PPI had healed 63.4 ± 6.6% of patients, while H2-RA required 12 weeks to achieve healing in a similar proportion of patients (60.2 ± 5.9%). Linear regression analysis of individual study results showed that PPI heal at an overall rate of 11.7% per week (95% CI: 10.7 to 12.6), twice as rapidly as H2-RA (5.9% per week, 95% CI: 5.5 to 6.3) and four times more rapidly than placebo (2.9, 95% CI: 2.4 to 3.4). Heartburn was present in all but 3.8% (95% CI: 2.1 to 5.5) of patients at baseline. Overall, heartburn relief was seen in 77.4 ± 10.4% of patients treated with PPI and in 47.6 ± 15.5% treated with H2-RA. Data for heartburn relief were plotted against time to create a “symptom relief time curve” (Figure 2.3). Linear regression analysis of the data yielded an overall heartburn relief rate of 11.5% per week

80

(2)

(3)

(26)

% Total healed

80 (27)

(4)

(22)

60

(25) (25)

(23)

40

(2)

20

(5) *

(8) *

(5) *

(9) *

(12)

60 (13) (10)

40 (10) 20

0

0

(3)

1−2

3−4

6−8

Time in weeks

2

4

6

8

12

Time in weeks Figure 2.2 Healing-time curve expressed as the mean total healing for each drug class per evaluation time in weeks. By week 4, PPIs (proton pump inhibitors) heal more patients than any other drug class, even after a much longer duration of treatment (12 weeks), implying a substantial therapeutic gain despite the fact that all drug classes achieve higher healing with longer durations of therapy. The number of studies is shown in parentheses. •: PPI; +: H2-RA, *: placebo. Reproduced with permission from Chiba N et al. Gastroenterology 1997; 112: 1798–1810 [13].

34

(17) % Total heartburn free

100

Figure 2.3 Symptom relief-time curve expressed as the mean total heartburn relief for each drug class corrected for patients free of heartburn at baseline at 1–2, 3–4, and 6–8 weeks. By week 2, more patients treated with PPIs (proton pump inhibitors) are asymptomatic compared with H2-RA (H2-receptor antagonists) even after a much longer duration of treatment (eight weeks), implying a substantial therapeutic gain despite the fact that both drug classes achieve greater symptom relief with longer durations of treatment. The number of studies is shown in parentheses. ■: PPI; x: H2-RA. Reproduced with permission from Chiba N et al. Gastroenterology 1997; 112: 1798–1810 [13].

CHAPTER 2

80

60

74·2% mild/moderate heartburn

{

50%

57·4%

{

{

60·4%

{

66·5%

40

4

6

8

{

% Symptomatic patients on H2-RA

100

20

0 Baseline

2

Time in weeks

100

80 64·3% 60 mild/mod heartburn

{ 40 30·4%

{ 18·4%

20

{

11·1%

{

4%

{

% Symptomatic patients on omeprazole

Figure 2.4 Shift in heartburn relief with H2-RAs (H2 receptor antagonists). From studies using a symptom scale of none, mild, moderate, or severe, the shift in symptom severity with duration of treatment can be observed. With H2-RAs, although there is an increase in the number of patients completely heartburn free, at the end of the study, more than half of the patients still have mild to moderate symptoms: none ( ); mild ( ); moderate ( ); severe ( ). Reproduced with permission from Chiba N et al. Gastroenterology 1997; 112: 1798–1810 [13].

0 Baseline

2

4

6

8

Time in weeks Figure 2.5 Shift in heartburn relief with PPIs. PPIs (omeprazole)-treated patients have a dramatic shift in the number of patients completely symptom free, particularly early in-treatment, and at the end of the study, very few patients have any residual heartburn in contrast to patients treated with H2-RAs: none ( ); mild ( ); moderate ( ); severe ( ). Reproduced with permission from Chiba N et al. Gastroenterology 1997; 112: 1798–1810 [13].

for PPI (95% CI: 9.9 to 13.0) and 6.4% per week for H2-RA (95% CI: 5.4 to 7.4). Some studies measured heartburn in categories of none, mild, moderate or severe and reported the shift in heartburn relief with treatment (Figures 2.4 and 2.5). The proportion of patients with residual mild to moderate symptoms after eight weeks of therapy was 11.1% for PPI and 57.4% for H2-RAs.

Gastroesophageal reflux disease

This meta-analysis provided evidence that PPI are significantly better than H2-RA for both healing esophagitis and relieving symptoms in patients with moderately severe esophagitis. There was also evidence in one RCT that PPI therapy is effective for healing persistent grade II–IV esophagitis after treatment failure with 12 weeks standard dose H2-RA [296]. Ald Other more recent Cochrane meta-analyses have demonstrated similar findings, with PPIs being superior to H2-RAs in healing and maintenance of healing of esophagitis [259, 297]. These data support a recommendation for the use of PPIs rather than H2-RAs for the healing and maintenance of healing of esophagitis, as well as for heartburn relief.

Differences in efficacy between proton pump inhibitors There are now five proton-pump inhibitors available in North America. These are omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole. For symptom relief, esomeprazole has been shown to be more rapidly effective than omeprazole [32, 290], lansoprazole [284, 298] and pantoprazole [299]. In other studies, lansoprazole was more rapidly effective than omeprazole [33] and pantoprazole non-inferior to esomeprazole [300]. However, differences in symptom relief were no longer apparent at the end of these studies [279, 287, 301, 302]. In another study, omeprazole and pantoprazole were found to be equivalent with each other but not with lansoprazole regarding rapidity of symptom relief [303]. Similar results were found in a comparison of rabeprazole and omeprazole [294]. Low, half-doses of PPIs compared with standard doses were not found to be as effective for healing esophagitis or for symptom relief [146, 279]. However, for maintenance therapy some data suggest that low dose PPIs are as effective as standard doses [37, 304, 305]. While there were small differences between overall study results, the data from these studies were insufficient to establish the superiority of any one drug over all others [306]. Vakil and Fennerty recently carried out a careful systematic review of randomized controlled trials that directly compared PPIs to determine whether there is a difference in clinical outcomes between any of these agents [306]. They restricted this review to more recent (1998–2002), better quality trials. They found similar healing rates for the following comparisons: • lansoprazole 30 mg daily compared with omeprazole 20 mg [301] or 40 mg [280], or pantoprazole 40 mg daily [291] • pantoprazole 40 mg [307] or rabeprazole 20 mg [281, 289] compared with omeprazole 20 mg daily A1c They found that for esophagitis healing, esomeprazole was superior to omeprazole and lansoprazole [32, 284, 290]. Earlier randomized trials comparing two different 35

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PPIs (lansoprazole, omeprazole, pantoprazole and rabeprazole) had also failed to show a difference in healing rates with drugs used at standard recommended doses [27, 31, 279, 280, 287, 301, 307, 308]. A1d Two other meta-analyses also have shown that esomeprazole was superior to omeprazole and that other PPIs did not produce higher healing rates than omeprazole [309– 311]. A1c Another review concluded that lansoprazole, pantoprazole and rabeprazole were comparable with omeprazole in terms of heartburn control, healing rates and relapse rates [312]. Systematic reviews of data from randomized trials performed up to 2005 that compared esomeprazole to other PPIs showed that esomeprazole was more effective than omeprazole, lansoprazole and pantoprazole for healing esophagitis at four and eight weeks, but there is still no direct comparative trial of esomeprazole against rabeprazole [311, 313]. Esomeprazole 40 mg daily was more effective for healing the more severe LA grades C and D esophagitis in randomized trials in which it was compared with omeprazole 20 mg daily [32, 290, 313], lansoprazole 30 mg [284, 298, 313] or pantoprazole [299, 313, 314]. A1d One randomized trial that included only 284 patients but was otherwise similar in design to the trial that included 5241 patients showed no difference between esomeprazole 40 mg and lansoprazole 30 mg for healing of erosive (or more severe) esophagitis in four or eight weeks; the smaller trial may have lacked statistical power [285]. A1c Subsequently, another study showed esomeprazole superior to pantoprazole [314]. Esomeprazole is the first PPI shown to be more effective than any other PPI; all other direct comparisons have shown that healing rates are essentially the same for all agents in this class [285]. However, in elderly patients over age 65 there may be some differences [315]. In a relatively small randomized trial, Pilotto and colleagues compared standard dose omeprazole, pantoprazole, rabeprazole and lansoprazole for healing of esophagitis using the outdated Savary-Miller classification [315]. They determined that at eight weeks, pantoprazole and rabeprazole were significantly more effective than omeprazole for healing esophagitis and were also more effective than omeprazole or lansoprazole for relieving symptoms. The authors were unable to provide an adequate explanation for apparent differences in response in the elderly population [315]. Esomeprazole, the (S)-isomer of omeprazole, produces potent acid suppression as a result of increased systemic exposure and less inter-individual variability in response to it. Hatlebakk [316] reviewed available data and concluded that esomeprazole 40 mg daily was significantly more effective at controlling gastric acidity than lansoprazole 30 mg daily, pantoprazole 40 mg daily and rabeprazole 20 mg daily in a mixed population of healthy volunteers and patients with GERD. Comparable results were also reported in patients with GERD symptoms [317]. Similar 36

results for greater potency of esomeprazole compared to pantoprazole have been reported [318–321]. Esomeprazole 20 mg daily was also significantly more effective than lansoprazole 15 mg daily. Another study reviewing half healing doses concluded that esomeprazole was significantly more effective than rabeprazole, lansoprazole or pantoprazole for control of intragastric acid [322]. Thus, the reports of greater clinical efficacy are consistent with the greater pharmacological potency of this drug. A study of the Food and Drug Administration database reported very few drug interactions for omeprazole, lansoprazole and pantoprazole [323]. Of the rare interactions, vitamin K antagonist reactions were most common, but even these were seen in only 0.09–0.11 per million packages prescribed. This report concluded that the safety of the drugs was likely to be a class effect, with no significant differences among the PPIs. In summary, these data indicate that there are statistically significant differences in potency and healing rates observed with the various proton pump inhibitors, with esomeprazole demonstrating the highest healing rates. However, these data do not indicate that the differences in healing or symptom response rates are sufficiently large to conclude that one agent should be used in preference to another.

Is there a rationale for higher dose proton pump inhibitor therapy? The standard doses of PPI are very effective for healing most cases of esophagitis, and it is clear that there is a correlation between the degree of acid suppression and healing [174]. In clinical practice, patients with persistent or recurrent symptoms are often told to double their dose of PPI, typically to take the doses on a twice daily regimen. This clinical recommendation was based on the 9–12 hour physiological effect these compounds have on gastric acid secretion; the pharmacological data demonstrated that a standard dose taken bid was more effective at prolonging acid control than a double dose taken once daily [324]. Patients with complicated or atypical GERD were randomly assigned to receive lansoprazole or pantoprazole once daily [325]. Esophageal acid exposure was normalized in all lansoprazole patients (in 35% of cases with double dose), whereas 25% of the pantoprazole treated patients did not have lowered or normalized esophageal acid exposure, even with the dose doubled (p = 0.008). A study in patients with stage II or III esophagitis randomized to pantoprazole 40 mg or 80 mg daily healing was observed in 78% and 72% of subjects at four weeks [282]. These data suggest that increasing the dose of pantoprazole beyond the standard dose is not likely to be of any benefit. Klinkenberg-Knol et al. have followed a cohort of GERD patients for many years and reported that doubling the

dose of omeprazole to 40 mg daily was effective to treat relapses [326]. A longer term report followed 230 patients for up to 11 years on continuous therapy [327]. Of those followed, a third each had grade II, III and IV disease. It was estimated that there was only one relapse for every nine years of treatment and the median maintenance dose was 20 mg daily. Dose titration (range 20 mg every second day to 120 mg once daily) allowed most patients to remain in remission. Another study showed that titrating the dose of omeprazole to 40–60 mg daily was as effective for maintenance of remission as anti-reflux surgery [328]. B4 In a randomized trial in which patients with erosive esophagitis were randomized to receive rabeprazole 20 mg daily or omeprazole 40 mg daily in for 4–8 weeks, there were no significant differences in the rates of symptom relief or healing [294]. A1d Further lack of support for using higher than normal doses of PPIs to treat GERD come from two recent metaanalyses of placebo controlled trials of standard and high doses of PPIs to treat laryngeal symptoms of GERD, providing no evidence for efficacy of these therapies for symptomatic improvement or resolution of laryngo-pharyngeal symptoms [329, 330]. There is also concern about having patients on multiple daily doses of PPIs, a practice that increases cost. Inadomi et al. [331] identified and recruited such patients through the use of pharmacy records of PPI prescriptions. Eligible subjects were stepped-down to single dose PPI (lansoprazole 30 mg or omeprazole 20 mg daily), and 80% did not report recurrent symptoms of heartburn or acid regurgitation. These authors concluded that “this intervention can decrease management costs without adversely affecting quality of life” [331]. B4 Additionally, Lee et al. performed a systematic review that also confirmed the over utilisation of both increased and standard dose PPIs in clinical practice [332]. In summary, there are insufficient data to support a recommendation for routinely using PPI doses higher than standard doses for healing esophagitis, treating symptomatic GERD or atypical symptoms of GERD, although higher doses may be effective in preventing relapse that occurs at standard doses of PPIs. Higher doses are appropriate in only a minority of patients.

Maintenance therapy for patients with documented healed esophagitis For mild forms of esophagitis, as seen at a community level, 46% of patients will heal spontaneously [334]. For moderately severe GERD, healing and symptom relief are more readily obtained with PPI therapy. However, within 6–12 months, irrespective of the initial healing agent, relapses are reported in 36–82% of patients in the absence of maintenance therapy [335–338]. When maintenance therapy is either not commenced after an initial course of

Proportion of patients (%)

CHAPTER 2

Gastroesophageal reflux disease

, Ome 20 mg od; , Ome 10 mg od; , Ran 150 mg bid; , Ome 20 mg weekends; , Placebo. 100 80 60

82·4% 71·9%

40

52·3% 42·7%

20 10·6%

0 0

30

60

90

120

150

180

Days Figure 2.6 Actuarial life-table analysis. Estimated proportion of patients in endoscopic remission at the end of the 6-month follow up period with maintenance treatment. Reproduced with permission from Carlsson et al. Aliment Pharmacol Ther 1997; 11: 473–482 [333].

therapy, or is stopped, symptoms often recur within a day, and erosive esophagitis can recur in many patients within 10 days [339] to one month [340]. Thus, maintenance therapy is required in most patients with esophagitis in order to maintain healing and symptom relief. However, a recent systematic review provided evidence that despite continuous therapy with PPI, 28% of patients suffer a relapse of esophagitis within six months [338]. A meta-analysis of the rate of relapse of erosive esophagitis reported in five omeprazole trials that included 1154 patients in whom erosive GERD was initially healed by omeprazole 20–40 mg was carried out by Carlsson et al. [341]. Figure 2.6 shows the effects of various regimens. Omeprazole 20 mg daily, which maintained 82.4% of patients in remission for six months, was significantly better than omeprazole 10 mg daily (p = 0.04). Both of these regimens were significantly better than ranitidine 150 mg twice daily and omeprazole 20 mg on weekends. PPI therapy taken on a regimen of three times in a week is less effective than daily dosing [342, 343]. Two trials have assessed maintenance over 12 months. Omeprazole 20 mg daily was superior to ranitidine 150 mg twice daily (omeprazole 80.2%, ranitidine 39.4%; ARR 40.8%, NNT 2). Ala The proportions of patients with asymptomatic endoscopic esophagitis relapse were: omeprazole 20 mg 4.5%, omeprazole 10 mg 12.5%, and ranitidine 14.6%. Regression analysis identified four risk factors for recurrence: pretreatment severity of esophagitis, younger age, non-smoking status and moderate to severe reflux pre-entry. A previous systematic review of continuous maintenance therapy [344] in patients with initial grades II–IV esophagitis was updated in the first and second editions of this book and readers are referred there for details [345, 346]. There are methodological issues in pooling these results. Not all studies provided precise numbers of patients in remission/relapse, and data were analysed on either an intention to treat basis or using data from all the evaluable patients in life-table analysis. 37

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Most trials were of only six months’ duration. The esomeprazole studies used the LA classification to grade esophagitis. LA grade A is not directly comparable to either the Hetzel-Dent or Savary-Miller grade I classifications. However, given these shortcomings, 12-month placebo relapse rates ranged from 71 to 91% [346], H2-blockers were not significantly more effective with relapse rates between 51 and 88% [346]. The data supported the concept that the greater degree of acid suppression resulted in better remission rates. PPIs resulted in the highest remission rate, particularly when the dose given was the full healing dose for omeprazole, lansoprazole, pantoprazole, rabeprazole and esomeprazole [346]. These data were also confirmed in a more recent Cochrane Review [297]. PPIs were rarely compared directly, but in one study, lansoprazole and omeprazole were comparable [347]. In trials comparing half doses, esomeprazole 20 mg was more effective than lansoprazole 15 mg once daily [348, 349]. With more severe LA grades of esophagitis, esomeprazole treatment provided a significantly longer time to relapse than was observed in the lansoprazole treated patients [348]. At six months, pantoprazole 20 mg and esomeprazole 20 mg were comparable [350]. Using half doses of these PPIs was less effective for maintenance therapy than full healing doses [346]. In the Cochrane Review of placebo-controlled trials, the observed relative risk of relapse was 0.46 for half doses of PPIs, compared to only 0.26 for full dose PPI therapy [297]. One trial [37] suggested that esomeprazole 20 mg was as effective as 40 mg daily. Another suggested that rabeprazole 10 mg was as effective as 20 mg daily [351], although this observation was not confirmed in two other similar trials [352, 353]. Studies looking specifically at patients aged 65 years and over have not found different esophagitis healing rates [354, 355]. There are no data indicating that the elderly respond any differently from younger patients with esophagitis. There are limited data from maintenance studies of greater duration than one year. An observational maintenance study with pantoprazole 40 mg once daily in 157 patients with healed stage II or III reflux esophagitis (Savary-Miller classification) showed endoscopic remission in 87% and 76% of patients after one and two years [356]. B4 Another five-year follow-up study in patients with both peptic ulcer and reflux esophagitis found estimated rates of remission on maintenance treatment with pantoprazole (n = 115) of 82% at one year, 75% at two years, 72% at three years, 70% at four years and 68% at five years [357]. There have been two randomized trials of five years’ duration. In the first, patients with initially healed erosive or worse esophagitis were randomized to receive rabeprazole 20 mg once daily, rabeprazole 10 mg once daily or omeprazole 20 mg once daily [351]. Of the initial 243 38

patients, 123 completed the five-year study. Relapse rates were 11.5%, 9.8% and 13.3%, respectively. In the second study, patients were randomized to rabeprazole 20 mg, 10 mg or placebo with five-year relapse rates of 11%, 23% and 63% respectively [358]. All treatments were safe and well tolerated. These data provide evidence that remission can be effectively maintained over long time periods. The problem of healing the more severe grades of esophagitis is well known. The proportion of patients who experience acute healing for grade II esophagitis ranges from 76–100%, for grade III from 63–95% and for grade IV from 56–75% [344]. Grade IV disease relapses more frequently than grade II and III disease [340, 359]. In summary, in clinical practice, it is suggested that the dose of PPI can be titrated upwards to maintain healing in most patients [326] or alternatively, the most potent PPI be used. A1d C5 In some patients, lower doses of PPIs may be effective for maintenance therapy in patients with healed esophagitis. B4

On-demand therapy as a strategy for maintenance of healing of mild/moderate esophagitis Lansoprazole (15 mg daily and 30 mg on alternate days) was studied for maintenance of endoscopic healing and symptom relief over a six-month period after healing of Savary-Miller grades I–III reflux esophagitis [360]. After six months, recurrence of esophagitis was observed in 12% of the 15 mg once daily group and in 19% of the 30 mg alternate day group. This difference was not statistically significant. However, 12.1% of patients who received 15 mg daily and 28.6% of those who received alternate day higher dose therapy (p = 0.007) had heartburn. A1d In another study, patients with esophagitis were initially treated until symptoms had resolved. Thereafter, they took “on-demand” lansoprazole (30 mg) or omeprazole (20 mg) for six months, only when reflux symptoms relapsed [361]. There were no differences observed in the frequency of reflux symptoms or in the number of doses taken by subjects in the lansoprazole (0.73 doses/day) and omeprazole (0.71 doses/day) groups. A1d In a study population of mild LA grades A and B esophagitis, esomeprazole 40 mg was more effective than omeprazole 20 mg once daily, on-demand for symptom relief and fewer tablets were consumed [362]. Another study examined patients with more severe LA grades A–D initially healed with esomeprazole 40 mg daily [363]. On continuous esomeprazole 20 mg once daily, 81% remained in remission at six months compared to 58% with ondemand treatment (ARR 23%, NNT = 4, p < 0.0001). Heartburn was significantly more common in the ondemand group, and continuous therapy more effectively maintained healing of erosive esophagitis [363].

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There are relatively few studies that have examined this strategy in patients with more severe initial erosive esophagitis compared to patients with mild esophagitis, uninvestigated heartburn or NERD. An important factor reducing efficacy of an on-demand strategy is obesity [364]. In a recent systematic review on the use of on-demand therapy, Pace and colleagues demonstrated that “ondemand therapy”, while effective for the treatment of GERD symptoms, was less effective than continuous PPI maintenance therapy for maintenance of healing of esophagitis [365]. In summary, these data do not support a recommendation for “on-demand” therapy for patients with documented erosive esophagitis, since relapse is more common with this strategy, patients must experience recurrent symptoms before treatment is taken, and these patients are left with unhealed lesions. C5

Cost-effectiveness of maintenance therapy PPIs are the most effective treatments available to treat GERD. PPIs are in general more costly than H2-RAs, although the availability of multiple generic forms and OTC formulations of PPIs has markedly narrowed this disparity in cost. Therefore, cost-effectiveness analyses can be important in decision making regarding treatment options. Studies differ substantially with respect to methods, assumptions, interventions and outcomes being evaluated, the inclusiveness of cost items and the jurisdiction to which the analyses are applied. No perfect cost-effectiveness study exists, and new advances in therapy and changes in cost over time tend to render the conclusions out of date rather quickly. However, despite these limitations, these modelling studies are useful to put the role of existing interventions into perspective. Many studies have indicated that PPIs are likely to be more cost-effective than H2-RAs in the treatment of patients with GERD, despite their higher initial acquisition costs [366–375].Cost-effectivenessdatafromCanada[376],Sweden [377] and the USA [378, 379] arrived at similar conclusions. Maintenance PPI over a one-year period is consistently the most effective, but also the most costly intervention [376–379]. Intermittent omeprazole to treat symptomatic relapse was more cost-effective than continuous omeprazole therapy, although there was an increase in the number of symptomatic weeks per year [376]. Maintenance therapy with ranitidine or cisapride was less effective for controlling symptoms, but was of intermediate cost. High dose H2-RA was both more costly and less effective than PPI, with more frequent relapses that ultimately led to PPI maintenance therapy [373]. Harris et al. [378] reported that treatment with continuous PPI becomes more costeffective than H2-RA if patients with active symptoms of GERD experience a 9% decrement in QoL. When consider-

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ing three different PPI maintenance strategies, starting continuous PPI after the second recurrence was least costly and least effective [379]. Continuous PPI started after the first recurrence added only a small increment of cost per recurrence prevented, compared with continuous PPI from the outset, which was ten times more costly [379]. However, for patients with a 22% decrement in QoL, continuous therapy became cost-effective when compared with maintenance after first relapse. All these strategies are modelled for only one year and may not be generalizable to lifelong treatment. Countering the potentially negative effect of acquisition costs is the fact that PPI unit costs have decreased substantially with the availability of multiple generic forms and OTC forms of this class of drugs. More recent work has focused on comparisons between PPIs and various dosings. One paper using a Markov model compared low versus standard dose PPI therapy [380]. The standard dose PPI was found to be the more cost-effective strategy on the strength of the highest number of symptom-free patient-years and the quality adjusted life years gained. However, this study did not include estimates based on data from studies of esomeprazole 20 mg or rabeprazole 10 mg daily, two effective lower dosing regimens that may have altered the results. In another study, esomeprazole was found to be more cost-effective than lansoprazole in the maintenance of healing of erosive esophagitis [381]. In a UK study that compared all the PPIs, generic omeprazole and rabeprazole dominated the other PPIs, i.e. they cost less and resulted in more symptom free days [382]. In summary, these data support a recommendation for the use of PPIs as the most cost-effective for maintance therapy for patients with GERD.

Treatment of non-erosive reflux disease (NERD) NERD or endoscopy-negative reflux disease (ENRD) is defined as GERD in the absence of macroscopic findings at endoscopy. Patients in this category are identified as having GERD, based on characteristic symptoms, occasionally an abnormal ambulatory esophageal pH test, a positive Bernstein test, or a positive symptom index and/or experience improvement with empirical acid suppressive therapy. These are patients with GERD symptoms often without objective abnormalities in other investigations undertaken. One of the first studies in this group of patients was reported by Bate et al. in 1996 [383]. Patients with NERD were randomized in a double blind trial to receive omeprazole 20 mg once daily (n = 98) or placebo (n = 111). At four weeks, omeprazole was more effective than placebo (p < 0.0001) with respect to the proportion of subjects with 39

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freedom from heartburn (omeprazole 57%, placebo 19%), or regurgitation (omeprazole 75%, placebo 47%) and complete relief of symptoms (omeprazole 43%, placebo 14%). A1c Patients in the omeprazole arm used less antacids and time to first heartburn-free day was more rapid with omeprazole. Another randomized trial in 495 patients with NERD compared low dose omeprazole 10 mg or a placebo for six months [163]. Placebo-treated patients were nearly twice as likely to discontinue treatment before the end of six months. Life-table estimates for cumulative remission at six months, were 73% for omeprazole and 48% for placebo (ARR 25%, NNT 4, p = 0.0001). QoL assessments showed a more significant deterioration in the GSRS reflux domain for placebo patients (p < 0.05), but no significant differences were noted in PGWB. Thus, a continuous dose of omeprazole 10 mg daily is effective maintenance therapy for the majority of patients with heartburn but no esophagitis (NERD). However, a larger dose of omeprazole may be required for up to a quarter of patients. A Cochrane Review evaluating short-term treatment in NERD was updated in 2006 [384], and determined that PPIs are more effective than H2-RA therapy, but the magnitude of benefit was smaller than was observed in patients treated empirically. A randomized trial compared omeprazole in doses of 20 mg or 10 mg daily and placebo in 509 patients with NERD in whom heartburn was the predominant complaint [80]. Symptomatic remission of heartburn (no more than one day of mild symptoms in the week prior to the final visit) was significantly more frequent after 2–4 weeks of therapy with omeprazole in either dose, and the standard dose of omeprazole was more effective than the lower dose. Symptom relief occurred in most patients by the end of the second week. With four weeks of treatment the proportion of patients indicating sufficient control of heartburn was 66% and 57% for the standard and low doses of omeprazole and only 31% for the placebo group. A1c The more abnormal the initial pH study, the better the response to a greater degree of acid suppression. There was a significant correlation of response to therapy with acid reflux, age and the presence of a hiatus hernia. No correlation was identified between body mass index and degree of acid exposure, despite the widely held view that being overweight worsens reflux. A randomized trial of four weeks’ duration in NERD patients in the USA [385] found omeprazole 20 mg once daily to be better than omeprazole 10 mg once daily or placebo for increasing the proportion of patients with no heartburn at both day 7 (omeprazole 20 mg 62%, 10 mg 41%, placebo 14%) or day 27 (omeprazole 20 mg 74%, 10 mg 49%, placebo 23%). Omeprazole was also significantly (p = 0.003) more effective than placebo for relief of acid regurgitation, dysphagia, epigastric pain and nausea. A1c 40

Katz et al. [386] reported the results of two randomized, double-blind trials with identical methodology that compared esomeprazole 40 mg once daily or 20 mg once daily with placebo for four weeks in 717 NERD patients. Complete resolution of heartburn was achieved in 65% of patients treated with either esomeprazole dose compared with 40% of placebo patients (ARR = 25%, NNT = 4, p < 0.001). A1a Two studies of lansoprazole in NERD patients have been reported by Richter [387, 388]. The first study [387] compared lansoprazole 15 mg, lansoprazole 30 mg or placebo for eight weeks. Lansoprazole patients reported less daytime and night-time heartburn and antacid usage, compared with placebo patients. The second study [388] found lansoprazole to be more effective than ranitidine 150 mg twice daily or placebo. In this study, lansoprazole 15 mg and 30 mg daily were equally effective. A1c A randomized trial compared pantoprazole 20 mg once daily versus omeprazole 20 mg once daily in patients with very mild grade I reflux esophagitis [389]. While these patients are not strictly a NERD population, grade I is considered by some investigators to be almost normal. The rates of symptom relief and healing were comparable at four and eight weeks. Another trial of pantoprazole 20 mg once daily versus ranitidine 150 mg twice daily in a similar patient group with grades 0–I GERD found pantoprazole to be superior to ranitidine [390]. A1c In a trial with a similar population of grade 0 and I esophagitis, pantoprazole 20 mg was more effective than placebo with lower numbers of patients showing “unwillingness to continue” or numbers of additional antacids taken [391]. In a similar trial, pantoprazole 20 mg and 40 mg were not significantly different and both were more effective than placebo [392]. A randomized trial comparing rabeprazole (10 mg or 20 mg once daily) with placebo in NERD patients with moderately severe symptoms found that rabeprazole, like other PPIs, rapidly and effectively relieved heartburn [393]. Other symptoms such as regurgitation, belching, bloating, early satiety and nausea were also improved. There was no difference in efficacy between the two rabeprazole doses. A six-month on-demand trial with rabeprazole 20 mg once daily was effective for symptom control in 85% of patients, limited PPI consumption to a mean of 0.3 tablets per day and improved HRQoL [394]. A1c Bytzer [395] has performed a comprehensive review of the studies dealing with symptomatic GERD [80, 146, 383, 385, 387, 388, 393, 396–401]. The studies included patients with mild erosive esophagitis as well as patients with NERD. Bytzer noted that the endpoint in many of these studies was that of complete heartburn relief, a result that most patients probably do not aim for in the long term. For example, in the “on-demand” studies, patients took their PPIs once every 2–3 days, suggesting that patients accept relapse of their symptoms before they took on-demand

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medication. Also, the lowest response rates were observed in the studies that evaluated complete symptom relief, compared with those studies in which the endpoint was less rigorous and which permitted continued therapy despite lack of complete symptom relief. In summary, these data support the recommendation for the use of PPIs as being more effective than H2-RAs for the treatment of NERD, but the magnitude of the treatment effect is not as great as that seen in patients with esophagitis [402, 403]. This apparent difference in efficacy may be explained in part by the difficulty of ensuring that patients enrolled in these studies actually have GERD rather than functional heartburn or dyspepsia.

Long-term treatment of non-erosive reflux disease Another approach in endoscopy negative heartburn patients is the use of patient-controlled, on-demand therapy. The first methodologically sound on-demand randomized trial in 424 NERD patients compared omeprazole 20 mg or 10 mg, with placebo [400] for the outcome of time to discontinuation of treatment (due to unwillingness to continue) over a six-month period. With life-table analysis, the remission rates were: omeprazole 20 mg 83% (95% CI: 77% to 89%) omeprazole 10 mg 69% (61% to 77%) and placebo 56% (46% to 64%) (p < 0–01 for all intergroup differences). A1c The mean number of study medications used daily was 0.43–0.47. Treatment failure was associated with more than a doubling of antacid use and deterioration in patient QoL. The results of several “on-demand” trials with esomeprazole have been published. The first of these compared esomeprazole 20 mg once daily with placebo in 342 NERD patients for six months after initial symptom relief with PPI [401]. The proportion of patients who discontinued treatment due to lack of heartburn relief were esomeprazole 14% and placebo 51% (ARR = 37%, NNT = 3, p < 0.0001). A1c Most patients took the study medication for periods of 1–3 consecutive days (esomeprazole) or 4–13 consecutive days (placebo). Use of antacids was more than twofold higher among placebo recipients. In the second study, patients who had achieved complete heartburn resolution after short-term esomeprazole or omeprazole treatment (n = 721) were randomized to esomeprazole 20 mg (n = 282), 40 mg, n = 293) or placebo (n = 146) on-demand (maximum one dose/day) for six months [404]. Treatment was discontinued (due to unwillingness to continue) less often by esomeprazole treated patients (esomeprazole 20 mg 8%, 40 mg 11%, placebo 42% ARR = 34%, 0.31, NNT = 3). A1c Patients took an average of one esomeprazole tablet every three days. In another trial, patients were randomized to either esomeprazole 20 mg on-demand or to lansoprazole 15 mg

Gastroesophageal reflux disease

daily continuously for six months [405]. Those in the esomeprazole 20 mg on-demand arm took a pill only 38% of the time as opposed to 100% of the time with lansoprazole, yet still reported greater willingness to continue taking on-demand therapy, and greater satisfaction [405]. This strategy greatly lowers the cost of treatment and the evidence from this trial indicates that not all PPI are the same with respect to maintenance. In an open study in patients with moderate to severe heartburn but normal endoscopy, rabeprazole at the low dose of 10 mg daily was highly effective, with an 83% complete response rate at four weeks [406]. Responders entered a six-month on-demand phase of rabeprazole 10 mg vs placebo and patients in the PPI arm had significantly lower rates of strategy discontinuation and antacid use [406]. A1d Cost-effectiveness analysis using a Markov model was designed to compare the following three strategies for six months: on-demand esomeprazole 20 mg daily, intermittent four-week acute treatment courses of omeprazole 20 mg daily, and continuous omeprazole 20 mg daily treatment following acute treatment. The expected number of relapses per patient was estimated to be 0.10 for the ondemand esomeprazole strategy, 0.47–0.75 for continuous omeprazole treatment and 0.57–1.12 for the intermittent omeprazole strategy. The on-demand treatment with esomeprazole 20 mg was found to be cost-effective compared with the other strategies [407]. Another study evaluated costs and effectiveness of on-demand maintenance therapy with all available PPIs: omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole. There were no significant differences in outcomes but differences in cost were significant [408]. A meta-analysis has also confirmed the utility of intermittent or “on-demand” therapy for milder forms of GERD. In this study adequate symptom relief and maintenance of QoL was demonstrated for on-demand therapy [365]. In summary, there is evidence that on-demand therapy for maintenance treatment of NERD is clinically effective and cost-effective.

Adverse effects of long-term antisecretory drug use While the short-term and long-term use of PPIs and H2-RAs has been proven to be remarkably safe and effective, the profound alteration on gastric secretory physiology that occurs with PPI use has been postulated potentially to result in deleterious effects. Even if such effects are rare, the widespread and ubiquitous use of these agents over the last 20 years and the expected continued widespread use increases the probability that even rare adverse effects may become commonly encountered clinical issues. The preponderance of data suggests that potent inhibition of parietal cell secretion can adversely impact cobalamin serum levels, although no discrete adverse clinical outcomes have been reported related to B12 deficiency [409]. There is also 41

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concern about the possibility that PPIs raise the risk of community acquired pneumonia [410]. The Canadian Association of Gastroenterology has presented a position statement with the conclusion that an association appears to be present, but this translates into an attributable risk of one case of community acquired pneumonia per 100 years of acid suppressive use [411]. An observed association between prolonged acid suppression with PPIs and an increase in hip fracture [412–414] may not be seen until seven years or more of exposure [415]. A recent matched nested case-control study in patients without major risk factors found no increased risk of hip fracture with PPIs [416]. This result suggests that confounding factors may account for the association found in earlier studies. Additionally, Moayyedi and Cranney critically reviewed the data and found no evidence to support either causation or biological plausibility [417]. Enteric infections, particularly those caused by Clostridium difficile, also appear to be more common in patients taking PPIs, even away from the usual hospital based setting for these infections. The adjusted odds ratio for this infection was nearly three for those taking PPIs in a large population based controlled study [418]. A systematic review of acid suppressive drugs and the risk of enteric infections has confirmed this association, but the authors also warned that this result does not prove causation [419]. In summary, these data suggest that the safety record for antisecretory treatment is substantial and enviable, but there are potential concerns with long-term use. Population based studies indicate an association between PPI use and complications such as community acquired pneumonia, hip fracture and C. difficile infection but causation has not been proven. Despite the apparent rarity of these events, the recommendation to use the lowest, effective dose of antisecretory medicine needed to control symptoms is justified, given the possibility of cause and effect.

Symptomatic gastroesophageal reflux disease: empirical therapy for uninvestigated patients At the primary care level, patients often present with predominant reflux symptoms of heartburn or acid regurgitation with no prior diagnostic studies or trials of therapy. If these patients do not have alarm symptoms, especially if they are under the age of 50 years, there is a considerable degree of agreement that they can be treated empirically with antisecretory therapy without prior endoscopy. With this approach in mind there has been an increase in the number of studies in patients with GERD-like symptoms without any initial investigations, i.e studies in which therapy is studied in uninvestigated patients with the predominant symptom of heartburn. These studies obviously 42

include a mixed group of patients, many of whom do not have esophagitis and some in whom GERD is not the cause of their symptoms. A randomized trial that included 424 patients with a history of proved esophagitis enrolled from general practices in the UK [420] showed that omeprazole 20 mg once daily was more effective for relief of heartburn and regurgitation than ranitidine 150 mg twice daily for four weeks (omeprazole 59%, ranitidine 27%, ARR = 22%, NNT = 5). Ala The prior history of esophagitis limits generalizability of this study to all patients in primary care practices, but the good relief of symptoms regardless of initial symptom severity is noteworthy. In a trial in primary care settings in the USA, 590 patients with moderately severe symptomatic GERD were randomized without endoscopy to receive ranitidine 150 mg twice daily or a placebo [421]. Ranitidine rapidly and significantly improved heartburn severity scores, physician global assessment of the response to treatment, and the SF-36 score for physical functioning, bodily pain and vitality dimensions. Ala Using a heartburn specific questionnaire a significant improvement in all dimensions: physical, heartburn pain, sleep, diet, social functioning and mental health was observed for ranitidine-treated patients. In another trial conducted in the USA, uninvestigated heartburn patients were randomized to receive either ranitidine, lansoprazole or stepped up therapy from ranitidine to lansoprazole or stepped down therapy from lansoprazole to ranitidine [422]. The continuous lansoprazole treatment was more effective than the other strategies in terms of reducing heartburn severity and increasing the number of heartburn-free days, and there appeared to be little rationale to stepping down to ranitidine. A randomized trial [423] of 307 patients with GERD symptoms in Australian primary care settings showed that even a low dose of pantoprazole (20 mg daily) was significantly more effective than ranitidine 300 mg daily for complete control of symptoms at four weeks (40% vs 19%; p < 0.001), eight weeks (55% vs 33%; p < 0.001), six months (71% vs 56%; p = 0007) and twelve months (77% vs 59%; p = 0.001). In the CADET-HR randomized, double blind trial in Canadian primary care settings, 390 patients with reflux predominant symptoms were randomized to receive ranitidine 150 mg twice daily or omeprazole 20 mg daily [424]. Heartburn relief at four weeks was reported by 55% of omeprazole and 27% of ranitidine-treated patients (ARR = 22%, NNT = 5). Ala Greater improvements in GSRS for indigestion, abdominal pain, and reflux (p < 0.05) and in the GASTROQoL health-related QoL scales (p < 0.003) were also observed in omeprazole patients. After four weeks, patients with inadequate symptom relief were stepped up every 4–8 weeks from ranitidine to omeprazole 20 mg once daily or from omeprazole 20 mg once to twice

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daily [424]. “Step up” occurred in 100 patients with ranitidine and 57 with omeprazole. With step-up therapy, by 16 weeks, heartburn relief resulted in 88% of patients who started with omeprazole and in 87% of those who started with ranitidine. Ala In the first eight weeks, omeprazole provided complete heartburn relief in 53% while it took 16 weeks to achieve a similar degree of relief in the group who were treated initially with ranitidine. Thus, starting with omeprazole therapy produced significantly faster symptom relief. Patient responders then had the medications stopped and 50% of patients experienced symptomatic relapse within nine days [424]. Only 10% of patients had no further relapse over a six-month period of follow-up. In a Cochrane Review evaluating short-term treatment in symptomatic, non-endoscoped patients updated in 2006 [384], van Pinxteren et al. identified 15 empiric treatment trials. The relative risk for heartburn remission in placebocontrolled trials was 0.37 for PPI, 0.77 for H2-RAs and 0.86 for prokinetics. In direct comparative trials PPIs were significantly more effective than H2-RAs (seven trials, RR 0.66, 95% CI: 0.60 to 0.73) and prokinetics. Thus, PPIs were superior to H2-RAs in empirical treatment of typical GERD symptoms. Ala In a large, methodologically sound, double-blind, randomized trial in 3034 patients in 360 sites in the USA, patients with symptomatic, uninvestigated GERD symptoms received lansoprazole 30 mg once daily or esomeprazole 40 mg once daily [425] and heartburn assessments were carried out at days 1, 3, 7 and 14. The study setting was unclear and was unlikely to include only primary care practice. No statistically significant difference in heartburn relief was observed [425]. Ala Patients indicated that they were very pleased with their treatment, experienced substantial benefit and would recommend the medication to others. However, nearly 40% of patients still had some degree of day or night heartburn at the end of two weeks. More studies are now available that compare various PPIs. Furthermore, longer term maintenance studies to assess the effectiveness of PPIs are now available [426–430], In a Norwegian study, patients were initially treated with esomeprazole 40 mg for four weeks. They were then randomized to esomeprazole 20 mg daily continuously or ondemand, or to ranitidine 150 mg twice daily for six months [428]. Either esomeprazole strategy gave better symptom relief and better patient satisfaction than was observed with ranitidine, indicating that on-demand therapy is a viable option. In a rabeprazole study 331 uninvestigated heartburnpredominant patients, were treated with rabeprazole 20 mg daily for four weeks [427]. Responders were then randomized to receive either rabeprazole 20 mg continuously daily (COT) or on demand (ODT) for six months. Not surprisingly, the continuous therapy arm experienced a greater mean percentage of heartburn-free days (COT

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90.3% +/− 14.8%, ODT 64.8% +/− 22.3%, p < 0.0001). Ninety-two percent of COT patients and 79% of ODT patients were either “satisfied” or “very satisfied” with treatment. While COT provides better symptom improvement, both strategies were acceptable [427]. An interesting study evaluated a patient’s willingness to pay for complete symptom relief in GERD [431]. The authors found that patients were willing to pay up to US$182 to obtain more complete and faster symptom relief without side effects. Older patients were less willing to pay than younger patients to obtain symptom relief. In summary, these data support a recommendation for the use of empirical antisecretory therapy for patients presenting with symptoms thought to be caused by GERD, without performing confirmatory diagnostic testing.

Economic evaluation in uninvestigated symptomatic heartburn The costs and effectiveness of each drug and of each management strategy need to be evaluated. However, there are many subtle variations between studies that render direct comparisons difficult. Furthermore, decision analyses suffer from the inherent weakness of having to rely on estimates of treatment outcomes. Ofman recently reviewed the cost-effectiveness studies in symptomatic GERD [432]. He concluded that the most cost-effective strategies are PPI based step-down or PPI on-demand strategies [432]. He noted that most decision analyses had been constructed around uninvestigated GERD symptoms. One recent study comparing esomeprazole 20 mg daily or on-demand provided estimates of similar efficacy with either strategy but reduced cost of the on-demand strategy over six months [426]. Similarly, it has been shown that esomeprazole 20 mg daily on-demand is more cost-effective than esomeprazole 20 mg continuously or than ranitidine [429]. In a large trial of 1357 uninvestigated heartburn patients, the esomeprazole 20 mg on-demand strategy was less costly, with comparable efficacy and satisfaction to esomeprazole 40 mg prescribed intermittently by the physician for either two or four weeks [430]. In summary, on-demand therapy requires that a patient becomes symptomatic before self-treating. However, patient satisfaction with this approach is high, and this management strategy is cost-effective and is recommended.

Does symptom improvement predict healing of esophagitis? There is evidence that relief of symptoms by H2-RAs does not reliably predict healing of mucosal damage. Patients with heartburn initially treated in a four-week study with omeprazole or cimetidine [433] were randomized to receive 43

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maintenance therapy with either omeprazole 10 mg once daily or cimetidine 800 mg qhs for 24 weeks [434]. Symptomatic remission, defined as no more than mild heartburn on one out of the seven previous days, was significantly more frequent with omeprazole (omeprazole 60%, cimetidine 24%; ARR 36%%, NNT 3). Erosive esophagitis was seen in only 10% of patients in symptomatic remission on omeprazole compared with 33% on cimetidine. One-third of patients with relapse of erosive esophagitis by endoscopy during maintenance therapy with famotidine 40 mg twice daily were completely asymptomatic [435]. A meta-analysis [333] suggested that if heartburn resolved, only 4.5% of patients treated with omeprazole 20 mg once daily, but 14.6% with ranitidine 150 mg twice daily, experienced asymptomatic relapse of erosive esophagitis at endoscopy. A1c The more recent trials show that significantly fewer esomeprazole-treated patients had persistent esophagitis, despite symptom relief, than is the case for omeprazoletreated patients [32, 290]. In patients with heartburn resolution at four weeks, esophagitis remained unhealed in 14.8% [290] to 16.8% [32] of patients receiving esomeprazole 40 mg daily compared with 23.2% [290] to 26.9% [32] of those receiving omeprazole 20 mg daily. Ala A similar result was seen in a comparison of esomeprazole 40 mg daily and lansoprazole 30 mg daily, with unhealed esophagitis in spite of heartburn resolution in 17.3% and 20.5% of these patients [284]. In the most severe forms of esophagitis, the healing was 11% more frequent for grade C and 17% for grade D disease in esomeprazole-treated patients. It is unclear why, despite effective symptom resolution, many patients still have esophagitis. The most likely explanation in these studies is that when patients were healed at four weeks, they came out of the studies, and the healing and symptom resolution could not be assessed at eight weeks. In all these studies, esophagitis healing was much more frequent at eight weeks than at four weeks. Therefore, if patients been endoscoped at that interval, the proportion of healed patients among those with heartburn resolution would have probably been higher. In summary, these data demonstrate that esophagitis relapse is unusual in patients who remain asymptomatic while being treated with PPIs, but relapse is more common in those without symptoms who are being treated with an H2-RA. Thus, continuous PPI therapy is recommended as maintenance therapy in patients with esophagitis, particularly with more severe esophagitis.

Treatment of esophageal peptic stricture Esophageal peptic stricture, the most severe GERD complication, can be difficult to manage. H2-RA are at best mar44

ginally more effective than a placebo for reducing the need for repeat dilatations [436, 437]. One study found no benefit from ranitidine 300 mg daily compared with placebo [438]. There are three randomized trials comparing standard dose omeprazole 20 mg daily with H2-RA [439–441] and one comparing lansoprazole with high dose ranitidine [442]. In one small study [440], 34 patients with strictures were randomized to receive omeprazole 20 mg once daily, or ranitidine 150 mg or famotidine 20 mg twice daily. After three months, if esophagitis remained unhealed, the dose of medication was doubled and the patient was re-endoscoped at six months. At three months, there was no significant difference between PPI and H2-RA for esophagitis healing or relief of dysphagia, although there was a trend in favor of the PPI. By six months, omeprazole treatment resulted in significantly better healing of esophagitis (omeprazole 100%, H2-RA 53%; ARR 47%, NNT 2; p < 0.01) and relief of dysphagia (omeprazole 94%, H2-RA 40%; ARR 54%, NNT = 2; p < 0.01). A1d Post hoc analysis also showed a trend toward reduction in the proportions of patients requiring dilatations in omeprazole-treated patients (omeprazole 41%, H2-RA 73%; ARR = 32%, NNT = 3, p = 0.07). The number of dilatations required was significantly less for the omeprazole treated patients (11 vs 31 dilatations, mean of 0.6 vs 2.1 sessions per patient, p < 0.01). Costeffectiveness analysis for healing and relief of dysphagia, that included costs of drugs, endoscopy and dilatations, and management of perforations, showed that omeprazole was 40–50% more cost-effective than H2-RA. A second adequately powered trial compared constant doses of omeprazole 20 mg once daily and ranitidine 150 mg twice daily for one year [439]. Endoscopy was done as required and at the end of the study. Repeat dilatation was required less frequently in omeprazole-treated patients (omeprazole 30%, ranitidine 46%; ARR = 16%, NNT = 6). A1c Fewer dilatation sessions were required in omeprazole-treated patients (omeprazole 0.48, ranitidine 1.08; p < 0.01). Omeprazole was also superior with respect to the number of patients without stricture at the end of the study, esophagitis healing and improved heartburn and dysphagia. In a study of 158 patients over six months, lansoprazole 30 mg daily was more effective than ranitidine 300 mg twice daily for relieving dysphagia. There was a trend toward a reduction in the need for repeat dilatations (lansoprazole 30.8%, ranitidine 43.8%; p = 0.09) over 12 months [442]. A1d Omeprazole 20 mg once daily was found to be more effective but more expensive than ranitidine in a cost-utility study [443]. In an observational study 30 of 36 patients with reflux esophagitis and stricture treated with dilatation and omeprazole 20 mg twice daily for 6–8 weeks experienced

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healing of esophagitis and relief of dysphagia [444]. These 30 patients were then randomized to receive omeprazole 20 mg twice daily, lansoprazole 30 mg twice daily or pantoprazole 40 mg twice daily (n = 10 each arm). After four weeks of treatment, significantly more omeprazole-treated patients remained healed, but no difference was seen with respect to the need to repeat dilatation of strictures. This small study may lack power to demonstrate differences between effects of these strategies. A1d In summary, these data lead to the recommendation for the use of PPI vs an H2-RA in those with peptic strictures as a means of reducing recurrence of the stricture or symptomatic dysphagia following dilatation.

Endoscopic treatments Several endoscopic techniques for treating GERD have now been investigated and all demonstrated some early promise [445–452]. However, all of these techniques (injection, radiofrequency ablation, endoscopic stapling and or suturing), were either less effective than hoped, produced more adverse effects than anticipated or were too expensive or complex to be incorporated into clinical practice. All have either been withdrawn from the marketplace or remain as investigational tools. A recently published systematic review details the devices, and preclinical and clinical studies published up to the end of 2006, before this field collapsed from a clinical standpoint [453]. However, there continue to be developments in endoscopic antireflux therapies, and one or more of these devices may be introduced for clinical use in the foreseeable future.

Anti-reflux surgery Medical therapy versus surgical anti-reflux therapy Early randomized trials comparing open anti-reflux surgery (ARS) with medical therapy (H2-receptor antagonists and or prokinetic agents) demonstrated that surgery was more effective than medical therapy in treating patients with esophagitis [454, 455]. However, these studies are no longer relevant, since they did not compare present day medical therapy with PPIs with surgical therapy using laparoscopic techniques. Spechler et al. have provided an update of a cohort of patients from the original study [456]. They were able to account for 97% (239/247) of the original cohort, 79 of whom had died. After a mean of 9–10 years follow-up, of the surviving and measurable patients 92% of the medical treated patients and 62% of the surgically treated patients (p < 0.001) were regularly taking antireflux medications. Patients with Barrett’s esophagus at

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baseline developed esophageal adenocarcinomas at an annual rate of 0.4%, whereas these cancers developed at a lower 0.07% annual rate in patients without Barrett’s. This study indicates that anti-reflux surgery should not be recommended, with the expectation that patients with GERD will no longer need to take antisecretory medications or that the procedure prevents esophageal cancer among those with GERD and Barrett metaplasia. A1c There are few direct comparisons of a PPI versus antireflux surgery. The first was a study by Lundell et al. with five-year follow-up [328]. Three hundred and ten patients were randomized to receive open surgical fundoplication or continuous omeprazole therapy and followed for up to five years. Only 11 of 155 patients randomized to surgery refused the treatment. Omeprazole-treated patients were allowed dose increases to 40–60 mg daily to control symptoms. No significant differences in efficacy were demonstrated and QoL assessments (PGWB and GSRS) improved in both groups. Thus, surgical therapy was demonstrated to be as effective as continuous omeprazole therapy in this trial. Ala However, laparoscopic fundoplication, the technique that is now widely used, was not performed. The seven-year follow up suggested that surgery was more effective than omeprazole but there were specific postfundoplication complaints that remained problematic [457]. A more recent, short-term observational study compared the efficacy of laparoscopic fundoplication and lansoprazole in normalizing abnormal reflux in patients with GERD [458]. After anti-reflux surgery, all 55 patients were heartburn free, and esophageal pH-monitoring 3–6 months after surgery was normal in 85% of patients. Patients treated with lansoprazole were titrated upwards to 90 mg daily and esophageal acid exposure was normalized in 96% of cases. Patients who became heartburn free did not necessarily normalize their esophageal acid exposure. The results suggest that either approach may be reasonable for any given patient. B4 A more recent study has compared outcomes of modern laparoscopic ARS and potent antisecretory therapy using esomeprazole. In this three-year interim analysis of 554 patients with GERD randomized as part of an open-label prospective randomized trial comparing laparoscopic ARS to esomeprazole, the proportion of patients in remission in the two groups was similar (surgically treated 90%, and medically treated 93%) in an intention to treat analysis [459]. These data do not support the contention that either antireflux surgery or use of PPIs is a more effective GERD therapy, as both are safe and similarly effective therapies [460]. Surgical proponents often argue that medical therapies do not correct the underlying anatomical abnormalities. However, there are no long-term data to support the view that surgery achieves this result permanently either. One small follow-up observational study of patients after 45

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20 years demonstrated that about 30% of the fundoplications were defective, and abnormal reflux on esophageal pH studies was also seen in about 30% of patients assessed [461]. B4 Another study of 441 patients after a mean followup of 18 years following the Hill procedure for GERD, reported good and excellent subjective results in 80% of patients [462]. B4 A ten-year follow-up study after laparoscopic anti-reflux surgery suggested that while 89% would select surgery again, 28% were taking acid suppressive drugs [463]. Thus, the long-term results of fundoplication are good but not completely durable. Even after one year, 6% of patients will require PPI therapy [464]. A retrospective questionnaire of 844 patients at a mean of six years after ARS identified that 26% of patients still had abnormal pH despite being on medication and in total, 37% were taking acid suppressive therapy [465]. There is also no credible evidence that surgery prevents progression to Barrett’s metaplasia or protects against esophageal cancer, an often claimed benefit of surgery [464]. One randomized trial of open versus laparoscopic fundoplication [466] found no difference between the two approaches and more than 85% of patients were satisfied with their results. The major advantage for laparoscopic fundoplication is a significant reduction in hospital stay from 8–9 days for an open procedure to 2–5 days [467–469], and less time off work for the patient (laparoscopic 21.3 days, open surgery 38.2 days, p = 0.02) [468]. Thus, the procedure of choice is laparoscopic fundoplication; A1d however, data on long-term outcomes are lacking. Surgical results continue to depend on surgical expertise, and the issue of a learning curve remains [468, 470]. An intra-operative complication rate of 8% has been reported [470]. The most frequent adverse effects are dysphagia, inability to belch or vomit, postprandial fullness, bloating, pain and flatus [471]. Also, laparoscopic fundoplication is not without serious complications such as esophageal perforation, paraesopheageal herniations, pneumothorax and splenic damage requiring splenectomy [472]. For some patients, there may be incomplete symptom relief with PPI therapy. In one randomized trial of antireflux surgery and omeprazole, those patients who were not improved on omeprazole 40 mg daily were offered anti-reflux surgery and fared well [464]. B4 Thus, some patients with a partial response to PPIs may improve with anti-reflux surgery. However, it is of concern that 6/178 (3%) of these patients experienced postoperative complications that necessitated reoperation. The best results with ARS are obtained in the patient with typical reflux symptoms, an abnormal esophageal pH study and good symptomatic response to PPIs [473]. Thus, the best indication for surgery is a patient who responds well to PPI but does not wish to take continuous medications to control their reflux [474, 475]. B4 C5 With the relative ease and safety of laparoscopic surgery, it has become 46

a reasonable alternative for selected patients. As with all surgery, patient selection has improved through objective testing with pre-operative esophageal pH-metry and manometry. Even if cost-effectiveness modelling studies favor surgery, a decision to have surgery should not be imposed upon a patient. Ultimately, the final decision should rest on the preferences of an informed patient. In summary, these data lead to a recommendation that surgery can be offered as an effective alternative to medical therapy in patients with reflux. The patients most likely to benefit from this treatment are patients who have been effectively treated for their symptoms with medication. Neither medical therapy nor surgery has proven more effective than the other in managing GERD symptoms or avoiding the complications of this disorder, and treatment choices should be based on patient preference for treatment.

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432 Ofman JJ. The economic and quality-of-life impact of symptomatic gastroesophageal reflux disease. Am J Gastroenterol 2003; 98: S8–S14. 433 Bate CM, Green JR, Axon AT et al. Omeprazole is more effective than cimetidine for the relief of all grades of gastro-oesophageal reflux disease-associated heartburn, irrespective of the presence or absence of endoscopic oesophagitis. Aliment Pharmacol Ther 1997; 11: 755–763. 434 Bate CM, Green JR, Axon AT et al. Omeprazole is more effective than cimetidine in the prevention of recurrence of GERDassociated heartburn and the occurrence of underlying oesophagitis. Aliment Pharmacol Ther 1998; 12: 41–47. 435 Bianchi Porro G, Pace F, Sangaletti O et al. High-dose famotidine in the maintenance treatment of refractory esophagitis: results of a medium-term open study. Am J Gastroenterol 1991; 86: 1585–1587. 436 Starlinger M, Appel WH, Schemper M, Schiessel R. Long-term treatment of peptic esophageal stenosis with dilation and cimetidine: factors influencing clinical results. Eur Surg Res 1985; 17: 207–214. 437 Ferguson R, Dronfield MW, Atkinson M. Cimetidine in treatment of reflux esophagitis with peptic stricture. BMJ 1979; 2: 472–474. 438 Farup PG, Modalsli B, Tholfsen JK. Long-term treatment with 300 mg ranitidine once daily after dilatation of peptic oesophageal strictures. Scand J Gastroenterol 1992; 27: 594–598. 439 Smith PM, Kerr GD, Cockel R et al. A comparison of omeprazole and ranitidine in the prevention of recurrence of benign esophageal stricture. The RESTORE Investigator Group. Gastroenterology 1994; 107: 1312–1318. 440 Marks RD, Richter JE, Rizzo J, Koehler RE, Spenney JG, Mills TP, Champion G. Omeprazole versus H2-receptor antagonists in treating patients with peptic stricture and esophagitis. Gastroenterology 1994; 106: 907–915. 441 Silvis SE, Farahmand M, Johnson JA, Ansel HJ, Ho SB. A randomized blinded comparison of omeprazole and ranitidine in the treatment of chronic esophageal stricture secondary to acid peptic esophagitis. Gastrointest Endosc 1996; 43: 216–221. 442 Swarbrick ET, Gough AL, Foster CS, Christian J, Garrett AD, Langworthy CH. Prevention of recurrence of oesophageal stricture, a comparison of lansoprazole and high-dose ranitidine. Eur J Gastroenterol Hepatol 1996; 8: 431–438. 443 Stal JM, Gregor JC, Preiksaitis HG, Reynolds RP. A cost-utility analysis comparing omeprazole with ranitidine in the maintenance therapy of peptic esophageal stricture. Can J Gastroenterol 1998; 12: 43–49. 444 Jaspersen D, Diehl KL, Schoeppner H, Geyer P, Martens E. A comparison of omeprazole, lansoprazole and pantoprazole in the maintenance treatment of severe reflux oesophagitis. Aliment Pharmacol Ther 1998; 12: 49–52. 445 Galmiche JP, Bruley d, V. Endoluminal therapies for gastrooesophageal reflux disease. Lancet 2003; 361: 1119–1121. 446 Vakil N, Sharma P. Review article: endoscopic treatments for gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2003; 17: 1427–1434. 447 Filipi CJ, Lehman GA, Rothstein RI et al. Transoral, flexible endoscopic suturing for treatment of GERD: a multicenter trial. Gastrointest Endosc 2001; 53: 416–422.

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Barrett’s esophagus Constantine A Soulellis1, Marc Bradette2, Naoki Chiba3, M Brian Fennerty4 and Carlo A Fallone1 1

Division of Gastroenterology, McGill University Health Center, Montreal, Canada Division of Gastroenterology, Centre Hospitalier Universitaire de Québec, Québec City, Canada 3 Division of Gastroenterology, McMaster University Medical Centre, Hamilton and Guelph General Hospital, Guelph, Canada 4 Oregon Health and Science University, Division of Gastroenterology and Hepatology, Oregon, USA 2

Introduction Barrett’s esophagus was first described by Norman Barrett in 1957 [1]. It is a condition in which the normally squamous mucosa of the esophagus is replaced by metaplastic columnar epithelium due to injury from gastroesophageal reflux. Barrett’s esophagus is thus one of the complications of gastroesophageal reflux disease (GERD). Its importance is derived entirely from its association with esophageal adenocarcinoma, the latter of which develops in approximately 0.5% of patients with Barrett’s esophagus per year [2].

Definition The definition of Barrett’s esophagus has changed over the last several years. From its original description as a columnar-lined lower esophagus [1, 3], to one requiring at least 3 cm of circumferential columnar lining or intestinal metaplasia [4], it has evolved most recently to the presence of any length of columnar epithelium in the tubular esophagus that is characterized histologically as intestinal metaplasia [5, 6]. In keeping with this evolution in diagnostic criteria the Practice Parameters Committee of the American College of Gastroenterology has most recently defined this entity as “a change in the distal esophageal epithelium of any length that can be recognized as columnar-type mucosa at endoscopy and is confirmed to have intestinal metaplasia by biopsy of the tubular esophagus” [7]. There are three important components to this definition that are worth highlighting. First, intestinal metaplasia must be present. It has been argued, however, that, even if

Evidence-Based Gastroenterology and Hepatology, Third Edition John WD McDonald, Andrew K Burroughs, Brian G Feagan and M Brian Fennerty © 2010 Blackwell Publishing Ltd. ISBN: 978-1-405-18193-8

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not present initially, intestinal metaplasia could be subsequently identified in endoscopically characteristic columnar mucosa. This has led to proposals from the British Society of Gastroenterology to exclude the requirement of intestinal metaplasia from the definition of Barrett’s esophagus [8]. However, the clinical significance of changing the definition is unclear, since it is the intestinal specialized epithelium that is associated with adenocarcinoma [6, 9, 10]. Second, this definition encompasses not only the classical Barrett’s esophagus (≥3 cm of columnar-lined mucosa of the distal esophagus with intestinal metaplasia) but also short segment Barrett’s esophagus (SSBE) defined as specialized columnar epithelium lining less than 3 cm of the distal esophagus [11]. Although the risk for developing dysplasia and esophageal cancer with SSBE is lower than with classical longer-segment Barrett’s esophagus (LSBE) (OR 0.55), it is not statistically significantly less. Moreover, as SSBE is much more common than LSBE, most adenocarcinomas arising from Barrett’s likely arise in SSBE not LSBE even if the incidence in LSBE is higher [12–18]. Finally, intestinal metaplasia must be present in the tubular esophagus (not just the gastric cardia) for a diagnosis of Barrett’s esophagus, as the latter does not have the same implications as intestinal metaplasia of the tubular esophagus and may actually be a variant of a normal histological finding of the cardia.

Epidemiology Incidence and prevalence The estimates of prevalence of Barrett’s vary according to the population studied and the definition used. Approximately 6–12% of patients undergoing endoscopy for symptoms of GERD have documented the presence of Barrett’s esophagus, with the majority having SSBE (≈ 6–10% versus 5% LSBE) [12, 19–21]. In patients with mod-

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erate to severe erosive esophagitis, rates of underlying Barrett’s esophagus may be as high as 27% [22]. For patients with dyspeptic symptoms as opposed to only GERD symptoms, the prevalence was 2.4% [23]. Another study of dyspeptic patients obtained a rate of only 0.3%, but this estimate excluded patients with alarm symptoms and those over 45 years [24]. Others have also obtained an estimate of ≤1% in unselected patient populations undergoing endoscopy [12, 25, 26]. Autopsy studies, on the other hand, suggest that the prevalence of Barrett’s esophagus is about 21 times higher than that detected endoscopically, and these data suggest that the vast majority of patients with Barrett’s esophagus remain unrecognized [27]. The incidence of Barrett’s esophagus has continued to increase since the 1970s, and has now reached approximately 10 new cases per 100,000/year [28–30]. The median age of development of the condition has been estimated at 40 years and the mean age at diagnosis at 63 years of age [25]. Although this increase in incidence parallels the increasing use of endoscopy, this is probably not the only explanation, and the true incidence has probably increased as well.

Risk factors Barrett’s esophagus appears to occur predominately in male Caucasians [6, 19]. Although the prevalence of Barrett’s esophagus in black, Asian and Hispanic populations has been occasionally found to be higher than expected [31–33], most observational data suggest that the prevalence of Barrett’s oesophagus is significantly lower (OR 0.35) for these groups compared to white populations [34, 35]. One might expect that as lifestyle and dietary habits change in developing regions, the prevalence will approximate that of the Western World. The decreasing prevalence of Helicobacter pylori infection has also been suggested to play a role in the increased incidence, but this association, although plausible, is controversial [36–38]. In addition to age, gender and race, longer duration of GERD is also a risk factor for Barrett’s esophagus [19, 38, 39]. Compared to patients with reflux symptoms of less than one year, Barrett’s esophagus was three times more common if reflux symptoms were present for one to five years, five times more common for symptoms present for five to ten years, or more than six times more common if reflux symptoms were present longer than ten years [39]. Increased severity of nocturnal reflux symptoms [38– 40] and increased complications of GERD such as esophagitis, ulceration, and bleeding are also associated with an increased prevalence [38] but the evidence regarding association with peptic strictures is conflicting [38, 41, 42]. There is also an association of hiatal hernia with Barrett’s esophagus [43, 44]. Although these findings are associated with a higher prevalence of Barrett’s esophagus, many

Barrett’s esophagus

patients with this condition have reflux symptoms no different than those experienced by other GERD patients [27, 45]. Within the last ten years, some controversy in the literature has emerged concerning the suggestion that obesity is a risk factor for reflux and, by extension, Barrett’s esophagus and esophageal adenocarcinoma. Recently, it has been shown that visceral fat deposition that is associated with an increased abdominal circumference (greater than 80 cm) appears to confer perhaps the greatest risk association, potentially explaining the male predominance of Barrett’s esophagus [46]. The reasons for this are not entirely clear, but it has been hypothesized that the metabolic activity of visceral fat interferes with the production of cytokines that protect against carcinogenesis [47]. Recently, some data have emerged implicating diet in the relationship between GERD, Barrett’s and cancer. In a case-control study, the odds ratio of Barrett’s was significantly less in the highest quartile of fruit/vegetable consumers (OR 0.25–0.56) compared with the lowest quartile. Supplemental antioxidants (Vitamin C, E and beta carotene) did not appear to affect the odds ratios [48]. Another recent study examining the effect of “Western” diet (fastfood and meat-based) versus “health-conscious” diet (fruits, vegetables, and non-fried fish) demonstrated a clear advantage for the latter in the association with Barrett’s (OR 0.35) [49]. Although no randomized trials have been conducted as of yet, such findings suggest a possible benefit to a diet rich in fruits and vegetables with minimal meat or fast-food consumption in decreasing the incidence of Barrett’s and its associated complication of esophageal adenocarcinoma.

Natural history The survival of a patient with Barrett’s esophagus is very similar to that of patients with benign esophageal disorders such as achalasia or Schatzki’s ring [50]. The overwhelming majority of patients with Barrett’s esophagus will never develop esophageal adenocarcinoma. Yet, if it were not for this association, Barrett’s esophagus would not have much clinical importance. Early studies estimated the incidence of esophageal adenocarcinoma in Barrett’s esophagus at 1–2% per annum. More recent analyses of epidemiologic studies have suggested an incidence ranging from 0.5 to 0.6% per annum, in part due to publication bias of the more positive results with initial studies [50]. This incidence is also probably an overestimate as it likely reflects a higher risk population, with men progressing twice as quickly as women [51–56]. Nevertheless, Barrett’s esophagus is definitely associated with the occurrence of esophageal adenocarcinoma (EAC), and this cancer is on a dramatic rise in Western societies. 63

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Since the mid-1970s, the incidence of EAC in Caucasian men from the USA rose from 0.7/100,000 person-years to an estimated 5.69/100,000 person-years by 2004 [12, 30]. This rise is not thought to be due to the previous misclassification of gastroesophageal junction esophageal carcinomas as gastric cancer, since there has not been a concomitant decrease of gastric cardia cancers [12]. The proportion of esophageal cancer due to adenocarcinoma has also increased substantially in the same period, but the absolute number of all esophageal cancers is still quite low in comparison to colorectal cancer, for example, which is ten times more common [12, 57]. Indeed, EAC remains a relatively uncommon cancer, ranked fourteenth for males and eighteenth for females in estimated new cancer cases in Canada in 2008 [58]. The length (extent) of Barrett’s esophagus is a risk factor for esophageal adenocarcinoma. A landmark study published in 2000 showed that a 5 cm difference in segment length was associated with a 1.7-fold (95% CI: 0.8–3.8) increase in cancer risk [17]. Although this difference is not statistically significant, a similar association has been repeatedly demonstrated. A meta-analysis published in 2007 demonstrated a statistically significant increase in adenocarcinoma with longer segments of Barrett’s esophagus [18]. Other reported risk factors for esophageal adenocarcinoma include severity, frequency and duration of reflux symptoms [59–61], size of hiatal hernia [62], obesity [63], smoking [64] and a diet low in raw fruit content [65]. The use of medications that reduce the lower esophageal sphincter pressure has also been found to be associated with esophageal cancer, in some but not in all studies [66, 67]. Also controversial is the possibility that H. pylori protects against GERD and esophageal cancer. A metaanalysis of twenty studies demonstrated a lower prevalence of H. pylori in patients with GERD (OR 0.6) [68]. A beneficial effect of H. pylori on reducing the risk of development of esophageal adenocarcinoma (OR 0.37 in patients under 50 years of age) has also been suggested by a case-control study [69]. It appears that infection with cagA + H. pylori is particularly protective [70, 71]. One study found the prevalence of H. pylori infection with cagA + strains to be inversely associated with GERD complications (non-erosive GERD 41% cagA +, erosive GERD 31%, Barrett’s esophagus 13% and Barrett’s with dysplasia or adenocarcinoma 0%) [70]. These apparent associations, however, still remain controversial and are not necessarily causal (or protective). The presence and degree of dysplasia associated with Barrett’s esophagus is also a risk factor for the subsequent development of esophageal adenocarcinoma. Dysplasia is a histological diagnosis primarily considered as absent, indefinite, low grade, or high grade. There is significant interobserver variability (less than 50% agreement) in the interpretation of low grade dysplasia and there are few prospective studies related to risk [72, 73]. Estimates of 64

progression from normal, indefinite or low-grade dysplasia to high-grade dysplasia or adenocarcinoma are highly variable but there appears to be a low risk [73]. Patients with high-grade dysplasia, however, have been shown to have a substantially increased risk of cancer. Reid et al. [74] found that cancer developed in 33 of 76 patients (43%) with high grade dysplasia, compared to 9 of 251 (4%) with negative, indefinite or low-grade dysplasia by five years. The results from different studies, however, vary substantially with five to seven-year cumulative cancer incidence estimates of 16% to 59%. This variation largely appears to be related to prevalent cancers (those found within a year of diagnosis of cancer) suggesting that the lower rate is the more accurate [72, 75, 76]. Other studies have suggested that flow cytometry can also be used to predict outcome [74].

Pathogenesis Barrett’s esophagus is felt to result from a perturbation in the repair of mucosal injury of the esophagus in an abnormal milieu of gastroesophageal reflux (abnormally acidic and/or acid- and bile-exposed esophageal environment) in a genetically predisposed individual. This hypothesis is based, in part, on animal studies, that demonstrated that excision of the esophageal mucosa results in re-epithelialization of the esophagus with columnar epithelium only if performed in an environment of acid reflux or acid and bile reflux [77, 78]. Although there is no direct human experimental evidence that reflux causes Barrett’s esophagus, this theory is supported by human ambulatory esophageal pH monitoring studies, which demonstrate a greater esophageal acid exposure in patients with Barrett’s esophagus compared to GERD patients without Barrett’s esophagus [79, 80]. In addition, the duration of esophageal acid exposure correlates with the length of Barrett’s esophagus [81]. The increase in esophageal acid exposure does not appear to be due to increased acid production, as no difference is present in gastric acid outputs [82]. The most widely accepted conceptual approach to GERD is that it represents a spectrum of disease that ranges from non-endoscopic reflux disease (NERD) to esophagitis, Barrett’s esophagus, dysplasia and esophageal adenocarcinoma (Figure 3.1a). Acid reflux is felt to contribute to esophagitis and Barrett’s, but the cause of development of dysplasia in Barrett’s patients is unknown. Patients with NERD, however, uncommonly develop erosive esophagitis [83] and Barrett’s esophagus is almost always diagnosed on first endoscopy [84]. It is for this reason that Fass et al. [85] have suggested a new conceptual model that divides GERD into three distinct groups of patients: NERD, erosive esophagitis and Barrett’s esophagus (Figure 3.1b). They suggested that patients do not usually move into a differ-

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Barrett’s esophagus

A Normal esophagus

GER

GER NERD

GER

EE

Intestinal metaplasia (BE) With epithelial injury

?

? Dysplasia

Adenocarcinoma

B NERD

GERD

Atypical GERD and Extraesophageal manifestations of GERD

EE

Stricture Bleed Ulceration

BE

Adenocarcinoma

Figure 3.1 (a) Conventional concept for GERD. (b) New concept of GERD as three distinct entities and complications associated with each, Fass et al. [85]. Abbreviations: GER: gastroesophageal reflux; NERD: nonendoscopic reflux disease; EE: erosive esophagitis; BE: Barrett’s esophagus.

ent group, but each group has its own potential complications (noted in Figure 3.1b).

Diagnosis As noted previously, the diagnosis of Barrett’s esophagus requires the demonstration of intestinal metaplasia on targeted biopsy sampling of endoscopically abnormal appearing esophageal mucosa [7]. The definition and diagnosis of Barrett’s is difficult for several reasons. First, there are no symptoms specific for this condition. For the most part, the symptoms are essentially identical to those of GERD and most patients are asymptomatic [27]. In addition, accurate identification of the location of the gastroesophageal junction is required in order to determine if the squamo-columnar junction is displaced proximal to this location, since this displacement is what alerts the endoscopist to the possibility of the diagnosis of Barrett’s and thus leads to biopsy of the mucosa. The former junction can at times be very difficult to determine endoscopically because of the presence of a hiatal hernia, esophagitis, and the constant movement of the area. This is highlighted by a multicenter study in which only 72% of the endoscopists correctly recorded endoscopic landmarks in the diagnosis of Barrett’s esophagus [86]. SSBE can thus be particularly difficult to identify and distinguish from an irregular Z line (a normal anatomical finding). This is very important because intestinal metaplasia in the gastric cardia does not seem to have the same implications as intestinal metaplasia of the esophagus and, indeed, may be a normal histological finding in this location. Erythema or erosive esophagitis can also impair the visual recognition of Barrett’s esophagus, and repeat endoscopy after treatment with acid suppression may be necessary to make the diagnosis of Barrett’s in this situation [87].

Currently, intestinal metaplasia is a prerequisite in order to make the diagnosis of Barrett’s esophagus. This fact, however, seems not to be fully understood as some pathologists continue to classify patients without intestinal metaplasia as Barrett’s esophagus. In one study, correct identification of intestinal metaplasia without dysplasia occurred in only 35% of 20 community-based pathologists [88]. The hematoxylin and eosin stain combined with alcian blue at pH 2.5 can be used to facilitate the recognition of the acid mucin-containing goblet cells characteristic of intestinal metaplasia [5]. A further difficulty with diagnosis is sampling error. When obtaining biopsies for Barrett’s esophagus, samples may miss the area with metaplasia and hence fail to lead to the diagnosis. This addresses the important issue of the number of biopsies required; intuitively, the more endoscopic biopsies taken, the more accurate the diagnosis of Barrett’s. It has also been suggested that endoscopic adjuncts such as chromoendoscopy and/or narrow band imaging (NBI) may help in targeting biopsies and thus increase the diagnostic yield. Methylene blue, toluene blue, indigo carmine, and Lugol’s iodine have all been used as chromoendoscopic agents to identify specialized intestinal metaplasia as well as the characteristic surface patterns suggestive of neoplasia [89–92]. These contrast agents are sprayed over the esophageal mucosa at the time of endoscopy, with areas of intestinal metaplasia and dysplasia demonstrating a variety of characteristic staining patterns. However, interpretation of the staining process may be tedious, and the results are not necessarily reproducible [93]. More recently, the pairing of magnification endoscopy [94] with narrow-band imaging (NBI) has emerged as a new modality that may obviate the need for staining altogether. Dysplasia is only detectable histologically. Dysplasia, the next step in the neoplastic process, represents a change in 65

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architecture of the metaplastic glands and is associated with individual cellular nuclear abnormalities. Dysplasia is felt to progress along a continuum from no dysplasia to low-grade dysplasia, high-grade dysplasia and finally adenocarcinoma, although the time course of this progression is highly variable and not inevitable. Furthermore, it is likely reversible in the stages leading up to adenocarcinoma. Dysplasia is often focal and not easily detectable endoscopically without the aid of stains, magnification and narrow-band imaging, rendering the targeting of biopsy sampling difficult. It has been established that random biopsies taken every 2 cm detect 50% fewer cancers than four-quadrant biopsies taken every 1 cm [95]. The latter approach has yet to be recommended in formal guidelines because of the effort involved in following such an intensive biopsy protocol. In addition, there is significant interobserver variation in the diagnosis and grading of dysplasia by both academic and non-academic pathologists [12]. Reactive change due to esophagitis is difficult to distinguish from dysplasia and further compounds the problem. However, recent data from a randomized controlled trial demonstrated that roughly half the biopsies are required to detect dysplasia with methylene blue-targeting compared with four-quadrant biopsies every 2 cm within Barrett’s metaplasia [96]. Furthermore, the combination of NBI and high-magnification endoscopy reportedly identifies microstructural changes suggestive of dysplasia with a sensitivity and specificity of 90% and 100% respectively [97]. Although not formally recommended yet, such advances in endoscopic imaging are likely to be incorporated into endoscopic practice if confirmed and reproducible. Although the diagnosis of Barrett’s esophagus can be difficult, if the endoscopist suspects that the level of the squamo-columnar junction is above the esophagogastric junction (the proximal margin of the gastric folds), biopsies are required. If intestinal metaplasia is present, then the diagnosis of Barrett’s esophagus has been established.

Treatment The goals of treatment for Barrett’s esophagus are the same as for GERD; the control of symptoms and maintenance of healed mucosa [6].

Acid suppression Lifestyle modifications (including dietary adjustment) may help control GERD symptoms somewhat, but these measures are unlikely to have an effect on the regression of Barrett’s metaplasia. In fact, some individuals with Barrett’s esophagus are asymptomatic, possibly due to the replacement of the normal squamous epithelium with the acid 66

insensitive Barrett’s epithelium. Nevertheless, these patients may still benefit from acid suppression given the potential regression of Barrett’s metaplasia as discussed below [6]. Histamine H2-receptor antagonists (H2-RA) often improve GERD symptoms but they do not effect regression of Barrett’s metaplasia [98, 99]. Proton pump inhibitors (PPI) are the most potent antisecretory agents, superior to H2-RA in the treatment of symptoms and the healing of esophagitis [100]. In Barrett’s esophagus, these same endpoints are effectively achieved with PPIs [101–103]. Some studies have also suggested a modest endoscopic regression of Barrett’s esophagus with use of PPIs, although these usually utilized a high dose PPI [99, 101, 104–106]. In a randomized controlled trial, Peters et al. [99] demonstrated that omeprazole 40 mg bid resulted in an 8% reduction of surface area of Barrett’s esophagus and a 6% decrease in length, superior to the comparator, ranitidine 150 mg bid (Table 3.1). There is also evidence that normalization of intra-esophageal acid exposure decreases cellular proliferation rates and use of PPIs has been associated with a decreased incidence of dysplasia [107, 108]. It is noteworthy that, despite adequate symptom control, even high dose PPI therapy often does not normalize esophageal acid exposure in patients with Barrett’s metaplasia [109–112]. However, there is no evidence that normalization of pH leads to a decreased incidence of adenocarcinoma and, therefore, it is not rational to routinely perform pH-metry to determine the level of acid suppression. What is often seen with acid suppression is an increase in islands of squamous epithelium within the Barrett’s segment. Biopsies of such islands have often shown underlying intestinal metaplasia, indicating that complete regression of Barrett’s does not occur with pharmacological acid inhibition [113]. At this point, no study has shown a reduction of esophageal adenocarcinoma or mortality, although a large randomized control trial examining PPIs and/or aspirin as a chemopreventive agent is underway [114]. Nevertheless, PPIs remain the best pharmacological treatment for Barrett’s presently available. B2 Given that even high dose PPI may fail to normalize esophageal pH [109–112, 115–117], some have considered anti-reflux surgery as an alternative to decreasing cancer risk with the consideration that continued reflux is the promoting agent. Surgery does provide excellent control of symptoms, and the development of squamous islands after surgery suggests possible regression. One randomized trial comparing medical therapy with anti-reflux surgery with follow up for one to eleven years (Table 3.1) demonstrated a 25% rate of some regression in the surgically treated group (9% progression, 3/32) compared to 7% regression (41% progression, 11/27) in the medical group [118]. However, complete regression of Barrett’s metaplasia with surgery is very uncommon and may, in fact, reflect “pseu-

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Barrett’s esophagus

Table 3.1 Summary of randomized controlled trials for the treatment of Barrett’s esophagus discussed in this chaptera. Therapy

Treatments compared (n)

Outcome

Reference

Acid suppression

Omeprazole 40 mg bid (26) Ranitidine 150 mg bid (27)

• Regression in Barrett’s length (p = 0.06) and area (p = 0.02) with omeprazole compared to ranitidine

Peters et al. [99]

Surgery

Medical (ranitidine or omeprazole) (27) Anti-reflux surgery (32)

• Length of Barrett’s esophagus decreased in 8/27, (increased in 3) in the surgical group compared to 2/32 (increased in 11) in the medical group (p < 0.01). • Dysplasia appeared in 6 medically treated patients (mild in 5, severe in 1) versus 1 surgically treated patient (which was severe)

Ortiz et al. [118]

Surgery

Medical (ranitidine 150 mg bid) (91)b Surgical therapy (38)b

• No difference in incidence of adenocarcinoma between groups, but insufficient power to detect such a difference

Spechler et al. [124]

Ablation

PDT with photophrin and omeprazole (138) Omeprazole 20 mg bid (70)

• Ablation of all high grade dysplasia in 77% of PDT group versus 39% in omeprazole group (p < 0.0001) • Cancer in 15% versus 29% respectively (p = 0.027)

Overholt et al. [141]

Ablation

PDT + 5 Aminolevulinic acid (ALA) (18) placebo + ALA (16)

• 16/18 of the PDT group had some response compared to 2/18 of the placebo group (p < 0.001)

Ackroyd et al. [142]

a

This list is not meant to be an exhaustive list of all randomized clinical trials in the literature. This includes all GERD patients, not just those with Barrett’s esophagus. Abbreviations: PDT: Photodynamic therapy.

b

doregression” due to surgical repositioning of the esophagus [12]. Some studies have also reported a reduced risk of progression of low grade dysplasia [119]. However, both dysplasia and cancer continue to occur after surgery [120– 124]. Csendes et al. [123] found that dysplasia developed in 17 (10.5%) and adenocarcinoma in 4 (2.5%) of 161 patients who had undergone surgery at late (7–21 years) follow-up. In a small randomized controlled trial comparing medical to surgical anti-reflux therapy, there was no significant difference between groups in incidence of esophageal cancer (Table 3.1) [124], although this study probably lacked power to demonstrate a true difference should one exist. A more recent retrospective observational study of Barrett’s patients who underwent Rosetti-Nissen fundoplication for medically-refractory reflux demonstrated regression of LGD to nondysplastic Barrett’s esophagus in six of eight patients, and complete regression of metaplasia to normal mucosa in eight of fifty-seven patients (14%). However, six of fifty-seven (11%) demonstrated an increase in length of involvement with Barrett’s postoperatively, and two patients went on to develop adenocarcinoma after surgery [125]. Hence, surgery does not reliably prevent dysplasia or cancer and, therefore, does not obviate the need for surveillance and should not be promoted as a cancer prevention therapy.

Chemoprevention of esophageal adenocarcinoma with anti-inflammatory agents The use of aspirin (ASA) or nonsteroidal anti-inflammatory drugs (NSAID) has been demonstrated to be associated with a significantly reduced risk of developing esophageal adenocarcinoma [126, 127]. Cycooxygenase-2 (COX-2) expression is increased in Barrett’s epithelium [128] and COX-2 inhibition has been shown to reduce cell growth in esophageal adenocarcinoma cell lines, as well as inhibit cancer formation in animal models of Barrett’s [129, 130]. Modeling the use of aspirin in patients with HGD suggests that this may be a very cost-effective intervention [131]. As such, it has been suggested that using NSAIDs and ASA as chemoprevention agents in Barrett’s esophagus may be a viable management option. In a randomized controlled trial reported in 2007 in which 100 patients with low or high-grade dysplasia were randomized to receive celecoxib 200 mg twice daily or placebo, no significant differences were demonstrated in progression of either extent of Barrett’s, dysplasia, or cancer at 48 weeks [132]. The possibility of a type II error exists in this study. Despite significant biological plausibility and epidemiological evidence of an ASA/NSAID chemoprevention effect in Barrett’s, at this time no recommendation for the use of 67

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NSAIDs as chemopreventive agents in patients with Barrett’s can be made. Studies involving larger populations and follow-up periods are in progress and may provide a definitive answer in the future [12, 133, 134].

Ablative therapies Given the theory that Barrett’s esophagus develops in the predisposed individual as a consequence of a perturbation in healing of the injured esophageal epithelium in an abnormal esophageal acidic environment, it was further hypothesized that reversal of Barrett’s would require reinjuring of the metaplastic epithelium with ablative therapy in an acid normalized esophageal environment, resulting in re-epithelialization with a native normal squamous epithelium. This effect could eliminate or decrease the risk for dysplasia and esophageal adenocarcinoma. Endoscopic injury or ablation of Barrett’s has been demonstrated with a variety of endoscopic techniques, including thermal techniques (radiofrequency energy, electrocoagulation, heater probe, argon plasma coagulation, or laser), cryotherapy, chemical induced injury with photodynamic therapy, or resection via endoscopic mucosal resection. Reports using a wide variety of different thermal techniques have suggested both complete and incomplete histological regression in Barrett’s esophagus, but complications are not uncommon [12]. Multipolar electrocoagulation (MPEC) has resulted in a fibrotic and friable esophagus with adhesions to the pleura in one patient [135]. Argon plasma coagulation (APC) has had significant complications including chest pain and odynophagia (58%), fever and pleural effusion (15%), strictures (9%), pneumomediastinum (3%) and perforation [136, 137]. In addition, one study using heater probe reported buried islands of intestinal metaplasia in 23% of patients [138]. Photodynamic therapy (PDT) is a process in which a light-sensitive agent, which concentrates in neoplastic tissue, is administered and subsequently activated by light of an appropriate wavelength. This results in selective damage of the neoplastic tissue. The sensitizing agents used include porfimer sodium, a hematoporphyrin derivative, or 5-aminolaevulinic acid (5-ALA). Reports describe elimination and regression of dysplasia and early cancers, but complete regression of Barrett’s was not achieved in the majority of patients [139]. A randomized trial compared PDT using sodium porfimer to medical therapy with omeprazole in 208 patients (Table 3.1) with high grade dysplasia [140]. At 12-month follow-up, 9% of the PDT group developed cancer compared to 19% of the omeprazole group (NS), but strictures developed in 38% of the patients who underwent PDT. The same authors reported five-year follow-up data on an incomplete subset of these patients in 2007. They demonstrated twice the rate of HGD elimination (77% versus 39%) and nearly half the progres68

sion to cancer (15% versus 29%) for the PDT group. The reported strictures were limited to the first phase of the trial in the PDT group, and all had resolved at five-year follow-up [141]. Another randomized study compared PDT with 5-ALA to placebo in low-grade dysplasia patients and achieved regression of dysplasia in 89% (16/18) versus 11% (2/18) of patients in the placebo group (Table 3.1), but only 30% of the surface area was eliminated in the 5-ALA group [142]. Hence, some risk of progression for residual neoplastic and non-neoplastic tissue still remains with this intervention. In fact, a case of adenocarcinoma developing underneath new squamous epithelium after treatment for high grade dysplasia with PDT using sodium porfimer has been reported [12]. A1d Radiofrequency ablation (RFA) is a relatively new technique that involves the application of high-frequency energy through an endoscopic balloon probe or contact device. The device, comprised of a radiofrequency energy generator and ablation catheter, is usually mounted on a balloon to ensure circumferential ablation. Early uncontrolled trials demonstrate considerable success with this technique. Sharma et al. demonstrated elimination of Barrett’s with RFA of 70% at one year of follow-up, in addition to a complete absence of buried IM (or squamous overgrowth) [143]. Recent studies have also examined the use of RFA for the treatment of low-grade and high-grade dysplasia, demonstrating elimination rates for both nondysplastic IM and dysplasia in excess of 90% after one to two years of follow-up [144, 145]. Furthermore, stricturing and buried islands of IM rarely (if ever) occurred in these studies, suggesting potential for this Barrett’s ablation modality as a safer (versus PDT) and/or more efficacious (versus MPE or APC) therapy. B4 Endoscopic mucosal resection (EMR) has also been performed in patients with and without visible lesions within Barrett’s esophagus. In one study, EMR resulted in complete local remission of 97% (34/35) of patients with low-risk lesions characterized by diameter of less than 20 mm, well or moderately differentiated histology, lesions limited to mucosa, or non-ulcerated lesions, compared to 59% (13/22) of patients with high-risk lesions characterized by diameter of greater than 20 mm, poorly differentiated histology, lesions extending into submucosa, or ulcerated lesions [146]. However, metachronous lesions or recurrent high-grade dysplasia or cancer were detected in the subsequent year in 17% of the low risk and 14% of the high risk group. Larger studies with longer follow-up are required, but EMR also appears to be relatively safe and promising as an effective non-surgical alternative for management of neoplastic Barrett’s metaplasia. B4

With all endoscopic Barrett’s ablative therapies, even if all of the Barrett’s epithelium is thought to be eliminated, some residual intestinal metaplasia may be present under-

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neath the neosquamous epithelium, along with the continued risk of cancer development. Thus, these patients have a continued need for surveillance which may be more difficult given that the endoscopic landmarks may be less easily identifiable after ablative therapy [12]. In addition, most of these techniques are associated with a small but significant risk of stricture and perforation. They are (for the most part) costly, the methods have not yet been standardized, and the results are likely very operator dependent. At this time, endoscopic ablative therapy is a reasonable option in the Barrett’s patient with high grade dysplasia or superficial adenocarcinoma. A1d There are no data allowing one to recommend these therapies in the Barrett’s patient without neoplasia, since continued surveillance will still be required, and the risk/benefit ratio is not firmly established.

Screening and surveillance Screening for the detection of Barrett’s esophagus is currently recommended in patients with chronic GERD symptoms, especially in those over age 50 [7, 147]. This recommendation is based in part on the observation that patients with a longer duration of symptoms have a higher prevalence of Barrett’s esophagus [39, 60]. GERD patients who are white, male or have more severe acid reflux also have a higher prevalence of Barrett’s esophagus [6, 79, 80]; hence the emphasis on screening this population. Most authors have recommended that a “once in a lifetime” endoscopy should be performed in all GERD patients (based on the premise that Barrett’s occurs early on in a GERD patient and thus repeat screening endoscopy is not required), although the optimal timing and utility of such a recommendation is unknown [148]. This approach seems to be favored by Canadian gastroenterologists, of whom 76% agreed that all patients with chronic GERD should have a “once in a lifetime” endoscopy [149]. Although the asymptomatic Barrett’s esophagus patient would not be picked up with this screening method, a generalized screening endoscopy in the general population is not recommended. The aim of the “once in a lifetime” gastroscopy in GERD patients is to detect Barrett’s esophagus, as this entity increases the risk of developing esophageal adenocarcinoma. Some have argued that cancer surveillance once non-neoplastic Barrett’s is discovered is too costly and/or may be ineffective in improving outcomes. In Barrett’s patients with dysplasia there is little controversy that either heightened surveillance or an intervention should be recommended, as it is the only method currently available to identify the high risk patients with dysplasia who may benefit from treatment, including new ablative therapies.

Barrett’s esophagus

Arguments in support of a screening and surveillance strategy The rationale for screening for and carrying out surveillance of patients with Barrett’s esophagus is based on the fact that GERD is a risk factor for esophageal adenocarcinoma (EAC) [60], that Barrett’s esophagus represents an intermediate step between esophagitis and adenocarcinoma (and is also the only known precursor of esophageal adenocarcinoma) [6], that the rate of esophageal adenocarcinoma is steadily increasing in Western societies [150] and the prognosis for esophageal adenocarcinoma is very poor unless detected early [151]. Over 50% of all esophageal tumors on the National Cancer database for 1988 were stage III or IV at the time of detection with five-year disease specific survivals of 15% and 3% respectively [152]. It is argued that surveillance programs will detect dysplasia or cancers at an earlier stage when the prognosis is much better. In stage I or II EAC cases the five-year disease specific survival rates were 42% and 29% respectively [152]. In addition, small retrospective observational studies suggest that Barrett’s surveillance improves survival. A comparison was made between patients who initially presented with esophageal adenocarcinoma (n = 54) versus those in whom the cancer had been detected during surveillance (n = 16) of Barrett’s esophagus [153]. Surveyed patients had significantly earlier stages than non-surveyed patients (75% had stage 0 or I, 25% stage II, and 0% stage III compared to 26%, 25% and 56% respectively, for non-surveyed patients). Survival was also significantly better in the surveyed group, with a two-year survival of 86% versus 43%. Similar results were also demonstrated in an earlier retrospective study comparing 17 adenocarcinoma patients found from surveillance programs versus 35 patients who had not been in a program [154]. Again, the cancers were at an earlier stage and survival was significantly greater in the surveyed group than in the non-surveyed group prior to diagnosis. A third study obtained similar results, with a five-year survival of 62% in those who underwent surveillance, compared to 20% in those that did not [155]. In addition, a prospective study from the UK reported on the results of a surveillance program involving 126 patients and spanning more than nine years; although there was no non-surveillance comparator group, 4% of all patients with Barrett’s developed adenocarcinoma, half of which were cured by esophagectomy [156]. These data lead to the recommendation by many experts to advocate for a Barrett’s screening and surveillance program in higher risk GERD patients. B3

Arguments against a surveillance strategy Although the incidence of esophageal adenocarcinoma is on the rise, the absolute prevalence of this condition 69

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remains relatively low in comparison to other malignancies such as colon cancer. In addition, the benefits of screening and surveying patients with Barrett’s esophagus are not as clear as they are with colonic polyps and colon cancer. Decision makers may believe that it is more appropriate to spend health care resources on proven cancer preventive strategies. Furthermore, 93–98% of esophageal adenocarcinomas occur in patients without prior diagnosis of Barrett’s esophagus [28, 157–159]. Most patients with Barrett’s esophagus do not die from esophageal cancer [160–162]. GERD is very common and approximately 90% of these patients do not have Barrett’s esophagus [21]. Surveillance is expensive, time consuming (prevents endoscopists from carrying out other tasks) and not error free; sampling error is a problem, as is interobserver variation in endoscopic and histological diagnosis. In addition, many patients with Barrett’s esophagus are asymptomatic. The prevalence of Barrett’s esophagus at autopsy was 20 times higher than the estimate from endoscopic diagnosis [27]. Thus, for each case of Barrett’s, up to another 20 cases go unrecognized. Considering that the true prevalence of Barrett’s esophagus in the community is much higher than previously thought, the observed incidence of adenocarcinoma of the esophagus is very small in relation to the community prevalence of Barrett’s epithelium [163]. A group of 166 patients with Barrett’s esophagus who chose not to undergo surveillance were re-examined a mean of 9.3 years later [162]. They determined that the incidence of esophageal cancer was one in 180 patient years; a 40-fold increased risk compared to an age and gender-matched group from the general population. All eight patients with cancer were symptomatic and the cancer was detected at diagnostic endoscopy. Only two of these patients died because of their esophageal cancer; one of postoperative complications and the other four years postoperatively with liver metastases. Three had successful surgery, and three died of unrelated illness (pancreatitis, myocardial infarction and asthma). During the follow-up period, there were 77 other unrelated deaths at a mean age of 75 years. The authors concluded that an endoscopic surveillance program in this population of patients with Barrett’s would have had marginal benefit, as so few actually died of esophageal cancer. A Danish study found that only 1.3% of patients had a diagnosis of Barrett’s esophagus more than one year before cancer was identified [157]. Thus, most cancers were detected in patients who would not have entered into a surveillance program, suggesting that such a strategy would be unlikely to reduce the death rate from esophageal cancer in the general population.

Cost-effectiveness Unfortunately, there are no randomized controlled trials of surveillance strategies. A cost-effectiveness study examin70

ing screening assumed that GERD patients underwent a one-time gastroscopy at age 60 [164]. The calculated screening cost of $24,700 per life-year saved, is considered to be reasonable for a cancer screening program. However, the results were based on a relatively high prevalence of Barrett’s esophagus, high-grade dysplasia, and adenocarcinoma, a high sensitivity and specificity of endoscopy, and a minor reduction in quality of life after esophagectomy. Any variation in these parameters altered the cost effectiveness of the strategy. Another report estimated the cost of detecting one esophageal cancer at $23,000 for male and $65,000 for female patients with Barrett’s esophagus [165]. Another found that the cost was lower than the cost of surveillance mammography [166]. Sonnenberg et al. [167] found that the incremental cost-effectiveness of surveillance every other year was approximately $16,700 per year of life saved. Provenzale et al. [51] evaluated surveillance strategies with a Markov model, and concluded that surveillance every five years was the preferred strategy, with a cost of $98,000 per quality-adjusted life-year gained.

Conclusions regarding screening and surveillance of Barrett’s metaplasia Applying the World Health Organization’s 10 principles of early disease detection helps determine whether screening for Barrett’s esophagus is beneficial [168, 169]. Although some of these criteria are met, many are not (Table 3.2), and thus one cannot make a recommendation for screening for Barrett’s either in the general population or in those with chronic GERD. Furthermore, at this time a recommendation as to whether surveillance should be undertaken once non-neoplastic Barrett’s is discovered cannot be made. In the absence of a definitive study, there are arguments to support both sides of the controversy. However, recognizing that Barrett’s mucosa is a risk factor for esophageal adenocarcinoma, it may be difficult to disregard present recommendations for surveillance endoscopy until evidence to the contrary is available.

How to perform surveillance Screening is currently recommended for patients with chronic GERD symptoms [6]. Some are certainly more at risk of Barrett’s, and perhaps screening should be focused on those at higher risk (such as white males over age 50 with greater than 10 years of GERD symptoms). Once Barrett’s is established, the patient should have the pros and cons of a surveillance program discussed with them. Patients who have co-morbid illness which would not allow them to be candidates for esophagectomy or ablative therapy are unlikely to receive much benefit from surveillance.

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Table 3.2 World Health Organization principles for early disease detection. Principles

Are principles met in Barrett’s esophagus?

1 The target health problem is important

Yes (esophageal cancer)

2 There should be an accepted treatment for the target problem

Yes (endoscopic ablation, surgery, or intensive endoscopic surveillance)

3 Facilities for diagnosis and treatment should be available

Yes

4 There should be a recognized latent or early symptomatic stage

Yes (dysplasia)

5 There should exist a suitable screening test or examination

Yes

6 The test should be acceptable to the population to be screened

Yes

7 The natural history and development of the condition should be adequately understood

Possibly

8 There should be an agreed policy on who to treat

No

9 The process of case finding should be cost effective

No

10 Case finding should be a continuing process

Possibly

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171–173]. Table 3.3 summarizes the most recent recommendations. Essentially, the guidelines provided by several groups are very similar. The American Society of Gastrointestinal Endoscopy (ASGE) guidelines (which were generated together with the Society for Surgery of the Alimentary Tract and the American Gastroenterological Association) are similar to those of the American College of Gastroenterology (ACG) and the Canadian Association of Gastroenterology (CAG). For patients without dysplasia, surveillance endoscopy should be repeated within one year, and can then be performed every two to five years, depending upon the guideline followed (Table 3.3). For patients with low-grade dysplasia, confirmation should be sought by a second expert pathologist and a repeat surveillance endoscopy should be performed at six to twelve months. Endoscopies should continue annually until there is no low-grade dysplasia on two successive occasions, at which point a normal surveillance protocol may resume. Finally, for patients with high-grade dysplasia, management should be individualized. The ACG guidelines stipulate that high-grade dysplasia requires expert pathologist confirmation, followed by a repeat endoscopy at three months to rule out esophageal adenocarcinoma. At this point, surgery or endoscopic ablative therapy should be offered to candidates. Those who are unfit for such procedures (or refuse) should be followed with surveillance endoscopy every three months. The recommendations of the French Society of Digestive Endoscopy (FSED) differ slightly from the other guidelines as is demonstrated in Table 3.3. [172].

Updated and modified from references 168 and 169.

Conclusion During surveillance gastroscopy, four-quadrant biopsy specimens should be obtained at least every 1–2 cm along the entire length of Barrett’s epithelium. The endoscopy should be performed in patients receiving acid suppressive therapy so that esophagitis and reactive changes do not confound the diagnosis. In addition, any mucosal abnormalities detected at endoscopy should be targeted for biopsy [12]. It has been suggested that 1 cm intervals with jumbo biopsy forceps is more accurate [95, 170], but this is more labor intensive and also requires endoscopy with a therapeutic gastroscope. Hence, this form of intensive surveillance may not be practical in community practice, despite appearing to be the optimal endoscopic surveillance method.

Summary of practice guidelines Guidelines for the diagnosis, surveillance and treatment of Barrett’s esophagus have been established and updated [7,

Barrett’s esophagus is likely a complication of chronic gastroesophageal reflux and a risk factor for esophageal adenocarcinoma. It should, however, be realized that esophageal cancer is uncommon and most patients with esophageal cancer do not have clinically recognized Barrett’s esophagus before cancer is diagnosed. Also, no randomized controlled trials or large cohort studies have convincingly demonstrated that an endoscopic screening or surveillance strategy prolongs survival or improves quality of life for these patients. However, for some patients, surveillance of Barrett’s esophagus may permit detection of cancer at an earlier stage, and therefore improve survival. Therefore, endoscopic screening for Barrett’s esophagus can be considered for patients with chronic symptoms of gastroesophageal reflux disease and, particularly, in certain high risk patients such as Caucasian males over the age of 50. At this time, there is insufficient scientific evidence that aggressive anti-reflux therapy with either high-dose PPI or surgery will revert Barrett’s esophagus to normal squa71

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Table 3.3 Current practice guidelines for surveillance of Barrett’s esophagus. Source

Date published

No Dysplasia

Surveillance Intervalsa Low-grade dysplasia

High-grade dysplasiab

Biopsy samplingc

ACG [7]

2008

3 years after 2 normal EGD (1 year apart) with biopsy

Confirmatory endoscopy in 6 months, then every year until no dysplasia

Continued 3-month surveillance or individualized intervention (ablative therapy, EMR, or surgery)

4 quadrants every 2 cm and mucosal abnormalities

SFED [172]

2007

SSBE – 5 years CBE 3–6 cm – 3 years, >6 cm – 2 years

6 months – 1 year, then annually

Surgery or alternative therapy if still present at 1 month after high dose PPI

4 quadrant CBE – every 2 cm SSBE – every 1 cm

ASGE [173]

2000

Periodic (interval not specified)

More frequent than if no dysplasia

Consider surgery

4 quadrants every 1–2 cm

CAG [171]

2005

2–5 years

Confirmatory endoscopy in 12 months, then annually

Confirmatory in 3 months, then surgery or esophageal mucosal ablation for poor risk patients

4 quadrants every 2 cm

a

Interval at which surveillance endoscopy should be performed; requires confirmation; c protocol to be followed for biopsy sampling. Abbreviations: ACG: American College of Gastroenterology ASGE: American Society for Gastrointestinal Endoscopy EGD: Esophagogastroduodenoscopy CBE: Classical Barrett’s esophagus (length > 3 cm) b

mous mucosa or reduce the risk of developing cancer. Likewise, there are insufficient data to support the routine use of the various ablative therapies in patients with nonneoplastic Barrett’s esophagus. These modalities remain experimental until proven to be effective in randomized trials. At present, patients with clinically recognized Barrett’s esophagus can be offered participation in a surveillance program, with surveillance every 2–3 years for patients without dysplasia (after two normal examinations) and every 6–12 months for patients with low-grade dysplasia. For patients with high-grade dysplasia, surgical intervention or endoscopic therapy should be considered once this change is confirmed by an expert gastrointestinal pathologist, preferably in a center performing a high volume of these procedures.

SFED: French Society of Digestive Endoscopy CAG: Canadian Association of Gastroenterology EMR: Endoscopic mucosal resection SSBE: Short segment Barrett’s esophagus (length < 3 cm)

4

5

6

7

8

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101 Sampliner RE. Effect of up to 3 years of high-dose lansoprazole on Barrett’s esophagus. Am J Gastroenterol 1994; 89: 1844–1848. 102 Neumann CS, Iqbal TH, Cooper BT. Long term continuous omeprazole treatment of patients with Barrett’s oesophagus. Aliment Pharmacol Ther 1995; 9: 451–454. 103 Cooper BT, Neumann CS, Cox MA, Iqbal TH. Continuous treatment with omeprazole 20 mg daily for up to 6 years in Barrett’s oesophagus. Aliment Pharmacol Ther 1998; 12: 893–897. 104 Gore S, Healey CJ, Sutton R et al. Regression of columnar lined (Barrett’s) oesophagus with continuous omeprazole therapy. Aliment Pharmacol Ther 1993; 7: 623–628. 105 Malesci A, Savarino V, Zentilin P et al. Partial regression of Barrett’s esophagus by long-term therapy with high-dose omeprazole. Gastrointest Endosc 1996; 44: 700–705. 106 Wilkinson SP, Biddlestone L, Gore S, Shepherd NA. Regression of columnar-lined (Barrett’s) oesophagus with omeprazole 40 mg daily: Results of 5 years of continuous therapy. Aliment Pharmacol Ther 1999; 13: 1205–1209. 107 Ouatu-Lascar R, Fitzgerald RC, Triadafilopoulos G. Differentiation and proliferation in Barrett’s esophagus and the effects of acid suppression. Gastroenterology 1999; 117: 327–335. 108 El-Serag HB, Aguirre TV, Davis S et al. Proton pump inhibitors are associated with reduced incidence of dysplasia in Barrett’s esophagus. Am J Gastroenterol 2004; 99: 877–883. 109 Ouatu-Lascar R, Triadafilopoulos G. Complete elimination of reflux symptoms does not guarantee normalization of intraesophageal acid reflux in patients with Barrett’s esophagus. Am J Gastroenterol 1998; 93: 711–716. 110 Fass R, Sampliner RE, Malagon IB et al. Failure of oesophageal acid control in candidates for Barrett’s oesophagus reversal on a very high dose of proton pump inhibitor. Aliment Pharmacol Ther 2000; 14: 597–602. 111 Ortiz A, Martinez de Haro LF, Parrilla P et al. 24-h pH monitoring is necessary to assess acid reflux suppression in patients with Barrett’s oesophagus undergoing treatment with proton pump inhibitors. Br J Surg 1999; 86: 1472–1474. 112 Katzka DA, Castell DO. Successful elimination of reflux symptoms does not insure adequate control of acid reflux in patients with Barrett’s esophagus. Am J Gastroenterol 1994; 89: 989–991. 113 Sharma P, Morales TG, Bhattacharyya A et al. Squamous islands in Barrett’s esophagus: What lies underneath? Am J Gastroenterol 1998; 93: 332–335. 114 Leedham S and Jankowski J. The evidence base of proton pump inhibitor chemopreventative agents in Barrett’s esophagus – the good, the bad, and the flawed! Am J Gastroenterol 2007; 102: 21–23. 115 Fiorucci S, Santucci L, Farroni F et al. Effect of omeprazole on gastroesophageal reflux in Barrett’s esophagus. Am J Gastroenterol 1989; 84: 1263–1267. 116 Kovacs BJ, Chen YK, Lewis TD et al. Successful reversal of Barrett’s esophagus with multipolar electrocoagulation despite inadequate acid suppression. Gastrointest Endosc 1999; 49: 547–553. 117 Katz PO, Anderson C, Khoury R, Castell DO. Gastrooesophageal reflux associated with nocturnal gastric acid breakthrough on proton pump inhibitors. Aliment Pharmacol Ther 1998; 12: 1231–1234. 118 Ortiz A, Martinez de Haro LF, Parrilla P et al. Conservative treatment versus antireflux surgery in Barrett’s oesophagus:

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Long term results of a prospective study. Br J Surg 1996; 83: 274–278. Low DE, Levine DS, Dail DH, Kozarek RA. Histological and anatomic changes in Barrett’s esophagus after antireflux surgery. Am J Gastroenterol 1999; 94: 80-85. McDonald ML, Trastek VF, Allen MS et al. Barretts’s esophagus: does an antireflux procedure reduce the need for endoscopic surveillance? J Thorac Cardiovasc Surg 1996; 111: 1135–1138. Yau P, Watson DI, Devitt PG et al. Laparoscopic antireflux surgery in the treatment of gastroesophageal reflux in patients with Barrett esophagus. Arch Surg 2000; 135: 801–805. Csendes A, Braghetto I, Burdiles P et al. Long-term results of classic antireflux surgery in 152 patients with Barrett’s esophagus: Clinical, radiologic, endoscopic, manometric, and acid reflux test analysis before and late after operation. Surgery 1998; 123: 645–657. Csendes A, Burdiles P, Braghetto I et al. Dysplasia and adenocarcinoma after classic antireflux surgery in patients with Barrett’s esophagus: The need for long-term subjective and objective follow-up. Ann Surg 2002; 235: 178–185. Spechler SJ, Lee E, Ahnen D et al. Long-term outcome of medical and surgical therapies for gastroesophageal reflux disease: Follow-up of a randomized controlled trial. JAMA 2001; 285: 2331–2338. O’Riordan JM, Byrne PJ, Ravi N et al. Long-term clinical and pathologic response of Barrett’s esophagus after antireflux surgery. Am J Surg 2004; 188: 27–33. Farrow DC, Vaughan TL, Hansten PD et al. Use of aspirin and other nonsteroidal anti-inflammatory drugs and risk of esophageal and gastric cancer. Cancer Epidemiol Biomarkers Prev 1998; 7: 97–102. Langman MJ, Cheng KK, Gilman EA, Lancashire RJ. Effect of anti-inflammatory drugs on overall risk of common cancer: Case-control study in general practice research database. BMJ 2000; 320: 1642–1646. Shirvani VN, Ouatu-Lascar R, Kaur BS et al. Cyclooxygenase 2 expression in Barrett’s esophagus and adenocarcinoma: Ex vivo induction by bile salts and acid exposure. Gastroenterology 2000; 118: 487–496. Buttar NS, Wang KK, Leontovitch O et al. Chemoprevention of esophageal adenocarcinoma by COX-2 inhibitors in an animal model of Barrett’s esophagus. Gastroenterology 2002; 122: 1101–1112. Souza RF, Shewmake K, Beer DG et al. Selective inhibition of cyclooxygenase-2 suppresses growth and induces apoptosis in human esophageal adenocarcinoma cells. Cancer Res 2002; 60: 5767–5772. Sonnenberg A, Fennerty M. Medical decision analysis of chemoprevention against esophageal adenocarcinoma. Gastroenterology 2003; 124: 1758–1766. Heath EI, Canto MI, Piantadosi S et al. Chemoprevention for Barrett’s Esophagus Trial Research Group. Secondary chemoprevention of Barrett’s esophagus with celecoxib: Results of a randomized trial. J Natl Cancer Inst 2007; 99: 545–557. Fennerty MB, Triadafilopoulos G. Barrett’s-related esophageal adenocarcinoma: Is chemoprevention a potential option? Am J Gastroenterol 2001; 96: 2302–2035.

134 Jankowsi J, Barr H. Improving surveillance for Barrett’s oesophagus: AspECT and BOSS trials provide an evidence base. BMJ 2006; 322: 1512. 135 Fennerty MB, Coreless CL, Sheppard B et al. Pathological documentation of complete elimination of Barrett’s metaplasia following endoscopic multipolar electrocoagulation therapy. Gut 2001; 49: 142–144. 136 Pereira-Lima JC, Busnello JV, Saul C et al. High power setting argon plasma coagulation for the eradication of Barrett’s esophagus. Am J Gastroenterol 2000; 95: 1661–1668. 137 Byrne JP, Armstrong GR, Attwood SE. Restoration of the normal squamous lining in Barrett’s esophagus by argon beam plasma coagulation. Am J Gastroenterol 1998; 93: 1810–1815. 138 Michopoulos S, Tsibouris P, Bouzakis H et al. Complete regression of Barrett’s esophagus with heat probe thermocoagulation: Mid-term results. Gastrointest Endosc 1999; 50: 165–172. 139 Overholt BF, Panjehpour M, Haydek JM. Photodynamic therapy for Barrett’s esophagus: Follow-up in 100 patients. Gastrointest Endosc 1999; 49: 1–7. 140 Overholt BF, Lightdale CJ, Wang KK et al. International Photodynamic Group for High-Grade Dysplasia in Barrett’s Esophagus. Photodynamic therapy with porfimer sodium for ablation of high-grade dysplasia in Barrett’s esophagus: International, partially blinded, randomized phase III trial. Gastrointest Endosc 2005; 62: 488–498. 141 Overholt BF, Wang KK, Burdick JS et al. International Photodynamic Group for High-Grade Dysplasia in Barrett’s Esophagus. . Five-year efficacy and safety of photodynamic therapy with Photofrin in Barrett’s high-grade dysplasia. Gastrointest Endosc 2007; 66: 460–468. 142 Ackroyd R, Brown NJ, Davis MF et al. Photodynamic therapy for dysplastic Barrett’s oesophagus: A prospective, double blind, randomised, placebo controlled trial. Gut 2000; 47: 612–617. 143 Sharma VK, Wang KK, Overholt BF et al. Balloon-based, circumferential, endoscopic radiofrequency ablation of Barrett’s esophagus: 1-year follow-up of 100 patients. Gastrointest Endosc 2007; 65: 185–195. 144 Sharma VK, Kim HJ, Das A et al. A prospective pilot trial of ablation of Barrett’s esophagus with low-grade dysplasia using stepwise circumferential and focal ablation (HALO system). Endoscopy 2008; 40: 380–387. 145 Gondrie JJ, Pouw RE, Sondermeijer CM et al. Stepwise circumferential and focal ablation of Barrett’s esophagus with highgrade dysplasia: Results of the first prospective series of 11 patients. Endoscopy 2008; 40: 359–369. 146 Ell C, May A, Gossner L et al. Endoscopic mucosal resection of early cancer and high-grade dysplasia in Barrett’s esophagus. Gastroenterology 2000; 118: 670–677. 147 Sharma P, McQuaid K, Dent J et al. AGA Chicago Workshop. A critical review of the diagnosis and management of Barrett’s esophagus: The AGA Chicago Workshop. Gastroenterology 2004; 127: 310–330. 148 Armstrong D. Motion – All patients with GERD should be offered once in a lifetime endoscopy: Arguments for the motion. Can J Gastroenterol 2002; 16: 549–551. 149 MacNeil-Covin L, Casson AG, Malatjalian D, Veldhuyzen van Zanten S. A survey of Canadian gastroenterologists about man-

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agement of Barrett’s esophagus. Can J Gastroenterol 2003; 17: 313–317. Devesa SS, Blot WJ, Fraumeni JF, Jr. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States. Cancer 1998; 83: 2049–2053. Farrow DC, Vaughan TL. Determinants of survival following the diagnosis of esophageal adenocarcinoma (United States). Cancer Causes Control 1996; 7: 322–327. Daly JM, Karnell LH, Menck HR. National Cancer Data Base report on esophageal carcinoma. Cancer 1996; 78: 1820–1828. van Sandick JW, van Lanschot JJB, Kuiken BW et al. Impact of endoscopic biopsy surveillance of Barrett’s oesophagus on pathological stage and clinical outcome of Barrett’s carcinoma. Gut 1998; 43: 216–222. Peters JH, Clark GWB, Ireland AP et al. Outcome of adenocarcinoma arising in Barrett’s esophagus in endoscopically surveyed and nonsurveyed patients. J Thorac Cardiovasc Surg 1994; 108: 813–821. Streitz JM Jr, Andrews CW Jr, Ellis FH, Jr. Endoscopic surveillance of Barrett’s esophagus: Does it help? J Thorac Cardiovasc Surg 1993; 105: 383–388. Aldulaimi DM, Cox M, Nwokolo CU, Loft DE. Barrett’s surveillance is worthwhile and detects curable cancers. A prospective cohort study addressing cancer incidence, treatment outcome, and survival. Eur J Gastroenterol Hepatol 2005; 17: 943–950. Bytzer P, Christensen PB, Damkier P et al. Adenocarcinoma of the esophagus and Barrett’s esophagus: A population-based study. Am J Gastroenterol 1999; 94: 86–91. Brown CM, Jones R, Shirazi T et al. Prior diagnosis of Barrett’s esophagus is rare in patients with esophageal adenocarcinoma. Gut 1996; 381(suppl. 1): A23. Menke-Pluymers MB, Schoute NW, Mulder AH et al. Outcome of surgical treatment of adenocarcinoma in Barrett’s oesophagus. Gut 1992; 33: 1454–1458. Van der Veen AH, Dees J, Blankensteijn JD, Van Blankenstein M. Adenocarcinoma in Barrett’s oesophagus: An overrated risk. Gut 1980; 30: 14–18. Macdonald CE, Wicks AC, Playford RJ. Final results from 10 year cohort of patients undergoing surveillance for Barrett’s oesophagus: Observational study. BMJ 2000; 321: 1252–1255.

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162 van der Burgh A, Dees J, Hop WC, van Blankenstein M. Oesophageal cancer is an uncommon cause of death in patients with Barrett’s oesophagus. Gut 1996; 39: 5–8. 163 Nandurkar S, Talley NJ. Barrett’s esophagus: The long and the short of it. Am J Gastroenterol 1999; 94: 30–40. 164 Soni A, Sampliner RE, Sonnenberg A. Screening for high-grade dyplasia in gastroesophageal reflux disease: Is it cost-effective? Am J Gastroenterol 2000; 95: 2086–2093. 165 Wright TA, Gray MR, Morris AI et al. Cost effectiveness of detecting Barrett’s cancer. Gut 1996; 39: 574–579. 166 Streitz JM Jr, Ellis FH Jr, Tilden RL, Erickson RV. Endoscopic surveillance of Barrett’s esophagus: A cost-effectiveness comparison with mammographic surveillance for breast cancer. Am J Gastroenterol 1998; 93: 911–915. 167 Sonnenberg A, Soni A, Sampliner RE. Medical decision analysis of endoscopic surveillance of Barrett’s oesophagus to prevent oesophageal adenocarcinoma. Aliment Pharacol Ther 2002; 16: 41–50. 168 Gudlaugsdottir S, van Blankenstein M, Dees J, Wilson JHP. A majority of patients with Barrett’s oesophagus are unlikely to benefit from endoscopic cancer surveillance. Eur J Gastroenterol Hepatol 2001; 13: 639–645. 169 Chiba N. Motion – Screening and surveillance of Barrett’s epithelium is practical and cost effective: Arguments against the motion. Can J Gastroenterol 2002; 16: 541–545. 170 Levine DS, Haggitt RC, Blount PL et al. An endoscopic biopsy protocol can differentiate high-grade dysplasia from early adenocarcinoma in Barrett’s esophagus. Gastroenterology 1993; 105: 40–50. 171 Armstrong D, Marshall JK, Chiba N et al. Canadian Association of Gastroenterology GERD Consensus Group. Canadian Consensus Conference on the management of gastroesophageal reflux in adults – update 2004. Can J Gastroenterol 2005; 19: 15–35. 172 Boyer J, Laugier R, Chemali M. French Society of Digestive Endoscopy SFED. French Society of Digestive Endoscopy SFED guideline: Monitoring of patients with Barrett’s esophagus. Endoscopy 2007; 39: 840–842. 173 SSAT, AGA, ASGE Consensus Panel. Management of Barrett’s esophagus. J Gastrointest Surg 2000; 4: 115–116.

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Esophageal motility disorders: Achalasia and spastic motor disorders Jason R Roberts1, Marcelo F Vela2 and Joel E Richter3 1

Division of Gastroenterology and Hepatology, Medical University of South Carolina, South Carolina, USA Gastroenterology Section, Baylor College of Medicine, Houston, Texas, USA 3 Department of Medicine, Temple University School of Medicine, Philadelphia, USA 2

Esophageal motility disorders present with dysphagia and chest pain as the main symptoms, accompanied by abnormalities on manometric studies. The best characterized esophageal motility disorders are achalasia and diffuse esophageal spasm. The treatment options for these disorders, which range from non-invasive medical therapy to surgery, are presented in this chapter.

Achalasia

jects [4, 5]. The presence of the disease is strongly supported by a barium esophagram showing a dilated esophagus that tapers into a “bird-beak” at the gastroesophageal junction with fluoroscopy revealing lack of normal peristalsis, usually with to-and-fro disordered bolus movement. The manometric features described above, the most important of which is abnormal LES relaxation, confirm the diagnosis.

Treatment of achalasia Overview

Achalasia is a primary esophageal motor disorder characterized by abnormal relaxation of the lower esophageal sphincter (LES) and absent esophageal peristalsis. With an estimated incidence of approximately 1/100 000 and a prevalence of close to 10/100 000 [1], this uncommon disease stands out among the esophageal motility disorders as the most clearly defined (clinically, manometrically and radiographically) and the most successfully treated. The exact etiology of achalasia remains unknown, but autoimmune, infectious, degenerative and hereditary processes, whether alone or in combination, lead to a chronic inflammatory response in the myenteric plexus that results in selective loss of inhibitory neurons [2]. Manometrically this is manifested by high LES pressure, abnormal LES relaxation and aperistalsis [3]. The combination of an atonic esophageal body with a functional obstruction at the gastroesophageal junction produce esophageal dilatation that can, over a prolonged period of time, lead to the development of a megaesophagus. The most common symptoms of achalasia are dysphagia for solids and liquids in over 90% of patients, and regurgitation of undigested food and saliva in approximately 75%. Chest pain is present in 40–50% of patients, weight loss in nearly 60%, and heartburn in approximately 40% of sub-

Currently, there is no available treatment that can correct the underlying neuropathology of achalasia; LES function and peristalsis cannot be restored. Therefore, therapy is based on reduction of the resting LES pressure to allow esophageal emptying by gravity. The goals of treatment are three-fold: relieve symptoms, improve esophageal emptying and prevent the development of megaesophagus. In assessing response to a therapeutic intervention, useful endpoints are symptom relief and physiologic evaluation, the latter through manometric determination of LES pressure and measurement of esophageal emptying by barium examination or nuclear scintigraphy. Reduction of the LES pressure can be achieved through different therapeutic modalities, including pharmacologic therapy, endoscopic injection of botulinum toxin, pneumatic dilatation and surgical myotomy [6]; the last two being the most effective treatments [4, 7]. “Endstage” cases presenting with a markedly dilated and sometimes sigmoid esophagus may require esophagectomy [8]. The choice of therapy depends on patient characteristics (age, co-morbid illnesses and disease stage), patient’s preference, degree of expertise and available modalities in the medical center, and a careful balance between risks and benefits.

Evidence-Based Gastroenterology and Hepatology, Third Edition John WD McDonald, Andrew K Burroughs, Brian G Feagan and M Brian Fennerty © 2010 Blackwell Publishing Ltd. ISBN: 978-1-405-18193-8

Pharmacological reduction of the LES basal pressure through smooth muscle relaxants has been attempted with

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CHAPTER 4

Table 4.1 Nitrates and calcium channel blockers in the treatment of achalasia.

Esophageal motility disorders

channel blockers decrease LES pressure by 13–49% and improve symptoms in 53–77% of patients [11, 12, 15–17]. B4

Authors

No. of patients

Treatment

% symptom improvement

Bortolotti and Labo [16] Traube et al. [15] Coccia et al. [17] Gelfond et al. [12] Gelfond et al. [12] Gelfond et al. [13] Rozen et al. [14] Eherer et al. [19]

20 10 14 15 15 24 15 3

Nifedipine Nifedipine Nifedipine Nifedipine ISDN ISDN ISDN Sildenafil

70 53 77 53 87 83 58 0

ISDN isosorbide dinitrate. Modified from Vaezi M, Richter JE. J Clin Gastroenterol 1998; 27: 21–35.

several medications. The most studied classes include nitrates, calcium channel blockers and, more recently, sildenafil (Table 4.1). Nitrates activate guanylate cyclase, leading to production of a protein kinase that inhibits smooth muscle contraction through dephosphorylation of the myosin light chain. Additionally, nitrates liberate nitric oxide (NO), an inhibitory neurotransmitter mediated by cyclic guanosine monophosphate (cGMP). Significant reduction of LES pressure has been demonstrated 10 minutes after sublingual administration of a 5 mg dose of isosorbide dinitrate [9]. Very few randomized controlled trials have evaluated the effect of nitrates on achalasia. Wong et al. [10] found a significant decrease in LES pressure and significant improvement in esophageal emptying 30 minutes after a single dose (0.4 mg) of sublingual nitroglycerin in a randomized crossover study. In several other small studies [11–14], nitrates have decreased LES pressure by 30–65%, with symptom improvement in 58–87% of patients (Table 4.1), but these were uncontrolled studies that traditionally tend to overemphasize the benefits of interventions. Calcium channel blockers produce smooth muscle relaxation by decreasing entry of calcium, necessary for contraction, into smooth muscle cells. In a double-blind randomized controlled trial in 10 achalasia patients [15], sublingual nifedipine (10–30 mg dose, titrated according to patient tolerance) given before meals achieved a significant reduction in LES pressures 30 minutes after administration. However, despite this reduction, LES pressures were still substantial after treatment (mean LES pressure of 30 mmHg). These investigators also reported a modest improvement of dysphagia with nifedipine, with a reduction in the average number of meals per day with dysphagia from 1.9 to 0.9. Ald Other uncontrolled studies suggest that calcium

In a small randomized controlled trial comparing calcium channel blockers and nitrates in 15 patients, 12 found sublingual isosorbide dinitrate (5 mg) to be superior to sublingual nifedipine (20 mg) for the treatment of achalasia. Ald In comparison to nifedipine, isosorbide dinitrate achieved a more pronounced reduction in basal LES pressure (47% vs 64%). Additionally, more patients receiving isosorbide dinitrate experienced complete radionuclide meal clearance at 10 minutes (53% vs 15%) and relief of dysphagia (87% vs 53%). Sildenafil (Viagra) inhibits smooth muscle contraction by promoting accumulation of NO stimulated cGMP (NOcGMP) through inhibition of NO phosphodiesterase type 5, an enzyme that degrades NO-cGMP. Recently, in a placebo-controlled randomized trial of sildenafil (50 mg) in 14 achalasia patients, Bortolotti et al. [18] showed that sildenafil by direct intragastric infusion significantly reduced basal LES pressure, post-deglutitive LES residual pressure and esophageal body contraction amplitude. Peak effect was reached 15–20 minutes after infusion and lasted less than one hour. Eherer et al. [19] administered sildenafil orally (50 mg) to 11 patients with esophageal motor disorders, three of whom had a diagnosis of achalasia. LES pressure decreased in two of these patients, but none had relief of symptoms. Overall, nitrates and calcium channel blockers can reduce LES pressure. The effect on symptoms is variable, shortlived, and usually suboptimal. Ald Additionally, adverse effects such as headache, hypotension, and pedal edema that are frequent may limit their use [11]. Therefore, these agents should be reserved for the short-term relief of achalasia symptoms, either as a temporizing measure while awaiting more definitive therapy, or in patients who are too sick or unwilling to undergo other treatments. Sildenafil merits further study in randomized controlled trials.

Botulinum toxin Endoscopic injection of botulinum toxin into the LES is a relatively recent addition to the treatment options for achalasia. It produces reduction in LES pressure by inhibiting acetylcholine release from nerve endings, thereby counterbalancing the effect of the selective loss of inhibitory neurotransmitters (nitrous oxide and vasoactive intestinal peptide) in achalasia. It is safe, easy to administer and provides symptom relief initially in approximately 85% of patients; however, the effect of a single injection is usually limited to six months or less in over 50% of patients [3]. B4 In a six-month randomized controlled trial of 21 patients, the administration of botulinum toxin (100 units) resulted in significant symptom score improvement (from 7.1 ± 1.2 to 1.6 ± 2.2), compared to placebo (from 5.9 ± 1.6 to 5.4 ± 2.0) 79

PA RT I

Gastrointestinal disorders

Table 4.2 Botulinum toxin injection for the treatment of achalasia: symptomatic improvement after one injection. Authors

No. of patients

OR = 1/2 Andreoli 1987 2.8% 6 3 6 2 9.0% 21 11 21 5 Jiang 2004 70 105 43.1% 78 115 Rachmilewitz 1989 28 12.3% 17 27 13 Rijk 1991 Subtotal (95% Cl) 169 160 67.2% 98 101 Total events Heterogeneity: Chi2 = 3.64, df = 3 (p = 0.30); I2 = 18% Test for overall effect: Z = 1.05 (p = 0.29) 5-ASA/SASP > OR = 1/1 Green 2002 29 11.4% 12 28 7 24 11.1% 9 26 13 Mansfield 2002 5.7% 10 8 21 12 Riley 1988 Subtotal (95% Cl) 75 63 28.2% Total events 32 29 Heterogeneity: Chi2 = 3.28, df = 2 (p = 0.19); I2 = 39% Test for overall effect: Z = 0.82 (p = 0.41)

Peto odds ratio Peto, fixed, 95% Cl

0.69 (0.12, 3.87) 0.69 (0.12, 3.87)

0.53 (0.06, 4.80) 0.31 (0.09, 1.05) 1.05 (0.60, 1.85) 0.61 (0.21, 1.74) 0.78 (0.50, 1.23)

0.48 (0.16, 1.44) 1.64 (0.54, 4.97) 0.38 (0.08, 1.79) 0.75 (0.37, 1.50)

Total (95% Cl)

264 232 100.0% 0.77 (0.53, 1.11) Total events 144 137 Heterogeneity: Chi2 = 6.96, df = 7 (p = 0.43); I2 = 0% 0.1 0.2 Test for overall effect: Z = 1.39 (p = 0.16) Test for subgroup differences: Chi2 = 0.03, df = 2 (p = 0.98); I2 = 0%

0.5

1

2

5

10

Figure 12.2 Failure to induce clinical or endoscopic remission in ulcerative colitis. Randomized controlled clinical trials of mesalamine (5-ASA) and sulfasalazine (SASP): (a) mesalamine (Expt) versus placebo (Ctrl), (b) mesalamine (Expt) versus sulfasalazine (Ctrl). (Source: Sutherland LR et al. Cochrane Database Syst Rev 2006; 2: CD000543 [34]).

randomized trial in the UK established the importance of continuous therapy [28]. Alc Azad Khan and the Oxford group established that 2 g/day of sulfasalazine provided the optimal trade-off between efficacy and adverse effects [29]. The finding that mesalamine (5-ASA) is the active moiety of sulfasalazine stimulated a decade of trials of induction and maintenance of remission [30, 31]. Numerous aminosalicylate delivery systems have been developed. These include drugs that release 5-ASA upon bacterial splitting of the azo bond (for example sulfasalazine, olsalazine and balsalazide), pH dependent release formulations (for example Asacol (pH 7) and Claversal/Mesasal/Salofalk (pH 6)), and a microsphere preparation (Pentasa) [32]. The efficacy of oral mesalamine has been evaluated by meta-analyses of randomized controlled trials [33–35]. As shown in Figure 12.2a, mesalamine is more effective than placebo for the induction of remission (pooled odds ratio 0.51; CI: 0.35–0.76) [34]. Ala The newer 5-ASA preparations 236

were not significantly more effective than sulfasalazine, however, for active disease (pooled odds ratio 0.75; CI: 0.50–1.13) (see Figure 12.2b). On the other hand, adverse events were less frequently noted with mesalamine than with sulfasalazine: the number of patients needed to treat (NNT) with mesalamine rather than sulfasalazine to avoid an adverse event in one patient is approximately 7. Ala Figure 12.3a illustrates the results of a meta-analysis that demonstrates the superiority of aminosalicylates over placebo for maintenance of remission (pooled odds ratio 0.47; CI: 0.36–0.62) [35]. Ala Conflicting results were obtained in studies comparing sulfasalazine with mesalamine for maintenance therapy. The overall results are shown in Figure 12.3b; sulfasalazine appeared to be more effective than mesalamine (pooled odds ratio 1.29; CI: 1.05– 1.57). Ala When only studies with a minimum of 12 months’ follow-up were included in the analysis, however, there was no statistically significant advantage for sulfasalazine (pooled odds ratio 1.15; CI: 0.89–1.50). There are a number

CHAPTER 12

Ulcerative colitis

Review: Ulc. Colitis: maintenance of remission, 5-ASA Comparison: 5-ASA vs sulfasalazine Outcome: Failure to maintain clinical or endoscopic remission Treatment Control Peto odds ratio Study or subgroup Events Total Events Total Weight Peto, fixed, 95% Cl 3 20 35 61 39 20 19 88 14 20 90

7 44 82 114 108 41 42 161 23 50 167

0.8% 5.7% 9.6% 14.7% 6.9% 5.1% 5.1% 20.9% 3.0% 6.4% 21.7%

3.11 (0.32, 30.11) 0.53 (0.23, 1.22) 2.13 (1.12, 4.05) 1.19 (0.71, 2.01) 1.17 (0.55, 2.50) 1.62 (0.67, 3.92) 0.67 (0.27, 1.61) 1.35 (0.87, 2.08) 1.67 (0.53, 5.27) 0.78 (0.36, 1.73) 1.61 (1.05, 2.48)

Total (95% Cl) 839 759 100.0% Total events 409 331 Heterogeneity: Chi2 = 12.61, df = 10 (p = 0.25); I2 = 21% Test for overall effect: Z = 2.47 (p = 0.01)

1.29 (1.05, 1.57)

Andreoli 1987 Ardizzone 1995 Ireland 1988 Kiilerich 1992 Kruis 1995 Mclntyre 1988 Mulder 1988 Nilsson 1995 Rijk 1992 Riley 1988 Rutgeerts 1989

1 27 21 55 13 14 20 76 11 23 70

6 44 82 112 40 38 36 161 23 50 167

0.1 0.2

Peto odds ratio Peto, fixed, 95% Cl

0.5

1

2

5

10

Figure 12.3 Failure to maintain clinical or endoscopic remission in ulcerative colitis. Randomized controlled clinical trials of mesalamine (5-ASA) and sulfasalazine (SASP): (a) mesalamine (Expt) versus placebo (Ctrl), (b) mesalamine (Expt) versus sulfasalazine (Ctrl). (Source: Sutherland LR et al. Cochrane Database Syst Rev 2006; 4: CD000544 [35]).

of possible explanations for this discrepancy. First, the observation in the overall analysis may be correct: sulfasalazine may be a more effective delivery system than mesalamine. Second, the analysis that was restricted to studies with 12 months’ follow-up might have lacked sufficient statistical power to detect a small difference in efficacy. Third, the high drop-out rate with olsalazine therapy might have biased the overall results against mesalamine. Finally, it is possible that the comparison studies suffered from selection bias. With the exception of one trial, the inclusion criteria included tolerance to sulfasalazine [36]. This factor would tend to minimize the occurrence of adverse events with sulfasalazine therapy. Several oral 5-ASA preparations are available, but two warrant special mention. Olsalazine and balsalazide appear to be approximately as effective as sulfasalazine and mesalamine in the treatment of active ulcerative colitis and in the maintenance of remission. There have been concerns about the development of secretory diarrhea with olsalazine [37, 38], due to interference with Na+/K+-ATPase, but the frequency of this adverse effect can be minimized by taking the medication in divided doses with meals [39, 40]. Moreover, systemic absorption of 5-ASA and its metabolites is less with olsalazine than with mesalamine, which might translate into a smaller risk of nephropathy [41, 42]. Several randomized controlled trials have demonstrated a slight (and statistically insignificant) advantage of balsalazide (in a dosage of 6.75 g/day) to sulfasalazine 3 g/ day or mesalamine 2.4 g/day in the treatment of active ulcerative colitis. Ald The newer agent may provide relief of symptoms and sigmoidoscopic healing more quickly

than mesalamine [43–45], and may be better tolerated [46]. Balsalazide 3 g/day appears to be as effective as mesalamine 1.2 g/day at maintaining remission, and may provide better relief of nocturnal symptoms in the first three months of maintenance therapy [47]. It should be noted that these observations suggesting small advantages of balsalazide over mesalamine depend on post hoc subgroup analyses of relatively small groups of patients and should be interpreted with some caution. Topical therapy is a logical option for patients with disease limited to the distal colon. In theory, it presents a high concentration of mesalamine to the affected area, while minimizing systemic absorption. Marshall and Irvine have published two meta-analyses of topical therapy [48, 49]. The first analysis established that topical mesalamine was effective for both induction and maintenance therapy in patients with distal disease [48]. Alc The second analysis found that mesalamine was more effective than topical corticosteroids for the induction of remission [49]. Alc Foam enemas can reliably deliver mesalamine to the rectum and sigmoid colon, and sometimes even to the descending colon, in healthy individuals and patients with ulcerative colitis [50–53]. Foam enemas are superior to placebo, and are at least as easily tolerated and effective as liquid enemas [54–56]. Gel enemas may be better tolerated than foam preparations [57]. Mesalamine suppositories have been shown to be effective for the maintenance of remission of ulcerative proctitis [58]. Ald Some patients may benefit from a combination of oral and topical 5-ASA preparations. A small randomized trial performed by Safdi et al. suggested that combined topical 237

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and oral 5-aminosalicylate therapy may be more effective than oral therapy alone [59]. This result was confirmed by Marteau et al. in a large randomized, double-blind, placebo-controlled trial in which 127 patients with mild to moderately active colitis were randomized to receive either a 5-aminosalicylate enema or a placebo enema for the first four weeks of treatment with oral 5-ASA 4 g/day [60]. At eight weeks the observed remission rates were: 5-ASA enema 64%, placebo enema 43%, p = 0.03.

and exhibited a more favorable adverse event profile [66]. Ald

Budesonide enemas have also been used for active distal disease. A meta-analysis published by Marshall and Irvine documented that they are as effective as conventional steroid enemas [67]. Alc The only published trial comparing budesonide enemas with 5-ASA enemas revealed no differences in endoscopic or histopathologic scores between the treatment groups, but the clinical remission rate was greater with 5-ASA (60% vs 38%, p = 0.03) [67]. Most reported trials have demonstrated no benefit for corticosteroids in the maintenance of remission of ulcerative colitis [68–70].

Corticosteroids Corticosteroids remain the standard therapy for moderate to severe ulcerative colitis. Truelove and Witts were the first to undertake a randomized, controlled trial of cortisone in patients with active colitis, and showed that 100 mg/day, followed by tapering over six weeks, was an effective treatment [61]. Alc Lennard-Jones and associates reported similar efficacy for prednisone [62]. It appears that once daily dosage yields similar effectiveness as divided doses of the medication [63]. The assumption that there is no additional benefit from the use of more than 40 mg/day of prednisone is based on a small randomized trial conducted by Baron and colleagues [64]. This trial compared the outcomes of 58 outpatients who were randomized to 20, 40, or 60 mg of prednisone per day. Although either 40 or 60 mg/day yielded better results than 20 mg/day, no difference in results was observed in patients given 40 versus 60 mg/ day. The study included too few patients, however, to have sufficient statistical power to rule out a relative benefit from the 60 mg dose. Ald Budesonide is a potent second-generation corticosteroid with 90% first pass metabolism, resulting in decreased systemic toxicity [65]. A randomized, controlled trial demonstrated that a targeted colonic release formulation of budesonide appeared to be as effective as prednisolone

Azathioprine and 6-mercaptopurine Most trials of anti-metabolite drugs in ulcerative colitis have been small. There is no evidence that azathioprine (2–5 mg/kg/day) combined with prednisolone induces remission more effectively than steroids alone [71]. Alc Nevertheless, azathioprine has been shown to have a steroid-sparing effect at doses between 1.5 and 2.5 mg/kg/ day, and the major indication for this drug in ulcerative colitis is for patients who require continuing steroid therapy [72, 73]. In the double-blind, randomized, controlled trial conducted by Jewell and Truelove, patients who had gone into remission during the acute stage were weaned off steroids and given either placebo or maintenance therapy with azathioprine for one year [71]. Overall, azathioprine offered no statistically significant advantage over placebo for reducing the relapse rate. There may have been some benefit to azathioprine, however, in the subgroup of patients who were treated for relapsing disease, as opposed to those who presented with their first episode of colitis, as illustrated in Table 12.1. Specifically, 9 of 24 azathioprinetreated patients in the former group had no relapse during

Table 12.1 Clinical course during trial in two treatment groups of patients according to whether patients entered trial in first attack of ulcerative colitis or in relapse. No. of relapses

0 1–2 3 or failed Total Significance of differencesa a

Admitted in first attack Azathioprine group

Control group

Azathioprine group

Control group

7 5 4 16

6 6 3 15 NS

9 8 7 24 p = 0.055

3 7 15 25

Fisher’s exact test. Reproduced from Jewell DP et al. BMJ 1974; iv: 627–630 [71].

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follow-up, compared with 3 of 25 patients given placebo. More detailed post hoc analysis revealed that only seven patients in the azathioprine group experienced at least three relapses or failed therapy, compared with 15 patients in the placebo group (p = 0.055). These analyses should be interpreted with caution because they represent post hoc subgroup analyses of small numbers of patients. Hawthorne and colleagues conducted an azathioprine withdrawal trial that suggested a benefit for this drug in the maintenance of remission [74]. In this study, patients who were in long-term remission while taking azathioprine were randomized to continue with the medication or take placebo. During the subsequent year of follow-up, patients receiving placebo relapsed significantly more often than did those who remained on azathioprine. Ald It should be pointed out, however, that this type of trial design cannot be used to estimate the size of the treatment effect from an intervention. It is possible that only a small proportion of patients can be maintained in remission with azathioprine, and that most of these patients would relapse if the drug were withdrawn. More recently, Sood et al. randomized 35 patients with newly diagnosed ulcerative colitis, all of whom received corticosteroids to induce remission, to receive either sulfasalazine and azathioprine, or sulfasalazine and a placebo for one year [75]. Four patients (23.5%) who received azathioprine suffered relapse of disease, compared to 10 (55.6%) who received sulfasalazine alone (p < 0.05). Ald This is somewhat stronger evidence that azathioprine is beneficial for maintenance of remission in ulcerative colitis, but the results should be confirmed with a larger study. A single small randomized trial reported by MatéJimenez et al. using 6-mercaptopurine rather than azathioprine showed 6-mercaptopurine to be more effective than methotrexate or 5-ASA for induction and maintenance of remission in ulcerative colitis (see below) [76]. Ald

Methotrexate There have been anecdotal reports of the steroid-sparing effects of methotrexate in patients with chronic active ulcerative colitis. In a double-blind, randomized, controlled trial 67 patients with steroid-dependent disease were randomized to either oral methotrexate 12.5 mg per week (30 patients) or placebo (37 patients) for nine months [77]. No benefit was demonstrated for methotrexate in terms of disease activity, remission rate or steroid dosage. Alc The dosage of methotrexate employed in this study, however, was smaller than those used in case reports (up to 25 mg intramuscularly per week). A subsequent small study using oral methotrexate at a dose of 15 mg/week in steroiddependent ulcerative colitis found that the dosage of corticosteroids could be reduced acutely but that the benefit was not maintained over the subsequent 76 weeks [76]. In

Ulcerative colitis

this study Maté-Jimenez et al. compared 6-mercaptopurine (1.5 mg/kg), methotrexate (15 mg orally weekly), and 5-ASA (3 g daily) for induction and maintenance of remission in 34 steroid-dependent patients with ulcerative colitis [76]. They reported that 6-mercaptopurine was more effective than either methotrexate or 5-ASA for both induction and maintenance of remission in these patients. Ald Larger studies using higher doses of methotrexate would be of interest.

Cyclosporin There have been no randomized controlled trials of oral cyclosporin in patients with ulcerative colitis, and case reports have not suggested impressive efficacy. Anecdotal reports of benefit from intravenous cyclosporin led to a randomized controlled trial by Lichtiger and associates, involving 20 patients with severe ulcerative colitis unresponsive to 7–10 days of intravenous hydrocortisone therapy [78]. Patients received either cyclosporin (4 mg/ kg) or placebo by continuous intravenous infusion. Nine of the eleven cyclosporin-treated patients went into remission without surgery, compared with none of the patients in the placebo group. Moreover, five of the placebo-treated patients achieved remission after receiving intravenous cyclosporin. Ald Since publication of Lichtiger ’s trial, intravenous cyclosporin has been extensively used for severe disease. Response rates between 60% and 85% have been reported outside of controlled trials, but many patients subsequently relapse and require colectomy [79, 80]. B4 Nevertheless, intravenous cyclosporin may be useful especially for patients experiencing their first episode of severe colitis and for those who need time before deciding to undergo surgery. Although most clinical investigators have continued to use 4 mg/kg intravenously, 2 mg/kg was as effective as the higher dose in a randomized trial of 73 patients with severe colitis [81]. Alc Further trials are necessary to determine the optimal length of treatment and especially to decide what to do with the responders. Many clinicians discontinue cyclosporin and add azathioprine on the basis that this approach may provide sufficient time for azathioprine to become effective while the corticosteroids are being tapered. For patients who either refuse intravenous corticosteroids or who have previously had major adverse effects (for example psychoses), no difference in effectiveness was demonstrated in a small randomized trial between intravenous cyclosporin as monotherapy and intravenous hydrocortisone [82]. Ald Several clinical trials have shown that oral cyclosporin is not an effective maintenance therapy in patients with steroid-resistant ulcerative colitis who achieved remission with either intravenous or oral cyclosporine [83–85]. Most patients either relapsed (and underwent colectomy) or 239

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required corticosteroid therapy. Uncontrolled trials suggest that azathioprine may be effective in maintaining remission in patients whose disease remitted with intravenous cyclosporine [86–88]. B4 Topical cyclosporine has been used for patients with resistant proctitis or distal colitis. Enemas containing 250 mg of the drug have yielded minimal plasma concentrations and no systemic adverse effects. Small clinical series have been reported from Copenhagen, the Mayo Clinic and Oxford. These patients had failed to respond to oral or topical mesalamine, corticosteroids or antimetabolites. Approximately 70% of the patients seemed to improve with topical cyclosporin, although many relapsed when treatment was discontinued. B4 No formal clinical trial has been conducted in patients with resistant proctitis, largely because of the negative results found by Sandborn and colleagues in a small randomized controlled trial [89]. Ald Because this study enrolled only 40 patients, it may not have had sufficient power to exclude a small therapeutic benefit. Furthermore, Sandborn’s trial differed from the open series in that it involved patients with active distal colitis instead of resistant proctitis.

Nicotine Cigarette smoking seems to protect against the development of ulcerative colitis; ex-smokers and non-smokers are at increased risk [90]. Three randomized controlled trials have examined the efficacy of transdermal nicotine, given concurrently with mesalamine and/or corticosteroids, in the treatment of ulcerative colitis [91–93]. Pullan and associates found that the nicotine patch was more effective than placebo (49% vs 24%) for the induction of remission [91]. Sandborn and colleagues showed that nicotine was superior to placebo (39% vs 9%) at producing clinical improvement [92]. The NNT to induce remission or result in clinical improvement in these two trials was 4 and 3 respectively. Alc

A six-week trial failed to demonstrate any benefit of transdermal nicotine over prednisolone 15 mg/day [93]. A more recent randomized controlled trial involving patients with left-sided ulcerative colitis that relapsed despite taking mesalamine 1 g twice daily, compared nicotine patches with prednisone, each given for five weeks [94]. The study found that the rate of relapse after nicotine was less than with prednisone (20% vs 60%), and that patients in the latter group relapsed earlier. Ald Two pilot studies found that nicotine enemas were effective for distal colitis, and randomized controlled trials are warranted [95, 96]. Thomas and associates reported the only randomized controlled trial of transdermal nicotine as maintenance therapy for ulcerative colitis [97]. The study demonstrated no benefit of nicotine 15 mg/day over placebo over a six240

month period, but this may be explained by poor compliance with the patch. Ald

New agents Many new approaches are being developed for the treatment of moderate to severe ulcerative colitis. Several have now been evaluated in randomized trials.

Apheretic techniques Apheretic techniques, in which leukocytes are removed by passing venous blood through absorption columns, have been widely reported to be effective, but virtually all the data are anecdotal, mainly from Japan. A single, small, randomized, controlled trial has been carried out in which 19 ulcerative colitis patients were randomized to receive apheresis or a sham procedure in addition to continuing their conventional therapy [98]. Apheresis appeared to be significantly more “effective” than the sham procedure (remission rates: apheresis 8/10, sham procedure 3/9, p < 0.05) and was well tolerated. However, in a randomized trial in which 168 patients were randomized in a 2 : 1 ratio to receive apheresis with the Adacolumn Apheresis System or sham apheresis for nine weeks of treatment, clinical remission rates (Mayo score 0–2, with scores of 0 on rectal bleeding and 0 or 1 on endoscopic examination) were: apheresis 17%, shamtreated 11%, p = 0.36. Clinical response was also observed to be similar in the two groups: apheresis 44%, shamtreated 39%, p = 0.62 [99]. Similar results were obtained in a smaller trial conducted in Europe and Japan. This form of therapy is not effective for patients with moderate to severe ulcerative colitis. A1c

Anti-integrin monoclonal antibodies Monoclonal antibodies to adhesion molecules, (a4ß7 integrin) have also been investigated in clinical trials, based on the hypothesis that inhibiting the recruitment of lymphocytes into the lamina propria might lead to a downregulation of the inflammation. Feagan et al. carried out a randomized placebo controlled trial of two doses (0.5 and 2.0 mg/kg) of the humanized α4β7 anti-body MLN02 in 181 patients with mildly to moderately active ulcerative colitis (median Ulcerative Colitis Clinical Score 7, median Modified Baron Score 3, minimum disease extent 25 cm) [100]. Remission rates two weeks after the two infusions were significantly greater in the MLN02-treated patients (MLN02 0.5 mg/kg 33%, 2.0 mg/kg 34%, placebo 15%; p = 0.03). Ala A single patient experienced mild angioedema following MLN02 infusion. Further studies of this agent are required.

Anti-interleukin-2 receptor antibodies Based on the favorable experience with intravenous cyclosporine, it is plausible that inhibition of interleukin-2

CHAPTER 12

Ulcerative colitis

by other, better tolerated, agents might be an effective therapeutic strategy. Preliminary studies that evaluated two different humanized monoclonal anti-bodies to the interleukin-2 receptor yielded promising results [101, 102]. However, this approach was not effective in a randomized, placebo-controlled dose ranging trial of daclizumab, a humanized antibody to the interleukin-2 receptor (CD25) in 159 patients with moderately severe colitis. The remission rates at week 8 were: daclizumab 1 mg/kg 2%, daclizumab 2 mg/kg 7% and placebo 10% (p = 0.11, 0.73 respectively, for comparisons of daclizumab doses with placebo). Alc

enemas were in clinical remission, as compared with 1 of 12 in the control group p < 0.001). Ald At the two-week assessment, disease-activity scores, sigmoidoscopic scores and histologic scores were all significantly better in the EGF group than in the placebo group (p < 0.01 for all comparisons), and this benefit was maintained at 4 weeks and at 12 weeks. Sandborn et al. conducted a randomized, placebo-controlled trial of the fibroblast growth factor repifermin at doses of 1–50 micrograms/kg infused daily for five days in patients with active ulcerative colitis who were receiving 5-ASA, steroids or azathioprine [110]. They found this agent to be safe but not effective at these doses. Ald

Anti-tumor necrosis factor (TNF) monoclonal antibodies

Probiotics

The anti-tumor necrosis factor (TNF) strategies have primarily been directed towards Crohn’s disease. Following many anecdotal reports of the use of infliximab for severe ulcerative colitis not responding to intravenous corticosteroids [103], and the reporting of two small randomized trials [104, 105], more definitive studies have been reported, and the results have been summarized in a Cochrane Review [106]. This systematic review included a meta-analysis of data from the two trials performed by Rutgeerts et al. that included 728 patients with moderate to severe ulcerative colitis refractory to conventional treatment using corticosteroids and/or immunosuppressive agents [107]. Infliximab (three intravenous infusions at 0, 2 and 6 weeks) was more effective than placebo in inducing clinical remission (Relative Risk (RR) 3.22; 95% CI: 2.18–4.76); inducing endoscopic remission (RR 1.88; 95% CI: 1.54–2.28); and in inducing clinical response (RR 1.99; 95% CI: 1.65–2.41) at eight weeks. A single infusion of infliximab was also more effective than placebo in reducing the need for colectomy within 90 days after infusion (RR 0.44; 95% CI: 0.22–0.87). A1a Severe adverse effects appear to be rare if patients are screened for latent tuberculosis.

Alpha interferon Pegylated interferon alpha in one of two doses (0.5 micrograms/kg or 1.0 micrograms/kg) infused weekly for 12 weeks was compared with placebo in a randomized trial in 60 patients who continued to receive conventional therapies (5-ASA, steroids, azathioprine) in stable doses [108]. A trend toward benefit with the lower dose of interferon was reported, but further studies are required. Ald

Epidermal and fibroblast growth factors Sinha et al. randomized 12 patients with active left-sided colitis or proctitis to receive daily enemas of the potent mitogenic epidermal growth factor (EGF), and 12 to receive placebo enemas for 14 days [109]. All patients received oral mesalamine. At two weeks 10 of the 12 patients given EGF

A popular theory regarding the pathogenesis of IBD contends that chronic inflammation is the result of an abnormal host response to the endogenous microflora. Thus, a sound rationale exists for attempts to modify host bacteria in the hope that this will down-regulate the pathological immune response [111]. Experiments in rodents have demonstrated the potential of this approach and preliminary studies in humans have been reported [112, 113]. Earlier studies evaluated single strains of non-pathogenic E. coli for maintenance of remission [114]. Kruis [109] randomly assigned 120 patients with ulcerative colitis in remission to receive either 1.5 g/day of 5-ASA or identically appearing tablets that contained Escherichia coli strain Nissle 1917 [115]. At the end of this one-year study 11.3% of patients who received 5-ASA relapsed as compared with 16.0% of those who received the probiotic (p > 0.05). Alc No serious adverse events were associated with active treatment. This study can be criticized because of the very low relapse rate observed in the control group, despite the rather modest dose of 5-ASA that was used. Moreover, the trial was not designed as a formal nonsuperiority study and therefore lacked sufficient statistical power to assess whether the treatments were clinically equivalent. Rembacken et al. randomized 116 patients with active disease to receive 5-ASA or the E. coli strain [114]. Treatment was continued for one year. At the end of the trial 73% of the patients who had entered remission with conventional therapy relapsed as compared with 67% of those assigned to the probiotic (p > 0.05). The authors concluded that the two strategies were of equivalent efficacy. Alc In a randomized trial that was designed as a formal non-superiority study, 109 randomized 327 patients with quiescent disease to 200 mg once daily of the probiotic or 500 mg three times daily of 5-ASA for 12 months of treatment. The rate of relapse was 45% in patients who received E. coli Nissle 1917 compared with 36% (absolute difference 9%) in favor of 5-ASA and met the investigators’ prespecified criterion for therapeutic equivalence [116]. Ala 241

(a) Topical and oral 5-ASA

Remission

Refractory

Oral 5-ASA

Topical steroid

Maintenance

Failure

Relapse

Resume topical therapy

Consider probiotic

Refractory

Consider oral steroid as for mild colitis

(b)

Moderate * MODERATE

MILD

SEVERE

Oral 5-ASA Remission

Refractory

Oral 5-ASA maintenance

Consider probiotic Remission

Refractory IV Steroid Oral steroid

Remission

Refractory

Remission

IV infliximab ± azathioprine

5-ASA maintenance Prolonged remission

Refractory

Remission

Refractory

Maintain

Early relapse

Relapse Azathioprine Relapse

Consider IV cyclosporine Failure or relapse Consider proctocolectomy

* A trial of therapy as for mild disease may be attempted prior to initiating steroid therapy Figure 12.4 (a) Algorithm for management of distal ulcerative colitis. (b) Algorithm for management of more extensive ulcerative colitis.

CHAPTER 12

In summary, these results from relatively large randomized trials provide evidence that probiotics are useful for maintenance of remission in ulcerative colitis. A1c More recently the probiotic preparation VSL #3 that contains a high concentration of eight lyophilized bacterial strains was compared to a placebo containing lyophilized maize powder for induction of remission in 47 patients with mild or moderately active ulcerative colitis [117]. A majority of patients continued with mesalamine therapy alone (VSL #3 89.6%, placebo 67.1%), or in combination with immunosuppressants (VSL #3 6.4%, placebo 21.4%). Clinical remission was observed significantly more frequently in the VSL #3 treated groups (VSL #3 42.9%, placebo 15.7%, p < 0.001). No major adverse events were encountered. This study provides evidence that probiotics may be useful as an adjunct to conventional therapy for induction of remission of mild to moderately active ulcerative colitis. A1d

Surgery Colectomy with construction of an ileal pouch-anal anastomosis has become the operation of choice for ulcerative colitis in major centers. Precise details of pouch construction may affect the eventual functional outcome, although a “J” pouch with 20 cm limbs and a stapled anastomosis 1.0–1.5 cm above the dentate line is the best for most patients [118–120]. Pouch dysfunction remains a frequent problem, and is often due to “pouchitis”. The management of this disorder is addressed in Chapter 13.

Algorithm for management of ulcerative colitis When endoscopic evaluation leads to the diagnosis of distal ulcerative colitis, the evidence for efficacy of interventions to induce and maintain remission supports the management algorithm shown in Figure 12.4a. Therapy should be initiated with topic and oral 5-ASA preparations. If the disease enters remission, maintenance therapy with an oral 5-ASA preparation should be continued. If the disease relapses, topical therapy may be resumed and may be continued for maintenance of remission. Distal disease that is refractory to a topical 5-ASA preparation may be treated with a topical steroid preparation. Although there is evidence that the 5-ASA preparations are more effective, and there is no good evidence that switching to topical steroids is effective, the latter approach is a logical one that may be successful in some patients. Failure to respond to oral and topical 5-ASA should also lead to consideration of adding a probiotic preparation (E. coli Nissile 1917 or VSL #3). Patients in whom distal disease is refractory to these interventions should be considered for interventions proven to be effective for mild but more extensive

Ulcerative colitis

disease, as outlined in Figure 12.4b. The choice of interventions for treatment of more extensive colitis should be made after classifying the clinical disease severity as mild, moderate or severe. Mild disease should be treated with an oral 5-ASA. If the disease is refractory to this approach the addition of the probiotic preparation VSL #3 may be considered. If remission is achieved with these interventions the 5-ASA preparation, and possibly the probiotic, should be continued for maintenance therapy. Moderately severe disease, and mild disease that is refractory to 5-ASA and probiotic therapy, should be treated with oral steroid. It is appropriate to treat some patients with moderately severe disease initially as outlined for mild disease, rather than initiating corticosteroid therapy, but the patients should be closely monitored for an increase in severity that would be a strong indication for steroid therapy. If remission is achieved maintenance therapy with oral 5-ASA is continued. Refractory colitis and early or frequently relapsing disease should lead to a consideration of introducing azathioprine therapy. Severe colitis should be treated with IV steroids for a minimum of five days. Severe colitis that is refractory to IV steroids, and moderately severe disease that is refractory to or relapses on the regimen outline above, may be treated with IV Remicade as the next line of induction therapy. If remission is achieved maintenance therapy with Remicade and/or azathioprine should be considered. Patients with severe or moderately severe disease that is either refractory to IV Remicade or relapses in spite of maintenance therapy, should be advised to consider proctocolectomy. This option, rather than immunosuppressive therapy with Remicade or azathioprine, may also be selected by some patients with less severe refractory or frequently relapsing disease. IV cyclosporine is another alternative therapy that may be considered for some patients with severe refractory disease who are reluctant to proceed to surgery, but the risk of severe adverse effects is relatively high, and a majority of such patients will eventually undergo proctocolectomy.

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102 Creed TJ, Norman MR, Probert CS et al. Basiliximab (anti-CD25) in combination with steroids may be an effective new treatment for steroid-resistant ulcerative colitis. Aliment Pharmacol Ther 2003; 18(1): 65–75. 103 Gornet JM, Couve S, Hassani Z et al. Infliximab for refractory ulcerative colitis or indeterminate colitis: an open-label multicentre study. Aliment Pharmacol Ther 2003; 18(2): 175–181. 104 Probert CS, Hearing SD, Schreiber S et al. Infliximab in moderately severe glucocorticoid resistant ulcerative colitis: a randomised controlled trial. Gut 2003; 52(7): 998–1002. 105 Ochsenkuhn T, Sackmann M, Goke B. Infliximab for acute, not steroid-refractory ulcerative colitis: a randomized pilot study. Eur J Gastroenterol Hepatol 2004; 16(11): 1167–1171. 106 Lawson MM, Thomas AG, Akobeng AK. Tumour necrosis factor alpha blocking agents for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2006; 3: CD005112. 107 Rutgeerts P, Sandborn WJ, Feagan BG et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005; 353(23): 2462–2476. 108 Tilg H, Vogelsang H, Ludwiczek O et al. A randomised placebo controlled trial of pegylated interferon alpha in active ulcerative colitis. Gut 2003; 52(12): 1728–1733. 109 Sinha A, Nightingale J, West KP, Berlanga-Acosta J, Playford RJ. Epidermal growth factor enemas with oral mesalamine for mild-to-moderate left-sided ulcerative colitis or proctitis. N Engl J Med 2003; 349(4): 350–357. 110 Sandborn WJ, Sands BE, Wolf DC et al. Repifermin (keratinocyte growth factor-2) for the treatment of active ulcerative colitis: a randomized, double-blind, placebo-controlled, dose-escalation trial. Aliment Pharmacol Ther 2003; 17(11): 1355–1364. 111 Shanahan F. Probiotics and inflammatory bowel disease: from fads and fantasy to facts and future. Br J Nutr 2002; 88(Suppl. 1): S5–9.

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112 McCarthy J, O’Mahony L, O’Callaghan L et al. Double blind, placebo controlled trial of two probiotic strains in interleukin 10 knockout mice and mechanistic link with cytokine balance. Gut 2003; 52(7): 975–980. 113 Madsen KL. Inflammatory bowel disease: lessons from the IL-10 gene-deficient mouse. Clin Invest Med 2001; 24(5): 250–257. 114 Rembacken BJ, Snelling AM, Hawkey PM, Chalmers DM, Axon AT. Non-pathogenic Escherichia coli versus mesalazine for the treatment of ulcerative colitis: a randomised trial. Lancet 1999; 354(9179): 635–639. 115 Kruis W, Schutz E, Fric P, Fixa B, Judmaier G, Stolte M. Doubleblind comparison of an oral Escherichia coli preparation and mesalazine in maintaining remission of ulcerative colitis. Aliment Pharmacol Ther 1997; 11(5): 853–858. 116 Kruis W, Fric P, Pokrotnieks J et al. Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine. Gut 2004; 53(11): 1617–1623. 117 Sood A, Midha V, Makharia GK et al. The probiotic preparation, VSL#3 induces remission in patients with mild-to-moderately active ulcerative colitis. Clin Gastroenterol Hepatol 2009; 7(11): 1202–1209, 1209.e1. 118 Romanos J, Samarasekera DN, Stebbing JF, Jewell DP, Kettlewell MG, Mortensen NJ. Outcome of 200 restorative proctocolectomy operations: the John Radcliffe Hospital experience. Br J Surg 1997; 84(6): 814–818. 119 Setti-Carraro P, Ritchie JK, Wilkinson KH, Nicholls RJ, Hawley PR. The first 10 years’ experience of restorative proctocolectomy for ulcerative colitis. Gut 1994; 35(8): 1070–1075. 120 McIntyre PB, Pemberton JH, Wolff BG, Beart RW, Dozois RR. Comparing functional results one year and ten years after ileal pouch–anal anastomosis for chronic ulcerative colitis. Dis Colon Rectum 1994; 37(4): 303–307.

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Pouchitis after restorative proctocolectomy Darrell S Pardi and William J Sandborn Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, USA

Introduction Approximately 30% of patients with ulcerative colitis will require colectomy for fulminant or medically refractory disease, or because of dysplasia or another complication [1, 2]. The preferred operation for most patients is a restorative proctocolectomy, also known as a total proctocolectomy with ileal pouch anal anastomosis (IPAA). Although many studies have shown excellent quality of life in patients who have undergone IPAA, complications are common after this operation [3, 4]. Pouchitis, an idiopathic inflammatory condition in the pouch, is the most common, occurring in up to 60% of patients after IPAA for ulcerative colitis [1–7]. It has been estimated that the number of patients with pouchitis in the USA will reach 30,000–45,000 persons, or a prevalence of 12–18/100,000 [8]. Thus, pouchitis has emerged as an important third form of inflammatory bowel disease (IBD). Despite these facts, criteria for diagnosis, classification and measurement of disease activity in pouchitis are still evolving. The previous lack of consensus on these issues hampered the design and conduct of randomized trials of proposed interventions, and medical therapy for pouchitis was largely empirical. This lack of consensus also makes it difficult to analyse the existing literature due to differing definitions or categories of disease and differing criteria for response or remission. In 1994, the Pouchitis Disease Activity Index (PDAI), an instrument to measure disease activity and efficacy of therapy, was developed [9]. This index facilitated clinical research in pouchitis, and there are now 13 controlled trials, and many more uncontrolled

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studies, of various agents for induction and maintenance therapy in pouchitis. The medical therapies reported to be of benefit for pouchitis are shown in Table 13.1. This chapter will assist physicians and surgeons in becoming familiar with the diagnosis and classification of pouchitis, and will review the results from reports of empirical medical therapies and controlled trials, and the rationale for using various treatments.

Diagnosis and classification Pouchitis is suggested by variable clinical symptoms, including increased stool frequency, decreased stool consistency, abdominal cramping, fecal urgency, tenesmus, incontinence, and occasionally rectal bleeding, fever or extra-intestinal manifestations such as arthralgias. Since these symptoms are non-specific, a clinical suspicion of pouchitis should be confirmed by endoscopy and biopsy of the pouch [1]. Endoscopic examination shows inflammatory changes, which may include mucosal edema, granularity, contact bleeding, loss of vascular pattern, hemorrhage and ulceration [10]. Histologic examination shows acute inflammation with neutrophil infiltration and occasionally mucosal ulceration, superimposed on a background of chronic changes including villous atrophy, crypt hyperplasia and chronic inflammatory cell infiltration [11, 12]. Endoscopic examination of the neo-terminal ileum above the ileal pouch should be normal. Significant inflammation in this location is suggestive of Crohn’s disease [10]. In addition, the anal transition zone, or rectal cuff, should also be inspected endoscopically [10]. Inflammation here is termed cuffitis, and can exist with or without pouchitis. The PDAI is a quantitative 19-point index of pouchitis activity based on clinical symptoms and findings on endoscopy and histology (Table 13.2). Active pouchitis is defined as a PDAI score ≥ 7 points and remission is defined as a

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Pouchitis after restorative proctocolectomy

Table 13.1 Treatments reported to be beneficial for pouchitis.

Table 13.2 Pouchitis disease activity index (PDAI).

Antibiotics • Single antibiotics Ciprofloxacin, metronidazole, amoxicillin/clavulanate, erythromycin, tetracycline, rifaximin • Combination antibiotics Ciprofloxacin + metronidazole, ciprofloxacin + rifaximin, ciprofloxacin + tinidazole

Clinical criteria

Score

Stool frequency Usual postop stool frequency 1–2 stools/day > postop usual 3 or more stools/day > postop usual

0 1 2

Rectal bleeding None or rare Present daily

0 1

Fecal urgency/abdominal cramps None Occasional Usual

0 1 2

Fever (temperature > 100.5° F) Absent Present

0 1

Endoscopic criteria Edema Granularity Friability Loss of vascular pattern Mucus exudate Ulceration

1 1 1 1 1 1

Probiotic bacteria • Lactobacilli, Bifidobacteria, Streptococci (VSL#3) • Escherichia coli strain Nissle 1917 5-Aminosalicylates • Mesalamine enemas • Oral mesalamine • Sulfasalazine Corticosteroids • Conventional corticosteroid enemas • Budesonide suppositories • Budesonide enemas • Oral corticosteroids Immune modifier agents • Cyclosporin enema • Azathioprine, 6-mercaptopurine • Infliximab Nutritional agents • Short chain fatty acids enemas or suppositories • Glutamine suppositories • Dietary fiber (pectin, methylcellulose, inulin) Oxygen radical inhibitors • Allopurinol Antidiarrheal/antimicrobial • Bismuth carbomer enemas • Bismuth subsalicylate Modified with permission from Mahadevan and Sandborn. Gastroenterology 2003; 124: 1636–1650.

PDAI score < 7 points, assuming other causes of pouch inflammation have been excluded. Patients with pouchitis can be classified according to disease activity (mild, moderate, or severe), symptom duration, disease pattern or response to antibiotics [1]. Duration can be classified as acute (20 mg per day) [10]. A small RCT on prednisolone, showed no statistically significant effect but the duration of the trial (two weeks) was probably too short.

Bismuth subsalicylate In a small pilot trial with oral bismuth subsalicylate 2.4 g daily vs placebo for eight weeks, patients with collagenous colitis given active treatment were more likely to improve clinically (p = 0.003) as well as histologically (p = 0.003). Patients with lymphocytic colitis given bismuth subsalicylate had no clinical or histological improvement, compared to placebo.

Other anti-inflammatory compounds Sulphasalazine and mesalazine have been extensively used in microscopic colitis, and in a recent trial, 64 patients with collagenous or lymphocytic colitis were randomised to mesalazine 2.4 g/day or mezalazine 2.4 g/day + cholestyramine 4 g/day for six months. A high remission rate was seen in both treatment arms, with 85% of patients with lymphocytic colitis and 91% of patients with collagenous colitis in remission at the end of the study. Combined therapy was superior in collagenous colitis and induced an earlier clinical response in both diseases [120]. Retrospective assessments of sulphasalazine and mesalazine have reported benefit in 34–50% of the patients [10, 109]. Antibiotics such as metronidazole and erythromycin have been used, but have not been studied in controlled trials. Two studies showed no statistical evidence for the effectiveness of Boswellia serrata extract, or probiotics, although these small studies probably lacked power [121, 122]. 262

Recommended therapy Based on a meta-analysis and RCTs, short or medium time therapy with oral budesonide is the drug of choice for the treatment of collagenous and lymphocytic colitis in patients with significant symptoms that cannot be controlled with loperamide, cholestyramine or aminosalicylates. A1c Oral budesonide may even be more efficacious than conventional systemic corticosteroids (e.g. prednisolone) [124]. Local effects of budesonide on the terminal ileum may be of importance in explaining this apparent advantage. Budesonide has a benign safety profile, as proven in other IBD-conditions, but it would be prudent to taper the dose to the minimum necessary for controlling symptoms in patients with microscopic colitis if more than eight weeks of therapy is required. C5 As mentioned above, there was no difference in the median time to relapse between budesonide and placebo after stopping treatment [117]. Most candidates for longer term budesonide treatment are females aged 50–70 years, a group with an increased risk for osteoporosis. In this respect, budesonide has been demonstrated to have less impact than prednisolone on bone mineral density in patients with Crohn’s disease during treatment for up to two years [125]. Budesonide therapy given on demand may be an attractive option for long-term control of symptoms. C5 Although we have positive expe-

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rience from this approach in our own clinical practice, controlled data are lacking. Bismuth subsalicylate therapy may be an alternative to budesonide, but it is not available in all countries due to toxicity concerns. A1d Severe attacks of microscopic colitis are rare, but a small number of patients may require hospitalisation, intravenous steroid therapy, bowel rest and total parenteral nutrition. For steroid-refractory or steroid dependent patients immunomodulators may be of value. In an uncontrolled trial azathioprine therapy resulted in partial or complete remission in eight of nine patients with microscopic colitis [126]. B4 In another uncontrolled trial low dose methotrexate (median dose 7.5 mg/week) showed benefit in 16 of 19 patients with prednisolone-refractory collagenous colitis [127]. B4

Surgical treatment If medical therapy fails and alternative diagnoses are ruled out surgery may be considered in a patient with intractable microscopic colitis. Split ileostomy was conducted successfully in nine women with collagenous colitis [43] and successful outcomes both in collagenous colitis and lymphocytic colitis have been reported after total or subtotal colectomy [128–132]. B4

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69 Piche T, Raimondi V, Schneider S, Hebuterne X, Rampal P. Acarbose and lymphocytic colitis. Lancet 2000; 356(9237): 1246. 70 Mennecier D, Gros P, Bronstein JA, Thiolet C, Farret O. Chronic diarrhea due to lymphocytic colitis treated with piroxicam beta cyclodextrin. Presse Med 1999; 28(14): 735–737. 71 Rassiat E, Michiels C, Sgro C, Yaziji N, Piard F, Faivre J. Lymphocytic colitis due to Modopar. Gastroenterol Clin Biol 2000; 24(8–9): 852–853. 72 Mahajan L, Wyllie R, Goldblum J. Lymphocytic colitis in a pediatric patient: a possible adverse reaction to carbamazepine. Am J Gastroenterol 1997; 92(11): 2126–2127. 73 Linares Torres P, Fidalgo Lopez I, Castanon Lopez A, Martinez Pinto Y. Lymphocytic colitis as a cause of chronic diarrhea: Possible association with carbamazepine. Aten Primaria 2000; 25(5): 366–367. 74 Macaigne G, Boivin JF, Chayette C, Cheaib S, Deplus R. Oxetorone-associated lymphocytic colitis. Gastroenterol Clin Biol 2002; 26(5): 537. 75 Ghilain JM, Schapira M, Maisin JM et al. Lymphocytic colitis associated with lansoprazole treatment. Gastroenterol Clin Biol 2000; 24(10): 960–962. 76 Bohr J, Tysk C, Yang P, Danielsson D, Järnerot G. Autoantibodies and immunoglobulins in collagenous colitis. Gut 1996; 39(1): 73–76. 77 Eusufzai S, Löfberg R, Veress B, Einarsson K, Angelin B. Studies on bile acid metabolism in collagenous colitis: No evidence of bile acid malabsorption as determined by the SeHCAT test. Eur J Gastroenterol Hepatol 1992; 4(4): 317–321. 78 Ung KA, Gillberg R, Kilander A, Abrahamsson H. Role of bile acids and bile acid binding agents in patients with collagenous colitis. Gut 2000; 46(2): 170–175. 79 Ung KA, Kilander A, Willen R, Abrahamsson H. Role of bile acids in lymphocytic colitis. Hepatogastroenterology 2002; 49(44): 432–437. 80 Fernandez-Banares F, Esteve M, Salas A, Forne TM et al. Bile acid malabsorption in microscopic colitis and in previously unexplained functional chronic diarrhea. Dig Dis Sci 2001; 46(10): 2231–2238. 81 Andersen T, Andersen JR, Tvede M, Franzmann MB. Collagenous colitis: are bacterial cytotoxins responsible? Am J Gastroenterol 1993; 88(3): 375–377. 82 Lundberg JON, Herulf M, Olesen M et al. Increased nitric oxide production in collagenous and lymphocytic colitis. Eur J Clin Invest 1997; 27(10): 869–871. 83 Perner A, Andresen L, Normark M, Rask-Madsen J. Constitutive expression of inducible nitric oxide synthase in the normal human colonic epithelium. Scand J Gastroenterol 2002; 37(8): 944–948. 84 Olesen M, Middelveld R, Bohr J et al. Luminal nitric oxide and epithelial expression of inducible and endothelial nitric oxide synthase in collagenous and lymphocytic colitis. Scand J Gastroenterol 2003 Jan; 38(1): 66–72. 85 Bonderup OK, Hansen JB, Madsen P, Vestergaard V, Fallingborg J, Teglbjaerg PS. Budesonide treatment and expression of inducible nitric oxide synthase mRNA in colonic mucosa in collagenous colitis. Eur J Gastroenterol Hepatol 2006 (Oct); 18(10): 1095–1099. 86 Perner A, Andresen L, Normark M et al. Expression of nitric oxide synthases and effects of L-arginine and L- NMMA on

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104 Mullhaupt B, Guller U, Anabitarte M, Guller R, Fried M. Lymphocytic colitis: clinical presentation and long term course. Gut 1998; 43(5): 629–633. 105 Bohr J, Jones I, Tysk C, Järnerot G. Serum procollagen III propeptide is not of diagnostic predictive value in collagenous colitis. Inflamm Bowel Dis 1995; 1: 276–279. 106 Kiesslich R, Hoffman A, Goetz M et al. In vivo diagnosis of collagenous colitis by confocal endomicroscopy. Gut 2006 (Apr); 55(4): 591–592. 107 Zambelli A, Villanacci V, Buscarini E, Bassotti G, Albarello L. Collagenous colitis: a case series with confocal laser microscopy and histology correlation. Endoscopy 2008 (Jul); 40(7): 606–608. 108 Bowling TE, Price AB, al-Adnani M, Fairclough PD, MenziesGow N, Silk DB. Interchange between collagenous and lymphocytic colitis in severe disease with autoimmune associations requiring colectomy: A case report. Gut 1996; 38(5): 788–791. 109 Pardi DS, Ramnath VR, Loftus EV, Jr., Tremaine WJ, Sandborn WJ. Lymphocytic colitis: clinical features, treatment, and outcomes. Am J Gastroenterol 2002; 97(11): 2829–2833. 110 Pardi DS, Smyrk TC, Tremaine WJ, Sandborn WJ. Microscopic colitis: A review. Am J Gastroenterol 2002; 97(4): 794–802. 111 Chande N, McDonald JWD, MacDonald JK. Interventions for treating collagenous colitis. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD003575. DOI: 10.1002/ 14651858.CD003575.pub5. 112 Chande N, McDonald JWD, MacDonald JK. Interventions for treating lymphocytic colitis. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD006096. DOI: 10.1002/14651858. CD006096.pub3. 113 Baert F, Schmit A, D’Haens G et al. Budesonide in collagenous colitis: a double-blind placebo-controlled trial with histologic follow-up. Gastroenterology 2002; 122(1): 20–25. 114 Miehlke S, Heymer P, Bethke B et al. Budesonide treatment for collagenous colitis: A randomized, double- blind, placebocontrolled, multicenter trial. Gastroenterology 2002; 123(4): 978–984. 115 Bonderup OK, Hansen JB, Birket-Smith L, Vestergaard V, Teglbjaerg PS, Fallingborg J. Budesonide treatment of collagenous colitis: A randomised, double blind, placebo controlled trial with morphometric analysis. Gut 2003; 52(2): 248–251. 116 Miehlke S, Madisch A, Bethke B et al. Budesonide for maintenance treatment of collagenous colitis – a randomized, doubleblind, placebo-controlled trial. United European Gastroenterology Week 2007. 2007: No. PS-M-13. 117 Bonderup OK, Hansen JB, Teglbjoerg PS, Christensen LA, Fallingborg JF. Long-term budesonide treatment of collagenous colitis: a randomised, double-blind, placebo-controlled trial. Gut 2009 (Jan); 58(1): 68–72. 118 Munck LK, Kjeldsen J, Philipsen E, Fischer Hansen B. Incomplete remission with short-term prednisolone treatment in collagenous colitis: A randomized study. Scand J Gastroenterol 2003; 38(6): 606–610.

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119 Fine KD, Ogunji F, Lee E, Lafon G, Tanzi M. Randomized, double blind, placebo-controlled trial of bismuth subsalicylate for microscopic colitis. Gastroenterology 1999; 116(4): A880. 120 Calabrese C, Fabbri A, Areni A, Zahlane D, Scialpi C, Di Febo G. Mesalazine with or without cholestyramine in the treatment of microscopic colitis: randomized controlled trial. J Gastroenterol Hepatol 2007 (Jun); 22(6): 809–814. 121 Wildt S, Munck LK, Vinter-Jensen L et al. Probiotic treatment of collagenous colitis: A randomized, double-blind, placebo-controlled trial with Lactobacillus acidophilus and Bifidobacterium animalis subsp. Lactis. Inflamm Bowel Dis 2006 May; 12(5): 395–401. 122 Madisch A, Miehlke S, Eichele O et al. Boswellia serrata extract for the treatment of collagenous colitis. A double-blind, randomized, placebo-controlled, multicenter trial. Int J Colorectal Dis 2007 (Dec); 22(12): 1445–14451. 123 Miehlke S, Madisch A, Bethke B et al. Budesonide in lymphocytic colitis – a randomized, double-blind, placebocontrolled trial. Gastroenterology 2007; 132(4, Suppl 2): A131–A132. 124 Lanyi B, Dries V, Dienes HP, Kruis W. Therapy of prednisonerefractory collagenous colitis with budesonide. Int J Colorectal Dis 1999; 14(1): 58–61. 125 Schoon EJ, Bollani S, Mills PR et al. Bone mineral density in relation to efficacy and side effects of budesonide and prednisolone in Crohn’s disease. Clin Gastroenterol Hepatol 2005 (Feb); 3(2): 113–121. 126 Pardi DS, Loftus EV, Jr., Tremaine WJ, Sandborn WJ. Treatment of refractory microscopic colitis with azathioprine and 6-mercaptopurine. Gastroenterology 2001; 120(6): 1483–1484. 127 Riddell J, Hillman L, Chiragakis L, Clarke A. Collagenous colitis: Oral low-dose methotrexate for patients with difficult symptoms: Long-term outcomes. J Gastroenterol Hepatol. 2007 (Oct); 22(10): 1589–1593. 128 Alikhan M, Cummings OW, Rex D. Subtotal colectomy in a patient with collagenous colitis associated with colonic carcinoma and systemic lupus erythematosus. Am J Gastroenterol 1997; 92(7): 1213–1215. 129 Yusuf TE, Soemijarsih M, Arpaia A, Goldberg SL, Sottile VM. Chronic microscopic enterocolitis with severe hypokalemia responding to subtotal colectomy. J Clin Gastroenterol 1999; 29(3): 284–288. 130 Williams RA, Gelfand DV. Total proctocolectomy and ileal pouch anal anastomosis to successfully treat a patient with collagenous colitis. Am J Gastroenterol. 2000; 95(8): 2147. 131 Varghese L, Galandiuk S, Tremaine WJ, Burgart LJ. Lymphocytic colitis treated with proctocolectomy and ileal J-pouch-anal anastomosis: report of a case. Dis Colon Rectum 2002; 45(1): 123–126. 132 Riaz AA, Pitt J, Stirling RW, Madaan S, Dawson PM. Restorative proctocolectomy for collagenous colitis. J R Soc Med 2000; 93(5): 261.

Plate 14.1 Biopsy from colon showing typical features of collagenous colitis-increased subepithelial collagen layer, inflammation of lamina propria and epithelial lesions with intraepithelial lymphocytes.

Plate 14.2 Biopsy from colon showing typical features of lymphocytic colitis-epithelial lesions with intraepithelial lymphocytes and inflammation in the lamina propria.

Evidence-Based Gastroenterology and Hepatology, Third Edition John WD McDonald, Andrew K Burroughs, Brian G Feagan and M Brian Fennerty © 2010 Blackwell Publishing Ltd. ISBN: 978-1-405-18193-8

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Drug-induced diarrhea Bincy P Abraham and Joseph H Sellin Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, USA

Drug induced diarrhea More than 700 drugs have been implicated as causing diarrhea, accounting for approximately 7% of all drug adverse effects [1]. However, the mechanism of action by which certain drugs contribute to this adverse effect is not well known. Drug-induced diarrhea is frequently suspected in patients who develop it soon after starting a new medication. However, there is usually only circumstantial evidence to support the link. The medication is usually stopped, and when the diarrhea resolves, the side effect will be attributed to that medication. The basic mechanisms are rarely investigated in these cases. Therefore, our understanding of specific drug-induced diarrheas may vary from solid understanding, to reasonable hypothesis, to considerable conjecture. Although it is clear that drug-induced diarrhea is common, employing an evidence-based approach to this topic quickly creates considerable conundrums. Evidencebased medicine focuses on both the accuracy of diagnosis and the efficacy of treatment. Both are problematic for drug-induced diarrhea. For well-established (i.e. “old”) drugs, there rarely are controlled trials to quantify and characterize the association between a specific agent and diarrhea. The information for these drugs is derived from cohort or case-control studies. Although these studies may provide weaker evidence than controlled trials due to potential for biases in statistical analysis, they do provide better evidence than case-reports or case-series that lack control groups. For newer drugs that have gone through clinical trials, the assessment of adverse events permits a reasonable opportunity to characterize the frequency of drug-associated

Evidence-Based Gastroenterology and Hepatology, Third Edition John WD McDonald, Andrew K Burroughs, Brian G Feagan and M Brian Fennerty © 2010 Blackwell Publishing Ltd. ISBN: 978-1-405-18193-8

diarrhea. However, even with clinical trials, there may be a considerable variability in the incidence of an adverse event such as diarrhea. This variability may depend on the underlying disease, the definition of the adverse event, and the type of clinical trial. For example, most randomized controlled trials (RCTs) are short in duration, thus magnifying or minimizing an adverse effect in reference to the time a patient is exposed to the drug, compared to longterm follow-up observational studies. Also, diarrhea as an adverse event is rarely defined clearly. Thus, a minimal change in consistency and a significant increase in stool volume would both be labeled “diarrhea”. Evidence of the mechanisms underlying the diarrhea elicited by a specific drug may be elusive and serendipitous. For example, theophylline has been a standard for eliciting intestinal secretion in basic physiology. Thus, the effects of xanthine oxidase inhibitors are well understood. Similarly, as moleculary-designed agents move from the bench to the bedside, there may be considerable understanding of the underlying mechanism. However, for many drugs, the purported mechanisms are based on small fragmentary studies or simple speculation. Table 15.1 lists drugs that cause diarrhea, according to the frequency with which they produce this adverse effect. In order to have a basic understanding on what mechanisms played a role in contributing to diarrhea, the patient’s stool characteristics can provide some clues. Diarrhea can be broadly categorized based on the following stool characteristics: (1) watery, a category that includes changes in ion transport, shortened transit time, or increased motility (2) inflammatory, and (3) fatty. This review will examine the mechanism of drug-induced diarrhea within these broad classifications. However, as with other diarrheas, the process is frequently multifactorial. The gastrointestinal tract is regulated through the integration of paracrine, immune, neural, and endocrine systems that coordinate changes in mucosal and muscular function and adapt to changing conditions (see Figure 15.1) [2]. These systems involve mechanisms that regulate mucosal permeability, 267

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Drugs that cause diarrhea in ≥ 10 % of patients Antibiotics Chemotherapeutic agents Cholinergic drugs Cisapride (off the market) Digoxin Immunosuppressives agents Metoclopramide Orlistat (lipase inhibitor) Osmotic laxatives Poorly or non-absorbable carbohydrates Selective serotonin reuptake inhibitors Ticlopidine Drugs that occasionally cause diarrhea 5-aminosalicylates (especially olsalazine) Acetylcholinesterase inhibitors Anticholinergics Caffeine Calcitonin Carbamazepine Chenodeoxycholic acid Cholestyramine Cholinesterase inhibitors Cimetidine Ferrous sulfate preparations (rare) Flavanoid related veinotonic agents HMG-CoA reductase inhibitors Irinotecan Isotretinoin Levodopa-benserazide Magnesium antacids Methyldopa Motilin agonists Non-steroidal anti-inflammatory drugs Octreotide Penicillamine Prebiotics Proton pump inhibitors Tacrine Tegaserod (off the market) Theophylline Thyroid hormones

268

Par

acr

rine doc En

Drugs that cause diarrhea in ≥ 20% of patients Alpha-glucosidase inhibitors Biguanides Auronafin (gold salt) Colchicine Diacerein Highly active antiretroviral therapy Prostaglandins Tyrosine kinase inhibitors

Ne ura l

i ne

Table 15.1 Drugs that cause diarrhea.

PINES

Paracellular pathway

Blood flow

Epithelium Muscle

Permeability

Transport

Motility

Metabolism

Figure 15.1 “PINES” regulatory system in the intestine. The regulatory system of the intestine integrates paracrine, immune, neural, and endocrine systems and produces coordinated changes in mucosal and muscular function that permit adaptive responses to changing conditions. The regulatory system can widen or narrow the paracellular pathway that governs passive transmucosal permeation of electrolytes, accelerate or retard the transepithelial movement of nutrients and electrolytes by affecting membrane channels and pumps, relax or contract the various muscle layers in the intestine, and increase or decrease mucosal blood flow. Acting simultaneously, these mechanisms regulate mucosal permeability, intestinal transport, and the motility and metabolism of the gut. (From Sellin JH (1997) Small intestine: Functional anatomy, fluid and electrolyte absorption. In: Feldman M and Schiller LR (eds) Gastroenterology and Hepatology. The Comprehensive Visual Reference, vol. 7. Current Medicine, Philadelphia, 1997. p. 1.11.)

intestinal transport, and the motility and metabolism of the gut [2]. Medications may influence this regulatory system through these different pathways and contribute to diarrhea. This influence may be part of the pharmacologic effect of the drug. In other cases there may be an allergic reaction, or possibly a pharmacogenomic component. Diarrhea may be an appropriate physiologic response to the drug. On occasion, the drug may cause direct tissue injury. Clinically, if drug-induced diarrhea is suspected, the simplest approach is to switch to an alternative medication or treat with an antidiarrheal agent. Novel approaches for certain drug-associated diarrheas have been shown to be effective in treatment. In some cases, diarrhea may resolve with continued use. Thus, for most examples of drug-induced diarrhea, therapeutic trials are not relevant. Only where there are no satisfactory alternatives, as is the case for some anti-cancer therapies, is there sufficient impetus to understand the mechanisms of drug-induced diarrhea. Thus, there probably has been more significant and novel evidence in druginduced diarrhea obtained in the field of oncology.

CHAPTER 15

Watery diarrhea Watery diarrheas have been classified as either secretory or osmotic to explain underlying pathophysiology. However, the clinical utility of this classification has not been rigorously tested.

Osmotic diarrhea Osmotic diarrheas can occur from intentional use of a drug as part of its mechanism of action, or unintentionally. Poorly absorbed solute traps fluid in the lumen, and these unabsorbable solutes account for osmotic activity of stool water [2]. The most common medications associated with osmotic diarrhea are magnesium containing salts and laxatives such as sodium phosphates and long-chain polyethylene glycols, e.g. Miralax (Schering-Plough, Kenilworth, NJ) used for treatment of constipation, and for pre-colonoscopy colon purging [3, 4]. Their cathartic action results from poor absorption in the gastrointestinal tract, leading to osmotically mediated water retention, stimulating peristalsis [4]. The usual dose of magnesium salts produces 300 to 600 ml of stool within six hours [4]. Sodium phosphates cause osmotic diarrhea, but without producing an osmotic gap [5]. Used for constipation and for the treatment of hepatic encephalopathy, lactulose is a synthetic non-absorbable disaccharide that is known to cause diarrhea through this mechanism. Poorly-absorbed fructose, found in fruit juices and carbonated beverages, and non-absorbable sorbitol and mannitol, found in sugar-free candies and gums, may not cause diarrhea until 24 to 48 hours after ingestion. Acarbose and miglitol, used for the treatment of diabetes, prevent the breakdown of carbohydrates to monosaccharides by inhibition of intestinal alpha-glucosidase, causing diarrhea. In a multicenter RCT of 286 patients comparing acarbose to placebo, tolbutamide and tolbutamide-plusacarbose in NIDDM, 27% of patients taking acarbose and 35% taking acarbose + tolbutamide complained of diarrhea in comparison to 6% of patients taking placebo or tolbutamide (p < 0.05) [6]. Diarrhea is minimized by starting therapy at low doses (50 mg three times daily), and tends to decrease with time [7]. In the large-scale, multinational study investigating different doses of acarbose (from 25 mg tid to 200 mg tid) good patient tolerability and compliance was observed, even at the highest dose [8]. The study also confirmed the marked tendency for adverse effects to decline after 4–6 weeks. Interestingly, in a post-market surveillance study of almost 20,000 patients (both NIDDM and IDDM, only 3.2% of those taking acarbose complained of diarrhea [9]. What can explain this difference between the surveillance study

Drug-induced diarrhea

and the RCT? During RCT, there may be more attention directed toward minimal changes in signs and symptoms. Acarbose-associated diarrhea is most common in the early phase of treatment. Finally, surveillance generally separates out those subjects who had already discontinued acarbose because of diarrhea. The prebiotics fructo-oligosaccharides and inulins, available in nutritional supplements and in functional foods, have been used for treatment of antibiotic-induced diarrhea at dose ranges of 4–10 g per day [10]. When given to healthy volunteers, doses higher than 30 g daily of these prebiotics caused significant gastrointestinal discomfort (flatulence, cramping, diarrhea) through fermentation in the colon and production of an osmotic effect in the intestinal lumen [11, 12]. If the dosage is split this usually alleviates the symptoms. Diagnosis can usually be made by checking fecal pH; a pH less than 6 is highly suggestive of carbohydrate malabsorption. Some formulas for enteral nutrition are hypertonic and may induce osmotic diarrhea by a mechanism similar to dumping syndrome. Changing to an isotonic formula or slowing the infusion rate usually resolves the diarrhea [4]. Once recognized, the treatment of osmotic diarrhea is simple. Removal of the osmotic agent usually resolves this adverse effect. Loperamide or tincture of opium can be added, especially in the case of enteral nutrition. Dose reduction or dose splitting can also help. In some cases, such as acarbose, the diarrhea usually resolves over time with continued use.

Secretory diarrhea Secretory diarrhea, on the other hand, produces voluminous stools that persist despite fasting. Drug-induced secretory diarrhea results from a medication either increasing the active secretion of ions and thus pulling fluid into the lumen, or from decreasing the absorption of large amounts of water and electrolytes in the gut lumen. In secretory diarrhea, a minimal osmotic gap is found. Specifically, drugs induce a secretory diarrhea by two main mechanisms: the inhibition of Na+ absorption and the stimulation of Cl-/HCO3- secretion. These changes may occur through either a direct effect on the transporter or changes in intracellular second messengers that alter the function of the transporter. The Na+ pump (Na+, K+-ATPase) is the final common pathway for Na+ absorption; inhibition of the Na+ pump blocks Na+ (and fluid) absorption and this may cause diarrhea. Digoxin’s therapeutic target is the cardiac Na+, K+-ATPase. However, inhibition of intestinal or colonic Na+ pumps may cause diarrhea, most frequently at supertherapeutic drug levels, especially in elderly patients [3]. In fact, digoxin was the second commonest cause of diarrhea in a study of 100 elderly patients [13]. Similarly, auranofin, 269

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used previously for rheumatoid arthritis, caused diarrhea in up to 74% of patients, requiring discontinuation in 14% of them [3]. By reducing K+ conductance and inhibiting calcium channels, the class I antiarrhythmic drugs quinidine and propafenone impede transepithelial Na+ and water absorption causing diarrhea in 8–30% of patients [14]. Lubiprostone was initially developed as a treatment for constipation, specifically because of its properties as a ClC2 channel opener; however, it is still unclear what specific role the ClC2 channel has in intestinal secretion. Olsalazine, used in the treatment of ulcerative colitis, causes diarrhea in 12–25% of patients through the stimulation of bicarbonate and sodium chloride secretion in the ileum [1, 15]. Similar azo compounds sulfasalazine and mesalazine may also cause diarrhea, but less frequently. The mechanism is unclear, but may involve a direct effect on anion transporters, rather than an anti-inflammatory action [16]. Some drugs cause a secretory diarrhea by altering intracellular signaling cascades, increasing cyclic AMP, cyclic GMP or calcium. The phosphodiesterase inhibitor, theophylline, causes diarrhea by increasing cyclic AMP, opening chloride channels and increasing secretion [17]. In our hypercaffeinated society, coffee is used as a “drug” by many, causing “Starbucks® diarrhea” through this similar mechanism. Caffeine administration in amounts ordinarily contained in many beverages and medications (75 to 300 mg) resulted in striking net secretion in the jejunum and in the ileum [18]. Prostaglandin analogs can cause diarrhea through many pathways, including altered permeability, motility, electrolyte transport and by affecting peptides that stimulate secretion [17]. Misoprostol specifically stimulates epithelial Cl- secretion through cyclic AMP, resulting in intraluminal fluid accumulation and diarrhea, which usually occurs within the first two weeks of treatment [3]. A secretory type of diarrhea limited the clinical use of chenodeoxycholic acid, a bile acid initially used to dissolve cholesterol gallstones. Early studies showed that the mechanism of secretory diarrhea in chenodeoxycholic acid therapy was due to a rise in intracellular cyclic AMP levels. However, recent in vitro studies using much lower doses of bile acids suggest a mechanism involving activation of luminal K+ channels and Cl- secretion mediated through increased intracellular Ca++ levels [19, 20]. Another dihydroxy bile acid, ursodiol causes diarrhea much less frequently. Presumably this difference is due to the alternative configuration of the hydroxyl groups compared to chenodeoxycholic acid. However, there are some reports of ursodiol causing diarrhea. A meta-analysis of ursodiol and its adverse effects revealed that diarrhea was the single most frequent adverse drug event in patients treated for gallstone disease, with an incidence of 2–9% [21]. If and when ursodiol is associated with diarrhea, there are two possible 270

mechanisms: an increase in the secretion of all bile salts including chenodeoxycholic acid and/or luminal conversion of ursodiol to chenodeoxycholic acid by intestinal bacteria (Alan Hoffman, personal communication). In primary biliary cirrhosis patients, on the other hand , diarrhea was rarely reported, in five large-scale randomized trials. No report of ursodiol-induced diarrhea was found in the largest placebo-controlled randomized study of its use in primary sclerosing cholangitis [21]. These conflicting data highlight some of the challenges of evaluating adverse events of RCTs. First of all, is this a real difference in that the incidence of diarrhea is truly higher in gallstone disease than in PBC/ PSC. Perhaps bile salt metabolism is different in gallstone disease, where there is an increased conversion of ursodiol to chenodeoxycholic acid which is a potent secretagogue. The gallbladder in patients with gallstones is likely to be hypo-functional and may be altered in its contractility in response to a meal or in its concentrating capacity, thus allowing more bile acid to enter the duodenum per ursodiol dose. In addition, ursodiol may be stimulatory to the inflamed bowel, while neutral or inhibitory to the bowel of patients with gallstones (Roger Soloway, personal communication). Alternatively, the design of RCTs may account for the difference. The definition of diarrhea as an adverse event, the focus on a more serious disease, or an already increased baseline bowel movement frequency in patients with PSC are possible examples of this factor. Used as an old home remedy, castor oil is hydrolyzed in the small bowel by the action of lipases into glycerol and the active agent, ricinoleic acid, which acts primarily in the colon to stimulate secretion of fluid and electrolytes by increasing cyclic AMP and speeding intestinal transit [22, 23]. Stimulant laxatives such as diphenylmethane derivatives and anthraquinones induce their effect by inducing a limited low-grade inflammation in the small and large bowel to promote accumulation of water and electrolytes and stimulate intestinal motility. This occurs through activation of prostaglandin-cyclic AMP and NO-cyclic GMP pathways, platelet-activating factor production and, perhaps, inhibition of Na+,K+-ATPase [4]. Anthraquinone laxatives are poorly absorbed in the small bowel, are activated in the colon, and produce giant migrating colonic contractions as well as water and electrolyte secretion. Other laxatives or stool softeners such as docusate (dioctyl sodium sulfosuccinate), can cause diarrhea when taken in large quantities, by stimulating fluid secretion by the small and large intestine [24]. Clinicians should thus be aware that surreptitious use of laxative may be the cause of diarrhea in patients who present with this complaint. Table 15.2 lists a number of commonly used laxatives. Diarrhea associated with medullary carcinoma of the thyroid suggested that calcitonin may cause a secretory

CHAPTER 15

Table 15.2 Stimulant laxatives. Anthraquinones Diphenylmethane derivatives (bisacodyl) Oxyphenisatin – withdrawn for hepatotoxicity Phenolphthalein – withdrawn for carcinogenicity Ricinoleic acid (castor oil) Sodium picosulfate – available outside US Sodium dioctyl sulfosuccinate (docusate)

type of diarrhea. Calcitonin in high doses can induce a secretory diarrhea in 1–3% of patients. Studies involving intravenous infusions showed prompt and marked increase in jejunal secretion of water, sodium, chloride and potassium, and reduced absorption of bicarbonate, which was reversed immediately with discontinuation of the infusion [25, 26]. However, in clinical practice, the use of salmon calcitonin for treatment of osteoporosis rarely causes diarrhea (Vassilopoulou-Sellin, R. personal communication) [27]. This paradox highlights the variable and sometimes unpredictable pattern of drug-induced diarrhea. Colchicine, besides causing secretory diarrhea through the inhibition of Na+,K+-ATPase activity, is a microtubule inhibitor and may induce diarrhea by interfering with the migration of epithelial cells from the crypt to the villus and/or interfere with intracellular trafficking of specific transport proteins [17]. The biguanide metformin, used in the treatment of type II diabetes, has an effect on the brush border, reducing disaccharidase activity and leading to malabsorptive diarrhea in 10–53% of patients [28, 29]. Animal studies have found that metformin or the older biguanide phenformin inhibits intestinal glucose absorption in a dose-dependent manner through effects on mucosal and serosal glucose transfer mechanisms [30–33]. Based on a systematic review evaluating common adverse events of metformin monotherapy in type II diabetes mellitus, patients receiving metformin are 3.4 times more likely to develop diarrhea compared to those taking placebo (p = 0.002) [34]. Most cases are transient and mild, but even in severe cases, lowering the dose usually resolves the diarrhea [35]. In clinical trials, only 5% of study participants discontinued metformin because of gastrointestinal side effects [34]. There have also been cases of metformin causing late-onset chronic diarrhea in whom discontinuation of the drug resolved the diarrhea [36]. Larger studies of 405 type II diabetics show that metformin was independently associated with chronic diarrhea with an odds ratio of 3.08 (CI: 1.29–7.36, p < 0.02) [37]. In a diabetic clinic, metformin was found to be the most common cause of diarrhea based on a questionnaire based survey of 285

Drug-induced diarrhea

randomly selected diabetic patients [38]. Diarrhea in a diabetic patient may be related to the disease process itself. However, diabetic diarrhea usually occurs in type I diabetes for which metformin is not a treatment. Some have speculated that anticholinergic drugs, which most often cause constipation by reducing intestinal motility, as well as the proton pump inhibitor omeprazole, can cause a secretory diarrhea. Although the proposed mechanism for diarrhea is thought to be bacterial overgrowth leading to bacterial deconjugation of primary bile salts to dihydroxy bile acids causing net fluid and electrolyte secretion in the colon, there is no substantial evidence to confirm this explanation [3]. In fact, a Cochrane systemic review showed no statistically significant difference in diarrhea occurrence in patients treated with PPI for reflux disease either at maintenance dose (PPI 1.1%, vs placebo 3.3% , RR 0.34; 95% CI:0.04 to 3.18) or at healing dose for esophagitis (PPI 5.2% vs placebo 2%, p = 0.11) [39]. A recent article suggesting a link between PPI use and small bowel bacterial overgrowth contributing to diarrhea predominant IBS shows that there is a common assumption among gastroenterologists that PPI can cause diarrhea, that is not necessarily supported by evidence [40]. Diarrhea is a common adverse effect with molecularly targeted agents. Epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib, and other tyrosine kinase inhibitors such as sorafenib, imatinib and bortezomib cause diarrhea in up to 60% of patients [41]. Erbitux® (cetuximab), used for the treatment of EGFR-expressing, metastatic colorectal carcinoma and squamous cell carcinoma of the head and neck and Iressa® (geftinib), used for nonsmall cell lung cancer, can cause diarrhea in 48–67% of patients, depending on dose [42, 43]. EGF can activate PI 3-kinase and the lipid products of this enzyme inhibit calcium-dependent Cl-transport in T84 human colonic epithelial cells [44, 45]. EGF-receptor inhibitors may cause diarrhea by blocking this inhibitory loop and causing secretion. Diarrhea can easily be managed by loperamide, dose reduction or treatment interruptions [41]. Flavopiridol, a cyclin-dependent kinase inhibitor, has undergone several clinical trials as an anti-tumor agent, with secretory diarrhea as a dose-limiting factor. Adding cholestyramine and loperamide as a prophylactic antidiarrheal treatment allowed for use of higher doses [46]. Diarrhea may be related to flavopiridol binding to the gut mucosa acting as a modest secretagogoue. Cholestyramine, by binding flavopiridol, eases the adverse effect [47]. Pharmacogenomics may play a role in drug-induced diarrhea. For example, those with extensive hepatic glucorinidation metabolism experienced less diarrhea than others [48]. The hepatic metabolism of the drug decreases the toxic metabolites that causes intestinal secretion. In this clinical study, mild cases of diarrhea were controlled by loperamide, whereas more severe diarrhea was controlled 271

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by octreotide infusion and reduction of flavopiridol dosages in subsequent cycles [48].

Disordered or deregulation motility Although not as elegantly delineated as epithelial transport changes, disordered or deregulated motility can also cause diarrhea. Prokinetic agents reduce intestinal contact time between luminal fluid and the epithelium. The decreased amount of time chyme is exposed to intestinal epithelium can limit absorption, and ultimately lead to diarrhea [2]. Cisapride and tegaserod are 5-HT4-receptor agonists that stimulate motility and accelerate gastrointestinal transit. However, both of these drugs have been removed from the market due to potential cardiotoxicity. Cholinergic drugs such as bethanecol, used for urinary retention and neurogenic bladder, have broad muscarinic effects via cholinergic receptors in the smooth muscle of the urinary bladder and the gastrointestinal tract [4, 49]. The effect of acetylcholine on smooth muscle of the gastrointestinal tract is mediated by two types of G proteincoupled muscarinic receptors, M2 and M3 in [4]. The activation of the M3 receptor increases intracellular Ca2+ mediated by the Gq-PLC-IP3 pathway [4, 28]. This results in increased gastrointestinal and pancreatic secretions, as well as increased peristalsis. Acetylcholinesterase inhibitors, such as those used for Alzheimer ’s disease, allow acetylcholine to accumulate in the synaptic and neuromuscular junctions. These drugs enhance contractile effects producing diarrhea in up to 14% of patients [1, 3]. RCTs comparing donepezil to placebo for the treatment of Alzheimer ’s disease revealed diarrhea incidence of 15% with donepazil compared to 10% in placebo [50]. The Cochrane Review of the use of donepazil with over 1000 patients revealed that diarrhea occurred more frequently in donepazil treated patients (OR 2.78; 95% CI: 2.10, 3.69) [51]. In another Cochrane Review of the three anticholinesterases (donepezil, galantamine and rivastigmine) used for Alzheimer ’s dementia, the odds ratio for diarrhea with the use of anticholinesterases in comparison to placebo was 1.91 (95% CI: 1.59, 2.3) [52]. Neostigmine, used off-label for acute colonic pseudo-obstruction (Ogilvie’s syndrome) and paralytic ileus, also can cause diarrhea [4]. Irinotecan, a chemotherapeutic agent, can cause severe diarrhea from cholinergiclike syndrome through the inhibition of acetylcholinesterase [3]. Motilin, a peptide hormone found in the gastrointestinal M cells, and in some enterochromaffin cells of the upper small bowel, is a potent contractile agent of the upper GI tract. The effects of motilin can be mimicked by macrolide antibiotics, especially erythromycin, and can cause diarrhea. In addition to its motilin agonistic effect, erythromycin at lower doses (40–80 mg) may also entail cholin272

ergic involvement, although the mechanisms are not well understood [4]. Just as in thyrotoxicosis, excess levothyroxine therapy can accelerate small and large intestinal transit, causing diarrhea [53–55]. Ticlopidine, an inhibitor of platelet aggregation, can cause diarrhea through many processes, including reported cases of lymphocytic colitis. However, increased motility is thought to be the principal mechanism based on manometric readings of jejunal motility revealing abnormal motility patterns [56]. The treatment of watery diarrhea includes discontinuation of the offending medication. Maintaining hydration is important to prevent dehydration from the amount of fluid loss. Loperamide, lomotil and bismuth subsalicylate can help relieve the symptom.

Inflammatory diarrhea Drug induced inflammatory diarrheas fall into several broad categories. Perhaps the most important is the disruption of colonic flora and precipitation of Clostridum difficile colitis. Other mechanisms include the direct damage to the integrity of the mucosa that occurs with NSAIDs and polyene antibiotics, stimulation of low grade inflammation causing microscopic colitis, disruption of the balance between proliferation and apoptosis with a resulting compromise of epithelial integrity seen with immunosuppressives and chemotherapeutic agents, and vascular compromise as occurs with ergotamine and cocaine. Antibiotics account for 25% of drug-induced diarrhea [1]. The most well-known complication is pseudomembranous colitis due to Clostridium difficile, especially seen with the antibiotics clindamycin, amoxicillin, ampicillin, and cephalosporins [3]. Clostridium difficile causes diarrhea by secreting enterotoxin A, which adheres to the brush-border membrane of enterocytes inducing an inflammatory response, and cytotoxin B that induces direct mucosal damage [2, 57]. Diarrhea may occur a few days after antibiotic therapy is initiated and up to eight weeks after discontinuation. In the appropriate clinical setting, diagnosis is based on detection of toxin in the stool. Endoscopy reveals raised white to yellow plaques covering a normal or moderately erythematous colonic mucosa [57]. Recently, non-antibiotic associated community acquired C. difficile has become more frequent with the use of acid reducing agents and immunosuppressives. Lansoprazole, and in the elderly, histamine antagonist use, are reported to be significant risk factors for carriage of C. difficile, increasing the risk of developing pseudomembranous colitis [3, 58]. In fact, a meta-analysis to assess risk factors for recurrent C. difficile infection revealed that use of concomitant antacid medications increased the risk by two fold (OR: 2.15; 95% CI: 1.13–4.08; p = 0.019) [59].

There has been a rise in the incidence of C. difficile colitis in hospitalized patients with inflammatory bowel disease [60]. This may be attributable to the use of immunosuppressives and biologic agents [61]. Treatment is discussed in detail in Chapter 20 of this book. Through multifactorial mechanisms, diarrhea occurs in 3 – 9% of patients treated with the non-steroidal antiinflammatory drugs (NSAIDs), especially the older drugs mefenamic acid and flufenamic acid [1, 62–64]. Thirty nine percent (34 of 87) of patients in a six-week study given meclofenamate at doses of 200 to 400 mg per day experienced diarrhea [65]. Since NSAIDs stimulate in vitro absorption (increased Na+ absorption and decreased Cl- secretion), other mechanisms must be involved in diarrhea [66]. NSAIDS most likely cause diarrhea through increased permeability and direct mucosal damage [67]. Histologic findings include prominent apoptosis and increased intraepithelial lymphocyte counts [68]. NSAIDs have been associated with both microscopic and pseudomembranous colitis. Ileal disease mimicking Crohn’s disease has also been described. Maiden and others have quantitatively analyzed by capsule endoscopy NSAID-induced pathology in 40 subjects taking diclofenac. Images revealed new pathology in 27 subjects (68%), with common lesions of mucosal breaks, bleeding, erythema and denuded mucosa, and the majority have concurrent lesions. These patients also had elevated fecal calprotectin (a marker for inflammation) levels from baseline. This study provides both biochemical and direct evidence of macroscopic injury to the small intestine from NSAID use [69]. In a case-control study of 105 cases of newly-diagnosed colitis based on endoscopic and histologic findings, 78 patients (74%) were taking NSAIDs or salicylates prior to or during the development of their disease [70]. These studies support NSAIDs as an important class of drugs in causing colitis. Acute proctocolitis has been documented in four separate cases of NSAID etiology, with the use of flufenamic acid, mefenamic acid, naproxen and ibuprofen. Symptoms and signs resolved in all cases with removal of the drug, but a rapid relapse occurred in three of the five patients who were subsequently rechallenged with the NSAID [71]. NSAIDs have also been implicated in causing collagenous colitis. Based on a case-control study of 31 patients with collagenous colitis and 31 controls, the use of NSAIDs was significantly more common in the study group (19/31) vs (4/31) in the control group (p < 0.02) [72]. Auranofin causes secretory diarrhea, but enterocolitis can also occur with relatively low dosages [62]. Over 30 cases have been reported of gold therapy causing severe enterocolitis. This adverse effect was unrelated to dosage, occurred within three months of beginning treatment and persisted despite withdrawal of the drug [3, 73].

Villus

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Drug-induced diarrhea

Na-nutrient contransport; apical Na-H exchange

Na pump; CI-HCO3 exchanger; basolateral Na-H exchanger

CI channel (CFTR)

Crypt

Figure 15.2 Gradients from crypt to villus. There is a significant spatial geometry of transport proteins along the crypt-villus (crypt-surface) axis. Some transport molecules are found at relatively constant concentrations along the axis, some exhibit a greater density in the base of the crypt, and others exhibit a greater density toward the villus or surface. (Adapted from Sellin JH (2002) Chapter 87: Intestinal electrolyte absorption and excretion. In: Feldman M, Friedman LS and Sleisenger MH (eds) Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/ Management, 7th edn. Saunders, Philadelphia, 2002. Figure 87.3, p. 1695.)

Penicillamine has been shown in a few cases to cause acute proctosigmoiditis [62]. Inflammatory diarrhea can also be caused by immunosuppressive and chemotherapeutic agents. The balance between absorption and secretion may be disrupted by a change in the balance between mature villus and immature crypt cells (see Figure 15.2). This loss of intestinal epithelial homeostasis with some superficial necrosis causes an imbalance between absorptive, secretory, and motility functions of the gut contributing to diarrhea [17, 24, 57]. Epithelial apoptosis of more than five apoptotic bodies (per 100 crypts) is considered an increase above normal. NSAIDS and sodium phosphate bowel preparations cause 12 to 24 apoptotic bodies [58]. Chemotherapeutic agents, especially fluorouracil can cause greater than 100 apoptotic bodies [58]. These agents usually cause diarrhea in a dose-related fashion. It is most commonly seen with fluoropyrimidines (fluorouracil, irinotecan, methotrexate and cisplatin), the fluorouracil prodrug capecitabine and the combination treatment uracil-tegafur [1]. The patient’s symptoms can range in severity from mild diarrhea to severe necrotizing enterocolitis [24]. Transplant immunosuppressives frequently cause diarrhea. This may be due to a similar apoptotic enteropathy. Mycophenolic acid may shift the balance between the pro and antiapoptotic factors Bcl-2 and Bax, leading to changes in mucosal homeostasis, and may also alter chloride secretion (Sellin, J unpublished observations). Irinotecan can cause acute or delayed diarrhea in 50– 88% of patients. Immediate-onset diarrhea is caused by 273

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acute cholinergic effects and usually responds rapidly to atropine. The delayed onset diarrhea usually occurs 24 hours to several days after administration, can be unpredictable, occurs at all dose levels and is worse with combination regimens with intravenous fluorouracil and leucovorin [41]. Several hypotheses have been proposed to explain the underlying mechanism. Evidence of a direct toxic effect on intestinal epithelium was provided by animal studies. Mice treated with irinotecan had intestinal wall thinning with epithelial vacuolation, vascular dilatation, an inflammatory cell infiltrate and evidence of apoptosis in the ileum [74, 75]. These studies led to the discovery of bacterial β-glucoronidase which deconjugates the irinotecan metabolite SN38 glucuronide causing its direct effect on the intestinal epithelium [24, 76]. Multiple agents have been studied in an attempt to reverse irinotecan-induced diarrhea. In humans, the use of the oral antibiotic, neomycin, which decreases βglucuronidase activity in the intestinal lumen, resulted in good control of irinotecan-induced diarrhea in seven colorectal cancer patients [77]. The Chinese herb Hange-Shashito (TJ-14), a natural inhibitor of the β-glucuronidase activity of bacterial microflora, has also been shown to prevent the delayed diarrhea from irinotecan [78]. Probenecid, a biliary inhibitor of irinotecan and SN-38 secretion, has been shown to reduce irinotecan intestinal toxicity in mice, but no evidence has confirmed this observation in humans [79]. Oral cyclosporin (to reduce SN38 and SN38G clearance into the small bowel lumen) used with irinotecan in a phase I clinical trial, prevented severe diarrhea. Only one patient out of 37 experienced grade 3 diarrhea, and grade 4 diarrhea did not occur [80]. At increased pH, equilibrium favors the less toxic carboxylate form of the irinotecan metabolite SN38. Reduced cellular damage and diarrhea was noted with bicarbonate administration in hamsters given irinotecan [81]. Phase II clinical trials also suggested benefit from sodium bicarbonate supplementation for irinotecaninduced severe delayed diarrhea [82]. Oxaliplatin combined with fluorouracil and irinotecan makes diarrhea even more common than the incidence observed with either agent alone [41]. Diarrhea can also result from an increase in opportunistic infections: invasive bacterial infections such as tuberculosis and yersinosis; ulcerating viral infections such as cytomegalovirus and herpes simplex; and invasive parasitic infections such as amebiasis and strongyloides. Neutropenic enterocolitis may also complicate chemotherapy in neutropenic patients with leukemia. This is especially associated with cytosine arabinoside, cisplatin, vincristine, adriamycin, fluorouracil and mercaptopurine [58]. Isotretinoid used for acne has been associated with inflammatory diarrheas [1]. Histology from these patients often shows acute focal superficial inflammatory infiltrate of the mucosa. HMG-CoA reductase inhibitors such as sim274

vastatin, lovastatin and pravastatin cause an inflammatory diarrhea in less than 5% of patients [1]. Several drugs have also been linked to microscopic colitis. These include NSAIDS, carbamazepine, ticlopidine, flutamide, and the selective serotonin receptor inhibitors, especially paroxetine and sertraline [1, 58]. Management of inflammatory diarrhea includes treatment of intercurrent infections such as CMV, antibiotic associated colitis, dose reduction of the etiologic agent, or cautious use of empiric therapy. Loperamide, diphenoxylate, deodorized tincture of opium and octreotide are effective for diarrhea from fluoropyridimoles [3]. Acetorphan, an enkephalinase inhibitor that blocks epithelial cyclic AMP mediated secretion, has shown moderate activity in clinical trials in patients with irinotecan-induced diarrhea [83]. Budesonide and octreotide have been used to slow intestinal motility and decrease water and electrolyte movement through the bowel [84–86].

Fatty diarrhea Fatty diarrhea occurs in the clinical setting of weight loss and steatorrhea. This is caused by either maldigestion or malabsorption. Table 15.3 lists several medications that can cause this adverse effect. Highly active antiretroviral therapy has been known to cause steatorrhea, although the mechanisms have not been elucidated [87]. Interestingly, in a study of 33 HIV patients who underwent evaluation for diarrhea, over 90% had steatorrhea, irrespective of HAART therapy (20/21 patients not on HAART vs 10/12 patients on HAART) [87]. Thus, the specificity of steatorrhea secondary to HAART may be called into question. Of the nucleoside analog reverse transcriptase inhibitors, didanosine causes diarrhea in 17–28% of patients, espe-

Table 15.3 Drugs inducing steatorrhea. Aminoglycosides Auranofin Biguanidesa Cholestyramine Colchicine Highly active antiretroviral therapya Laxatives Methyldopa Octreotide Orlistat (lipase inhibitor)b Polymixin, bacitracin Tetracyclines a b

≥20% incidence of diarrhea. >10% incidence of diarrhea.

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cially in the buffered formulations [57]. Enteric-coated tablets decrease this incidence. Abacavir can produce diarrhea, especially in association with a hypersensitivity reaction that occurs in 3–5% of treated individuals [88, 89]. Diarrhea, among other symptoms, appears one to four weeks after initiation of therapy, and usually resolves within one to two days after discontinuation. Re-challenge with the drug, even at a decreased dose, may cause the return of symptoms within hours with increased severity [88]. Virtually all protease inhibitors cause diarrhea. Ritonavir causes diarrhea in up to 52% of patients [90, 91]. Adverse effects appear to be more common in patients with more advanced HIV/AIDS, and in patients with higher plasma drug levels. Effects are greatest at the beginning of therapy, before ritonavir induces an increase in its own metabolism [88]. Combination therapy, especially lopinavir with ritonavir increases the risk of diarrhea [88]. In vitro studies showed that several protease inhibitors inhibited lipase significantly at or below physiological concentrations [92]. Thus, besides the use of antidiarrheal medications such as loperamide that have been shown to control diarrhea, the use of pancrealipase with protease inhibitors may in theory reduce or eliminate steatorrhea in these patients [88, 92]. Orlistat, used as a prescription gastrointestinal lipase inhibitor for weight loss, is now available over the counter as “alli” (2007, GlaxoSmithKline, Pennsylvania) which contains half the prescription dose. Those using this drug can have malabsorptive diarrhea if fat intake is high. Of those taking orlistat, 60– 80% experience steatorrhea in a doserelated mechanism [93]. This resolves when fat intake is reduced to 45 g per day [93]. Olestra is a lipid that possesses properties of conventional fats and oils, but is neither digested nor absorbed. Olestra was approved by the FDA in January 1996 for use in snacks such as potato chips and crackers [94]. Although consumers complained of “diarrhea”, a randomized control trial using higher than consumption doses showed no effect on stool frequency, but a modest stool softening effect measured by stool viscosity in subjects consuming olestra compared to controls [94]. Long-term use of oral antibacterials such as neomycin, polymixin and bacitracin can also cause malabsorptive diarrhea. These antibiotics damage the small intestinal mucosa, leading to a reduction of the enzyme activity of enterocytes [3, 49, 68]. They may also bind bile acids in the intestinal lumen and reduce the absorption of fat [1]. In in vitro transport studies, both neomycin and amphotericin act as membrane detergents, functionally “dissolving” the apical memberane of enterocytes or colonocytes. Administering 1g of neomycin with a test meal to five healthy subjects caused a marked increase in fatty acid and bile acid in their aspirated intestinal contents [95]. However, a subsequent study of 2 g per day dose of neomycin given

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to four patients revealed no evidence of steatorrhea, although daily stool weight increased in three or four patients [96]. Cholestyramine usually causes constipation, but in doses of 24–30 g per day may cause steatorrhea [1]. Animal studies show that increasing the dietary amount of cholestyramine markedly increased the excretion of both free and esterified fat in the stool [97]. Octreotide, used as an antidiarrheal, has a paradoxical effect at higher doses, causing steatorrhea in 5 – 13% of patients by a possible synergistic inhibition of biliary and pancreatic function through decreased bicarbonate and lipase secretion [1, 98]. L-dopa, allopurinol, tetracycline and NSAIDs, especially mefanamic acid, can cause steatorrhea through changes in jejunal mucosa [28, 66]. Several medications have been implicated for inducing steatorrhea in addition to other types of diarrhea. For example, in addition to its effects on intestinal transit, levothyroxine has been implicated in bile acid malabsorption because of abnormal selenohomocholyltaurine (SeHCAT) testing. This test can be used to diagnose bile acid malabsorption as a cause of chronic diarrhea, but it best predicts the benefit of cholestyramine in these patients [99]. However, this adverse effect of levothyroxine may be a secondary effect of increased motility. Colchicine can cause secretory and inflammatory diarrhea, but can also cause malabsorption in large doses by causing villous atrophy [3]. Three out of twelve patients evaluated for gastrointestinal effects of the long-term use of colchicine prophylaxis for recurrent polyserositis developed mild steatorrhea [100]. Chemotherapeutic agents, besides causing inflammatory diarrhea, can damage immature epithelial cells in the crypts causing functionally compromised mature enterocytes. This effect leads to decreased nutrient absorptive capacity and potentially a malabsorptive diarrhea [3]. Rapamycin administration in rabbits showed significantly decreased jejunal and ileal villous surface areas and decreased fat and cholesterol uptake, possibly contributing to malabsorption [101]. Treatment of drug induced steatorrhea may require dose reduction or withdrawal of the drug. In some cases such as diarrhea due to metformin, continued symptoms may resolve with time even if the drug is continued, as the gastrointestinal system adjusts to the drug. Antidiarrheals such as loperamide and probiotics may help. In the case of antiretroviral drugs, soluble fiber and L-glutamine have been found to be helpful [102]. If prolonged, replacement of fat soluble vitamins maybe needed.

Conclusion Ideally, decisions about diagnosis or therapy should be evidence-based; however, as emphasized above, there is 275

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frequently a dearth of high quality evidence to guide the clinician in the area of drug-induced diarrhea. Determining the etiology of drug induced diarrhea depends on a careful history to identify the offending agent. Any history of drug allergies or intolerances, and any new prescription medications taken within the six to eight weeks prior to symptom onset may reveal the etiology. One should always consider prescription as well as non-prescription drugs, nutritional supplements, excessive caffeine consumption and artificial sweeteners found in diet foods as potential causes. Most cases of drug-induced diarrhea resolve spontaneously within a few days after withdrawal of the drug, or with dose reduction. If diarrhea is severe or persistent, patient management should include replenishment of any fluid and electrolyte deficits with oral hydration or, if warranted, with intravenous fluids. Non-specific antidiarrheal agents can reduce stool frequency and stool weight as well as decrease abdominal cramps. Opiates (loperamide, diphenoxylate with atropine), intraluminal agents (bismuth subsalicylate) and adsorbents (kaolin) also can help reduce the fluidity of bowel movements [2, 58]. A low residue diet, specific treatment as described in above sections such as antibiotics for C. difficile colitis, and reduction of fat intake for patients taking orlistat, can also help. Probiotics as possible treatment or prevention have not been well studied, but future studies may prove to be useful.

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rositis (familial Mediterranean fever). Dig Dis Sci 1982; 27: 723–727. 101 Dias VC, Madsen KL, Mulder KE et al. Oral administration of rapamycin and cyclosporine differentially alter intestinal function in rabbits. Dig Dis Sci 1998; 43: 2227–2236.

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102 Heiser CR, Ernst JA, Barret JT et al. Probiotics, soluble fiber and L-Glutamine (GLN) reduce nelfinavir (NFV)- or lopinavir/ ritonavir (LPV/r)-related diarrhea. J Int Assoc Physicians AIDS Care (Chic Ill) 2004; 3: 121–130.

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Metabolic bone disease in gastrointestinal disorders Ann Cranney1, Alaa Rostom2, Catherine Dubé3, Rachid Mohamed3, Peter Tugwell4, George Wells5 and John WD McDonald6 1

Canadian Protective Medical Association and Clinical Epidemiology, Ottawa Hospital Research Institute and Faculty of Medicine, University of Ottawa, Ottawa, Canada 2 Forzani and MacPhail Colon Cancer Screening Centre, University of Calgary, Calgary, Canada 3 Division of Gastroenterology, University of Calgary, Calgary, Canada 4 Department of Medicine and Epidemiology, University of Ottawa, Ottawa, Canada 5 Department of Epidemiology and Community Medicine and Cardiovascular Research Methods Centre , University of Ottawa, Ottawa, Canada 6 Robarts Clinical Trials, Robarts Research Unit, University of Western Ontario, London, Ontario, Canada

Introduction Metabolic bone disease is seen in patients suffering from a variety of gastrointestinal disorders, including chronic liver disease, inflammatory bowel disease (IBD), and malabsorption syndromes such as celiac disease. In the setting of gastrointestinal disorders, bone disease can be broadly divided into osteoporosis and osteomalacia. Osteoporosis is a systemic skeletal disorder of reduced bone mass per unit volume (i.e. bone density) and disrupted micro-architecture, resulting in decreased bone strength and an increased risk of fragility fractures mainly of the hip, wrist and vertebrae [1]. Bone mass is a major determinant of bone strength. Osteomalacia, however, is characterized by defective mineralization of bone matrix, usually due to a disturbance of vitamin D and calcium homeostasis. It is clinically associated with pain, bone fractures, muscle weakness, difficulty walking and, radiologically, with pseudofractures (radiolucent bands perpendicular to surface of cortical bone) and loss of trabeculae. There are two types of bone: cortical, which primarily makes up the long bones, and trabecular bone, which makes up most of the axial skeleton. Bone formation and resorption is a continuous process in which osteoblasts are responsible for the formation of new bone including the mineralization of bone, and osteoclasts are responsible for bone resorption. Metabolic bone disease results from abnormalities in the normal remodeling cycle. Osteoporosis is associated with disability, impaired quality of life and osteoporotic fractures can be associated with increased mortality [2]. Evidence-Based Gastroenterology and Hepatology, Third Edition John WD McDonald, Andrew K Burroughs, Brian G Feagan and M Brian Fennerty © 2010 Blackwell Publishing Ltd. ISBN: 978-1-405-18193-8

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This chapter will focus on metabolic bone disease associated with chronic liver disease, IBD, celiac disease and will review corticosteroid-induced osteoporosis and the potential link between proton pump inhibitors and osteoporotic fractures.

Assessment of bone mass Age-related bone loss begins during the fourth decade, and in women there is an accelerated bone loss at the time of menopause (5–15% in the initial five years after menopause), due to declines in estrogen. Perimenopausal bone loss is characterized by increased bone resorption and bone loss is greater at trabecular bone sites compared to cortical sites. Women experience greater rates of bone loss than men and their lifetime risk of an osteoporotic fracture is about 15% compared with 5% in men [3]. Osteoporosis can be detected by measurement of bone mineral density. Bone density is the most accurate predictor of fracture risk and it is a useful guide for monitoring therapy [4]. Prospective trials have established the ability of bone density to predict site-specific fractures [5]. For each reduction in bone density of the hip by 1 standard deviation (SD) from the mean for young normal individuals, the risk of hip fracture increases by a factor of 1.5–2.6 [6]. In men, low bone mineral density (BMD) has been demonstrated to be predictive of vertebral fractures [7]. In a prospective study which included 1690 men, it was estimated that a 1 SD decrease in femoral neck bone density was associated with a two-fold increase in risk of a traumatic fracture [8]. Increasing age and a history of a previous vertebral fracture are very important predictors of fracture. Bone mass can be evaluated at a number of sites, such as the proximal femur, spine and distal radius. The most commonly used technique to evaluate BMD is dual energy X-ray absorptiometry (DXA). The reproducibility, accuracy

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and precision of DXA are excellent, with a coefficient of variation of 2%. Another technique, quantitative computed tomography (QCT), provides a three-dimensional image which makes it possible to separate trabecular and cortical bone. The accuracy of QCT is not as good (5–15%) as DXA, and is associated with a higher radiation dose. Bone mineral content (BMC) is the total amount of mineralized tissue (g) in the bone scan, usually normalized to the length of the scan path (grams per mineral per centimeter of bone or g/cm). BMD, on the other hand, is the amount of mineralized tissue in the scanned area (g/cm2). BMD can be expressed as a T-score (comparison of the patient’s bone density with the peak bone mass in young normal individuals) or Z-score (comparison of patient’s BMD to other age-matched controls). Individuals with a T-score or BMD less than 1 SD below the mean in young adults are considered to be osteopenic, while those with a BMD less than 2.5 SD below the young normal value are osteoporotic [1]. A study group on densitometry hosted by the World Health Organization (WHO) in 1993 defined these four diagnostic thresholds based on reference populations of healthy young women. Since these thresholds are based on young women, this definition does not account for biological variation and age-related bone loss and many have argued against the use of T-scores. In addition to BMD, bone strength and fracture risk depend on other skeletal and non-skeletal factors such as trabecular micro-architecture and muscle strength. As a result, there has been a shift to the development of fracture risk prediction models which incorporate BMD, age and other clinical factors. The increased use of DXA has resulted in more gastroenterology patients being diagnosed with osteoporosis. However, it is not clear what a diagnosis of osteopenia in gastrointestinal patients means in terms of increased fracture risk. On the basis of BMD, osteomalacia cannot be distinguished from osteoporosis.

Hepatic osteodystrophy Hepatic osteodystrophy, or chronic liver disease-associated metabolic bone disease, was previously thought to arise mainly in cholestatic liver diseases, as a result of calcium and vitamin D malabsorption. However, hepatic osteodystrophy has now been described in association with most types of chronic liver diseases, whether cholestatic or noncholestatic [9]. Increased bone loss and/or increased incidence of fractures have been described in primary biliary cirrhosis (PBC) [10], primary sclerosing cholangitis (PSC) [11], alcoholic liver disease (ALD) [12, 13], autoimmune hepatitis (AIH) [14], hemochromatosis [15, 16], as well as viral cirrhosis [17–20]. Additionally, hepatic osteodystrophy has important clinical repercussions in the early period

Metabolic bone disease

after liver transplant, where immobilization, co-morbidity, corticosteroids and immunosuppressive drugs further reduce an already compromised bone mass [10], resulting in spontaneous vertebral fractures [21, 22].

Prevalence The prevalence of hepatic osteodystrophy varies from 13– 56% [11, 17, 23, 24], while the incidence of fractures in ambulatory and non-alcoholic patients with chronic liver disease ranges from 6–18%. The prevalence of vertebral fractures ranges from 7– 44% and is approximately twice that of age and sex-matched controls, with the highest rates in those individuals with AIH [17, 23–25]. The degree of bone loss correlates with the severity of the cirrhosis and increasing age, making patients with endstage liver disease the group most at risk of fractures [5, 23, 26]. The situation in PBC is becoming less clear as some studies show an association with osteoporosis and fractures [24, 25, 27], while some recent studies including a prospective cohort study showed an association with age, postmenopausal status and BMI, but not with cirrhosis or serum bilirubin [28]. While another showed no increased risk of fractures in PBC [29]. Similarly, a study in PSC showed that bone mineral density did not correlate with the severity of the disease [30]. The fracture risk in chronic liver disease was best studied by Diamond et al., in a case-control study of 115 patients with chronic liver disease (72 men and 43 women), who were matched for age, sex and menopausal status with healthy controls [23]. The etiology of the chronic liver disease was ALD (n = 40), chronic active hepatitis (n = 27), hemochromatosis (n = 25), PBC (n = 10), and PSC (n = 13). Fifty-two percent of the patients were cirrhotic, while 30% had clinical and biochemical evidence of hypogonadism. It is important to note that, in men, hypogonadism correlates with the degree of liver dysfunction. All patients were ambulatory and none were on cholestyramine, vitamin D, estrogen, or calcium. From the data in this study, the relative risk (RR) of either spinal or peripheral fractures can be calculated, based on the absolute number of fractures (as opposed to the number of patients with fractures). In men this RR is 3.03 (95% CI: 1.35–11.09), while in women the RR is 2.13 (95% CI: 1.38–7.46). These authors did a stepwise regression analysis to define the main predictors of fracture and osteoporosis. Variables used were: age, sex, gonadal status, presence of cirrhosis, type of liver disease, liver function, 25(OH) D3 level and parathyroid hormone (PTH) level. Lumbar spine bone density, liver dysfunction and hypogonadism were the main predictors of spinal fracture, while hypogonadism and the presence of cirrhosis were the main predictors of peripheral fractures. There was no association with serum PTH or 25-hydroxy-vitamin D3. Because of the potential for impaired absorption of calcium and vitamin D [31, 32], as well as impaired hepatic 281

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uptake and metabolism of vitamin D [33], osteomalacia was initially thought to be the major cause of hepatic osteodystrophy in cholestatic liver diseases [33, 34]. However, it then became evident that bone disease was still prevalent despite treatment with calcium and vitamin D, and that most patients with cholestatic liver disease and osteopenia did not have low 25-hydroxyvitamin D3 levels [11] or histomorphometric characteristics of osteomalacia [26, 35, 36]. Osteoporosis appears to be the major metabolic bone disease found with chronic liver disease. The mechanisms responsible for the osteoporosis in this setting are uncertain, and evidence exists for both decreased bone formation [26, 37–39] and increased bone resorption [11, 35, 40]. The presence of cirrhosis seems to play an important role through several mechanisms. Testosterone, 25-hydroxy-vitamin D, and insulin-like growth factor 1 (IGF-1) levels are all reduced in advanced liver disease and correlate inversely with the degree of osteopenia [17, 23]. As well, bone mass starts to increase within six months to a year after liver transplantation [10]. Other factors may also affect bone metabolism independently of cirrhosis: bone formation is directly suppressed by alcohol [13, 41], and possibly by iron in hemochromatosis. The majority of patients with advanced PBC are also postmenopausal females, which adds to the list of pathogenic factors of hepatic osteodystrophy [23]. Malnutrition, treatment with corticosteroids [14, 42] or immunosuppressive agents plays a role in some cases.

Treatment Osteomalacia Osteomalacia secondary to vitamin D deficiency is characterized by low serum 25-hydroxy-vitamin D (25(OH) D < 25 nmol/L), low or normal calcium, low phosphate and elevated alkaline phosphatase and usually increased serum parathyroid hormone levels. Based on measurement of 25(OH) D level and bone histomorphometry, osteomalacia can be successfully treated and prevented with combined calcium and vitamin D supplementation (oral or parenteral) [43, 44]. B4 Vitamin D does not need to be given as its 25hydroxy metabolite, since the capacity of the liver to hydroxylate vitamin D is maintained, even in advanced liver disease. However, since its absorption and/or hepatic uptake may be decreased, sufficient doses should be administered [32]. Successful treatment of osteomalacia has been achieved with calcium and either oral vitamin D2 2000–4000 IU daily, intramuscular vitamin D2 150,000 IU weekly [43], or oral 25-hydroxy-D3 1000–4000 IU daily [44], for a duration of 3–6 months. B4

Osteoporosis The evidence for interventions for the treatment of osteoporosis in chronic liver disease is summarized in Tables 282

16.1 and 16.2. There are a number of observational trials and randomized controlled trials (RCTs), most of which have relatively small numbers of patients. Vitamin D and calcium Therapy with vitamin D has been studied in osteoporotic patients with either cholestatic [40, 51] or non-cholestatic liver disease [12] and low 25(OH) D levels. Uncontrolled studies in PBC (Table 16.1) suggest that normalization of 25(OH) D levels failed to arrest bone loss [40] or to prevent spontaneous fractures. B4 In one of these two reports, improvements in bone mass occurred only in patients whose calcium absorption increased as a result of therapy [51]. However, in an RCT of 18 abstinent patients with alcoholic liver disease, Mobarhan et al. showed that normalization of 25(OH) D levels was associated with a significant increase in BMD after a mean duration of 10 months (Table 16.2) [12]. Ald Unfortunately, a bone biopsy to rule out osteomalacia was done in only 9 of 18 patients. Shiomi et al. studied the efficacy of 1,25-dihydroxy-vitamin D3 (0.5 micrograms) on lumbar spine BMD in 76 individuals with cirrhosis secondary to hepatitis B or C infection. The results suggested that calcitriol may be effective for increasing bone mass at the lumbar spine over a 12-month period [52]. B4 Calcium supplementation appeared to prevent or diminish bone loss compared with untreated controls [53]. Antiresorptive and anabolic agents A retrospective study of 107 females with PBC suggested that hormone replacement therapy (HRT) is associated with a significant reduction of annual bone loss (Table 16.1) [50]. B4 A small RCT of HRT compared to vitamin D supplements showed statistically significant improvement in BMD of LS and FN with HRT [55], and a small prospective non-randomized study showed a significant 2.25% improvement in LS BMD with one year of HRT compare with vitamin D alone (0.87%) [46]. Another small prospective study showed a non-significant trend towards less FN bone loss and fewer fractures with HRT [54]. In another non-randomized study, four years of clodronate and calcium/vitamin D3 supplements did not significantly improve osteoporosis or osteopenia in menopausal PBC patients but reduced “natural bone loss” [45]. Table 16.2 summarizes the results of randomized trials of a variety of other interventions. Guanabens et al., in a two-year RCT of 32 women with PBC, compared cyclical etidronate at a dose of 400 mg for two weeks every 78 days, to sodium fluoride (NaF) 50 mg per day [59]. In the fluoride-treated group, the bone density of the lumbar spine decreased by 1.94% and the femoral neck decreased by 1.4%. By contrast, etidronate increased bone mass in the lumbar spine by 0.53% and femoral neck BMD was stable and was better tolerated. Ald

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Metabolic bone disease

Table 16.1 Case series of interventions for hepatic osteodystrophy. Study

Disease (no. of patients)

Therapy (duration)

Measurement (site)

Comments

Floreani et al. (2007) [45]

PBC (100)

oral calcium carbonate (1000 mg/day) + vit D3 (880 IU/day) + i.m. disodium clodronate 100 mg every 10 days) (four years)

DXA LS (L2-L4).

Clodronate + calcium/vitamin D3 supplements did not significantly improve osteoporosis or osteopenia, but reduced “natural bone loss”

Pereira et al. (2004) [46]

PBC (42)

Transdermal HRT vs oral vitamin D supplement (one year)

DXA LS

2.25% increase in BMD with HRT vs 0.87% with vitamin D

Floreani et al. (1997) [47]

PBC (34)

1,25(OH)2-D3 1 micrograms/day × 5d, calcitonin 40 U IM 3/week x four weeks every three months CaCO3 1–5 g/day × four weeks (three years)

DPA (LS)

Reduced bone loss in treated (uncontrolled)

Riemens et al. (1996) [48]

OLT (53)

1-OHD 1 microgram/day; Ca 1 g/day; etidronate 400 mg/day 2/15 week (one year)

DPA (LS)

No reduction in bone loss compared with historical controls

Neuhaus et al. (1995) [49]

OLT (150)

25-OH-D3 0.25–0.5 micrograms/day ± Ca 1 g/day ± NaF 25 mg/day (two years)

DXA (LS/FN)

Reduced bone loss in any of the treatment groups compared with untreated controls

Crippin et al. (1994) [50]

PBC (107)

Estrogen (low dose oral or patch) (one year)

DPA (LS)

Reduction in bone loss in estrogen group

Matloff et al. (1982) [51]

PBC (10)

25-OH-D3 40–120 micrograms/day (one year)

PBA (radius)

Normalization of 25-OH-D levels but ongoing bone loss and fractures

Herlong et al. (1982) [40]

PBC (15)

25-OH-D3 50–100 micrograms/day (one year)

PBA (radius)

Normalization of 25-OH-D levels but ongoing bone loss

Wagonfeld et al. (1976) [33]

PBC (8)

PO or SC D vs 25-OH-D3 100–200 micrograms/day (three months)

X-ray and PBA (hand)

Failure of oral or parenteral vitamin D to normalize 25-OH-D or to prevent accelerated bone loss

PBC: primary biliary cirrhosis; OLT: orthotopic liver transplantation; CAH: chronic active hepatitis; ALD: alcoholic liver disease; HA: hydroxyapatite; NaF: sodium fluoride; UDCA: ursodeoxycholic acid; DPA: dual photon absorptiometry; DXA: dual X-ray absorptiometry; PBA: photon beam absorptiometry; SPA: single photon absorptiometry; LS: lumbar spine; FN: femoral neck; 25-OH-D3: 25-hydroxy-vitamin D3; PO: per os; SC: subcutaneous; IM: intramuscular.

Wolfhagen et al. compared etidronate plus calcium with calcium alone in a randomized trial in 12 women with PBC on corticosteroids [61]. There was a statistically significant difference in the percentage change in mean lumbar BMD between the etidronate and calcium-treated groups (etidronate + 0.4%, calcium −3.0%, p = 0.01) [61]. Ald In a randomized trial that was not blinded, Shiomi et al. evaluated etidronate in 45 women with cirrhosis due to underlying viral hepatitis and also found a statistically significant difference in the percentage change in lumbar spine BMD [57]. Guanabens et al. compared alendronate with etidronate in an RCT of 36 women with PBC [56]. After two years, both treatments increased bone density but the increase was significantly greater in women on alendronate. Ald Camisasca et al. [60] evaluated the effect of a six-month course of calcitonin 40 IU every other day, given subcutaneously in a trial with a crossover design. The control group received 1 IU of porcine calcitonin (no metabolic effect).

Both groups received calcium and 100,000 IU of parenteral vitamin D2 (n = 25). Treatments were administered for six months with a three-month washout. There was no difference in bone density between the two treatment groups in either of the crossover periods. It is possible that this study was inadequately powered to detect a statistically significant difference. Ald In another trial of 22 women with PBC followed for two years, Guanabens et al. [62] compared NaF to calcium in a two-year RCT. In the NaF group, the bone density of the lumbar spine increased by 2.9% compared with the control group in which it decreased by 6.6%. However, there was a high frequency of adverse effects, mainly gastrointestinal. Since NaF therapy was also less effective than etidronate in another study, this intervention is not recommended. In summary, both cholestatic and non-cholestatic types of liver disease may be complicated by metabolic bone 283

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Table 16.2 Randomized trials of interventions for hepatic osteodystrophy. Study

Disease (no. of patients)

Intervention (duration)

Measurement (site)

Comments

Boone et al. (2006) [54]

PBC (31)

Two years’ estrogen/progestin

DXA, FN

High treatment drop-out rate Less bone loss with treatment, and no fractures vs two with placebo (NS)

Ormarsdottir et al. (2004) [55]

PBC (18)

Two years’ transdermal oestradiol + medroxyprogesterone vs vitimin D

DXA, LS, FN

BMD increased with HRT at LS, and FN (p < 0.05)

Guanabens et al. (2003) [56]

PBC (36)

Two-year cyclical etidronate vs alendronate

DXA, LS, FN

Both treatments increased BMD, but increases with alendronate were significantly larger

Shiomi et al. (2002) [57]

Viral hepatitis (50)

Two years’ cyclical etidronate

DXA LS

Significant reduction in bone loss in etidronate treated group

Lindor et al. (2000) [58]

PBC (67)

One year cyclical etidronate

DXA LS, FN

No significant difference from placebo

Shiomi et al. (1999) [52]

Cirrhosis, PBC and secondary to hepatitis B and C (76)

0.5 micrograms calcitriol twice daily 15 months

DXA (LS)

Significant reduction in bone loss in calcitriol group

Guanabens et al. (1997) [59]

PBC (32)

Etidronate 400 mg/day 2/15 week vs NaF 50 mg/day (two years)

DPA (LS)

Significant reduction in bone loss in etidronate group

Camisasca et al. (1994) [60]

PBC (25)

Carbicalcitonin 40 U SC every day vs porcine calcitonin IU SC 2/week (15 months)

DPA (LS)

No difference between groups

Wolfhagen et al. (1997) [61]

PBC (12)

Etidronate 400 mg/day × two weeks + Ca 500 mg/day, 11/13 week vs Ca 500 mg/day (one year)

DXA (LS/FN)

Significant reduction in LS bone loss in etidronate group

Guanabens et al. (1992) [62]

PBC (22)

NaF 50 mg/day vs placebo (two years)

DPA (LS)

Significant reduction in bone loss in NaF group

Lindor et al. (1995) [63]

PBC (88)

UDCA 13–15 mg/kg/day (three years)

DPA (LS)

No difference between groups

Stellon et al. (1985) [64]

CAH (36)

HA 8 g/day (two years) X-ray/SPA

Reduced bone loss in HA group

Mobarhan et al. (1984) [12]

ALD (18)

D2 50 000 U 2–3×/wk v 25-OHD 20–50 micrograms/day vs control (one year)

DPA (LS)

Significant increase in BMD compared to baseline in all groups a crossover design

PBC: primary biliary cirrhosis; OLT: orthotopic liver transplantation; CAH: chronic active hepatitis; ALD: alcoholic liver disease; HA: hydroxyapatite; NaF: sodium fluoride; UDCA: ursodeoxycholic acid; DPA: dual photon absorptiometry; DXA: dual X-ray absorptiometry; PBA: photon beam absorptiometry; SPA: single photon absorptiometry; LS: lumbar spine; FN: femoral neck; 25-OH-D3: 25-hydroxy-vitamin D3; PO: per os; SC: subcutaneous; IM: intramuscular.

disease, predominately osteoporosis. The prevalence of bone disease increases with the degree of cirrhosis. Accelerated bone loss is most severe after liver transplantation. Patients with advanced liver disease, awaiting transplantation, on prolonged corticosteroid therapy or with a history of fragility fractures, should be investigated with BMD testing. C5 Low 25-(OH) D3 levels should be cor284

rected and calcium supplementation given. Bisphosphonates should be considered in patients with known osteoporosis or vertebral fractures, based on the evidence from a number of small randomized trials. Ala Testosterone therapy should be considered in males with hypogonadism. C5 There is a need for population-based studies of fracture risk in patients with chronic liver disease.

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Inflammatory bowel disease Prevalence The importance of metabolic bone disease in patients with IBD has been recognized for some time. However, the point prevalence of bone disease in this population varies greatly from one study to another, with estimates as low as 5% to as high as 78%. This variation reflects a number of factors, including the definition of osteoporosis used, the site of bone density measurement and the heterogeneous nature of the IBD population. Furthermore, morphometric vertebral deformities also appear to be relatively common and are seen in 25% of both Crohn’s disease, and ulcerative colitis patients [65]. A list of potential factors that need to be considered when evaluating studies in this area is provided in Table 16.3. In a well-conducted study, Abitbol et al. [66] evaluated the BMD of 84 consecutive patients with IBD (34 Crohn’s disease, 50 ulcerative colitis, excluding proctitis). Overall, 43% had osteopenia in the lumbar spine. Steroid users were at significantly greater risk of osteopenia (58% vs 28% in non-users, p = 0.03). Six patients with a mean age of 50 had vertebral crush fractures (mean Z-score was −1.63). Five patients were found to have low 25(OH) D3 levels; however, the cause of this deficiency was felt to be extra-intestinal in all but one case. Multiple regression analysis of the lumbar spine Z-score revealed a significant correlation between osteopenia and age, cumulative corticosteroid dose, inflammatory status as assessed by the erythrocyte sedimentation rate (ESR), and low osteocalcin levels (r2 = 0.76, p < 0.05). The rate of bone loss in IBD has been studied in several longitudinal studies [67–73]. In the majority of the studies

Table 16.3 Factors influencing interpretation of studies of bone disease in gastrointestinal patients. Definition of osteopenia

Z-scores of ≤ 1 (? T-scores of −1 to −2.5)

Diagnostic method

X-ray, SPA, DPA, QCT, DXA, US

Results expressed (outcome)

BMD, BMC, radiological or clinical fracture (vertebral or non-vertebral)

Bone site studied

Spine, forearm, femoral neck or total hip

High risk patients

Included or excluded

Control of confounders

Smoking, steroid use, BMI

SPA: single photon absorptiometry; QCT: quantitative computed tomography; DPA: dual photon absorptiometry; DXA: dual energy X- ray absorptiometry; BMD: bone mineral density; BMC: bone mineral content.

Metabolic bone disease

the annual rate of bone loss appears to be greater in the spine than at the radius, and varies from 2% to 6%. Schulte et al. studied the rate of BMD change in 80 IBD patients and found that the annual rate of bone loss was small (0.8%/ year for spine) [71]. Corticosteroid use [67] and low body mass index [68] were found, in some studies, to affect bone mass negatively. Overall, metabolic bone disease is an important problem among patients with IBD, with an estimated prevalence in the range of 45%. Malabsorption of calcium and vitamin D because of small bowel disease appears to play a minor role in the pathogenesis of metabolic bone disease in IBD. Both low and normal 25(OH) D levels have been documented in patients with Crohn’s disease and there is no clear correlation between vitamin D levels and bone mass [74, 75]. Osteomalacia appears to be much less common than osteoporosis in IBD. Hessov et al. did a bone biopsy and serum 25(OH) D determinations on 36 randomly selected Crohn’s disease patients with previous surgical resections (mean length 105 cm). Only two patients were found to have below normal 25-hydroxy-vitamin D3 levels and/or histomorphometric evidence of osteomalacia. However, the mean trabecular bone volume was reduced in this group compared with controls, suggestive of osteoporosis. This finding did not correlate with any of the measured clinical characteristics, including length of resection and serum 25(OH) D level [76]. Another bone histomorphometry study in IBD revealed decreased bone formation without evidence of osteomalacia [77]. Comparisons between Crohn’s disease and ulcerative colitis patients suggest that osteoporosis may be more prevalent in the former [78–80]. However, careful review of these publications suggests that the analysis may not have been fully controlled for the effects of disease activity and/or steroid use. Jahnsen et al. in an age and sex-matched cross-sectional study of 60 Crohn’s disease patients, 60 ulcerative colitis patients and 60 controls, found no differences in BMD between the patients with ulcerative colitis and the controls [79]. However, Crohn’s disease patients had significantly lower BMD. Overall 16% of ulcerative colitis patients and controls had Z-scores 25% for men and >15% for women 50 years and older; mean colonoscope withdrawal times >6 minutes in normal colonoscopies. Standardized colonoscopy reporting systems [87] and public reporting by individual endoscopists have been proposed to facilitate quality improvement [88]. Evidence

Colorectal cancer: Surveillance

to support these indicators includes reports of highly variable adenoma detection rates among endoscopists in practice and an association between higher detection rates and longer colonoscope withdrawal times [89]. Clearly, withdrawal time is a proxy for careful technique. In one large institution, increasing withdrawal time alone had no effect on polyp detection [90]. The colonoscopy quality program in the UK focuses on adenoma detection rates rather than withdrawal time (personal communication: Roland Valori, September 2008). Tandem colonoscopy studies [91] and studies of CTC followed by colonoscopy [92] report colonoscopy miss rates for adenomas >1 cm of 6–12%. In addition, the colonoscopy miss rate for CRC is about 5%. Evidence to support this estimate includes a retrospective study at 20 Indiana hospitals that reported 47 (5%) of 941 CRC patients who had a colonoscopy within three years prior to their diagnosis of CRC had a reportedly normal colonoscopy [67]. An Ontario population-based cohort study of 12,487 persons with CRC reported a CRC miss rate of 2–6%, depending on cancer site, with right-sided CRC associated with higher (6%) miss rates [93]. A recent study of 1819 (largely) male veterans reported a 9.4% prevalence of non-polypoid (flat and depressed) colorectal neoplasia [94]. The investigators used indigo carmine dye to spray the mucosa to assist in the detection of these lesions at colonoscopy. The implications of this study for usual clinical practice are unclear. Whether this rather high prevalence is generalizable to other populations, whether missing such lesions contributes to missed CRCs, and whether advanced colonoscopy techniques will be required to detect these lesions remain unresolved. The rates of colonoscopy-associated bleeding, perforation and death have been reported in two population-based studies that used information from administrative databases with validation using chart review. A US study evaluated 16,318 individuals 40 years of age and older who underwent outpatient colonoscopy at Kaiser Permanente of Northern California between January 1994 and July 2002. The rates of colonoscopy-related bleeding and perforation within 30 days following the procedure were 3.2/1000 and 0.9/1000 respectively, and the risk of death was 0.06/1000 or approximately 1/16,000 [95]. A Canadian study evaluated 97,091 persons 50 to 75 years of age who had an outpatient colonoscopy during 2002–2003 [96]. The rates of colonoscopy-related bleeding and perforation requiring hospital admission were 1.64/1000 and 0.85/1000 respectively, and the risk of death was 0.074/1000 or approximately 1/14,000. In both studies older age and having a polypectomy were associated with increased risk of bleeding or perforation. Given the central role of polypectomy in CRC prevention and its strong association with bleeding and perforation, best practice in terms of polypectomy technique needs to be defined [97]. Although colon317

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oscopy-related bleeding and perforation have received the most attention, these do not account for all serious complications of colonoscopy. We currently lack estimates of the risks of other important complications of colonoscopy, such as cardiovascular events, in usual clinical practice.

Costs The direct cost per patient for a single episode of screening using colonoscopy exceeds the cost for FOBT. In addition, the indirect costs, including time off work for the screened subject and any accompanying caregiver, travel, and out of pocket expenses (e.g. for bowel preparation) are substantial and account for one-third of the total cost of the colonoscopy [98]. The burden of indirect costs may lead to reduced uptake of screening colonoscopy. In addition, the estimated additional cost in the USA of CRC care (screening, diagnosis, complications, treatment) with widespread screening colonoscopy at 75% compliance, was an additional $3.8 billion per year [99].

Capacity A US simulation study evaluated capacity to provided CRC screening for the 41.8 million US adults who had not been screened in 2002 [100]. The results indicate that sufficient capacity for population screening exists only for FOBT. A screening colonoscopy program would require 10 years to screen the unscreened population because the demand would exceed supply [100]. This result has also been reported by others [101]. These findings provide a strong stimulus for screening approaches that focus constrained colonoscopy resources on those most likely to benefit.

Patient acceptance Screening colonoscopy requires a motivated patient, given the need for bowel preparation and conscious sedation, as well as the time involved, including time off work. Studies of patient preferences for CRC screening show no consistent preference among screening tests [102–104]. Not all patients will choose to undergo screening colonoscopy when provided with alternatives.

Implementing screening Cost effectiveness CRC screening is not only effective, but also cost-effective. In 2002, the USPSTF performed a systematic review of the cost-effectiveness of CRC screening (using gFOBT; FS; gFOBT and FS; DCBE; or colonoscopy) and reported that 318

compared with no screening, cost-effectiveness ratios for screening with any of these methods were between $10,000 and $25,000 per life-year saved [105]. No particular screening strategy was consistently found to have the best incremental cost-effectiveness ratio. A more recent costeffectiveness study incorporated new information on costs and test performance of the stool-based CRC tests (gFOBT, FIT, fDNA) and compared these tests with colonoscopy [106]. All three stool-based tests were cost-effective, with gFOBT and FIT preferred if adherence to yearly testing is high, whereas FIT was preferred if adherence is poor. Importantly, the authors note that as the costs of care of patients with colorectal cancer increases because of the use of costly biologic agents, screening with inexpensive gFOBT and FIT may actually be cost saving. A recent decision analysis assessed life-years gained and colonoscopy requirements for several CRC screening strategies [7]. This analysis was done to inform the USPSTF recommendation. CRC screening with colonoscopy every 10 years, annual screening with a sensitive FOBT, or flexible sigmoidoscopy every five years with a midinterval FOBT, for persons age 50 to 75 years, provided similar gains in life-years assuming perfect adherence.

Practical considerations Although the cost per life-year saved for CRC screening compared with no screening is comparable to other interventions that are currently endorsed, such as breast cancer screening with mammography in women 50 years and older, this is only one aspect to consider in deciding whether to move forward with implementing populationbased screening. In an organized screening program funding must be allocated to run the program. In addition, social marketing and health care provider campaigns are needed. Laboratory services and colonoscopy capacity must be in place, as well as treatment capacity. Clear referral pathways must be established. Finally, there must be quality assurance and monitoring and reporting systems [19]. In jurisdictions with publicly funded health care systems, a jurisdiction-wide policy must be in place that defines the target age group, the screening test to be implemented, and the testing interval. In Canada, Ontario was the first province to implement a population-based CRC screening program. In 1999, Cancer Care Ontario (CCO), the provincial agency responsible for cancer, convened an expert panel to develop recommendations for an organized CRC screening program in Ontario. The panel recommended a province-wide gFOBT-based CRC screening program for average-risk individuals 50 to 74 years of age (Ontario Expert Panel on Colorectal Cancer. Colorectal cancer screening: final report of the Ontario Expert Panel. Toronto, Ontario: CCO; 1999.) In 2002, this recommendation was

CHAPTER 18

echoed at the national level by a committee convened by Health Canada (National Committee on Colorectal Cancer Screening, Recommendations for population-based colorectal cancer screening, Ottawa, Canada: Public Health Agency of Canada; 2002). A one-year pilot study to evaluate recruitment strategies for gFOBT screening was funded by the Ontario Ministry of Health and Long-Term Care (MOHLTC) in June 2003 (CCO: Ontario FOBT Project Steering Committee. Ontario FOBT project: final report (monograph on the Internet). Toronto, Ontario: CCO; 2006 Mar (cited 2007 Apr 05). Available from: http://cancercare. on.ca/documents/OntarioFOBTProject-FinalReport.pdf). In June 2005 CCO submitted a proposal to the MOHLTC for a provincial population-based CRC screening program. Based on the existing evidence for effectiveness and costeffectiveness, coupled with the provincial and national consensus on CRC screening policy, and taking into account findings from the Ontario Pilot, the MOHLTC announced funding for the program in January 2007. Implementation began in April 2007. In March 2008 the MOHLTC and Cancer Care Ontario announced the public launch of the program, called ColonCancerCheck. ColonCancerCheck involves gFOBT for average risk individuals and colonoscopy for those at increased risk because of a family history of one or more first-degree relatives with CRC. Operational challenges are multiple. Stakeholder engagement is crucial, particularly among physicians and their professional societies. This is especially the case when there is skepticism about the choice of screening test and program model. Laboratory professionals must be engaged and committed to quality assurance. In Ontario, CCO developed evidence-based FOBT standards to guide laboratory processing and kit performance [107]. CCO also developed colonoscopy standards [108] to set forth endoscopist, institution and performance standards for colonoscopy. For example, the standards state that endoscopists are required to perform at least 200 colonoscopies per year. Contracts with the laboratories set forth requirements for processing gFOBT kits, quality assurance and reporting to the Program. Funding was provided to 71 public hospitals to deliver additional colonoscopies to support the Program. The contracts with the public hospitals set forth requirements for monthly reporting to the Program of volumes, wait times and performance. The IM/IT system to support monitoring and reporting requirements, as well as letters of invitation to the target population and letters of recall for those with a negative gFOBT is under development. In the USA, quality report cards for health plans, such as the Healthcare Effectiveness Data and Information Set (HEDIS), provide impetus for health insurers to compete on quality. Using published guidelines as a basis for setting specification, a hybrid of claims data and chart review is used to measure screening rates. Northern California

Colorectal cancer: Surveillance

Kaiser Permanente reported that screening rates increased from 37% to 53% between 2005 and 2008, with a rate over 65% expected in 2009. The increase in screening rates has required an unprecedented investment in colonoscopy capacity and organized screening.

Comparing guidelines In 2008 two high profile, influential US organizations have published colorectal cancer screening guidelines: the American Cancer Society, US Multi-Society Task Force on Colorectal Cancer and American College of Radiology (ACS/USMSTF/ACR) [60, 61], and the US Preventive Services Task Force (USPSTF) (Table 18.1) [6]. The authors took somewhat different approaches, and this resulted in some differences in emphasis and recommendations [109]. The USPSTF undertook a formal, systematic, in-depth evidence review [28], and used simulation modeling when the evidence base was not sufficient to guide recommendations [7]. The ACS/MSTF/ACR process was more driven by expert opinion, when the evidence base was lacking. As a result, the USPSTF is more conservative in its recommendations, emphasizing the balance of risks and harms of screening. In the end, the guidelines are similar with several key differences. Both guidelines, summarized in Table 18.1 emphasize a menu of options, recognizing that existing evidence and modeling studies do not support one clearly preferred

Table 18.1 Comparison of guidelines for screening persons at average risk for colorectal cancer. Screening method or variable

ACS-MSTF Recommendation

USPSTF Recommendation

Standard guaiac FOBT (gFOBT)

No

Annually

High sensitivity FOBT (gFOBT or FIT)

Annually

Annually

Flexible sigmoidoscopy alone

Every five years

Every five years

Double contrast barium enema

Every five years

Not recommended

CT colonography

Every five years

Not recommended

Colonoscopy

Every 10 years

Every 10 years

Stool DNA tests

Interval Uncertain

Not recommended

Age to begin screening

50

50

Age to end screening

Not stated

75

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Gastrointestinal disorders

screening approach. Both guidelines recommend fecal occult blood testing, done annually in average risk patients. The ACS/MSTF/ACR makes a clear statement in favor of high sensitivity fecal blood tests, either gFOBT or FIT. Both guidelines recommend flexible sigmoidoscopy every five years, and the USPSTF model demonstrates an advantage of the five-year interval over the 10-year interval [7]. Both guidelines recommend colonoscopy every 10 years. The USPSTF explicitly rejects VC, citing inadequate information about the harms of radiation exposure and the problem of extracolonic findings as reasons to be cautious about VC. The ACS/MSTF/ACR included VC, as a screening option to be done every five years, citing the diagnostic accuracy studies demonstrating sensitivity approaching that of colonoscopy for larger polyps. Barium enema and stool DNA are both options on the ACS/MSTF/ACR guideline, but the USPSTF has excluded them due to a lack of evidence supporting their use. Two other differences between the guidelines bear mentioning, and reflect the process differences between the two groups. The ACS/MSTF/ACR guideline came out with a strong statement in favor of tests that prevent cancer through the early detection and removal of adenomas, including flexible sigmoidoscopy, colonoscopy, virtual colonoscopy and double contrast barium enema [60, 61]. The USPSTF made no such distinction, taking a more firm evidence-based approach. The only evidence for the cancer prevention benefit of colonoscopy comes from the National Polyp Study [9]. A major limitation of that study was the lack of a concurrent control group [110]. In addition, the USPSTF made a firm statement about the age to begin and end screening for CRC screening, based on its simulation model, recommending discontinuing screening after age 75 in people who have had prior screening, or 85 for all patients [6]. Relying on the consensus of expert opinion, the ACS/MSTF/ACR guideline did not comment on a stopping age for screening. How should the practicing physician handle the discrepancy between guidelines and the challenges with the implementation of a menu of screening options? The best approach is one that is organized, consistent and evidencebased. It is most effective for a group of physicians to decide together on an approach that will work for their setting, based on achievable capacity, patient acceptance, and the balance of risks and benefits. Once that approach has been agreed upon, efforts should be made to ensure that all eligible members of the target population receive the invitation to be screened, and that barriers to patient acceptance are removed, through the development of reminders, tracking systems and ease of appointments. It matters less which test is performed, since there is no clearly dominant strategy. The key issue is that patients receive regular screening at appropriate intervals and with adequate quality control. 320

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Prevention and treatment of travelers’ diarrhea Herbert L DuPont Center for Infectious Disease, University of Texas Health Science Center at Houston, School of Public Health and Internal Medical Service, St. Luke’s Episcopal Hospital, Department of Medicine, Baylor College of Medicine, Houston, USA

Background The first studies of travelers’ diarrhea were carried out in the 1950s and 1960s by Kean and colleagues [1]. Kean’s research team found that antibiotic drugs would successfully prevent TD during high-risk travel. Despite more than 50 years of research aimed at defining the cause and source of the causative agents we have seen no reduction in frequency of TD among persons venturing into tropical and semi-tropical areas from industrialized countries [1–3]. Following studies defining the importance of bacterial enteropathogens in TD, it was shown that antibacterial drugs could shorten the illness [4]. Recent studies have provided evidence that TD not only produces a full day of disability when it occurs but an important number of affected persons develop chronic functional bowel disease as a complication of TD. This review looks at the available scientific evidence supporting the use of drugs and vaccines to prevent TD and therapies, new and old, aimed at shortening the duration of illness when it develops.

Epidemiology of travelers’ diarrhea The world can be divided into three regions depending upon the rate of TD among visitors from industrialized countries (Figure 19.1). The high-risk regions of the world for TD are Latin America, Africa and Southern Asia, the moderate-risk regions are certain Caribbean islands (e.g. Jamaica), the Middle East, China, Thailand and Russia and the low-risk areas are the United States, Canada, north-

Evidence-Based Gastroenterology and Hepatology, Third Edition John WD McDonald, Andrew K Burroughs, Brian G Feagan and M Brian Fennerty © 2010 Blackwell Publishing Ltd. ISBN: 978-1-405-18193-8

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western Europe, Japan, New Zealand and Australia. The rate of diarrhea when people from low-risk areas visit the three regions are 40% [5, 6], 8–15% [6, 7] and ∼4% [6], respectively. The 4% for groups moving from one low-risk area to another, is approximately the same as is seen when people from a high-risk area visits a low-risk region [8, 9]. Why diarrhea develops among people traveling to low-risk areas probably relates to multiple factors, including eating all meals at public restaurants with its increased risks of enteric infection compared with self-preparation of meals in homes [10], increased stress leading to autonomic intestinal motility alterations [11], and possibly excessive alcohol ingestion in a subset of travelers [12].

Etiology of travelers’ diarrhea Studies in the 1970s identified enerotoxigenic Escherichia coli (ETEC) as the principal cause of TD [13–16]. In the last two decades enteroaggregative E. coli (EAEC) [17] and a variety of other bacteria [18] have been shown to be important causes of TD. The diarrheagenic E. coli (ETEC and EAEC) cause a majority of the diarrhea in Latin America [3, 18, 19] and Africa [20, 21]. While ETEC and EAEC are important causes of TD in Asia [18, 22, 23] other bacteria are important, including Shigella, Campylobacter, Salmonella and Aeromonas spp. [18, 22, 24–26]. The fact that invasive enteropathogens are relatively more important causes of TD in Asia influences recommendations on self-treatment for travel to these countries. Noroviruses explain between 10%–20% of cases of TD [27].

Evidence-base evaluation Guidelines used to establish the evidence base for evaluating evidence of efficacy of drugs and vaccines are outlined in Table 19.1.

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Prevention and treatment of travelers’ diarrhea

Travelers’ diarrhea: Areas at risk Risk Level Low Intermediate High-risk regions include Latin America, Africa and Southern Asia (diarrhea rates ~40%), moderate-risk regions include China, Russia, the Middle East, Caribbean Islands such as Jamaica, South Africa, southern cone of South America, and Thailand (diarrhea rates 8–15%) and low-risk areas include the USA, northwestern Europe, Japan, Australia and New Zealand (diarrhea rates < 4%).

High

Figure 19.1 World map showing variation in risk of acquiring travelers’ diarrhea among international visitors from low-risk regions. The figure is reprinted with permission from Aliment Pharmacol Ther [95].

Table 19.1 Grading of clinical evidence in the chemoprevention and chemotherapy of travelers’ diarrhea [80]. Category

Grade

Definition

Strength of evidence

A

Good evidence to support a recommendation for use Moderate evidence to support a recommendation for use Poor evidence to support a recommendation Moderate evidence to support a recommendation against use Good evidence to support a recommendation against use

B C D E

Quality of evidence

I II

III

Evidence from ≥1 properly randomized, controlled trial Evidence from ≥1 well-designed clinical trial without randomization, from casecontrolled analysis of cohort study Consensus evidence, evidence from one authority or reports of expert committees

Prevention of travelers’ diarrhea Given the high risk of acquiring TD and the importance of bacterial enteropathogens it is easy to see why there is such an active interest in preventing the illness through chemo or immune-prophylaxis.

Historical considerations The first evidence that bacterial enteropathogens were responsible for TD was provided by Kean and colleagues, showing the value of antibiotics in preventing the disease [1]. Prophylactic use of antibiotics during international travel in the 1950s was widely practiced. A study carried out in 1957 demonstrated that more than 35% of persons returning to the USA from Mexico were taking prophylactic antibiotics to prevent diarrhea during their trip [28]. During the 1968 Olympic Games in Mexico City, the British team credited taking multiple doses of oral sulfonamides and oral streptomycin for keeping them well during competition; the American. and Australian teams had higher rates of diarrhea, probably because they relied upon a single daily dose of sulfonamide for protection [29]. 325

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Bradley and David Sack from Johns Hopkins then demonstrated the value of doxycycline in preventing TD [30, 31] until resistance to the drug prevented further evaluation [32]. In the 1980s studies were conducted showing the effectiveness of liquid [33] or tablet formulation [34] of bismuth subsalicylate (BSS) in preventing TD. BSS was safely given to the trial participants, with only darkening of stools and tongues from harmless bismuth sulfide, and mild tinnitus, presumably from the absorbed salicylate, as adverse effects. The drug was more effective when it was taken in a total dose of 2.1 g/d in four equally divided doses than when it was taken in a similar daily dose on a twice a day regimen, or in half of this dose four times a day [35]. Trimethoprim/sulfamethoxazole was shown to prevent TD in studies carried out in the 1980s [36]. Also, in the 1980s and 1990s, a number of trials established the value of the fluoroquinolones in preventing TD [37–40]. General use of antibiotics for chemoprophylaxis during travel was largely stopped by a Consensus Development Conference held at the National Institutes of Health in 1985 [41], because of concern about adverse effects, and the stimulation of resistance by widespread use of systemically absorbed antibiotics and also because of the difficulty in identifying appropriate recipients of preventive drugs. The concept became of interest once more with the availability of non-absorbed (2 years

Rome I [4]

1990

Abdominal pain or discomfort relieved with defecation, or associated with a change in stool frequency or consistency, plus two or more of the following on at least 25% of occasions or days: Altered stool frequency Altered stool form Altered stool passage Passage of mucus Bloating or distension

≥3 months

Rome II [6]

1999

Abdominal discomfort or pain that has two of three features: Relieved with defecation Onset associated with a change in frequency of stool Onset associated with a change in form of stool

≥12 weeks (need not be consecutive) in last one year

Rome III [1]

2006

Recurrent abdominal pain or discomfort ≥3 days per month in the last three months associated with two or more of: Improvement with defecation Onset associated with a change in frequency of stool Onset associated with a change in form of stool

Symptom onset ≥6 months prior to diagnosis

This difference may exist because the latter criteria are more restrictive and require minimum symptom duration of three months. The prevalence may also vary according to the demographics of the population under study. Irritable bowel syndrome is commoner in females [17, 18], and younger individuals [9, 19, 20] while the evidence for an effect of socioeconomic status on prevalence of IBS is conflicting [15, 21, 22]. The prevalence of IBS appears to be comparable among Western nations and those of the developing world and the Far East [9, 13, 23, 24], although there are fewer data available from the latter regions. The prevalence of IBS is reported to remain relatively stable over short periods of time [11, 25, 26], with the reso356

lution of symptoms in some individuals matched by the onset of new symptoms in others. However, individuals readily change their subgroup, as defined by predominant stool pattern [27]. Over longer time-frames an increase in prevalence of IBS has been reported after 7 and 10 years of follow-up [28, 29]. The incidence of IBS is poorly reported. In a longitudinal study conducted in Sweden the threemonth incidence was 0.2% [25]. A medical records review of a random sample of residents of Olmsted County, Minnesota, estimated that the incidence of clinically diagnosed IBS was 2 per 1000 adults per year [30]. Since many people with IBS do not seek health care, the true incidence may well be higher. In a more recent study, conducted in

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almost 4000 individuals from a UK population based sample, the incidence was 1.5% per year during a 10-year period of follow-up [29].

Irritable bowel syndrome and health services

Irritable bowel syndrome

ferers experience, and it seems unlikely that a single unifying mechanism explains them. It is more plausible that a combination of factors contributes to the abdominal pain and disturbance in bowel habit. Several proposed etiologies are discussed below.

Evidence for genetic susceptibility Individuals with IBS are more likely to consume health care resources than those without GI symptoms [31]. Up to 80% of sufferers may consult their primary care physician as a result of symptoms [32, 33]. Factors that drive this choice are poorly understood, but symptom frequency and severity, fear of serious underlying illness, poor quality of life, and other coexisting functional GI diseases have all been shown to predict consultation behaviour [13–15, 32– 35]. It has been estimated that IBS accounts for at least 3% of all consultations in primary care [35]. Of those who do consult a primary care physician, the majority are diagnosed and managed in primary care [36], but a significant proportion will be referred for a specialist opinion at some point [9, 10, 15, 33, 35]. The condition accounts for up to 25% of a gastroenterologist’s time in the outpatient department [37], and medical treatment is considered to be unsatisfactory, with patients with IBS representing a significant financial burden to health services. Despite the recommendations made by various medical organisations for a diagnosis of IBS to be made on clinical grounds alone [38–41], rather than following attempts to exclude all possible organic pathology by exhaustive investigation, many patients with symptoms suggestive of IBS will undergo colonic investigation, performed presumably in an attempt to reassure both the patient and the physician due to the potential uncertainty that may surround the diagnosis [42], or incur other medical costs [31, 35]. The annual cost of drug therapy for IBS has been estimated at $80 million in the USA [43]. In addition, patients with IBS are more likely to undergo unnecessary surgical procedures, with cholecystectomy, appendicectomy and hysterectomy rates two to three-fold higher than those observed in controls without IBS [44]. A recent systematic review of 18 studies from the UK and USA examined direct and indirect costs to the health service arising from IBS [45]. The authors estimated that IBS accounted for direct costs of between $348 and $8750 per patient per year, indirect costs of between $355 and $3344 per patient per year, and between 8.5 and 21.6 days of IBS-related sickness absence per patient per year.

Pathogenesis of irritable bowel syndrome There is no known structural, anatomical, or physiological abnormality that accounts for the symptoms that IBS suf-

Irritable bowel syndrome aggregates within families. Relatives of a patient with IBS are almost three times more likely to report symptoms compatible with IBS than relatives of the patient’s spouse [46]. Whether this is due to genetic susceptibility, shared childhood environment, or learned illness-behaviour is unclear. Twin studies demonstrate that there is a greater concordance of IBS in monozygotic versus dizygotic twins [47, 48]. However, having a parent with IBS was a stronger predictor than having a twin with IBS [48]. There is also evidence that children with a parent with IBS are more likely to report GI symptoms and have GI symptom-related absence from school [49]. There have been studies of various candidate genes [50, 51], but the results are conflicting, and their clinical significance is debatable.

Evidence for disturbed gastrointestinal motility Disturbances in GI motility are thought to play a role in IBS. Previous studies have demonstrated evidence of delayed gastric emptying [52], abnormalities in small bowel and colonic transit time [53], and an increase in colonic motility in response to meal ingestion in IBS [54]. However, these abnormalities are not always reproducible, cannot be used to aid diagnosis, and vary from patient to patient. Some of this variability may be related to the predominant stool pattern experienced by the patient, but as this pattern does not exhibit great stability during followup [27], it is conceivable that the disturbances themselves change with time.

Evidence for visceral hypersensitivity and abnormalities of central pain processing Abdominal pain in IBS is proposed to be related to visceral hypersensitivity, due to abnormal sensitisation of the peripheral and central nervous system. The cause of this sensitisation is unknown, but IBS sufferers report lower thresholds of pain during colonic, rectal and foregut stimulation [55, 56], with radiation to extra-abdominal sites. In addition, patients demonstrate enhanced activation of regions in the brain that are required for central pain processing in functional magnetic resonance imaging studies conducted during gut stimulation compared to controls [57, 58]. 357

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Evidence for a post-infectious etiology and altered gut flora There are numerous studies reporting an increase in symptoms that meet diagnostic criteria for IBS in individuals who have been exposed to an acute gastroenteritis of either bacterial or viral origin [59–61]. The development of postinfective IBS in one study was more likely to occur with younger age, female gender, and certain features of the initial acute illness, including bloody stools, abdominal pain and prolonged diarrhea [59]. Biopsies from the colon and terminal ileum of patients with post-infectious IBS demonstrate an increased inflammatory cell infiltrate [62], and when intestinal permeability is measured in these subjects it is increased compared to that of healthy individuals [63], which may allow luminal gut bacteria to activate an immune response in the GI mucosa, thereby leading to chronic low-grade inflammation in a subset [64]. The existence of post-infectious IBS has led to an increased interest in possible abnormalities in gut flora as a cause for the condition. Some investigators have reported altered gut flora in subjects with IBS compared to healthy controls [65], and others have reported a higher prevalence of small intestinal bacterial overgrowth in IBS patients than controls, as demonstrated by lactulose and glucose hydrogen breath testing [66, 67], as well as an improvement in symptoms after therapy with non-absorbable antibiotics [68].

Making a diagnosis of irritable bowel syndrome The assessment of a patient with suspected IBS should begin with a structured history to assess whether the individual’s symptoms are compatible with the diagnosis. In a patient presenting with lower GI symptoms it is important to elicit the presence of alarm (red flag) symptoms such as weight loss, diarrhea and rectal bleeding as, if these are present, they are thought to predict colorectal cancer and therefore require urgent lower GI investigation, though their diagnostic utility in this situation is suboptimal [69]. Physical examination, including digital rectal examination, is unlikely to confirm the diagnosis of IBS, but should be conducted in order to exclude other organic causes of lower GI symptoms and, if normal, may reassure both the physician and patient.

sensus panel reported that existing criteria were insufficiently broad for use in primary care [70], and a recent survey demonstrated that few physicians in primary care were familiar with these criteria, or used them to make a diagnosis of IBS, yet could still diagnose the condition with confidence using a pragmatic approach [71]. Guidelines for the management of IBS in primary care still advocate the use of diagnostic criteria [40, 72]. Unfortunately, there are no published studies reporting on the utility of a physician’s opinion in making a diagnosis of IBS.

Utility of individual lower gastrointestinal symptoms The prevalence of symptoms such as lower abdominal pain, mucus per rectum, incomplete evacuation, looser or more frequent stools at the onset of abdominal pain, patient-reported visible distension and pain relieved by defecation has been reported in individuals with IBS compared to individuals without the syndrome [2–3,73–76]. Unfortunately, nocturnal diarrhea, a symptom that is often used by physicians when taking a clinical history, as an indicator of organic disease, was not studied. Since none of the other lower GI symptoms has good sensitivity or specificity for making the diagnosis of IBS [77], combinations of symptoms, in the form of symptom based diagnostic criteria, have been recommended as a means of reaching a clinical diagnosis.

Utility of symptom based diagnostic criteria Utility of the Manning criteria The Manning criteria have been validated prospectively in three subsequent studies since their original description in 1978 [75, 76, 78]. Therefore in total they have been validated in over 500 patients. They performed best in the original validation study [2], but also performed well in a study conducted in secondary care in Turkey [78]. However, they performed poorly in the two other studies in India [76] and Korea [75]. A recent systematic review of pooled data from these four studies assessed the utility of the Manning criteria in predicting a diagnosis of IBS [77]. The presence of three or more of the Manning criteria appeared to increase the likelihood of IBS almost three-fold, while if only two or fewer criteria were present the likelihood of the diagnosis was reduced by over 70%.

Utility of the Kruis scoring system

Utility of a physician’s diagnosis As all the current available symptom-based diagnostic criteria for IBS have been developed by gastroenterologists in secondary or tertiary care, their generalisability to patients presenting to a primary care physician is debatable. A con358

The utility of the Kruis scoring system has also been examined prospectively in three studies published since the original report in 1984 [73, 78, 79]. When data were pooled from all four studies [77], containing almost 1200 patients, a Kruis score of 44 or more increased the likelihood of IBS eight-fold, whilst a score less than 44 reduced the likeli-

CHAPTER 21

hood of the diagnosis by 70%. Whilst the Kruis score appears to have good utility in confirming a diagnosis of IBS, it is probably too complex to be used in routine clinical practice. In addition, one of the items it collects, “a history pathognomonic for any diagnosis other than IBS”, and the fact that symptom duration is required to be in excess of two years, probably account for its higher utility than the Manning criteria, which do not require minimum symptom duration.

Utility of the Rome criteria Only one study has validated the Rome I criteria in a tertiary care setting in the UK [80]. The Rome I criteria had a sensitivity of 71%, a specificity of 85%, and their presence in a patient made a diagnosis of IBS four times more likely [77]. The Rome III criteria were validated in questionnaire form prior to their publication in two studies, using a group of patients with functional GI disorders as well as population controls, and were reported to have sensitivity of 71% and specificity of 88% for the diagnosis of IBS, as well as good test-retest reliability [81]. However, there have been no published studies that have validated either the Rome II or Rome III criteria prospectively, so their utility is relatively unknown. Given that the Rome I criteria were first described almost 20 years ago, and the Rome II criteria 10 years ago, the lack of validation is disappointing, particularly as these have become the gold standard, in research terms, for making a clinical diagnosis of IBS.

Role of investigations in excluding organic disease in patients meeting diagnostic criteria for irritable bowel syndrome Patients with IBS may have a degree of symptom overlap with individuals with organic diseases. Thyroid disease, celiac disease, inflammatory bowel disease, microscopic colitis, lactose intolerance, small intestinal bacterial overgrowth and even colorectal cancer, in the absence of alarm symptoms, may all present with similar symptoms. As we have discussed, current diagnostic criteria are not infallible, so there may be some value to performing a limited number of clinical investigations in individuals with suspected IBS in order to exclude organic diseases that may present in a similar manner. There have been numerous studies conducted in subjects meeting diagnostic criteria for IBS that have examined the role of applying various diagnostic tests, and which report the prevalence of organic disease in these individuals (Table 21.2). The available evidence is summarized below.

Role of lower gastrointestinal investigations in irritable bowel syndrome Five studies have reported findings following lower GI investigation in patients with IBS defined according to

Irritable bowel syndrome

various diagnostic criteria [79, 82–85]. Three of these utilized complete colonic investigation in over 600 patients, two with either full colonoscopy, or barium enema in combination with flexible sigmoidoscopy [83, 85], and one with either full colonoscopy or barium enema alone [79]. Only seven patients (1.1%) had an organic explanation for their symptoms, such as inflammatory bowel disease or colorectal cancer, after complete colonic investigation. One study used complete colonic investigation in patients aged over 50, and flexible sigmoidoscopy alone in the under 50s [84]. The study included 306 patients with IBS, according to the Rome I criteria, and only four (1.3%) had organic disease after investigation. Finally, one study used flexible sigmoidoscopy with routine rectal biopsy in 89 IBS patients [82]. None of these patients had organic disease diagnosed following this. This observation is in contrast to a series of patients diagnosed with microscopic colitis between 1985 and 2001 from Olmsted County, Minnesota, 40% to 55% of whom reported symptoms that met the Rome or Manning criteria, and one-third had been previously labeled as having IBS [86]. It appears, therefore, that colonic investigation has a very low yield in patients presenting with symptoms that are highly suggestive of IBS in the absence of alarm features.

Role of celiac antibodies and distal duodenal biopsy in irritable bowel syndrome Several case-control studies have examined the role of testing for celiac disease in patients meeting diagnostic criteria for IBS, but the results are conflicting. Studies from the UK and Iran have demonstrated an increased prevalence of positive celiac serology and biopsy-proven celiac disease in individuals with IBS [87–89], as defined using the Rome II criteria, compared to controls, but data from studies conducted in the USA and Turkey do not support this association [90–92]. Of the available current guidelines for the management of IBS, only those from the National Institute of Health and Clinical Excellence in the UK, which are written from a primary care perspective, recommend routinely screening for celiac disease, using serology, in patients with suspected IBS [40]. A recent systematic review and meta-analysis has examined this issue [93]. Pooled prevalence of positive IgA-class anti-gliadin antibodies was 4% in subjects meeting diagnostic criteria for IBS in seven studies. Six were case-control studies, and the odds of a positive test in cases was threefold that of controls. Pooled prevalence of positive antiendomysial antibodies or tissue transglutaminase was 1.6% in subjects meeting diagnostic criteria for IBS in 13 studies. Seven of these were case-control studies, with an odds ratio of almost 3 for a positive test in those meeting diagnostic criteria for IBS. The pooled prevalence of biopsyproven celiac disease, following positive serology of any type, was 4% in seven studies. Five of these were case359

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Table 21.2 Yield of investigations in subjects meeting diagnostic criteria for irritable bowel syndrome. Investigation used

Number of studies

Number of subjects meeting diagnostic criteria for IBS

Number with organic disease after investigation applied (%)

Complete colonic imaging

3

636

7 (1.1)

Complete colonic imaging for 50 years and over, flexible sigmoidoscopy for under 50s

1

306

4 (1.3)

Flexible sigmoidoscopy and rectal biopsy

1

89

IgA-class antigliadin antibodies

7

1104

36 (3.3)

13

2021

41 (2.0)

Celiac serology of any type followed by distal duodenal biopsy if positive

7

1464

62 (4.2)

Lactose hydrogen breath testing

7

2149

756 (35)

Lactulose hydrogen breath testing

4

612

379 (62)

Glucose hydrogen breath testing

2

208

75 (36)

Jejunal aspirate and culture

1

162

7 (4.3)

Full blood count

2

496

1 (0.2)

C-reactive protein/erythrocyte sedimentation rate

1

300

3 (1)

Thyroid function tests

5

2160

91 (4.2)

Stool ova, cysts and parasites

2

1324

19 (1.4)

Barium meal and follow-through

1

114

1 (0.9)

Abdominal ultrasound scan

1

125

22 (18)

Anti-endomysial or tissue transglutaminase antibodies

control studies, and the odds of biopsy-proven celiac disease in cases meeting diagnostic criteria for IBS was over four-fold that of controls. The odds of biopsy-proven celiac disease were not significantly different in those with constipation-predominant, diarrhea-predominant, or mixed bowel pattern, suggesting that screening for celiac disease should not be reserved for individuals with diarrhea-predominant IBS. The pooled prevalence of biopsy-proven celiac disease in individuals meeting diagnostic criteria for IBS was estimated to be between 2% and 7% [93]. The true prevalence may be higher in these studies for several reasons. First, only individuals with positive serology were offered duodenal biopsy. Second, studies did not screen these individuals for IgA deficiency, which can lead to false negative serological tests. Third, a recent report has demonstrated that the sensitivity of serology is substantially lower in individuals who do not have total villous atrophy on duodenal biopsy [94]. Economic modelling studies suggest that if the prevalence of celiac disease in subjects meeting diagnostic criteria for IBS were between 5% and 8% then screen360

0 (0)

ing using serology, with duodenal biopsy for those testing positive, could be cost-effective depending on the willingness to pay, with a cost per quality adjusted life year gained of $5000 [95, 96]. These data indicate that testing for celiac disease in patients with suspected IBS may be a worthwhile strategy.

Role of testing for lactose intolerance in irritable bowel syndrome Seven studies have screened IBS patients for lactose intolerance using lactose hydrogen breath testing [83, 84, 97–101]. Two studies conducted in Italy reported a prevalence of lactose intolerance in excess of 60% among those meeting diagnostic criteria for IBS [ 97, 100], but in the majority of studies the prevalence was around 25%, although in one study it was only 4% [101]. Of these seven studies, three were case-control studies [97, 98, 101], two of which used healthy controls from the general population [97, 101], and the third used healthy volunteers from among hospital staff [98]. Again results were conflicting, with one study suggesting a five-fold increase in lactose intolerance in IBS

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Irritable bowel syndrome

subjects compared to controls, one study showing no difference in prevalence between the two, and the third a more modest increase in prevalence in cases with IBS. The data to support the role of lactose hydrogen breath testing in IBS are therefore conflicting, and at present no recommendation for the routine exclusion of lactose intolerance can be made.

Role of stool examination

Role of testing for small intestinal bacterial overgrowth in irritable bowel syndrome

Role of other abdominal investigations

Small intestinal bacterial overgrowth has been proposed as a possible etiological factor in IBS. Lactulose and glucose hydrogen breath tests, and jejunal aspirate and culture, have been utilized in suspected IBS patients. Three studies have demonstrated a positive lactulose hydrogen breath test in 50–80% of patients with IBS defined according to the Rome I or II criteria [67, 102, 103], whilst the prevalence of a positive glucose hydrogen breath test has been reported to be between 30% and 40% in patients defined by Rome II criteria [66, 104]. These studies have caused considerable interest, and as a result of their findings antibiotics, such as rifaximin, have been used for the treatment of IBS [68]. However, a Swedish case-control study has reported that the prevalence of small intestinal bacterial overgrowth, following jejunal aspirate and culture, is no higher in subjects meeting the Rome II criteria for IBS than in healthy controls from the general population [105]. Only 7 (4%) of 162 IBS patients had a positive culture compared to 1 (4%) of 26 controls. These data are supported by a large case-control study conducted recently in the USA [106], in which the prevalence of a positive lactulose hydrogen breath test was equally high between IBS patients defined by Rome II criteria and healthy controls, suggesting that the high rates of positive breath testing may not be specific to individuals with IBS.

Role of blood tests in irritable bowel syndrome Several studies have reported on the yield of certain blood tests in suspected IBS patients [83, 84, 87, 107, 108]. Two of these reported on the utility of a full blood count [83, 87], but only one patient had an organic explanation for their symptoms, biopsy-proven celiac disease, after applying the test. Five studies have utilized thyroid function tests in IBS [83, 84, 87, 107, 108]. When data from these studies are combined, 91 (4.2%) of 1860 IBS patients had abnormal thyroid function. One study performed C-reactive protein and erythrocyte sedimentation rate in 300 IBS patients, only three of whom had organic disease after applying the tests [87]. A panel of blood tests, often performed when patients with IBS are first seen in the outpatient clinic, therefore has a low yield in detecting organic disease in this situation. However, it would appear that the routine checking of thyroid function in subjects meeting diagnostic criteria for IBS is a reasonable strategy.

Two studies, which used the Rome I criteria and the International Congress definition of IBS [83, 84], tested stool for ova, cysts and parasites in over 1300 patients with suspected IBS. Of these, only 19 (1.4%) had a positive result. In one study none of the subjects meeting diagnostic criteria for IBS patients had a positive test.

Only one study has reported on the utility of abdominal ultrasound scan in 125 individuals with Rome I IBS [109]. Of these subjects, 22 (18%) had abnormal ultrasound findings, 6 (5%) of whom had gallstones. However, the detection of gallstones did not lead to a revision of the diagnosis of IBS in any of the included patients. One study used barium meal and follow-through in 114 patients meeting Rome I criteria for IBS [107]. Only one patient was found to have Crohn’s disease after investigation. These limited data do not support the routine use of either of these investigations in the diagnostic workup of patients with suspected IBS.

Summary There remains some uncertainty surrounding the diagnosis of IBS for both the patient and clinician. Despite the fact that many physicians, particularly those in primary care, are either unaware of or do not use current recommended diagnostic criteria for IBS, there is no evidence that IBS can be reliably diagnosed using a physician’s opinion. Individual symptom items from the clinical history are unsatisfactory. Of the current symptom-based diagnostic criteria, the Manning criteria perform only modestly well overall, and less well in the two of the three prospective studies conducted since the original validation was performed. There are few data to support the use of the Rome I criteria, and no studies have validated the Rome II or III criteria, which is disappointing given that the latter are the current gold standard for the diagnosis of IBS. The best evidence appears to exist for the Kruis scoring system, although this system is probably too unwieldy for everyday use. Either further well-designed studies are required to validate current diagnostic criteria, or more accurate ways of diagnosing IBS without the need for investigation need to be developed. In terms of investigating individuals with symptoms suggestive of IBS, there is limited evidence for a routine panel of blood tests, and more invasive investigations such as colonoscopy, breath testing, or barium studies appear to either have a very low yield, or have limited discriminatory value between IBS patients and normal individuals. In addition, the vast majority of studies have been conducted in secondary care settings, where the yield of organic disease is likely to be higher, and the findings should not 361

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be extrapolated to patients presenting to a primary care physician with symptoms suggestive of IBS. Current evidence does suggest, however, that screening all individuals with suspected IBS for thyroid dysfunction and celiac disease, with distal duodenal biopsy in those with positive serology, is a worthwhile strategy.

Treatment of irritable bowel syndrome As IBS is a prevalent condition, with a chronic, relapsing and remitting course physicians need to have effective therapies available to them in order to drive down the costs of consultation and investigation in sufferers. Unfortunately, many of the traditional therapies, when studied in randomized controlled trials (RCTs), have shown variable efficacy in terms of their effect on resolution or cure of symptoms and follow-up in many cases has been limited to two or three months. In addition, newer agents such as the 5-hydroxytryptamine (5-HT) receptor agonists and antagonists, which showed initial promise, have been withdrawn due to concerns over their safety profile, though some of these are now available on a restricted use basis. Data from individual RCTs of various therapies are conflicting in many cases, and systematic reviews and metaanalyses do not always produce consistent evidence of benefit [110–117]. However, recently a number of systematic reviews and meta-analyses have been completed as part of the update of the American College of Gastroenterology’s monograph on IBS [118], and have demonstrated some clinically useful results.

Efficacy of fiber in irritable bowel syndrome Traditionally, patients with IBS were told to increase the amount of fiber in their diet, due to potentially beneficial effects on intestinal transit time [119]. However, evidence for any benefit on global IBS symptoms from individual placebo-controlled trials has been conflicting [120–123], although many of these studies are small and may have lacked sufficient power to detect a significant benefit, should one exist. Previous systematic reviews have also disagreed on whether fiber has any therapeutic effect [110, 114, 117], and current guidelines for the management of IBS make varying recommendations concerning the role of fiber [38–41]. The use of insoluble fiber, such as bran, is generally discouraged due to concerns that it may exacerbate symptoms, particularly pain and bloating. A recent systematic review and meta-analysis identified 12 placebo-controlled trials of fiber in IBS [124]. The main results of the meta analysis are shown in Figure 21.1. Overall, there appeared to be a modest benefit of fiber supplementation in IBS, with a number needed to treat (NNT) of 11. However, this effect was limited to ispaghula, a 362

soluble fiber, with a number needed to treat of 6. Insoluble fiber did not lead to any improvement in symptoms of IBS, though there was no convincing evidence that it worsened symptoms when data were pooled. Adverse events were very rare. Unfortunately, the method of concealment of allocation was not reported in any of the trials, which may have led to an overestimation of the efficacy of fiber in IBS [125]. In addition, none of the trials adhered to the recommendations of the Rome committee for the design of trials of therapies for the functional GI disorders [126], most having been designed and conducted before these were published. Despite the methodological limitations of many of these RCTs, ispaghula is cheap and available over the counter, so it is probably a worthwhile first-line agent in patients with constipation-predominant IBS. A1c

Efficacy of antispasmodics and peppermint oil in irritable bowel syndrome The pain, discomfort and altered bowel habit that IBS sufferers report may result from a combination of altered GI motility, smooth muscle spasm, visceral hypersensitivity and abnormalities of central pain processing [54, 56, 127]. Smooth muscle relaxants could therefore ameliorate some of the symptoms of IBS. Numerous antispasmodic agents have been studied, but the existing RCTs have produced disparate results [128–131]. Peppermint oil may also have antispasmodic properties [132]. In contrast to antispasmodics, the available RCT evidence for peppermint oil shows definite benefit [133–136]. A systematic review and meta-analysis identified 22 placebo-controlled trials of various antispasmodics in IBS [124], and demonstrated an overall benefit with active therapy, with NNT = 5 (Figure 21.2). There were significantly more adverse events in participants randomized to antispasmodics, though the majority consisted of dry mouth, dizziness, and blurred vision, and none were serious. When subgroup analyses were conducted according to the type of antispasmodic used, it became apparent that many of the antispasmodics that are most commonly used in clinical practice, such as mebeverine, alverine and dicycloverine had little or no evidence of efficacy in IBS. The best evidence, in terms of the number of patients studied, appeared to exist for otilonium (435 patients) and hyoscine (426 patients), with NNT = 5 and 4 respectively. A1a When data were pooled for the four RCTs of peppermint oil in a systematic review, there was evidence of a clear benefit, NNT = 3 (Figure 21.3) [124]. A1a Adverse events with peppermint oil were very rare, and not more frequent than were observed with placebo. Again, the majority of these studies predated the Rome recommendations for RCTs of therapies for IBS [126], and none reported the method of concealment of allocation, so

CHAPTER 21

Irritable bowel syndrome

Review: Efficacy of fibre, antispasmodics, and peppermint oil irritable bowel syndrorne: systernatic review and meta-analysis Comparsion: 01 Fibre Outcome: 01 Global IBS symptoms or abdominal pain unimproved or persistent after therapy Study or sub-category

Treatment n/N

Control n/N

RR (random) 95% Cl

01 Bran 12/27 17/32 Soltoft 1976 7/12 7/14 Manning 1977 28/40 29/40 Kruis 1986 4/14 3/14 Lucey 1987 7/14 6/14 Rees 2005 107 114 Subtotal (95% Cl) Total events: 62 (treatment), 58 (control) Test for Heterogeneity: Chi2 = 0.99, df = 4 (p = 0.91), I2 = 0% Test for overall effect: Z = 0.16 (p = 0.88) 02 Ispaghula Ritchie 1979 12/12 7/12 Longstreth 1981 16/40 17/37 Arthurs 1983 14/38 11/40 Nigam 1984 21/21 13/21 Prior 1987 37/40 33/40 Jalihal 1990 3/9 2/11 Subtotal (95% Cl) 160 161 Total events: 83 (treatment), 103 (control) Test for Heterogeneity: Chi2 = 7.63, df = 5 (p = 0.18), I2 = 34.4% Test for overall effect: Z = 2.31 (p = 0.02) 03 Fibre (unspecified) 10/25 Fowlie 1992 25 Subtotal (95% Cl) Total events: 10 (treatment), 7 (control) Test for Heterogeneity: not applicable Test for overall effect: Z = 0.79 (p = 0.43)

7/24 24

300 291 Total (95% Cl) Total events: 155(treatment), 168 (control) Test for Heterogeneity: Chi2 = 12.82, df = 11 (p = 0.31), I2 = 14.2% Test for overall effect: Z = 1.93 (p = 0.05) 0.1 0.2

0.5

Favors treatment

1

2

5

Weight %

RR (random) 95% Cl

6.19 3.65 17.86 1.13 2.91 31.75

1.20 (0.70, 2.04) 0.86 (0.42, 1.74) 1.04 (0.78, 1.37) 0.75 (0.20, 2.75) 0.86 (0.39, 1.91) 1.02 (0.62, 1.27)

7.50 6.56 4.26 13.54 32.59 0.80 65.24

0.58 (0.36, 0.94) 1.15 (0.69, 1.92) 0.75 (0.39, 1.43) 0.62 (0.44, 0.87) 0.89 (0.75, 1.05) 0.55 (0.11, 2.59) 0.78 (0.63, 0.96)

3.00 3.00

1.37 (0.62, 3.01) 1.37 (0.62, 3.01)

100

0.87 (0.76, 1.00)

10

Favors control

Figure 21.1 Forest plot of randomized controlled trials of fiber versus placebo or low fiber diet in irritable bowel syndrome. Ford AC, Talley NJ, Spiegel BMR et al. Effect of fiber, antispasmodics, and peppermint oil in irritable bowel syndrome: Systematic review and metaanalysis. Br Med J 2008; 337: a2313.

the number needed to treat may well be higher. The rationale for the efficacy of these drugs in IBS is speculative. Diarrhea-predominant IBS patients have a reduced colon diameter and accelerated small bowel transit on magnetic resonance imaging [137], so it may be that antispasmodics have their beneficial action via a combination of reduced colonic contraction and transit time, which may in turn lead to reduced pain and stool frequency. Peppermint oil has been shown to have antagonistic effects on the calcium channel [132], and may bring about smooth muscle relaxation, and therefore reduced contractility and pain. As with ispaghula, antispasmodics and peppermint oil are cheap, and the latter is available over the counter. These therapies should probably be used as first-line interven-

tions for diarrhea-predominant IBS, although most of the trials predated the creation of these diagnostic subgroups, eliminating the possibility of analysis according to predominant stool pattern. A1a These agents may also benefit individuals whose predominant symptoms are either pain or bloating. Of the available antispasmodics, the strongest evidence base exists for hyoscine.

Efficacy of antidepressants in irritable bowel syndrome Patients with IBS demonstrate visceral hypersensitivity [56, 127], and exhibit lower pain thresholds to balloon distension of the rectum than normal individuals [56]. 363

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Gastrointestinal disorders Review: Efficacy of fibre, antispasmodics, and peppermint oil in irritable bowel syndrorne: systernatic review and meta-analysis Comparsion: 02 Antispasmodics Outcome: 01 Global IBS symptoms or abdominal pain unimproved or persistent after therapy Study or sub-category

Treatment n/N

Control n/N

RR (random) 95% Cl

Weight %

RR (random) 95% Cl

2.72 3.89 2.25 8.87

0.21 (0.08, 0.53) 0.58 (0.29, 1.17) 0.36 (0.13, 1.03) 0.38 (0.20, 0.71)

6.38 6.31 7.17 19.86

0.67 (0.45, 0.99) 0.52 (0.35, 0.79) 0.67 (0.49, 0.93) 0.63 (0.51, 0.78)

3.62 3.15 5.66 12.44

0.33 (0.16, 0.70) 0.46 (0.20, 1.05) 0.54 (0.34, 0.87) 0.47 (0.33, 0.67)

1.78 5.29 3.39 10.46

0.75 (0.22, 2.52) 1.31 (0.78, 2.19) 0.80 (0.37, 1.74) 1.08 (0.72, 1.61)

8.06 8.06

1.25 (0.99, 1.58) 1.25 (0.99, 1.58)

0.70 1.95 4.24 8.79 15.68

0.25 (0.03, 1.97) 0.43 (0.14, 1.35) 0.40 (0.21, 0.76) 0.81 (0.70, 0.94) 0.55 (0.31, 0.97)

31/54 54

6.82 6.82

0.85 (0.60, 1.22) 0.85 (0.60, 1.22)

33/49 49

6.64 6.64

0.65 (0.45, 0.95) 0.65 (0.45, 0.95)

6/12 12

3.61 3.61

1.17 (0.26, 2.45) 1.17 (0.26, 2.45)

6/9 9

2.29 2.29

0.50 (0.18, 1.40) 0.50 (0.18, 1.40)

3/36 36

1.36 1.36

1.23 (0.30, 5.13) 1.23 (0.30, 5.13)

10/30 30

3.93 3.93

1.10 (0.55, 2.19) 1.10 (0.55, 2.19)

100.00

0.68 (0.57, 0.81)

01 Cimetropium 4/24 19/24 Centonze 1988 7/20 12/20 Passaretti 19989 4/35 11/35 Dobrilla 1990 79 79 Subtotal (95% CI) Total events: 15 (treatment), 42 (control) Test for heterogeneity: Chi2 = 3.18, df = 2 (p = 0.20), I2 = 37.2% Test for overall effect: Z = 3.02 (p = 0.002) 02 Hyoscine Ritchie 1979 8/12 12/12 Nigam 1984 11/21 21/21 Schafer 1990 44/182 64/178 Subtotal (95% CI) 215 211 Total events: 63 (treatment), 97 (control) Test for heterogeneity: Chi2 = 1.06, df = 2 (p = 0.59), I2 = 0% Test for overall effect: Z = 4.29 (p < 0.0001) 03 Pinaverium 6/25 18/25 Levy 1977 6/30 13/30 Delmont 1981 14/39 26/39 Virat 1987 94 94 Subtotal (95% CI) Total events: 26 (treatment), 57 (control) Test for heterogeneity: Chi2 = 1.16, df = 2 (p = 0.56), I2 = 0% Test for overall effect: Z = 4.15 (p < 0.0001) 04 Trimebutine Moshal 1979 3/10 4/10 Fielding 1980 17/30 13/30 Ghidini 1986 8/30 10/30 Subtotal (95% CI) 70 70 Total events: 28 (treatment), 27 (control) Test for heterogeneity: Chi2 = 1.48, df = 2 (p = 0.48), I2 = 0% Test for overall effect: Z = 0.36 (p = 0.72) 05 Mebeverine Kruis 1986 35/40 Subtotal (95% CI) 40 Total events: 35 (treatment), 28 (control) Test for heterogeneity: not applicable Test for overall effect: Z = 1.87 (p = 0.06)

28/40 40

06 Otilonium 1/14 4//14 D’Arienzo 1980 3/15 7/15 Baldi 1983 8/30 20/30 Castiglione 1991 99/157 124/160 Glende 2002 216 219 Subtotal (95% CI) Total events: 111 (treatment), 155 (control) Test for heterogeneity: Chi2 = 7.40, df = 3 (p = 0.06), I2 = 59.5% Test for overall effect: Z = 2.06 (p = 0.04) 07 Alverine Mitchell 2002 26/53 Subtotal (95% CI) 53 Total events: 26 (treatment), 31 (control) Test for heterogeneity: not applicable Test for overall effect: Z = 0.86 (p = 0.39) 08 Dicycloverine 21/48 Page 1981 48 Subtotal (95% CI) Total events: 21 (treatment), 33 (control) Test for heterogeneity: not applicable Test for overall effect: Z = 2.25 (p = 0.02) 09 Pirenzipine Gilvarry 1989 7/12 Subtotal (95% CI) 12 Total events: 7 (treatment), 6 (control) Test for heterogeneity: not applicable Test for overall effect: Z = 0.41 (p = 0.68) 10 Prifinium 3/9 Piai 1979 9 Subtotal (95% CI) Total events: 4 (treatment), 6 (control) Test for heterogeneity: not applicable Test for overall effect: Z = 1.32 (p = 0.19) 11 Propinox Pulpeiro 2000 4/39 Subtotal (95% CI) 39 Total events: 4 (treatment), 3 (control) Test for heterogeneity: not applicable Test for overall effect: Z = 0.29 (p = 0.78) 12 Rociverine Ghidini 1986 11/30 Subtotal (95% CI) 30 Total events: 11 (treatment), 10 (control) Test for heterogeneity: not applicable Test for overall effect: Z = 0.27 (p = 0.79)

905 903 Total (95% CI) Total events: 350 (treatment), 495 (control) Test for heterogeneity: Chi2 = 58.88, df = 22 (p < 0.0001), I2 = 62.6% Test for overall effect: Z = 4.22 (p < 0.0001) 0.1 0.2 0.5 1 Favors treatment

2 5 10 Favors control

Figure 21.2 Forest plot of randomized controlled trials of antispasmodics versus placebo in irritable bowel syndrome.

364

CHAPTER 21

Irritable bowel syndrome

Review: Efficacy of fibre, antispasmodics, and peppermint oil irritable bowel syndrorne: systernatic review and meta-analysis Comparsion: 03 Peppermint oil Outcome: 01 Global IBS symptoms or abdominal pain unimproved or persistent after therapy Study or sub-category Lech 1988 Liu 1997 Capanni 2005 Cappello 2007

Treatment n/N

Control n/N

10/23 14/55 18/91 10/28

18/24 34/55 56/87 19/29

RR (random) 95% Cl

197 195 Total (95% CI) Total events: 52 (treatment), 127 (control) Test for heterogeneity: Chi2 = 4.36, df = 3 (p = 0.23), I2 = 31.1% Test for overall effect: Z = 5.39 (p < 0.00001)

Weight %

RR (random) 95% Cl

23.82 25.33 29.58 21.27

0.58 (0.34, 0.98) 0.41 (0.25, 0.68) 0.31 (0.20, 0.48) 0.55 (0.31, 0.96)

100.00

0.43 (0.32, 0.59)

0.1 0.2 0.5 1 2 5 10 Favors treatment Favors control Figure 21.3 Forest plot of randomized controlled trials of peppermint oil versus placebo in irritable bowel syndrome.

Antidepressants are often used to treat chronic pain, due to their modulatory effects on pain perception, and previous systematic reviews have demonstrated their efficacy in this situation [138, 139]. For these reasons, it has been postulated that tricyclic antidepressants (TCADs) or serotonin re-uptake inhibitors (SSRIs) may be beneficial in IBS, but existing data from both RCTs [140–143], and systematic reviews and meta-analyses are conflicting [113, 114, 117]. Therefore, recommendations made in IBS management guidelines are equivocal [38–41]. There has been a recent systematic review and metaanalysis identifying 13 RCTs of antidepressant therapy in IBS, reporting a number needed to treat with antidepressants of four [144]. It appeared that both TCADs and SSRIs were effective, with NNT = 4 (Figure 21.4). A1a Adverse events were commoner in those receiving active therapy, though this difference was not statistically significant, and none were serious. Trials of antidepressant therapy were generally of higher quality than those of fiber, antispasmodics and peppermint oil. Imipramine has been shown to prolong orocecal transit time, whilst paroxetine reduces it [145]. It could be hypothesized, therefore, that TCADs will work better in diarrheapredominant IBS and SSRIs in patients with the constipation-predominant pattern. C5 Unfortunately, the majority of trials did not report data according to predominant stool pattern reported by the patient, so it was not possible to examine this issue in the systematic review. An alternative explanation for the beneficial effect of antidepressants in IBS is the treatment of coexistent depression. However, improvements in IBS symptoms did not correlate with depression scores in the included RCTs that reported these data, as is also the case for their effects in neuropathic pain [139]. As the RCTs identified in the systematic review used several different TCADs and SSRIs, it is difficult to know

if this is a true class effect, or whether the benefit is limited to specific drugs within these groups. Individual trials that demonstrated the greatest benefit of TCADs over placebo used amitriptyline, trimipramine and imipramine [142, 146, 147], whilst for SSRIs RCTs using fluoxetine, citalopram and paroxetine all demonstrated a greater efficacy than placebo [141, 143, 148]. It would therefore seem reasonable to use a TCAD, such as amitryptiline, in subjects with diarrhea-predominant IBS who do not respond to antispasmodics or peppermint oil, or an SSRI, such as citalopram, in constipation-predominant patients who have failed therapy with ispaghula. C5

Efficacy of probiotics in irritable bowel syndrome The role of altered gut flora in IBS is controversial [149], but there are studies that have demonstrated changes in intestinal microbiota in IBS patients compared to controls [65]. In addition, there have been many reports of new onset of symptoms compatible with IBS following acute bacterial and viral gastroenteritis [61]. Probiotics, which are live, or attenuated bacteria, or bacterial products that are beneficial to the host, have the potential to alter gut flora and have been shown to reduce the risk of antibioticassociated diarrhea [150], and traveller ’s diarrhea [151], and to reduce the duration of acute illness in acute gastroenteritis [152]. They may have a beneficial effect on symptoms of IBS through a similar mechanism of action. The effect of probiotics on IBS has been the subject of numerous RCTs, but results have been conflicting. A systematic review and meta-analysis identified 10 RCTs reporting dichotomous outcome data, and 15 RCTs reporting the effect of probiotics on overall IBS symptom scores [153]. The NNT for probiotics to improve or cure one patient’s IBS symptoms was four, though there was statisti365

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Gastrointestinal disorders

Review:

Efficacy of antidepressants and psychological therapies in irritable bowel syndrorne: systernatic review and meta-analysis Comparsion: 01 Antidepressants Outcome: 01 Global IBS symptoms or abdominal pain unimproved or persistent after therapy Study or subcategory

Treatment n/N

Control n/N

RR (random) 95% Cl

01 Tricyclic antidepressants 10/22 12/22 Heefner 1978 5/30 10/31 Myren 1982 14/21 21/21 Nigam 1984 16/42 19/41 Boerner 1988 5/19 14/16 Bergmann 1991 14/25 20/25 Vij 1991 60/115 36/57 Drossman 2003 0/18 5/16 Talley 2008 8/27 16/27 Vahedi 2008 319 256 Subtotal (95% CI) Total events: 132 (treatment), 153 (control) Test for heterogeneity: Chi2 = 10.94, df = 8 (p = 0.21), I2 = 26.9% Test for overall effect: Z = 3.86 (p = 0.0001) 02 Selective serotonin re-uptake inhibitors 9/19 12/21 Kuiken 2003 25/44 36/46 Tabas 2004 6/22 19/22 Vahedi 2005 5/11 11/12 Tack 2006 5/17 5/16 Talley 2008 113 117 Subtotal (95% CI) Total events: 50 (treatment), 83 (control) 2 Test for heterogeneity: Chi = 6.46, df = 4 (p = 0.17), I2 = 38.1% Test for overall effect: Z = 2.74 (p = 0.006) Total (95% CI) 435 373 Total events: 182 (treatment), 236 (control) Test for heterogeneity: Chi2 = 17.66, df = 13 (p = 0.17), I2 = 26.4% Test for overall effect: Z = 4.95 (p < 0.00001)

Weight %

RR (random) 95% Cl

5.94 2.66 14.74 7.63 3.82 10.67 16.77 0.33 5.02 67.56

0.83 (0.46, 1.51) 0.52 (0.20, 1.33) 0.67 (0.49, 0.90) 0.82 (0.50, 1.36) 0.30 (0.14, 0.65) 0.70 (0.47, 1.04) 0.83 (0.63, 1.08) 0.08 (0.00, 1.36) 0.50 (0.26, 0.97) 0.68 (0.56, 0.83)

5.85 14.90 4.52 4.90 2.27 32.44

0.83 (0.45, 1.51) 0.73 (0.54, 0.98) 0.32 (0.16, 0.64) 0.50 (0.25, 0.97) 0.94 (0.33, 2.65) 0.62 (0.45, 0.87)

100.00

0.66 (0.57,0.78)

0.1 0.2 0.5 1 2 5 10 Favors treatment Favors control Figure 21.4 Forest plot of randomized controlled trials of antidepressants versus placebo in irritable bowel syndrome. Ford AC, Talley NJ, Schoenfeld PS, et al. Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis. Gut 2009; 58: 367–378.

cally significant heterogeneity, possibly associated with the clinical heterogeneity inherent in the use of many different probiotics in these studies. Global IBS symptom scores were also reduced by a significantly greater amount with probiotics than with placebo, symptom scores for abdominal pain were significantly reduced, and there was a trend towards a reduction in bloating scores. When subgroup analyses were conducted to examine the effect on symptom status according to the probiotic preparation used, there were no significant differences detected between Lactobacillus, Bifidobacterium, Streptococcus and combinations of probiotics. When effect on symptom scores was assessed, it appeared that combinations of probiotics had the greatest effect, followed by Bifidobacterium, with Lactobacillus having no effect. How probiotics may exert their effects on patients with IBS is unclear, but animal models have demonstrated attenuation of post-infective intestinal dysmotility and improve366

ments in visceral hypersensitivity with probiotics [154–156]. Certain strains of probiotics have demonstrated the ability to induce the expression of cannabinoid and opioid receptors on intestinal cells [157], and to reduce circulating levels of cytokines [158]. These properties may explain possible benefits in IBS, by leading to a reduction in both visceral hypersensitivity and inflammation. It would appear from the available evidence that probiotics are more effective than placebo in IBS. They may be of use as second-line interventions in individuals with particularly troublesome abdominal pain and bloating. A1c

Efficacy of psychological therapies in irritable bowel syndrome Subjects with IBS are more likely to report a low quality of life [159–161], and have a higher prevalence of mood disorder, anxiety and neuroticism than patients with organic

CHAPTER 21

disease or healthy controls [162]. Studies of IBS patients consulting in tertiary care settings have shown that a significant proportion have an underlying psychiatric illness [163, 164]. Even individuals who do not consult a physician with symptoms have higher levels of depression than normal subjects [165, 166]. Psychological interventions, such as cognitive behavioural therapy (CBT) [167, 168], relaxation therapy [169, 170], dynamic psychotherapy [171, 172] and multi-component psychological therapy [173, 174] have all been used in IBS. A previous systematic review identified 17 studies [175], 10 of which provided extractable dichotomous data, and reported an NNT of two for these interventions to improve or cure one patient’s symptoms. However, there were less than 200 patients in total included in these ten studies, and nine of these were published by the same group of researchers, meaning that the validity of the findings of this review are questionable. A more recent systematic review and meta-analysis published in 2008 identified 20 RCTs of psychological therapies in almost 1300 IBS patients [144]. The results are shown in Figure 21.5. When data from all studies were pooled the NNT was four, but there was significant heterogeneity between studies and evidence of publication bias, suggesting that this may be an overestimate of the treatment effect. In addition, there were nine studies emanating from the same centre, and when these were excluded from the analysis, the treatment effect was lower, but still statistically significant. There appeared to be a beneficial effect of CBT, hypnotherapy, multi-component psychological therapy, and dynamic psychotherapy, but no effect was demonstrated for relaxation therapy or stress management. The largest number of trials studied CBT, and it may be that this modality has the greatest efficacy, but when the three RCTs originating from the same centre were excluded from the analysis the effect of CBT on IBS symptoms in the remaining four trials was no longer statistically significant. These interventions are time-consuming and expensive, and may not be cost-effective as an initial management strategy for IBS. As a result, they should be reserved for individuals who are unresponsive to, or intolerant of, more conventional therapies. A1d

Efficacy of 5-HT3 antagonists and 5-HT4 agonists in irritable bowel syndrome Abnormal levels of 5-hydroxytryptamine have been demonstrated in individuals with IBS, and this plays an important role in GI motility and sensation [176]. Pharmaceutical agents that act on this receptor have therefore been developed as a potential treatment for IBS. Alosetron, a 5-HT3 antagonist, and tegaserod, a 5-HT4 agonist, showed initial promise for the treatment of diarrhea and constipationpredominant IBS respectively, particularly in females [177–

Irritable bowel syndrome

180]. Unfortunately, both of these drugs demonstrated serious adverse effects during subsequent routine clinical use, with alosetron causing a number of cases of ischaemic colitis and severe constipation [181], and tegaserod being associated with an excess of cardiac and cerebrovascular ischaemic events [182]. As a result, both were withdrawn by the manufacturers, though alosetron is now available on a restricted use basis. Other agents that act on the 5-HT receptor that have been studied in IBS include cisapride, which is also only available on a restricted basis due to concerns about cardiovascular adverse effects. Systematic reviews and meta-analyses conducted as part of the American College of Gastroenterology’s monograph on IBS have studied the efficacy of all available 5-HT3 antagonists and 5-HT4 agonists [183]. Both alosetron and cilansetron were more effective than placebo in IBS, with numbers needed to treat of eight and six respectively [183]. Tegaserod was also more effective than placebo in 11 RCTs, with a number needed to treat of 10 [183]. Neither cisapride or renzapride appeared to have any benefit over placebo in IBS. The NNTs for these agents are higher than those for ispaghula, antispasmodics, peppermint oil, antidepressants and psychological therapies. However, this may be due, in part, to the much higher quality of RCTs of 5-HT3 antagonists and 5-HT4 agonists [184], and adherance to the Rome committee recommendations for the design of treatment trials for functional GI disorders [126]. Due to their adverse safety profile, these drugs cannot be recommended as first-line therapies for the management of IBS and, where available, should probably be held in reserve for patients non-responsive to first-line therapies. A1a

Efficacy of lubiprostone in irritable bowel syndrome Lubiprostone is a prostaglandin E1 derivative that activates a specific chloride channel in the GI tract, causing increased fluid secretion, and thereby improving GI transit. The drug has been used in chronic idiopathic constipation, and has been shown to be effective, leading to a significant improvement in patient-reported spontaneous bowel movements [185]. Recent trials have demonstrated both a statistically significant improvement in mean abdominal pain scores in patients with constipation-predominant IBS randomized to 12 weeks of lubiprostone compared with placebo [186]. A significant improvement in global symptoms [187], in terms of the responder rates, using an a priori definition based on the number of weeks during the trial that the treatment was deemed to be effective by the patient was also observed. Individual symptoms including abdominal pain or discomfort, stool consistency, straining and severity of constipation were all significantly improved with lubiprostone compared with placebo [187]. The only 367

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Gastrointestinal disorders

Review:

Efficacy of antidepressants and psychological therapies in irritable bowel syndrorne: systernatic review and meta-analysis Comparsion: 02 Psychological therapies Outcome: 01 Global IBS symptoms or abdominal pain unimproved or persistent after therapy Study or sub-category

Treatment n/N

Control n/N

Weight %

RR (random) 95% Cl

1.44 2.06 4.88 6.81 6.69 0.34 5.56 27.78

0.22 (0.06, 0.78) 0.28 (0.10, 0.76) 0.51 (0.31, 0.82) 1.05 (0.80, 1.38) 0.72 (0.54, 0.96) 0.08 (0.00, 1.25) 0.71 (0.48, 1.07) 0.60 (0.42, 0.87)

6/6 9/14 20

2.83 2.35 5.18

0.50 (0.22, 1.11) 0.44 (0.18, 1.11) 0.48 (0.26, 0.87)

8/10 8/9 29/39 35/47 105

2.74 2.86 6.27 6.36 18.23

0.50 (0.22, 1.14) 0.45 (0.20, 0.99) 0.78 (0.56, 1.08) 0.70 (0.51, 0.96) 0.69 (0.56, 0.86)

5.84 6.82 12.66

0.47 (0.33, 0.69) 0.74 (0.57, 0.97) 0.60 (0.39, 0.93)

2.92 5.57 2.43 7.08 7.98 25.97

0.36 (0.17, 0.79) 0.80 (0.54, 1.20) 0.49 (0.20, 1.20) 1.17 (0.92, 1.49) 0.87 (0.77, 0.98) 0.82 (0.63, 0.93)

10/11 11

7.24 7.24

1.04 (0.83, 1.29) 1.04 (0.83, 1.29)

14/17 17

2.94 2.94

0.34 (0.16, 0.73) 0.34 (0.16, 0.73)

100.00

0.67 (0.57, 0.79)

01 Cognitive behavioral therapy 9/10 2/10 Greene 1994 9/10 3/12 Payne 1995 9/10 11/24 Vollmer 1998 25/34 27/35 Boyce 2003 36/57 51/112 Drossman 2003 6/14 0/14 Tkachuk 2003 36/77 24/72 Kennedy 2005 212 279 Subtotal (95% CI) Total events: 118 (treatment), 130 (control) 2 2 Test for heterogeneity: Chi = 20.48, df = 6 (p = 0.002), I = 70.7% Test for overall effect: Z = 2.68 (p = 0.007) 02 Hypnotherapy Galovski 1998 3/6 Simren 2004 4/14 Subtotal (95% CI) 20 Total events: 7 (treatment), 15 (control) Test for heterogeneity: Chi2 = 0.04, df = 1 (p = 0.84), I2 = 0% Test for overall effect: Z = 2.42 (p = 0.02) 03 Multi-component psychological therapy Blanchard 1992a 4/10 Neff 1987 4/10 Blanchard 1992b 22/38 Heitkemper 2004 25/48 Subtotal (95% CI) 106 Total events: 55 (treatment), 80 (control) 2 Test for heterogeneity: Chi = 2.26, df = 3 (p = 0.52), I2 = 0% Test for overall effect: Z = 3.39 (p = 0.0007)

04 Dynamic psychotherapy Guthrie 1991 20/53 39/49 Creed 2003 41/85 56/86 Subtotal (95% CI) 138 135 Total events: 61 (treatment), 95 (control) Test for heterogeneity: Chi2 = 3.62, df = 1 (p = 0.06), I2 = 72.4% Test for overall effect: Z = 2.26 (p = 0.02) 05 Relaxation training or therapy 4/11 10/10 Lynch 1989 10/14 8/9 Blanchard 1993 3/7 7/8 Keefer 2001 31/36 25/34 Boyce 2003 46/54 50/51 van der Veek 2007 122 112 Subtotal (95% CI) Total events: 94 (treatment), 100 (control) 2 2 Test for heterogeneity: Chi = 12.56, df = 4 (p = 0.01), I = 68.2% Test for overall effect: Z = 1.39 (p = 0.16) 06 Self-administered cognitive behavioral therapy Sanders 2007 16/17 Subtotal (95% CI) 17 Total events: 16 (treatment), 10 (control) Test for heterogeneity: not applicable Test for overall effect: Z = 0.31 (p = 0.76) 07 Stress management 5/18 Shaw 1991 18 Subtotal (95% CI) Total events: 5 (treatment), 14 (control) Test for heterogeneity: not applicable Test for overall effect: Z = 2.74 (p = 0.006)

700 612 Total (95% CI) Total events: 356 (treatment), 444 (control) 2 2 Test for heterogeneity: Chi = 77.58, df = 21 (p < 0.00001), I = 72.9% Test for overall effect: Z = 4.72 (p < 0.00001)

RR (random) 95% Cl

0.1 0.2 0.5 1 2 5 10 Favors treatment Favors control Figure 21.5 Forest plot of randomized controlled trials of psychological therapies versus control therapy or a physician’s “usual management” in irritable bowel syndrome.

368

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adverse events occurring more frequently in those receiving lubiprostone were diarrhea and nausea, particularly with higher doses [186, 187]. In an open-label extension of one of these trials, patients originally randomized to either lubiprostone or placebo were treated with the drug for a further 36 weeks [188]. Initial response rates were 15% with lubiprostone and 8% with placebo at 12 weeks, and these increased to 37% and 31% respectively at week 48. There were no serious adverse events in over 450 patients treated, suggesting that longer term treatment is both effective and safe. In another trial, patients receiving lubiprostone were randomized after 12 weeks of therapy to either a further four weeks of treatment, or four weeks of placebo [189]. The response rates at week 16 were 38% with lubiprostone compared to 40% with placebo, indicating a possible sustained effect of the initial 12 weeks of therapy on symptoms. The drug has recently been approved for the treatment of constipation-predominant IBS in women in some jurisdictions, but not in others. A1a Additional data from other RCTs may establish lubiprostone’s true efficacy and place in the treatment of IBS.

Efficacy of anti-diarrheals in irritable bowel syndrome In individuals with diarrhea-predominant or alternating IBS there may be a role for anti-diarrheal agents, such as loperamide. These drugs are relatively safe, and are often available over the counter, but unfortunately there are few data to support their routine use in IBS patients. There have been only two placebo-controlled trials conducted in Scandinavia [190, 191], which when pooled contain fewer than 50 patients. Stool consistency and frequency improved in a greater proportion of individuals randomized to loperamide than placebo in both trials, but in terms of this translating into an improvement in other symptoms of IBS the results were conflicting. One study demonstrated a clear improvement in abdominal pain with loperamide after 13 weeks of therapy [191], but the second showed no beneficial effect on global IBS symptoms [190]. There are insufficient data to make any clear recommendations for the use of loperamide in IBS at the present time, but the drug class does improve diarrhea. A1d

Efficacy of an exclusion diet in irritable bowel syndrome Some individuals with IBS believe that they have food allergy or intolerance and therefore the exclusion of certain foods from the diet may have a beneficial effect in these individuals. In a UK study of over 100 subjects with IBS, IgG4 titres were significantly higher in IBS cases compared to controls for wheat, beef, lamb and pork [192], and symptoms improved significantly among sufferers following the

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exclusion of some of these items [193]. Celiac disease may be more prevalent in patients with symptoms suggestive of IBS, and these individuals may respond to a gluten-free diet [88, 89]. There is now limited evidence that a glutenfree diet will alleviate symptoms in some IBS patients who do not have histological evidence of celiac disease [194]. As mentioned in the previous section, there is little convincing evidence that lactose intolerance is any commoner in IBS sufferers, though if an individual feels that their symptoms are made worse by dairy products a trial of withdrawal of these from the diet may be worthwhile. A systematic review of exclusion diets in individuals with IBS suggested that symptoms improved in a subset of patients [195], but the majority of these studies were non-randomized. As there are limited data from high quality studies to support a role for exclusion diets in the management of IBS these should not be used as a first-line therapy.

Summary Insoluble fiber such as wheat bran appears to have no benefit in IBS, but does not exacerbate symptoms, whilst soluble fiber in the form of ispaghula is beneficial and should be considered first line in constipation-predominant patients. Antispasmodics, particularly hyoscine, and peppermint oil are also effective in IBS, and should be used first line in diarrhea-predominant patients and those whose main complaints are pain and bloating. Anti-diarrheal agents, such as loperamide, improve stool form and frequency in IBS patients, but there is no clear evidence that this translates into a beneficial effect on either pain or global IBS symptoms. Antidepressants should be considered second line, in patients failing these therapies: TCADs for patients with the diarrhea-predominant pattern; and SSRIs for constipation-predominant IBS. Probiotics may also be considered second line in those with particularly troublesome pain and bloating. Psychological interventions, alosetron and lubiprostone should be considered for individuals who are non-responsive to first and secondline therapies, though psychological interventions are likely to be expensive and time-consuming to administer, alosetron has potentially serious side effects, and there are relatively few published data for lubiprostone. Exclusion diets do not have any high-quality evidence to support their use, but may still be helpful in a minority of challenging patients. A suggested treatment algorithm for patients with IBS, according to predominant symptom, is provided in Table 21.3.

Prognosis of irritable bowel syndrome Individuals with IBS suffer from a chronic relapsing and remitting medical disorder. Longitudinal studies have 369

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Table 21.3 Suggested order of medical therapies for irritable bowel syndrome according to predominant symptom. Predominant symptom

First line

NNT

Pain and bloating

Antispasmodics (preferably hyoscine), peppermint oil

5 4

Constipation

Ispaghula

6

Diarrhea

Antispasmodics (preferably hyoscine), peppermint oil, loperamide (for diarrhea only)

5 4

Strength of recommendation and quality of evidence

Second line

NNT

Strength of recommendation and quality of evidence

Third line

NNT

Strength of recommendation and quality of evidence

Probiotics

4

A1c

Psychological therapies

4

A1d

A1c

SSRIs

4

A1c

Lubiprostone (where approved)

13

A1a

A1a A1a A1a A1d

TCADs

4

A1a

Alosetron

8

A1a

A1a A1a

3

3

examined the natural history of the condition. It appears that up to two-thirds of those reporting symptoms compatible with IBS in such surveys continue to experience symptoms over prolonged periods of follow-up [28, 29]. As these studies did not administer questionnaires to individuals at several points in time it is difficult to know whether symptoms were present continuously. This would seem unlikely, given that functional GI symptoms tend to fluctuate, with individuals developing symptoms compatible with other functional GI disorders, such as dyspepsia and reflux, during prolonged periods of follow-up [28, 196, 197]. Evidence of the degree of fluctuation in IBS is conflicting, however, with a seven-year follow-up study from Sweden suggesting that IBS was the most stable of all the functional GI disorders [28], whilst a study with 10 years of follow-up conducted in the UK demonstrated the opposite [197], with only 20% of individuals still meeting diagnostic criteria for IBS at 10 years. Even among those who do remain symptomatic, the predominant stool pattern experienced is reported to change in up to three-quarters of individuals [27]. Thus, individuals with IBS may need to be reassessed intermittently, and their current treatment reviewed. Despite potential uncertainty surrounding the diagnosis of IBS it is unlikely to be revised during future follow-up. In a cohort of 112 IBS patients at the Mayo Clinic, less than 10% developed a subsequent organic GI disease, after a median length of follow-up of almost 30 years, and in almost all cases this was felt to be unrelated to their original presentation with symptoms that were compatible with IBS [198]. In another study from the USA, individuals meeting diagnostic criteria for IBS were followed up 370

between 10 and 13 years later [199]. Almost 50% had undergone a repeat structural evaluation of the lower GI tract in the intervening years, but this had not led to a diagnosis of organic disease in any of the subjects. As there is no single pathophysiological abnormality that explains all the symptoms of IBS, there is no specific target for medical therapies. Treatment for the condition is largely directed toward relieving symptoms. This situation may be viewed as unsatisfactory, particularly from the patient’s perspective, but there is now evidence from systematic reviews and meta-analyses of randomized controlled trials that many of the interventions that have been used traditionally in IBS are effective, despite earlier reports to the contrary, and newer agents continue to be developed.

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125 126

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tive, US multi-center trial. Gastroenterology 2007; 132(suppl 1): A678. Francis CY, Duffy JN, Whorwell PJ et al. Does routine abdominal ultrasound enhance diagnostic accuracy in irritable bowel syndrome? Am J Gastroenterol 1996; 91: 1348–1350. Bijkerk CJ, Muris JWM, Knottnerus JA et al. Systematic review: The role of different types of fiber in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther 2004; 19: 245–251. Cremonini F, Delgado-Aros S, Camilleri M. Efficacy of alosetron in irritable bowel syndrome: A meta-analysis of randomized controlled trials. Neurogastroenterol Motil 2003; 15: 79–86. Evans BW, Clark WK, Moore DJ, Whorwell PJ. Tegaserod for the treatment of irritable bowel syndrome and chronic constipation. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD003960. DOI: 10.1002/14651858.CD003960.pub3. Jackson JL, O’Malley PG, Tomkins G et al. Treatment of functional gastrointestinal disorders with antidepressant medications: A meta-analysis. Am J Med 2000; 108: 65–72. Lesbros-Pantoflickova D, Michetti P, Fried M et al. Metaanalysis: The treatment of irritable bowel syndrome. Aliment Pharmacol Ther 2004; 20: 1253–1269. Pittler MH, Ernst E. Peppermint oil for irritable bowel syndrome: A critical review and meta-analysis. Am J Gastroenterol 1998; 93: 1131–1135. Poynard T, Regimbeau C, Benhamou Y. Meta-analysis of smooth muscle relaxants in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther 2001; 15: 355–361. Quartero AO, Meiniche-Schmidt V, Muris J, Rubin G, de Wit N. Bulking agents, antispasmodic and antidepressant medication for the treatment of irritable bowel syndrome. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD003460. DOI: 10.1002/14651858.CD003460.pub2. American College of Gastroenterology Task Force. An evidence based review of the management of irritable bowel syndrome. Am J Gastroenterol 2009; 104(suppl I): S1–S35. Harvey RF, Pomare EW, Heaton KW. Effects of increased dietary fibre on intestinal transit. Lancet 1973; 301: 1278– 1280. Longstreth GF, Fox DD, Youkeles L et al. Psyllium therapy in the irritable bowel syndrome: A double-blind trial. Ann Intern Med 1981; 95: 53–56. Nigam P, Kapoor KK, Rastog CK et al. Different therapeutic regimens in irritable bowel syndrome. J Assoc Physicians India 1984; 32: 1041–1044. Ritchie JA, Truelove SC. Treatment of irritable bowel syndrome with lorazepam, hyoscine butylbromide, and ispaghula husk. Br Med J 1979; 278: 376–378. Soltoft J, Krag B, Gudmand-Hoyer E et al. A double-blind trial of the effect of wheat bran on symptoms of irritable bowel syndrome. Lancet 1976; 307: 270–272. Ford AC, Talley NJ, Spiegel BMR et al. Effect of fibre, antispasmodics and peppermint oil in irritable bowel syndrome: Systematic review and meta-analysis. Br Med J 2008; 337: 1388–1392. Juni P, Altman DG, Egger M. Assessing the quality of controlled clinical trials. Br Med J 2001; 323: 42–46. Veldhuyzen Van Zanten SJ, Talley NJ, Bytzer P et al. Design of treatment trials for functional gastrointestinal disorders. Gut 1999; 45(suppl II): II69–II77.

127 Aziz Q, Thompson DG, Ng VW et al. Cortical processing of human somatic and visceral sensation. J Neurosci 2000; 20: 2657–2663. 128 Fielding JF. Double blind trial of trimebutine in the irritable bowel syndrome. Ir Med J 1980; 73: 377–379. 129 Glende M, Morselli-Labate AM, Battaglia G et al. Extended analysis of a double blind, placebo-controlled, 15-week study with otilinium bromide in irritable bowel syndrome. Eur J Gastroenterol Hepatol 2002; 14: 1331–1338. 130 Kruis W, Weinzierl M, Schussler P et al. Comparison of the therapeutic effects of wheat bran and placebo in patients with the irritable bowel syndrome. Digestion 1986; 34: 196–201. 131 Page JG, Dirnberger GM. Treatment of the irritable bowel syndrome with Bentyl (dicyclomine hydrochloride). J Clin Gastroenterol 1981; 3: 153–156. 132 Hills JM, Aaronson PI. The mechanism of action of peppermint oil on gastrointestinal smooth muscle. Gastroenterology 1991; 101: 55–65. 133 Capanni M, Surrenti E, Biagini M et al. Efficacy of peppermint oil in the treatment of irritable bowel syndrome: A randomized, controlled trial. Gazz Med Ital 2005; 164: 119–126. 134 Cappello G, Spezzaferro M, Grossi L et al. Peppermint oil (Mintoil) in the treatment of irritable bowel syndrome: A prospective double blind placebo-controlled randomized trial. Dig Liver Dis 2007; 39: 530–536. 135 Lech Y, Olesen KM, Hey H et al. Treatment of irritable bowel syndrome with peppermint oil. A double-blind investigation with a placebo. Ugeskr Laeger 1988; 150: 2388–2389. 136 Liu J-H, Chen G-H, Yeh H-Z et al. Enteric-coated peppermint-oil capsules in the treatment of irritable bowel syndrome: A prospective, randomized trial. J Gastroenterol 1997; 32: 765–768. 137 Marciani L, Foley S, Hoad CL et al. Accelerated small bowel transit and contracted transverse colon in diarrhea-predominant irritable bowel syndrome (IBS-D): Novel insights from magnetic resonance imaging (MRI). Gastroenterology 2007; 132(suppl 1): A141. 138 McQuay HJ, Tramer M, Nye BA et al. A systematic review of antidepressants in neuropathic pain. Pain 1996; 68: 217– 227. 139 Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD005454. DOI: 10.1002/14651858.CD005454.pub2. 140 Heefner JD, Wilder RM, Wilson ID. Irritable colon and depression. Psychosomatics 1978; 19: 540–547. 141 Tack J, Broekaert D, Fischler B et al. A controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome. Gut 2006; 55: 1095–1103. 142 Talley NJ, Kellow JE, Boyce P et al. Antidepressant therapy (imipramine and citalopram) for irritable bowel syndrome: A double-blind, randomized, placebo-controlled trial. Dig Dis Sci 2008; 53: 108–115. 143 Vahedi H, Merat S, Rashidioon A et al. The effect of fluoxetine in patients with pain and constipation-predominant irritable bowel syndrome: A double-blind randomized-controlled study. Aliment Pharmacol Ther 2005; 22: 381–385. 144 Ford AC, Talley NJ, Schoenfeld PS et al. Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: Systematic review and meta-analysis. Gut 2009; 58: 367–378.

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145 Gorard DA, Libby GW, Farthing MJ. Influence of antidepressants on whole gut orocaecal transit times in health and irritable bowel syndrome. Aliment Pharmacol Ther 1994; 8: 159–166. 146 Bergmann M, Heddergott A, Schlosser T. Die therapie des colon irritabile mit trimipramin (Herphonal) – Eine kontrollierte studie. Z Klin Med 1991; 46: 1621–1628. 147 Vahedi H, Merat S, Momtahen S et al. Clinical trial: The effect of amitriptyline in patients with diarrhea-predominant irritable bowel syndrome. Aliment Pharmacol Ther 2008; 27: 678–684. 148 Tabas G, Beaves M, Wang J et al. Paroxetine to treat irritable bowel syndrome not responding to high fiber diet: A doubleblind placebo-controlled trial. Am J Gastroenterol 2004; 99: 914–920. 149 Shanahan F. Irritable bowel syndrome: Shifting the focus towards the gut microbiota. Gastroenterology 2007; 133: 340–342. 150 Colombel JF, Cortot A, Neut C et al. Yoghurt with Bifidobacterium reduces erythromycin induced gastrointestinal effects. Lancet 1987; 330: 43–44. 151 Katelaris PH, Salam I, Farthing MJ. Lactobacilli to prevent traveller ’s diarrhea. N Engl J Med 1995; 333: 1360–1361. 152 Allen SJ, Okoko B, Martinez EG, Gregorio GV, Dans LF. Probiotics for treating infectious diarrhea. Cochrane Database of Systematic Reviews 2003, Issue 4. Art. No.: CD003048. DOI: 10.1002/14651858.CD003048.pub2. 153 Moayyedi P, Ford AC, Brandt LJ et al. The efficacy of probiotics in the therapy of irritable bowel syndrome: A systematic review. Gut 2008 (published online 17 Dec) doi: 10.1136/Gut.2008.167270. 154 Verdu EF, Bercik P, Bergonzelli GE et al. Lactobacillus paracasei normalizes muscle hypercontractility in a murine model of postinfective gut dysfunction. Gastroenterology 2004; 127: 826–837. 155 Verdu EF, Bercik P, Verma-Gandhu M et al. Specific probiotic therapy attenuates antibiotic induced visceral hypersensitivity in mice. Gut 2006; 55: 182–190. 156 Kamiya T, Wang L, Forsythe P et al. Inhibitory effects of Lactobacillus reuteri on visceral pain induced by colorectal distension in Sprague-Dawley rats. Gut 2006; 55: 191–196. 157 Rousseaux C, Thuru X, Gelot A et al. Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat Med 2007; 13: 35–37. 158 O’Mahony L, McCarthy J, Kelly P et al. Lactobacillus and bifidobacterium in irritable bowel syndrome: Symptom responses and and relationship to cytokine profiles. Gastroenterology 2005; 128: 541–551. 159 Hahn BA, Kirchdoerfer LJ, Fullerton S et al. Patient perceived severity of irritable bowel syndrome in relation to symptoms, health resource utilization and quality of life. Aliment Pharmacol Ther 1997; 11: 553–559. 160 Halder SLS, Locke GR, Talley NJ et al. Impact of functional gastrointestinal disorders on health-related quality of life: A population-based case-control study. Aliment Pharmacol Ther 2004; 19: 233–242. 161 Koloski NA, Talley NJ, Boyce PM. The impact of functional gastrointestinal disorders on quality of life. Am J Gastroenterol 2000; 95: 67–71. 162 Henningsen P, Zimmermann T, Sattel H. Medically unexplained physical symptoms, anxiety and depression: A metaanalytic review. Psychosom Med 2003; 65: 528–533.

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163 Solmaz M, Kavuk I, Sayar K. Psychological factors in the irritable bowel syndrome. Eur J Med Res 2003; 8: 549–556. 164 Sykes MA, Blanchard EB, Lackner J et al. Psychopathology in irritable bowel syndrome: Support for a psychophysiological model. J Behav Med 2003; 26: 361–372. 165 Osterberg E, Blomquist L, Krakau I et al. A population study on irritable bowel syndrome and mental health. Scand J Gastroenterol 2000; 35: 264–268. 166 Whitehead WE, Palsson O, Jones KR. Systematic review of the comorbidity of irritable bowel syndrome with other disorders: What are the causes and implications? Gastroenterology 2002; 122: 1140–1156. 167 Drossman DA, Toner BB, Whitehead WE et al. Cognitivebehavioral therapy versus education and desipramine versus placebo for moderate to severe functional bowel disorders. Gastroenterology 2003; 125: 19–31. 168 Kennedy T, Jones R, Darnley S et al. Cognitive behaviour therapy in addition to antispasmodic treatment for irritable bowel syndrome in primary care: Randomised controlled trial. Br Med J 2005; 331: 435–437. 169 Boyce PM, Talley NJ, Balaam B et al. A randomized controlled trial of cognitive behavior therapy, relaxation training, and routine clinical care for the irritable bowel syndrome. Am J Gastroenterol 2003; 98: 2209–2218. 170 van der Veek PPJ, van Rood YR, Masclee AAM. Clinical trial: Short- and long-term benefit of relaxation training for irritable bowel syndrome. Aliment Pharmacol Ther 2007; 26: 943–952. 171 Creed F, Fernandes L, Guthrie E et al. The cost-effectiveness of psychotherapy and paroxetine for severe irritable bowel syndrome. Gastroenterology 2003; 124: 303–317. 172 Guthrie E, Creed F, Dawson D et al. A controlled trial of psychological treatment for the irritable bowel syndrome. Gastroenterology 1991; 100: 450–457. 173 Heitkemper M, Jarrett ME, Levy RL et al. Self-management for women with irritable bowel syndrome. Clin Gastroenterol Hepatol 2004; 2: 585–596. 174 Neff DF, Blanchard EB. A multi-component treatment for irritable bowel syndrome. Behav Ther 1987; 18: 70–83. 175 Lackner JM, Mesmer C, Morley S et al. Psychological treatments for irritable bowel syndrome: A systematic review and metaanalysis. J Consult Clin Psychol 2004; 72: 1100–1113. 176 Atkinson W, Lockhart S, Whorwell PJ et al. Altered 5-hydroxytryptamine signaling in patients with constipation-and diarrhea-predominant irritable bowel syndrome. Gastroenterology 2006; 130: 34–43. 177 Bardhan KD, Bodemar G, Geldof H et al. A double-blind, randomized, placebo-controlled dose-ranging study to evaluate the efficacy of alosetron in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther 2000; 14: 23–34. 178 Camilleri M, Mayer EA, Drossman DA et al. Improvement in pain and bowel function in female irritable bowel patients with alosetron, a 5-HT3 receptor antagonist. Aliment Pharmacol Ther 1999; 13: 1149–1159. 179 Kellow J, Lee OY, Chang FY et al. An Asia-Pacific, double-blind, placebo-controlled, randomised study to evaluate the efficacy, safety, and tolerability of tegaserod in patients with irritable bowel syndrome. Gut 2003; 52: 671–676. 180 Muller-Lissner SA, Fumagalli I, Bardhan KD et al. Tegaserod, a 5-HT4 receptor partial agonist, relieves symptoms in irritable

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183

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189

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bowel syndrome patients with abdominal pain, bloating and constipation. Aliment Pharmacol Ther 2001; 15: 1655–1666. Anonymous. Glaxo Wellcome withdraws irritable bowel syndrome medication. FDA Consum 2001; 35: 3. FDA public health advisory: Tegaserod maleate (marketed as Zelnorm). 2007. Published online at http://www.fda.gov/ cder/drug/advisory/tegaserod.htm Ford AC, Brandt LJ, Young C, Chey WD, Foxx-Orenstein AE, Moayyedi P. Efficacy of 5-HT3 antagonists and 5-HT4 agonists in irritable bowel syndrome: Systematic review and meta-analysis. Am J Gastroenterol 2009;104:1831–1843 Jadad AR, Moore RA, Carroll D et al. Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Control Clin Trials 1996; 17: 1–12. Johanson JF, Ueno R. Lubiprostone, a locally acting chloride channel activator, in adult patients with chronic constipation: A double-blind, placebo-controlled, dose-ranging study to evaluate efficacy and safety. Aliment Pharmacol Ther 2007; 25: 1351–1361. Johanson JF, Drossman DA, Panas R et al. Clinical trial: Phase 2 study of lubiprostone for irritable bowel syndrome with constipation. Aliment Pharmacol Ther 2008; 27: 685–696. Drossman DA, Chey WD, Panas R et al. Lubiprostone significantly improves symptom relief rates in adults with irritable bowel syndrome and constipation (IBS-C): Data from two twelve-week, randomized, placebo-controlled,double-blind trials. Gastroenterology 2007; 132: 2586–2587. Drossman DA, Chey WD, Johanson JF, et al. Clinical trial: Lubiprostone in patients with constipation-associated irritable bowel syndrome – results of two randomized, placebo-controlled studies. Aliment Pharmacol Ther 2009; 29: 329–341. Chey WD, Saad RJ, Panas RM et al. Discontinuation of lubiprostone treatment for irritable bowel syndrome with constipation is not associated with symptom increase or recurrence: Results

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from a randomized withdrawal study. Gastroenterology 2008; 134(suppl 1): A401. Hovdenak N. Loperamide treatment of the irritable bowel syndrome. Scand J Gastroenterol 1987; 130: 81–84. Lavo B, Stenstam M, Nielsen A-L. Loperamide in treatment of irritable bowel syndrome – A double-blind placebo controlled study. Scand J Gastroenterol 1987; 130: 77–80. Zar S, Benson MJ, Kumar D. Food-specific serum IgG4 and IgE titers to common food antigens in irritable bowel syndrome. Am J Gastroenterol 2005; 100: 1550–1557. Zar S, Mincher L, Benson MJ et al. Food-specific IgG4 antibodyguided exclusion diet improves symptoms and rectal compliance in irritable bowel syndrome. Scand J Gastroenterol 2005; 40: 800–807. Wahnschaffe U, Schulzke JD, Zeitz M et al. Predictors of clinical response to gluten-free diet in patients diagnosed with diarrheapredominant irritable bowel syndrome. Clin Gastroenterol Hepatol 2007; 5: 844–850. Park MI, Camilleri M. Is there a role of food allergy in irritable bowel syndrome and functional dyspepsia? A systematic review. Neurogastroenterol Motil 2006; 18: 595–607. Halder SLS, Locke III GR, Schleck CD et al. Natural history of functional gastrointestinal disorders: A 12-year longitudinal population-based study. Gastroenterology 2007; 133: 799–807. Ford AC, Forman D, Bailey AG et al. Fluctuation of gastrointestinal symptoms in the community: A 10-year longitudinal follow-up study. Aliment Pharmacol Ther 2008; 28: 1013– 1020. Owens DM, Nelson DK, Talley NJ. The irritable bowel syndrome: Long-term prognosis and the physician-patient interaction. Ann Intern Med 1995; 122: 107–112. Adeniji OA, Barnett CB, Di Palma JA. Durability of the diagnosis of irritable bowel syndrome based on clinical criteria. Dig Dis Sci 2004; 49: 572–574.

22

Ogilvie’s syndrome Michael D Saunders Digestive Diseases Center, University of Washington School of Medicine, Washington, USA

Introduction Acute colonic pseudo-obstruction (ACPO), also referred to as Ogilvie’s syndrome [1], is a clinical condition with symptoms, signs and radiographic appearance of acute large bowel obstruction without a mechanical cause. ACPO occurs most often in hospitalized or institutionalized patients with serious underlying medical and surgical conditions. ACPO is an important cause of morbidity and mortality. The mortality rate is estimated at 40% when ischemia or perforation occurs [2]. Early detection and prompt appropriate management are critical to minimizing morbidity and mortality.

Pathogenesis The pathogenesis of ACPO is not completely understood but likely results from an alteration in the autonomic regulation of colonic motor function [3]. Colonic pseudoobstruction was first described in 1948 by Sir Heneage Ogilvie, who reported two patients with chronic colonic dilation associated with malignant infiltration of the celiac plexus [4]. Ogilvie attributed the syndrome to sympathetic deprivation. A better understanding of the autonomic nervous system in the gut has modified this hypothesis. The parasympathetic nervous system increases contractility, whereas the sympathetic nerves decrease motility [3]. An imbalance in autonomic innervation, produced by a variety of factors, leads to excessive parasympathetic suppression or sympathetic stimulation. The result is colonic atony and pseudo-obstruction.

Evidence-Based Gastroenterology and Hepatology, Third Edition John WD McDonald, Andrew K Burroughs, Brian G Feagan and M Brian Fennerty © 2010 Blackwell Publishing Ltd. ISBN: 978-1-405-18193-8

Multiple predisposing factors or conditions have been associated with ACPO (Table 22.1). In a large retrospective series of 400 patients, the most common predisposing conditions were non-operative trauma (11.3%), infections (10%) and cardiac disease (10%) [2]. Cesarean section and hip surgery were the most common surgical procedures, with the onset of the syndrome occurring postoperatively at an average of 4.5 days. In another retrospective analysis of 48 patients, the spine or retroperitoneum had been traumatized or manipulated in 52% [4]. Over half the patients were receiving narcotics, and electrolyte abnormalities were present in approximately two-thirds. Thus, multiple metabolic, pharmacologic, or traumatic factors appear to alter the autonomic regulation of colonic function, resulting in pseudo-obstruction.

Clinical features The exact incidence of ACPO is unknown. In the retrospective series of patients undergoing orthopedic procedures reported by Norwood and colleagues [5], the incidence of ACPO was 1.3%, 1.19%, and 0.65% following hip replacement, spinal operations and knee replacement respectively. ACPO most often affects those in late middle age (mean of 60 years of age), with a slight male predominance (60%) [2]. ACPO occurs almost exclusively in hospitalized or institutionalized patients with serious underlying medical and surgical conditions. Abdominal distention usually develops over three to seven days but can occur as rapidly as over a 24 to 48-hour period [2]. In surgical patients, symptoms and signs develop at a mean of five days postoperatively. The clinical features of ACPO include abdominal distension, abdominal pain (80%), and nausea and/or vomiting (60%) [2]. Passage of flatus or stool is reported in up to 40% of patients. There is no significant difference in symptoms of patients with ischemic or perforated bowel, except for a 377

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Table 22.1 Predisposing conditions associated with acute colonic pseudo-obstruction – an analysis of 400 casesa. Condition

No. of patients

Proportion (%)

Trauma (non-operative)

45

11.3

Infection (pneumonia, sepsis most common)

40

10.0

Cardiac (myocardial infarction, heart failure)

40

10.0

Obstetrics/gynecology

39

9.8

Abdominal/pelvic surgery

37

9.3

Neurologic

37

9.3

Orthopedic surgery

29

7.3

Miscellaneous medical conditions (metabolic, cancer, respiratory failure, renal failure) Miscellaneous surgical conditions (urologic, thoracic, neurosurgery)

128

47

32

11.8

a

Associated conditions in approximately 400 patients, reported by Vanek and Al-Salti [2]. Some patients had more than one associated condition.

higher incidence of fever [2]. On examination, the abdomen is tympanitic and bowel sounds are typically present. Fever, marked abdominal tenderness and leukocytosis are more common in patients with ischemia or perforation but also occur in those who have not developed these complications [2]. The diagnosis of ACPO is confirmed by plain abdominal radiographs, which show varying degrees of colonic dilatation (Figure 22.1). Air fluid levels and dilatation can also be seen in the small bowel. Typically, the right colon and cecum show the most marked distension, and cutoffs at the splenic flexure are common. This distribution of colonic dilation may be caused by the different origins of the proximal and distal parasympathetic nerve supply to the colon [3]. A water soluble contrast enema or computed tomography (CT) scan should be obtained to exclude mechanical obstruction if gas and distension are not present throughout all colonic segments including the rectum and sigmoid colon. Keys to management of ACPO include (1) early recognition and diagnosis, (2) evaluation to exclude mechanical obstruction or other causes of pseudo-obstruction (such as Clostridium difficile colitis [6], (3) assessment for signs of ischemia or perforation which would warrant urgent surgi378

Figure 22.1 Abdominal radiographs of a patient with acute colonic pseudo-obstruction. The plain abdominal film shows marked dilatation, especially of the right colon. In addition, moderate small bowel dilatation is present.

B O X 2 2 . 1 Supportive therapy for acute colonic pseudo-obstruction

• • • • • •

Nil per os Correct fluid and electrolyte imbalances Nasogastric tube suction Rectal tube to gravity drainage Limit offending medications (especially narcotics) Frequent position changes, ambulate if possible

cal intervention, and (4) initiation of appropriate treatment measures.

Management Treatment options for ACPO include appropriate supportive measures, medical therapy, colonoscopic decompression, and surgery. Despite extensive literature documenting the clinical features of ACPO, there are very few randomized controlled clinical trials on the treatment of this condition, and most evidence for efficacy of treatments comes from uncontrolled studies.

Supportive therapy Supportive therapy (Box 22.1) should be instituted in all patients as it appears to be successful as the primary treatment in the majority of patients [7]. B4 Patients are given nothing by mouth. Intravenous fluids are administered

CHAPTER 22

and electrolyte imbalances are corrected. Nasogastric suction is provided to limit swallowed air from contributing further to colonic distension. A rectal tube should be inserted and attached to gravity drainage. Medications that can adversely affect colonic motility, such as opiates, anticholinergics and calcium channel antagonists are discontinued if possible. Ambulation and mobilization of patients are encouraged. The knee-chest position with hips held high has been advocated as aiding in evacuation of colonic gas [8]. None of these supportive measures has been studied in a randomized trial. C5 The reported success of supportive management is variable, with pooled rates from several retrospective series of approximately 85% [7, 9–13]. In these combined series, 111 patients were treated conservatively, of which 95 (86%) had resolution of the pseudo-obstruction. B4 Sloyer et al. reported outcomes of 25 cancer patients with ACPO (mostly non-gastrointestinal malignancies) [7]. The mean cecal diameter was 11.7 cm (range 9–18 cm). Of the 24 patients treated conservatively, 23 (96%) improved by clinical and radiologic criteria with the median time to improvement of 1.6 days (mean 3 days). There were no perforations or ACPO-related deaths. The authors concluded that early endoscopic or surgical decompression is not necessary in patients with ACPO. B4 In another recent retrospective series of 151 patients reported by Loftus et al., 117 (77%) had spontaneous resolution of ACPO with conservative treatment [14]. B4 These studies demonstrate that the initial management of ACPO should be directed towards eliminating or reducing the factors known to contribute to the problem.

Patient outcome The clinical dilemma facing the clinician caring for a patient with ACPO is whether to treat the patient with conservative measures and close observation versus proceeding with medical or endoscopic decompression of the dilated colon. The outcome of patients with ACPO is determined by multiple factors. The severity of the underlying illness appears to exert the greatest influence on patient outcome. ACPO often afflicts debilitated patients, which explains the significant morbidity and mortality even with successful treatment of the colonic dilatation. Other factors that appear to influence outcome are increasing age, maximal cecal diameter, delay in decompression and status of the bowel [2]. The risk of spontaneous colon perforation in ACPO is low but clearly exists. Rex reviewed all available reports in the literature and estimated the risk of spontaneous perforation to be approximately 3% [15]. The mortality rate in ACPO is approximately 40% when ischemia or perforation are present, compared with 15% in patients with viable bowel [2]. Retrospective analyses of patients with ACPO [2, 13] have attempted to identify clinical factors that

Ogilvie’s syndrome

predict which patients are more likely to have complications such as ischemia or perforation. The risk of colonic perforation has been reported to increase with cecal diameter greater than 12 cm and when distension has been present for more than six days [13]. In the large series reported by Vanek and Al-Salti, no cases of perforation were seen when the cecal diameter was less than 12 cm [2]. However, at diameters greater than 12 cm, there was no clear relationship between risk of ischemia or perforation and the size of the cecum. The duration and progression of colonic distension may be more important. Johnson and Rice reported a mean duration of distension of six days in patients who perforated compared with two days in those who did not [13]. A two-fold increase in mortality occurs when cecal diameter is greater than 14 cm and a five-fold increase when delay in decompression is greater than seven days [2]. Thus, the decision to intervene with medical therapy, colonoscopy or surgery is dictated by the patient’s clinical status. On the basis of the limited available evidence patients with marked cecal distension (>10 cm) of significant duration (>3–4 days) and those not improving after 24–48 hours of supportive therapy are considered to be candidates for further intervention. B4 In the absence of signs of ischemia or perforation, medical therapy with neostigmine should be considered the initial therapy of choice.

Medical therapy Neostigmine The only randomized controlled trial of an intervention for ACPO involves the use of neostigmine [16]. Neostigmine, a reversible acetylcholinesterase inhibitor, indirectly stimulates muscarinic receptors, thereby enhancing colonic motor activity, inducing colonic propulsion and accelerated transit [17]. The rationale for using neostigmine stems from the imbalance in autonomic regulation of colonic function that is proposed to occur in ACPO. Neostigmine was first used for manipulation of the autonomic innervation to the gastrointestinal tract by Neely and Catchpole over 30 years ago in studies on small bowel paralytic ileus [18]. Neostigmine, administered intravenously, has a rapid onset (1–20 minutes) and short duration (1–2 hours) of action [19]. The elimination half-life averages 80 minutes, but is more prolonged in patients with renal insufficiency [20]. A randomized double-blind, placebo-controlled trial evaluated neostigmine in patients with ACPO with a cecal diameter of >10 cm and no response to 24 hours of conservative therapy [16]. Exclusion criteria were suspected ischemia or perforation, pregnancy, severe active bronchospasm, cardiac arrhythmias and renal failure. Patients 379

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were randomized to receive neostigmine, 2 mg, or saline by intravenous infusion over 3–5 minutes. The primary endpoint was the clinical response to infusion, defined as a prompt reduction in abdominal distension by physical examination. Secondary endpoints included the change in measurements of colonic diameter on radiographs and abdominal girth. Patients not responding within three hours to initial infusion were eligible for open label neostigmine. A clinical response was observed in 10 of 11 patients (91%) randomized to receive neostigmine compared to 0 of 10 receiving placebo. Ald The median time to response was four minutes. Median reduction in cecal diameter (5 cm vs 2 cm) and abdominal girth (7 cm vs 1 cm) were significantly reduced in neostigmine-treated patients. Open-label neostigmine was administered to eight patients who failed to respond to the initial infusion (seven placebo, one neostigmine), and all had prompt decompression. Of the 18 patients who received neostigmine, either initially or during open-label treatment, 17 (94%) had a clinical response. The recurrence rate of colonic distension after neostigmine decompression was low (11%). The most common adverse effects observed with neostigmine were mild abdominal cramping and excessive salivation. Symptomatic bradycardia requiring atropine occurred in 2 of 19 patients. Neostigmine was also evaluated in a double-blinded, placebo-controlled trial involving 24 critically ill, ventilated patients with ileus (defined as absence of stools for three

days) [21]. No details of the extent and duration of colonic distention were provided. Neostigmine was administered as a continuous infusion (0.4 mg/hour for 24 hours). Of the 13 patients receiving neostigmine, 11 passed stools, whereas none of the placebo treated patients passed stools (p < 0.001). No acute serious adverse events occurred, but three patients had ischemic colonic complications 7 to 10 days after treatment. There are also several uncontrolled observational studies supporting the use of neostigmine in this condition [14, 22–27]. Collectively, rapid decompression of colonic distension was observed in 88% of patients with a recurrence rate of 7% (Table 22.2). B4 In the case series reported by Mehta and colleagues [28], a response to neostigmine was more likely in the postoperative setting (11 of 15 patients (73%) versus one of four patients (25%), p = 0.07), and less likely in those with electrolyte imbalance or receiving antimotility agents (3 of 15 (20%) versus 4 of 4, p = 0.003). This study suggests that it may be important to correct electrolyte abnormalities and to limit potentially exacerbating medications. Repeated infusions or more prolonged treatment with neostigmine have not been evaluated fully. There have been reports of patients with ACPO receiving repeated infusions and prolonged treatment with resolution [29]. This experience suggests that cautious repeated infusions can be successful and merits further study in patients with persistent or recurrent pseudo-obstruction.

Table 22.2 Neostigmine for colonic decompression in patients with acute colonic pseudo-obstruction. Study

No. of patients

Design

Dose

Decompression

Recurrence

Ponec et al. (1999) [16]

21 (neostigmine 11, placebo 10)

RCT; (OL in non-responders)

2.0 mg IV over 3–5 min

Neostigmine 10/11 in RCT; 17/18 total; placebo 0/10

2

Hutchinson and Griffiths (1992) [22]

11

OL

2.5 mg IV in one min.

8/11

0

Stephenson et al. (1995) [23]

12

OL

2.5 mg IV over 1–3 min.

12/12 (two patients required two doses)

1

Turegano-Fuentes et al. (1997) [24]

16

OL

2.5 mg IV over 60 min

12/16

0

Trevisani et al. (2000) [25]

28

OL

2.5 mg IV over 3 min

26/28

0

Paran et al. (2001) [26]

11

OL

2.5 mg IV over 60 min

10/11 (two patients required two doses)

0

Abeyta et al. (2001) [27]

8

Retrospective

2.0 mg IV

6/8 (two patients required two doses)

0

Loftus et al. (2002) [14]

18

Retrospective

2.0 mg IV

16/18

5

RCT: randomized controlled trial; OL: open-label trial; IV: intravenous.

380

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The cost of neostigmine is minimal, with a 2 mg ampoule for parenteral use costing only US$3 [16]. The cost to the patient after storage and handling fees are included is approximately US$15. Although neostigmine was associated with a favorable safety profile in the reported clinical trials, caution should be used when administering the medication. Neostigmine should be administered with the patient kept supine in bed with continuous electrocardiographic monitoring, physician assessment and measurement of vital signs for 15–30 minutes following administration [16]. Contraindications to its use include mechanical bowel obstruction, presence of ischemia or perforation, pregnancy, uncontrolled cardiac arrhythmias, severe active bronchospasm and renal insufficiency. Thus, neostigmine appears to be an effective, safe and inexpensive method of colonic decompression in ACPO. The published data support its use as the initial therapy of choice for patients not responding to conservative therapy if there are no contraindications to its use. Ald, B4 In patients with only a partial response or recurrence after an initial infusion, a repeated dose is reasonable and often successful. If the patient fails to respond after two doses, proceeding with colonoscopic decompression is advised.

Ogilvie’s syndrome

proportion of patients receiving either laxative: (placebo 31%, PEG 74% and lactulose 69%, p = 0.001). ACPO occurred in 4.1% of patients in the placebo group, 5.5% of patients in the lactulose group and 1.0% of patients in the polyethylene glycol group. Thus, it appears that the use of PEG in critically ill patients to promote defecaton may prevent the development of ACPO, and that its use following a pseudo-obstruction episode decreases the recurrence rate. A1c There are only anecdotal reports using other prokinetic agents in ACPO, and their use for the treatment of this condition cannot be recommended. Erythromycin, a motilin receptor agonist, has been reported to be successful in treating patients in a few case reports [32, 33]. Armstrong et al. reported decompression in two patients with ACPO with oral erythromycin (500 mg four times daily) for 10 days [32]. In another report, one patient had resolution of ACPO after three days of intravenous erythromycin therapy [33]. Cisapride, a partial 5-HT4-receptor agonist, has also been employed with some success in patients with ACPO [34]. However, this agent is no longer available for use in the USA and Canada due to class III arrhythmogenic properties. Lubiprostone, a novel chloride 2 channel activator approved for the treatment of constipation [35], has not been studied in pseudo-obstruction.

Other medications Administration of polyethylene glycol electrolyte solution (PEG) in patients who have ACPO after initial resolution may decrease the recurrence rate of colonic dilation. Sgouros and colleagues [30] evaluated PEG in a randomized, controlled trial in ACPO patients who had initial resolution of colonic dilation. The study enrolled 30 patients with cecal diameter 10 cm or greater that had resolution of the colonic dilation with either neostigmine (22 patients) or endoscopic decompression (eight patients). Patients then were randomized to receive daily PEG 29.5 g or placebo. Recurrence was defined as a cecal diameter of 8 cm or greater with a concomitant 10% increase after the initial successful decompression. Five (33%) patients in the placebo group had recurrent cecal dilation compared with none in the PEG group (p = 0.04). A1d Therapy with PEG resulted in a significant increase in stool and flatus output, decrease in colonic distention on radiographic measurements and improvement in abdominal girth [30]. There are few data on strategies to prevent the development of ACPO. A recent double-blind, randomized, placebo-controlled trial evaluated whether lactulose or PEG were effective in promoting defecation in critically ill patients, whether either of the two is superior, and whether the use of enteral laxatives is related to clinical outcome [31]. Three hundred and eight consecutive patients with multiple organ failure in whom defecation did not occur on the third day of admission to the ICU were included. Defecation occurred during the study period in a larger

Endoscopic decompression Colonoscopic decompression may be required in patients with persistent, marked colonic dilatation that has failed to respond to supportive therapy and neostigmine, or when neostigmine is contraindicated. There is no well-defined standard of care regarding the use of colonoscopy in ACPO [8]. Colonoscopic decompression appears to be beneficial in ACPO, but it is associated with a greater risk of complications, is not completely effective and can be followed by recurrence [36]. B4 Colonoscopy is done to prevent bowel ischemia and perforation. It should not be done if these complications have already developed. Colonoscopy in ACPO is a technically difficult procedure and should be carried out by experts. Oral laxatives and bowel preparations should not be administered prior to colonoscopy [37]. Air insufflation should be minimized and the entire colon need not be examined. Prolonged attempts at cecal intubation are not necessary because reaching the hepatic flexure usually appears to be effective. Gas should be aspirated and the viability of the mucosa assessed during slow withdrawal of the endoscope. A tube for decompression should be placed in the right colon with the aid of a guidewire and fluoroscopic guidance. Commercially available, single use, over-the-wire colon decompression tubes are available. The guidewires for these kits are quite flexible (0.035 inches (0.89 mm)) and must be watched under fluoroscopy during advancement 381

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Table 22.3 Observational studies of colonoscopic decompression in acute colonic pseudo-obstruction. Study

No. of patients

Successful initial decompression (%)

Overall colonoscopic success (%)

Complications

Nivatvongs et al. (1982) [38] Strodel et al. (1983) [39] Bode et al. (1984) [40] Jetmore et al. (1992) [4] Geller et al. (1996) [41]

22 44 22 45 41

68 61 68 84 95

73 73 77 36 88

3 days

Resolution

Repeat dose if IV neostigmine recurrence or partial response

Resolution

No improvement

Colonoscopy

No improvement

Surgery Figure 22.2 Algorithm for suggested management for acute colonic pseudo-obstruction. IV: intravenous.

maximal cecal diameter, duration of colonic distension and viability of the bowel. Of these factors affecting outcome, the latter three are amenable to intervention. Thus, early recognition and management are critical to minimizing morbidity and mortality.

References 1 Ogilvie WH. Large intestine colic due to sympathetic deprivation: A new clinical syndrome. BMJ 1948; 2: 671–673. 2 Vanek VW, Al-Salti M. Acute pseudo-obstruction of the colon (Ogilvie’s syndrome). An analysis of 400 cases. Dis Colon Rectum 1986; 29: 203–210. 3 Dorudi S, Berry AR, Kettlewell MGW. Acute colonic pseudoobstruction. Br J Surg 1992; 79: 99–103. 4 Jetmore AB, Timmcke AE, Gathright Jr BJ et al. Ogilvie’s syndrome: Colonoscopic decompression and analysis of predisposing factors. Dis Colon Rectum 1992; 35: 1135–1142. 5 Norwood MG, Lykostratis H, Garcea G et al. Acute colonic pseudo-obstruction following major orthopedic surgery. Colorectal Dis 2005; 7: 496–499. 6 Sheikh RA, Yasmeen S, Pauly MP et al. Pseudomembranous colitis without diarrhea presenting clinically as acute intestinal pseudo-obstruction. J Gastroenterol 2001; 36: 629–632.

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7 Sloyer AF, Panella VS, Demas BE et al. Ogilvie’s syndrome. Successful management without colonoscopy. Dig Dis Sci 1988; 33: 1391–1396. 8 Eisen GM, Baron TH, Dominitiz JA et al. Acute colonic pseudoobstruction. Gastrointest Endosc 2002; 56: 789–-792. 9 Wandeo H, Mathewson C, Conolly B. Pseudo-obstruction of the colon. Surg Gynecol Obstet 1971; 133: 44. 10 Meyers MA. Colonic ileus. Gastrointest Radiol 1977; 2: 37–40. 11 Bachulis BL, Smith PE. Pseudo-obstruction of the colon. Am J Surg 1978; 136: 66–72. 12 Baker DA, Morin ME, Tan A et al. Colonic ileus: Indication for prompt decompression. JAMA 1979; 241: 2633–2634. 13 Johnson CD, Rice RP. The radiographic evaluation of gross cecal distention. Am J Radiol 1985; 145: 1211–1217. 14 Loftus CG, Harewood GC, Baron TH. Assessment of predictors of response to neostigmine for acute colonic pseudo-obstruction. Am J Gastroenterol 2002; 97: 3118–3122. 15 Rex DK. Acute colonic pseudo-obstruction (Ogilvie’s syndrome). Gastroenterology 1994; 2: 223–228. 16 Ponec RJ, Saunders MD, Kimmey MB. Neostigmine for the treatment of acute colonic pseudo-obstruction. N Engl J Med 1999; 341: 137–141. 17 Law NM, Bharucha AE, Undale AS et al. Cholinergic stimulation enhances colonic motor activity, transit, and sensation in humans. Am J Physiol Gastrointest Liver Physiol 2001; 281: G1228–1237. 18 Neely J, Catchpole B. Ileus: The restoration of alimentary tract motility by pharmacologic means. Br J Surg 1971; 58: 21–28. 19 Aquilonius SM, Hartvig P. Clinical pharmacokinetics of cholinesterase inhibitors. Clin Pharmacokinet 1986; 11: 236–249. 20 Cronnelly R, Stanski DR, Miller RD et al. Renal function and the pharmacokinetics of neostigmine in anesthetized man. Anesthesiology 1979; 51: 222–226. 21 van der Spoel JI, Oudemans-van StraatenHM, Stoutenbecek CP et al. Neostigmine resolves critical illness-related colonic ileus in intensive care patients with multiple organ failure a prospective, double-blind, placebo-controlled trial. Intensive Care Med 2001; 27: 822–827. 22 Hutchinson R, Griffiths C. Acute colonic pseudo-obstruction: A pharmacologic approach. Ann R Coll Surg Engl 1992; 74: 364–367. 23 Stephenson BM, Morgan AR, Salaman JR et al. Ogilvie’s syndrome: A new approach to an old problem. Dis Colon Rectum 1995; 38: 424–427. 24 Turegano-Fuentes F, Munoz-Jimenez F, Del Valle-Hernandez E et al. Early resolution of Ogilvie’s syndrome with intravenous neostigmine. A simple, effective treatment. Dis Colon Rectum 1997; 40: 1353–1357. 25 Trevisani GT, Hyman NH, Church JM. Neostigmine: Safe and effective treatment for acute colonic pseudo-obstruction. Dis Colon Rectum 2000; 43: 599–603. 26 Paran H, Silverberg D, Mayo A et al. Treatment of acute colonic pseudo-obstruction with neostigmine. J Am Coll Surg 2000; 190: 315–318. 27 Abeyta BJ, Albrecht RM, Schermer CR. Retrospective study of neostigmine for the treatment of acute colonic pseudo-obstruction. Am Surg 2001; 67: 265–268. 28 Mehta R, John A, Nair P et al. Factors predicting successful outcome following neostigmine therapy in acute colonic pseudo-

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29

30

31

32 33

34

35

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obstruction: A prospective study. J Gastroenterol Hepatol 2006; 21: 459–461. Cherta I, Forne M, Quintana S et al. Prolonged treatment with neostigmine for resolution of acute colonic pseudo-obstruction. Aliment Pharmacol Ther 2006; 23: 1678–1679. Sgouros SN, Vlachogiannakos J, Vassilliadis K et al. Effect of polyethylene glycol electrolyte- balanced solution on patients with acute colonic pseudo-obstruction after resolution of colonic dilation: A prospective, randomized, placebo controlled trial. Gut 2006; 55: 638–642. van der Spoel JI, Oudemans-van Straaten HM, Kuiper MA et al. Laxation of critically ill patients with lactulose or polyethylene glycol: A two-center randomized, double-blind, placebo-controlled trial. Critical Care Medicine 2007; 35: 2726–2731. Armstrong DN, Ballantyne GH, Modlin IM. Erythromycin for reflex ileus in Ogilvie’s syndrome. Lancet 1991; 337: 378. Bonacini M, Smith CJ, Pritchard T. Erythromycin as therapy for acute colonic pseudo-obstruction (Ogilvie’s syndrome). J Clin Gastroenterol 1991; 13: 475–476. MacColl C, MacCannell KL, Baylis B et al. Treatment of acute colonic pseudo-obstruction (Ogilvie’s syndrome) with cisapride. Gastroenterology 1990; 98: 773–776. Johanson JF, Morton D, Geenen J, Ueno R. Multicenter, 4-week, double-blind, randomized, placebo-controlled trial of lubiprostone, a locally-acting type-2 chloride channel activator, in patients with chronic constipation. Am J Gastroenterol 2008 Jan; 103(1): 170–177.

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36 Rex DK. Colonoscopy and acute colonic pseudo-obstruction. Gastrointest Endosc Clin North Am 1997; 7: 499–508. 37 Saunders MD, Cappell MS. Endoscopic management of acute colonic pseudo-obstruction. Endoscopy 2005; 37: 760–763. 38 Nivatvongs S, Vermeulen FD, Fang DT. Colonoscopic decompression of acute pseudo-obstruction of the colon. Ann Surg 1982; 196: 598–600. 39 Strodel WE, Nostrant TT, Eckhauser FE et al. Therapeutic and diagnostic colonoscopy in non-obstructive colonic dilatation. Ann Surg 1983; 19: 416–421. 40 Bode WE, Beart RW, Spencer RJ et al. Colonoscopic decompression for acute pseudo-obstruction of the colon (Ogilvie’s syndrome): Report of 22 cases and review of the literature. Am J Surg 1984; 147: 243–245. 41 Geller A, Petersen BT, Gostout CJ. Endoscopic decompression for acute colonic pseudo-obstruction. Gastrointest Endosc 1996; 44: 144–150. 42 van Sonnenberg E, Varney RR, Casola G et al. Percutaneous cecostomy for Ogilvie’s syndrome: Laboratory observations and clinical experience. Radiology 1990; 175: 679–682. 43 Chevallier P, Marcy PY, Francois E et al. Controlled transperitoneal percutaneous cecostomy as a therapeutic alternative to the endoscopic decompression for Ogilvie’s syndrome. Am J Gastroenterol 2002; 97: 471–474. 44 Baraza W, Brown S, McAlindon M, Hurlstone P. Prospective analysis of percutaneous endoscopic colostomy at a tertiary referral centre. Br J Surg 2007; 94: 1415–1420.

23

Gallstone disease Laura VanderBeek1, Calvin HL Law2 and Véd R Tandan3 1

McMaster University, Hamilton, Ontario, Canada Hepatobiliary, Pancreatic and Gastrointestinal Surgery, Department of Health Policy, Management and Evaluation, University of Toronto and Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada 3 Department of Surgery, St Joseph’s Healthcare Hamilton, McMaster University, Hamilton, Ontario, Canada 2

Introduction Surgical therapy for gallstones can be associated with morbidity and mortality, which has led to debate on its use, especially in asymptomatic and mildly symptomatic patients. Advancements in minimally invasive and endoscopic techniques make it imperative to understand the current evidence concerning the benefits and risks of surgical therapy for gallstone disease and its complications.

Elective cholecystectomy Asymptomatic cholelithiasis in the general population As abdominal ultrasound has become a routine investigation for abdominal symptoms, asymptomatic cholelithiasis is being diagnosed more frequently. Management of uncomplicated gallstones poses a dilemma as there are no controlled trials comparing prophylactic surgery with expectant management in asymptomatic patients with cholelithiasis. However, a number of cohort studies have been done to assess the probability of developing biliary pain and biliary complications in asymptomatic persons with gallstones. Through the 1980s, a series of cohort studies were conducted by Gracie and Ransohoff [1], McSherry et al. [2], and Freidman et al. [3,4]. Gracie’s study had complete followup on 123 people for 11–24 years. The cumulative probability of the development of biliary pain was 10% at five years, 15% at ten years, and 18% at twenty years. However, the fact that 89% of the study population were white American

Evidence-Based Gastroenterology and Hepatology, Third Edition John WD McDonald, Andrew K Burroughs, Brian G Feagan and M Brian Fennerty © 2010 Blackwell Publishing Ltd. ISBN: 978-1-405-18193-8

males, and all were faculty members of the University of Michigan, limits the generalizability of this study. McSherry’s study retrospectively identified 135 patients with asymptomatic cholelithiasis who were subscribers to the Health Insurance Plan of Greater New York, a mainly middle-income population of diverse ethnic origin. Over a mean follow-up of 46 months, 10.4% of patients developed symptoms, yielding a 2.7% annual rate of developing symptoms. Similarly, Friedman followed 123 ethnically diverse patients with asymptomatic gallstones in the Kaiser Permanente Medical Care Program (San Francisco) for 16–25 years. There was a 3–4% annual rate of biliary events in the initial ten years, and a 1–2% annual rate in the following ten years. At five years, 18% of patients had developed biliary symptoms. One death was attributable to cholangitis secondary to gallstones. A more detailed explanation of Gracie’s data revealed that three patients eventually experienced biliary complications (2.4% of the population), but all of these had presented with pain before the complication. In McSherry’s study, 10% of the population eventually developed symptoms and 71% of these patients had biliary colic as their only indication for elective cholecystectomy. Although the remaining patients had biliary complications prior to surgery (3% of the study population), it is unclear if they presented with pain first. Overall these studies yield an estimate of an annual rate of 1–2% of symptom development, and provide evidence that 90% of patients will present with pain prior to developing a biliary complication. Only 10% of patients will present with a biliary complication as the first manifestation of their biliary tract disease [4]. The Group for Epidemiology and Prevention of Cholelithiasis (GREPCO) in Italy prospectively followed 118 patients with asymptomatic cholelithiasis [5]. The cumulative probability of developing biliary colic was 12% at two years, 17% at four years and 26% at ten years. The cumulative probability of biliary complications was 3% at ten years. One patient died of gallbladder carcinoma. This represents a higher rate of symptoms, but not a higher rate 385

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of complications than the studies from the 1980s. This study also showed that 74% of patients remained asymptomatic at ten years. Ransohoff et al. performed a decision analysis on data first published by Gracie [1, 6, 7]. Using cholecystectomy mortality figures up to 1983, they found prophylactic cholecystectomy slightly decreased survival. The economic analysis did not favor prophylactic cholecystectomy. Although the models were constructed using data prior to laparoscopic cholecystectomies, the new approach is unlikely to alter the results. Considering the current evidence, expectant management rather than prophylactic cholecystectomy is indicated for the typical patient with asymptomatic gallstones. However, certain populations who are more at risk for complications of gallstone disease should be considered separately.

Asymptomatic cholelithiasis in diabetic patients More liberal thresholds for elective cholecystectomy in asymptomatic diabetic patients have been suggested [8], based on early evidence suggesting a higher incidence of gallstone disease and biliary complications, and poorer outcomes for emergency surgery for biliary complications. Only Grade B evidence is available, which supports expectant management of asymptomatic cholelithiasis in this population rather than a more aggressive approach. Chapman reviewed 308 diabetic patients and 318 nondiabetic controls [9]. The incidence of cholelithiasis was higher in the diabetic population (32.7% vs 20.8%, p < 0.001). However, when the data were subjected to multivariate analysis, diabetes did not correlate strongly with the incidence of cholelithiasis, except in a subgroup of females with non-insulin dependent diabetes. Del Favero prospectively studied the natural history of cholelithiasis in diabetes by following a cohort of 47 diabetic patients with asymptomatic cholelithiasis [10]. After five years, five patients presented with pain as their first symptom, one patient presented with cholecystitis and another patient presented with jaundice. The percentage of initially asymptomatic non-insulin dependent diabetic patients who went on to develop symptoms (14.9%) or complications (4.2%) compares favorably with the data available from studies of the general population. Higher complication rates with emergency surgery for biliary complications in diabetic patients have been observed. Hickman et al. studied 72 diabetic patients who underwent cholecystectomy for cholecystitis and matched them for age, sex and date of operation with 72 nondiabetic patients [11]. Morbidity for the diabetic patients was 38.9% compared with 20.8% in the non-diabetic population. Mortality in the diabetic population was 4.2%, compared with zero in the control population and was 386

attributed to sepsis. The septic complication rate was higher in the diabetic (19.4%) than in the non-diabetic group (6.9%). This higher rate was maintained whether the diabetic patients had concurrent medical illness or not. Landau et al. (1992) analyzed 566 cholecystectomies performed in the presence of acute cholecystitis [12]. Of these patients, 123 had diabetes mellitus and 433 did not have diabetes. The diabetic patients were found to have a higher rate of infected bile, gangrenous changes and perforation of the GB, in comparison with non-diabetic patients. Also, the morbidity rate of surgery for acute cholecystitis was significantly higher (21% vs 9%) in diabetic patients. Sandler used logistic regression when analyzing 126 diabetic patients and 855 non-diabetic patients with cholecystectomy and found diabetics have an increased morbidity primarily because they are older and have other medical problems [13]. Diabetes itself was not statistically significant for associated increased morbidity. The natural history of asymptomatic cholelithiasis in diabetic patients appears to be similar to that in the general population. Asymptomatic cholelithiasis in diabetics should be managed expectantly and preventative surgery should not be recommended routinely. However, once symptoms develop early laparoscopic cholecystectomy is recommended to prevent complications.

Asymptomatic cholelithiasis and the risk of cancer Autopsy data have provided evidence that more than 80% of patients with gallbladder cancer have concomitant cholelithiasis. Maringhini et al. followed 2583 patients with known gallstones [14]. Only five patients (0.2%) developed gallbladder carcinoma. Ransohoff et al. reviewed 1000 patients with silent gallstones for a total of 7000 patient years and no patients developed gallbladder cancer [6]. The GREPCO in Italy followed up 118 patients with asymptomatic gallstones for ten years and only one patient developed and died of gallbladder cancer [5]. The incidence of gallbladder cancer varies widely in different populations, even in the presence of gallstone disease. Lowenfels et al. reported a case-control study of 131 patients with gallbladder carcinoma and 2399 patients without gallbladder carcinoma [15]. The 20-year cumulative risk for gallbladder cancer ranged from 0.13% in black males to 1.5% in native American females. The authors calculated that 769 cholecystectomies were required to prevent one gallbladder cancer in a low-risk population. However, only 67 cholecystectomies would be necessary to prevent one gallbladder malignancy in a high-risk population. B3 Hsing et al. conducted a population-based study from Shanghai of 627 patients with biliary tract cancers, 368 being gallbladder cancer [16]. Gallbladder cancer risk was

CHAPTER 23

higher among subjects with both gallstones and selfreported cholecystitis, with an OR of 34.4. The OR associated with gallstones and gallbladder cancer was 23.8. Patients with gallstones greater than 3 cm may be at risk for the development of gallbladder carcinoma. In 1983 Diehl reported this in a case-control study and the study by Lowenfels confirmed this observation in 1989 [17, 18]. These studies provided evidence for a nine to ten-fold increase in relative risk of developing gallbladder carcinoma for patients with stones greater than 3 cm in diameter compared to patients with stones less than 1 cm in diameter. Srikanth et al. found that one-half of gallbladders with a wall thickness >3 mm on US are likely to have xanthogranulomatous cholecystitis, and the risk of the patient having a gallbladder cancer is higher (3.3%) [19]. Grade B evidence supports the view that the risk of developing gallbladder cancer may be higher in patients with cholelithiasis. However, the increased risk appears to be insufficient to support a recommendation for prophylactic cholecystectomy. Although some subsets of the population (especially native American females) and patients with stones greater than 3 cm or gallbladder wall thickness >3 mm may be at sufficient risk to justify prophylactic cholecystectomy, further evidence would be needed to support a firm recommendation. B3, B4

Porcelain gallbladder and risk of gallbladder cancer Early case reports and small series initially indicated a correlation between porcelain gallbladder and carcinoma, which guided a recommendation for surgical therapy. However, more relevant information has only recently been published. A retrospective assessment by Towfigh et al. [20] examined 10,741 gallbladder specimens. Only 15 (0.14%) were porcelain gallbladders. All porcelain gallbladder specimens demonstrated chronic cholecystitis and partial calcification of the gallbladder wall and nine had cholelithiasis (60%). During this same period, 88 (0.82%) patients developed gallbladder cancer, none of whom showed calcification of the gallbladder wall. From these data, the authors challenged the link between porcelain gallbladder and gallbladder cancer. However, further insight may be gained from a study by Stephen and Berger [21]. This study reported data on 25,900 gallbladder specimens, of which 150 cases of gallbladder cancer and 44 cases of porcelain gallbladder (defined as the presence of wall calcifications) were identified. This study demonstrated that there are two types of wall calcification – diffuse intramural calcification and selective mucosal calcification. Gallbladder cancer was found in 7% of cases with selective mucosal calcification, but no case of gallbladder cancer was identified in the specimens with diffuse intramural calcification. Thus, conflicting data in the past may be attribut-

Gallstone disease

able to misclassification. However, in the preoperative setting, it may be difficult to distinguish these types of calcifications with standard imaging modalities. As a result, the authors still recommend cholecystectomy for patients with porcelain gallbladder, especially in those where there is incomplete calcification of the gallbladder wall. CS

Symptomatic cholelithiasis Grade B evidence supports the current approach to patients with symptomatic cholelithiasis. Patients with uncomplicated biliary colic should be offered surgery as an option to controlling symptoms. Patients with complications of cholelithiasis should have surgery to prevent further complications. The previously discussed natural history studies of McSherry et al. and Friedman et al. included a group of patients with symptomatic cholelithiasis [2, 3]. Additional data are also available from the National Cooperative Gallstone Study (NCGS) [22, 23]. McSherry followed 556 patients with symptomatic cholelithiasis [2]. During an average follow-up of 83 months, 169 (30%) patients reported worsening or continued severe symptoms, nine (1.6%) patients developed jaundice, and 47 (8.5%) patients developed cholecystitis. These data indicate a 4.3% annual rate of worsening or persistently severe symptoms and a 1.5% annual rate of biliary complications arising from symptomatic cholelithiasis. Friedman followed 298 patients with mild or non-specific symptoms and cholelithiasis for 16–25 years [3, 4]. The annual rate of developing cholecystitis or jaundice was 1%. The NCGS was designed as a double-blind, randomized controlled trial of chenodiol [22, 23]. The group of patients who had received placebo provided another opportunity to study the natural history of symptomatic cholelithiasis. Seventy-seven patients presented with worsening symptoms of biliary colic or prolonged biliary pain during two years of follow-up. Seven patients “required cholecystectomy” during the follow-up, which represents a 34% annual incidence of “requiring a cholecystectomy”. The patients with symptomatic cholelithiasis in these studies did not suffer any greater mortality during the follow-up period than was experienced by patients in the asymptomatic population. The rate of complications secondary to symptomatic cholelithiasis appears to be higher than that in patients with asymptomatic cholelithiasis. Recurrent or worsening symptoms may develop but there is no increased mortality from observation, at least in the short term. Therefore, “the subjective experience of the patient should be the principal determinant of whether and when the procedure should be performed”. Early surgical treatment is indicated once cholelithiasis is complicated by acute cholecystitis, choledocholithiasis, or cholangitis. 387

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Elective laparoscopic versus open cholecystectomy Laparoscopic cholecystectomy is now considered standard of care for elective cholecystectomy. This approach has been “accepted” despite the lack of any evidence from a randomized controlled trial comparing standard open cholecystectomy and standard laparoscopic cholecystectomy. There is a lack of convincing evidence of decreases in length of stay, recovery time or economics (hospital or societal). However, the general acceptance of laparoscopic cholecystectomy as the standard of care, as well as public demand for minimally invasive surgery, will prevent a future randomized controlled trial that may definitively answer these questions. Nonetheless, laparoscopic cholecystectomy has had a significant impact on the management of gallstone disease, as evidenced by increasing rates

of elective cholecystectomy since its introduction in the 1980s [24, 25]. Evidence from five randomized controlled trials comparing elective laparoscopic cholecystectomy and minilaparotomy cholecystectomy is available [26–30] (Table 23.1). Alc There is no statistically significant difference in the incidence of biliary tract injuries, although in a study by McMahon et al. the only major biliary injury occurred in the laparoscopic group [27]. Quality of life data were obtained by both Barkun et al. and McMahon et al. [26, 27]. The laparoscopic group experienced a faster improvement in quality of life, but the two treatment groups were equal in this respect at three months. Similarly, there was better satisfaction with scarring in the laparoscopic group, but both groups were equally satisfied with their result at three months. The data from Majeed revealed no difference in time off work or time to return to full activity [29]. A cost minimization economic analysis was carried out by

Table 23.1 Randomized controlled trials of laparoscopic cholecystectomy (LC) and mini-cholecystectomy (MC). Study Barkun et al. [26]

McMahon et al. [27]

McGinn et al. [28]

Majeed et al. [29]

Keus et al. [30]

151 148

155 155

100 100

105 118

57a 71a

74a 50

No. of patients

LC MC

37 25

Operative time (minutes)

LC MC

85.9 73.1

Conversion to standard open cholecystectomy

LC MC

1 (3%) 0 (0%)

Time to oral intake

LC MC

1.1 daysa 1.7 daysa

Hospital stay (days)

LC MC

3a 4a

Non-biliary complications

LC MC

1 (3%) 1 (4%)

30 (20%)b 26 (17%)c

12 (7.7%)a 2 (1.3%)a

11 (11%) 14 (14%)

20 (19%) 10 (8.5%)

Biliary complications

LC MC

0 (0%) 1 (4%)

5 (3%)d 3 (2%)d

1 (0.6%) 2 (1.3%)

1 (1%) 0 (0%)

1 (1%) 3 (2.5%)

Mortality

LC MC

0 (0%) 0 (0%)

0 (0%) 1 (0.7%)

1 (0.6%) 0 (0%)

0 (0%) 1 (1%)e

0 (0%) 0 (0%)

15 (10%) 14 (10%)

20 (13%) 6 (4%)

N/A N/A

N/A N/A

2a 4a

2b 3b

69.2a 45.4a 20 (20%) 22 (22%) 24.7 hrs 22.4 hrs 3 3

71.9a 60.4a 14 (11.7%) 22 (16.1%) N/A N/A 2.4 3.1

N/A, data not available. Indicates differences reached statistical significance. b This difference was statistically significant but did not include patients who were converted to standard cholecystectomy. If included, there was no statistically significant difference in length of hospital stay. c Total complications. d This included 1 (0.7%) major biliary injury in the LC group and no major biliary injuries in the MC group. e Histology revealed a carcinoma of the gallbladder and ultrasound at three months showed multiple liver metastases and the patient died two months later. a

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McMahon [27]. Laparoscopic cholecystectomy was more costly after considering both perioperative and hospitalization costs (£1486 compared with £1090, p < 0.001). Keus et al. found no significant difference in complications, but there was a significantly shorter operative time in the small-incision technique (mean 60.4 min.) compared to the laparoscopic cholecystectomy (mean 71.9 min.) [30]. Further data comparing laparoscopic to open cholecystectomy are available from the meta-analysis of Shea et al. of the outcomes of 78,747 patients undergoing laparoscopic cholecystectomy and 12,973 patients undergoing open cholecystectomy [31]. Mortality rates were lower for laparoscopic cholecystectomy than for open cholecystectomy, while common bile duct injury was higher for laparoscopic cholecystectomy than for open cholecystectomy. The data for common bile duct injury were re-analyzed by grouplevel logistic regressions to identify the differences in rates among the studies. A pattern of infrequent common duct injury in early studies, an increased incidence in studies initiated in early 1990, followed by a subsequent decrease in rate was revealed. However, the data were quite variable in terms of reporting of results and length of follow-up. The authors conceded, “there are still some considerable uncertainties that need to be addressed by better-designed studies and more complete reporting”. Considering the current evidence, in the elective setting, laparoscopic cholecystectomy appears to be as safe as open cholecystectomy and may provide short-term improvement in quality of life. Ala, C There is a lack of convincing evidence of decreases in length of stay, recovery time or economics (hospital or societal). However, the general acceptance of laparoscopic cholecystectomy as the standard of care as well as public demand for minimally invasive surgery will prevent a future randomized controlled trial that may definitively answer these questions.

Further issues in elective laparoscopic cholecystectomy With the advent of the laparoscopic cholecystectomy, there has been a move towards ambulatory surgery. Grade A evidence from two randomized trials which compared outpatient to inpatient laparoscopic cholecystectomy are available [32, 33]. Exclusion criteria included American Society of Anesthesiologists (ASA) III/IV, patients less than 18 and more than 70 years old, lack of a capable caregiver at home and complicated cholelithiasis (common bile duct stones or acute cholecystitis). The degree of pain, readmission and complication rates were the same in both groups. Late complications such as bile leaks became evident several days later and there was no benefit from 24-hour admission. Keulemans et al. found that 92% of the outpatients preferred outpatient care to clinical observa-

Gallstone disease

tion [33]. Of the 504 planned outpatient laparoscopic cholecystectomies, Bueno Lledo et al. found that 88.8% were discharged the same day [34]. Fifty-one patients required overnight stays (10.1%), most of them for “social” causes, and five patients required 1–2 day admission for intraoperative and postoperative complications. Six patients (1.1%) required readmission. In summary, outpatient laparoscopic cholecystectomy is a safe and feasible option for selected patients (defined by the exclusion criteria in the randomized trials). Alc There are two randomized trials comparing threeport versus four-port laparoscopic cholesyctectomy [35, 36]. In both studies there was no significant difference in operative time or complications. The main advantages of the three-port technique are that it causes less pain and leaves fewer scars. Again, this technique was carried out by expert hands and may not be generalized to all surgeons.

Acute cholecystitis Acute cholecystitis, inflammation secondary to obstruction of the cystic duct, is the most common complication of cholelithiasis. Laparoscopic cholecystectomy has become the treatment of choice for acute cholecystitis and there is now little controversy concerning the use of laparoscopic versus open cholecystectomy. Controversy remains over the timing of cholecystectomy. In the pre-laparoscopic era, the question of early versus delayed cholecystectomy was heavily debated. Evidence from five randomized trials carried out in the 1970s and 1980s is available [37–41]. Alc These studies demonstrated that cholecystectomy could be carried out in the acute stage with shorter hospital stay, decreased mortality and fewer operative complications (Table 23.2). The introduction of laparoscopic cholecystectomy caused a movement to return to delayed cholecystectomy for acute cholecystitis. This movement arose because laparoscopic cholecystectomy was considered to be associated with more complications and an increased risk of common bile duct injuries than interval laparoscopic cholecystectomy after the resolution of the acute episode. Grade A evidence from six randomized controlled trials on early versus delayed laparoscopic cholecystectomy is available (Table 23.3) [42–47]. Once again, the data show that early cholecystectomy, even if carried out with the laparoscopic approach, is safer and better for patients in terms of shorter illness and hospital stay, compared with delayed surgery. Evidence regarding laparoscopic versus open cholecystectomy for acute cholecystitis is available from two randomized trials [48, 49]. Alc The results are summarized in Table 23.4. The laparoscopic approach did not increase mortality or morbidity compared with the open approach 389

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Table 23.2 Randomized controlled trials comparing early versus delayed open cholecystectomy for acute cholecystitis. Study McArthur et al. [37]

Lahtinen et al. [38]a

van der Linden et al. [39]a

Jarvinen and Hastbacka [40]

No. of patients

Early Delayed

15 13

47 44

70 58

80 75

Operative time (minutes)

Early Delayed

N/A N/A

76.7 98.0

N/Ab N/Ab

93 85

Hospital stay (days)

Early Delayed

13.1 24.2

13.0 25.0

10.1 10.9 + 8c

10.7 18.2

Biliary complications

Early Delayed

1 (6.7%) 0

1 (2.1%) 3 (6.8%)

0 0

3 (3.8%) 2 (2.7%)

Non-biliary complications

Early Delayed

3 (20%) 5 (38.4%)

12 (25.5%) 16 (36.4%)

10 (14.3%) 2 (3.4%)

11 (13.8%) 13 (17.3%)

Mortality

Early Delayed

0 0

0 4 (9.1%)

0 0

0 1 (1.3%)

3 (23.1%)

7 (15.9%)

0

10 (13.3%)

Failure of delayed treatmentd

N/A, data not available. Also showed decreased insurance payments (for time off work) for the patients treated with early cholecystectomy. b No average or mean time for surgery was given but the distributions of operative times were similar. c The mean stay for initial conservative management was 10.9 days followed by a mean stay of 8.0 days at the time of the delayed cholecystectomy. d Patients randomized to conservative treatment initially who failed and required urgent cholecystectomy. a

Table 23.3 Randomized controlled trials comparing early versus delayed laparoscopic cholecystectomy for acute cholecystitis. Study Lo et al. [42]

Lai et al. [43]

Kolla et al. [44]

Johansson et al. [45]

Serralta et al. [46]

No. of patients

Early Delayed

45 41

53 51

20 20

74 71a

82 87

Operative time (minutes)

Early Delayed

135b 105b

122.8b 106.6b

104 93

98 100

75b 93b

Conversion

Early Delayed

5 (11%) 9 (23%)

(21%) (24%)

5 (25%) 5 (25%)

23 (31%) 20 (29%)

2 (2%)b 15 (17%)b

Hospital stay (days)

Early Delayed

6b 11b

7.6b 11.6b

4.1b 10.1b

5b 8b

6b 13b

Biliary complications

Early Delayed

1 (2.2%) 3 (7.3%)

1 (%) 0 (0%)

2 (10%) 0

6 (8%) 1 (1%)

1 (1%) 1 (1%)

Non-biliary complications

Early Delayed

5 (11.1%) 9 (22.0%)

4 (8%) 3 (8%)

2 (10%) 3 (15%)

7 (9%) 6 (9%)

9 (11%) 12 (14%)

Mortality

Early Delayed

0 0

0 0

0 0

0 0

0 0

8(19.5%)

8 (16%)

0

18 (26%)

8 (9%)

Failure of delayed treatmentc a

Two patients refused surgery and were excluded. Indicates differences reached statistical significance. c Patients randomized to conservat ive treatment initially who failed and required urgent cholecystectomy. b

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Table 23.4 Randomized controlled trials comparing open (OC) versus laparoscopic (LC) cholecystectomy for acute cholecystitis. Study Kiviluoto et al. [48]

Lujan et al. [49]

No. of patients

OC LC

31 32

110 114

Operative time (minutes)

OC LC

99.8 108.2

77 88

Conversion

LC (only)

5 (16%)

17 (15%)

Hospital stay (days)

OC LC

6 4

8.1 3.3

Biliary complications

OC LC

0 0

1 (0.9%) 4 (3.5%)a

OC

28 (25.5%)

LC

7 (minor) (23%) 6 (major) (19%) 1 (minor) (3%)

14(12.3%)

OC LC

0 0

0 0

Non-biliary complications

Mortality

a

Two out of four were retained common bile duct stones.

and offered the benefit of shorter hospital stay. Both studies found that the rate of conversion to the open procedure was slightly higher than the average observed in elective cholecystectomy series. A retrospective study of 202 consecutive laparoscopic cholecystectomy patients compared complications and conversion rates when performed in the acute (5 weeks) settings [50]. There was no significant difference in conversion rates (11–20%) or complication rates (7–16%) between the three groups and it was concluded that cholecystectomy can be performed safely during initial hospitalization regardless of symptom duration. Considering the current evidence, acute cholecystitis should be treated with early laparoscopic cholecystectomy (within the first 96 hours of symptoms).

Cholecystectomy via NOTES Natural orifice transluminal endoscopic surgery (NOTES) is a new technique that can be used to perform cholecystectomies through a transvaginal approach. The first human case was reported on 13 March 2007 by Zorron on a 43-year-old female with biliary colic [51]. Since then, Zornig reports 20 patients who have had transvaginal cholecystectomies with no intra- or postoperative compli-

Gallstone disease

cations [52]. Another three females of varying BMIs have successfully undergone cholecystectomy using the NOTES technique with no postoperative complications [53]. Also, there was a case report of a morbidly obese female with a BMI of 35.8 who had a cholecystectomy via transvaginal NOTES approach with no postoperative analgesic use and no postoperative complications [54]. Transvaginal endoscopic cholecystectomies may in the future provide a safe surgical technique for women of varying BMIs with less visible scars and less postoperative pain, but it is currently still under investigation and further research is required before its use is widely accepted.

Gallstone pancreatitis Early endoscopic retrograde cholangiopancreatography Evidence from three randomized controlled trials on early endoscopic retrograde cholangiopancreatography (ERCP) with stone extraction versus conservative therapy as a treatment for biliary pancreatitis is available [55–57]. Alc In patients with severe pancreatitis or with evidence of biliary obstruction or cholangitis, early ERCP within 72 hours of presentation probably decreases morbidity and mortality rates. In patients without these criteria, early ERCP has no benefit and may in fact increase morbidity and mortality. Therefore, patients must be carefully selected for early ERCP. (See Chapter 24 for further discussion.)

Preoperative endoscopic retrograde cholangiopancreatography versus cholecystectomy with cholangiogram Gallstone pancreatitis is considered to be an indication for imaging the biliary tree with either ERCP or intraoperative cholangiogram (IOC). In order to determine if ductal evaluation is always necessary before or during cholecystectomy for biliary pancreatitis, Ito et al. examined 148 patients undergoing cholecystectomy for biliary pancreatitis [58]. Only those patients at low risk for choledocholithiasis were included (normal or decreasing liver function tests and no ductal dilation on non-invasive preoperative imaging). The choice to perform IOC was based on the preference of the operating surgeon. Twenty-seven patients underwent IOC and 121 patients did not undergo IOC. There was no difference in recurrent pancreatitis, cholangitis and asymptomatic elevation of liver function tests three months after discharge. This study suggests that direct ductal evaluation can be omitted safely in patients with low risk of choledocholithiasis. Seven observational studies, two with controls, have assessed the optimal approach to imaging the biliary tree 391

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following an attack of gallstone pancreatitis [59–65]. Gallstone pancreatitis does not appear to be a strong predictor of CBD stones without evidence of a dilated CBD, persistently abnormal alkaline phosphatase or bilirubin, or evidence of cholangitis. Patients with these features may be considered for preoperative ERCP. C5 In one retrospective study, the incidence of procedure-induced pancreatitis was 19% in the ERCP group and 6% in the surgical/IOC group [59]. The other retrospective study demonstrated similar results with pancreatic-biliary complications in 24% of the ERCP group and 6% of the surgical/IOC group [65]. The data suggest that preoperative ERCP may in fact increase overall morbidity compared with cholecystectomy with IOC, further supporting the approach of selective ERCP in this group of patients. C5

Timing of surgery with gallstone pancreatitis A number of studies have evaluated early versus delayed cholecystectomy in patients with gallstone pancreatitis. Burch et al. evaluated patients who underwent surgery after recovering from acute pancreatitis either during the same hospital admission or following discharge and scheduled elective surgery [66]. Although surgical complication rates were the same in both groups, total hospital stay was significantly longer in the delayed surgery group (14 vs 17 days, p = 0.01). Furthermore, in the delayed group only 60% returned for surgery, and 29% of the original cohort required emergency treatment for recurrent pancreatitis or biliary disease before elective surgery. Kelly et al. randomized patients to early (less than 48 hours) and delayed (more than 48 hours) surgery [67]. With early surgery the morbidity and mortality rates were 30.1% and 15.1%, as compared with 5.1 and 2.4% in the delayed group (p < 0.005). Alc When patients were stratified for disease severity based on Ranson’s criteria, the differences in morbidity and mortality rates between early and delayed surgery were not statistically significant in patients with three or fewer Ranson’s criteria. In patients with severe pancreatitis (more than three Ranson’s criteria), the differences remained significant. A retrospective review identified 164 patients with gallstone pancreatitis: 90 patients were discharged for readmission cholecystectomy and 74 patients had the cholecystectomy before discharge [68]. The patients in the discharged group waited on average 40+/−69 days versus 8+/−10 days in the group which remained in hospital (mean+/−SD). Of those patients who were discharged 20% (18 of 90) xperienced an adverse event requiring readmission while awaiting their cholecystectomy: three had recurrent pancreatitis, ten had recurrent pain, and five developed acute cholecystitis. Grade B/C evidence has recently been published examining the issue of whether cholecystectomy is even neces392

sary after successful ERCP with endoscopic sphincterotomy (ES) and clearance of bile duct stones [69, 70]. Kaw et al. followed patients prospectively to compare outcome after laparoscopic cholecystectomy and ERCP with ES or ERCP and ES alone for an average of 33 and 34 months respectively [69]. During follow-up, there was no significant difference in biliary complications or procedure-related complications. They concluded that laparoscopic cholecystectomy should only be attempted in patients with overt biliary symptoms and not for the prevention of gallstone pancreatitis. Kwon et al. found that only 4.8% of patients required a cholecystectomy for biliary complications at an average of 18.4 months following ERCP and ES [70]. This issue should be examined further by randomized controlled trials, but at this point there is no clear evidence that biliary complications can be completely avoided by ERCP and ES alone. In addition, these data conflict with Grade A evidence from studies looking at CBD stones (see below). Based on these data, it is recommended that patients with acute severe gallstone pancreatitis undergo cholecystectomy following resolution of the acute episode but during the initial hospital stay. Patients with mild to moderate pancreatitis (three or fewer Ranson’s criteria) can be considered for early laparoscopic cholecystectomy. Alc, C5

Choledocholithiasis Once CBD stones have been identified, the standard of care is to remove them, since stones left in the CBD may cause subsequent biliary complications including obstructive jaundice, pancreatitis and cholangitis. See Chapter 24 for further discussion. The surgical method for identifying CBD stones is operative cholangiography. However, the choice of routine versus selective cholangiography remains somewhat controversial [71–73]. Flum et al. performed a retrospective nationwide cohort analysis of 1,570,361 patients undergoing cholecystectomy from 1 January 1992, to 31 December 1999 [73]. There were 7911 common bile duct injuries (0.5%) with 2380 (0.39%) occurring in the 613,706 patients undergoing cholecystectomy with IOC and 5531 (0.58%) occurring in the 956,655 patients undergoing cholecystectomy without IOC (unadjusted relative risk, 1.49). After controlling for patient-level factors and surgeon-level factors, the risk of common bile duct injury was increased when IOC was not used (adjusted relative risk, 1.71). In a review of 2043 patients undergoing routine laparoscopic operative cholangiography, the incidence of unsuspected CBD stones was 2.8% [71]. Only 0.30% of patients not undergoing operative cholangiography ever became symptomatic. In order to better use resources, other studies have attempted to determine criteria for selective operative cholangiography. Borjeson et al. proposed criteria that included: normal liver

CHAPTER 23

function tests, CBD diameter 8 in the first 24 hours of admission, and C reactive protein levels >150 mg/l, Glasgow score 3 or more, or persisting organ failure after 48 hours in hospital.a Patients with persisting organ failure, signs of sepsis, or deterioration in clinical status 6–10 days after admission will require CT.

2005

A

1998

C

2005

C

2005

B

2005

B

1998

B

2005

B

2005

B

All cases of severe acute pancreatitis should be managed in an HDU or ITU setting with full monitoring and systems support. Every hospital that receives acute admissions should have a single nominated clinical team to manage all patients with acute pancreatitis. Management in, or referral to, a specialist unit is necessary for patients with >30% necrosis or with other complications. The evidence for antibiotic prophylaxis against infection of pancreatic necrosis is conflicting and difficult to interpret. At present there is no consensus on this issue.a If antibiotic prophylaxis is used, it should be given for a maximum of 14 days. Further studies are needed.a A German trial which compared ciprofloxacin-metronidazole and placebo is the only double-blind, placebo-controlled trial published to date. The results do not support the use of prophylactic antibiotics. This study was stopped after interim analysis of 76 patients with necrosis showed no differences in the primary outcomes of infected necrosis, systemic complications and mortality rates.a The evidence is not conclusive to support the use of enteral nutrition in all patients with severe acute pancreatitis. However, if nutritional support is required, the enteral route should be used if that can be tolerated. The nasogastric route for feeding can be used as it appears to be effective in 80% of cases. All patients with biliary pancreatitis should undergo definitive management of gall stones during the same hospital admission, unless a clear plan has been made for definitive treatment within the next two weeks. Patients with signs of cholangitis require endoscopic sphincterotomy or duct drainage by stenting to ensure relief of biliary obstruction. Urgent therapeutic ERCP should be performed in patients with acute pancreatitis of suspected or proven gall stone etiology who satisfy the criteria for predicted or actual severe pancreatitis, or when there is cholangitis, jaundice, or a dilated common bile duct.a All patients undergoing early ERCP for severe gall stone pancreatitis require endoscopic sphincterotomy whether or not stones are found in the bile duct.

1998

B

2005

C

2005

B

2005

C

2005 2005 2005

B C C

2005

A

2005 2005

B C

2005

A

2005

B

2005

C

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Table 24.1 Continued Heading

Recommendations for management of acute pancreatitis

Date

Grade

Intervention for necrosis

All patients with persistent symptoms and greater than 30% pancreatic necrosis, and those with smaller areas of necrosis and clinical suspicion of sepsis, should undergo image guided FNA to obtain material for culture 7–14 days after the onset of the pancreatitis. Patients with infected necrosis will require intervention to completely debride all cavities containing necrotic material. The choice of surgical technique for necrosectomy, and subsequent postoperative management depends on individual features and locally available expertise.

2005

B

2005

B

2005

B

CT: computed tomography. Grade indicates a recommendation based on: A, at least one randomised controlled trial as part of evidence of overall good quality and consistency; B, clinical studies without randomisation; C, expert consensus. a Indicates recommendations that should be reconsidered in light of new evidence.

USA indicates that overall mortality from acute pancreatitis is falling and is now less than 2% [13].

the presence of inflammatory changes in and around the pancreas on abdominal CT) confirms the diagnosis. These cutoffs for lipase and amylase are widely accepted [18], but the World Association Guidelines [10] point out that:

Diagnosis Although amylase is widely available and provides acceptable accuracy of diagnosis, where lipase is available it is preferred for the diagnosis of acute pancreatitis. Lipase is more specific and more sensitive than amylase. Amylase levels generally rise within a few hours after the onset of the symptoms and return to normal values within 3–5 days. However, serum lipase concentrations remain high for a longer period of time than do amylase concentrations, which gives slightly greater sensitivity for lipase than for amylase in patients with delayed presentation [14]. The correct diagnosis of acute pancreatitis should be made within 48 hours of admission. Although this may strain support and diagnostic facilities, the risk of missing an alternative life-threatening intra-abdominal catastrophe demands full investigation. Where doubt exists, imaging may be useful for diagnosis: ultrasonography is often unhelpful and pancreatic imaging by contrast enhanced CT provides good evidence for the presence or absence of pancreatitis. Clinical diagnosis is usually straightforward, but overlap may exist with the clinical presentation of perforated viscus or gangrenous bowel. These serious alternative diagnoses may require urgent intervention and in case of doubt they must be excluded, usually by CT. It has been known for many years that contrast-enhanced CT shortly after admission has 87–90% sensitivity and 90–92% specificity to confirm the diagnosis of pancreatitis [15–17]. The presence of two of three diagnostic features (typical abdominal pain, elevated concentrations of serum amylase, or lipase above three times the upper limit of normal, and 398

Pancreatic enzymes are released into the circulation during an acute attack. Levels peak early and decline over 3–4 days. An important concept derives from this: the diagnosis of acute pancreatitis should not rely on arbitrary limits of values three or four times greater than normal, but values should be interpreted in light of the time since the onset of abdominal pain.

Severe acute pancreatitis In 1992, our understanding of acute pancreatitis was greatly improved by a consensus conference that took place in Atlanta [19]. This conference defined the terminology of acute pancreatitis and its complications, and has been the basis for much progress in improved management. However, some problems with terminology and definitions have been noted in the Atlanta document. Currently, the International Association of Pancreatology is attempting to revise these definitions by international consensus, focusing on the diagnosis and imaging of severe acute pancreatitis during two distinct phases: the first week (early phase characterized by Systemic Inflammatory Response Syndrome, SIRS, and organ failure), and a later phase characterized by depressed immune response and local complications, especially pancreatic and peripancreatic necrosis. This consensus, led by Doctors Michael Sarr and Peter Banks, aims to collate the views of numerous pancreatic specialists around the world and to present an evidence base to shape clinical practice for the next decade.

CHAPTER 24

Definition of severe pancreatitis The definitions of severity, as proposed in the Atlanta criteria, should be used. However, organ failure present within the first week, which resolves within 48 hours, should not be considered an indicator of a severe attack (UK Guidelines 2005). The Atlanta criteria [19] for severe pancreatitis remain widely accepted. In this definition, severe acute pancreatitis is characterized by the presence of any systemic or local complication. Other criteria of severe disease accepted by the Atlanta conference include the presence of a high Ranson or APACHE-II score (which are markers for systemic complications). The Atlanta criteria represent the first attempt to define cutoff values for organ failure in acute pancreatitis (Table 24.2). This was a useful step to clarify thinking about systemic complications, but it has become clear that the crossing of a threshold for organ failure is an inadequate definition for severe acute pancreatitis. It is now understood that organ failure in acute pancreatitis is preceded by a phase of activation of the Systemic Inflammatory Response syndrome (SIRS) [20, 21]. The presence of SIRS is clinical evidence of inflammation (Table 24.3), and indicates high risk of progression to complications, but SIRS may resolve without consequence. However, the presence of SIRS in patients on admission to hospital is associated with increased risk of organ failure and death [21]. If SIRS persists for more than 48 hours beyond admis-

Acute pancreatitis

sion to hospital, the mortality rate rises to more than 20% [21], and the patient should be regarded as having severe pancreatitis (Figure 24.1). Since the beginning of this century, it has become clear that the crucial feature of severity in relation to systemic complications during the first week of acute pancreatitis is the duration of organ failure, and that organ failure which resolves during the first week is associated with a very low mortality rate [22]. We showed in a national sample from 78 hospitals [23] that persistence of organ failure for more than 48 hours during the first week of the attack is associated with a 35% risk of fatal outcome. These patients also have a high risk of local complications. Others have confirmed this observation [21, 24, 25], and it is now established that persistent organ failure (>48 hours) during the first week of illness is part of the definition of severe acute pancreatitis. The severity of early organ failure has also been shown by some authors [26, 27] to be associated with high risk of fatal outcome, but the interaction between severity and duration of organ failure has not been clarified. Three organ systems are usually sufficient to assess organ failure: respiratory, cardiovascular and renal. In our study of 290 patients with predicted severe acute pancreatitis, these organs were always involved in patients with persistent organ failure, and only 3 of 71 patients with transient organ failure did not have one of these systems affected [23]. Organ failure is easily defined in accordance with the Marshall scoring system [28] as a score ≥2 for at least one of respiratory, renal or cardiovascular function

Table 24.2 Atlanta criteria for severe acute pancreatitis (16). Criteria for severe acute pancreatitis – presence of one or more of the following: (1) Ranson score during the first 48 hours, 3 or more (2) APACHE II score at any time, 8 or more (3) Presence of one or more organ failures (4) Presence of one or more local complications Organ failures include: (1) Shock: systolic blood pressure,less than 90 mm Hg (2) Pulmonary insufficiency: PaO2 on room air, 60 mm Hg or lower (3) Renal failure: serum creatinine, >2 mg/dL after fluid replacement (4) gastrointestinal bleeding: blood loss (5) coagulopathy: thrombocytopenia hypofibrinogenemia (6) severe hypocalcemia: calcium

more than 500 mL/24 hours fibrin split products in plasma 7.5 mg/dL or lower

Local complications include (1) pancreatic necrosis (2) pancreatic abscess (3) pancreatic pseudocyst

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Table 24.3 Definition of SIRS [17]. Severe pancreatitis is diagnosed if SIRS criteria persist for >48 hours. SIRS is defined by the presence of two or more of the following: >90 beats/min 38°C 12,000 per mm3 >20/min 8 in the first 24 hours of admission, and C-reactive protein levels >150 mg/l, Glasgow score 3 or more, or persisting organ failure after 48 hours in hospital. These recommendations are still relevant, but a new simple scoring system has been reported (see below). The management of acute pancreatitis is supportive; mild attacks resolve without specific measures other than ensuring adequate analgesia, oxygenation and circulating volume. For many years it has been believed that early identification of patients with severe disease would be advantageous, leading to early institution of aggressive support for failing systems and early transfer to an appropriate critical care facility. This approach led to many reports of various tests and scoring systems designed to predict severe disease. As noted above, we now identify such patients by the presence of specific clinical markers of severity, especially the presence of persistent SIRS, or persistent organ failure. However, the observation of high risk predictive scores (e.g. Ranson, Glasgow, APACHE II) or high levels of confirmed markers or risk factors of severe disease (C-reactive protein >150 mg/l [10, 30], BMI > 30 [12, 31]) may help focus clinical attention on potentially ill patients.

Clinical markers of severity and predictive scores Table 24.5 summarizes features that predict a severe attack of acute pancreatitis and that are available shortly after admission to hospital. Age is an independent risk factor, and age >70 years is associated with 17% mortality risk [32]. Obesity is a risk factor for complications and death

CHAPTER 24

Acute pancreatitis

Table 24.4 Criteria from the Marshall Scoring System [25] which define organ failure and measure its severity. Any value scoring 2 or more indicates an organ failure; the total score is a marker of the severity of organ failure. Organ system

Score 0

1

2

3

4

Respiratory (PO2/FIO2)

>400

301–400

201–300

101–200

≤101

Renal (serum creatinine, μmol/l) (serum creatinine, mg/dl)

≤134 439 >4.9

Cardiovascular (systolic blood pressure, mmHg)

>90

150 mg/l

48 h after admission

Clinical impression of severity Glasgow score 3 or more C reactive protein > 150 mg/l Persisting organ failure for 48 h Multiple or progressive organ failure

[31]. The mechanism of this increased risk is unclear, but it seems that obesity is associated with an increased inflammatory response [33, 34]. Other proposed mechanisms include greater risk of respiratory complications and the presence of poorly perfused fat in and around the pancreas,

increasing the risk of pancreatic and peripancreatic necrosis. Objective parameters should be used to support the clinical examination in the first 24 hours of admission, as clinical examination is specific, but it is not sensitive when used alone [12]. The APACHE II score is widely used as a predictor of severity, and for monitoring progress early in the illness. The Atlanta criteria selected a cutoff score of 8 or more to define severe disease. This cutoff in the first 24 hours identifies almost all patients who will develop a complication. In a meta-analysis of three well-documented series comprising 627 cases (20% severe), Larvin [35] found no deaths in patients with initial APACHE II score below 10. A score of 10 or 11 was very unlikely to lead to death, but scores of 12 or more had a mortality rate over 20%, increasing with higher initial scores (Figure 24.2). Recently, the Early Warning Score (EWS), based on routine nursing observations, and widely used to monitor the clinical condition of ill patients, has been proposed as a simple means of identifying high risk patients [36, 37]. The EWS also responds to the dynamic nature of the illness: deterioration of scores is associated with a worse outcome [36]. The ability of this system to predict severe pancreatitis has been compared with APACHE II scores, modified organ dysfunction scores, Glasgow scores, CT severity index and Ranson criteria for 181 admissions with acute 401

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suggests that this study used “real world” data including all cases of mild disease in the contributing hospitals. The BISAP score promises to simplify the assessment of acute pancreatitis, particularly by the rapid identification of the large majority of patients who are at low risk of complications and death.

100

Risk (%)

80

60

Laboratory markers

40

20

0

0 2 4 6 8 10 12 14 16 18 20 22 24+

Complications Death

APACHE-II score

Figure 24.2 Percentage risk of death or complications associated with different initial APACHE-II scores (reproduced from Larvin [35]).

pancreatitis. Scores were calculated daily for the first three days. The APACHE II and EWS performed best in receiver operating curve analysis, with similar areas under the curve (APACHE II 0.876, 0.892 and 0.911; EWS 0.827, 0.910 and 0.934, on days 1, 2 and 3 respectively). These findings suggest that the simple and easily assessed EWS could be used at the bedside to monitor progress and identify severe acute pancreatitis soon after admission to the hospital. In particular, EWS reflects the dynamic nature of the illness in the same way as SIRS and organ failure. This simple clinical observation should permit reliable identification of patients at risk of complicated or fatal course in any hospital setting. Importantly, improvement in the EWS (or other scores discussed above) is reassuring that the patient is likely to recover without complications. A large population based survey [13] has developed and validated a predictive system for severe acute pancreatitis based on easily obtained features present at the time of admission to hospital. The authors reviewed records of 17,992 patients for features associated with severe disease, that were present within 24 hours of admission. They identified five independent predictors: blood urea nitrogen >25 mg/dL (>8.93 mmol/L), impaired mental state, SIRS, age > 60 years and pleural effusion on chest X-ray (acronym BISAP score). Allocation of one point for each feature gives a simple BISAP score, which identifies low risk patients with low score, and high risk groups with a >10% risk of death for scores of 4, and >20% risk of death for scores of 5. The strength of this report is that the predictive ability of the scores was confirmed in a new sample of patient records, comprising over 18,000 patients treated in the years 2004–2005. The development and validation cohorts had mortality rates of 1.9% and 1.28% respectively, which 402

Plasma C-reactive protein is accurate, but delayed in its response, not peaking until 72–96 hours into the illness. A value >150 mg/l identifies patients at risk of pancreatic necrosis and potentially fatal outcome [12]. There is some evidence that serum or urine concentrations of the trypsinogen activation peptide (TAP) [38–41] and urine anionic trypsinogen 2 [42–44] might be useful to predict severity, although to date only the trypsinogen 2 test is available as a rapid bedside test. Another promising early marker of severity is procalcitonin (PCT). Despite some contrary views (based on relatively small numbers) [45, 46], there is considerable evidence that PCT is a useful early marker of severe disease, and especially of pancreatic necrosis, or infected necrosis. A meta-analysis of the early evidence [47] reviewed nine reports. There was considerable variation of methodological quality. Considering only high quality reports, the sensitivity and specificity of PCT in the first 24 hours in hospital to predict severe disease were 82% and 89%, with an area under the curve value of 94%, indicating very good discrimination. The meta-analysis indicated that PCT may be especially useful for the identification of patients at risk of infected necrosis. Two further studies support these findings. Rau has long advocated using this marker, and her latest publication [48] provides more evidence from a study of 104 patients in five European centers enrolled within 96 hours of symptom onset. Initial PCT concentrations were significantly elevated in patients with pancreatic infections and associated multi-organ dysfunction syndrome (MODS), all of whom required surgery (n = 10), and in non-survivors (n = 8). PCT levels were only moderately increased in seven patients with pancreatic infections in the absence of MODS, all of whom were managed non-operatively without mortality. A PCT value of 3.5 ng/ml or higher on two consecutive days had a sensitivity and specificity of 93% and 88% for the assessment of infected necrosis with MODS or nonsurvival. This prediction was possible on the third and fourth day after onset of symptoms with a sensitivity and specificity of 79% and 93% for PCT 3.8 ng/ml or higher. Another study of 40 patients (11 severe) supports these findings [49]. There is now strong evidence that early estimation of procalcitonin can identify patients at risk of infected necrosis or death, and the test may be repeated to improve the detection of these most severe cases.

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Role of CT in acute pancreatitis During the first week As noted above, at the time of admission to hospital CT may be required if the diagnosis is in doubt: this may arise with delayed presentation, for example when the plasma enzyme levels have fallen below the diagnostic threshold. Sometimes CT may be helpful to exclude other diagnoses, such as perforation or gangrene of bowel. There is no evidence that early CT is helpful in the management of confirmed acute pancreatitis. Indeed, the UK guidelines [12] recommend that the first scan be delayed until 6–10 days after onset of symptoms. Arguments against early CT in all cases of pancreatitis are that early CT with intravenous contrast has the potential risk of worsening the renal impairment, and that an early CT may underestimate the full extent of pancreatic necrosis, which may evolve for at least four days after the onset. Most importantly, CT is unlikely to change management decisions in the first week. At this stage, treatment is supportive, and surgical or other intervention is avoided, and CT does not affect clinical decision-making. Early CT may be used to assess the severity of the illness if this is required, for example to stratify patients in treatment trials. Balthazar and colleagues [50] proposed the CT severity index (Table 24.6) based on the grade of inflammation and the extent of pancreatic necrosis determined by enhancement. The sum of these two scores is used to calculate the severity index.

After the first week Patients with persisting organ failure, signs of sepsis, or deterioration in clinical status 6–10 days after admission will require CT. CT is usually performed after 6–10 days in patients with persistent SIRS or organ failure to assess local complications such as fluid collections and necrosis [12, 50]. There is some evidence that MRI identifies necrosis and fluid collections better than does CT [51], although the practical difficulty of ensuring MR compatible equipment attached to a patient with organ failure may be a problem in some settings. The Atlanta criteria are not clear on the distinction between fluid collections, pseudocyst and necrosis. The current international consensus revision of the Atlanta criteria mentioned above is likely to advocate the use of contrast enhanced CT for the characterisation of morphological changes in and around the pancreas, after the first week of the illness, and will probably recognise a number of local complications, namely pancreatic and peripancreatic necrosis, acute peripancreatic collections within four weeks from onset of symptoms, and pseudocyst and walled off

Acute pancreatitis

Table 24.6 Computed tomography (CT) grading of severity. Computed tomography (CT) grading of severity CT grade (A) Normal pancreas (B) Oedematous pancreatitis (C) B plus mild extrapancreatic changes (D) Severe extrapancreatic changes including one fluid collection (E) Multiple or extensive extrapancreatic collections Pancreatic necrosis (extent) None Up to one third Between one third and one half More than half

Score

0 1 2 3 4

0 2 4 6

CT severity index = CT grade + necrosis score Observed rates of complications and death related to CTSI score

Complications

0–3 4–6 7–10

8% 35% 92% Deaths 3% 6% 17%

0–3 4–6 7–10

Modified from the World Association guidelines [10] and based on Balthazar and colleagues [47].

pancreatic necrosis more than four weeks from onset. The extent of pancreatic necrosis on CT is useful information, because this is related directly to the risk of local and systemic complications [52, 53]. CT is unreliable for the discrimination of pseudocyst from necrosis. The Santorini consensus conference [30] recommended that either ultrasound or magnetic resonance imaging (MRI) should be used to differentiate between fluid and necrotic tissue. In practice, it is wise to consider all localized collections following necrotising pancreatitis to be pancreatic or peripancreatic necrosis until proved otherwise.

Organization of care All cases of severe acute pancreatitis should be managed in an HDU or ITU setting with full monitoring and systems support. Every hospital that receives acute admissions should have a single nominated clinical team to manage all patients with acute pancreatitis. Management in, or referral 403

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to, a specialist unit is necessary for patients with >3 0% necrosis or with other complications. It seems self-evident that the care of these potentially difficult and seriously ill patients should be concentrated in the hands of interested clinicians with appropriate expertise. C5

Initial management and resuscitation Early fluid resuscitation and oxygen supplementation are simple measures that seem likely to be helpful in early resolution of organ failure [54]. Whether these interventions significantly reduce the mortality rate is not known, but it seems sensible to provide simple circulatory and respiratory support designed to achieve rapid resolution of organ failure. C5 This approach may break the cycle of hypotension and hypoxaemia that can sustain and provoke more organ system failures. The fluid replacement with a mix of crystalloid and colloid solutions should aim to maintain good urine output (0.5 ml/kg) and can be monitored by central venous pressure reading in selected patients. Oxygenation ideally should maintain the arterial saturation above 95%. Oxygen saturations lower than this are associated with significant hypoxaemia [55].

Prophylactic antibiotics The evidence for antibiotic prophylaxis against infection of pancreatic necrosis is conflicting and difficult to interpret. At present there is no consensus on this issue. If antibiotic prophylaxis is used, it should be given for a maximum of 14 days. Further studies are needed. It is pleasing to note that we now have evidence to resolve this issue, outlined below. Since infected pancreatic necrosis is associated with high mortality rates (40%) and it is one of the leading causes of death in acute pancreatitis, many trials have been done to establish the role of prophylactic antibiotics in reducing the mortality rate and other infective and non-infective complications. The trials discussed up to 2005 had shown benefit for prophylaxis, but there were concerns that the improvements in outcome were seen for different endpoints in different studies. The guidelines quoted above should be re-evaluated in light of the publication of more high quality evidence. An interesting analysis [56] has shown an inverse relationship between the quality of studies and the observed effect, i.e. as study quality improves, the differences in outcome diminish. In discussing the available evidence, the UK guidelines noted: A German trial [57] which compared ciprofloxacin-metronidazole and placebo is the only double blind placebo 404

controlled trial published to date. The results do not support the use of prophylactic antibiotics. This study was stopped after interim analysis of 76 patients with necrosis showed no differences in the primary outcomes of infected necrosis, systemic complications, and mortality rates.

A Cochrane Review [58] evaluated all the randomized trials with placebo controls, published up to July 2006. The conclusion of this review was that: Antibiotic prophylaxis appeared to be associated with significantly decreased mortality but not infected pancreatic necrosis. Beta lactam antibiotics were associated with significantly decreased mortality and infected pancreatic necrosis, but quinolone plus imidazole regimens were not.

The review includes a trial from Finland [59] which compared cefuroxime with placebo, and demonstrated a difference in mortality. The validity of these data has been questioned, because only patients with alcohol related pancreatitis were included, and because the excess deaths in the placebo group all occurred in the first week of the illness, before any effect on infection of necrosis could be expected. The Cochrane Review also noted that there were variations in methodological quality and treatment regimens in the trials reviewed. More reliable data were awaited. A subsequent meta-analysis of prophylactic antibiotic use in acute necrotizing pancreatitis [60] assessed whether intravenous prophylactic antibiotic use reduces infected necrosis and death in acute necrotizing pancreatitis. Six randomized controlled trials were analyzed, including the five analyzed for preparation of the UK Guidelines, and an additional trial published only in abstract form [61]. Primary outcome measures were infected necrosis and death. Secondary outcome measures were non-pancreatic infections, surgical intervention and length of hospital stay. Prophylactic antibiotic use was not associated with a statistically significant reduction in infected necrosis (RR = 0.77; 95% CI: 0.54–1.12; p = 0.173), mortality (RR = 0.78; 95 CI: 0.44–1.39; p = 0.404), non-pancreatic infections (RR = 0.71; 95% CI: 0.32–1.58; p = 0.402) or surgical intervention (RR = 0.78; 95% CI: 0.55–1.11; p = 0.167). A double-blind randomized trial of meropenem versus placebo, published in May 2007, is probably the definitive study [62]. This trial was performed in 32 centers within North America and Europe and included one hundred patients with clinically severe, confirmed necrotizing pancreatitis who were randomized within five days of the onset of symptoms to receive Meropenem (1 g intravenously every eight hours) or placebo for 7 to 21 days. The trial was well designed, with entry criteria (>30% necrosis)

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that selected patients at greatest risk of infection. The sample size calculation indicated that approximately 120 subjects per group (240 subjects in all) would be required to detect a reduction of pancreatic infection rates by meropenem compared with placebo from 40% to 20% with 90% power and a 5% two-sided significance level. The trial included appropriate secondary endpoints (need for surgery, death). Recruitment was slow, because patients with >30% necrosis are relatively rare. (It is widely agreed that antibiotics should not be given to patients without necrosis, as they are very unlikely to develop pancreatic infections.) The trial was closed early, when it was clear that pancreatic infection rates overall (15%) were lower than expected. Pancreatic or peripancreatic infections developed in 18% (9 of 50) of patients in the meropenem group compared with 12% (6 of 50) in the placebo group. Despite the early closure, this RCT of antibiotic prophylaxis recruited more patients with pancreatic necrosis than any previous trial and it seems improbable that recruitment of a further 140 patients to achieve the initial target would have shown a different outcome. The results of this trial showed no statistically significant advantage for early use of meropenem for prevention of pancreatic or peripancreatic infection, requirement for surgical intervention, or death (Table 24.7). Further evidence of lack of effect is presented in a singlecentre, double-blind RCT of ciprofloxacin in patients with confirmed necrosis [63]. Although this trial included only 41 patients, it produced no evidence of benefit, consistent with the result of the larger trials discussed above. The weight of evidence has shifted since preparation of the UK Guidelines Revision to favor the position that prophylactic antibiotics, prescribed early in the illness to prevent subsequent infection of necrotic tissue, confer no benefit and should not be part of the treatment plan. A1c There is no evidence of benefit in several recent welldesigned RCTs, and the unnecessary use of antibiotics has

Table 24.7 Outcomes in the trial [59] of Meropenem versus placebo in the prevention of infection in severe acute pancreatitis. No differences were observed. Pancreatic or peripancreatic infections

Requirement of surgical intervention

Mortality

Meropenem group

18% (9 of 50)

26% (13 of 50)

20% (10 of 50)

Placebo group

12% (6 of 50)

20% (10 of 50)

18% (9 of 50)

P value

0.401

0.476

0.799

Acute pancreatitis

well-known adverse consequences, notably related to hospital acquired infection. However, it is not easy to define the need for antibiotics on purely clinical grounds. Patients with severe acute pancreatitis are likely to have signs of SIRS; this should not be taken as evidence of infection. In the early stages of the illness antibiotics should be used only when there is proof of infection from a positive culture.

Nutrition in acute pancreatitis patients The evidence is not conclusive to support the use of enteral nutrition in all patients with severe acute pancreatitis. However, if nutritional support is required the enteral route should be used if tolerated. A1d The nasogastric route for feeding can be used as it appears to be effective in 80% of cases. B4 We have found no additional evidence that requires a change to this advice. In mild, acute pancreatitis there is no benefit from passage of a nasogastric tube [64, 65]. These patients can be allowed to drink small volumes of fluids as tolerated from the outset. A full oral diet can be restarted in most patients after a few days, when the pain has settled [66]. In severe disease, enteral feeding may be beneficial for two reasons. First, it may help to reduce the risks of complications when started early in the disease; second, in established, severe pancreatitis nutritional supplements will be required and the enteral route is preferred. Most studies have assumed that the enteral feeding solution should be delivered beyond the duodenum, by means of a nasojejunal tube. However, this placement is often unnecessary [67, 68]. A1d About 80% of patients with severe disease tolerate early enteral feeding by nasogastric tube, and this route is simpler and cheaper to establish. Nasojejunal feeding should be reserved for those patients in whom nasogastric feeding is unsuccessful because of failure of gastric emptying.

Prevention of complications Enteral feeding is believed to be superior to parenteral nutrition in most critical care conditions. Reasons advanced to support this belief include the suggestion that enteral nutrition may maintain splanchnic protein synthesis and help to maintain normal gut mucosal function, including the mucosal barrier. This helps to reduce bacterial translocation, which may be the main driver for organ failure and sepsis. C5 Although there were fears that enteral feeding might exacerbate acute pancreatitis because of the stimulatory effect of luminal nutrients on pancreatic enzyme synthesis, this adverse effect has not been found in practice, perhaps because pancreatic enzyme synthesis is inhibited immediately after onset of pancreatitis [69]. Data from 405

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patients with acute pancreatitis show lower rate of secretions compared to healthy individuals, and this rate is inversely related to the severity of the pancreatitis [70]. In any attempt to prevent complications of pancreatitis, it is logical that enteral feeding should be started early in the course of the disease. Few RCTs have been performed to specifically address this point. In the first small trial 38 patients with severe pancreatitis were randomized to receive either enteral or parenteral nutrition [71]. Significantly fewer infected complications occurred in the enteral feeding group. Windsor et al. [72] and Gupta et al. [73] investigated markers of the inflammatory response in patients offered enteral or parenteral nutrition. Both studies showed less activation of inflammation with enteral feeding. The superiority of early enteral compared to parenteral nutrition has been confirmed in a meta-analysis [74] of eleven trials. A1c This meta-analysis showed benefit in terms of lower infection rates for enteral feeding started within 48 hours of admission, but no difference between the two routes if feeding was started later than this. It is possible that the results of these trials are due to stimulation of inflammation and increased septic complications in patients given parenteral feeding, rather than to a specific benefit of enteral feeding. In a small RCT which compared early enteral nutrition with no nutritional support in 27 patients, Powell et al. [75] found no difference in clinical outcomes or in immune markers, but this trial probably lacked adequate power.

Nutritional support Concerning the requirement for nutritional support in patients with severe disease, there is conclusive evidence that the outcome is better and the cost is lower if the enteral rather than the parenteral route is used. Several RCTs and two meta-analyses have demonstrated improved infection rates and glucose control with enteral compared to parenteral nutrition [71, 76–79]. A1c Enteral nutrition is the cheaper option, and has become the new “gold standard” for nutritional support in acute pancreatitis.

“Immune-enhanced nutrition” The type of feeding solution used may influence outcome, by providing a beneficial stimulus to the immune system, and perhaps by specific effects that enhance gut mucosal function. So-called “immune-enhanced nutrition” has been used in a variety of situations, but has not been shown to be superior to routine feeding solutions in acute pancreatitis. Although Hegazi [80] favored the use of immuneenhanced solutions, largely on the basis of experimental data, McClave performed a systematic review [77] that included assessment of the value of specific supplements added to EN, such as arginine, glutamine, omega-3 poly406

unsaturated fatty acids and probiotics. The analysis indicated that these agents may be associated with a positive impact on patient outcome in acute pancreatitis, compared with EN alone, but the studies are too few to support strong treatment recommendations. The case of probiotic bacteria is of interest, because several small studies have shown benefit from enteral nutrition supplemented with various Lactobacillus species, often with added dietary fiber [81–83]. However, when tested in a large multicentre study, the probiotic group suffered an excess of deaths, largely due to bowel perforation, usually at the cecum [84]. This well-designed, doubleblind trial included 298 patients with severe pancreatitis (APACHE II 8 or more) randomly allocated within 72 hours of onset to receive either a multispecies probiotic preparation (n = 153) or placebo (n = 145), administered enterally twice daily for 28 days. The groups were well matched. There was no difference in infective complications (probiotic 46 (30%), placebo 41 (28%)), but 24 (16%) of the probiotic group died, compared with nine (6%) of the controls. There were nine cases of bowel ischemia in the trial, of which eight were fatal, and all occurred in the probiotic group. This well designed RCT did not confirm the treatment benefit suggested by earlier smaller studies, in patients with severe acute pancreatitis. A1a

Management of gallstones causing pancreatitis All patients with biliary pancreatitis should undergo definitive management of gallstones during the same hospital admission, unless a clear plan has been made for definitive treatment within the next two weeks. It is essential to deal promptly with gallstones, to prevent a further attack of pancreatitis. A recurrence of pancreatitis may occur at any time, and reports from health care systems in which early cholecystectomy is not universally available confirm the risk of fatal recurrence while awaiting treatment. B4 Definitive treatment is usually by laparoscopic cholecystectomy with intra-operative cholangiography, carried out as soon as symptoms of pain and anorexia have resolved. Some experts prefer a pre-operative cholangiogram obtained by MRCP. Cholecystectomy is usually achieved within 4–7 days of onset of symptoms. At this time, cholangiography will demonstrate bile duct stones in fewer than 10% of these patients (Figure 24.3) [85]. Bile duct stones may be dealt with by laparoscopic bile duct exploration, or by ERCP and sphincterotomy. Approximately 90% of patients will have a normal bile duct at this time. They need no intervention on the bile duct and avoid the risks associated with endoscopic sphincterotomy. The endoscopic approach carries a well-recognised risk of 5–10% of exacerbation of the pancreatitis and of sphincterotomy

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Percentage of CBD stones

35 30 25 20 15 10 5 0

0–1

2–3

4–5 Days

6–7

>7

Figure 24.3 Prevalence of gallstones within the common bile duct at the time of cholangiography (days after onset of symptoms) (reproduced from De Waele et al. [85]).

bleeding. However, pancreatic duct stenting may reduce the risk of pancreatitis. Endoscopic sphincteroromy may be appropriate in patients in whom there is co-morbidity, which increases the risks of general anaesthesia for cholecystectomy. C5 In particular, elderly patients without preexisting symptoms of cholelithiasis may be appropriate for endoscopic sphincterotomy, with conservative management of the gall bladder stones unless further symptoms arise. C5 In acute necrotizing pancreatitis, when surgery is indicated, cholecystectomy should always be done at the time of necrosectomy, if that can be achieved safely. C5 Patients with severe disease who do not undergo surgery should also have the definitive management of their gallstones planned and carried out before discharge from hospital, although there may be circumstances in which a short delay is acceptable, for example to allow combined management of the stones and a pseudocyst. In any case, management of the gallstones must be integrated into the care plan for each individual.

The role of early ERCP in severe biliary pancreatitis Patients with signs of cholangitis require endoscopic sphincterotomy or duct drainage by stenting to ensure relief of biliary obstruction. Urgent therapeutic ERCP should be performed in patients with acute pancreatitis of suspected or proven gallstone etiology who satisfy the criteria for predicted or actual severe pancreatitis, or when there is cholangitis, jaundice, or a dilated common bile duct. All patients undergoing early ERCP for severe gallstone pancreatitis require endoscopic sphincterotomy whether or not stones are found in the bile duct. The indications for early ERCP now seem clearer. Gallstone related pancreatitis is diagnosed when pancreatitis occurs and there are gallstones in the gall bladder, and

Acute pancreatitis

in the absence of any other known reason. The mechanism is related to the passage of a gallstone through the ampulla, with temporary obstruction of flow of pancreatic juice, and possible reflux of bile into the pancreatic duct. ERCP and endoscopic sphincterotomy (ES) prevents further damage by releasing stones form the bile duct, and by preventing further obstruction of, or reflux into, the pancreatic duct. Thus, early ES has been proposed as a preventive measure, to reduce complications. Clearly, there can be no rationale for using early ES in this way in mild disease, where the risk if complications is low, or in non-biliary pancreatitis, where there are no stones to pass through the ampulla. There is general agreement in published guidelines and in one large RCT that in pancreatitis associated with cholangitis, early ES can bring about a marked improvement in the patient’s condition and should be performed as soon as practicable, ideally within 24 hours [8, 10–12, 86]. If ERC is attempted in patients with pancreatitis, ES should always be performed to minimize the risk of procedure induced cholangitis. This has been recommended on the basis of an RCT published only in abstract form [87], expert opinion and critical analysis of RCT data. A further preliminary report from Katowice [88] has described a randomized comparison of ERCP with or without ES, in patients with acute biliary pancreatitis who had ERCP within 12 hours of admission, but who had no evidence of cholangitis, biliary obstruction or bile duct stones. The complication rate was higher than expected in patients who did not have a sphincterotomy, especially in patients with mild pancreatitis. This result supports the view that if ERCP is undertaken early in acute pancreatitis, ES should be performed. A1d The first two reported trials of early ERCP +/− ES found a significant reduction in the complication rate in severe biliary pancreatitis [89, 90], but subsequently a debate arose whether early ERCP is appropriate, driven by the results of a large RCT performed in Germany [86], which did not show benefit in a group of patients with mild or severe pancreatitis in whom cholangitis had been excluded. This study included patients with mild disease and sphincterotomy was not performed routinely after cholangiography, making it difficult to interpret the results. A Cochrane Review [91] of these three trials pooled data from 172 patients with severe biliary pancreatitis. The reduction in mortality was not statistically significant, but complications were much less likely after early ERCP (OR 0.27; 95% CI: 0.14–0.53) [91]. Two further studies have helped to clarify the indications for early ERCP. Acosta [92] studied 61 patients with gallstone pancreatitis who had evidence of biliary obstruction but no signs of cholangitis, in whom the obstruction persisted for 24 hours. Patients were randomized to early ERCP or to ERCP in the recovery phase; ES was performed only if there was evidence of obstruction. There were no 407

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deaths in this series, but immediate complications (which are likely to be systemic complications) were reduced from 26% to 3% in the early ERCP group. A1d There is no comment on the incidence of organ failure in this study, and this study is too small to enable firm conclusions to be drawn. However, the focus on patients with persistence of signs of obstruction is appropriate: there seems little point in early ES if a patient has passed a stone and if signs of systemic disturbance are resolving. C5 Oria [93] randomized 103 patients with a dilated bile duct or raised bilirubin, but without evidence of cholangitis, to undergo ES within 72 hours of onset of symptoms, or to standard management without endoscopy. They found no difference in the incidence of organ failure or local complications in the two groups. A crucial unanswered question in considering these trials is the definition of cholangitis. If the presence of SIRS together with biliary obstruction is taken to indicate likely cholangitis, then all patients with severe disease by currently understood definitions are likely to have been excluded. A recent meta-analysis [94] concluded that there is no benefit from early sphincterotomy in severe gallstone pancreatitis, in the absence of signs of cholangitis. There was no difference in outcome in the treated and control patients in the three trials selected for analysis [86, 90, 93]. This analysis must be questioned, as the inclusion criteria used are puzzling. Two trials were excluded from analysis. The study of Fan et al. [89] was excluded on the grounds that all patients with pancreatitis were included, despite the fact that the outcomes for patients with severe pancreatitis and with gallstones are clearly presented in the report. There was a clear reduction in complications in these patients. This trial had been included in the Cochrane Review cited above [88]. The second trial [92] excluded by Petrov et al. examined the interesting question of the value of ES in patients who had failed to improve in the first 24 hours of admission. In other words, the investigators did not intervene in patients who did not meet current criteria for severity. Again, this trial showed benefit for early ES in appropriately selected patients. Finally, Petrov et al. did include the German study [86] which has been discussed above. This trial is flawed by the inclusion of patients with mild disease, and by the fact that sphincterotomy was not performed routinely. This trial did not support the use of early ES. Thus, the meta-analysis of Petrov et al. excluded two trials supportive of early ES and included a flawed trial that failed to support this approach, and the conclusions cannot be accepted. A new study is consistent with these observations. Patients enrolled in the PROPATRIA trial [84] were randomly allocated to receive probiotics or not in association with enteral feeding. As noted above, the trial intervention did not produce any benefit. The trial data have been secondarily analyzed to throw light on the role of ERCP/ES, 408

which was used at the discretion of the responsible clinician. All patients had predicted severe pancreatitis and half had cholestasis (bilirubin > 40 micromol/l and or CBD > 8 mm). Differences in baseline features were taken into account in the recent preliminary report [95]. Of 78 patients with cholestasis, 56 had early ERCP/ES, with significant reduction in overall complications and the frequency of necrosis affecting more than 30% of the pancreas. Early ERCP/ES (n = 29) had no effect on complication rates in the 75 patients without evidence of cholestasis. A1d Early ( or = 6). Pancreatology 2003; 3(5): 406–413. Petrov MS, Pylypchuk RD, Uchugina AF. A systematic review on the timing of artificial nutrition in acute pancreatitis. Br J Nutr 2008; 101: 787–793. Powell JJ, Murchison JT, Fearon KC et al. Randomized controlled trial of the effect of early enteral nutrition on markers of the inflammatory response in predicted severe acute pancreatitis. Br J Surg 2000; 87(10): 1375–1381. Abou-Assi S, Craig K, O’Keefe SJ. Hypocaloric jejunal feeding is better than total parenteral nutrition in acute pancreatitis: Results of a randomized comparative study. Am J Gastroenterol 2002; 97(9): 2255–2262. McClave SA, Chang WK, Dhaliwal R et al. Nutrition support in acute pancreatitis: A systematic review of the literature. JPEN J Parenter Enteral Nutr 2006; 30(2): 143–156. Petrov MS, van Santvoort HC, Besselink MG et al. Enteral nutrition and the risk of mortality and infectious complications in patients with severe acute pancreatitis: A meta-analysis of randomized trials. Arch Surg 2008; 143(11): 1111–1117. Marik PE, Zaloga GP. Meta-analysis of parenteral nutrition versus enteral nutrition in patients with acute pancreatitis. BMJ 2004; 328(7453): 1407. Hegazi RA, O’Keefe SJ. Nutritional immunomodulation of acute pancreatitis. Curr Gastroenterol Rep 2007; 9(2): 99–106. Karakan T, Ergun M, Dogan I et al. Comparison of early enteral nutrition in severe acute pancreatitis with prebiotic fiber supplementation versus standard enteral solution: A prospective randomized double-blind study. World J Gastroenterol 2007; 13(19): 2733–2737. Olah A, Belagyi T, Issekutz A et al. Randomized clinical trial of specific lactobacillus and fibre supplement to early enteral nutrition in patients with acute pancreatitis. Br J Surg 2002; 89(9): 1103–1107. Qin HL, Zheng JJ, Tong DN et al. Effect of Lactobacillus plantarum enteral feeding on the gut permeability and septic complications in the patients with acute pancreatitis. Eur J Clin Nutr 2008; 62(7): 923–930. Besselink MG, van Santvoort HC, Buskens E et al. Probiotic prophylaxis in predicted severe acute pancreatitis: A randomized , double-blind, placebo-controlled trial. Lancet 2008; 371(9613): 651–659. De Waele E, Op de Beeck B, De Waele B et al. Magnetic resonance cholangiopancreatography in the preoperative assessment of patients with biliary pancreatitis. Pancreatology 2007; 7(4): 347–351. Folsch UR, Nitsche R, Ludtke R et al. Early ERCP and papillotomy compared with conservative treatment for acute biliary pancreatitis. The German Study Group on Acute Biliary Pancreatitis. N Engl J Med 1997; 336(4): 237–242. Nowak A, Nowakowska-Dulawa E, Marek TA. Final results of the prospective, randomized, controlled study on endoscopic sphincterotomy versus conventional management in acute biliary pancreatitis. Gastroenterology 1995; 108: A380. Nowakowska-Dulawa E, Nowak A, Marek TA et al. Urgent endoscopic sphincterotomy in patients with acute biliary pancreatitis without common bile duct stones. Pancreatology 2008; 8: 348.

89 Fan ST, Lai EC, Mok FP et al. Early treatment of acute biliary pancreatitis by endoscopic papillotomy. N Engl J Med 1993; 328(4): 228–232. 90 Neoptolemos JP, Carr-Locke DL, London NJ et al. Controlled trial of urgent endoscopic retrograde cholangiopancreatography and endoscopic sphincterotomy versus conservative treatment for acute pancreatitis due to gallstones. Lancet 1988; 2(8618): 979–983. 91 Ayub K, Slavin J, Imada R. Endoscopic retrograde cholangiopancreatography in gallstone-associated acute pancreatitis. Cochrane Database of Systematic Reviews 2004, Issue 3. Art. No.: CD003630. DOI: 10.1002/14651858.CD003630.pub2. 92 Acosta JM, Katkhouda N, Debian KA et al. Early ductal decompression versus conservative management for gallstone pancreatitis with ampullary obstruction: A prospective randomized clinical trial. Ann Surg 2006; 243(1): 33–40. 93 Oria A, Cimmino D, Ocampo C et al. Early endoscopic intervention versus early conservative management in patients with acute gallstone pancreatitis and biliopancreatic obstruction: A randomized clinical trial. Ann Surg 2007; 245(1): 10–17. 94 Petrov MS, van Santvoort HC, Besselink MG et al. Early endoscopic retrograde cholangiopancreatography versus conservative management in acute biliary pancreatitis without cholangitis: A meta-analysis of randomized trials. Ann Surg 2008; 247(2): 250–257. 95 van Santvoort HC, Besselink MG, de Vries AC et al. Early ERCP is only beneficial in predicted severe acute biliary pancreatitis in presence of cholestasis. Pancreatology 2008; 8: 337. 96 Rau B, Steinbach G, Baumgart K et al. The clinical value of procalcitonin in the prediction of infected necrois in acute pancreatitis. Intensive Care Med 2000; 26 (Suppl 2): S159–S164. 97 Pezzilli R, Uomo G, Zerbi A et al. Diagnosis and treatment of acute pancreatitis: The position statement of the Italian Association for the study of the pancreas. Dig Liver Dis 2008; 40(10): 803–808. 98 King NK, Siriwardena AK. European survey of surgical strategies for the management of severe acute pancreatitis. Am J Gastroenterol 2004; 99(4): 719–728. 99 Teerenhovi O, Nordback I, Eskola J. High volume lesser sac lavage in acute necrotizing pancreatitis. Br J Surg 1989; 76(4): 370–373. 100 Berzin TM, Mortele KJ, Banks PA. The management of suspected pancreatic sepsis. Gastroenterol Clin North Am 2006; 35(2): 393–407. 101 Owera AM, Ammori BJ. Laparoscopic endogastric and transgastric cystgastrostomy and pancreatic necrosectomy. Hepatogastroenterology 2008; 55(81): 262–265. 102 Parekh D. Laparoscopic-assisted pancreatic necrosectomy: A new surgical option for treatment of severe necrotizing pancreatitis. Arch Surg 2006; 141(9): 895–902. 103 Adamson GD, Cuschieri A. Multimedia article. Laparoscopic infracolic necrosectomy for infected pancreatic necrosis. Surg Endosc 2003; 17(10): 1675. 104 Hamad GG, Broderick TJ. Laparoscopic pancreatic necrosectomy. J Laparoendosc Adv Surg Tech A 2000; 10(2): 115– 118. 105 Carter CR, McKay CJ, Imrie CW. Percutaneous necrosectomy and sinus tract endoscopy in the management of infected pan-

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107 108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

creatic necrosis: An initial experience. Ann Surg 2000; 232(2): 175–180. Zuber-Jerger I, Zorger N, Kullmann F. Minimal invasive necrosectomy in severe pancreatitis. Clin Gastroenterol Hepatol 2007; 5(11): e45. Windsor JA. Minimally invasive pancreatic necrosectomy. Br J Surg 2007; 94(2): 132–133. Shelat VG, Diddapur RK. Minimally invasive retroperitoneal pancreatic necrosectomy in necrotising pancreatitis. Singapore Med J 2007; 48(8): e220–e223. Risse O, Auguste T, Delannoy P et al. Percutaneous videoassisted necrosectomy for infected pancreatic necrosis. Gastroenterol Clin Biol 2004; 28(10 Pt 1): 868–871. Loveday BP, Mittal A, Phillips A et al. Minimally invasive management of pancreatic abscess, pseudocyst, and necrosis: A systematic review of current guidelines. World J Surg 2008; 32(11): 2383–2394. Horvath KD, Kao LS, Wherry KL et al. A technique for laparoscopic-assisted percutaneous drainage of infected pancreatic necrosis and pancreatic abscess. Surg Endosc 2001; 15(10): 1221–1225. Endlicher E, Volk M, Feuerbach S et al. Long-term follow-up of patients with necrotizing pancreatitis treated by percutaneous necrosectomy. Hepatogastroenterology 2003; 50(54): 2225– 2258. Connor S, Ghaneh P, Raraty M et al. Minimally invasive retroperitoneal pancreatic necrosectomy. Dig Surg 2003; 20(4): 270–277. Cheung MT, Ho CN, Siu KW et al. Percutaneous drainage and necrosectomy in the management of pancreatic necrosis. ANZ J Surg 2005; 75(4): 204–207. Bucher P, Pugin F, Morel P. Minimally invasive necrosectomy for infected necrotizing pancreatitis. Pancreas 2008; 36(2): 113–119. Bruennler T, Langgartner J, Lang S et al. Percutaneous necrosectomy in patients with acute, necrotizing pancreatitis. Eur Radiol 2008; 18(8): 1604–1610. Hocke M, Will U, Gottschalk P et al. Transgastral retroperitoneal endoscopy in septic patients with pancreatic necrosis or infected pancreatic pseudocysts. Z Gastroenterol 2008; 46(12): 1363– 1368. Mathew A, Biswas A, Meitz KP. Endoscopic necrosectomy as primary treatment for infected peripancreatic fluid collections (with video). Gastrointest Endosc 2008; 68(4): 776–782. Antillon MR, Bechtold ML, Bartalos CR et al. Transgastric endoscopic necrosectomy with temporary metallic esophageal stent placement for the treatment of infected pancreatic necrosis (with video). Gastrointest Endosc 2009; 69: 178–180. Schrover IM, Weusten BL, Besselink MG et al. EUSguided endoscopic transgastric necrosectomy in patients with infected necrosis in acute pancreatitis. Pancreatology 2008; 8(3): 271–276. Voermans RP, Veldkamp MC, Rauws EA et al. Endoscopic transmural debridement of symptomatic organized pancreatic necrosis (with videos). Gastrointest Endosc 2007; 66(5): 909– 916. Papachristou GI, Takahashi N, Chahal P et al. Peroral endoscopic drainage/debridement of walled-off pancreatic necrosis. Ann Surg 2007; 245(6): 943–951.

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123 Charnley RM, Lochan R, Gray H et al. Endoscopic necrosectomy as primary therapy in the management of infected pancreatic necrosis. Endoscopy 2006; 38(9): 925–928. 124 Besselink MG, van Santvoort HC, Nieuwenhuijs VB et al. Minimally invasive “step-up approach” versus maximal necrosectomy in patients with acute necrotising pancreatitis (PANTER trial): Design and rationale of a randomized controlled multicenter trial [ISRCTN38327949]. BMC Surg 2006; 6: 6. 125 Runzi M, Niebel W, Goebell H et al. Severe acute pancreatitis: Nonsurgical treatment of infected necroses. Pancreas 2005; 30(3): 195–199. 126 Mier J, Leon EL, Castillo A et al. Early versus late necrosectomy in severe necrotizing pancreatitis. Am J Surg 1997; 173(2): 71–75. 127 Hunter JD. Abdominal compartment syndrome: An underdiagnosed contributory factor to morbidity and mortality in the critically ill. Postgrad Med J 2008; 84(992): 293–298. 128 An G, West MA. Abdominal compartment syndrome: A concise clinical review. Crit Care Med 2008; 36(4): 1304–1310. 129 Schein M, Wittmann DH, Aprahamian CC et al. The abdominal compartment syndrome: The physiological and clinical consequences of elevated intra-abdominal pressure. J Am Coll Surg 1995; 180(6): 745–753. 130 Gecelter G, Fahoum B, Gardezi S et al. Abdominal compartment syndrome in severe acute pancreatitis: An indication for a decompressing laparotomy? Dig Surg 2002; 19(5): 402–404. 131 De Waele JJ, Hesse UJ. Life saving abdominal decompression in a patient with severe acute pancreatitis. Acta Chir Belg 2005; 105(1): 96–98. 132 Wong K, Summerhays CF. Abdominal compartment syndrome: A new indication for operative intervention in severe acute pancreatitis. Int J Clin Pract 2005; 59(12): 1479–1481. 133 Jonsson M, Linder S, Soderlund C. Life-saving decompression in abdominal compartment syndrome and severe acute pancreatitis. Lakartidningen 2008; 105(40): 2770–2771. 134 Siebig S, Iesalnieks I, Bruennler T et al. Recovery from respiratory failure after decompression laparotomy for severe acute pancreatitis. World J Gastroenterol 2008; 14(35): 5467– 5470. 135 Leppaniemi A, Mentula P, Hienonen P et al. Transverse laparostomy is feasible and effective in the treatment of abdominal compartment syndrome in severe acute pancreatitis. World J Emerg Surg 2008; 3: 6. 136 Leppaniemi AK, Hienonen PA, Siren JE et al. Treatment of abdominal compartment syndrome with subcutaneous anterior abdominal fasciotomy in severe acute pancreatitis. World J Surg 2006; 30(10): 1922–1924. 137 Leppaniemi A, Johansson K, De Waele JJ. Abdominal compartment syndrome and acute pancreatitis. Acta Clin Belg Suppl 2007; 1: 131–135. 138 Chen H, Li F, Sun JB et al. Abdominal compartment syndrome in patients with severe acute pancreatitis in early stage. World J Gastroenterol 2008; 14(22): 3541–3548. 139 Al-Bahrani AZ, Abid GH, Holt A et al. Clinical relevance of intra-abdominal hypertension in patients with severe acute pancreatitis. Pancreas 2008; 36(1): 39–43. 140 Pupelis G, Plaudis H, Snippe K et al. Increased intra-abdominal pressure: Is it of any consequence in severe acute pancreatitis? HPB (Oxford) 2006; 8(3): 227–232.

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141 Zhang WF, Ni YL, Cai L et al. Intra-abdominal pressure monitoring in predicting outcome of patients with severe acute pancreatitis. Hepatobiliary Pancreat Dis Int 2007; 6(4): 420–423. 142 Rosas JM, Soto SN, Aracil JS et al. Intra-abdominal pressure as a marker of severity in acute pancreatitis. Surgery 2007; 141(2): 173–178.

414

143 Keskinen P, Leppaniemi A, Pettila V et al. Intra-abdominal pressure in severe acute pancreatitis. World J Emerg Surg 2007; 2: 2. 144 Tao J, Wang C, Chen L et al. Diagnosis and management of severe acute pancreatitis complicated with abdominal compartment syndrome. J Huazhong Univ Sci Technolog Med Sci 2003; 23(4): 399–402.

25

Obesity management: Considerations for the gastroenterologist Leah Gramlich1, Marilyn Zeman1 and Arya M Sharma2 1 2

Division of Gastroenterology, Royal Alexandra Hospital, University of Alberta, Edmonton, Canada Division of Endocrinology, University of Alberta, Edmonton, Canada

Introduction Obesity is one of the most prevalent health problems in the Western world [1]. Obesity increases the risk of medical illness and premature death [2] and imposes an enormous economic burden on the health care system [3]. Obesity is also associated with a reduced quality of life, resulting from substantial limitations and restrictions in activities of daily living [4]. Obese individuals are less likely to obtain insurance, employment or promotion or to enjoy personal relationships [5]. Prevention and treatment of obesity is now widely recognized as an important priority for most health care systems. Obesity is best defined as the accumulation of excess body fat that threatens or affects an individual’s mental, physical or economic well-being. At a population level, the body-mass index (BMI) has been widely used to characterize and define obesity. In individuals, however, it is a rather poor measure of health or well-being [6]. Furthermore, current anthropometric definitions of obesity have been challenged with regard to their sensitivity and specificity to determine cardiometabolic risk across ethnic groups. Therefore, in addition to BMI other measures that better characterize fat distribution (waist circumference, waist-tohip ratio) have been recommended [7], but have yet to be widely used in clinical practice.

Background Assessing obesity Obesity, or the accumulation of excess body fat, is best described as a “sign” of a derangement in energy balance (as edema is a “sign” of fluid retention). Given that energy

balance is affected by a wide range of sociocultural, psychological, biological and iatrogenic factors, it is important in each case to determine the root cause of the derangement in energy balance. Derangements can occur in energy intake (e.g. homeostatic or hedonic hyperphagia), energy metabolism (e.g. hypothyroidism, beta-blockers) or energy expenditure (exercise or non-exercise thermogenesis). Work up of the obese patient must include assessment of all components of energy balance [7]. In assessing obesity it is also helpful to remember that overeating (hyperphagia), when present, in itself is not a diagnosis or a “root cause”. Rather, increased food intake has to be interpreted as a perturbation of ingestive behavior that may have multiple causes [8]. These can range from simply overeating at meals in response to hunger precipitated from meal skipping or irregular eating (homeostatic hyperphagia), to emotional overeating, binge-eating disorder, or reward-seeking behaviors not unlike other addictions (hedonic hyperphagia). Asking a hyperphagic obese individual simply to eat less without attempting to determine the underlying problem or help develop specific alternative coping strategies is rarely effective or sustainable. As with ingestive behavior, physical activity levels are also determined by a wide range of sociocultural, psychological, physical and economic factors [9]. Lack of time is probably the most common factor implicated in lack of exercise. However, as with emotional overeating, lack of motivation and low energy levels can be a sign of an underlying depression, sleep disorder, obstructive sleep apnea or vital exhaustion. Physical limitations to increasing physical activity may include back pain, osteoarthritis, trauma or plantar fasciitis. Again, determining the “root cause” of inactivity is important to determine the most likely line of treatment and approach to behavior change.

Assessing barriers Evidence-Based Gastroenterology and Hepatology, Third Edition John WD McDonald, Andrew K Burroughs, Brian G Feagan and M Brian Fennerty © 2010 Blackwell Publishing Ltd. ISBN: 978-1-405-18193-8

Long-term efficacy and effectiveness of obesity treatments is notoriously poor. This may in part be attributable to the 415

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substantial barriers that undermine long-term obesity management strategies [10]. These can include lack of recognition of obesity as a chronic condition, low socioeconomic status, time constraints, “intimate saboteurs” and a wide range of co-morbidities, including mental health, sleep disorders, chronic pain and musculoskeletal, cardiovascular, respiratory, digestive and endocrine diseases. Furthermore, medications used to treat some of these disorders may further undermine weight-loss efforts. Lack of specific obesity training of health professionals, attitudes and beliefs, as well as insurance coverage and availability of obesity treatments can likewise pose important barriers. Health professionals need to take care to identify, acknowledge and address these barriers where possible to increase patient success, compliance and adherence to treatments. Failure to do so may further undermine the sense of failure, low self-esteem and self-efficacy already common among obese individuals. Addressing treatment barriers can therefore save resources and increase the prospect of longterm success.

Managing expectations Patients and health care providers generally have exaggerated expectations of what is possible in obesity management [11]. Current studies show that lifestyle management alone is generally associated with a mean weight loss of

Study or subcategory

N

Treatment mean (SD)

Derosa 2003w5

25

Krempf 2003w10

346

Swinburn 2005w15 170 Hollander

1998w8

163

Sjostrom 1998w14 343

N

Control mean (SD)

–8.60 (5.00)

23

–5.30 (9.30)

350

–4.70 (7.70)

169

about 3–5% that can be maintained over 3–5 years [12]. Adding pharmacotherapy to lifestyle management can help achieve 5–15% weight loss, but the vast majority of patients will likely discontinue treatment and regain most of the weight within 3–5 years (Figures 25.1 and 25.2) [13]. Thus, as with other pharmacological treatments for chronic diseases, the importance of long-term adherence to antiobesity medications cannot be overemphasized. The best long-term results are currently reported for surgical treatment of obesity, with an average sustained weight loss of 20–30% of initial body weight [14]. However, to achieve and sustain this degree of weight loss, surgical patients have to make substantial changes to their lifestyles, without which, a significant proportion of surgical patients will regain weight and/or develop nutritional deficiencies. In this context, it is important to remember that even a 5% weight loss can produce dramatic improvements in cardiometabolic risk factors and even quality of life measures [15]. The benefits of even modest weight loss should therefore not be underestimated. Given the natural progression of obesity, even helping patients to maintain their current weight may be deemed successful obesity management. It is not uncommon for a patient to be asked to lose an unreasonable amount of weight before undergoing an elective diagnostic or therapeutic procedure (e.g. joint replacement). The providers are often unaware that their request

Weighted mean difference (random) (95% Cl)

Weight (%)

Weighted mean difference (random) (95% Cl)

–7.60 (3.36)

1.99

–1.00 (–3.39 to –1.39)

–2.40 (9.35)

5.93

–2.90 (–4.29 to –1.51)

–0.90 (4.20)

6.54

–3.80 (–5.12 to –2.48)

–6.19 (6.51)

159

–4.31 (7.18)

5.07

–1.88 (–3.38 to –0.38)

–10.30 (16.61)

340

–6.10 (16.61)

1.83

–4.20 (–6.69 to –1.71)

Davidson 1999w4

657

–8.76 (9.48)

223

–5.81 (10.00)

5.06

–2.95 (–4.45 to –1.45)

Finer 2000w6

110

–3.29 (6.05)

108

–1.31 (6.05)

4.41

–1.98 (–3.59 to –0.37)

Hauptman

2000w7

210

–7.94 (8.26)

212

–4.14 (8.15)

4.64

–3.80 (–5.37 to –2.23)

Rossner 2000w13

242

–9.40 (6.40)

237

–6.40 (6.70)

8.26

–3.00 (–4.17 to –1.83)

Bakris 2002w1

267

–5.40 (6.40)

265

–2.70 (6.40)

9.62

–2.70 (–3.79 to –1.61)

Broom 2002w3

259

–5.80 (8.50)

263

–2.30 (6.40)

6.81

–3.50 (–4.79 to –2.21)

Kelly 2002w9

266

–3.89 (4.48)

269

–1.27 (4.59)

19.26

–2.62 (–3.39 to –1.85)

Miles 2002w12

250

–4.70 (4.74)

254

–1.80 (4.78)

16.47

–2.90 (–3.73 to –2.07)

XENDOSw16

1640

–5.80 (24.30)

1637

–3.00 (24.30)

4.11

–2.80 (–4.46 to –1.14)

4948 4509 Total (95% Cl) Test for heterogeneity: χ2 = 11.05, df = 13, P = 0.61, I2 = 0% Test for overall effect: z = 16.67, P < 0.001

100.00 –2.87 (–3.21 to –2.53) –10

–5

Favors treatment Figure 25.1 Placebo subtracted weight reduction (kg) with orlistat [17].

416

0

5

10 Favors control

CHAPTER 25

Study or subcategory

N

Treatment mean (SD)

N

Control mean (SD)

Weighted mean difference (random) (95% Cl)

Obesity management

Weight (%)

Weighted mean difference (random) (95% Cl)

Weight loss studies Hauner 2004w18

174

–8.10 (7.70)

174

–5.10 (6.70)

11.03

–3.00 (–4.52 to –1.48)

Kaukua 2004w20

111

–7.10 (10.26)

121 –2.60 (10.26)

4.23

–4.50 (–7.14 to –1.86) –5.30 (–6.83 to –3.77)

McNulty

2003w24

68

–5.40 (4.95)

64

–0.20 (4.00)

10.86

Sanchez-Reyes 2004w25

44

–4.10 (10.45)

42

–1.40 (10.78)

1.55

–2.70 (–7.19 to 1.79)

McMahon 2000w22

142

–4.40 (5.10)

69

–0.50 (3.80)

15.15

–3.90 (–5.13 to –2.67)

Smith 2001w26

153

–6.40 (6.63)

157

–1.60 (4.47)

14.57

–4.80 (–6.06 to –3.54)

McMahon 2002w23

145

–4.50 (4.50)

72

–0.40 (3.60)

17.45

–4.10 (–5.21 to –2.99)

Subtotal (95% Cl)

837

74.83

–4.20 (–4.77 to –3.64)

699

Test for heterogeneity: χ2 = 5.99, df = 6, P = 0.42, I2 = 0% Test for overall effect: z = 14.65, P < 0.001 Weight maintenance studies Apfelbaum 1999w17

81

–5.20 (7.50)

78

0.50 (5.70)

6.58

–5.70 (–7.77 to –3.63)

James 2000w19

350

–8.90 (8.10)

114

–4.90 (5.90)

12.82

–4.00 (–5.38 to –2.62)

Mathus-Vliegen 2005w21 94

–10.70 (7.50)

95

–8.50 (8.10)

5.77

–2.20 (–4.43 to 0.03)

25.17

–4.01 (–5.73 to –2.28)

100.00

–4.16 (–4.73 to –3.59)

Subtotal (95% Cl)

525

287

Test for heterogeneity: χ2 = 5.11, df = 2, P = 0.08, I2 = 60.9% Test for overall effect: z = 4.56, P < 0.001

986 1362 Total (95% Cl) Test for heterogeneity: χ2 = 11.18, df = 9, P = 0.26, I2 = 19.5% Test for overall effect: z = 14.39, P < 0.001

–10

–5

Favors treatment

0

5

10 Favors control

Figure 25.2 Placebo subtracted weight reduction (kg) with sibutramine [17].

for weight loss is unreasonable. For example, even a 20 lb weight loss requires a total energy deficit of 70,000 Kcal. Using the recommended daily energy deficit of 500 Kcal, this would take a patient at least 20 weeks to achieve. However, safely achieving a daily energy deficit of 500 Kcal can be a challenge for sedentary individuals, who may often not need much more than 1500–2000 Kcal to sustain their weight. Thus, reducing energy intake to around 1000– 1500 Kcal to achieve the recommended weight loss and still maintain a healthy nutritious balanced diet will pose a major challenge even for the most highly motivated patient. Without professional help, recommendations to lose an unrealistic amount of weight will not only substantially delay the elective procedure, but also increase the patient’s sense of frustration and failure and risk promoting nutritional deficiencies.

Approach to treatment Given the chronic progressive nature of obesity, obesity management has to be approached with the same persever-

ance and diligence as the management of other chronic diseases [7]. All behavioral, medical or surgical interventions have to be continued beyond the weight-loss phase to prevent weight regain. Therefore, in a given patient, any intervention aimed at weight loss has to be reasonably sustainable in the long term to avoid recidivism or weight regain. A wide range of behavioral interventions has been shown to be successful in the long term. These include selfmonitoring with food journals and pedometers, regular weighing and regular provider contact [7]. Patients with emotional and binge-eating disorder may benefit from cognitive behavioral therapy [16]. Failure to identify and manage binge-eating appropriately is associated with virtually 100% recidivism. Overall the long-term, weight-loss benefit of behavioral intervention is rather modest. In a recent multicentre study that randomized 1029 participants, who had lost an average of 8.5 kg through lifestyle change over six months, to various strategies for weightloss maintenance (personal contact, unlimited access to an interactive technology-based intervention, or self-directed 417

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control) over 30 months, resulted in weight loss ranging between 2.9 to 4.2 kg at the end of the study [12]. A1 Pharmacological treatment for obesity should be considered in all patients who need to achieve a 5–10% weight loss [7]. In Canada and the USA there are currently two compounds licensed for the long-term treatment of obesity: orlistat, a gastrointestinal lipase inhibitor that reduces digestion and absorption of fat by around 30% [17] and sibutramine, a serotonin and norepinephrine reuptake inhibitor that increases satiety and may have modest effects on thermogenesis. Major adverse effects of orlistat include steatorrhea and oily rectal discharge. Use of sibutramine can be associated with xerostomia, constipation, hyperhydrosis, insomnia, palpitation and, in rare cases, an increase in blood pressure [17]. Both compounds have been shown to significantly increase weight loss when added to moderately caloric-restrictive diets. More importantly, continuation of pharmacotherapy is associated with a more significant reduction in weight regain than behavioral treatment alone. Therefore, long-term use of these agents in patients who respond to and tolerate these drugs is recommended. Despite documented effects on obesity-related morbidity, it should be noted that thus far, there is no evidence that behavioral or pharmacological therapy of obesity reduces overall or obesity-related mortality. A1a Bariatric surgery is currently the most effective longterm treatment of severe obesity and has been shown to dramatically reduce the risk for co-morbidities including cardiovascular disease, type II diabetes, obstructive sleep apnea and certain cancers, and the risk for overall mortality alone (by up to 30% ). Thus, for example, the recent Swedish Obesity Study was a prospective case control study comparing 2010 surgical to 2037 non-surgical matched controls [14]. During an average of 10.9 years of follow-up (followup rate, 99.9%) there were 129 deaths in the control group and 101 deaths in the surgery group (hazard ratio adjusted for sex, age, and risk factors was 0.71; p = 0.01). The most common causes of death were myocardial infarction (control group, 25 subjects; surgery group, 13 subjects) and cancer (control group, 47; surgery group, 29). These benefits were seen with average weight loss after 10 years of 25% (gastric bypass), 16% (vertical-banded gastroplasty) and 14% (gastric banding). Currently, the most common surgical procedures are laparoscopic adjustable gastric banding (LABG) and laparoscopic Roux-en-Y gastric bypass (RYGB) surgery. While overall complication rates at experienced centers are low (1–2%), surgical complications are even lower with LABG. However, weight loss with this procedure is less pronounced and is more dependent on patient compliance than is the case for RYGB. Other surgical approaches including sleeve gastrectomies and endoluminal approaches are currently under investigation. 418

Given the complexity of obesity management, interventions are best provided by an interdisciplinary team of nurses, psychologists, physiotherapists, dieticians, social workers, occupational therapists, physicians and surgeons. In light of the widespread bias and discrimination of health professionals against obese clients, bariatric personnel should undergo sensitivity training [5]. Currently there is no cure for obesity – only long-term treatments that require ongoing support and follow-up of all patients to ensure adherence and reduce recidivism. Therefore, it is important to make every effort possible to prevent the development of this chronic and debilitating condition.

The role of the gastrointestinal tract in ingestive behavior Appetite is regulated by a complex interaction between central and peripheral signals that affect both the sensation of hunger and how an individual responds to food. While older models suggested that hypoglycemia stimulates food intake and post-prandial hyperglycemia activates the satiety centre of the brain [18], in the last decade a much more complex system has emerged that involves a multitude of neuropeptide and neurotransmitter systems, the enteroendocrine system and peripheral signals derived from adipose tissue (e.g. leptin). The response to food ingestion is traditionally considered to occur in three phases. The cephalic phase is characterized by the secretion of saliva, gastric acid and pancreatic enzymes that is triggered by visual and olfactory stimulation. Relaxation of the sphincter of Oddi and the gastric fundus, and increased contractions of the gall bladder occur [19]. This cephalic phase is followed by the gastric phase, which involves relaxation of the proximal stomach. This is caused by the activation of inhibitory neurons on the gastric wall (accommodation). Finally, the intestinal or post-ingestion phase is characterized by a combination of duodenal, intestinal and colonic responses that may also play a role in satiety. A multitude of enteroendocrine hormones or peptides play a role in regulating food intake by activating nearby extrinsic sensory fibers (vagal and spinal) or via the bloodstream (Table 25.1) [20]. They generally have a short halflife, interact with other hormones and they can modulate the sensitivity of the vagal response. Through activation of the vagus nerve or through direct neural stimulation, these peptides stimulate the hypothalamus, which then integrates these signals. The main site of integration is the arcuate nucleus of the hypothalamus (ARC). Two major sub-populations of neurons in the ARC are implicated in the regulation of feeding; cocaine and amphetamine related transcript (CART) and pro-opiomelanocortin (POMC)

CHAPTER 25

Obesity management

Table 25.1 Role of enteroendocrine hormones and peptides in regulation of food intake. Hormone

Effect on hunger

Stimulus for secretion

Location secreted

Effect

Ghrelin

↑

Cephalic phase

A-X like cells of the oxyntic glands (stomach)

• Enhances NPY/AgRP and inhibits POMC pathways. • Endogenous ligand for growth hormone secretagogue receptors. • Controls secretion of ACTH, prolactin, and plays a role in glucose and lipid metabolism. • Increases gastric mobility, gastric acid secretion and insulin secretion.

Cholecystokinin (CCK)

↓

Nutrients (especially lipids and proteins)

I-cells of the duodenum and ileal

• Enduces satiety and reduces meal intake through vagus nerve stimulation. • Inhibitory effect on gastric motility.

Glucagon-like peptide-1 (GLP-1)

↓

Nutrients (especially lipids and proteins)

L-cells of the distal small intestine

• Enhances the glucose-induced stimulation of insulin synthesis and secretion, while suppressing glucagon secretion. • Delays gastric acid secretion and emptying.

Peptide YY (3-36) (PYY3-36)

↓

Nutrients (proportional to caloric intake)

L-cells of the distal small intestine

• Thought to act at the level of the hypothalamus; however, exact mechanism unclear.

Oxyntomodulin

↓

Nutrients (proportional to caloric intake)

L-cells of the distal small intestine

• Inhibits gastric acid secretion and gastric emptying. • In animals, found to increases gastric somatostatin release, potentiates the effects of PYY and found to inhibit insulin secretion. • Thought to work through GLP-1 receptor stimulation

Leptin

↓

Short chain fatty acids

Adipose tissue

• Low leptin activates anabolic and inhibits catabolic circuits. • Enhances NPY/AGRP while blocking POMC/CART release.

Pancreatic polypeptide (PP)

↓

Nutrients (proportional to caloric intake)

Pancreas

• Thought to act at level of hypothalamus and brainstem to decrease intake. • Effect unclear as PP injected directly into the brain increases food intake in rats. • May potentially affect gastric emptying.

Insulin

↓

Glucose

Pancreas

• Centrally, insulin reduces feeding by activating POMC. • Insulin also increases AgRP synthesis, which would increase hunger.

inhibit food intake, whereas neuropeptide Y (NPY) and agouti-related protein (AgRP) stimulate it. Both influence how the hypothalamus signals pituitary hormone secretion and appetite [21]. The neurophysiological pathways involved in triggering hunger and satiety are complex and beyond the scope of this chapter. In the stomach, neural sensors perceive changes in the tension, stretch and volume of the stomach wall and outputs from these mechanoreceptors are relayed to the brain via the vagus and spinal sensory nerves [20] to the nucleus tractus solitarius (caudal brainstem) and then to the hypothalamus. Gastric distension induces a feeling of satiety [22]. Persistent delayed gastric emptying is known to decrease food intake, and artificial distension of the proximal stomach with a water-filled balloon has been found to reduce oral intake [23, 24]. On the other hand, the stomach is also the source of ghrelin, the only enteric hormone so far known to promote hunger and food intake.

In contrast, there are a number of enteric satiety signals, the best studied of which include cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) [21]. Parental administration of CCK induces satiety in animals and humans [25, 26, 27], an effect that is eradicated by vagotomy. CCK also delays gastric emptying [28] resulting in gastric distension. Due to its short duration of action, attempts to utilize CCK as a treatment for obesity have failed. PYY, another satiety hormone released from the colon, also inhibits fasting small bowel motility and gastric emptying [29]. Parenteral PPY injection decreases food intake in normal and obese humans [30], potentially via a central mechanism. Exogenous GLP-1 has been found to decrease food intake [31], only when administered at doses much higher than those physiologically achieved after a normal meal [32].

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Gastrointestinal symptoms and disease in the obese patient Gastro-esophageal reflux disease (GERD) Obesity is a significant risk factor for GERD. Obese individuals are more than twice as likely as non-obese individuals to admit to a history of GERD or symptomatic heartburn [33] [34]. The prevalence of GERD ranges from 8–26% in individuals with obesity [35] [36]. Similarly, endoscopically diagnosed erosive esophagitis is also more common in individuals with an increased BMI, with an odds ratio (OR) of 1.76 [37]. Several mechanisms have been described to explain this correlation. An increased intraabdominal and resulting increase in intragastric pressure can precipitate reflux into the esophagus or hiatus hernia [38]. In addition, derangements of esophageal motility, including hypertensive contractions (nutcracker esophagus) or disordered contractions (non-specific motility disorder), decreased lower esophageal sphincter pressure, inappropriate lower esophageal relaxation, a sliding hiatus hernia and delayed gastric emptying have also been implicated (see motility section below) [39]. Finally, diet, refluxate composition and an increased incidence of Helicobacter pylori may also play significant roles in increasing the incidence of GERD in obese individuals. Several (but not all) studies suggest that weight loss is associated with decreased esophageal acid exposure and an improvement in GERD symptoms [40]. The lack of symptomatic improvement in many patients following weight loss may be attributed to the persistence of a hiatus hernia [41]. Modifications in dietary composition may be more effective than an actual change in weight [42, 43]. Symptomatic improvement following bariatric surgery is likely secondary to both weight loss and a change in the anatomy of the gastrointestinal (GI) tract. Roux-en-Y consistently results in a favorable response as an anti-reflux procedure, with a significant improvement in reflux symptoms and a decrease in the use of GERD medication noted postoperatively. Adjustable gastric banding may not be a suitable option in obese individuals with symptomatic GERD, unless combined with anti-reflux surgery, since banding can precipitate the reflux of gastric contents into the esophagus from the small gastric reservoir [44].

Acute pancreatitis Severe hypertriglyceridemia, not uncommon in overweight and obese individuals, is a rare but well recognized cause of acute pancreatitis [45]. Increased BMI is, however, considered to be a risk factor for a worse outcome in patients with acute pancreatitis [46, 47]. In a recent meta-analysis severe acute pancreatitis was more frequent in obese 420

patients (BMI ≥ 30 kg/m2) (OR 2.6), who also tended to develop more systemic (OR 2.0) and local complications (OR 4.3). Local complications from the greater accumulation of peripancreatic fat included fat necrosis, with necrosis becoming a nidus for infection [46]. This is particularly problematic in obese individuals with hyperinsulinemia and insulin resistance [48]. Obesity is also associated with respiratory, renal and circulatory compromise as well as an increased incidence of death [49]. In light of these observations, adding an obesity score (BMI ≥ 26 kg/m2) to the APACHE II (Acute Physiology and Chronic Health Evaluation) score has been recommended to improve its predictive value for overweight and obese patients [50, 51]. Thus, the composite APACHE-O (APACHE-II plus obesity) score >8 has greater predictive accuracy than the APACHEII score, with a sensitivity of 82%, specificity of 86%, positive predictive value (PPV) of 74% and a negative predictive value of 91% (NPV) in predicting morbidity and mortality [50].

Gallstone disease and cholecystitis Both obesity and rapid weight loss are associated with an increased risk of gallstone disease, particularly in women. Risk appears highest when obesity begins in late adolescence [52] or if obesity is truncal [53]. The three major factors important in the development of gallstones include gall bladder dysmotilty, cholesterol hypersaturation of bile (i.e. a higher concentration of cholesterol to bile or phospholipids), and cholesterol nucleation. Obese patients have an increased biliary secretion of cholesterol from the liver, which leads to the formation of bile supersaturated with cholesterol and the precipitation of cholesterol microcrystals [54]. Both diabetes mellitus and insulin resistance are known to be confounding factors with respect to the association of obesity and gallstone disease [55]. Increased hepatic cholesterol synthesis and diets high in calories and refined carbohydrates, but low in fiber, also increase the risk. There is contradictory evidence, however, on the specific role of total fat intake [56]. There has been no correlation found between serum cholesterol level and a predisposition to gallstone formation [57]. Impaired gall bladder emptying or gall bladder stasis, and further cholesterol saturation, as would occur in individuals who lose weight rapidly with restricted dieting or following bariatric surgery, also precipitates stone formation [58]. Low calorie and low fat diets affect biliary lipid composition with increases in the hepatic uptake of cholesterol and hepatic cholesterol synthesis [59]. Weight loss is clearly associated with the development of gallstones, especially in women [51]. In several studies, approximately 11–28% of obese patients who severely restricted their dietary intake [60–62], and 27–43% of patients who underwent bariatric surgery developed gallstones within a

CHAPTER 25

period of 1–5 months [63, 64]. Routine concomitant cholecystectomy with bariatric surgery has been suggested, but remains controversial. The rate of weight loss also influences gallstone development. As gallstone formation appears particularly high when weight loss is more than 1.5 kg per week [65], preventive strategies have been suggested. These include controlling the rate of weight loss, administration of ursodeoxycholic acid to decrease cholesterol saturation, limiting between meal fasting time and maintaining a small amount of fat in the diet [66]. Ursodeoxycholic acid has been shown in several small studies to reduce gallstone formation post-bariatric surgery. These studies are difficult to compare as they used different doses of ursodeoxycholic acid (i.e. 500 [67] to 1000 [68] mg/ day), for different lengths of time (i.e. 3 [68] to 24 [67] months). The presence of gallstone formation is based upon different diagnostic imaging modalities. Miller [68], in the longest study to date, found that after 24 months the incidence of finding gallstones by ultrasound or CT scan was 8% in 76 patients treated with 250 mg ursodeoxycholic acid bid for six months postoperatively versus 30% in 76 patients treated with placebo. The true incidence of symptomatic cholecystitis in unknown. Miller [68] reported that 4.7% of patients in the ursodeoxycholic group and 12% in the placebo group underwent postoperative cholecystectomy for symptomatic gallstone disease. Though adverse effects of ursodeoxycholic acid are minor (nausea, constipation), and were not found to be significantly different in the treatment and placebo groups [68], ursodeoxycholic acid is relatively expensive and the pills are large, making passage through a small gastric reservoir difficult. Postoperative prophylactic treatment with ursodoxycholic acid at this time is not routinely recommended.

Diverticular disease and diverticulitis The relationship between diverticular disease and obesity remains unclear. Obese patients are more likely than patients of normal body weight to present with diverticulitis and diverticular perforations. This association has been particularly noted in younger individuals [69, 70], in whom the diagnosis may be missed [71]. In one retrospective case series, individuals diagnosed with recurrent diverticulitis or diverticular perforations were significantly more likely to be obese [72]. Obesity has also been identified as a significant risk factor for mortality following elective sigmoid resection done specifically for diverticular complications.

Cancer Several mechanisms have been proposed to explain the increased risk of malignancy in obese individuals. These include the insulin and insulin-like growth factor axis, the

Obesity management

role of sex steroids and the influence of adipokines. Hyperinsulinemia or insulin resistance reduces insulin-like growth factor (IGF) binding protein, which increases free IGF-1 levels. Both insulin and IGF-1 are associated with increased cell growth and proliferation and both may promote neoplastic cell growth [73]. Hyperinsulinemia also reduces sex hormone-binding globulin, which leads to increased estrogen and androgen levels. These hormones have been shown to be involved in the regulation of cell differentiation, proliferation and apoptosis, and to selectively enhance the growth of preneoplastic and neoplastic cells [74]. Increased serum leptin, an adipocyte-derived hormone is considered to be an obesity signal, which acts centrally as a catabolic agent to regulate body weight. In vitro leptin has been found to stimulate cancer cells derived from the colon and esophagus [75, 76]. Obesity is also thought to be involved in the immunologic or inflammatory response as described above. Increased levels of cytokines and adipokines, such as adiponectin [77] and transforming growth factor beta [78], may contribute to cell growth and differentiation. A large prospective cohort study assessing cancer mortality in over 900,000 Americans determined that the death rate from all cancers (GI and non-GI) was 52% higher in obese men and 62% higher in obese women compared to men and women of normal body weight. The authors suggested that more than 90,000 deaths per year from cancer could be avoided by maintaining a BMI less than 25 kg/m2 throughout life. The strongest association between obesity and gastrointestinal cancer risk has been demonstrated for esophageal, gall bladder, pancreas, liver and colorectal cancers [79]. A recent systematic review and meta-analysis found GI malignancies to be more prevalent in obese individuals, with a 5 kg/m2 increase in BMI leading to an increased risk for gall bladder (RR = 1.59), esophageal (RR = 1.51) and colon adenocarcinomas (RR = 1.09) in women, and esophageal (RR = 1.52) and colon (RR = 1.24) adenocarcinomas in men [80]. For colon cancer, the association was significantly stronger in men than in women, an observation that gives credence to the finding that estrogen plus progestin may be protective against colon cancer formation [81].

Barrett’s esophagus and esophageal adenocarcinoma Both GERD and high BMI are considered risk factors for esophageal adenocarinoma. In a recent meta-analysis, individuals with a BMI > 25 kg/m2 had an OR of 1.52 for esophageal adenocarcinoma compared to an OR of 2.78 in individuals with a BMI > 30 kg/m2 [37]. Whether or not this risk is directly mediated by obesity remains unclear. It appears that the risk for Barrett’s esphagus, the precursor to esophageal adenocarcinoma, may be entirely mediated through the increased risk of GERD in obese individuals [82]. Nevertheless, recent studies have suggested that adi421

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pokines like adiponectin and leptin [83] may be directly associated with Barrett’s metaplasia. Whether or not weight loss results in a decreased risk of esophageal adenocarcinoma is not known.

Proximal gastric adenocarcinoma/cancer of the gastric cardia The difficulty in endoscopically differentiating proximal gastric adenocarcinoma from distal esophageal adenocarcinoma complicates risk factor assessment. Several studies have confirmed that obesity is a significant independent risk factor for the development of proximal gastric adenocarcinoma [84–88] but not gastric non-cardiac adenocarinoma [84, 85, 88]. In a large study of over 500,000 US patients, a BMI > 35 kg/m2 was found to be a significant risk factor for esophageal and gastric cardia adenocarinoma, with a hazard ratio of 2.27 and 2.46 respectively [84]. The association between these two cancers is unclear, as GERD was found to be a significant risk factor for the development of esophageal adenocarcinoma (see above esophageal adenocarcinoma section) but not for proximal gastric cancers [84, 88].

Pancreatic cancer The only universally accepted risk factors for the development of pancreatic cancer are smoking and family history [89]. Data regarding any association with obesity and pancreatc cancer risk are based largely on case-control studies and may be biased by high fatality rates. The RR of obesity as a risk factor for pancreatic cancer was reported to range between 1.2 and 3.0. A recent meta-analysis of six casecontrol and eight cohort studies found a weak RR of 1.19 for men with a BMI > 30 kg/m2 compared to individuals with a BMI < 22 kg/m2, but not for women [90]. Not all studies corrected for the significant confounders of smoking and diabetes. Much like the mechanism by which non-alcoholic steatosis leads to liver fibrosis and cirrhosis [91], it has been suggested that non-alcoholic fatty pancreas disease may lead to non-alcoholic steatopancreatitis, which can progress to pancreatic fibrosis and dysfunction (chronic pancreatitis), and eventually pancreatic cancer. The adipose-derived cytokines, IL-1 beta and TNF- alpha are thought to promote this progression [92].

Hepatocellular cancer (HCC) The relative risk of mortality from primary HCC is 1.68 times higher among women and 4.52 times higher for men, with a baseline BMI ≥ 35 kg/m2 compared to a BMI of 18.5–24.9 kg/m2 [79]. In men, HCC had the highest obesityrelated relative risk of all cancers. Hepatocellular cancer is a well-recognized complication of cirrhosis, and non-alcoholic fatty liver disease associated with obesity and the metabolic syndrome is a known cause of cirrhosis. A study, 422

by Nair et al. [93] of nearly 20,000 US patients found obesity to be an independent risk factor for HCC. However, on multivariate analysis, obesity was only found to be a significant risk factor in patients with either alcoholic or cryptogenic cirrhosis. This association was not found in patients with other causes of liver cirrhosis such as hepatitis C viral (HCV) infection. Similarly, diabetes mellitus has been suggested to be a risk factor for HCC development [94, 95], though obesity is a significant confounding variable. A recent study in nearly 1500 patients with chronic HCV cirrhosis followed for a mean of six years found that being overweight or obese were significant independent risk factors for HCC development, with a hazard ratio of 1.86 and 3.10 respectively [96]. Obesity, diabetes mellitus and hyperlipidemia are conditions known to have a synergistic effect on the progression of liver fibrosis in patients infected with HCV [97]. It is difficult to know whether fatty infiltration worsens HCV progression itself or whether non-alcoholic fatty liver disease is a potential secondary cause of liver cirrhosis in obese individuals.

Cholangiocarcinoma Studying the risk factors associated with the development of cholangiocarcinoma is hindered by the fact that it is such a rare disease, and that only 10% of cases are associated with a recognized risk factor [98]. Obesity has been suggested to be a potential risk factor in some studies [99, 100] but not in others [101]. As with other cancers, studies are limited by the presence of confounding variables. Specifically, gallstone disease is a recognized risk factor for the development of cholangiocarcinoma, and obesity is a recognized risk factor for the development of gallstones [102].

Colorectal adenocarcinoma A recent meta-analysis of 31 prospective studies performed between 1966 and 2007 found that a five-unit increase in BMI was associated with a 30% increased risk of colon cancer in men and a 12% increased risk in women [103]. BMI was a significant risk factor for the development of proximal colon cancer in men, and with distal colon cancer in both sexes. Rectal cancer was significantly related to BMI in men but not in women. Abdominal obesity showed a stronger relationship than overall obesity [103]. The reason for the apparent sex difference in the association between colon cancer rates and obesity is unclear. While obesity imposes a greater risk of colon cancer for men of all ages, the risk has been reported to be higher in premenopausal than in postmenopausal women [104]. Although, increased estrogen levels and insulin resistance in premenopausal women have been suggested to contribute [105], this would not explain why colon cancer risk is higher in men than in women [80] or why exogenous estrogen in the form of hormone replacement therapy may be protective [81].

CHAPTER 25

Confounding factors for all studies related to cancer, but specifically to colon cancer, include the influence of exercise and diet. Physical activity is associated with lower rates of colon cancer [106]. The theoretical explanation for this is that physical activity increases colonic motility [107]. Dietary factors which have been associated with an increased risk of colon cancer include the high consumption of red meat, low consumption of fresh fruits and vegetables, low-fiber diets and diets low in certain vitamins and minerals including calcium and folate [108]. These diets may be more common in overweight individuals.

Gastrointestinal dysmotility Alterations in gastrointestinal motility have been recognized in obese individuals, resulting in a variety of symptoms, most notably reflux, nausea, diarrhea and bloating.

Obesity management

Gastric dysmotility The relationship between obesity and gastric motility, as assessed by gastric emptying studies, has been contradictory [109]. In general, it is suggested that obese individuals have a larger gastric capacity and accelerated solid food gastric emptying [117]. Rapid emptying may reduce the negative feedback satiety signal and trigger hunger [118]. Myoelectrical studies suggest that individuals with morbid obesity have a decreased gastric slow wave frequency and an increased frequency of dysgastria in both the fasting and fed state, which would explain any increased gastric emptying [119]. No difference in either the gastric emptying of liquids or in gastric accommodation has been found in the obese [118]. Gastric electrical stimulation studies performed so far only in dogs have suggested that this intervention may become a viable therapeutic option to promote weight loss in the future [120].

Gall bladder dysmotility Esophageal dysmotility In the esophagus, transient lower esophageal sphincter (LES) relaxation and decreased esophageal clearance capacity may contribute to GERD [109]. Studies on esophageal dysmotility and obesity, however, have produced inconsistent results [110, 111]. Other pathophysiological factors that may contribute to the higher incidence of GERD in overweight and obese individuals include increased esophageal acid sensitivity [112] and the presence of a hiatal hernia. Koppman et al. [113] evaluated 116 obese individuals who presented for esophageal assessment by manometry prior to laparoscopic gastric banding, regardless of any dyspepsia or dysphagia history. An abnormal motility pattern was found in 41% of these patients, of whom 23% were diagnosed with non-specific esophageal motility disorders, 11% with nutcracker esophagus, 3% with isolated hypertensive LES, 3% with isolated hypotensive LES, 1% with esophageal spasm and 1% with achalasia. Interestingly, only one patient with abnormal esophageal motility had a history of non-cardiac chest pain. This observation is contrary to what one would expect given the relationship between obesity and GERD. One explanation for the apparent lack of GERD symptoms in this study is that patients with morbid obesity may have a depressed autonomic nervous system and may lack sensory perception through the vagus nerve. In addition, only 3% had evidence of an isolated hypotensive LES. Other studies have suggested a higher incidence of hypotensive LES in obesity, with a prevalence ranging from 14–69% [114–116] and with potential worsening of reflux following adjustable gastric banding [116]. There was no mention in Koppman’s study of the number of transient LES relaxations, which has been suggested to be the most significant abnormality causing GERD in this population, through frequent overeating [109].

Although decreased gall bladder motility has been implicated as a risk factor for the more frequent prevalence of gall bladder disease in obese individuals, the findings from motility studies have been inconsistent [121]. Insulin resistance [122] and hyperinsulinemia, which may decrease gall bladder sensitivity to cholecystokinin, and thus gall bladder contractions, may also play a role [123].

Small and large bowel dysmotility While small and large bowel motility in obese individuals remain to be studied [118], no differences were found between obese and normal weight individuals in intestinal transit time as measured by hydrogen breath test [124].

Functional GI symptoms Obesity and its relationship to upper GI symptoms, specifically GERD and dyspepsia, are well studied (see GERD section). In clinical practice, however, it has been well recognized that many obese patients appear to have gastrointestinal (GI) complaints for which no etiology can be found. Functional GI disorders are thought to be secondary to an initial inflammatory insult on the GI tract that affects visceral sensitivity and/or motility. The proinflammatory effects of obesity are only now being recognized. Functional GI disease may be related to unrecognized changes in GI motility affecting GI function, or to a relative difference in the levels of some GI peptides induced by altered food habits or binge eating [125] and their endocrine or neurological effects. Four studies have addressed the relationship between obesity and GI symptoms [126–129]. The largest, a cross-sectional survey study, done in Olmsted County, evaluated the association of self-reported GI symptoms with BMI in nearly 2000 individuals [126]. Four symptoms were found to be significantly more prominent 423

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in overweight and obese individuals: vomiting, upper abdominal pain, bloating and diarrhea. Similar results, with some variation, were found in the other three studies to date [127–129]. A linear increase in prevalence across BMI categories was not observed for any of the symptoms, though an incremental increase in OR across categories was found for diarrhea (overweight OR 1.0, class I OR 1.7, class II OR 2.7 and class III OR 2.8). An impressive 40.7% of individuals with class II obesity complained of diarrhea. However, 17.1% of patients with a normal weight also listed this as a GI complaint [126]. The authors suggested that the increased frequency of diarrhea may be secondary to changes in GI motility, such as increased gastric emptying, or decreased intestinal or colonic transit time, which have been reported in some studies (see motility section) in overweight individuals, or to the altered intestinal secretory response induced by the direct endocrine effects of some gut released adipokines [126]. Concomitant diabetes mellitus and the use of anti-obesity medications may be significant confounding variables [126]. In type II diabetics, diarrhea but not abdominal pain is associated with BMI independent of glycemic control, suggesting a causal link

between diarrhea and obesity independent of any effect of diabetes on GI function [130]. The Olmsted study [126] also found that upper but not lower abdominal pain is significantly associated with BMI. The association between obesity and irritable bowel syndrome is unclear. Two studies evaluating this relationship have found contradictory results [125, 131]. Despite this contradiction, individuals with abdominal pain have been found to have a significant improvement in their symptoms following laparoscopic Roux-en-Y gastric bypass (LRNY) [132].

Bariatric surgery – a primer for the gastroenterologist Bariatric surgical procedures reduce caloric intake and/ or nutrient absorption by modifying the anatomy of the gastrointestinal tract [133]. Expected results include a durable and significant weight loss of 24% of total weight after two years and 16% at 10 years (Figure 25.3) [134], with a remarkable reduction in obesity-related co-morbidities

0

Change in weight (%)

Control

–10 Banding

Vertical-banded gastroplasty –20

Gastric bypass –30

0

1

2

3

4

6

8

10

15

886 237 746 58

190 52 108 10

Years No. Examined Control 2037 1768 1660 1553 1490 Banding 376 363 357 328 333 Vertical-banded gastroplasty 1369 1298 1244 1121 1086 Gastric bypass 265 245 245 211 209

1281 298 1004 166

982 267 899 92

Figure 25.3 Mean per cent weight change during a 15-year period in the control group and the surgery group, according to the method of bariatic surgery.

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and mortality. In addition, with the advent of laparoscopic surgery, complications have been dramatically reduced [135, 136]. In 2001, the NIH consensus statement identified bariatric surgery as the only long-term treatment for morbidly obese individuals (BMI > 40 kg/m2) [137]. More recently, there has been a dramatic increase in the frequency of bariatric surgical procedures in the USA and worldwide [138, 139]. As a result, the practicing gastroenterologist must be familiar with the common bariatric surgical procedures, their complications and the implications for endoscopy.

with restriction in the form of a sleeve gastrectomy. This procedure results in a relatively larger pouch and a greater predisposition to malabsorption (common channel of 50–100 cm). The anatomic implications of bariatric surgery are of significant interest to the gastroenterologist and endoscopist. It is vital to understand the type of surgery that was undertaken, the expected results of this surgery, and the interpretation of patient symptoms and to implement and evaluate a treatment strategy in light of this understanding.

Surgical approaches to obesity

Complications of bariatric surgery

Bariatric surgery reduces nutrient intake and/or absorption by restrictive and/or malabsorptive modification of the gastrointestinal tract. Please see Figure 25.4 [133]. Restrictive procedures create an anatomically smaller proximal stomach (10–20 ml), resulting in early satiety and reduced oral intake. Procedures include gastric stapling gastroplasty, vertical banded gastroplasty (VBG)) and the placement, most commonly laparascopically, of a synthetic, inflatable band around the stomach to create a narrow outlet (LAGB) (Figure 25.4a). These techniques rely on foreign material (silicone or mesh) to maintain a narrow stoma to restrict the passage of food into the stomach. The size of the stomal outlet is typically 10–12 mm. Another recently developed procedure is the “sleeve gastrectomy” (Figure 25.4b), in which resection of much of the gastric body leaves a narrow tube of stomach in continuity with duodenum. While VBG is now largely considered to be obsolete, the use of LAGB is increasing because of its simplicity, ease of implementation, maintenance of intestinal continuity and reversibility [138]. The device can be manipulated in outpatient settings by altering the volume in the band, hence impacting the degree to which the stomal outlet is compromised. Malabsorptive procedures (Figure 25.4c, d) include the Roux-en-Y gastric bypass (RYGB) in which the small intestine is divided at mid-jejunum and the distal portion is anastamosed to the stomach (often in combination with a restrictive gastrectomy, leaving a small residual gastric pouch to which the intestine is connected). The distal portion of stomach and proximal small bowel (bilio-pancreatic limb) are anastamosed end-to-side further down the jejunum. Although this length can vary (depending upon the amount of malabsorption that is desired) up to 150 cm, it is usually 60–75 cm. The degree of nutrient malabsorption is proportional to the length of the roux limb and inversely proportional to the length of the “common channel” – the portion of bowel remaining where pancreaticobiliary secretions and food come together. Another, less common malabsorptive procedure is the biliopancreatic diversion (BPD), often accompanied by a duodenal switch,

The complications of bariatric surgery are the topic of several recent review articles [140–142]. In individuals who have undergone Roux-en-Y gastric bypass, complications relate to the anastamosis and to bowel manipulation, and include mortality (0.2%), leaks (2.3%), staple line disruption (1.5%), marginal ulcers (2.5%), strictures (9.9%), bowel obstruction (3.3%), hernias (2.4%) and wound infections (3.4%). Following LAGB, complications relate to band malposition and/or malfunction and include mortality (0.14%), band slippage (5.5%), pouch enlargement (5.5%), obstruction/stenosis (1.9%), band erosion (2.7%), hardware infection (1.2%), hardware leak (3.6%), severe esophageal dilation (3.0%) and esophageal or gastric perforation (1.2%) [141].

Gastrointestinal symptoms and complications Post-bariatric surgery patients will present in a number of different ways. Early complications occur within two months of the surgical procedure and are usually managed by the surgeon. In this population, because of large abdominal girth, physical findings may not correlate with postoperative complications, and there should be a low threshold for ordering contrast radiologic studies or computed tomograms. Later complications are more likely to require investigation by a gastroenterologist, and patients may present with various ill-defined symptoms, including abdominal pain, nausea and vomiting, abnormal, insufficient or excessive degrees of weight loss, diarrhea and gastrointestinal bleeding (Table 25.2). Abdominal pain in the post-bariatric surgery patient may simply be due to the effects of rapid food consumption in the setting of a relatively fixed outlet. In patients with RYGB, pain may be related to stomal ulceration or stenosis or from an internal hernia. Biliary tract disease including cholelithiasis and choledocholithiasis occurs in up to 20% of patients in the setting of obesity and rapid weight loss and must be considered in the differential diagnosis. In individuals with RYGB, accessing the biliary tree is problematic and deserves special consideration, as does consideration for cholecystectomy in patients with gallstones at 425

A Laparoscopic adjustable gastric banding

B Sleeve gastrectomy

Stomach Common bile duct Gastric pouch Gastric band Common bile duct

Subcutaneous reservoir

D Biliopancreatic diversion with duodenal switch

C Roux-en-Y gastric bypass

Gastric pouch

Common bile duct

Stomach

Common bile duct Roux limb Biliopancreatic limb

Biliopancreatic limb Alimentary limb Common channel

Common channel

Figure 25.4 Common surgical procedures for weight loss. Restrictive operations for the treatment of morbid obesity and its coexisting conditions, popular today particularly because of laparoscopic surgical approaches, include adjustable gastric banding (LAGB) (a) and vertical (sleeve) gastrectomy (b). Roux-en Y gastric bypass (RYGB) (c), a procedure that combines restriction and malabsorption, is considered by many to be the gold standard because of its high level of effectiveness and its durability. More extreme malabsorption accompanies biliopancreatic diversion procedures, commonly performed with a duodenal switch (BPD-DS) (d), in which a short, distal, common-channel length of small intestine severely limits caloric absorption. This procedure also includes a sleeve gastrectomy.

426

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Table 25.2 Diagnostic considerations after bariatric surgery. Gastrointestinal symptom

Risk by procedure

Luminal considerations

Hepatobiliary considerations

Abdominal pain Vomiting Insufficient weight change Excessive weight change Diarrhea GI bleeding

RYGB LABG, RYGB LAGB RYGB, BPD RYGB, BPD RYGB

Stomal ulceration, stenosis, hernia, adhesions, band erosion Stenosis, ulceration, functional Dehiscence, diet, fistulae, pouch enlargement Obstruction, bacterial overgrowth, neoplasm Dumping, bile salt diarrhea, bacterial overgrowth, IBS, diet Ulceration, gastric remnant, NSAIDS

Gallstones Bile reflux

the time of bariatric surgery, although this approach is somewhat controversial [143–145]. Post-LAGB, the differential diagnosis includes band erosion or migration. Nausea and vomiting may be seen in any of these patients, but is more common post-LAGB, and an excessively tight band must be ruled out. Pre-existing esophageal and gastric motility disorders and functional upper gastrointestinal disorders may also play a role in the genesis of these symptoms. Insufficient weight loss (less than 50% of excess weight) is seen in 15% of patients. This lack of efficacy may be due to dietary indiscretion (high calorie liquids and snacks), insufficient activity or surgical result. Surgical considerations include enlarged pouch, deflation of band, a long common channel and dehiscence of the staple line. Excessive weight loss is less common after LAGB and more common after BPD or duodenal switch, because of the malabsorptive implications of these surgeries. Undernutrition in these individuals may be difficult to recognize. Other considerations include stomal stenosis or ulceration leading to obstruction. Eating disorders may also play a role in patients with excessive weight loss postbariatric surgery, and history pertaining to this problem must be pursued. Diarrhea in the post-bariatric surgery patient may simply be a reflection of malabsorption and maldigestion expected from intestinal bypass, or it may be due to bile salt diarrhea or dumping. Dumping syndrome symptoms of flushing, lightheadedness, fatigue and postprandial diarrhea may occur following intake of sugars and can be seen in 5–10% of patients. Bacterial overgrowth in the bypassed intestinal limb may also contribute to the development of secretory diarrhea and may also be associated with symptoms of bloating and flatulence. Gastrointestinal bleeding may occur from stomal ulceration in both RYGB and BPD patients and may be exacerbated by concomitant use of NSAIDS or steroids. It is important to identify the site of bleeding endoscopically and to recognize that ulceration at the distal intestinal anastamosis and in the gastric remnant may not be accessible endoscopically using standard techniques. In the evaluation of patients post-bariatric surgery who have GI complaints, radiologic imaging modalities includ-

Bile salt diarrhea

ing contrast studies to assess the possibility of leakage or perforation, computed tomography to detect herniation, bowel obstruction or fluid collections, and ultrasound to aid visualization of the hepatobiliary system are appropriate.

Nutritional complications Medical professionals caring for bariatric surgery patients must be aware of the potential risk of nutritional deficiencies that are common in these patients and of strategies to prevent and treat nutrient deficiencies. It is recognized that management of post-operative nutrition begins pre-operatively with nutritional status assessment, education and reinforcement of principles associated with long-term weight loss. This topic has recently been reviewed [146, 147]. Prior to bariatric surgery, micronutrient deficiencies that have been documented include vitamin D (60–80%), B-complex vitamins (important for carbohydrate metabolism), iron (50%), zinc, selenium and the antioxidant vitamins A, E and C. The risk of micronutrient depletion is greatest in patients with surgical interventions affecting digestion and absorption of nutrients (RYGB, BPD). These procedures can result in either primary or secondary nutrient deficiency. BPD is thought to cause weight loss through both protein (25%) and fat (75%) malabsorption. This has implications for (mal) absorption of micronutrients, including vitamins A, D, E, K and zinc. The decrease in transit time associated with intestinal bypass can also result in the secondary malabsorption of nutrients bypassing the duodenum and jejunum. Malabsorption can also be due to limited contact with the intestinal mucosa secondary to a short common channel. Inadequate dietary intake in these patients may also result in nutrient deficiencies. This is particularly relevant for iron, calcium, vitamin B12, thiamine and folate. Purely restrictive procedures such as LAGB usually result in micronutrient deficiencies due to changes in dietary intake (Table 25.3). Vitamins and minerals are factors and cofactors in many biologic processes that regulate body size, including appetite, hunger, nutrient absorption, metabolic rate, thyroid 427

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Table 25.3 Nutrient deficiencies and suggested treatments after bariatric surgery[46]. Nutrient

Preoperative deficiency

Postoperative deficiency

Screening

Symptom of deficiency

Suggested treatment: AGB

Suggested treatment: RYGB

Suggested treatment: BPD/DS

Iron

9–16%

20–49%

ferritin

anemia

MVM* May require extra Fe

MVM bid +18–27 mg/d elemental Fe

MVM bid + 18–27 mg elemental Fe

Vitamin B12

10–13%

12–33%

Serum B12, methylmalonic acid

Megaloblastic anemia, neuropathy, delusions, hallucinations

MVM

MVM + 1000 ug/ mo or 350–500 ug po/d

MVM

Folate

Uncommon

Uncommon

RBC folate

Megaloblastic anemia, neurologic symptoms

MVM, B-complex

MVM

MVM

Vitamin B1 (Thiamine)

15–29%

Rare but can occur

Serum thiamine

WernikeKorsakoff syndrome

MVM, thiamine 50– >100 mg/d (consider parenteral repletion with WKS)

MVM

MVM

Vitamin A

Uncommon (>7%)

Common (50%) with BPD, may occur with RYGB/ LAGB

Plasma retinol

Ocular findings, night blindness

MVM

MVM

MVM + 10,000 IU/d vitamin A

Vitamin D

Common (60–70%)

Common, prevalence unknown

25(OH) D

Osteoporosis, associated risks of malignancy, autoimmune disease

MVM, 400–800 IU/d

MVM

MVM + 2000 IU/d vitamin D

Vitamin E

Uncommon

Uncommon

Plasma alpha tocopherol

MVM

MVM

MVM

Vitamin K

Variable

Uncommon

INR

MVM

MVM

MVM + 300 ug/d vitamin K

Zinc

Uncommon but increased risk with obesity

Common with BPD after one year, may occur with RYGB

Plasma zinc

Change taste acuity

MVM

MVM

MVM

Protein

Uncommon

Rare but can occur

Serum albumin, total protein

Calcium

Common

Common

Bone density, PTH

Osteoporosis

1500 mg/d

1500 mg/d

1500 mg/d

and adrenal function, energy storage, glucose homeostatsis and others. Micronutrient repletion is vital for maximal weight loss and weight loss maintenance. Although obtaining micronutrients from food is the most desirable way to ensure adequacy of minerals and vitamins, for patients 428

with severe obesity, multivitamin and mineral supplementation (MVM) is essential for repleting micronutrients before and after surgery. Table 25.3 identifies the prevalence of micronutrient deficiencies before and after bariatric surgery. Various algorithms have been designed to help

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the bariatric surgery team proactively address the potential for micronutrient deficiency and support the use of standard MVMs. Strategies must target the maintenance of stores as well as the repletion of losses and take into account the time course of development following a given bariatric surgery procedure.

Considerations in endoscopy Endoscopy units providing care to the bariatric surgery patient need to be properly equipped for the care of these patients, commensurate with standards for a bariatric center of excellence. This equipment includes stretchers designed to support weights in excess of 350 lbs and physiologic monitoring equipment for larger individuals. Conscious sedation in patients with morbid obesity may be complicated due to the high prevalence of obstructive sleep apnea and increased risk for desaturation [148, 149]. Increased BMI has also been recognized as an independent risk factor predictive of difficult colonoscopy [150]. The role of endoscopy in the bariatric surgery patient has recently been reviewed by the American Society for Gastrointestinal Endoscopy [151]. The value of routine endoscopy before bariatric surgery in the patient without symptoms is controversial but is recommended in some guidelines [152]. Considerations for the endoscopist include the presence of a large hiatus hernia, which represents a relative contraindication to LAGB because of increased risk of band slippage. In patients undergoing RYGB and BPD/ DS, because the surgery renders the distal stomach and/or duodenum inaccessible by a standard upper endoscope, the threshold for performing a pre-operative endoscopic evaluation of the upper GI tract is lower than for other surgeries. Helicobacter pylori infection is present in 30–40% of patients scheduled for bariatric surgery and may be associated with abnormal endoscopy and risk for marginal ulcers postoperatively. Pre-operative testing in these patients may be useful. In the postoperative patient, endoscopy may be performed because of the symptoms discussed previously. The endoscopist should be aware of which operative procedure was performed and of findings on pre-procedural imaging studies. The choice of endoscope will depend on the indication and on the need for intubation of the excluded limb or on the need for therapeutic intervention (e.g. ERCP). In the early postoperative patient, insufflation may have potentially detrimental effects, and the endoscopist should first consider contrast radiography studies. After a RYGB, endoscopic findings should include a normal esophagus and gastroesophageal junction, a variably sized gastric pouch and a gastrojejunal stoma with a width of 10–12 mm in diameter. There may be a short blind limb

Obesity management

visible alongside of the efferent jejunal limb. The distal or excluded stomach cannot be visualized in the absence of a fistula. A VBG produces a pouch similar to the appearance of a RYGB with a 10–12 mm stoma and once this is traversed, the distal stomach and duodenum can be seen. LAGB produces a variable amount of extrinsic circumferential compression on the proximal stomach, evident at endoscopy. The endoscopist should note the length of the pouch and should evaluate the possibility of band erosion into the gastric wall. Morbid obesity is a risk factor for gallstone formation, and rapid weight loss is an independent and potentially compounding risk factor. Whereas an ERCP can usually be performed after LAGB, an ERCP in an individual who has undergone RYGB represents a significant technical challenge. Factors influencing success in this group include endoscopic skill, jejunal loop length and afferent loop length. When standard endoscopy is not possible, laparascopically assisted transgastric ERCP has been employed [153, 154]. Alternative diagnostic modalities such as magnetic resonance cholangiopancreatography (MRCP) and therapeutic modalities such as percutaneous trans-hepatic intervention should also be considered. Both prophylactic cholecystectomy and the administration of ursodiol in these patients have been shown to reduce the incidence and complications of gallstones [155, 156]. A1d

Endoscopic treatments for obesity Current endoscopic devices used for the treatment of obesity are space occupying balloons placed endoscopically into the stomach to promote weight loss. In a recent review of 30 studies, of which 18 were prospective including 5 randomized trials – and 12 were retrospective case studies, only one of three sham controlled studies found a significantly higher weight loss with the gastric balloon. In non-randomized studies, the average weight loss was17.8 kg, with resolution or improvement in comorbidities in 52–100% of patients. Complications from these devices include gastric perforation (0.2%) and obstruction (0.2%) and intolerance necessitating removal (2.5%) [157]. These devices are not approved for use in the USA and the best indications for this intervention remain to be defined. Natural orifice translumenal endoscopic surgery (NOTES), using a hybrid of endoscopic and laparoscopic approaches, is increasingly described in patients with morbid obesity or with complications from bariatric surgery. Although not ready for “prime time”, surgeons and endoscopists together are devising approaches to care of the bariatric surgery patient, and there is a large potential for development in this field [158]. 429

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116 Merrouche M, Sabete M, Jouet P et al. Gastro-esophageal reflux and esophageal motility disorders in morbidly obese patients before and after bariatric surgery. Obes Surg 2007; 17: 894–900. 117 Tosetti C, Corinaldesi R, Stanghellini V et al. Gastric emptying of solids in morbid obesity. Int J Obes relat Metab Disord 1996; 20: 200–205. 118 Xing J, Chen J DZ. Alterations of Gastrointestinal Motility in Obesity. Obesity Research 2004; 12(11): 1723–1732. 119 Jones TF, Lin Z, Sarosiek I, Moncure M, McCallum RW. Assessment of gastric emptying and myoelectric activity in the morbidly obese patients. Gastroenterology 2001; 120: A1500 (abstract) 120 Guyang H, Yin J, Chen JD. Therapeutic potential of gastric electrical stimulation for obesity and its possible mechanism: A preliminary canine study. Dig Dis Sci 2003; 48(4): 698–705. 121 Fraquelli M, Pagliarulo M, Colucci A, Paggi S, Conte D. Gallbladder motility in obesity, diabetes mellitus and celiac disease. Dig Liv Dis 2003; 35: S12–16. 122 Nakeeb A, Comuzzie AG, Al-Azzawi H, Sonnenberg GE, Kissebah AH, Pitt HA. Insulin resistance causes human gallbladder dysmotility. J Gastrointest Surg 2006; 10(7): 948–949. 123 Gielkens HA, Lam WF, Coenraad M et al. Effect of insulin on basal and cholecystokinin-stimulated gallbladder motility in humans. J Hepatol 1998; 28: 595–602. 124 Wisen O, Johansson C. Gastrointestinal function in obesity: Motility, secretion and absorption following a liquid test meal. Metabolism 1992; 41: 390–395. 125 Crowell MD, Cheskin LJ, Musial F. Prevalence of gastrointestinal symptoms in obese and normal weight binge eaters. Am J Gastr 1994; 8: 387–391. 126 Delgado-Aros S, Locke R, Camilleri M, Talley N, Fett S, Zinsmeister AR, Melton JM. Obesity is associated with increased risk of gastrointestinal symptoms: A population-based study. Am J Gastro 2004; 99: 1801–1806. 127 Talley NJ, Howell S, Pouton R. Obesity and chronic gastrointestinal tract symptoms in young adults: A birth cohort study. Am J Gastr 2004; 99: 1807–1814. 128 Levy RL, Linde JA, Feld JA, Crowell MD, Jeffrey RW. The association of gastrointestinal symptoms with weight, diet, and exercise in weight-loss program participants. Clin Gastr Hepatol 2005; 3: 992–996. 129 Talley NJ, Quan C, Jones MP, Horowitz M. Association of upper and lower gastrointestinal tract symptoms with body mass index in an Australian cohort. Neurogastroenterol Motil 2004; 16: 413–419. 130 Bulpitt CJ, Palmer AJ, Battersby C, Fletcher AE. Association of symptoms of type 2 diabetic patients with severity of disease, obesity, and blood pressure. Diabetes Care 1998; 21: 111–115. 131 Svelberg P, Johannson S, Wallander MA, Hamelin B, Pedersen NL. Extra-intestinal manifestations associated with irritable bowel syndrome: A twin study. Aliment Pharmacol Ther 2002; 16: 975–983. 132 Clements RH, Gonzalez QH, Foster A, Richards WO, McDowell J, Bondora A, Laws HL. Gastrointestinal symptoms are more intense in morbidly obese individuals and are improved with laparoscopic Roux-en-Y gastric bypass. Obes Surg 2003; 13(4): 610–614. 133 DeMaria EJ. Bariatric surgery for morbid obesity. N Engl J Med 2007; 356: 2176–2183.

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134 Sjostrom L, Lindroos AK, Peltonen M et al. Lifestyle, diabetes and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004; 351: 2683–2693. 135 Flum DR, Cheadle A, Chan L et al. Early Mortality among Medicare Beneficiaries Undergoing Bariatric Surgical Procedures. JAMA 2005; 294(15): 1903. 136 Livingston EH. Obesity, Mortality, and Bariatric Surgery Death Rates. JAMA 2007; 298(20): 2406–2408. 137 NIH Conference. Consensus development conference. Gastrointestinal surgery for severe obesity. Ann Intern Med 1991; 115, 956–961. 138 Santry HP, Gillen DL, Lauderdale DS. Trends in Bariatric Surgical Procedures. JAMA 2005; 294(15): 1909–1917. 139 Wolfe BM, Morton JM. Weighing in on Bariatric surgery: Procedure use, readmission rates and mortality. JAMA 2005; 294(15): 1960–1963. 140 Huang CS, Farraye FA. Endoscopy in the Bariatric surgery patient. Gastroenterology Clinics of North America 2005; 34(1): 151–166. 141 Lee CW, Kelly J, Wassel WY. Complications of Bariatric surgery. Current Opinion in Gastroenterology 2007; 23: 636–643. 142 Tang S, Rockey DC. The role of endoscopy in Bariatrics. Gastroeintestinal Endoscpy 2008; 16(1): 1–4. 143 Liem RK, Niloff PH. Prophylactic cholecystectomy with open gastric bypass operation. Obes Surg 2004; 14: 763–765. 144 Villegas L, Schneider B, Provost D et al. Is routine cholecystectomy required during laparascolic gastric bypass? Obes Surg 2004; 14: 60–66. 145 Elton E, Hanson BL, Quaseem T et al. Diagnostic and therapeutic ERCP using an enteroscope and pediatric colonoscope in long limb surgical bypass patients. Gastrointes Endoscopy 1998; 47: 62–67. 146 Nutrition Committee, Aills A, Blankenship J, Buffington C, Furtado M, Parrott J. ASBMS Allied Health Nutrition Guidelines for the Surgical Weight Loss Patient. Surgery for Obes and Related Diseases 2008. 4(5, Sept–Oct suppl): s73–108. 147 Schweitzer DH, Posthuma EF. Prevention of Vitamin and Mineral Deficiencies after Bariatric surgery: Evidence and Algorithms. Obes Surg 2008; 18: 1028–1034. 148 Villegas T. Sleep Apnea and moderate sedation. Gastroenterol Nurs 2004; 27(3): 121–124. 149 Weaver JM. Increased anaesthetic risk for patients with obesity and obstructive sleep apnea. Anesth prog 2004; 51: 75. 150 Anderson JC, Messina CR, Cohn W et al. Factors predictive of difficult colonoscopy. Gastrointest endosc 2001; 54(5): 558– 562. 151 Anderson, MA, Gan I, Fanelli RD et al. Role of endoscopy in the bariatric surgery Patient. Gastrointestinal Endoscopy 2008; 68: 1–10. 152 Sauerland S, Agrisani L, Belachew M et al. Europena Association for Endoscopic Surgery. Obesity Surgery: Evidence based guidelinies of the European Association for Endoscopic Surgery (EAES), Surg Endosc 2005; 19: 200–221. 153 Ceppa DA, Gagne DJ, Papasavas PK et al. Laparascopic transgastric endoscopy after RYGB. Surg Obes Relat Dis 2007; 3: 21–24. 154 Martinez J, Guerrero L, Buyers P et al. Endoscopi retrograde cholangiopancreatography and gastroduodnoscopy after RYGB. Surg Endosc 2006; 20: 1548–1550.

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155 Mason EE, Renquist KE. Gallbladder management in obesity surgery. Obes Surg 2002; 12: 222–229. 156 Miller K, Hell E, Lang B et al. Gallstone formation prophylaxis after gastric restrictive procedures for weight loss: A randomized double-blind placebo-controlled trial. Ann Surg 2003; 238: 697–702.

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157 Dumonceau JM. Evidence –based review of the Bioenterics intragastric balloon for weight loss. Obes Surg 2008; 18(12): 1611–1617. 158 Swain P. NOTES and anastamosis. GI Endoscopy clinics of NA 2008; 8: 261–277.

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Liver disease

Evidence-Based Gastroenterology and Hepatology, Third Edition John WD McDonald, Andrew K Burroughs, Brian G Feagan and M Brian Fennerty © 2010 Blackwell Publishing Ltd. ISBN: 978-1-405-18193-8

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Hepatitis C Keyur Patel, Hans L Tillmann and John G McHutchison Division of Gastroenterology, Duke Clinical Research Institute and Duke University Medical Center, North Carolina, USA

Introduction Hepatitis C virus (HCV) was identified in 1989 as a major cause of the parenterally transmitted non-A non-B hepatitis. The majority of patients develop chronic hepatitis C infection (CHC) that has a global prevalence of 2.2% and infects over 120 million people worldwide [1]. CHC is characterized by varying degrees of inflammation and hepatic fibrosis, and 20% of patients are likely to develop progressive liver damage with cirrhosis and complications of endstage liver disease over 20 to 40 years. CHC is now the leading indication for liver transplantation in developed nations and is expected to pose a significant health and economic burden over the next 10 to 20 years.

HCV genome Hepatitis C virus (HCV) is an enveloped positive-sense virus classified in the Hepacivirus genus within the Flaviviridae family, and was discovered in 1989 from a cDNA clone derived from blood-borne non-A non-B viral hepatitis genome sequences. The virus consists of a single open reading frame of 9.6 kb flanked by 5′ and 3′ untranslated regions that are required for viral translation and replication. The 5′ UTR contains the internal ribozyme entry site (IRES) that initiates translation of a 3000 aminoacid polyprotein, which is subsequently processed by viral and host cellular proteases into ten mature structural (core, E1, E2 and p7) and non-structural HCV proteins (NS2, NS3, NS4A, NS5A and NS5B). The non-structural proteins encode several key enzymes involved in viral replication such as the NS3 protease and NS5B RNA-dependent

Evidence-Based Gastroenterology and Hepatology, Third Edition John WD McDonald, Andrew K Burroughs, Brian G Feagan and M Brian Fennerty © 2010 Blackwell Publishing Ltd. ISBN: 978-1-405-18193-8

RNA polymerase. The lack of small animal model systems for HCV has rather limited our understanding of HCV replication and pathogenesis, but the recent development of in vitro and cell culture systems has resulted in significant progress in this regard in recent years [2]. HCV is characterized by a high degree of heterogeneity, resulting from the high replication rate (∼1012 particles per day) and the lack of a proof-reading repair mechanism in the viral RNA polymerase. The genetic heterogeneity of HCV is complex and may contribute to immune escape and the development of chronic infection in the majority of patients [3]. HCV has evolved into at least six major genetic groups (genotype) and over 50 subtypes, and is recognized by sequence variation in E1 and NS5b regions [4]. Different isolates of the same subtype may vary as much as 5–15%, and differing genotypes by more than 30% in nucleotide sequence. There is significant variation in the geographic distribution of HCV genotypes: genotype 1a is the prototype genotype and found commonly in the USA and Northern Europe; subtype 1b is common in Japan and Southern and Eastern Europe. Genotypes 2a and 2b represent 10–30% of all types and are particularly common in Japan and Northern Italy; genotype 3 is prevalent in the Indian subcontinent and Australasia; genotype 4 is common in Africa and the Middle East; genotypes 5 and 6 are found in South Africa and South East Asia respectively. Clinical studies have been able to identify that viral genotype affects response to antiviral therapy, but it does not have a significant influence on transmission, pathogenesis and the natural history of the disease.

Prevalence and transmission There are significant differences in the global prevalence of CHC, with seroprevalence rates ranging from 0.6% to 22%. Lower rates are seen in industrialized nations such as Germany (0.6%), France (1.1%), USA (1.8%), Japan (1.5– 437

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2.3%), and higher rates in developing nations such as China (3.2%) and Pakistan (2.5–6.5%) [1]. The highest reported seroprevalence rates are in Egypt (22%) due to past exposure through parenteral antischistosomal therapy [5]. HCV infection is transmitted by percutaneous or permucosal exposure to infected blood or body fluids. Although routes of infection may vary by geographic region, injection drug use (IDU) and receipt of a blood transfusion prior to implementation of donor screening in 1992 are the most common factors associated with transmission in developed nations. In these countries, transmission risks have been further reduced following the use of nucleic acid testing for HCV in donor blood, and the American Red Cross estimates that the risk of HCV infection is now 1/2,000,000 blood units [6]. However, most developing countries do not screen blood donations for HCV, and transmission risks from blood product transfusion remain much higher. Injection drug use remains the most significant risk factor for HCV transmission in developed nations, accounting for 68% of newly acquired cases, with high seroprevalence rates of 60–90% amongst those with long-term IDU [7]. In the USA, the incidence of HCV amongst IDU has continued to decline over the last decade, and current prevalence rates among IDU are likely to be lower [8]. Other routes of HCV transmission include sexual exposure to an infected partner, or multiple sex partners that account for 18% of new infections in epidemiological surveys, although transmission is rare between long-term monogamous heterosexual partners. The US Centers for Disease Control does not recommend barrier protection for heterosexual monogamous couples [9]. Nosocomial, iatrogenic and perinatal exposures are responsible for around 1% of cases, but in 9% of cases no definite source is identified. Indeterminate risk factors include household transmission (e.g. sharing razor blades or toothbrushes), tattooing, body piercing, intranasal cocaine use, dental procedures and acupuncture [7]. In general, although screening and testing of blood donors in developed nations has been successful in reducing the risk of HCV transmission, strategies for eliminating transmission from high risk behavior still need to be widely implemented.

Acute hepatitis C infection Most patients with acute HCV infection are asymptomatic, and only 10–15% may develop symptoms, such as jaundice, febrile illness, abdominal pain and nausea, that may be indicative of acute hepatitis. Marked elevations in serum alanine aminotransferase (ALT) levels of 10–20 times upper limit of normal may be observed at this time. HCV RNA appears in the serum within 1–2 weeks of exposure, and HCV antibodies become detectable over the subsequent 4–6 weeks. Diagnosis of acute infection relies on HCV RNA 438

detection, as antibody responses such as HCV-IgM antibody remain detectable during both acute and chronic infection [10]. Spontaneous viral clearance and resolution of infection may occur in 10–35% of asymptomatic individuals, but in up to 52% of symptomatic cases [11]. There are no reliable factors in acute hepatitis C that predict progression to chronic infection, but age, gender and mode of transmission may be important [12, 13]. There are no specific guidelines for post-exposure prophylaxis, but HCV RNA and ALT, and HCV antibodies are usually measured at baseline, at 4–8 weeks and at three months after potential exposure, as these tend to fluctuate significantly during the acute phase of illness. Controversies still exist regarding the optimal regimen and timing of antiviral therapy in acute hepatitis C infection. To allow for spontaneous clearance, antiviral therapy may be delayed for three months following exposure. B4 Depending on viral genotype, HCV RNA levels, and early viral response, sustained virologic response rates of over 80% are possible with a 12–24 week duration of pegylated interferon-alpha (PEG-IFN) therapy, either as monotherapy or in combination with ribavirin [14]. B4 However, due to inherent difficulties in performing clinical studies in this population, the optimal treatment regimen has yet to be determined [15]. B4

Natural history and progression of chronic infection Persistent or chronic infection, as defined by detectable serum HCV RNA for at least six months, develops in 65– 85% of HCV-infected patients, based on data from posttransfusion hepatitis, blood donors and injection drug use cohorts (Figure 26.1). Women and younger patients may have lower rates of chronic infection of 55–71% following exposure to contaminated blood products [12, 13, 16]. Factors such as age at infection, gender, race, severity of acute illness, and immune status likely determine persistence or spontaneous resolution of HCV infection. A broad multispecific CD4+ and CD8+ T-lymphocyte immune response targeting multiple HCV epitopes is associated with viral clearance and resolution of infection, and a weaker cellular immune response is associated with development of chronic infection. Patients with chronic infection are often asymptomatic or may have non-specific complaints of malaise, fatigue and abdominal discomfort. The diagnosis of CHC often follows routine investigations that have noted elevated ALT levels. However, at least onethird of patients may have persistently normal ALT levels and the majority of these patients are likely to have mild and non-progressive disease. Following a diagnosis of CHC, estimating the duration of infection and an assessment of disease severity may also help guide treatment decisions. The rate of fibrosis pro-

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15–35%

Acute HCV

65–85%

Chronic hepatitis C

Resolved infection

20% Mild Figure 26.1 Natural history and progression of HCV infection. Following acute infection, 15–35% of patients achieve spontaneous viral clearance. The majority of patients develop chronic infection with variable rates of disease progression. A small proportion of patients with chronic infection will develop progressive disease over >20 years, with subsequent complications of end-stage liver disease.

gression varies amongst CHC infected patients. Host, viral and environmental factors can all influence disease progression in CHC infection (Table 26.1). Some of these cofactors may be potentially modifiable, including alcohol consumption, smoking, metabolic factors (insulin resistance, obesity, steatosis) and HIV co-infection [17, 18]. Studies assessing fibrosis progression have mostly been cross-sectional, and based on a single liver biopsy and estimated duration of infection. Prospective studies have been based on selected cohorts attending tertiary referral centers. These estimates indicate that fibrosis progression is nonlinear and may be slow, moderate or rapid. For example, only 0–2% of younger women that acquired HCV from anti-D immune globulin progressed to cirrhosis over a 20year period, compared to an average of 13 years for older male patients that consumed at least 50 g of alcohol daily [12]. CHC patients with compensated cirrhosis have slowly progressive disease, with an estimated annual hepatic decompensation rate of 4–5%, and 1–4% for incidence of hepatocellular carcinoma (HCC) that remains the most frequent initial complication in these patients [19, 20]. Current estimates of HCC incidence rates are higher in countries such as Japan that have a longer natural history of HCV infection, but these are expected to double in the USA over the next decade.

Diagnosis and evaluation Diagnostic tests for HCV infection comprise serologic assays for antibodies and molecular techniques for virus particle detection. Anti-HCV is typically identified using second or third generation enzyme immunoassays that detect antibodies directed against various epitopes in the core, NS3, NS4 and NS5 proteins, with a specificity of 99%.

Hepatitis C

Moderate

> 20 years Severe

Cirrhosis 1–4% Hepatic decompensation

Liver transplant

Hepatocellular carcinoma

Death

Table 26.1 Host-viral factors associated with disease progression. Established factors

Possible factors

Age

Genotype 1b

Duration of infection

Quasispecies diversity

Male gender

Race

HIV or HBV co-infection

Smoking, cannabis use

Alcohol abuse

Genetic polymorphisms

Co-morbid disease (NAFLD, iron, schistosomiasis)

Environmental toxins

Increased ALT, necroinflammation or fibrosis

Source of Infection

Metabolic factors (insulin resistance, obesity) HLA class II polymorphisms NAFLD: non-alcoholic fatty liver disease; ALT: alanine aminotransferase; HLA: human leucocyte antigen.

In low-risk populations, false-positive tests may occur, and recombinant immunoblot assays (RIBA) are used in some centers to confirm positive EIAs. False negative tests may occur in HIV-1 infection, renal failure and HCV-associated cryoglobulinemia. Confirmatory testing involves molecular techniques that are useful in detecting and quantifying viral genomes using target or signal amplification methods. Several reliable qualitative and quantitative assays for detection are now commercially available. The newer realtime PCR and target mediated amplification assays have lower limits of detection for HCV of below 10 IU/ml. 439

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However, these tests are expensive and not recommended for low prevalence population screening. They are used for confirmatory testing in acute infection prior to development of anti-HCV, immunocompromised patients, newborns, and in CHC patients to predict and monitor virologic responses to antiviral therapy. All patients with confirmed CHC should have genotype testing to determine duration and likelihood of response to currently available antiviral therapy. A liver biopsy in CHC patients also provides useful baseline information in regards to necroinflammatory activity and fibrosis stage that can help determine prognosis, urgency of therapy, prediction of response to treatment, and evaluation of comorbid states such as steatosis. In the absence of co-morbid issues that preclude treatment, patients with HCV genotype 2 and 3 infection have excellent predicted responses to antiviral therapy, and may not require a biopsy prior to therapy. However, percutaneous liver biopsy is an invasive procedure that is costly, and may be associated with a significant risk of complications that increase with age and the presence of cirrhosis. An additional concern with liver biopsy is that it samples only 1/50000th of the liver, and thus is subject to sampling error, particularly in nonhomogenously distributed chronic liver disease. Several studies have highlighted the inaccuracy of liver biopsy even for staging of advanced liver disease [21]. Some countries have adopted non-invasive serum tests of fibrosis, or imaging modalities such as transient elastography, as an alternative to liver biopsy to guide therapeutic decisions in CHC patients [22]. Despite these limitations, most experienced clinicians considering treatment for CHC infection are likely to recommend obtaining a liver biopsy, unless there are obvious contraindications.

Treatment for chronic hepatitis C The main goal of treatment of patients with CHC infection is the prevention of progressive hepatic fibrosis through long-term eradication of HCV. The benefits of a sustained virologic response (SVR), defined as the absence of serum HCV RNA at 24 weeks after the end of treatment measured by a sensitive molecular assay, include normalization of serum alanine aminotranferase levels, improvement in hepatic necroinflammation and fibrosis, potential healthrelated quality-of-life benefits, reduced mortality and risk of developing complications of end-stage liver disease, in the majority of patients. Current standard-of-care therapy results in SVR rates that appear to be durable in at least 99% of patients over the subsequent five years, although 1–2% of patients may still harbor intrahepatic virus despite undetectable serum HCV RNA [23, 24]. A1b However, the presence of intrahepatic virus alone in these patients is likely to remain clinically insignificant. 440

Table 26.2 Contraindications to current pegylated IFN and ribavirin therapy. Definite contraindication

Relative contraindication

Severe cardiovascular disease (e.g. symptomatic coronary artery disease, severe hypertension, severe congestive heart failure)

Poor compliance

Uncontrolled diabetes mellitus

Active substance abuse

Severe pulmonary disease

Chronic renal insufficiency

Recent or active malignancy

Reduced life expectancy from co-morbid illness

Decompensated liver disease

Seizure disorder

Major psychiatric illness

Poorly controlled inflammatory disease (e.g. rheumatoid, connective tissue, inflammatory bowel disease)

Pregnancy or age < 3 yrs

Inability to comply with birth control recommendations

Active autoimmune disease Non-liver organ transplant Significant anemia (e.g. hemoglobinopathy) or other cytopenia

Patient selection All patients with CHC without definite contraindications to currently available IFN-based treatment should be considered as potential candidates for antiviral therapy (Table 26.2) [25]. A1a The decision to treat patients must take into account the variable natural history and rate of disease progression, associated co-morbid states, social situation and supports, risk-benefit aspects and cost-effectiveness of therapy in the individual. Patient preferences need to be considered, along with an assessment of behavioral and lifestyle aspects that may influence their ability to adhere to a prolonged duration of therapy associated with significant side effects. Patients also need to be reminded that CHC may be associated with non-specific symptoms such as fatigue, lethargy, asthenia and abdominal discomfort, which may significantly impact upon the quality of life of the individual, but do not correlate with severity of liver disease, and may not remit with successful viral eradication. Patients with significant co-morbid states that pose a relative contraindication to antiviral therapy require assessment and management in a multi-disciplinary setting with experienced health care providers. Several host and virus

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Table 26.3 Factors predictive of favorable virologic response to current therapy. Before therapy Treatment naive to IFN Genotype 2 or 3 Low HCV RNA levels (105 kg = 1400 mg/d) and at a fixed dose of 800 mg/day for HCV genotype 2 and 3) [30, 31]. A1c Combination PEG-IFN and ribavirin therapy can achieve a sustained virologic response in 54–56% of patients, including 42–46% of patients with genotype 1 infection, and around 80% of those with genotype 2 and 3 infection. Most patients with genotype 1 require 48 weeks of combination therapy and those with genotypes 2 and 3 can be treated for only 24 weeks. Many of the large clinical trials have been based in Europe or North America, and there is limited treatment efficacy data available for genotypes 4–6. As a result, these patients should continue to receive treatment as for HCV genotype 1 infection [25, 32].A1c

Early response prediction Studies of early viral kinetics in response to PEG-IFN and ribavirin indicate a rapid initial first phase decline in HCV RNA, due to virus inhibition, and a slower second phase response due to loss of HCV from infected hepatocytes. This resulted in the development of early virologic predictors in the first 12 weeks of therapy to select patients that would benefit from ongoing therapy, thereby reducing duration of treatment, cost and continued exposure to poorly tolerated drugs for non-responders. Early virologic response (EVR) is defined as a decline in HCV RNA of at least 2 log10 units or to undetectable levels by the first 12 weeks of treatment. Although 75–85% of patients receiving combination therapy achieve EVR, failure to achieve this early response is associated with a minimal (1.6%) chance of achieving SVR with continued treatment [33]. B2 Assessment of EVR at week 12 of combination therapy has thus been adopted into clinical practice for HCV genotype 1 patients. Response predictors at earlier stages during treatment have also been evaluated in relation to shortening the duration of therapy for CHC patients. A study evaluating shorter 24-week duration therapy for HCV genotype 1 patients with low baseline HCV RNA (40 U/l [21]. The presence of fibrosis can also be assessed using hepatic elastography [22]. Patients with cirrhosis have a 5.5-fold relative risk of death compared with non-cirrhotic hemochromatosis patients [23, 24]. Cirrhotic patients are also at risk of hepatocellular carcinoma. The mean age of cirrhotic patients with hepatocellular carcinoma was 68 years in a Canadian series, but was lower in Italian patients with concomitant viral hepatitis [25]. Although early detection of hepatocellular cancer has been clearly demonstrated by serial ultrasound and α-fetoprotein determination, curative treatment options remain limited. An elderly cirrhotic patient may not withstand a major resection and the residual cirrhotic liver remains a fertile ground for new tumor development. Organ shortages often preclude the possibility of immediate liver transplantation, although living related adult liver transplantation may improve this situation in the future.

Hepatic iron concentration and hepatic iron index The traditional method of assessing iron status by liver biopsy uses the semi-quantitative staining method of Perls. However, when moderate iron overload is present, the degree of iron overload can be difficult to interpret. Iron concentration can be measured using atomic absorption spectrophotometry. This can be done on a piece of paraffin embedded tissue, so special preparation is not required at the time of the biopsy. An advantage of cutting the tissue from the block is that one can be more certain that the tissue assayed is the same as the tissue examined microscopically. The normal reference range for hepatic iron concentration 486

Imaging studies of the liver Magnetic resonance imaging (MRI) can demonstrate moderate to severe iron overload of the liver. The technology is advancing and it is possible that eventually it may become as precise as hepatic iron determination [26, 27]. Proponents of MRI have emphasized the non-invasive nature of the test for the diagnosis and alleviated need for liver biopsy. As previously discussed, the role of liver biopsy has now shifted from a diagnostic tool to a prognostic tool. It is likely that the presence of an elevated ferritin with a positive genetic test will satisfy the non-invasive clinician more than an MRI study. MRI can also demonstrate the clinical features of cirrhosis such as nodularity of the liver, ascites, portal hypertension and splenomegaly as well as hepatocellular carcinoma. These features can be more readily assessed by abdominal ultrasound at a lower cost.

Genetic testing for hemochromatosis A major advance, which stems from the discovery of the HFE gene, is the diagnostic genetic test. The original publication reported that 83% of a group of patients with suspected hemochromatosis had the characteristic C282Y mutation of the HFE gene. In this report, the gene was called HLA-H but this name was later changed to HFE [1]. The C282Y mutation is also reported as 845A in some laboratories, reflecting the base pair change rather than the amino acid change. Subsequent studies in well-defined hemochromatosis pedigrees reported that 90–100% of typical hemochromatosis patients had the C282Y mutation [28]. The presence of a single mutation in most patients was in marked contrast to other genetic diseases in which multiple mutations have been discovered (cystic fibrosis, Wilson’s disease, α-1-antitrypsin deficiency). A second minor mutation, H63D, was also described in the original report [1]. This mutation does not cause the same intracellular trafficking defect of the HFE protein and many homozygotes for H63D have been found without iron overload in the general population. Compound heterozygotes (C282Y/H63D) and H63D homozygotes (H63D/ H63D) may resemble homozygotes with mild to moderate iron overload, particularly if a co-factor is present, for example NAFLD, HCV, or alcohol. However, these compound heterozygote (C282Y/H63D) patients usually have normal iron studies [9, 29]. The interpretation of the genetic test in several settings is shown in Box 30.1. The test may also be performed on DNA extracted from paraffin embedded tissue such as

CHAPTER 30

Hemochromatosis

BOX 3 0 .1 Interpretation of C282Y, genetic testing for hemochromatosis

C282Y homozygote: This is the classic genetic pattern that is seen in >90% of typical cases. Expression of disease ranges from no evidence of iron overload to massive iron overload with organ dysfunction. Siblings have a one in four chance of being affected and should have genetic testing. For children to be affected the other parent must be at least a heterozygote. If iron studies are normal, false positive genetic testing or a non-expressing homozygote should be considered. C282Y/H63D (compound heterozygote): This patient carries one copy of the major mutation and one copy of the minor mutation. Most patients with this genetic pattern have normal iron studies. A small percentage of compound heterozygotes have been found to have mild to moderate iron overload. Severe iron overload is usually seen in the setting of another concomitant risk factor (alcoholism, viral hepatitis, NAFLD). C282Y heterozygote: This patient carries one copy of the major mutation. This pattern is seen in about 10% of the Caucasian population and is usually associated with normal or mildly increased iron studies. In rare cases the iron studies are high in the range expected in a homozygote rather than a heterozygote. These cases may carry an unknown hemochromatosis mutation and measurement of body iron stores is helpful to determine the need for venesection therapy. H63D homozyote: This patient carries two copies of the minor mutation: Most patients with this genetic pattern have normal iron studies. A small percentage of these cases have been found to have mild to moderate iron overload. Severe iron overload is usually seen in the setting of another concomitant risk factor (alcoholism, or viral hepatitis). H63D heterozygote: This patient carries one copy of the minor mutation. This pattern is seen in about 20% of the Caucasian population and is usually associated with normal iron studies. This pattern is so common in the general population that the presence of iron overload may be related to another risk factor. Liver biopsy may be required to determine the cause of the iron overload and the need for treatment in these cases. No HFE mutations: There are currently some newly recognized mutations associated with iron overload that are

liver explants. Studies of explanted livers have demonstrated that many liver transplant patients classified as hemochromatosis patients are negative for the C282Y mutation [30]. This suggests that those patients may have had iron overload secondary to chronic liver disease rather than hemochromatosis. Therefore any interpretation of iron reaccumulation post liver transplant for hemochromatosis must be done with caution and with the benefit of genetic testing.

being studied in research laboratories (ferroportin, transferrin receptor 2, hepcidin, hemojuvelin). There will likely be other hemochromatosis mutations discovered in the future. If iron overload is present without any HFE mutations, a careful history for other risk factors must be reviewed and liver biopsy may be useful to determine the cause of the iron overload and the need for treatment. Many of these cases are isolated, non-familial cases. Non-expressing C282Y homozygotes: As genetic testing becomes more widespread an increasing number of persons have been found with the hemochromatosis gene without iron overload. Large-scale population studies in North America and northern Europe have demonstrated that approximately 50% of C282Y homozygous women and 86% of homozygous men will have an elevated ferritin. It is apparent that the prevalence of HFE mutations far exceeds the prevalence of biochemical iron overload and clinical symptoms attributable to hemochromatosis. Patients who are homozygous for the C282Y mutation should be considered at risk of developing iron overload, but if there are no abnormalities in transferrin saturation or ferritin in adulthood, it seems more likely that they are non-expressing homozygotes rather than patients who will develop iron overload later in life [36]. Family studies in hemochromatosis: Once the proband case is identified and confirmed with genetic testing for the C282Y mutation, family testing is imperative. Siblings have a one in four chance of carrying the gene and should be screened with the genetic test and serum ferritin. The risk to a child is dependent on the prevalence of heterozygotes in the community and is approximately 1 in 20 and much lower if the spouse is non-Caucasian. A cost-effective strategy now possible with the genetic test is to test the spouse for the C282Y mutation to assess the risk in the children. If the spouse is not a heterozygote or homozygote, the children will be obligate heterozygotes. This assumes paternity and no other gene or mutation causing hemochromatosis. This strategy is particularly advantageous where the children are geographically separated or may be under a different physician or health care system [37]. Genetic testing in general raises many perplexing questions, such as premarital testing, in utero testing, and paternity issues, which have not yet been tested in hemochromatosis.

Genetic discrimination has been a concern with the widespread use of genetic testing. A positive genetic test even without iron overload could disqualify a patient for health or life insurance. In the case of hemochromatosis, the advantages of early diagnosis of a treatable disease outweigh the disadvantages of genetic discrimination. Recent population studies have demonstrated that genetic discrimination is rare with hemochromatosis genetic testing [31]. 487

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Genotypic-phenotypic correlation in hemochromatosis If we define the presence of homozygosity for the C282Y mutation as a predisposition for the development of hemochromatosis, it provides for the first time a benchmark for the assessment of the phenotypic diagnostic tools that have been used for decades. In one study transferrin saturation, ferritin, hepatic iron index and iron removed by venesection were evaluated in referred putative homozygotes with a high pre-test probability of hemochromatosis. Ninetyfive percent (122/128) patients were homozygous for the C282Y mutation. The hepatic iron index was >1.9 in 91.3% of these cases, transferrin saturation >55% in 90%, serum ferritin >300 micrograms/l in 96% of men and >200 micrograms/l in 97% of women, and iron removed >5 g in 70% of men and 73% of women. Four homozygotes for C282Y had no biochemical evidence of iron overload. The sensitivity of the phenotypic tests in decreasing order was: serum ferritin, hepatic iron index, transferrin saturation and iron removed by venesection. Although the genetic test is useful in the diagnostic algorithm (see Figure 30.3), this study demonstrated both iron loaded patients without the mutation and homozygous patients without iron overload [17]. However, population-based studies have revealed a different clinical profile for C282Y homozygotes. It appears that many C282Y homozygotes will have no obvious symptoms related to iron overload and that 50% of women and 20% of men will have normal serum ferritin [1]. The biochemical clinical expression of hemochromatosis is illustrated in screening studies in Figure 30.2. The prevalence of signs and symptoms of hemochromatosis is more difficult to assess since there are not standardized criteria for their assessment. A recent study by Allen et al. suggested that 28% of male and 1% of female C282Y homozygotes from a population screening study had hemochromatosis related symptoms [32, 33]. A screening

study from Norway which utilized 149 liver biopsies, demonstrated cirrhosis in 4% of male and in none of the female C282Y homozygotes [12]. Only the presence of liver disease was significantly different between C282Y homozygotes and a control population in a screening study from San Diego, California [34]. Several studies have demonstrated that there is no increase in diabetes compared to control participants [1, 34, 35]. If an isolated heterozygote is detected by genetic testing, it is recommended to test siblings. Extended family studies are less revealing than a family study with a homozygote but more likely to uncover a homozygote than random population screening. It is important to remember that there will be patients with a clinical picture indistinguishable from genetic hemochromatosis who will be negative for the C282Y mutation. Most of these patients will be isolated cases, although a few cases of familial iron overload (ferroportin, transferrin receptor 2 and hepcidin mutations) have been reported with negative C282Y testing [38]. A negative C282Y test should alert the physician to question the diagnosis of genetic hemochromatosis and reconsider secondary iron overload related to cirrhosis, alcohol, viral hepatitis, NAFLD or iron loading anemias. If no other risk factors are found, the patient should begin venesection treatment similar to any other hemochromatosis patient.

Population screening Soon after the development of the genetic test for hemochromatosis, it seemed that hemochromatosis would be an ideal disease for population screening. It seemed to have a high prevalence, could be detected with low-cost iron tests, confirmed by a specific genetic test and could easily be treated. Hemochromatosis meets many of the guidelines

100

% with elevated ferritin

80

60

40

20

0 Olynyk 1999 Asberg 2001 Beutler 2002 Deugnier 2002 HEIRS 2005 Delatycki 2005 Allen 2008

3011

488

65,238

41,038

9396

99,711

11,307

31,314

Figure 30.2 The percentage of C282Y homozygotes discovered in population screening studies that have an elevated serum ferritin (>200 ug/l in women, >300 ug/l in men).

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Hemochromatosis

Patient has clinical features suggesting hemochromatosis and elevated transferrin saturation and/or serum ferritin

C282Y and H63D genotyping

C282Y homozygote

C282Y/H63D H63D homozygote

Ferritin < 1000 μg/l AST, ALT normal

C282Y heterozygote

Ferritin > 1000 μg/l AST, ALT elevated

No HFE mutations H63D heterozygote

Reassess other causes of iron overload

Liver biopsy with elevated liver iron concentration

Weekly phlebotomy until serum ferritin = 50 μg/l Genetic counseling Family studies Figure 30.3 Diagnostic algorithm for a patient suspected of having hemochromatosis. AST: aspartate transaminase; ALT: alanine transaminase.

established by the World Health Organization for screening (see Table 30.2). Large population screening studies have been done in North America, Europe and Australia using a variety of approaches and patient populations. A common finding is that there appear to be more genetic mutations than clinical illness. The natural history of untreated disease is the Achilles heel of screening for hemochromatosis. If the survival in untreated patients appears similar to control participants or treated patients, there is little rationale for identifying patients in the general population. Several epidemiological studies performed genetic testing for hemochromatosis many years after the initiation of the study and presented data on the serum ferritin and long-term survival of C282Y homozygotes and other genotypes that were followed for up to 25 years without treatment or awareness of their underlying condition (see Figure 30.4) [33, 39, 40]. A similar longitudinal study in type 2 diabetes found that there was no associa-

tion of HFE mutations or ferritin levels with all cause mortality or cardiovascular complications [41]. Universal screening is unlikely to be widely implemented, but selective screening in high-risk populations, such as men of northern European ancestry may be a preferred strategy. Other strategies include more intense physician and patient education about iron overload and extended pedigree studies. Screening patients with established causes of liver disease (e.g. HCV, HBV, autoimmune liver disease, etc.) for hemochromatosis is important as this will identify another co-factors causing liver damage and potentially fibrosis that is treatable.

Treatment of hemochromatosis Patients are initially treated by the weekly removal of 500 ml of blood. Patients attend either a blood transfusion 489

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Table 30.2 Population screening for hemochromatosis. WHO criteria for screening for medical disease

Phenotypic testing (serum iron, transferrin saturation, UIBC, ferritin)

Genotypic testing (C282Y mutation)

Is the disease an important health problem?

Yes (1 in 300)

Yes (1 in 200)

Is there an effective treatment?

Yes

Yes

Are there facilities for diagnosis and treatment?

Yes

Yes

Is there a presymptomatic stage?

Yes

Yes

Is the cost of screening reasonable?

Yes

If limited to few mutations

Is continuous case finding on an ongoing basis feasible?

Yes

Yes

Is there a suitable test?

Yes

Yes

Is the testing acceptable to the population?

Yes

Genetic discrimination?

Is the natural history of disease understood?

Natural history of untreated disease has not been well studied

Uncertain in non-expressing homozygotes

Is there agreement on whom to treat?

Yes, but the impact of treatment is difficult to assess

Yes

WHO; World Health Organization; UIBC: unsaturated iron binding capacity.

100

C282Y/C282Y

Survival probility

75

50

25

N = 15,792 C282Y homozygotes = 48

5

10 Years of follow up

service, where red cells and plasma are used for transfusion, or an ambulatory care facility. The venesection is carried out by a nurse using a kit containing a 16-gauge straight needle and collection bag. Blood is removed with the patient lying flat over 15–30 minutes. A haemoglobin test is done at the time of each venesection. If the hemoglobin decreases to less than 100 g/l the venesection schedule is modified to 500 ml every other week. Serum ferritin is measured periodically (every three months in severe iron overload, monthly in mild iron overload) and weekly ven490

15

20

Figure 30.4 The long-term survival in C282Y homozygotes (C282Y/C282Y) was not significantly different from patients with all of the other HFE genotypes in the ARIC study.

esections are continued until the serum ferritin is approximately 50 micrograms/l. Transferrin saturation often remains elevated despite therapy. Patients may then begin maintenance venesections three to four times per year. Iron reaccumulation is an inconsistent observation and many patients will go for years without treatment and without a rise in serum ferritin [41]. Chelation therapy is not commonly used for the treatment of hereditary hemochromatosis. The newest oral iron chelator, deferasirox, has been undergoing a clinical trial in hemochromatosis but its high

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cost and potential side effects (GI side effects, elevation in serum creatinine) may limit its use to secondary iron overload. There have been some studies, now, documenting reversal of fibrosis following iron depletion therapy [42, 43]. There are no randomized trials comparing venesection therapy to no treatment. Iron depletion before the development of cirrhosis can prevent cirrhosis and the development of hepatocellular carcinoma. Other disabling diseases such as arthritis, diabetes and impotence will likely be prevented. Therefore the goal is early detection and treatment before the development of cirrhosis.

References 1 Feder JN, Gnirke A, Thomas W et al. A novel MHC class I-like gene is mutated in patients with hereditary hemochromatosis. Nature Genetics 1996; 13: 399–408. 2 Adams PC, Barton JC. Haemochromatosis. Lancet 2007; 370: 1855–1860. 3 Andrews NC. Forging a field: the golden age of iron biology. Blood 2008; 112: 219–230. 4 Olynyk J, Trinder D, Ramm GA, Britton R, Bacon BR. Hereditary hemochromatosis in the post-HFE era. Hepatology 2008; 48: 991–1001. 5 Bridle K, Frazer D, Wilkins S et al. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homeostasis. Lancet 2003; 361: 661–673. 6 Piperno A, Girelli D, Nemeth E et al. Blunted hepcidin response to oral iron challenge in HFE-related hemochromatosis. Blood 2007; 110: 4096–4100. 7 Muckenthaler M, Vujic-Spasic M, Kiss J et al. HFE acts in hepatocytes to prevent hemochromatosis. Cell Metab 2008; 7: 173–178. 8 Babitt JL, Huang FW, Wrighting DM et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet 2006; 38: 531–539. 9 Adams PC, Reboussin DM, Barton JC et al. Hemochromatosis and iron-overload screening in a racially diverse population. N Eng J Med 2005; 352: 1769–1778. 10 Moirand R, Adams PC, Bicheler V, Brissot P, Deugnier Y. Clinical features of genetic hemochromatosis in women compared to men. Ann Int Med 1997; 127: 105–110. 11 Adams PC, Valberg LS. Evolving expression of hereditary hemochromatosis. Sem Liv Dis 1996; 16: 47–54. 12 Asberg A, Hveem K, Thorstensen K et al. Screening for hemochromatosis – high prevalence and low morbidity in an unselected population of 65,238 persons. Scand J Gastroenterol 2001; 36: 1108–1115. 13 Beutler E, Felitti V, Gelbart T, Ho N. The effect of HFE genotypes on measurement of iron overload in patients attending a health appraisal clinic. Ann Int Med 2000; 133: 329–337. 14 Adams P, Reboussin D, Press R et al. Biological variability of transferrin saturation and unsaturated iron binding capacity. Am J Med 2007; 120: 999.e1–7.

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15 Brissot P, Bourel M, Herry D et al. Assessment of liver iron content in 271 patients: a re-evaluation of direct and indirect methods. Gastroenterology 1981; 80: 557–565. 16 Adams PC, Kertesz AE, Valberg LS. Clinical presentation of hemochromatosis: a changing scene. Am J Med 1991; 90: 445–449. 17 Adams PC, Chakrabarti S. Genotypic/phenotypic correlations in genetic hemochromatosis: evolution of diagnostic criteria. Gastroenterology 1998; 114: 319–323. 18 Tavill AS. Diagnosis and management of hemochromatosis. Hepatology 2001; 33: 1321–1328. 19 Adams PC. Factors affecting rate of iron mobilization during venesection therapy for hereditary hemochromatosis. Am J Hematology 1998; 58: 16–19. 20 Morrison E, Brandhagen D, Phatak P et al. Serum ferritin levels predicts advanced hepatic fibrosis among US patients with phenotypic hemochromatosis. Ann Int Med 2003; 138: 627–633. 21 Beaton M, Guyader D, Deugnier Y, Moirand R, Chakrabarti S, Adams P. Non-invasive prediction of cirrhosis in C282Y-linked hemochromatosis. Hepatology 2002; 36: 673–678. 22 Adhoute X, Foucher J, Laharie D et al. Diagnosis of liver fibrosis using FibroScan and other noninvasive methods in patients with hemochromatosis: a prospective study. Gastroenterol Clin Biol 2008; 32: 180–187. 23 Niederau C, Fischer R, Purschel A, Stremmel W, Haussinger D, Strohmeyer G. Long-term survival in patients with hereditary hemochromatosis. Gastroenterology 1996; 110: 1107–1119. 24 Wojcik J, Speechley M, Kertesz A, Chakrabarti S, Adams P. Natural history of C282Y homozygotes for haemochromatosis. Can J Gastro 2002; 16: 297–302. 25 Fargion S, Mandelli C, Piperno A et al. Survival and prognostic factors in 212 Italian patients with genetic hemochromatosis. Hepatology 1992; 15: 655–659. 26 Gandon Y, Olivie D, Guyader D et al. Non-invasive assessment of hepatic iron stores by MRI. Lancet 2004; 363: 357–360. 27 St Pierre T, Clark P, Chua-anusorn W et al. Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance. Blood 2005; 105: 855–861. 28 The UK Haemochromatosis Consortium. A simple genetic test identifies 90% of UK patients with haemochromatosis. Gut 1997; 41: 841–845. 29 Rossi E, Olynyk J, Cullen D et al. Compound heterozygous hemochromatosis genotype predicts increased iron and erythrocyte indices in women. Clin Chem 2000; 46: 162–166. 30 Minguillan J, Lee R, Britton R et al. Genetic markers for hemochromatosis in patients with cirrhosis and iron overload. Hepatology 1997; 26: 158A. 31 Hall M, Barton J, Adams P et al. Genetic screening for iron overload: no evidence of discrimination at one year. J Fam Practice 2007; 56: 829–833. 32 Allen KJ, Gurrin LC, Constantine CC et al. Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med 2008; 358: 221–230. 33 Gurrin L, Osborne N, Constantine C et al. The natural history of serum iron indices for HFE C282Y homozygosity associated with hereditary hemochromatosis. Gastroenterology 2008; 135: 1945–1952.

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34 Beutler E, Felitti V, Koziol J, Ho N, Gelbart T. Penetrance of the 845G to A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 2002; 359: 211–218. 35 McLaren GD, McLaren C, Adams PC et al. Clinical manifestations of hemochromatosis in HFE C282Y homozygotes identified by screening. Can J Gastro 2008; 11: 923–930. 36 Yamashita C, Adams PC. Natural history of the C282Y homozygote of the hemochromatosis gene (HFE) with a normal serum ferritin level. Clinical Gastroenterology and Hepatology 2003; 1: 388–391. 37 Adams PC. Implications of genotyping of spouses to limit investigation of children in genetic hemochromatosis. Clinical Genetics 1998; 53: 176–178. 38 Pietrangelo A. Non-HFE hemochromatosis. Sem Liv Disease 2005; 25: 450–460. 39 Andersen R, Tybjaerg-Hansen A, Appleyard M, Birgens H, Nordestgaard B. Hemochromatosis mutations in the general

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population: iron overload progression rate. Blood 2004; 103: 2914–2919. Pankow J, Boerwinkle E, Adams PC et al. HFE C282Y homozygotes have reduced low-density lipoprotein cholesterol: the Atherosclerosis Risk in Communities (ARIC) Study. Translational Research 2008; 152: 3–10. Adams PC, Kertesz AE, Valberg LS. Rate of iron reaccumulation following iron depletion in hereditary hemochromatosis. Implications for venesection therapy. J Clin Gastroenterol 1993; 16: 207–210. Falize L, Guillygomarch A, Perrin M et al. Reversibility of hepatic fibrosis in treated genetic hemochromatosis: a study of 36 cases. Hepatology 2006; 44: 472–477. Powell L, Dixon J, Ramm G et al. Screening for hemochromatosis in asymptomatic subjects with or without a family history. Arch Int Med 2006; 166: 294–301.

31

Wilson’s disease James S Dooley1 and Aftab Ala2 1

Centre for Hepatology, University College London Medical School (Royal Free Campus), University College London and the Royal Free Sheila Sherlock Liver Centre, Royal Free Hampstead NHS Trust, London, UK 2 Centre for Gastroenterology, Hepatology and Nutrition, Department of Medicine, Frimley Park Hospital NHS Foundation Trust, Surrey, UK

Introduction

Physiological copper metabolism

Wilson’s disease (WD) is a rare autosomal recessive genetic disorder of copper metabolism. Mutations in the copper transporter ATP7B result in the accumulation of copper in the liver because excretion in bile is defective. Accumulation of copper in the body results in tissue damage which particularly affects the liver and brain so that patients present with either hepatic and/or neurological disease. The prevalence of Wilson’s disease is between 1:30,000 and 1:100,000. It was first described as a clinical syndrome in 1912 by Dr Kinnier Wilson. Until the development of oral copper chelators in the 1950s by Dr John Walshe, WD was uniformly fatal. In the majority of patients treatment halts disease progression and allows reversal of organ dysfunction, such that patients, although needing lifelong treatment, usually return to a normal life. The understanding of the molecular genetics, cellular biology and pathogenesis of WD has advanced over the last twenty years. However, there is still a lack of universal consensus on the optimal treatment regimen, which by implication means that several are effective. There are very few randomized or comparative studies of therapy and current recommendations are based predominantly on observational data published over the last 50 years. There is no single diagnostic test and evidence-based examination of the diagnostic approach shows that a combination of features is best used. Certain features allow a confident straightforward diagnosis of WD; ruling out WD (particularly in those with liver disease) may be challenging. Clinical issues include delayed diagnosis and deterioration during treatment.

Around 40% of dietary copper (intake being approximately 2–5 mg/day) is absorbed in the duodenum and upper jejunum. Absorbed copper passes in the portal vein to the liver. The copper is taken up across the sinusoidal aspect of the hepatocyte via the copper transporter 1 (CTR1) (Figure 31.1). This transporter is essential for healthy development and is thought to be the main mammalian process for the uptake of copper into cells [1]. Copper is potentially toxic in the cytoplasm; glutathione and metallothioneins are thought to bind copper, rendering it non-toxic. Another protein (ATOX1) is thought to deliver copper to ATP7B by a copper-dependent protein – protein interaction [2]. ATP7B transports copper into the trans-Golgi where it is incorporated into apoceruloplasmin to produce holoceruloplasmin. When hepatic copper levels are high, ATP7B is expressed in cytoplasmic vesicles, allowing excretion of copper into bile. This process involves COMMD1 (previously called MURR1), a protein which interacts directly with ATP7B [3]. Copper toxicosis of Bedlington Terriers, where there is deficient biliary copper excretion, is a result of mutations in COMMD1 [3]. Studies in non-Wilsonian copper storage disorders in humans have, to date, shown no abnormality in this protein [4]. The evidence for the normal function of ATP7B is based on studies of the trafficking of this protein between different cellular compartments in response to the concentration of copper [5]. In HepG2 hepatoma cells cultured in medium with a low copper concentration ATP7B localized to the trans-Golgi network. With increased levels of copper there is redistribution of APT7B to vesicles and thence to vacuoles. Immunohistochemical studies on human liver demonstrate punctuate immunoreactivity within the cell and localization also to the apical membrane adjacent to the bile canaliculus [6]. When the intracellular copper concentration is low or normal, ATP7B is found in the trans-Golgi

Evidence-Based Gastroenterology and Hepatology, Third Edition John WD McDonald, Andrew K Burroughs, Brian G Feagan and M Brian Fennerty © 2010 Blackwell Publishing Ltd. ISBN: 978-1-405-18193-8

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Sinusoidal blood

Cp-Cu

MT GSH CTR1 Cu

ATP7B

Nucleus

Atox1 Cp

ated with defective phosphorylation of ATP7B by adenosine triphosphate (ATP). This finding parallels the fact that the histidine 1069 is in a conserved motif within the ATP binding domain of ATP7B [13]. Techniques are now available for the analysis of various APT7B mutations and show their effect on copper transport activity [14].

Golgi

Molecular genetics

MURR1 Junction with adjacent hepatocyte Bile canaliculus Figure 31.1 Pathways of copper metabolism in the hepatocyte. See text for explanation (Cu=copper, CTR1=copper transporter1. MT=metallothioneins. GSH=glutathione. Cp=ceruloplasmin.) (reproduced with permission from Ala et al, Lancet 2007; 369: 397–408)

network described above. With excess intracellular copper the ATP7B moves towards the canalicular pole of the hepatocyte. Ceruloplasmin (Cp) is a member of the multi copper oxidase family of enzymes. It is also an acute phase protein. Cp itself is not essential for normal copper metabolism; it is for iron metabolism in which it is an important ferroxidase. It seems likely that the reason for the low Cp in WD is not the lack of hepatic expression of apoceruloplasmin (due to a low copper in the secretory pathway) but the change in the proportion of apo- to holoceruloplasmin in the circulation and the lower stability of apoceruloplasmin [7].

Molecular pathogenesis In WD there are mutations in the ATP7B gene. This gene was identified by three groups in 1993 [8-11]. The ATP7B gene is highly expressed in the liver, kidney and placenta. It encodes a transmembrane ATPase which is a copper-dependent P type ATPase. Mutations in ATP7B are associated with lack of entry of copper into bile and into the Golgi. This leads to hepatic copper accumulation which, depending on its severity, leads to hepatic and neurological features of WD. Mutations within the ATP7B gene variously affect the function of the ATP7B protein. The H1069Q mutation (which results in histidine to glutamate substitution at amino acid 1069) is the most common mutation found in patients of European origin. Studies on liver tissue from patients homozygous for this mutation with WD show that the ATP7B resided in the endoplasmic reticulum rather than the trans-Golgi network [12]. This mutation is associ494

Phenotype/genotype relationship Over 400 disease-related mutations in the ATP7B have been reported in WD (www.wilsondisease.med.ualberta. ca/database.aspdatabase). Most patients are compound heterozygotes. This makes phenotype/genotype correlation problematic. In some populations, particular mutations predominate [15]. Because of this, screening of specific mutations may be fruitful. Thus, around 50–80% of patients with WD from Central, Eastern and Northern Europe carry at least one allele with the H1069Q mutation [15]. There is a wide range of mutations in the Mediterranean region and their frequency varies between different countries. In some countries, for example Sardinia and Spain, other particular mutations are common. Studies of genotype/phenotype correlations of WD have been more made difficult by the large number of mutations that exist. Because of the prominence of the H1069Q mutation this has received most attention. Homozygosity for this mutation has been reported to correlate with late onset neurological disease in individual studies and in a metaanalysis [16]. There have been studies of genotype/phenotype associations with mutations in other genes but there is as yet no clinically applicable result [17].

Family screening using genetics Family screening for WD is covered later in this chapter. Clinical and biochemical tests should be done, but molecular genetics with identification of mutations is an invaluable tool. If both mutations are known in the index patient with WD, testing of indeterminate siblings for the same mutations will define whether or not they are either affected, heterozygote carriers or normal.

Clinical manifestations The clinical spectrum of manifestations of Wilson’s disease is wide (Table 31.1). Patients can present acutely with liver failure, hemolysis or both. They may also present with chronic liver disease or neuro-psychiatric problems or a

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Table 31.1 Clinical features of Wilson’s disease. Hepatic Acute liver failure (+/− hemolysis) Chronic hepatitis (persistent transaminitis) Cirrhosis (compensated or decompensated) Neurological Tremor Choreiform movements Parkinsonian or akinetic rigid syndrome – i.e. partial Parkinsonism Gait disturbances Dysarthria Pseudobulbar palsy Rigid dystonia Seizures Migraine headaches Insomnia Ophthalmological Kayser Fleischer rings Sunflower cataracts Psychiatric Depression Neuroses Personality changes Psychosis Other manifestations Renal tubular acidosis, aminoaciduria, nephrolithiasis Skeletal

combination of the two. Patients who present initially with neurological or psychiatric features tend to be older than those who present with clinical manifestations of liver disease or hepatic decompensation. Classically, WD is recognized as presenting most often in children and young adults, and indeed it had been considered that it did not occur in individuals aged more than 40 years. However, it is now recognized that later presentation does occur, with a recent report of neurological presentation in a group aged 40–52, and hepatic presentation at up to 58 years of age [18]. This emphasizes the need to have WD within the differential diagnosis of patients with unexplained liver disease and particular neurological symptoms presenting anywhere from teenage years to the fifth decade, and beyond. Most patients with central nervous system involvement are believed to have liver disease at the time of presentation but they may not be symptomatic from their liver disease. However, hepatic histology is not generally available for these patients because the diagnosis is usually established solely on the basis of the presence of Kayser Fleischer rings with a decreased ceruloplasmin concentration.

Wilson’s disease

It is generally the case that those presenting with acute liver disease, even in the younger age group, already have cirrhosis. Deterioration at this stage appears to be based upon the toxic effect of free copper causing decompensation of liver disease [19], or hemolysis [20].

Hepatic disease Pathology In the early stages of the disease, diffuse cytoplasmic copper accumulation can only be seen with special immunological stains detecting copper. These are not routinely available. The early accumulation of cytoplasmic copper is associated with macrosteatosis, microsteatosis and glycogenated nuclei. Ultra structural abnormalities (on electron microscopy) include enlargement and separation of the mitochondrial inner and outer membranes, with widening of the intercrystal spaces, to increases in the density of granularity of the matrix, or presence of larger vacuoles. In the absence of cholestasis, these changes are regarded as pathognomonic of Wilson’s disease. These initial stages of WD progress to an intermediate stage which is characterized by periportal inflammation, mononuclear cellular infiltrates, erosion of the limiting plate, lobular necrosis and bridging fibrosis. These features may be indistinguishable from those of an autoimmune hepatitis [21, 22]. Mallory bodies are seen in up to 50% of liver biopsy specimens [23]. Cirrhosis almost invariably follows with either a micro-nodular or mixed macro-micro nodular pattern. In patients with fulminant hepatic failure, parenchymal apoptosis, necrosis and collapse may be prominent, often, as already mentioned, on a background of cirrhosis [24]. One series of results of liver biopsy in WD showed cirrhosis in 54% of 83 patients with a hepatic presentation, and 41% in 34 with a neurological presentation [25]. Confirmation of excess copper histologically (rhodanine, rubeanic acid) may be helpful in diagnosis but if absent does not exclude Wilson’s disease. The lack of immunoreactivity to copper binding protein (orcein stain) may occur because of the diffuse presence of copper in the cytoplasm and because of the stain’s low sensitivity.

Clinical features Wilson’s disease can present as fulminant hepatic failure. There is worsening coagulopathy and encephalopathy. There may be an associated Coombs’ negative hemolytic anemia, when there is a substantial increase in serum total and free copper as well as a high urinary copper concentra495

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tion. This complication is recognized as potentially leading to renal failure. Around 5% of patients present in this manner [26], with most patients being in the second decade of life, when KF rings may not yet be formed. Almost all such patients already have cirrhosis, although some might show evidence of massive necrosis with only bridging fibrosis, which clearly would progress to cirrhosis with time. Concentration of serum alkaline phosphatase is frequently low and this feature has led to the suggestion that a ratio of alkaline phosphatase concentration (in IU/L) to serum bilirubin concentration (mg/dl) is diagnostically useful. A ratio of less than 2 [27, 28] or 4 [29], may be diagnostic or very suggestive of Wilsonian fulminant hepatic disease. In those with a more chronic hepatic presentation, the clinical picture can be similar to other forms of chronic hepatitis, which, as already noted, emphasizes the need for WD to be in the differential diagnosis of such patients. Some patients present with an asymptomatic cirrhosis. These would have the usual clinical features, including spider nevi, splenomegaly, portal hypertension and ascites. Cirrhosis may be well compensated. Hepatocellular carcinoma is very rarely associated with Wilson’s disease, but as in other causes of cirrhosis it may occur [30, 31]. In a series of 11 patients reported (from a total cohort of 363) there were cholangiocarcinomas (three cases) and malignancies of uncertain origin (three cases) as well as three hepatocellular carcinomas [30]. If neurological features occur in patients with liver disease, they usually do so 2–5 years later [32].

Eye changes The classic finding in patients with WD is the Kayser Fleischer (KF) ring. KF rings are caused by the granular deposition of copper on the inner surface of the cornea in Descemet’s membrane. They are most apparent at the periphery of the cornea. The upper pole is affected first. Although sometimes visible to the naked eye as a goldenbrown ring on the periphery of the cornea, slit lamp examination by an experienced ophthalmologist is necessary to confirm the presence or absence of KF rings. Appearances indistinguishable from KF rings have also been seen in other forms of chronic liver disease, in particular chronic cholestasis, and cryptogenic cirrhosis [33]. Sunflower cataracts, also only visible by slit lamp examination, are brilliantly multi-coloured [34]. Interestingly, they do not impair vision. Both of these findings disappear with successful medical therapy or after liver transplantation. The re-appearance in “the medically treated” patient suggests non-compliance with therapy [35]. Other less common ophthalmological findings include night blindness, exotropic strabismus, optic neuritis and optic disc pallor. 496

Neurological and neuro-psychiatric disease Pathology Histologically, there is an increase in astrocytes in the grey matter, associated with swollen glia, liquefaction, and appearances of spongiform degeneration. Neuronal loss is often accompanied by gliosis and active glial fibrillary protein. The characteristic astrocytes are Alzheimer type I and type II cells. Opalski cells are distinctive for WD [36]. These cells are thought to be derived from from degenerating astrocytes [37].

Clinical features Neuropsychiatric signs are present in 40–50% of patients with WD [26]. The neurological changes have been classified as: (1) an akinetic-rigid syndrome similar to Parkinson’s disease; (2) pseudosclerosis dominated by a tremor; (3) ataxia; and (4) a dystonic syndrome [38]. Subtle changes can appear before the characteristic neurological features. These include changes in behavior, deterioration of schoolwork or an inability to carry out activities that require good hand-eye coordination. There may be deterioration of hand writing and consequent micrographia – as in Parkinson’s disease. Other neurological features include tremor, plasticity, lack of motor coordination, dysarthria, drooling and dystonia. Seizures, migraine, headaches and insomnia have also been reported. As well as behavioral changes already described, depression, anxiety and frank psychosis are seen [39]. Cognitive dysfunction in patients with WD may be present with neurological changes, often in the absence of detectable cortical changes or hepatic encephalopathy. This lends support to pathological changes of basal ganglia as being the primary cause in WD of cognitive deficit [40]. All patients with WD should have a neurological examination. Patients with obvious symptoms or signs need to be seen by a neurologist, preferably with a special interest in movement disorders, before treatment. A specific assessment tool with neurological features (based on that for Huntingdon’s disease) has been used in clinical trials to assess patients [41]. However, a new Unified Wilson’s Disease Rating Scale (UWDRS) has value in assessing disease severity [42].

Imaging Structural brain MRI for WD has shown widespread lesions in the putamen, globus pallidus, caudate, thalamus, mid brain, pons and cerebellum as well as cortical atrophy and

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white matter changes. Broadly, these lesions show high signal intensity on T2 weighted images and low intensity on T1 scanning [43]. These changes tend to be more severe and widespread in patients with neurological WD [44], although MRI changes may be present in those without neurological symptoms or signs.

Other clinical changes There may be bone and peri-articular abnormalities, including osteomalacia, osteoporosis, spontaneous fractures, adult rickets, osteoarthritis, osteochondritis dissecans, chondrocalcinosis, subchondrial cyst formation and azure lunulae of the fingernails. The most common sites for skeletal and articular abnormalities are the knee joints and spine [45]. Myocardial copper accumulation can cause cardiomyopathy and arrhythmias although these are clinically rare [46]. Other rare extra hepatic/neural manifestations include hypoparathyroidism, infertility, repeated miscarriages [47] and renal abnormalities [48], including renal tubular acidosis with aminoaciduria and nephrocalcinosis.

Diagnostic approach Certain tests are essential when the possibility of WD has been raised. No single one of these on its own has 100% specificity or sensitivity for WD. A combination of features is necessary for a definitive diagnosis to be made [49]. The important observations or biochemical measurements used in the work-up of patients with suspected WD are: serum ceruloplasmin, serum total and free copper, ophthalmological examination (for KF rings); 24-hour urine excretion of copper, and measurement of liver copper content. One might add to this the presence of two mutations found on molecular analysis of the ATP7B gene, but since some of these may be polymorphisms caution is needed in making a diagnosis based on molecular analysis alone. Other useful measures include: (1) urinary excretion of copper after penicillamine challenge (this test has been described and validated in the pediatric age group) [50]; (2) the presence of rhodamine staining on liver biopsy histology, if hepatic copper measurement has not been done. There are potential problems with all the observations and measurements described above. Serum ceruloplasmin concentrations are well recognized to be normal in a proportion of patients presenting particularly with hepatic WD [51]. Urinary copper excretion can be increased in some other types of liver disease. The same is true for liver copper concentration, particularly in cholestatic disease.

Wilson’s disease

However, if an individual with neurological symptoms consistent with Wilson’s disease has Kayser Fleischer rings and a low serum ceruloplasmin concentration, the diagnosis is made. Kayser Fleischer rings are usually present in patients presenting with neurological Wilson’s disease – 18 of 20 patients in one report [51]. In patients presenting with liver disease, diagnosis can be more difficult [51]. Roberts and Schilsky [49] have provided several valuable algorithms for the diagnostic approach for patients with different initial features suggesting WD. They provide specific recommendations on the basis of previous published work and the authors’ experience in caring for pediatric and adult patients with WD. To provide further help with the diagnostic route, Ferenci et al. [52] have proposed a scoring system (Table 31.2). Within this, clinical, biochemical, histological and molecular genetic data are allocated a score. The cumulative total gives an indication of the possibility of a particular individual having WD. This scoring system may be helpful if diagnosis of the disease is being considered [53]. The recent report of a group of pediatric patients as part of the analysis of the Euro Wilson’s Group of patients gives some information on this scoring system [54].

Liver function tests Serum aminotransferase activity is in general abnormal in WD except at a very early stage. The rise in aminotransferase activity is often mild and does not necessarily reflect the severity of liver disease. The ratio of alkaline phosphatase to serum bilirubin in mg/dl has already been discussed. This may be valuable in raising the possibility of WD in patients with fulminant hepatic failure but again is not 100% specific and may only be valuable in particular patient groups [55].

Ceruloplasmin A low serum ceruloplasmin concentration (normal range 0.2–0.5 g/l) should raise the question as to whether WD is a possible diagnosis. However, it should be emphasized that many patients presenting to a hepatology clinic can have a low ceruloplasmin, but in only a small fraction is WD diagnosed [56]. On the other hand, a low ceruloplasmin may be found in hypoproteinemic states due, for example, to the nephrotic syndrome, in copper deficient states (due to malabsorption) and in inherited diseases such as aceruloplasminemia [57]. In the latter two situations, the serum ceruloplasmin may be so low as to be undetectable by laboratory methods. A normal serum ceruloplasmin in WD patients presenting with active liver disease is interpreted as due to an 497

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Table 31.2 Proposed scoring system for diagnosis of Wilson’s disease (from Ferenci et al, 2003; ref 52). Score Clinical Kayser Fleischer rings (slit lamp exam) present absent

2 0

Neuropsychiatric symptoms suggestive of WD (or typical MRI features) present 2 absent 0 Coombs’ negative haemolytic anemia (plus high serum copper) present absent

1 0

Laboratory results Urinary copper (in absence of acute hepatitis) normal 1–2x upper limit normal >2x upper limit normal

0 1 2

normal but > 5x normal after D-penicillamine challenge (2x 0.5 gm)

2

Liver copper concentration normal up to 5x upper limit normal >5x upper limit normal

−1 1 2

Rhodanine positive hepatocytes (only if quantitative Cu measurement not available) absent present

0 1

Serum ceruloplasmin (nephelometric assay normal > 20 mg/dl) Normal 10–20 3 ULN or AST > 2 ULN, or bilirubin > 17 μmol/l) (RR, 2.3) [48]. There is no good evidence that the AMA titer correlates with the course of PBC [54] (although it can fall with treatment [55]), but some groups have suggested specific anti-nuclear antibodies may delineate subtypes of PBC [27]. This, however, remains to be validated widely [56]. Aside from the increasing rarity of liver deaths from PBC, it has also become very difficult to use death as an endpoint, since most patients with decompensated PBC, if they have no contraindication, are referred for liver transplantation. As liver transplantation has become established for end-stage liver disease in particular, it has been used as a final outcome measure by many. Even transplant has some variability; however, certainly as some patients in the past have been transplanted for symptoms, different centers have longer waiting times, whilst factors such as blood group and body size can alter the duration of waiting. With the advent of scoring systems such as MELD, these issues will be largely addressed. Furthermore, perhaps because of therapy the rates of those patients with PBC 512

going to transplant continues to fall markedly [24]. Over a 12-year period (1995 to 2006) PBC and PSC transplant data of first-time liver recipients from the United Network for Organ Sharing database were collected. Although the absolute number of liver transplantations in the USA increased by an average of 249 transplants per year the absolute number of transplants performed for PBC decreased by an average of 5.4 cases per year. The absolute number of transplantations for PSC showed no statistical change.

Therapeutic trial design: assessment of credibility Understanding the limitations of the available evidence is essential for those interested in the evidence base for treatments of PBC. Numerous trials form the basis of the current treatment offered to patients. In evaluating such work a number of concerns arise for a disease such as PBC which is relatively uncommon and has a slow and varied natural history. To establish appropriate study size requires not only a large sample of historical data to chart the natural history of untreated disease but also pilot data, from which an estimate of the expected benefit can be calculated (sample size must also assess the frequency of adverse events). Historical data may not, though, always remain valid, for example the exclusion of chronic hepatitis C was only possible after approximately 1990, and patterns of presentation may change with time. The pivotal patient descriptions in the New England Journal of Medicine by Sherlock in 1973 clearly do not reflect those seen now [23, 57]. Recognized improvements in trial management have helped produce more robust data, with much thought given to careful trial design (e.g. double blinded, prior sample size calculation, stopping rules, crossover arms, and intention-to-treat analysis). The intention-to-treat principle is particularly relevant when carrying out statistical analysis of outcome to avoid as much bias as possible when interpreting the data. This means that all patients who are randomized need to be included in the final analysis, even though they may have been censored at a very early point in the trial because of untimely death, need to withdraw from the study, non-compliance, etc. Using the intention to treat principle allows for a very conservative analysis of the effectiveness of therapy, but permits assessment of the “real life” situation, that is, the generalizability of the study. Meta-analysis can also overcome some concerns, particularly sample size, but many assumptions are made about inclusion and exclusion of studies, and original raw data is not always accessed. Additionally, meta-analysis is a tool to define the gaps in knowledge (and thus to help the design of better studies), rather than a true grading system for an intervention, meaning conclusions drawn may

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reflect the quality and quantity of the evidence available as much as anything else. Variability in clinical practice, referral biases and varied ethnicity also generate difficulties as clinicians pool their patient resources. Finally, a major challenge relates to early detection of disease such that significant events, for example death or liver transplantation are unlikely to occur during any single trial. The use of surrogate markers (biochemical response, histological change, disease risk scores) as endpoints are by necessity employed, but their own origin and limitations need to be recognized as already discussed [58].

Randomized controlled trials of treatment for primary biliary cirrhosis Immunosuppression As the archetypal presumed autoimmune disease, inevitably immunosuppression has been evaluated as a therapy. Because the majority of patients with PBC are women and osteoporosis is prevalent (but not necessarily causally related to PBC [59–61]), corticosteroid therapy has for the most part been avoided. Trials of immunosuppressive therapy in PBC have employed azathioprine, cyclosporin, methotrexate, prednisolone, chlorambucil, thalidomide and, more recently, budesonide and mycophenolate mofetil. Neither of the two trials of azathioprine showed a beneficial effect of this drug on survival [62, 63]. The first trial had an inadequate sample size, lacked a placebo control group and predetermined stopping rules, and the results were not analyzed according to intention to treat. The second trial of azathioprine although much larger (248 patients), did not include a sample size calculation to assure that it had adequate power, and the withdrawal rate was greater than 20% in both the azathioprine and placebo groups. Despite randomization, the two groups were not stratified for factors known to influence survival and were not comparable at baseline. Only after employment of the Cox multiple regression analysis to adjust for these baseline differences was a benefit of treatment on survival observed. This difference in survival between the treatment groups could only be measured in months, which may not be clinically meaningful. Patients were followed for up to ten years, but the number of patients still being followed at that period was only nine in the azathioprine and none in the placebo group. It appears that the intention to treat principle was not used in the analysis, since 32 patients were excluded from the analysis because of incomplete data. Thus, the validity of the small benefit in survival can be further questioned. A1d Mycophenolate mofetil similarly has been disappointing, with no important clinical benefits, albeit in data from a single, small pilot study of 25 patients with PBC lasting one year [64].

Primary biliary cirrhosis

Several small trials and one large trial (349 patients) of cyclosporin therapy have been published [65–68]. This trial ran into the same problems as had been encountered with the large azathioprine trial, that is, lack of comparability of the two treatment groups at baseline. Even though there were a similar number of deaths, 30 in the cyclosporin group and 31 in the placebo group, the authors concluded that survival was improved in the cyclosporin-treated patients. Renal impairment was observed in 9% and systemic hypertension in 11% of the cyclosporin-treated patients (1.7% and 1% in placebo-treated respectively). These two serious adverse effects in patients whose disease is relatively slowly progressive precludes the use of this drug in the long-term treatment of PBC. A1d Tacrolimus, a similar agent, has not been studied to date formally in PBC, neither has the other increasingly popular immunosuppressant, rapamycin. Methotrexate was suggested to be of value in pilot studies [69, 70]. In one RCT of therapy sixty patients were recruited, 30 randomized to low-dose therapy (2.5 mg three times per week). At the end of six years, the serum bilirubin and Mayo risk score were higher in those receiving methotrexate, suggesting that the drug may be toxic in patients with PBC [71]. In a large NIH effort (placebo-controlled, randomized, multicenter trial comparing the effects of methotrexate plus UDCA to UDCA alone on the course of PBC) methotrexate when added to UDCA for a median period of 7.6 years had no effect on the course of PBC treated with UDCA alone [72]. A1d This study illustrates some of the difficulties of trial design: at the time of planning, it was anticipated that the five-year, transplant-free survival would be 83%, whereas the experience in this trial corresponded instead to a 94.5% five-year and 84.3% eightyear transplant free survival probability. The lower event rate meant that patients had to be followed for a longer time period, and this in turn probably contributed to a higher rate of patients discontinuing methotrexate. The authors calculated, using the log rank statistic to compare the distributions of time to an event in a randomized trial, that they needed to observe 88 events in order to have 90% power to detect a two-fold improvement in the risk of an event. With their calculations in a study that followed subjects for an average of eight years (with an expected 7% rate of death and 16% rate of transplant or death), this implied they needed to randomize a total of 1257 subjects when using the endpoint of overall survival, or 550 subjects when using the endpoint of transplant-free survival. If one then appreciates their recruitment reality, the enormous challenges for investigators planning future studies is clear: in this case investigators at 12 centers in the USA screened 535 patients for possible entry into the trial. At screening 393 of the 535 patients were determined to meet the defined inclusion criteria, and 385 patients went on to meet the screening inclusion and exclusion criteria. Three hundred 513

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patients progressed to a pre-entry evaluation phase and ultimately 265 patients were randomized with equal probability in a double-blind fashion. A small, three-year RCT of prednisolone has been done [73]. A1d A significant reduction in the serum bilirubin level (a valid surrogate outcome measure) was observed in treated patients, but osteoporosis in those who received corticosteroids worsened. However, a trial with a very small sample size of bisphosphonates in patients with PBC treated with corticosteroids indicates that etidronate significantly stabilizes bone mineral density in vertebrae of patients with PBC receiving corticosteroids [74]. Hence, it may be appropriate that corticosteroids be re-evaluated in the therapy of PBC now that patients can be given preventive therapies to reduce the complication of osteoporosis. Budesonide is an oral corticosteroid which is eliminated on first pass through the liver. Thus it was hoped that this agent could benefit patients with PBC without having a deleterious effect on bone mineral density. In the first small RCT by Leuschner et al., improvement in liver biochemistry, IgM values and liver histology was observed in the few patients studied, most of whom had very early disease [75]. In a second study by Angulo et al., no benefit was observed and the Mayo risk score increased significantly in those randomized to budesonide for a year and bone mineral density measurements deteriorated in the lumbar spine (p < 0.01); it is likely that many of these patients had advanced PBC so that the benefit of the first-pass effect was lost [76]. Subsequent work from Finland has alluded to a histological benefit when combined with UDCA and the observation that interface hepatitis on baseline biopsy is predictive of outcome in PBC (as well as a failure to normalize transaminases with UDCA) does suggest that a subgroup may benefit from immunosuppression [77]. A1d Interest therefore remains in using budesonide adjunctively in those with more florid hepatitic features. However, Wolfhagen et al. in another small RCT involving 50 patients with PBC with suboptimal response to UDCA, treated patients with additional prednisone (30 mg/day tapered to 10 mg/day) and azathioprine (50 mg/day) [78]. There was no improvement in bilirubin. The trial was too small and of too short a duration to examine the effect on survival. A1d

A small study of 13 patients randomized to 0.5–4 mg daily of chlorambucil (mean 2 mg daily) compared with placebo has been reported [79]. All treated patients developed some degree of bone marrow suppression and discontinuation of therapy was required in four. A 30% withdrawal rate due to drug toxicity indicates that this drug should not undergo further evaluation in patients with PBC. A1d A very small and short (six-month) RCT of 18 PBC patients taking thalidomide has been reported, showing little benefit of this treatment [80]. However, this study lacked adequate power to evaluate this form of 514

therapy in any meaningful way. No benefit on serum bilirubin was observed during the six months of treatment. An alternative approach has been to use drugs that may not interfere with the primary cause, that is, immune-mediated bile duct destruction, but interfere with the progression of the disease, either by reducing fibrogenesis or by reducing cholestasis. Two potential antifibrotic drugs have been assessed: colchicine in four good studies [81–84] and D-penicillamine in many more [85–92]. The studies of colchicine therapy are interesting, but unfortunately all the size of the populations studied are small. A Cochrane Hepato-Biliary Group systematic review of randomized clinical trials for this agent included ten trials involving 631 patients, only four of which were high-quality [93]. No significant differences were detected between colchicine and placebo/no intervention regarding mortality (relative risk (RR), 1.21; 95% CI: 0.71–2.06), mortality or liver transplantation (RR = 1.00; 95% CI: 0.67–1.49), liver complications, liver biochemical variables, liver histology, or adverse events. A1c While the numerous trials of D-penicillamine demonstrated great interest, the results are also disappointing. Unlike patients with Wilson’s disease, adverse effects of therapy were particularly common, resulting in a high withdrawal rate, similar to the experience with rheumatoid arthritis. This drug is not recommended for the treatment of PBC and a meta-analysis is consistent with this (including seven trials randomizing 706 patients) [94]. A1c

Reduction of cholestasis: ursodeoxycholic acid The prevailing view remains that UDCA improves the natural history of PBC [95], although the evidence for efficacy has been cumulative, is imperfect, and has been appropriately challenged as dogma [96, 97]. A1a Japanese researchers first isolated UDCA from bear bile in 1927; bear bile itself having a track record in traditional medicine as a choleretic [98]. UDCA is the natural intestinal metabolite of chenodeoxycholic acid (7-ß epimer). In the 1960s patients with gallstones were found to have lower biliary levels of cholic acid and chenodeoxycholic acid, which led to trials of oral bile salt supplementation in hepatobiliary disease. UDCA is less hydrophobic and more hydrophilic than other bile acids, with apparently less toxicity towards the hepatobiliary epithelium. Its therapeutic mechanism of action includes expansion of the hydrophilic bile acid pool, a direct choleretic effect (administration results in a bicarbonate-rich choleresis and modulation of biliary transporter proteins), anti-inflammatory effects (UDCA interacts with the glucocorticoid receptor in vitro) and anti-apoptotic effects on hepatic epithelia [99]. Cessation of therapy with UDCA leads to a return of abnormal liver biochemistry in those with PBC who respond, demonstrating that the initiating and perpetuating factors of PBC remain unresolved.

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UDCA normally accounts for about 4% of bile acids but with pharmacotherapy UDCA becomes the predominant bile acid. Leuschner showed that when treating gallstones with UDCA in those with histologically confirmed HBsAgnegative chronic active hepatitis a fall in transaminases occurred [100]. In further work to investigate the doseresponse relationship for UDCA, three different doses were given to patients with PBC, PSC and chronic hepatitis. This allowed Podda et al. to show that significant falls in liver biochemistry occurred at dosages of 4–5 mg/kg daily, but higher doses (8–10 mg/kg and 12–15 mg/kg) induced further improvements, with the changes correlated approximately with the enrichment of bile by UDCA [101]. Subsequent studies confirmed a correlation between the degree of bile enrichment and improvement in liver biochemistries and PBC Mayo risk score, and overall in PBC the data suggest that the optimum dose of UDCA if used should be 13 to 15 mg/kg per day, given as a single daily dose [40, 55, 102, 103]. UDCA at this dose is very safe, with minimal side effects: weight gain (approx. 3 kg in the first 12 months [104]), hair loss and, rarely, diarrhea and flatulence. Additionally, nothing suggests UDCA is teratogenic but it is usually stopped before and during the first trimester, and restarted subsequently, with there being a good safety profile from its use in intrahepatic cholestasis of pregnancy [105].

Justification for the widespread use of UDCA Many studies have attempted to demonstrate clinical efficacy for UDCA, particularly following initial studies showing a fall in bilirubin levels in patients with PBC, with most trials showing beneficial effects of UDCA on biochemical parameters in particular. With such a slow natural history any individual trial will inevitably lack the power to address endpoints such as death or liver transplantation. Additional criticism can be made for assuming that every patient benefits equally, that is, identifying and treating more patients with mild disease may be self-fulfilling if those patients were never destined to progress. Moreover whilst appealing to assume that the natural history of the disease is unchanged, the absence of a clear cut pathophysiologic understanding means that such an assumption should not necessarily be considered correct. The cumulative evidence that convinces most to prescribe UDCA, has nevertheless come from individual and pooled analysis. Of note the Mayo Clinic followed up patients with PBC treated with UDCA and have demonstrated a treatment-related prolongation in transplant free survival [106–108]. French cohorts with long-term followup similarly demonstrate survival benefit [109], and this was reiterated and furthered by a Spanish cohort including nearly 200 patients treated for a mean of 6.7 years [47]. Pathophysiologically early disease is most likely to respond to intervention before duct loss is established and fibrosis

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present. In those with early stage disease, a biochemical response to UDCA (normalization or a 40% reduction from baseline) after one year was associated with a similar survival to the matched control population. In the Netherlands ter Borg and colleagues were able to show a survival benefit without transplant for low-risk patients compared to survival predicted by the Mayo risk model (which, as discussed, may not be a perfect risk score to employ in this case if the comparison group has predominantly early stage disease, as survival may be underestimated); moreover overall survival was nearly the same as for a control population [110]. B4 A UK study that examined a large cohort not receiving UDCA did not, however, demonstrate differences in outcomes between treated and untreated patients [111]. A recent publication, as discussed, looked at defining the biochemical response a year after treatment, to identify UDCA-treated patients at risk of death or transplant and showed how UDCA responders had a ten-year, transplant-free survival rate of 90%, compared to 51% for those who did not [48]. B4 Three larger double-blind randomized trials used the same dose of UDCA (13–15 mg/kg per day), and thus the results have been analyzed according to an intention to treat principle [102, 107, 112, 113]. In two of these a composite “treatment failure” outcome measure was used, and in the third the percentage change in total serum bilirubin over two years was used as the primary outcome measure. Detailed sample size calculations and clear-cut predetermined definition of study duration were only described for this latter study. Few adverse effects of UDCA were reported and the withdrawal rate was less than 20% in all three studies. In two of the three trials, some patients initially randomized to placebo were switched to open label UDCA after the first 24 months, that is, the studies have a crossover design. However, the results were analyzed according to intention to treat (methodologically this can be criticized in studies with large crossover designs), so that those patients initially randomized to receive placebo and subsequently switched to receive UDCA remained in the placebo group for the purposes of analysis. Ultimately, then, this combined analysis of the three trials (548 patients) showed a one-third reduction in the risk of death or transplant, for patients with moderate to severe PBC, that is, UDCA therapy for up to four years led to an increase in time free of liver transplantation. Subgroup analyses did not show any benefit in patients who, at baseline, had a total serum bilirubin of less than 17–68 μmol/l and/or stage I/II liver histology. These subgroup analyses do not prove that UDCA is ineffective in patients with asymptomatic and/or early disease, but they do suggest that clinical trials in such patients would require very large numbers of patients and would be required to be of such long duration to show any benefit of the treatment that they would not be feasible. One other concern raised was the observa515

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tion that those patients crossed over to UDCA, continued to have a poorer clinical course. A further large trial (151 patients) employed a smaller dose (10–12 mg/kg bodyweight daily) and a different preparation of UDCA [114]. After two years of treatment no difference in survival was seen, there being eight deaths in those randomized to UDCA and 12 in those randomized to placebo. Prolonged follow-up also showed no survival benefit [115].

Meta-analysis findings It should be pointed out that the pooled analysis of the three trials is not a systematic review or meta-analysis, but rather was done by pooling of results from three trials which were of similar design. This procedure differs from a systematic review or formal meta-analysis, which attempts to minimize bias by the consideration and inclusion of all relevant trials, justifies the exclusion of trials from the analysis, and explores heterogeneity between trials and the reasons for variation in results. A formal meta-analysis which demonstrates benefit from an intervention may also include a sensitivity analysis to indicate the number of unpublished or excluded trials of specified size with negative results which would be required to negate the results of the meta-analysis. Meta-analyses may suffer from the opposite weakness cited for the combined analysis of similar trials, that is, they may involve pooled analysis of trials which differ sufficiently in their design that they are not truly comparable. Accordingly, caution should be exercised in interpreting both combined analyses and meta-analyses. For PBC much debate has been generated because the various meta-analyses have been inconsistent. Some conclude no beneficial effect on the incidence of death and/or transplant, despite improvements in serum bilirubin, jaundice and ascites [96, 97]; thus, UDCA treatment offers no benefit. This contrasts with others showing that long-term treatment with the optimal dose of UDCA could improve survival free of transplant [116]. One needs to appreciate the varying, and often inadequate sample size and duration of several studies, as well as inclusion of data from trials using suboptimal doses. Both Goulis et al. and the Cochrane group have performed detailed analyses of the heterogeneous studies in which treatment periods ranged from as little as six months up to four years, the daily dose of UDCA ranged from 7.7 mg/ kg to 15 mg/kg, and there was a wide range of disease severity. In addition, the Jadad scores for methodological quality were only ≥ 4 in five of the 16 trials. Sensitivity analyses for dose, length of study, and quality did not show differences in the first meta-analysis. The Cochrane group attempted to take these variations into consideration and observed a marginally significant effect of UDCA on liver transplantation only in the later period in which all the patients were treated with open label UDCA, but not in the original period in which patients were treated with 516

UDCA or placebo/no intervention. However, transplant is not a perfect endpoint, as already alluded to. Survival without transplant was not significantly influenced by UDCA therapy (see Figure 32.2). Since not all placebo or non-intervention patients were eventually given UDCA (although the majority were), the evaluation of the non-randomized phases of these trials has intrinsic biases and lacks the appropriate basis for an intention-to-treat analysis. Of the 16 randomized clinical trials evaluating UDCA against placebo, nearly half of the trials had high risk of bias [97]. In all studies, the administration of UDCA was associated with an improvement of liver biochemistry. The latest updated Cochrane meta-analysis shows that overt ascites and obvious jaundice are less frequent in patients randomized to UDCA, but there was no difference in the number of patients with bleeding varices or hepatic encephalopathy. These data suggest that prolonged treatment with UDCA, started before onset of severe disease, may be required to exert a beneficial effect on the natural history of PBC; appropriately powered studies have not been performed to date, however, to definitively confirm the concept that patients with early disease benefit most from UDCA. The meta-analysis that was confined to trials using an appropriate dose of UDCA (>10 mg per kilogram of body weight per day) and with sufficient follow-up (at least two years) included a total of 1038 patients (522 who received UDCA and 516 who received placebo) [116]. Treatment with UDCA resulted in significant improvement in liver biochemical values. Histologic evidence of disease progression was similar for the two treatment groups, but subjects without evidence of fibrosis (stages I and II) who were treated with UDCA had slower disease progression than did subjects in the control group. A total of 160 patients who were treated with UDCA and 186 control subjects died or underwent liver transplantation. This difference was significant in a fixed-effect model (OR, 0.76; 95% CI: 0.57– 1.00; p = 0.05) but not in a random-effects model (OR, 0.77; 95% CI: 0.50–1.21; p = 0.30). This particular analysis is open to criticism because of the difference seen between the fixed-effect and random-effects model.

Osteoporosis There are modest increases in both the absolute and relative fracture risks in people with PBC compared with the general population, with the excess risks similar in those with more severe disease [117, 118]. No effect of UDCA on bone mineral density was, however, demonstrated in the RCT of UDCA in PBC published by Lindor et al., although the study may have lacked power [119]. A small study assessing bone mineral density and vertebral fractures in PBC patients randomized to cyclosporin A or placebo suggested that cyclosporin-treated patients have less bone loss and better biochemical parameters of bone remodelling

CHAPTER 32

Study or subgroup

UDCA

Control

Risk ratio

Primary biliary cirrhosis

Weight

n/N

n/N

Athens

21/43

17/43

18.9%

1.24 (0.76, 2.00)

Barcelona

17/99

11/93

12.6%

1.45 (0.72, 2.93)

Dallas

12/77

11/74

12.5%

1.05 (0.49, 2.23)

Frankfurt

0/10

0/10

0.0%

Not estimate

Goteborg

3/60

4/56

4.6%

0.70 (0.16, 2.99)

Helsinkj

0/30

5/31

6.0%

0.09 (0.01, 1.63)

Manchester

4/14

2/14

2.2%

2.00 (0.43, 9.21)

Mayo-I

7/89

12/91

13.2%

0.60 (0.25, 1.45)

Milan

0/44

0/44

0.0%

Not estimate

0/9

0/10

0.0%

Not estimate

3/22

4/24

4.3%

0.82 (0.21, 3.25)

Taipei

0/6

0/6

0.0%

Not estimate

Tokyo

0/26

0/26

0.0%

Not estimate

Toronto

12/111

19/111

21.2%

0.63 (0.32, 1.24)

Villejuif

4/73

4/73

4.5%

1.00 (0.26, 3.85)

713

706

100.0%

0.92 (0.71, 1.21)

Newark-I Newcastle

Total (95% Cl)

M-H, feed, 95% Cl

Risk ratio M-H, feed, 95% Cl

Total events: 83 (UDCA), 89 (control) Heterogeneity: Chi2 = 8.91, df = 9 (p = 0.45) i2 = 0.00% Test for overall effect: z = 0.59 (p = 0.56) 0.01

0.1 1 10 100

UCDA better

Control worse

Figure 32.2 Meta-analysis of ursodeoxycholic acid for primary biliary cirrhosis: outcome mortality or liver transplantation [97].

[120]. With regard to specific treatment of osteoporosis in PBC, a number of small trials have been performed. Etidronate was not shown to be beneficial whereas alendronate was well tolerated and did significantly improve bone density in a double-blinded randomized, placebocontrolled trial, including a total of 34 patients followed for one year [121, 122]. Estrogen therapy can be used safely (from the hepatic perspective) and there is limited data on its efficacy [123–125].

Fatigue and pruritus Although there are now some very sophisticated methods to measure these symptoms [126], none of the RCTs of therapy for PBC employed such instruments to monitor the effect of therapy. There are many anecdotal case reports of marked improvement and marked worsening of both fatigue and pruritus in patients receiving UDCA. Pilot studies of methotrexate have reported dramatic improvement in both fatigue and pruritus, but these uncontrolled

studies provide only weak evidence for benefit. The Newcastle group have reported a study of the CNS-acting drug modafinil in patients with PBC suffering from significant daytime somnolence and associated fatigue [127]. Open label modafinil therapy was associated, where tolerated by patients, with improvement in excessive daytime somnolence and associated fatigue in PBC, but clearly placebo-controlled trials are needed. Effective treatments for pruritus, a distressing symptom in PBC are more readily available [128]. Although randomized controlled data is limited [129], treatment approaches include cholestryramine [130, 131], rifampin [132], sertraline [133], opioid antagonists [134, 135] and plasma exchange or albumin dialysis [136–138].

Histology In the study by Pares et al. the apparent benefit of five years of UDCA therapy on liver histology in terms of stage of disease, progression of bile duct destruction and interface 517

PA RT I I

Liver disease

hepatitis was significantly greater than that observed in those randomized to placebo [139]. The majority of patients included in this trial had early asymptomatic disease. Assessment of liver histology from the French multicenter study using the Markov model indicated that regression of cirrhosis was never seen, but that the progression to cirrhosis was markedly delayed in those who received UDCA [140]. It must be emphasized that follow-up liver histology was not available in all randomized patients, some refused to have a second biopsy, and more importantly, no second biopsy was obtained from those patients who died or required a liver transplant, that is, those whose liver disease clearly had progressed. Only 44% of patients had second biopsies available for evaluation. This factor introduces the potential for significant bias into observations concerning effect of both UDCA and placebo on histology. However, a further pooled study showed that two years of UDCA treatment reduced periportal necroinflammation and improved ductular proliferation; if UDCA was initiated at the earlier stages disease (I–II) it also delayed the progression of histologic stage [141].

Cost-effectiveness of ursodeoxycholic acid therapy in primary biliary cirrhosis Cost-efficacy analyses are limited to one paper, which used data from two previously published trials, and determined the effectiveness of UDCA by comparing the annual reduction in the development of ascites, varices, variceal bleeding, encephalopathy, liver transplantation, and death between the treatment groups [142]. Average annual costs for each of these events were estimated based on literature and institutional data. Approximately twice as many major events occurred in the placebo group compared with the UDCA group. Based on the estimated annual cost of managing these events and the then annual costs of UDCA ($2500), there was an annual cost saving per patient of $1372. Compared with the placebo group, patients receiving UDCA had a lower incidence of major complications and lower medical care costs.

The future for therapy in primary biliary cirrhosis Although most physicians will prescribe UDCA for patients with PBC, newer and more targeted therapies are needed. Specific targets may arise when there is a better biologic understanding of disease. The group of patients most appropriate for new agents would logically be those who fail to respond adequately to UDCA (around 40% of patients) and a number of agents are worthy of comment. The addition of bezafibrate (which may increase phospholipid translocation into the bile) has been investigated, but the results to date are early and a well-powered study is needed [146, 147]. Atorvastatin, with many anti-inflammatory properties beyond its lipid lowering effects, was recently shown not to be of value for PBC [148]. In view of the cloning of a human retrovirus from a cDNA library derived from PBC biliary epithelia cells, anti-retrovirals have been investigated, but convincing data is still awaited [149, 150]. More selective immunosuppression (e.g. rituximab) is also being studied. More specific approaches focusing on fibrosis modulation may eventually prove efficacious, for example rapamycin, angiotensin blockade, or adhesion molecule modulation. Finally, other ways of targeting the bile acid pathway are being pursued. Modifications to UDCA (e.g. nor-UDCA) may appeal [151], as well as interfering with nuclear hormone receptors [152]. The Farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor highly expressed in both the liver and gastrointestinal tract. It has a role in regulating bile and cholesterol metabolism and FXR agonists (e.g. novel bile acids or small molecule agonists such as INT747) may have a place in treating cholestatic liver diseases. The first ever genome wide association study in PBC published in 2009 [153] identified the IL-12 signaling axis as highly relevant to disease, and so rational therapy may now truly be on the horizon for patients.

References Recurrent PBC following liver transplantation After around five years, perhaps approaching one in five patients transplanted for PBC will have histological evidence of recurrence [143]. Diagnosis needs to be carefully evaluated in view of the broad differential in transplant recipients, but disease progression is slow and retransplantation exceptional. Some data suggests lower recurrence with cyclosporin use as opposed to tacrolimus [144], and whilst UDCA appears to improve liver biochemistry, in the short term it does not alter histological progression [145].

518

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98 Makino I, Tanaka H. From a choleretic to an immunomodulator: historical review of ursodeoxycholic acid as a medicament. J Gastroenterol Hepatol 1998; 13: 659–664. 99 Beuers U. Drug insight: Mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat Clin Pract Gastroenterol Hepatol 2006; 3: 318–328. 100 Leuschner U, Leuschner M, Sieratzki J et al. Gallstone dissolution with ursodeoxycholic acid in patients with chronic active hepatitis and two years follow-up. A pilot study. Dig Dis Sci 1985; 30: 642–649. 101 Podda M, Ghezzi C, Battezzati PM et al. Effect of different doses of ursodeoxycholic acid in chronic liver disease. Dig Dis Sci 1989; 34: 59S–65S. 102 Poupon RE, Poupon R, Balkau B. Ursodiol for the long-term treatment of primary biliary cirrhosis. The UDCA-PBC Study Group. N Engl J Med 1994; 330: 1342–1347. 103 Angulo P, Dickson ER, Therneau TM et al. Comparison of three doses of ursodeoxycholic acid in the treatment of primary biliary cirrhosis: a randomized trial. J Hepatol 1999; 30: 830–835. 104 Siegel JL, Jorgensen R, Angulo P, Lindor KD. Treatment with ursodeoxycholic acid is associated with weight gain in patients with primary biliary cirrhosis. J Clin Gastroenterol 2003; 37: 183–185. 105 Kondrackiene J, Beuers U, Kupcinskas L. Efficacy and safety of ursodeoxycholic acid versus cholestyramine in intrahepatic cholestasis of pregnancy. Gastroenterology 2005; 129: 894– 901. 106 Lindor KD, Dickson ER, Baldus WP et al. Ursodeoxycholic acid in the treatment of primary biliary cirrhosis. Gastroenterology 1994; 106: 1284–1290. 107 Lindor KD, Therneau TM, Jorgensen RA et al. Effects of ursodeoxycholic acid on survival in patients with primary biliary cirrhosis. Gastroenterology 1996; 110: 1515–1518. 108 Jorgensen R, Angulo P, Dickson ER, Lindor KD. Results of longterm ursodiol treatment for patients with primary biliary cirrhosis. Am J Gastroenterol 2002; 97: 2647–2650. 109 Corpechot C, Carrat F, Bahr A et al. The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. Gastroenterology 2005; 128: 297–303. 110 ter Borg PC, Schalm SW, Hansen BE, van Buuren HR. Prognosis of ursodeoxycholic Acid-treated patients with primary biliary cirrhosis. Results of a 10-yr cohort study involving 297 patients. Am J Gastroenterol 2006; 101: 2044–2050. 111 Chan CW, Gunsar F, Feudjo M et al. Long-term ursodeoxycholic acid therapy for primary biliary cirrhosis: a follow-up to 12 years. Aliment Pharmacol Ther 2005; 21: 217–226. 112 Heathcote EJ, Cauch-Dudek K, Walker V et al. The Canadian Multicenter Double-blind Randomized Controlled Trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology 1994; 19: 1149–1156. 113 Poupon RE, Lindor KD, Cauch-Dudek K et al. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology 1997; 113: 884–890. 114 Combes B, Carithers RLJ, Maddrey WC et al. A randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology 1995; 22: 759–766. 115 Combes B, Luketic VA, Peters MG et al. Prolonged follow-up of patients in the US multicenter trial of ursodeoxycholic acid

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133 Mayo MJ, Handem I, Saldana S et al. Sertraline as a first-line treatment for cholestatic pruritus. Hepatology 2007; 45: 666–674. 134 Bergasa NV, Talbot TL, Alling DW et al. A controlled trial of naloxone infusions for the pruritus of chronic cholestasis. Gastroenterology 1992; 102: 544–549. 135 Wolfhagen FH, Sternieri E, Hop WC et al. Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study. Gastroenterology 1997; 113: 1264–1269. 136 Cohen LB, Ambinder EP, Wolke AM et al. Role of plasmapheresis in primary biliary cirrhosis. Gut 1985; 26: 291–294. 137 Pusl T, Denk GU, Parhofer KG, Beuers U. Plasma separation and anion adsorption transiently relieve intractable pruritus in primary biliary cirrhosis. J Hepatol 2006; 45: 887–891. 138 Pares A, Cisneros L, Salmeron JM et al. Extracorporeal albumin dialysis: a procedure for prolonged relief of intractable pruritus in patients with primary biliary cirrhosis. Am J Gastroenterol 2004; 99: 1105–1110. 139 Pares A, Caballeria L, Rodes J et al. Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. UDCA-Cooperative Group from the Spanish Association for the Study of the Liver. J Hepatol 2000; 32: 561–566. 140 Corpechot C, Carrat F, Bonnand AM et al. The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis. Hepatology 2000; 32: 1196–1199. 141 Poupon RE, Lindor KD, Pares A et al. Combined analysis of the effect of treatment with ursodeoxycholic acid on histologic progression in primary biliary cirrhosis. J Hepatol 2003; 39: 12–16. 142 Pasha T, Heathcote J, Gabriel S et al. Cost-effectiveness of ursodeoxycholic acid therapy in primary biliary cirrhosis. Hepatology 1999; 29: 21–26. 143 Mottershead M, Neuberger J. Transplantation in autoimmune liver diseases. World J Gastroenterol 2008; 14: 3388–3395. 144 Dmitrewski J, Hubscher SG, Mayer AD, Neuberger JM. Recurrence of primary biliary cirrhosis in the liver allograft: the effect of immunosuppression. J Hepatol 1996; 24: 253– 257. 145 Charatcharoenwitthaya P, Pimentel S, Talwalkar JA et al. Longterm survival and impact of ursodeoxycholic acid treatment for recurrent primary biliary cirrhosis after liver transplantation. Liver Transpl 2007; 13: 1236–1245. 146 Iwasaki S, Ohira H, Nishiguchi S et al. The efficacy of ursodeoxycholic acid and bezafibrate combination therapy for primary biliary cirrhosis: A prospective, multicenter study. Hepatol Res 2008; 38: 557–564. 147 Walker LJ, Newton J, Jones DE, Bassendine MF. Comment on biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology 2008; 49: 337–338. 148 Stojakovic T, Putz-Bankuti C, Fauler G et al. Atorvastatin in patients with primary biliary cirrhosis and incomplete biochemical response to ursodeoxycholic acid. Hepatology 2007; 46: 776–784. 149 Mason AL, Farr GH, Xu L et al. Pilot studies of single and combination antiretroviral therapy in patients with primary biliary cirrhosis. Am J Gastroenterol 2004; 99: 2348–2355.

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150 Mason AL, Lindor KD, Bacon BR et al. Clinical trial: randomized controlled trial of zidovudine and lamivudine for patients with primary biliary cirrhosis stabilized on ursodiol. Aliment Pharmacol Ther 2008; 28: 886–894. 151 Fickert P, Wagner M, Marschall HU et al. 24-norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 2006; 130: 465–481.

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152 Zollner G, Marschall HU, Wagner M, Trauner M. Role of nuclear receptors in the adaptive response to bile acids and cholestasis: pathogenetic and therapeutic considerations. Mol Pharm 2006; 3: 231–251. 153 Hirschfield GM, Liu X, Xu C et al. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N Engl J Med 2009; 360: 2544–2555.

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Autoimmune hepatitis Michael MP Manns and Arndt Vogel Department of Gastroenterology, Hepatology and Endocrinology, Medical School, Hanover, Germany

Introduction Autoimmune hepatitis is a self-perpetuating necroinflammatory disease of unknown etiology, which is characterized by a loss of tolerance towards the patient’s own liver tissue. If left untreated the disease leads to cirrhosis and liver failure. Since the recognition of immunologically based liver disease in the 1950s, efforts have been directed toward the development of tools for diagnosis, classification according to serological markers and clinical course, and distinguishing autoimmune hepatitis from other liver diseases. In the early years diagnosis of autoimmune hepatitis was hampered by the lack of knowledge about the etiology of most acute and chronic liver diseases. The detection of hepatitis viruses and a better understanding of the etiology of other forms of liver disease allowed for the exclusion of patients with these disorders from studies of autoimmune hepatitis and a more accurate determination of prognosis and effects of immunosuppressive drugs. The characterization of distinctive autoantibodies and the identification of autoantigens led to a more specific diagnosis of the disease and to the ability to characterize distinct subclasses according to prognosis, treatment response and outcome.

Features of autoimmune hepatitis Autoimmune hepatitis is a syndrome which is characterized by a typical constellation of epidemiological, laboratory and clinical features: female predominance (female: male ratio 4 : 1), overrepresentation of the human leukocyte antigen (HLA) alleles DR3 and DR4, hypergammaglob-

Evidence-Based Gastroenterology and Hepatology, Third Edition John WD McDonald, Andrew K Burroughs, Brian G Feagan and M Brian Fennerty © 2010 Blackwell Publishing Ltd. ISBN: 978-1-405-18193-8

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ulinemia, circulating autoantibodies, response to immunosuppressive therapy and coexistence of extrahepatic autoimmune diseases. The disease is seen in all ethnic groups and at all ages [1–5]. The mean annual incidence of AIH among white Northern Europeans is ∼2 per 100,000 inhabitants, and its point prevalence is ∼17 per 100,000 [6].

Clinical features Although autoimmune hepatitis occurs mainly in young women, the disease may develop at any age and in either sex [5]. Patients with AIH frequently complain about nonspecific symptoms such as fatigue, jaundice, nausea and abdominal pain at presentation, but the clinical spectrum is wide, ranging from an asymptomatic presentation to fulminant disease. Forty percent of patients present with acute hepatitis [7]. Fulminant liver failure may occur but is rare. Hepatomegaly is common and an enlarged spleen is palpable in 50% of patients. In some patients the disease progresses without major symptoms, and the diagnosis is not made until symptoms of severe liver disease are present. Amenorrhea occurs in women with severe hepatic inflammation. Coexisting extrahepatic autoimmune diseases are frequently found in patients with autoimmune hepatitis. Whereas arthropathies and periarticular swelling of both large and small joints occurs in 6–36% of patients, arthritis with joint erosions is rarely seen. Additional clinical features are listed in Table 33.1. The risk of hepatocellular carcinoma in autoimmune liver disease varies considerably between the different diseases PBC, PSC and AIH. Particular PSC can be complicated by cholangiocarcinoma, gallbladder carcinoma and hepatocellular carcinoma [8]. In contrast, the incidence of HCCs in patients with AIH was not well documented for a long time. However, several recent retrospective studies indicate that about 2% of AIH patients eventually develop HCCs [9–11]. Similar to other chronic liver diseases, cirrhosis is the sine qua non for HCC development in AIH.

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Table 33.1 Extrahepatic autoimmune syndromes in autoimmune hepatitis. Frequent symptoms

Rare symptoms

Arthritis Vitiligo Autoimmune thyroid Insulin dependent diabetes Hirsutism, cushingoid features

Mixed connective tissue disease Lichen planus Ulcerative colitis disease

Serological features Autoantibodies are an important tool for the diagnosis of AIH [12]. However, autoantibodies are not specific to AIH and their expressions can vary during the course of AIH [13]. Furthermore, a low autoantibody titer does not exclude the diagnosis of AIH and a high titer (in the absence of other supportive findings) does not establish the diagnosis. Importantly, autoantibodies do not cause the disease nor alter in titer in response to treatment (at least in adult populations); as such, they do not need to be serially monitored [12]. ANA, SMA and LKM are pivotal components for the diagnosis of AIH and should be first tested in suspicious patients [14]. ANA were the first autoantibodies to be associated with AIH and led Mackay to create the term “lupoid” hepatitis as early as 1956. ANA are the most nonspecific marker of AIH and can also be found in PBC, PSC, viral hepatitis, drug-related hepatitis, and alcoholic and non-alcoholic, fatty liver disease [15, 16]. Additionally, serum ANAs have been reported to occur in up to 15% of the general healthy populations from different countries, increasing with age. SMA are frequently found in AIH, and are directed against components of the cytoskeleton such as actin and non-actin components, including tubulin, vimentin, desmin and skeletin [15]. They frequently occur in high titers in association with ANA and are, like ANA, present in a variety of liver and non-liver diseases such as rheumatic diseases. Antibodies to LKM were first discovered in 1973 by indirect immunofluorescence and are reactive with the proximal renal tubule and hepatocellular cytoplasma [17, 18]. They form a heterogeneous group and are associated with several immune mediated diseases, including AIH, drug-induced hepatitis, the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED or APS-1), and chronic hepatitis C and D infection [15]. A 50 kilo Dalton antigen of LKM-1 was identified as the cytochrome mono-oxygenase P450 2D6 (CYP2D6). LKM-3 antibodies are directed against family 1 uridine 5′-diphosphate glucuronosyltransferase (UGT1A), which belong to the drug metabolizing enzymes located in the endoplasmatic reticulum.

Autoimmune hepatitis

Patients who present without these antibodies may be tested for other, characterized autoantibodies. Antibodies against LC-1, SLA/LP, pANCA and the asialoglycoprotein receptor may be helpful to extend the diagnosis of AIH in these patients. Anti-LC1 antibodies are visualized by indirect immunofluorescence. However, their characteristic staining may be masked by the more diffuse pattern of LKM-1 antibodies. Therefore, other techniques such as ouchterlony double diffusion, immunoblot and counterimmunoelectrophoresis are also used for their detection. The antigen recognized by anti-LC1 was identified as formiminotransferase cyclodeaminase (FTCD) [19]. Contrary to most other autoantibodies in AIH, anti-LC1 seems to correlate with disease activity and may be useful as a marker of residual hepatocellular inflammation in AIH [20]. Anti-SLA/LP antibodies are detectable by radioimmunoassay and enzyme linked immunosorbent assays (ELISA) but cannot be detected by immunofluorescence [15]. Anti-SLA/LP antibodies are considered to be highly specific for AIH, in which they are detectable in about 10–30% of patients. In some patients, they are the only serological marker of autoimmune hepatitis. Screening of cDNA expression libraries identified a UGA tRNA suppressor as anti-SLA target autoantigen [21]. Several studies suggest that patients with anti-SLA/LP antibodies display a more severe course of the disease [22–25]. Additionally, antibodies against cardiolipin, chromatin and Saccharomyces cerevisiae have been described in AIH, which, however, do not define patients with a distinctive clinical phenotype [26–28]. There have been several proposals to classify AIH according to different antibody profiles. According to this approach, AIH type I is characterized by the presence of ANA and/or anti-SMA antibodies. AIH type II is characterized by anti-LKM-1 and with lower frequency against LKM-3 antibodies. AIH type III is characterized by autoantibodies against SLA/LP. AIH-2 displays a regionally variable prevalence, with only 4% in the USA and up to 20% in western Europe [18, 29]. Patients with AIH-II are younger at presentation, show a more severe course at onset and are more likely to progress to cirrhosis [30]. Both entities of AIH are characterized by a high incidence of other organ specific immune mediated diseases, for example autoimmune thyroid disease, which are not only detected in patients with AIH, but also in their first degree relatives.

Histological features Autoimmune hepatitis cannot be diagnosed by liver histology alone, since there are no pathognomonic histological features. Histology can only support the diagnosis and is used to classify disease activity (grading) and the degree of fibrosis (staging). There is a general agreement that bridging necrosis and multilobular necrosis should be 525

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Table 33.2 HLA alleles and autoimmune hepatitis. HLA allele

Population

DRB1*0301 DRB1*0301 DRB1*0301 DRB1*0404 DRB1*0405 DRB1*0405 DRB1*1301 DRB1*1301 DRB1*1302 DRB1*14 DRB1*1501 DRB1*0301/ DRB1*0301 DRB1*0301/DRB1*04

Argentina North America, India Mexico Argentina Japan Argentina India Argentina India North America, North America, North America,

Adults/Children

# Pat.

#Contr.

Risk ratio

Children

122 297 20 30 84 77 122 20 122 20 297 297 297

208 236 113 175 208 248 208 113 208 113 236 236 236

3.0 3.39 3.79 7.71 10.4 4.97 16.3 6.47 0.1 3.25 0.52 7.61 5.09

UK Adults Mixed Adults Adults Children Adults Children Adults UK UK UK

regarded as factors associated with a poor prognosis. Interface hepatitis, also known as piecemeal necrosis or periportal hepatitis, is the histological hallmark and plasma cell infiltration is typical [14, 30–32]. Up to 30% of adult patients have histological features of cirrhosis at diagnosis [5, 33]. Recent data indicate that only a small number of patients develop cirrhosis during therapy and that fibrosis scores are stable or improve in up to 75% patients [34]. However, it is important to note that the presence of cirrhosis at baseline significantly increases the risk of death or liver transplantation [5, 35]. Almost half of children with AIH already have cirrhosis at the time of diagnosis [36, 37]. In elderly patients a more severe histological grade has been reported, but the frequency of cirrhosis does not seem to be different from that in younger patients [38, 39].

Genetic features It is generally accepted that occurrence and probably the severity of autoimmune hepatitis is influenced by genetic factors. However, the heritable component of AIH is currently regarded as small. The most conclusive genetic association with autoimmune hepatitis is related to the major histocompatibility complex alleles. Among white northern European and Americans there is a well-recognized association between increased susceptibility to AIH and inheritance of HLA DR3 and HLA DR4 (later identified as DRB1*0301 and DRB1*0401 respectively) [40, 41]. HLA DR3 is the main susceptibility factor in white Caucasians, and HLA DR4 is a secondary but independent risk factor for the disease. Eighty-five percent of white patients with type I AIH from the USA and northern Europe have HLA DR3, DR4, or DR3 and DR4. Table 33.2 summarizes confirmed associations of HLA DRB1 alleles in AIH patients 526

from different populations [42]. Based on these data, different models have been created whereby genetic susceptibility and resistance to AIH is best related to specific amino acid sequence motifs within DRB1 polypeptides. Donaldson has suggested three different models: one, for type I AIH is dependent on histidine or other basic amino acid residues at position 13 of the DRβ polypeptide; the second is based on the amino acid residue LLEQKR at positions 67–72 of the DRβ polypeptide and the third model is based on valine/glycine dimorphism at position 86 [43]. HLA alleles associated with AIH confer not only susceptibility towards AIH but also appear to influence the course of the disease. Most strikingly, patients with the DRB1*0301 were found to be younger at disease onset and have a higher frequency of treatment failure, relapse after treatment withdrawal and liver transplantation. Patients with DRB1*0401 are at greater risk to develop additional autoimmune disorders, but are thought to be associated with milder disease, seen in older patients, which is easier to treat [41, 44, 45].

Diagnosis Because signs and symptoms of AIH are not specific, an international panel (the International Autoimmune Hepatitis Group (IAIHG)) established a consensus on diagnostic criteria, and its recommendations were published in 1993 [46], and revised in 1999 [14]. These criteria include clinical, laboratory and histological findings at presentation, as well as response to corticosteroid therapy and are in most cases sufficient to make the diagnosis of autoimmune hepatitis and to distinguish it from other forms of chronic hepatitis. Response to corticosteroids may help to clarify the diagnosis even in patients who lack other typical

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features (see Table 33.3) [14, 30, 42, 47]. Additionally, a scoring system was established assigning points (both negative and positive) to specific findings to allow for the distinction between a definitive diagnosis and a probable diagnosis. Prior to corticosteroid treatment, a definitive diagnosis requires a score greater than 15; after treatment, a definitive diagnosis requires a score greater than 17. The AIH scoring system was subsequently subjected to validation testing in several studies, which consistently showed that the sensitivity was very high (97–100%) but that the specificity for excluding AIH in patients with biliary disorders was markedly lower (44–65%) (see Table 33.3). The notable weakness of the original system in excluding cholestatic syndromes justified the subsequent revision to further downgrade cholestatic findings [14]. The new scoring system more precisely differentiated between biliary diseases and AIH, and application of the revised system in PBC and PSC patients revealed significantly less patients who scored for definite and probable AIH [48, 49]. However, the above-described criteria were primarily introduced to allow comparison of studies from different centers. Because these criteria are complex and include a variety of parameters of questionable value, the IAIHG decided to devise a simplified scoring system for wider applicability in routine clinical practice. A limited number of routinely available measurements were therefore selected to design the score. Liver histology (demonstration of hepatitis on histology is required), autoantibody titers, gamma-globulin/IgG levels, and the absence of viral hepatitis were found to be independent predictors for the presence of AIH (see Table 33.4) [50]. The score was found to have good sensitivity and specificity in a second validation set. Therefore a simple score based on four measurements may be sufficient to differentiate between patients with or without AIH, with a high degree of accuracy. However, additional studies are required to validate this score in patients with different chronic liver diseases.

Treatment The indication for treatment of AIH is based on inflammatory activity and not so much on the presence of cirrhosis. In the absence of inflammatory activity immunosuppressive treatment has only limited effects. An indication for treatment is present when aminotransferases are elevated two-fold, gamma globulin levels are elevated two-fold and histology shows moderate to severe periportal hepatitis. Symptoms of severe fatigue are also an indication for treatment. An absolute indication exists in cases with a ten-fold or higher elevation of aminotransferase levels, histological signs of severe inflammation and necrosis, and upon disease progression.

Autoimmune hepatitis

Table 33.3 Scoring system for diagnosis of autoimmune hepatitis. Parameter

Score

Gender Female Male

+2 0

Serum biochemistry Ratio of elevation of serum alkaline phosphatase vs aminotransferase >3.0 −2 2.0 1.5–2.0 1.0–1.5 1 : 80 +3 1 : 80 +2 1 : 40 +1 1 : 20 +3 1 : 10 or 1 : 20 +2 1 : 20 +3 1 : 20 +2 80 gm/day; female > 60 gm/day −2 Genetic factors: HLA DR3 or DR4 Other autoimmune diseases in patient or first degree +1 relatives Interpretation of aggregate scores: definite AIH, greater than 15 before treatment and greater than 17 after treatment; probable AIH 10 to 15 before treatment and 12 to 17 after treatment. Alvarez F, Berg PA, Bianchi FB et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999; 31: 929–938.

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Conventional corticosteroids and azathioprine Three controlled trials provided evidence that corticosteroid therapy reduces mortality in autoimmune hepatitis, and this benefit was further substantiated by longer followup of the patients in one of these studies (see Table 33.5). The magnitude of the reduction of mortality produced by steroids can be estimated from the original analysis of the study of Cook et al. (control 55%, steroid 14%, absolute risk reduction (ARR) 42%, numbers needed to treat (NNT) = 3) and from the analysis conducted after ten-year follow-up

Table 33.4 Simplified criteria for diagnosis of autoimmune hepatitis. Concentration of serum IgG IgG > 16 g/l IgG > 18 g/l

1 point 2 points

Serum auto antibodies (ANA, SMA, SLA/LP, LKM) ANA, SMA or LKM > 1 : 40 >1 : 80, or SLA/LP positive

1 point 2 points

Histology of chronic hepatitis Compatible with AIH Typical for AIH

1 point 2 points

Exclusion of viral hepatitis

2 points

Score > 6 = probable AIH Score > 7 = definite AIH Cutoff 6 : 88% sensitivity und 97% specificity Cutoff 7 : 81% sensitivity und 99% specificity

of the same patient groups (control 73%, steroid 37%, ARR 36%, NNT = 3) [51, 52]. A1d Treatment with prednisone monotherapy or in combination with azathioprine remains the standard therapy for patients with AIH [53]. Both are equally effective and the decision for either strategy involves the consideration of patient profiles [54]. Data from the randomized trials and from uncontrolled studies suggest that the remission rate is approximately 80% with initial therapy [55]. About 9% percent of patients deteriorate despite compliance to treatment, 13% improve, but not to a degree to reach remission and 13% are intolerant to standard therapy [56, 57]. Longterm remission is maintained by low-dose corticosteroids alone or in combination with azathioprine (1–2 mg/kg body weight) or with azathioprine monotherapy [53]. B4 Controlled trials have not been performed in patients with mild asymptomatic autoimmune hepatitis. In these patients, who numerically far outnumber patients with severe liver disease, the role for steroid therapy remains unclear and the decision to treat must be weighed against the risk of medication. A recent study revealed that the overall survival and survival to liver related endpoints of asymptomatic patients who received no therapy was not different to that of the total cohort [5]. B4 However, asymptomatic patients not receiving therapy require a close follow-up since 25% of this group subsequently developed symptoms [5]. Treatment withdrawal should not be attempted less than 2–3 years from the start of therapy to prevent early relapse. Drug withdrawal should be preceded by liver biopsy if a long-term biochemical remission is not documented. The rate of relapse depends on the degree of continuing inflam-

Table 33.5 Effect of prednisone on mortality in randomized controlled trials of chronic autoimmune hepatitis (CAH). Study

Patients

Steroid regimen

Control intervention

Mortality Control

Steroid

p

Cook et al. (1971)

49 patients with CAH, 35 with cirrhosis; no previous steroids; 5 patients (4 in steroid group) excluded from analysis because of change in diagnosis

Prednisone 15 mg (3–72 months) attempts to withdraw after 1 month

“No specific treatment”

3/22

15/27

16 mmHg [94]. Villanueva et al. showed that HVPG > 20 mmHg and a decrease ≤10 mmHg under vaso-active therapy were independent predictors of further bleeding [95]. An HVPG > 20 mmHg has been shown to correlate with important clinical outcomes, such as more difficulty in controlling acute variceal bleeding, more early re-bleeding, more blood transfusion need, more days in intensive care and increased hospital mortality [96]. Avgerinos et al. showed that HVPG > 16 mmHg was independently associated with death and/or early re-bleeding, evaluating HVPG measurements before and immediately after endoscopic treatment and every 24 hours for a fiveday period [97]. Interestingly, there was sustained rise of portal pressure after sclerotherapy, but not band ligation. In addition, Vlachogiannakos et al. showed that somatostatin but not octreotide effectively prevents the post567

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endoscopic increase of HVPG [98]. With the prognostic association of high HVPG with the course of bleeding (using vasoactive drugs and endoscopic therapy) and mortality, a randomized study showed that urgent TIPS in patients with HVPG > 20 mmHg, protected against continued or repeated bleeding and reduced mortality [96]. This study clearly demonstrated the therapeutic benefit of intervention based on HVPG measurement and validated the value of 20 mmHg HVPG as a cutoff. The question then arises about the applicability of measuring HVPG in this setting, which although accurate and reproducible, with little co-efficient of variation in measurement, and with few complications is not currently feasible outside a research setting [99]. Several studies have evaluated factors associated with failure to control bleeding and mortality. A consensus has determined that control of variceal bleeding spans the first five days and mortality is death within six weeks of onset of bleeding [89]. Ben-Ari et al. showed that in 385 cirrhotics treated initially with vasoactive drugs and then endosopic therapy if bleeding continued or recurred (within five days) active bleeding at endoscopy (independent of the interval from onset of melena and/or haematemesis or the interval to admission to hospital), the severity of liver disease (mainly Child-Pugh grade C) as well as encephalopathy, platelet count and history of alcoholism were all independently associated with failure to control bleeding (internal validation of the model was performed) [100]. There were some interactions between variables in that active bleeding was associated with transfusion need and transfusion need was associated with Child-Pugh class, and shorter interval to admission. Interestingly a higher Child-Pugh score and increased mortality was independent of transfusion requirement. Independent factors associated with mortality within 30 days were failure to control bleeding within five days, raised bilirubin, encephalopathy, shorter interval to admission to hospital and plasma urea. Lecleire et al. evaluated prospectively 468 consecutive patients with cirrhosis and upper gastrointestinal bleeding (23.5% died during hospitalization) [101]. The independent factors associated with in hospital mortality were: presentation with hematemesis, bleeding starting in hospital, prothrombin time 60 years and a concomitant hepatocellular cancer. Thomopoulos et al. retrospectively evaluated 141 patients with acute variceal bleeding (18.6% 6 week mortality) treated with somatostatin started before endoscopy and endoscopic ligation [102]. Early re-bleeding, Child-Pugh grade C and shock at admission were independent predictors of mortality at six weeks, whilst active bleeding and presence of infection (prophylactic antibiotics were not routinely used) were not adverse factors. 568

Lo et al. also found active bleeding to be independently associated with recurrent bleeding, but not mortality, although this was higher in the group with active bleeding at endoscopy [103]. In addition, the presence of hepatocellular carcinoma may alter the immediate prognosis [101, 104, 105] so that early imaging (large tumors will be detected by a bedside ultrasound) to detect HCC may alter the therapeutic algorithm, for example TIPS rescue therapy may not be indicated and only vasoactive and endoscopic methods applied. A concomitant portal vein thrombosis, whether due to tumor or not may also worsen prognosis as often bleeding is more difficult to control. The use of prophylactic antibiotics should be standard therapy for patients with cirrhosis who have variceal bleeding [106]. The association with failure to control was shown prospectively [107], following a hypothesis that proposed infection as a trigger for bleeding [108], and the causal association was shown in two randomized trials [109, 110]. Antibiotics result in better control of bleeding and less early re-bleeding. Alc The prognostic models that assess control of bleeding should now be based in cohorts of patients who have had prophylactic antibiotics. In a prospectively evaluated cohort of 117 patients with cirrhosis [111], HVPG was measured within 48 hours. As in a previous study HVPG > 20 mmHg was independently predictive of failure to control bleeding at five days, together with shock (systolic blood pressure at admission 8; ChildPugh B = 26%, C = 74%) were randomized equally to: placebo; 600 μg/kg rFVIIa (200 + 4x 100 μg/kg); or 300 μg/ kg rFVIIa (200 + 100 μg/kg). The primary composite endpoint consisted of failure to control bleeding within 24 572

hours, or failure to prevent re-bleeding or death by day five. Administration of rFVIIa had no significant effect on the composite endpoint compared with placebo (p = 0.37). There was no significant difference in five-day mortality between groups; however, 42-day mortality was significantly lower, with 600 μg/kg rFVIIa compared with placebo (odds ratio 0.31; 95% CI: 0.13–0.74), and bleeding-related deaths were reduced from 12% (placebo) to 2% (600 μg/ kg), but this was not associated with differences in control of bleeding. There is no evidence that recombinant activated factor VIIa improves outcome in acute variceal bleeding. Alb

Randomized controlled trials of emergency sclerotherapy in the management of acute variceal bleeding Injection sclerotherapy, first introduced in 1939 and “rediscovered” in the late 1970s, has been used for the control of

CHAPTER 36

acute variceal bleeding over the past two decades. Paradoxically the best evidence for the value of sclerotherapy in the management of acute variceal bleeding has come from a more recently published study by the Veterans Affairs Cooperative Variceal Sclerotherapy Group [177]. In this study sclerotherapy, compared with sham sclerotherapy, stopped hemorrhage from actively bleeding esophageal varices (91% in sclerotherapy arm compared with 60% in sham sclerotherapy, p < 0.001, ARR = 29%, NNT = 3) and significantly increased hospital survival (75% vs 51%, p = 0.04 ARR = 24%, NNT = 3). Ald Today it is generally accepted that sclerotherapy should be carried out at the diagnostic endoscopy, which should take place as soon as possible, because there is evidence that this is beneficial compared with delayed injection [178, 179]. No more than two injection sessions should be used to arrest variceal bleeding within a five-day period [92]. Several sclerosing agents have been used for injection, polidocanol 1–3%, ethanolamine oleate 5%, sodium tetradecyl sulfate 1–2% and sodium morrhuate 5%. There is no evidence that any one sclerosant can be considered the optimal sclerosant for acute injection, as it has been shown that a substantial proportion of intravariceal sclerosant ends up in the paravariceal tissue and vice versa. B4 There is no evidence that one technique is better than the other. One of the main shortcomings of sclerotherapy is the risk of local and systemic complications, although this varies greatly between trials and may be related to the experience of the operator [180].

Sclerotherapy plus drugs/balloon tamponade versus drugs/balloon tamponade The five trials, three papers [181–183] and two abstracts [184, 185] comprised 400 patients (413 episodes): three used

Portal hypertensive bleeding

vasopressin [181, 182, 184], one somatostatin [183] and one octreotide [185]. Treatment effect was evaluated within 24 hours up to 120 hours, except in one study at two weeks [181]. Specific definitions of failure to control bleeding are given in four [181–183, 185]; only three [181, 182, 186] report complications; blood transfusion was reported in four [181–183, 185]; three report less transfusion with sclerotherapy [181–183]; and one no difference [185]. Median quality score was 58 (49–68.5). Failure to control bleeding was reported: 214 episodes of variceal bleeding in the sclerotherapy and vasoactive drugs/balloon tamponade group and 199 in the vasoactive drugs/balloon tamponade alone. Failure to control bleeding was significantly more frequent without sclerotherapy, with pooled difference being 16.3% (95% CI: 8.7–23.9%; p = 0.0001)). Alc The NNT was 6 (95% CI: 4–11). The publication bias assessment was 15 null or negative studies. The sensitivity analyses differed from the main metanalysis as follows: abstracts alone showed no differences between trial groups. In only one study, octreotide added to sclerotherapy did not improve control of bleeding. Fewer deaths occurred with sclerotherapy combined with drugs than with drugs/balloon tamponade alone (Q, p = 1.0), with a 5.5% difference (95% CI: −1.8– 12.7%; p = 0.138) with no significant changes in the sensitivity analyses. Complications: reported in three studies [181–183] and two [181, 183] did not report per patient. A systematic evaluation was not possible (see Table 36.6).

Sclerotherapy versus drugs There are 15 studies comprising 1296 patients (1324 episodes), 11 papers [187–197] and four abstracts [198–201]; one used vasopressin [196], one used terlipressin [188], four used somatostatin [191–193, 198] and nine used octreotide [187, 189, 190, 194, 195, 197, 199–201]. Treatment effect

Table 36.6 Randomized controlled trials of sclerotherapy plus drugs/balloon tamponade versus drugs/balloon tamponade alone for the treatment of the acute bleeding episode. Study

Compared treatment

No. of patients S + D/D

Child C n (%)

Soderlund and Ihre (1985) [182]

Vasopressin ± tamponade

57/50

70 (65)

Larson et al. (1986) [181]

Vasopressin ± tamponade

44/38

Alexandrino et al. (1990) [184]

Vasopressin/ nitroglycerin ± tamponade

Novella et al. (1996) [185] Villanueva et al. (1999) [183]

Failure to control bleeding n (S + D/D)

Death n (S + D/D)

Complications n (S + D/D)

3/8

16/18

10/8

47 (57)

5/14

2/5

25/42

41/42

41 (49)

12/12

16/17

NR

Octreotide

22/19

NR

3/7

3/2

NR

Somatostatin

50/50

25 (26)

7/21

7/10

11/4

S + D/D: sclerotherapy + drugs/drugs; NR: not reported.

573

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Table 36.7 Randomized controlled trials of sclerotherapy versus drugs for the treatment of the acute bleeding episode. Study

Compared treatment

No. of pts S/D

Child C (%)

Failure to control bleeding (S/D)

Death n (S/D)

Complications (S/D)

Westaby et al. (1989) [196] Di Febo et al. (1990) [198] Shields et al. (1992) [193] Sung et al. (1993) [195] Planas et al. (1994) [191] Poo et al. (1996) [201] Jenkins et al. (1997) [190] El-Jackie et al. (1998) [199] Lopez et al. (1999) [200] Escorsell et al. (2000) [188] Bildozola et al., (2000) [187] Freitas et al. (2000) [189] Sivri et al. (2000) [194] Yousuf et al. (2000) [197] Ramires et al. (2000) [192]

Vasopressin Somatostatin Somatostatin Octreotide Somatostatin Octreotide Octreotide Octreotide Octreotide Terlipressin Octreotide Octreotide Octreotide Octreotide Somatostatin

33/31 24/23 41/39 49/49 35/35 21/22 77/73 50/50 33/31 114/105 25/25 53/58 36/30 48/48 19/21

22 (34) 19 (40) 42 (52–5) 43 (43) 24 (34) 20 (47) 80 (53) NR NR 69 (31) 5 (10) 39 (35) 35 (53) 20 (21) 12 (30)

4/11 2/5 7/9 13/15 6/7 2/1 14/11 3/21 4/5 36/35 7/10 12/12 9/8 2/4 5/5

9/12 5/6 8/12 20/14 8/10 5/3 13/22 NR 7/6 19/26 2/5 8/13 1/1 5/5 6/6

NR 2/1 12/5 18/5 10/5 1/1 15/19 NR NR 34/21 8/9 NR 5/1 6/8 NR

S: sclerotherapy; D: drugs; NR: not reported.

was evaluated at the end of drug infusion (12–168 hours). The efficacy of sclerotherapy was 83% (57–94%) in studies of 12–48-hour drug infusion [189–192, 194–196, 198–201] and 73% (68–83%) when 120–168 hours [187, 188, 193]. All except three trials [189, 199, 200] report complications. One study had less transfusion with sclerotherapy (units, 2.1 ± 0.41 vs 2.9 ± 0.79; p < 0.05) [199], ten found no difference [187–195, 197], one study did not state [201], and three had no report [196, 198, 200]. Median quality score was 60 [51–73]. Considering failure to control bleeding, there was significant heterogeneity (p = 0.01), but only in the magnitude and not in the direction of treatment effect; in only two were drugs better than sclerotherapy, but without reaching statistical significance [190, 201]. Excluding abstracts there was no heterogeneity (p = 0.4). Failure to control bleeding was less frequent with sclerotherapy with a difference of 3.4% (95% CI: −1.8–8.5%; p = 0.2) with no change following sensitivity analyses. If all papers are considered then sclerotherapy was more effective, with a 5.9% difference (95% CI: 1.5–10.3%) (p = 0.008). The other sensitivity analyses showed that octreotide in nine studies (p = 0.04) and vasopressin (one study) as well as the combined group of somatostatin and octreotide were significantly worse than sclerotherapy. In the trials there were no differences between treatment groups considering only patients with cirrhosis, or abstracts, or somatostatin, or drug infusion more or less than 120 hours, or combined group of vasopressin and terlipressin or terlipressin alone. There were fewer deaths with sclerotherapy – 4.3% (95% CI: 0.6–8.1%) (p = 0.02). Ala The NNT was 23 (95% CI: 574

12–157). The effect is not robust, as publication bias assessment was four null or negative studies. Sensitivity analyses did not change the main meta-analysis. Complications in 12 studies [187, 188, 190–198, 201] had significant heterogeneity (p = 0.0001) and were less frequent with any drug 8.8% (95% CI: 0.2–15.6%; p = 0.01) (see Table 36.7).

Sclerotherapy plus drugs versus sclerotherapy alone The eight trials, six papers [189, 202, 205–208] and two abstracts [203, 204] (the first with two treatment arms) comprised 1026 patients; four studies were placebo controlled [202, 203, 205, 206, 208]. Vasoactive drug was administered for 120 hours in six trials [202–206, 208] and 48 hours in two [189, 207]. The efficacy of sclerotherapy was 82.5% (81–84%) with 48 hour drug administration and 61.5% (36–77%) with 120 hours (p = ns). In all studies but one the average units transfused were significantly less with combination therapy [189]. Median quality score was 60 (49.5–75). Failure to control bleeding was less frequent with sclerotherapy combined with drugs: 13.2% (95% CI: 8.4–18.1%; p < 0.0001). Ala The NNT was 8 (95% CI: 5–15). The publication bias assessment was 47 null or negative studies, that is, the result is very robust. In the sensitivity analyses, terlipressin did not have an advantage: there was no advantage of any drug added to sclerotherapy for 48 hours administration and no advantage of combined therapy when no placebo drug was used. The difference in mortality was 3.4% (95% CI: −0.4– 7.1%) in favor of combined therapy (p = 0.08). Sensitivity

CHAPTER 36

Portal hypertensive bleeding

Table 36.8 Randomized controlled trials of sclerotherapy plus drugs versus sclerotherapy alone for the treatment of the acute bleeding episode. Study

Compared treatment

Besson et al. (1995) [202] Signorelli et al. (1996) [203] Signorelli et al. (1996) [203] Signorelli et al. (1999) [204] ABOVE (1997) [205] Zuberi and Balock (2000) [206] Freitas et al. (2000) [189] Farooqi 2000 [207] Cales et al. (2001) [208]

Sclerotherapy Sclerotherapy Sclerotherapy Sclerotherapy Sclerotherapy Sclerotherapy Sclerotherapy Sclerotherapy Sclerotherapy

+ + + + + + + + +

octreotide somatostatin octeotide octreotide somatostatin octreotide octreotide octreotide vapreotide

No. of patients S/S + D

Child C (%)

Failure to control bleeding (S/S + D)

Death n (S/S + D)

Complications (S/S + D)

101/98 30/33 30/31 45/43 75/77 35/35 42/44 69/72 98/98

73(37) NR NR NR NR 0(0) 29(37) 38(27) 73(37)

25/11 11/6 11/8 18/8 48/31 13/4 18/9 11/3 49/33

12/12 5/4 5/5 NR 24/27 1/1 13/12 6/1 7/5

33/34 NR NR NR 37/37 NR NR 27/31 8/6

S: sclerotherapy; S + D: sclerotherapy plus drugs; NR: not reported.

Author

Year

S+D

S

Besson Signorelli Signorelli Signorelli Avgerinos Freitas Zuberi Farooqi Cales

1995 1996 1996 1999 1997 2000 2000 2000 2001

11/98 6/33 8/31 8/43 31/77 16/44 2/35 3/72 31/98

25/101 11/30 11/30 18/45 48/75 8/42 8/35 11/69 46/98

1/64

1/16

Pooled (fixed effect) 116/531 186/525 2.066 (1.564 / 2.730) Better S

1/4

1

4

16

64

Better S+D

Figure 36.3 Acute bleeding: Forrest plot of risk difference for control of bleeding in trials of sclerotherapy (S) vs sclerotherapy combined with vasoactive agents (S + D).

analysis showed that in placebo controlled trials in which drug was given for 120 hours the difference was 1.3% (95% CI: −3.3–5.8%), strongly suggesting no benefit in mortality despite benefit for control of bleeding. For complications, five studies had data but only two reported per patient [202, 205], with no statistical differences (see Table 36.8 and Figures 36.3 and 36.4).

Sclerotherapy versus variceal ligation The twelve trials, eight papers [209–216] and four abstracts [217–220], comprised 1309 patients. In seven trials only patients with cirrhosis were included [209–213, 216, 219]. The same ligating device (Bard Interventional Products, Tewksbury, Massachusetts) with an overtube was used in eight [209–212, 214–216]; in three this was not mentioned [217–219] and one used a six-shooter [220]. A definition of failure to control bleeding is stated in five [209, 210, 212,

213, 216]. The efficacy of sclerotherapy for initial hemostasis at the end of endoscopy was 95% (76–100%) compared with 97% (86–100%) with ligation EBL group (p = 0.4). In only one [213] of documenting transfusion requirements [211–213, 215, 216, 218], was this less in the ligation group (units, 4.5 ± 1.8 (0–12) versus 3.2 ± 1.2 (0–6) p < 0.01); in others there was no difference. Median quality score was 68.5 (50.5–79). Failure to control of bleeding: there was a difference favoring ligation −2.5% (95% CI: 0.4–4.6%) (p = 0.018). Ala Sensitivity analyses did not show differences from the main metanalysis, including an evaluation defining failure versus those in which there was no failure. Regarding mortality, the percentage difference was 1.3% favoring ligation (95% CI: −2.3–4.9%, p = 0.46). Sensitivity analyses did not show differences from the main metanalysis. In another recent trial [221] patients admitted with acute gastrointestinal bleeding and with suspected cirrhosis 575

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Year

Besson

1995

Signorelli

1996

4/33

5/30

Signorelli

1996

5/31

5/30

Avgerinos

1997

27/77

24/75

Freitas

2000

27/44

31/42

Zuberi

2000

1/35

1/35

Farooqi

2000

1/72

6/69

Cales

2001

14/98

21/98

S+D

S

1/64

1/16

1/4

1

4

16

64

12/98 12/101

Pooled (fixed effect) 91/488 105/480 1.291 (0.914 / 1.825) Better S

Better S+D

Figure 36.4 Acute bleeding: Forrest plot of risk difference for mortality in trials of sclerotherapy (S) vs sclerotherapy combined with vasoactive agents (S + D).

Table 36.9 Randomized controlled trials of sclerotherapy versus variceal ligation for the prevention of re-bleeding. Study

No. of pts (S/L)

Child C (%)

Failure of initial hemostasis

Re-bleeding S/L

Death S/L

Variceal obliteration S/L

Variceal recurrence S/L

Stiegmann et al. (1992) [216] Laine et al. (1993) [211] Gimson et al. (1993) [209] Jensen et al. (1993) [242] Mundo et al. (1993) [243] Young et al. (1993) [244] Lo et al. (1995) [212] Hou et al. (1995) [210] Jensen et al. (1993) [242] Jain et al. (1996) [218] Mostafa et al. (1996) [245] Baroncini et al. (1997) [246] Lo et al. (1997) [213] Sarin et al. (1997) [214] Masci et al. (1997) [247] Avgerinos et al. (1997) [248] Shiha and Farag (1997) [249] Fakhry et al. (1997) [217] De la Pena et al. (1998) [250] Shafqat et al. (1998) [215] Salem et al. (1999) [220]

65/64 39/38 23/21 18/14 11/8 13/10 59/61 67/67 26/24 24/22 89/69 54/57 34/37 48/47 50/50 40/37 43/42 41/43 46/42 28/24 180/180

19 23 26 NR 37 78 48 39 NR 46a NR 27 60 14 NR 8 NR NR NR NR NR

3 : 13/2 : 14 1 : 9/1 : 9 3/3 0/3 NR NR 3 : 15/1 : 18 2 : 16/0 : 20 NR 2/3 1 : 21/1 : 18 NR 8/1 1 : 7/1 : 5 NR NR 4 : 19/2 : 17 1 : 17/1 : 18 NR 6/1 32/16

31/23 17/10 26/16 9/6 3/2 5/2 30/20 28/13 9/7 5/9 9/6 10/9 10/6 10/3 26/16 19//0 10/6 6/7 23/13 NR NR

29/18 6/4 17/21 3/2 4/2 4/2 19/10 11/14 9/4 NR 2/3 12/12 12/7 3/3 10/12 8/8 2/2 NR 10/8 6/3 NR

22/27 27/22 27/32 NR 4/4 11/9 37/45 53/58 NR 24/20 82/63 50/53 NR 45/44 41/43 39/35 37/37 40/42 29/31 NR NR

11 : 22/9 : 27 — — — — — — — — 2 : 24/5 : 20 7 : 82/12 : 63 7 : 50/17 : 53 — 3 : 45/10 : 44 6 : 37/11 : 37 17 : 39/11 : 35 6 : 37/11 : 37 8 : 41/9 : 42 13 : 29/19 : 31 NR —

S: sclerotherapy; L: variceal ligation; NR: not reported.

received somatostatin infusion for five days. Endoscopy was performed within six hours and those with esophageal variceal bleeding were randomized to receive either sclerotherapy (n = 89) or ligation (n = 90). Therapeutic failure occurred in 21 patients treated with sclerotherapy (24%) and in nine treated with ligation (10%) (RR = 2.4, 95% CI: 1.1–4.9). However, in those with active bleeding there was no difference between ligation and sclerotherapy. Failure 576

to control bleeding occurred in 15% vs 4%, respectively (p = 0.02). Treatment group, shock and HVPG > 16 mmHg were independent predictors of failure. Side effects occurred in 28% of patients receiving sclerotherapy vs 14% with ligation (RR = 1.9; 95% CI: 1.1–3.5), being serious in 13% vs 4% (p = 0.04). Six-week survival probability without therapeutic failure was better with ligation (p = 0.01) (see Table 36.9 and Figures 36.5 and 36.6).

CHAPTER 36

1/64

1/16

1/4

Author

Year

Ligation

Sclerotherapy

Stiegmann Laine Gimson Jensen Lo Hou Jain Lo Sarin Fakhry Shafqat Salem

1992 1993 1993 1993 1995 1995 1996 1997 1997 1997 1998 1999

2/64 1/38 3/54 3/14 1/61 0/67 3/22 1/37 1/47 1/43 1/24 16/180

3/65 1/39 3/49 0/18 3/59 2/67 2/24 8/34 1/48 1/41 6/28 32/180

33/651

62/652 1.951 (1.277 / 2.982) Better sclerotherapy

Pooled (fixed effect)

1

4

Portal hypertensive bleeding 16

64

Better ligation

Figure 36.5 Forrest plot of risk difference for control of bleeding in trials of sclerotherapy vs variceal ligation.

Author

Year

Ligation

Sclerotherapy

Stiegmann 1992

1/64

1/16

1/4

10/64

15/65

Jensen

1993

2/14

3/18

Jain

1996

3/22

2/24

Lo

1997

7/37

12/34

Sarin

1997

3/47

3/48

Fakhry

1997

1/43

1/41

Salem

1999

14/180

16/180

40/407

52/410 1.349 (0.867 / 2.100)

Pooled (fixed effect)

Better sclerotherapy

1

4

16

64

Better ligation

Figure 36.6 Forrest plot of risk difference for mortality in trials of sclerotherapy vs variceal ligation.

Ligation plus sclerotherapy vs ligation There were 113 patients with either active bleeding or stigmata of recent bleeding from esophageal varices who were randomly assigned to receive ligation plus sclerotherapy, or ligation alone. Hemostasis of active bleeding was achieved at the time of the index treatment in eight of ten of the patients in the combined group (80%) and in ten of twelve of the patients in the ligation group (83%, p > 0.05) [222].

Ligation + terlipressin vs ligation + octreotide In a recent randomized trial [223] 88 patients with cirrhosis with variceal bleeding allocated to terlipressin (n = 43) or octreotide (n = 45) succesfull hemostasis was achieved in 98% of patients. Early re-bleeding, which included rebleeding within six weeks of therapy was seen in 28% of terlipressin group and 24% of octreotide group. The two treatments were equally effective for acute esophageal

variceal bleeding with regard to hemostatic effect and prevention of re-bleeding.

Randomized controlled trials of emergency surgery in the management of acute variceal bleeding Four randomized trials, carried out in the 1980s, compared sclerotherapy to emergency staple transaction [224–226]. Failure to control bleeding was reported only in two of these studies, with divergent results. Teres et al. reported that efficacy of transection in their study was only 71%, the lowest in the literature, compared with 83% in the sclerotherapy arm [226]. In contrast, in the largest study by Burroughs et al., a five-day bleeding-free interval was achieved in 90% of the patients who underwent transection (none re-bled from varices) compared with 80% in those who had two emergency injection sessions [227]. There was 577

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no difference in mortality between the two treatment modalities. Cello et al. showed that emergency portacaval shunt was more effective than emergency sclerotherapy (followed by elective sclerotherapy) in preventing early re-bleeding (19% vs 50%) [228]. Hospital and 30-day mortality were not significantly different. Alc Finally, Orloff et al. in a small study, reported that portacaval shunt, carried out in less than eight hours from admission, was significantly better than medical treatment (vasopressin/ balloon tamponade) in the control of acute variceal bleeding [229]. Survival was also better in the patients who had shunts, but the difference was not statistically significant.

Randomized controlled trials of other endoscopic therapies in the management of acute variceal bleeding Two types of tissue adhesives (n-butyl-2-cyanoacrylate, Histoacryl and isobutyl-2-cyanoacrylate, Bucrylate) have been used for the control of variceal bleeding [230]. The adhesives potentially result in better immediate control of bleeding because they harden within seconds upon contact with blood. However, extra care must be taken to ensure that the adhesive does not come into contact with the endoscope and block suction and operator channels. This can be prevented if the adhesive is mixed with lipiodol to delay hardening. Moreover, the sclerotherapy needle must be carefully placed within the varix prior to injection, to avoid leak. A small randomized trial showed that cyanoacrylate was superior to conventional sclerotherapy with 3% ethanolamine oleate solution for control of bleeding and reduction of hospital mortality in Child-Pugh class C patients [231]. Two randomized controlled trials compared sclerotherapy alone with the combination of sclerotherapy and n-butyl-2-cyanoacrylate [232, 233]. The combined treatment was more effective than sclerotherapy alone in both studies. Alc Moreover, in two studies n-butyl-2-cyanoacrylate was compared with variceal ligation for the control of bleeding from esophageal [234] or esophagogastric varices [235]. The overall success rate for initial hemostasis of both treatment modalities was similar in these studies. Alc However, n-butyl-2-cyanoacrylate was superior to variceal ligation for the control of fundal variceal bleeding, but it was less effective for the prevention of rebleeding (67% vs 28%). In a small randomized study [236], a biological fibrin glue (Tissucol) was more effective than sclerotherapy with polidocanol in the prevention of early re-bleeding and had a significantly lower incidence of complications. Finally, another study found that fibrin glue was as effective and safe as ligation for acute bleeding and for prevention of re-bleeding from esophageal varices, but had superior tissue compatibility [237]. More studies are necessary to confirm these data and examine the potential risks 578

of activating coagulation, systemic embolism and particularly transmission of infections with the human plasmaderived fibrin glue. The literature available on thrombin is limited. Bovine thrombin was effective in small series, but has been withdrawn due to its infection risk [238]. In addition, in a prospective randomized controlled trial [239], cirrhotic patients with acute or recent esophageal variceal bleeding were assigned randomly to percutaneous transhepatic varices embolization, PTVE (52 patients) or EVL (50 patients). During the follow-up period (median 24 and 25 months in the PTVE and EVL groups respectively) UGI re-bleeding developed in eight patients in the PTVE group and 21 patients in EVL group (p = 0.004). Recurrent bleeding from esophageal varices occurred in three patients in the PTVE group and 12 in the EVL group (p = 0.012, relative risk 0.24, 95% CI: l 0.05–0.74). Survival in these two groups was not significantly different. An endoscopic detachable snare is another ligation device which has the advantage of allowing an unlimited number of ligations by reloading the nylon minisnare while the endoscope remains in the esophagus. The first prospective randomized trial showed that the mini snare performed equally well when compared with a multiple variceal ligator [240]. Ald In another study 50 patients with acute esophageal variceal bleeding were recruited: 25 were treated by elastic band ligation and 25 by endoloop ligation: re-bleeding 12% endoloop group and 28% ligation was not significantly different [241].

Gastric varices The incidence of bleeding from gastric varices varies between 3% and 30%, but in most series it is less than 10% [251]. Patients with gastric variceal hemorrhage bleed more profusely and require more transfusions than patients with esophageal variceal bleeding [252]. B4 Moreover, these patients have a higher risk of re-bleeding and a decreased survival rate compared with patients bleeding from esophageal varices. The optimal treatment of gastric variceal bleeding is not known. Limited information is available on the role of vasoactive drugs in the control of gastric fundal bleeding and balloon tamponade has been used with little success. Use of standard sclerosants is associated with unacceptable re-bleeding, particularly from necrotic ulceration, as the gastric mucosa appears much more sensitive to this than the esophagus. Because of this, alternative sclerosant agents have been evaluated. The tissue adhesives n-butyl-2-cyanoacrylate and isobutyl-2-cyanoacrylate, mixed with lipiodol to delay premature hardening, have been evaluated, and found to be efficacious in observational, studies [253]. Isobutyl-2cyanoacrylate has been shown to be superior to ethanolamine, in a non-randomized study, achieving

CHAPTER 36

hemostasis in 90% of 23 patients, as opposed to 67% of 24 patients (p < 0.005) [254]. In a randomized controlled trial of 37 patients with isolated fundic varices (acute and recent bleeding) with follow-up of 15 months, cyanoacrylate glue was shown to be more effective than sclerotherapy with alcohol for variceal obliteration (100% vs 44%, p < 0.005) [255]. There was a trend in favor of cyanoacrylate glue for the control of acute bleeding (89% vs 62%) and the need of surgical intervention (10% vs 35%), although both were statistically nonsignificant. Mortality was similar in the two groups. Ald In another randomized trial [256] 48 patients received endoscopic band ligation (GVL) and another 49 patients received endoscopic n-butyl-2-cyanoacrylate injection (GVO). Both treatments were equally successful in controlling active bleeding (14/15 vs 14/15, p = 1.000). More of the patients who underwent GVL had GV re-bleeding (GVL vs GVO, 21/48 vs 11/49; p = 0.044). The two-year and three-year cumulative rate of GV re-bleeding were 63.1% and 72.3% for GVL, and 26.8% for both periods with GVO; p = .0143, log-rank test. Multivariate Cox regression indicated that concomitance with HCC (relative hazard: 2.453, 95% CI: 1.036–5.806, p = 0.041) and the treatment method (GVL vs GVO, relative hazard: 2.660, 95% CI: 1.167–6.061, p = 0.020) were independent factors predictive of GV re-bleeding. There was no difference in survival between the two groups. In the study by Lo et al. cirrhotic patients with a history of gastric variceal bleeding were randomized to two groups [257]. The group receiving endoscopic obturation (group A) comprised 31 patients and the group receiving band ligation (group B) comprised 29 patients. Butyl cyanoacrylate and pneumatic-driven ligator were applied, respectively. Active bleeding occurred in 15 patients in group A and 11 patients in group B. Initial hemostatic rate was 87% in group A and 45% in group B (p = 0.03). The sessions required to achieve variceal obliteration and obliteration rates were similar in both the groups. However, re-bleeding rates were significantly higher in group B (54%) than group A (31%) (p = 0.0005). Nine patients of group A and 14 patients of group B died (p = 0.05). Authors concluded that endoscopic obturation using cyanoacrylate proved more effective and safer than band ligation in the management of bleeding gastric varices. However, reports of cerebral embolism, with tissue adhesives identified at postmortem as well splenic embolization and development of retrogastric abscesses, cause concern. Interest has therefore focused on thrombin. This is much easier to administer, and has been shown to provide good early hemostasis [258]. However, in all of these studies, re-bleeding rates have remained high. Hence, in patients with re-bleeding or uncontrolled bleeding from gastric varices, devascularization surgery or portosystemic shunting has been proposed. “Salvage” TIPS is very effec-

Portal hypertensive bleeding

tive in this situation, with more than 95% success rate for initial hemostasis and an early re-bleeding rate of less than 20% [251]. TIPS appears to be as effective for gastric varices as for esophageal varices. Non-actively bleeding patients with fundal varices constitute a discrete population. The efficacy of cyanoacrylate in these patients is controversial and bleeding rates in this group can be relatively high. The Japanese experience with balloon-occluded transvenous obliteration as a prophylactic procedure in this patient population appears promising [259, 260]. TIPS, shunt surgery and, of course, liver transplantation are the only other therapeutic options for recurrent bleeding from gastric varices. The consensus at Baveno IV was to use endoscopic therapy with tissue adhesive (e.g. N-butyl-cyanocrylate) [89]. Lastly, in a recent trial TIPS proved more effective than glue injection in preventing re-bleeding from gastric varices, with similar survival and frequency of complications [261].

Uncontrolled variceal bleeding The definition of uncontrolled variceal bleeding includes the continued/early variceal re-bleeding (within five days) despite two sessions of therapeutic endoscopy, continued variceal bleeding despite balloon tamponade and continued/early gastric or ectopic variceal bleeding despite vasoconstrictor therapy. Predictive models indicate grade C patients with signs of significant bleeding are the patients at risk of failure. Balloon tamponade has most often been used to arrest lifethreatening hemorrhage or if other measures fail. It has also been used in the absence of a definite diagnosis if bleeding from varices is strongly suspected. The usual tube is a modified four-lumen Sengstaken-Blakemore tube (SBT). The airway should be protected by an endotracheal tube under a short general anesthetic, as the risk of aspiration is very high, particularly in unskilled hands [262]. If blood is still coming up the gastric aspiration lumen, then varices are less likely to be the cause of blood loss, although gastric fundal varices are not always controlled by tamponade. In fact, whenever this occurs, if the position of the SBT has been checked and adequate traction applied, the diagnosis of variceal bleeding should be questioned, and emergency angiography performed. In a recent report the use of self-expandable metallic stents was evaluated to arrest uncontrollable acute variceal bleeding (20 patients mean age 52, 8 Child pugh C) [112]. The patients had not been successfully managed with prior pharmacologic or endoscopic therapy. The stents were successfully placed in all of the patients and were left in place for 2–14 days. Bleeding from the esophageal varices ceased immediately after implantation of the stent in all cases. No recurrent bleeding, morbidity, or mortality occurred during 579

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treatment with the esophageal stent. All of the stents were extracted without any complications after definitive treatment had been started.

Randomized trials of TIPS TIPS stops bleeding in a significant percentage of patients [263]. In uncontrolled studies TIPS is effective in stopping variceal hemorrhage [251, 264, 265], but there is still a high mortality [266]. Monescillo et al. evaluated variceal bleeders with HVPG ≥ 20 mmHg randomly allocated to receiving transjugular intrahepatic portosystemic shunt (TIPS; HRTIPS group, n = 26) within the first 24 hours after admission or not (HR-non-TIPS group) [96]. The HR-non-TIPS group had more treatment failures (p = 0.0001). Early TIPS placement reduced treatment failure (p = 0.003), in-hospital and one-year mortality (p < 0.05). Overall TIPS remains a good choice as a rescue therapy although when it is not available staple transection of the esophagus could be considered [267]. Ald In another multicentre trial an early decision for PTFE-TIPS improved survival in high risk cirrhotic patients admitted with acute variceal bleeding [268]. New diagnostic and treatment algorithms of acute variceal bleeding are needed using known predictive factors of failure to control bleeding and mortality in order to identify the group of bleeders with poor outcome. In this group more effective vasoactive regimens, early TIPS after diagnostic endoscopy, and the use of self-expanding covered esophageal stents could be considered [269].

Conclusion The available data suggest that emergency endoscopic treatment with banding ligation or sclerotherapy, at the time of the initial diagnostic endoscopy, should be the gold standard for the management of the acute variceal bleeding episode. Sclerotherapy may be more applicable in some acute situations compared with ligation. A diagnostic endoscopy, with visualization unhindered by the ligation device, should be done first as varices may not be the source of bleeding. If ligation is to be used then this entails a double intubation and does lengthen the procedure. Sclerotherapy is also significantly better than drug treatment alone and there is no need for further studies directly comparing sclerotherapy or ligation with one of the currently available drugs. However, the combination of sclerotherapy with a drug, given as soon as possible after admission is currently the best option. The drugs of choice for this combination are terlipressin (as mortality is reduced albeit in small placebo-controlled studies) and somatostatin (which has less side effects and has been successfully tested over five days). Further studies are needed to assess the role of tissue adhesives or fibrin glues in patients’ unresponsive to vasoactive drugs or sclerotherapy. 580

The role of emergency TIPS as “salvage therapy” for uncontrolled bleeding from esophageal or gastric varices is now common practice but only certain centres can offer an emergency service. Randomized trials with other therapies such as esophageal stent should be performed.

Prevention of recurrent variceal bleeding Patients surviving the first episode of variceal bleeding are at very high risk of recurrent bleeding (70% or more) and death (30–50%). All patients who have previously bled from varices should have secondary therapy to prevent further variceal bleeding [89]. There is no role for an observational policy, as all randomized studies have shown active therapy to be better than observation alone. Ala Hence, in clinical practice the risk indicators of long-term re-bleeding are of less clinical value, than those for first variceal bleeding. However, severity of liver disease, continued alcohol abuse and variceal size have been associated with variceal re-bleeding. A recent development has been the proposed use of hemodynamic indices to identify patients who are more likely to re-bleed. Two such indices have been reported, using the technique of hepatic venous pressure measurement as an indicator of portal pressure. From the analysis of the Barcelona-Boston-New Haven Primary Prophylaxis trial, it was concluded that variceal bleeding did not occur with an HVPG < 12 mmHg, in patients with predominantly sinusoidal portal hypertension. However, with an HVPG > 12 mmHg, the correlation between portal pressure and bleeding risk is inconsistent. An hemodynamic index was proposed by Feu et al. [270]. Patients who had a percentage reduction of HVPG of 20% or more from baseline had a re-bleeding rate of 15% compared with 50% in those who did not achieve this hemodynamic target. Unfortunately, these HVPG targets are achieved in only about one-third of patients on β-blockers, hence the introduction of combined pharmacologic therapy. Several studies on secondary prevention have used hemodynamic monitoring during combination pharmacotherapy in their design. In these studies the target values are reached only in 45–60% of patients subjected to therapy with β-blockers and nitrates. Moreover, because most rebleeding episodes occur within one month of the index bleed, early repeat HVPG measurements are needed in order to identify the nonresponders. However, the above approach has not been confirmed in one study [271]. A randomized study has shown greater likelihood of HVPG reduction with sequential monitoring of portal pressure but no reduction in rebleeding compared to combined ligation and nadolol without monitoring of HVPG [272]. There are several options including pharmacologic, endoscopic and surgical/radiological therapies.

CHAPTER 36

Randomized controlled trials for the prevention of variceal re-bleeding β-blockers versus no treatment A comprehensive meta-analysis of 12 trials comprising 769 patients [273–284] has been published [285]. The mean follow-up was 21 ± 5 months. There was significant heterogeneity in the evaluation of re-bleeding (p < 0.01). Treatment with β-blockers significantly decreased the risk of re-bleeding (Der Simonian and Laird method: POR 21%; 95% CI: 10–32%). The NNT with β-blockers to prevent one re-bleeding episode was 5. Survival was also significantly improved in patients treated with β-blockers. (Der Simonian and Laird method: POR 5.4%, 95% CI: 0–11%) although there was significant heterogeneity in this analysis (p < 0.01). Ala The NNT to prevent one death is 14. Adverse events occurred in 17% of patients and were generally mild. No fatal complication has been reported with β-blockers. The use of hemodynamic targets (20% reduction of HVPG and/or fall 20% from baseline value) from 38% to 59%, and these patients experienced less bleeding (10% vs 64% for non-responders; p < 0.05)[294].

Sclerotherapy versus no treatment There are seven trials, including 1111 patients [182, 281, 295–299]. The re-bleeding rate was reduced in all studies except one [295]. Meta-analysis showed that the pooled odds ratio was significantly reduced (POR 0.63; 95% CI: 0.49–0.79). Mortality was also reduced significantly in the sclerotherapy arm (POR 0.77; 95% CI: 0.61–0.98). Ala However, complications were frequent and did not differ from those of prophylactic or emergency sclerotherapy.

Sclerotherapy versus drugs Eleven trials, involving 971 patients compared sclerotherapy with drugs (propranolol in ten studies [281, 300–307, 309] and nadolol plus ISMN in one study [308] for the prevention of recurrent bleeding (from any source, for example varices, portal hypertensive bleeding, or sclerotherapy ulcers) (see Table 36.10). There was a striking heterogeneity in the evaluation of re-bleeding (p = 0004): in five studies [281, 301, 305, 306, 308] re-bleeding was less frequent in patients randomized to drugs and in six studies in patients randomized to sclerotherapy [300, 302–304, 307, 309] the POR showed that there was no significant difference between the two treatment modalities (Der Simonian and Laird method: POR 0.88; 95% CI: 0.72–1.25). Ala There was no significant heterogeneity in the evaluation of survival (p = 0.15). More patients randomized to sclerotherapy survived, but the result was not statistically significant (POR 0.95; 95% CI: 0.58–1.32). Moreover, the number of patients free of adverse events was significantly higher in the drug group compared with sclerotherapy group (POR 0.85; 95% CI: 0.65–1.11).

Sclerotherapy plus drugs versus sclerotherapy Twelve trials of sclerotherapy and drugs (eight propranolol [310–317], three nadolol [318–320] and one isosorbide-5mononitrate [321] versus sclerotherapy alone, comprising 853 patients are summarized in Table 36.11). Theoretically the administration of drugs might prevent re-bleeding 581

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Table 36.10 Randomized controlled trials of sclerotherapy versus β-blockers for the prevention of re-bleeding. Study

No. of patients D/S

Child C (%)

Bleeding D/S

Death D/S

Adverse events D/S

Alexandrino et al. [300] Dollet et al. [301] Fleig et al. [302] Westaby et al. [303] Liu et al. [304] Martin et al. [305] Rossi et al. [281] Andreani et al. [306] Dasarathy et al. [307] Teres et al. [226] Villanueva et al. [308]

34/31 27/28 57/58 52/56 58/60 34/42 27/26 35/40 53/51 58/58 43/43

— 27 NR — NR 24 38 35 34 14 —

25/17 11/18 26/26 29/28 33/20 18/23 13/13 12/17 31/19 37/26 11/23

11/9 12/15 16/20 22/21 27/17 8/13 7/6 9/17 19/10 23/21 4/9

24/28 0/10 NR 4/0 NR 0/19 3/8 ND 5/9 10/23 —

D; drug; S: sclerotherapy; NR: not reported.

Table 36.11 Randomized controlled trials of sclerotherapy plus drugs versus sclerotherapy for the prevention of re-bleeding. Study

No. of patients S/S + D

Bleeding S/S + D

Death S/S + D

Westaby et al. [317] Jensen and Krarup [313] Lundell et al. [314] Bertoni et al. [318] Gerunda et al. [319] Vinel et al. [316] Avgerinos et al. [311] Villanueva et al. [320] Acharya et al. [310] Vickers et al. [315] Bertoni et al. [321] Elsayed et al. [312]

27/26 26/25 22/19 14/14 30/30 36/39 40/45 18/22 56/58 34/39 37/39 87/91

8/7 12/3 11/12 4/1 7/6 10/4 21/14 7/12 12/10 14/17 15/4 34/13

7/9 1/1 NR 3/1 3/1 5/5 9/8 0/2 7/5 9/9 9/2 10/11

S: sclerotherapy; S + D: sclerotherapy plus drugs; NR: not reported.

before variceal obliteration. One problem with this group of studies is that only one study evaluated β-blockers after obliteration [313]. In the others, the drug was stopped at eradication. There was statistically significant heterogeneity caused by differences between studies both in the direction and in the size of the effect of treatment: three studies were in favor of sclerotherapy alone [314, 315, 320], while nine were in favor of sclerotherapy plus β-blockers [310, 313, 316–319, 321], statistically significant difference reported in three [312, 313, 321] POR showed that there was statistically significantly less re-bleeding in the combined treatment arm (Der Simonian and Laird method: POR 0.55; 95% CI: 0.35–0.86). There was no statistically significant heterogeneity in the evaluation of survival, with no signifi582

cant difference between the treatments treatments (POR 0.77; 95% CI: 0.5–1.1) (see Figures 36.7 and 36.8). Ala Combination sclerotherapy plus subcutaneous octreotide was also compared with sclerotherapy alone for the prevention of early re-bleeding, as well as for long-term management of patients after variceal hemorrhage [322]. This last study showed significantly less re-bleeding and mortality rates in the combined treatment group. However, the possibility of a severe selection bias was raised due to the exceedingly high re-bleeding rates in the sclerotherapy group. Therefore the clinical efficacy of subcutaneous octreotide in reducing re-bleeding rates remain uncertain, despite the post-prandial increase in portal pressure being blunted by octreotide but not by propranolol.

Sclerotherapy plus drugs vs drugs In a single randomized trial 131 patients were randomly assigned to sclerotherapy plus propranolol with propranolol alone. Twenty-eight patients from the propranolol group but only 12 patients from the propranolol-plussclerotherapy group had recurrent bleeding from esophageal variceal rupture (p less than 0.01). The total number of blood units per patient with recurrent bleeding was slightly but not significantly more important in the propranolol group (8 +/− 7) than in thepropranolol-plus-sclerotherapy group (5 +/− 5; p = 0.09) [323]. Ald

Sclerotherapy versus variceal ligation Sclerotherapy does significantly decrease re-bleeding rates and mortality, but it has been associated with serious complications, the most common of which are esophageal stricture and bleeding from treatment-induced ulcers. Variceal ligation was developed with the aim to provide an endo-

CHAPTER 36

Author

Year

SCL

Westaby Jensen and KF Lumdell Bertoni Gerunda Vinel Avgerinos Acharya Vickers Bertoni Villanueva Elsayed

1986 1989 1990 1990 1990 1992 1993 1993 1994 1994 1994 1996

8/27 12/26 11/22 4/14 7/30 10/36 21/40 12/56 14/34 15/37 7/18 34/87

SCL+ drugs 7/26 3/25 12/19 1/14 6/30 4/39 14/45 10/58 17/39 4/39 12/22 13/91

1/64

1/16

1/4

1

4

Portal hypertensive bleeding 16

64

0.550 (0.351 / 0.863) Better SCL

Pooled (random effect) 155/427 103/447 Better SCL+drugs

Figure 36.7 Secondary prevention: Forrest plot of randomized trials of sclerotherapy plus drugs versus sclerotherapy in secondary prevention of variceal bleeding. Variceal bleeding. SCL: sclerotherapy. Data are expressed as OR (95% CI) in a log scale.

Author

Year

Westaby Jensen and KF Bertoni Gerunda Vinel Avgerinos Acharya Vickers Bertoni Villanueva Elsayed

1986 7/27 1989 1/26 1990 3/14 1990 3/30 1992 5/36 1993 9/40 1993 7/56 1994 9/34 1994 9/37 1994 0/18 1996 10/87

Pooled (fixed effect)

1/64

SCL SCL+drugs

63/405

1/16

1/4

1

4

16

64

9/26 1/25 1/14 1/30 5/39 8/45 5/58 9/39 2/39 2/22 11/91 54/428 Better SCL+drugs

0.775 (0.521 / 1.152) Better SCL

Figure 36.8 Secondary prevention: Forrest plot of randomized trials of sclerotherapy plus drugs versus sclerotherapy in secondary prevention of variceal bleeding. Mortality. SCL: sclerotherapy. Data are expressed as OR (95% CI) in a log scale.

scopic therapy at least as effective as sclerotherapy, but with fewer complications. There are 20 studies [209, 210, 212–218, 220, 242–249, 324, 325] (n = 1634) comparing sclerotherapy to variceal ligation for the prevention of recurrent bleeding. Thirteen studies included only patients with cirrhosis [209–213, 216, 242–244, 246–248, 324], six studies involved patients with cirrhosis or non-cirrhotic portal hypertension [214, 215, 218, 220, 245, 249], and one study included only patients with hepatic fibrosis due to schistosomiasis [217]. The sclerosing agent used was sodium tetradecyl sulfate (eight trials [210–213, 216, 242, 244, 324]), ethanolamine oleate (four trials [209, 217, 245, 248]) polidocanol (two trials [243, 246]) absolute alcohol (one trial [214]) and was not reported in five studies [215, 218, 220, 247, 249]. The same ligation equipment (Bard Interventional Products, Tewksbury, Massachusetts, USA) was used in all trials. All treatment sessions were done at intervals of 1–3 weeks. Meta-analysis showed that re-bleeding was significantly less common with variceal ligation than with sclerotherapy

(POR 0.53; 95% CI: 0.42–0.67), without significant heterogeneity amongst trials. Ala The NNT with variceal ligation rather than with sclerotherapy to prevent one re-bleeding episode is 10 (95% CI: 7–17). Publication bias assessment showed that 121 null or negative studies would be needed to render the results of the meta-analysis statistically nonsignificant. Variceal ligation was also associated with significantly lower mortality when compared with sclerotherapy as the result just reached statistical significance (POR 0.77; 95% CI: 0.59–0.99, p = 0.048). Complications were also less common in patients treated with variceal ligation in all studies except one [209], although the size of the difference varied between studies, causing significant heterogeneity (p = 0.004). Meta-analysis showed that the difference was statistically significant in favor of variceal ligation (Der Simonian and Laird method: POR 0.29; 95% CI: 0.19–0.44). In addition, the number of treatment sessions needed to achieve variceal obliteration was less with variceal ligation in all studies (2.7–4.1 sessions with variceal ligation compared with 4–6.5 sessions with sclerotherapy). 583

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Table 36.12 Randomized controlled trials of variceal ligation versus variceal ligation plus sclerotherapy for the prevention of re-bleeding. No. of patients L/L + S

Child C (%)

Re-bleeding L/L + S

Death L/L + S

Variceal eradication L/L + S

Complications L/L + S

Combined Laine et al. (1996) [325] Djurdjevic et al. (1999) [222] Argonz et al. (2000) [327] Saeed et al. (1997) [328] Traif et al. (1999) [329] El-Khayat et al. (1997) [330] Hou et al. (2001) [331] Bobadilla-Diaz et al. (2002) [332]

20/21 51/52 29/30 25/22 31/29 30/34 47/47 15/18

44 21% NR 28 25 NR 20 NR

6/6 5/7 11/5 6/8 7/5 2/2 11/13 1/0

3/3 6/7 9/4 4/8 7/3 ¾ 6/7 NR

12/15 47/46 16/24 16/12 NR NR 40/41 NR

2/3 1/3 1/8 5/13 7/6 4/6 23/31 NR

Sequential Bhargava and Pokharna (1997) [333] Lo et al. (1998) [334]

25/25 35/37

18 21

4/5 11/3

NR 10/7

5/20

8/14

Study

L, variceal ligation; L + S, variceal ligation plus sclerotherapy; NR, not reported.

There was no difference between the endoscopic modalities in the number of patients with varices obliterated (POR 1.23; 95% CI: 0.93–1.61), while the recurrence of varices was more frequent in patients treated with variceal ligation (POR 1.36; 95% CI: 0.96–1.92). Ala However, re-bleeding after initial eradication seems unusual especially if patients are in a regular endoscopic follow-up, and varices that recur are re-obliterated (see Table 36.12) [326].

Variceal ligation versus variceal ligation plus sclerotherapy To further improve the results achieved with variceal ligation, which requires between three and four therapeutic sessions for variceal eradication (and 25% of patients would have an episode of recurrent bleeding before completion of therapy), variceal ligation combined with low-volume sclerotherapy has been assessed. This could lead to more rapid eradication of varices than the use of variceal ligation alone. Sclerotherapy obliterates deeper paraesophageal varices that serve as feeder vessels for the submucosal vessels, whereas ligation can only be applied to submucosal varices. Eight studies, involving 501 patients have tested this hypothesis: six were published as peer-reviewed articles [222, 325, 327–329, 331] and two as abstracts [330, 332] (see Table 36.12). Meta-analysis showed no significant differences between the two endoscopic treatments in the number of patients with varices eradicated (POR 1.32; 95% CI: 0.77–2.25), in re-bleeding (POR 0.93; 95% CI: 0.58–1.4) or deaths (POR 0.94; 95% CI: 0.57–1.55). However, complications were significantly higher from the combined therapy compared with variceal ligation alone (POR 2.71; 584

95% CI: 1.48–4.96). Alc Moreover, the number of sessions required to achieve eradication was greater in the combined therapy arm in all studies and significantly in one [325]. A detailed meta-analysis has been published [335]. Two other randomized studies investigated whether there was an additive effect of sclerotherapy for small varices (not amenable to variceal ligation) after the completion of repeated variceal ligation treatment. Bhargava and Pokharna reported that the combined treatment eradicated the varices in a significantly greater number of patients than variceal ligation alone, but they did not find any difference in re-bleeding [333]. In contrast Lo et al. reported that the combined treatment resulted in significantly less recurrence of esophageal varices and re-bleeding [334]. Finally, three studies of comparison between combined variceal ligation and sclerotherapy with sclerotherapy alone have been reported [330, 336, 337]. There was no difference in re-bleeding and mortality between the two treatment modalities in any of these studies. Moreover, this comparison is now redundant since sclerotherapy has been replaced by variceal ligation for the secondary prevention of variceal bleeding.

Variceal ligation versus drug combination (β-blockers plus nitrates) Six randomized controlled trials [186, 338–342] (two published as abstracts [338, 339], two using propranolol [339, 340] and the others nadolol), involving 719 patients, assessed the efficacy of variceal ligation versus drug combination of β-blockers (propranolol or nadolol) and nitrates (ISMN). We performed a meta-analysis including the updated results [342] of a previous trial [343]. There is no

Author

Year

EVL

NSBB+I

Minyana

1999

35/70

24/69

Villanueva

2001

35/72

24/72

Agrawall

2002

10/53

13/51

Patch

2002

27/51

19/51

Romero

2006

24/52

27/57

Lo

2008

28/60

49/61

Pooled (fixed effect) 159/358

156/361

1/64

1/16

1/4

CHAPTER 36

Portal hypertensive bleeding

1

16

4

64

0.941 (0.696 / 1.273) Better EVL

Better NSBB+I

Figure 36.9 Forrest plot of randomized trials of variceal ligation versus β-blockers plus nitrates in secondary prevention of variceal bleeding. Variceal bleeding. EVL: variceal ligation; NSBB + I: β-blockers plus nitrates. Data are expressed as OR (95% CI) in a log scale.

Author

Year

EVL

NSBB+I

Minyana

1999

27/70

22/69

Villanueva

2001

30/72

23/72

Agrawall

2002

7/53

7/51

Patch

2002

17/51

17/51

Romero

2006

10/52

11/57

Lo

2008

42/60

30/61

Pooled (fixed effect) 133/358

110/361

1/64

1/16

1/4

1

4

16

64

0.722 (0.523 / 0.998) Better NSBB+I

Better EVL

Figure 36.10 Forrest plot of randomized trials of variceal ligation versus β-blockers plus nitrates in secondary prevention of variceal bleeding. Mortality (EVL: variceal ligation, NSBB + I: β-blockers plus nitrates). Data are expressed as OR (95% CI) in a log scale.

difference in re-bleeding rate (REM, OR 0.98; 95% CI: 0.5– 1.9). Importantly, regarding survival combined medical therapy is better than ligation (FEM, OR 0.72; 95% CI: 0.5– 0.9). Ala One randomized trial has compared obliteration of n-butyl-2-cyanoacrylate versus propranolol, with no difference in re-bleeding rates nor survival, but with more complications with the adhesive injection (see Table 36.13 and Figures 36.9 and 36.10) [344].

Variceal ligation plus drugs vs ligation In a prospective randomized trial, a total of 122 patients with a history of esophageal variceal bleeding were randomized to receive EVL only (group A, 62 patients) or triple therapy (group B, 60 patients, ligation plus nadolol and sucralfate) [345]. After a median follow-up of 21 months, recurrent upper gastrointestinal bleeding developed in 29 patients (47%) in group A and 14 patients (23%) in group B (p = 0.005). Recurrent bleeding from esophagogastric varices occurred

in 18 patients in group A and 7 patients in group B (p = 0.001). Twenty-one patients in group A (50%) and 12 patients (26%) in group B experienced variceal recurrence after variceal obliteration (p < 0.05). Treatment failure occurred in 11 patients (18%) in group A and in 4 patients (7%) in group B (p = 0.05). Twenty patients from group A and 10 patients from group B died (p = 0.08); 9 and 4 of these deaths, respectively, were attributed to variceal hemorrhage (p = 0.26). The combination of ligation, nadolol and sucralfate (triple therapy) proved more effective than banding ligation alone in terms of prevention of variceal recurrence and upper gastrointestinal re-bleeding as well as variceal re-bleeding. Ald In another multicentre trial 80 patients randomized to receive EVL plus nadolol or EVL alone [250]. The variceal bleeding recurrence rate was 14% in the EVL plus nadolol group and 38% in the EVL group (p = 0.006). Mortality was similar in both groups. The actuarial probability of variceal recurrence at one year was lower in the EVL plus nadolol group (54%) than in the EVL group (77%; p = 0.06). Ald 585

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TIPS versus drug therapy Escorsell et al. compared TIPS with drug therapy and found that the two-year re-bleeding rate was significantly lower in the TIPS group [346]. A total of 91 Child-Pugh class B/C cirrhotic patients surviving their first episode of variceal bleeding were randomized to receive TIPS (n = 47) or drug therapy (propranolol + isosorbide-5-mononitrate) (n = 44) to prevent variceal re-bleeding. Re-bleeding occurred in six (13%) TIPS-treated patients versus 17 (39%) drug-treated

Table 36.13 Randomized controlled trials of variceal ligation versus β-blockers plus nitrates. Study

No. of patients Lig/D

Re-bleeding Lig/D

Death Lig/D

Minyana et al. (1999) [338]

70/69

35/24

27/22

Villanueva et al. (2001) [186]

72/72

35/24

30/23

Agrawall et al. (2002) [339]

53/51

10/13

7/7

Romero et al. (2006) [341]

52/57

24/27

10/11

Patch et al. (2002) [340]

51/51

27/19

17/17

Lo et al. (2008) [342]

60/61

28/49

42/30

patients (p = 0.007). The two-year re-bleeding probability was 13% versus 49% (p = .01). Encephalopathy was more frequent in TIPS than in drug-treated patients (38% vs 14%, p = 0.007). Child-Pugh class improved more frequently in drug-treated than in TIPS-treated patients (72% vs 45%; p = 0.04). The two-year survival probability was identical (72%). Medical therapy was less effective than TIPS in preventing re-bleeding. However, it caused less encephalopathy, identical survival, and more frequent improvement in Child-Pugh class with lower costs than TIPS in high-risk cirrhotic patients.

TIPS versus sclerotherapy or variceal ligation and covered stents Thirteen trials, involving 948 patients, compared TIPS with endoscopic treatment (with or without the addition of propranolol): nine with sclerotherapy [347–355] and four with variceal ligation [356–359] (one in abstract form [350]) (see Table 36.14). The median range of follow up was from 10 to 32 months. Re-bleeding was significantly less common in patients randomized to TIPS (POR 3.28; 95% CI: 2.28– 4.72). However, there was a trend toward fewer deaths in the endoscopic treatment arm, although the difference was not statistically significant (POR 0.87; 95% CI: 0.65–1.17). Ald In addition, hepatic encephalopathy was statistically significantly more common in patients randomized to TIPS (POR 0.48; 95% CI: 0.34–0.67). These results are a mirror image of the surgical trials for the secondary prevention of variceal bleeding. However, an important difference is that the mean follow up was less than two years in all but two of these trials [354, 359], whereas the surgical shunt trials had a much greater average follow-up (3–4 years). As TIPS

Lig: variceal ligation; D: β-blockers + nitrates; NR: not reported.

Table 36.14 Randomized controlled trials of TIPS versus sclerotherapy/variceal ligation for the prevention of re-bleeding. Study

No. of patients TIPS/Scl

Child C (%)

Re-bleeding TIPS/Scl

Death TIPS/Scl

PSE TIPS/Scl

GEAIH (1995) [350] Cabrera et al. (1996) [347] Sanyal et al. (1997) [354] Cello et al. (1997) [348] Rossle et al. (1997) [353] Sauer et al. (1997) [355] Merli et al. (1998) [351] Garcia-Villarreal et al. (1999) [349] Jalan et al. (1997) [356] Pomier-Layrargues et al. (1997) [357] Narahara et al. (2001 ) [352] Gulberg et al. (2002) [358] Sauer et al. (2002) [359]

32/33 31/32 41/39 24/25 61/65 42/41 38/43 22/24 31/27 41/39 38/40 28/26 43/42

100 10 49 NR 18 24 12 32 47 NR NR 11 29

13/20 7/16 10/9 3/12 9/29 6/21 7/17 2/12 3/15 10/22 7/13 7/7 7/10

16/14 6/5 12/7 8/8 8/8 12/11 9/8 1/8 13/10 17/12 11/7 4/4 8/7

— 10/4 12/5 12/11 18/9 14/3 21/10 5/6 5/3 13/10 13/6 2/1 17/9

Scl: sclerotherapy; NR: not reported; POR: pooled odds ratio; TIPS: transjugular intrahepatic portosystemic shunt; PSE: porto-systemic encephalopathy.

586

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stenosis occured in 50–70% of patients within the first year, this approach involves regular monitoring with Doppler/ ultrasound, and repeat procedures for recanalization [359]. A similar conclusion was reached in a trial comparing TIPS to propranolol and ISMN in 91 patients with cirrhosis and a Child-Pugh score >7 [346]. TIPS, although effective in reducing re-bleeding did not improve survival, caused hepatic encephalopathy and had a worse cost-benefit profile than pharmacological treatment. However, current TIPS shunts are covered stents with a much reduced chance of dysfunction. Finally, in a recent trial patients who required TIPS for the prevention of esophageal variceal re-bleeding were randomized to either TIPS alone (n = 39, group 1) or TIPSS plus VBL (n = 40, group 2) [361]. In group 1, patients underwent long-term TIPS angiographic surveillance. In group 2, patients entered a banding programme with TIPS surveillance only continued for up to one year. There was a tendency to higher variceal rebleeding in group 2, although this did not reach statistical significance (8% vs 15%; relative hazard 0.58; 95% CI: 0.15– 2.33, p = 0.440). Mortality (47% vs 40%; relative hazard 1.31; 95% CI: 0.66–2.61, p = 0.434) was similar in the two groups. Hepatic encephalopathy was significantly less in group 2 (20% vs 39%; relative hazard 2.63; 95% CI: 1.11–6.25; p = 0.023). Hepatic encephalopathy was not statistically different after correcting for sex and portal pressure gradient (p = 0.136). Therefore, VBL with short-term TIPS surveillance is an alternative to long-term TIPS surveillance in the prevention of esophageal variceal bleeding. A covered stent was evaluated in a randomized trial of 80 patients with cirrhosis with uncontrolled bleeding (n = 23) or recurrent bleeding (n = 25), or refractory ascites (n = 32) who received either a polytetrafluoroethylene-covered stent (group 1: 39 patients) or the usual uncovered prosthesis (group 2: 41 patients) [361]. After a median follow-up of 300 days, five patients (13%) in group 1 and 18 (44%) in group 2 experienced shunt dysfunction (p < 0.001). Clinical relapse occurred in three patients (8%) in group 1 and 12 (29%) in group 2 (p < 0.05). Actuarial rates of encephalopathy were 21% in group 1 and 41% in group 2 at one year (not significant). Estimated probabilities of survival were 71% and 60% at one year and 65% and 41% at two years in groups 1 and 2 respectively (not significant). Thus, the use of polytetrafluoroethylene-covered prostheses improves transjugular intrahepatic portosystemic shunt patency and decreases the number of clinical relapses and reinterventions without increasing the risk of encephalopathy, and is the standard stent to be used.

Endoscopic histoacryl obliteration vs propranolol and other studies In a randomized study 41 patients with a first bleeding from esophageal (n = 31) or gastric (n = 10) varices were

Portal hypertensive bleeding

after primary hemostasis with obliteration using Histoacryl® were randomly allocated either to undergo complete Histoacryl® obliteration of the remaining varices (group A, n = 21) or to long-term propranolol administration (group B, n = 20), for the prevention of re-bleeding [344]. No significant difference was observed between groups A and B with regard to the incidence of early rebleeding (during the first 6 weeks; 5/21 and 3/20), bleeding-related deaths by six weeks (3/21 and 6/20), long-term re-bleeding (11/21 and 5/20), or overall number of deaths (9/21 and 9/20). The incidence of complications was higher in group A (10/21) than group B (2/20) (p < 0.03). Ald In two trials treatment with ligation followed by argon plasma coagulation (APC) was superior compared with ligation alone [363, 364]. In another randomized trial 50 cirrhotic patients with esophageal varices randomized into two groups: endoscopic sclerotherapy (ES) (n = 25) vs EUSguided sclerotherapy (EUS-ES) (n = 25)[365]. EUS-ES was as safe and effective as ES in variceal eradication. Recurrence tended to be less frequent and occured later.

Surgical shunts The ideal patients for a decompressive surgical shunt, should be well compensated patients with cirrhosis, who have had troublesome bleeding, either failing at least one other modality of therapy (drugs or sclerotherapy), or had bleeding from gastric varices despite medical or endoscopic therapy, or who live far from suitable medical services. These shunts achieve an overall re-bleeding rate of 14.3% and a survival rate of 86%, but they may cause encephalopathy in 20.6% of patients (severe encephalopathy in 3%). The advent of TIPS has had a major impact on the need for these operations. Today, a common indication for a surgical shunt is in patients who have had TIPS, without major encephalopathy, but have had recurrent symptomatic TIPS dysfunction. In essence, they have had a non-surgical trial of shunting, and have selected themselves as good candidates. Small diameter portacaval H-graft or distal splenorenal shunts are probably the favored surgical option, as the portal vein is then still available should liver transplantation be required.

Randomized controlled trials of surgical therapy Total portacaval shunt versus selective distal splenorenal shunt Selective distal splenorenal shunt (DSRS) was designed to reduce the incidence of hepatic encephalopathy and liver failure following total portacaval shunt (PCS) by partially maintaining portal liver perfusion while decreasing portal 587

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blood flow to varices. Six trials, including 336 patients, compared PCS with DSRS [366–371]. A meta-analysis of these trials has been published [26]. There was no statistical significance in re-bleeding between the two surgical treatments (POR 0.88; 95% CI: 0.54–1.45). Patients with DSRS showed a trend toward less hepatic encephalopathy (POR 1.29; 95% CI: 0.76–2.17) and better long-term survival (POR 1.28; 95% CI: 0.82–2.01), but the differences were not statistically significant. Ala The calibrated small-diameter portacaval H-graft shunt (PCHGS) is effective in the control of variceal hemorrhage and has been associated with reduced hepatic encephalopathy when compared with total PCS [372]. Ald

Surgery versus drugs A randomized controlled trial including 119 patients compared the effectiveness of portal blood flow preserving procedures (selective shunts and the Sugiura-Futagawa operation), β-blockers and sclerotherapy for secondary prevention of variceal hemorrhage [373]. The re-bleeding rate was significantly lower in the surgical group compared with patients receiving drugs (16.6% vs 77.5%, p < 0.0001) and survival was better for Child’s A cirrhosis in all groups, but there was no significant difference between treatment groups considered as a whole. Ald

Surgery versus sclerotherapy DSRS was compared with sclerotherapy in four trials, involving 292 patients (see Table 36.15) [374–377]. A comprehensive meta-analysis of these studies, using individual patient data provided by the principal authors, has been previously published [378]. Ala Re-bleeding was statistically significantly reduced by DSRS (pooled relative risk (PRR) 0.16; 95% CI: 0.10–0.27). There was statistically significant heterogeneity in the evaluation of mortality, as the risk of death was increased in one study [376] and decreased in the other three [374, 375, 377]. The pooled relative risk was not statistically significant between the treatment modalities (PRR 0.78; 95% CI: 0.47–1.29). Chronic hepatic

encephalopathy was increased after DSRS but the difference was not statistically significant (PRR 1.86; 95% CI: 0.90–3.86). Ala The results of this meta-analysis are in accordance with the trial discussed above in which significantly lower re-bleeding rates were documented in the surgical compared with sclerotherapy group (16.7% vs 63%, p < 0.0001), but no difference in mortality was observed [309]. However, this study was heavily criticized for the different exclusion criteria that were used in different treatment arms, the lack of information regarding cause of portal hypertension and differences in the surveillance endoscopy program. Finally, two trials [379, 380] (one an abstract [379]) have compared PCS with sclerotherapy in the elective treatment of variceal hemorrhage. Re-bleeding was significantly less in the portacaval shunt group. However, the incidence of hepatic encephalopathy was significantly increased with the surgical treatment and there was no difference in survival.

Surgery versus TIPS Recently Rosemurgy et al. extended the follow-up (median four years) of a previously published randomized trial comparing 8 mm prosthetic H-graft portacaval shunts (HGPCS) with TIPS as definitive therapy for bleeding varices who failed non-operative management [381]. Ald The trial included 132 patients and shunting was carried out as an elective, urgent or emergency procedure. Placement of TIPS (non-covered stents) resulted in more re-bleeding (16% vs 3%), liver transplantations (7.5% vs 0%) and late deaths (34% vs 13.2%). According to a costbenefit analysis carried out by the same group of investigators, TIPS was associated with much higher costs than HGPCS, due to subsequent occlusion and re-bleeding [382]. DSRS has also been shown to be superior to TIPS in terms of recurrent bleeding (6.25% vs 25.7%), encephalopathy (18.75% vs 42.86%) and shunt occlusion (6.25% vs 68.57%) in a comparative study with 67 patients with Child’s A and B cirrhosis [383]. Finally Zachs et al. recently showed that in a population of Child’s A cirrhosis, DSRS is a more cost-effective treatment than TIPS [384]. Given

Table 36.15 Randomized controlled trials of DSRS versus sclerotherapy for the prevention of re-bleeding. Study

No. of patients DSRS/Scl

Child C (%)

Re-bleeding DSRS/Scl

Death DSRS/Scl

PSE DSRS/Scl

Henderson et al. (1990) [376 Teres et al. (1987) [375] Rikkers et al. (1987) [374] Spina et al. (1990) [377]

35/37 57/55 30/30 34/32

43 7.3a 42 0

1/22 6/18 5/18 1/10

20/12 9/15 12/20 4/8

5/3 8/3 6/4 2/2

a

Child score. DSRS: distal splenorenal shunt; Scl: sclerotherapy; NR: not reported; PSE: porto-systemic encephalopathy.

588

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the better results with covered stents it is likely that if TIPS is available, surgical shunts will be reserved for patients in whom TIPS cannot be placed for technical reasons.

Conclusion Pharmacological treatment with β-blockers is a safe and effective long-term treatment for the prevention of recurrence of variceal bleeding. The combination of β-blockers with isosorbide-5-mononitrate needs further testing in randomized controlled trials. The use of hemodynamic targets of HVPG response should be further evaluated for their applicability in clinical practice during pharmacologic therapy for the prevention of re-bleeding. If endoscopic treatment is chosen, variceal ligation is the modality of choice. The combination of simultaneous variceal ligation and sclerotherapy does not offer any benefit. However, the use of additional sclerotherapy for the complete eradication of small varices after variceal ligation should be further addressed in future trials. The results of randomized controlled trials comparing variceal ligation with pharmacologic treatment showed that combination treatment with non-selective β-blockers and nitrates and variceal ligation are equally effective. Combined endoscopic and pharmacological therapy gives the lowest re-bleeding rates but survival is no different. However non-selective beta-blockers also prevent other complications of cirrhosis [385–389] and so will be a fixed component of combination therapy. Finally, the use of TIPS for the secondary prevention of variceal bleeding is not supported by the current data, mainly because of its worse cost-benefit profile compared with other treatments. However, this conclusion is based on uncovered stents. Covered stents may be more effective, and are the stent of choice. There is a limited role for the selective surgical shunts (DSRS or HGPCS) in the modern management of portal hypertension. The ideal patient should have well compensated cirrhosis, have had troublesome bleeding, have failed at least one other modality of therapy (drugs or ligation), or have bled from gastric varices despite medical or endoscopic therapy or live far from suitable medical services, or for whom TIPS is not available.

Summary In conclusion, this critical review of the studies of treatment in portal hypertension has highlighted several issues with regard to the design of clinical trials and the analysis of the data that should be addressed in future trials. The quality of future trials will also be significantly improved if standardized definitions of critical endpoints (for example bleeding or re-bleeding episodes, treatment failure, etc.), agreed upon in consensus conferences are applied. This will aid the reduction of the heterogeneity

Portal hypertensive bleeding

that is present in randomized controlled trials in portal hypertension and lead to better evidence for the optimal treatment options.

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308 Villanueva C, Balanzo J, Novella MT et al. Nadolol plus isosorbide mononitrate compared with sclerotherapy for the prevention of variceal re-bleeding. N Engl J Med 1996; 334(25): 1624–1629. 309 Teres J, Bosch J, Bordas JM et al. Endoscopic sclerotherapy (ES) vs propranolol (Pr) In the elective treatment of variceal bleeding – preliminary results of a randomized controlled clinical-trial (Abstract). J Hepatol 1987; 5: S210. 310 Acharya SK, Dasarathy S, Saksena S, Pande JN. A prospective randomized study to evaluate propranolol in patients undergoing long-term endoscopic sclerotherapy. J Hepatol 1993; 19(2): 291–300. 311 Avgerinos A, Rekoumis G, Klonis C et al. Propranolol in the prevention of recurrent upper gastrointestinal bleeding in patients with cirrhosis undergoing endoscopic sclerotherapy. A randomized controlled trial. J Hepatol 1993; 19(2): 301–311. 312 Elsayed SS, Shiha G, Hamid M, Farag FM, Azzam F, Awad M. Sclerotherapy versus sclerotherapy and propranolol in the prevention of re-bleeding from oesophageal varices: a randomised study. Gut 1996; 38(5): 770–774. 313 Jensen LS, Krarup N. Propranolol in prevention of re-bleeding from oesophageal varices during the course of endoscopic sclerotherapy. Scand J Gastroenterol 1989; 24(3): 339–345. 314 Lundell L, Leth R, Lind T, Lonroth H, Sjovall M, Olbe L. Evaluation of propranolol for prevention of recurrent bleeding from esophageal varices between sclerotherapy sessions. Acta Chir Scand 1990; 156(10): 711–715. 315 Vickers C, Rhodes J, Chesner I et al. Prevention of re-bleeding from oesophageal varices: two-year follow up of a prospective controlled trial of propranolol in addition to sclerotherapy. J Hepatol 1994; 21(1): 81–87. 316 Vinel JP, Lamouliatte H, Cales P et al. Propranolol reduces the re-bleeding rate during endoscopic sclerotherapy before variceal obliteration. Gastroenterology 1992; 102(5): 1760–1763. 317 Westaby D, Melia W, Hegarty J, Gimson AE, Stellon AJ, Williams R. Use of propranolol to reduce the re-bleeding rate during injection sclerotherapy prior to variceal obliteration. Hepatology 1986; 6(4): 673–675. 318 Bertoni G, Fornaciari G, Beltrami M et al. Nadolol for prevention of variceal re-bleeding during the course of endoscopic injection sclerotherapy: a randomized pilot study. J Clin Gastroenterol 1990; 12(3): 364–365. 319 Gerunda GE, Neri D, Zangrandi F et al. Nadolol does not reduce early re-bleeding in cirrhotics undergoing endoscopic variceal sclerotherapy (Evs) – a multicenter randomized controlled trial (Abstract). Hepatology 1990; 12: 988. 320 Villanueva C, Martinez FJ, Torras X et al. Nadolol as an adjuvant to sclerotherapy of esophageal varices for prevention of recurrent hemorrhaging. Rev Esp Enferm Dig 1994; 86(1): 499–504. 321 Bertoni G, Sassatelli R, Fornaciari G et al. Oral isosorbide-5mononitrate reduces the re-bleeding rate during the course of injection sclerotherapy for esophageal varices. Scand J Gastroenterol 1994; 29(4): 363–370. 322 Vorobioff JD, Gamen M, Kravetz D et al. Effects of long-term propranolol and octreotide on postprandial hemodynamics in cirrhosis: a randomized, controlled trial. Gastroenterology 2002; 122(4): 916–922. 323 Ink O, Martin T, Poynard T, Reville M et al. Does elective sclerotherapy improve the efficacy of long-term propranolol for

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338 Minyana J, Gallego A, Sola V et al. Endoscopic ligation versus nadolol plus isosorbide-5-mononitrate for the prevention of variceal re-bleeding. A prospective and randomized trial. Hepatology 1999; 30: 214A. 339 Agrawall SR, Gupta R, Marthy NS et al. Comparable efficacy of propranolol plus isosorbide monitrate and endoscopic variceal ligation in prevention of variceal re-bleed (Abstract). J Hepatol 2002; 36: 631A. 340 Patch D, Sabin CA, Goulis J et al. A randomized, controlled trial of medical therapy versus endoscopic ligation for the prevention of variceal re-bleeding in patients with cirrhosis. Gastroenterology 2002; 123(4): 1013–1019. 341 Romero G, Kravetz D, Argonz J et al. Comparative study between nadolol and 5-isosorbide mononitrate vs. endoscopic band ligation plus sclerotherapy in the prevention of variceal re-bleeding in cirrhotic patients: a randomized controlled trial. Aliment Pharmacol Ther 2006; 24(4): 601–611. 342 Lo GH, Chen WC, Lin CK et al. Improved survival in patients receiving medical therapy as compared with banding ligation for the prevention of esophageal variceal re-bleeding. Hepatology 2008; 48(2): 580–587. 343 Lo GH, Chen WC, Chen MH et al. Banding ligation versus nadolol and isosorbide mononitrate for the prevention of esophageal variceal re-bleeding. Gastroenterology 2002; 123(3): 728–734. 344 Evrard S, Dumonceau JM, Delhaye M, Golstein P, Deviere J, Le Moine O. Endoscopic histoacryl obliteration vs propranolol in the prevention of esophagogastric variceal re-bleeding: a randomized trial. Endoscopy 2003; 35(9): 729–735. 345 Lo GH, Lai KH, Cheng JS et al. Endoscopic variceal ligation plus nadolol and sucralfate compared with ligation alone for the prevention of variceal re-bleeding: a prospective, randomized trial. Hepatology 2000; 32(3): 461–465. 346 Escorsell A, Banares R, Garcia-Pagan JC et al. TIPS versus drug therapy in preventing variceal re-bleeding in advanced cirrhosis: a randomized controlled trial. Hepatology 2002; 35(2): 385–392. 347 Cabrera J, Maynar M, Granados R et al. Transjugular intrahepatic portosystemic shunt versus sclerotherapy in the elective treatment of variceal hemorrhage. Gastroenterology 1996; 110(3): 832–839. 348 Cello JP, Ring EJ, Olcott EW et al. Endoscopic sclerotherapy compared with percutaneous transjugular intrahepatic portosystemic shunt after initial sclerotherapy in patients with acute variceal hemorrhage. A randomized, controlled trial. Ann Intern Med 1997; 126(11): 858–865. 349 Garcia-Villarreal L, Martinez-Lagares F, Sierra A et al. Transjugular intrahepatic portosystemic shunt versus endoscopic sclerotherapy for the prevention of variceal re-bleeding after recent variceal hemorrhage. Hepatology 1999; 29(1): 27–32. 350 Groupe d Etude des Anastomoses Intrahepatiques. TIPS vs sclerotherapy plus propranolol in the prevention of variceal rebleeding – preliminary results of a multicenter randomized trial (Abstract). Hepatology 1995; 22: 761. 351 Merli M, Salerno F, Riggio O et al. Transjugular intrahepatic portosystemic shunt versus endoscopic sclerotherapy for the prevention of variceal bleeding in cirrhosis: a randomized multicenter trial. Gruppo Italiano Studio TIPS (GIST). Hepatology 1998; 27(1): 48–53.

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352 Narahara Y, Kanazawa H, Kawamata H et al. A randomized clinical trial comparing transjugular intrahepatic portosystemic shunt with endoscopic sclerotherapy in the long-term management of patients with cirrhosis after recent variceal hemorrhage. Hepatol Res 2001; 21(3): 189–198. 353 Rossle M, Deibert P, Haag K et al. Randomised trial of transjugular-intrahepatic-portosystemic shunt versus endoscopy plus propranolol for prevention of variceal re-bleeding. Lancet 1997; 349(9058): 1043–1049. 354 Sanyal AJ, Freedman AM, Luketic VA et al. Transjugular intrahepatic portosystemic shunts compared with endoscopic sclerotherapy for the prevention of recurrent variceal hemorrhage. A randomized, controlled trial. Ann Intern Med 1997; 126(11): 849–857. 355 Sauer P, Theilmann L, Stremmel W, Benz C, Richter GM, Stiehl A. Transjugular intrahepatic portosystemic stent shunt versus sclerotherapy plus propranolol for variceal re-bleeding. Gastroenterology 1997; 113(5): 1623–1631. 356 Jalan R, Forrest EH, Stanley AJ et al. A randomized trial comparing transjugular intrahepatic portosystemic stent-shunt with variceal band ligation in the prevention of re-bleeding from esophageal varices. Hepatology 1997; 26(5): 1115–1122. 357 Pomier-Layrargues G, Dufresne MP, Bui B et al. TIPS versus endoscopic variceal ligation in the prevention of variceal rebleeding in cirrhotic patients: a comparative randomized clinical trial (interim analysis) (Abstract). Hepatology 1997; 26: 35. 358 Gulberg V, Schepke M, Geigenberger G et al. Transjugular intrahepatic portosystemic shunting is not superior to endoscopic variceal band ligation for prevention of variceal re-bleeding in cirrhotic patients: a randomized, controlled trial. Scand J Gastroenterol 2002; 37(3): 338–343. 359 Sauer P, Hansmann J, Richter GM, Stremmel W, Stiehl A. Endoscopic variceal ligation plus propranolol vs. transjugular intrahepatic portosystemic stent shunt: a long-term randomized trial. Endoscopy 2002; 34(9): 690–697. 360 Casado M, Bosch J, Garcia-Pagan JC et al. Clinical events after transjugular intrahepatic portosystemic shunt: correlation with hemodynamic findings. Gastroenterology 1998; 114(6): 1296–1303. 361 Tripathi D, Lui HF, Helmy A et al. Randomised controlled trial of long term portographic follow up versus variceal band ligation following transjugular intrahepatic portosystemic stent shunt for preventing oesophageal variceal re-bleeding. Gut 2004; 53(3): 431–437. 362 Bureau C, Garcia-Pagan JC, Otal P et al. Improved clinical outcome using polytetrafluoroethylene-coated stents for TIPS: results of a randomized study. Gastroenterology 2004; 126(2): 469–475. 363 Nakamura S, Mitsunaga A, Murata Y, Suzuki S, Hayashi N. Endoscopic induction of mucosal fibrosis by argon plasma coagulation (APC) for esophageal varices: a prospective randomized trial of ligation plus APC vs ligation alone. Endoscopy 2001; 33(3): 210–215. 364 Cipolletta L, Bianco MA, Rotondano G, Marmo R, Meucci C, Piscopo R. Argon plasma coagulation prevents variceal recurrence after band ligation of esophageal varices: preliminary results of a prospective randomized trial. Gastrointest Endosc 2002; 56(4): 467–471.

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365 de Paulo GA, Ardengh JC, Nakao FS, Ferrari AP. Treatment of esophageal varices: a randomized controlled trial comparing endoscopic sclerotherapy and EUS-guided sclerotherapy of esophageal collateral veins. Gastrointest Endosc 2006; 63(3): 396–402. 366 Reichle FA, Fahmy WF, Golsorkhi M. Prospective comparative clinical trial with distal splenorenal and mesocaval shunts. Am J Surg 1979; 137(1): 13–21. 367 Fischer JE, Bower RH, Atamian S, Welling R. Comparison of distal and proximal splenorenal shunts: a randomized prospective trial. Ann Surg 1981; 194(4): 531–544. 368 Langer B, Taylor BR, Mackenzie DR, Gilas T, Stone RM, Blendis L. Further report of a prospective randomized trial comparing distal splenorenal shunt with end-to-side portacaval shunt. An analysis of encephalopathy, survival, and quality of life. Gastroenterology 1985; 88(2): 424–429. 369 Millikan WJ, Jr., Warren WD, Henderson JM et al. The Emory prospective randomized trial: selective versus nonselective shunt to control variceal bleeding. Ten year follow-up. Ann Surg 1985; 201(6): 712–722. 370 Harley HA, Morgan T, Redeker AG et al. Results of a randomized trial of end-to-side portacaval shunt and distal splenorenal shunt in alcoholic liver disease and variceal bleeding. Gastroenterology 1986; 91(4): 802–809. 371 Grace ND, Conn HO, Resnick RH et al. Distal splenorenal vs portal-systemic shunts after hemorrhage from varices: a randomized controlled trial. Hepatology 1988; 8(6): 1475–1481. 372 Fernandez-Aguilar JL, Bondia Navarro JA, Santoyo SJ et al. Calibrated portacaval H-graft shunt in variceal hemorrhage. Long-term results. Hepatogastroenterology 2003; 50(54): 2000–2004. 373 Orozco H, Mercado MA, Chan C, Guillen-Navarro E, Lopez-Martinez LM. A comparative study of the elective treatment of variceal hemorrhage with beta-blockers, transendoscopic sclerotherapy, and surgery: a prospective, controlled, and randomized trial during 10 years. Ann Surg 2000; 232(2): 216–219. 374 Rikkers LF, Burnett DA, Volentine GD, Buchi KN, Cormier RA. Shunt surgery versus endoscopic sclerotherapy for long-term treatment of variceal bleeding. Early results of a randomized trial. Ann Surg 1987; 206(3): 261–271. 375 Teres J, Bordas JM, Bravo D et al. Sclerotherapy vs. distal splenorenal shunt in the elective treatment of variceal hemorrhage: a randomized controlled trial. Hepatology 1987; 7(3): 430–436. 376 Henderson JM, Kutner MH, Millikan WJ, Jr et al. Endoscopic variceal sclerosis compared with distal splenorenal shunt to prevent recurrent variceal bleeding in cirrhosis. A prospective, randomized trial. Ann Intern Med 1990; 112(4): 262–269. 377 Spina GP, Santambrogio R, Opocher E et al. Distal splenorenal shunt versus endoscopic sclerotherapy in the prevention of variceal re-bleeding. First stage of a randomized, controlled trial. Ann Surg 1990; 211(2): 178–186. 378 Spina GP, Henderson JM, Rikkers LF et al. Distal spleno-renal shunt versus endoscopic sclerotherapy in the prevention of variceal re-bleeding. A meta-analysis of 4 randomized clinical trials. J Hepatol 1992; 16(3): 338–345. 379 Korula J, Yellin A, Yamada S, Weiner J, Cohen H, Reynolds TB. A prospective randomized controlled comparison of chronic endoscopic variceal sclerotherapy and portalsystemic shunt for

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Hepatic outflow syndromes and splanchnic venous thrombosis Marco Senzolo1, Neeral Shah2, David Patch3 and Stephen Caldwell2 1

Department of Surgical and Gastroenterological Sciences, University-Hospital of Padua, Padua, Italy Department of Hepatology, University of Virginia, Charlottesville, Virginia, USA 3 The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital, and University College London, London, UK 2

Budd-Chiari syndrome Introduction Budd-Chiari syndrome (BCS) is caused by obstruction of hepatic venous outflow at any level from the small hepatic veins to the junction of the inferior vena cava (IVC) with the right atrium in the absence of right heart failure or constrictive pericarditis [1]. It occurs in 0.2 per million inhabitants per year with a prevalence ranging from 1/1,000,000 of the general population in Eastern countries to 1/100,000 in Nepal [2–4]. The most common presentation is with ascites, but the range is from fulminant liver failure to asymptomatic forms. Obstruction of hepatic venous outflow is mainly caused by primary intravascular thrombosis, which may occur suddenly or repeatedly over time, accompanied by some revascularization accounting for the variable parenchymal hepatic damage and presentation. An important differential diagnosis is constrictive pericarditis or other obstructive cardiac causes. The prognosis of BCS is dictated by the rapidity of disease onset, the severity of liver dysfunction, anatomical sites of thrombosis and etiology.

Staging the venous obstruction Budd-Chiari syndrome is classified into four disease types according to the site of the venous obstruction and in addition to the presence or absence of portal vein thrombosis: hepatic vein obstruction/thrombosis without IVC obstruction/compression; hepatic vein obstruction/thrombosis with IVC obstruction (as a result of compensatory caudate lobe hypertrophy, or IVC thrombosis) [5]; isolated hepatic webs; isolated IVC webs. Concomitant portal vein thromEvidence-Based Gastroenterology and Hepatology, Third Edition John WD McDonald, Andrew K Burroughs, Brian G Feagan and M Brian Fennerty © 2010 Blackwell Publishing Ltd. ISBN: 978-1-405-18193-8

bosis occurs about 15% of patients with BCS, and when extensive, may preclude shunting. Coexisting PVT is associated with a mean survival of one month compared with 6.3 years without PVT [6]. Moreover, five-year survival was reported to be 85% in non-PVT BCS patients versus 58% when PVT was present [7]. Medical or mechanical thrombectomy combined with TIPS is, however, changing this poor prognosis [8, 9]. Primary membranous obstruction of the IVC is a sequela of thrombosis, occurring without hepatic vein thrombosis and accounting for 60% of BCS patients in Asia [2, 10]. However this pattern has changed over time and IVC obstruction now accounts for a lesser proportion of cases in India [11]. Diagnosis is based on the demonstration of an obstructed hepatic venous outflow tract. Color and pulsed Doppler ultrasound has a diagnostic sensitivity of almost 80% and is the recommended first-line investigation [12]. CT scan or MRI, in addition, shows the typical diagnostic feature of patchy enhancement of hepatic parenchyma which is typical of all diseases involving perfusion defects of the liver. Three-dimensional contrast-enhanced magnetic resonance angiography has been shown to have similar sensitivity to hepatic venography which was considered the most accurate diagnostic imaging [13]. Although non-invasive imaging is sufficient for the diagnosis, hepatic venography is still useful to determine the extent of the thrombosis, as well as to measure caval pressures. In addition, the portal vein can be outlined by CO2 portography. A transjugular liver biopsy and dilatation and/or stenting of hepatic venous and IVC webs can also be performed, as well as disruption of portal vein thrombus and placement of a TIPS [14]. If a TIPS procedure is planned and hepatic veins cannot be cannulated, the portal vein can sometimes be reached via a transcaval puncture [15]. Liver histology is of potential importance when thrombosis is limited to the small intrahepatic veins as well as to estimate liver reserve and potential reversibility of the liver injury when deciding whether shunting procedures will be 603

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safe. However, sampling error is an under-studied but potentially important consideration in this setting.

Functional staging and clinical presentation A typical patient with BCS is female, about 35 years old, with underlying thrombophilia, and often taking oral contraception [3, 4]. BCS should be suspected in patients with acute abdominal pain; an enlarged liver, particularly with known thrombophilic disorders; or when fulminant liver failure is associated with ascites [16]. Chronic BCS should be excluded when there is refractory ascites, particularly if liver function tests are relatively normal [17]. Leg edema and venous collaterals on the trunk indicate IVC compression/thrombosis [10]. Ascitic fluid typically reveals a high serum-ascites albumin gradient and total protein above 25 g/l, that is, non-cirrhotic ascites. The severity of presentation has led to a traditional classification of fulminant (5%) [18], acute (20%) [7], subacute or chronic BCS (60%) [17], with these proportions seen in reported series. However, the prognostic value of this classification has not been prospectively validated and several authors no longer recommend it to predict mortality [19– 21]. Asymptomatic BCS accounts for about 15% of cases (no ascites or abdominal pain) and is usually diagnosed fortuitously, following investigation of slightly abnormal results of liver function tests [17]. The absence of ascites is attributed to long-standing, venous collaterals. In acute BCS, 58% of patients have histological evidence of chronic disease as recent thromboses compound previous subclinical thromboses [22]. Hepatocellular carcinoma appears to complicate BCS with an incidence similar to other chronic liver diseases. HCC developed in 11 of 97 patients in a recent cohort followed up for a mean of five years [23]. However, the incidence of HCC in patients with membranous IVC obstruction is reported to range from 25% to 47.5% [24].

Etiology A recent advance in the diagnosis of myeloproliferative disorders as aetiological factors in both Budd Chiari and splanchnic venous thrombosis is the identification of a mutation in the auto-inhibitory domain of a growth factor receptor kinase-the Janus tyrosine kinase-2 (JAK2) gene in myeloid cells, resulting in disinhibited kinase activity. This is a routine investigation in patients with Budd Chiari syndrome and splanchnic venous thrombosis, and the JAK2 mutation has been detected in 50–80% of patients with MPD, 37–45% of BCS patients, and 80% of BCS patients with MPD [28]. In the remaining patients bone marrow biopsy should be performed to exclude the diagnosis. Amongst other acquired thrombophylic conditions, Behcet’s disease is the leading cause of BCS in endemic 604

areas. Paroxysmal nocturnal hemoglobinuria is an extremely rare disease with a severe prognosis and a close association with BCS. The incidence of BCS during the course of the disease is about 35%. Flow cytometry on peripheral blood for detection of the CD55 and CD59 deficient clone is the current standard for diagnosis. Treatment therapies include monoclonal antibodies and bone marrow transplant. The diagnosis of antiphospholipid syndrome is difficult due to the high prevalence of anticardiolipin antibodies in chronic liver disease. Using lupus anticoagulant as diagnostic criteria, a prevalence of antiphospholipid syndrome is seen in about 15% of BCS patients [4]. Other thrombophilic disorders are seen as a cause of BCS in 20%; the factor V Leiden mutation is commonly found [26]. However, the G20210A prothrombin gene mutation appears to be less over represented among BCS patients. Diagnosing protein C and S deficiency is not straightforward as reduced concentrations can be caused by impaired hepatic synthesis. However, a normal factor II concentration together with a 20% or more reduction of protein C or S can confirm the presence of true deficiency [29]. Oral contraceptive use is a risk factor for BCS, (particularly high estrogen content pills), related to heterozygosity or homozygosity for thrombophilic defects, including ones as yet unknown [30]. BCS in pregnancy (usually postpartum) is associated with estrogen changes, IVC compression and physiologic hyperfibrinogenemia. A summary of prevalence of BCS prothrombotic defects with suggested diagnostic panel is represented in Table 37.1.

Prognosis and survival The natural history of BCS is not well known, as most publications report on treated patients. Mortality rates have decreased over time [17, 31]. In 120 patients, five-year survival before 1985 was 50%, compared with 75% thereafter. Mortality is highest within two years of diagnosis and independent of treatment in one study, with 77%, 65% and 57% of patients surviving one, six and ten years respectively [31]. Clinicopathological factors, including treatment variables, derived from multivariable prognostic models are shown in Table 37.2 [7, 19–21, 31, 32]. In the largest cohort of 237 patients the severity of encephalopathy, ascites, serum prothrombin time and bilirubin resulted in defining three groups with statistically different five-year survival rates of 89%, 74% and 42% [7]. Histopathological features do not help to determine prognosis [7, 21, 31, 33]; in only one study of surgical shunts (n = 24) was advanced fibrosis associated with increased mortality [32]. Chronic histological changes accompanying an acute presentation of BCS resulted in lower survival compared to acute or chronic BCS [19]. IVC obstruction has a good short-term prognosis, but there is a lack of long-term data [2]. In Japan, patients with

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Hepatic outflow syndromes

Table 37.1 Prevalence of thrombophilic conditions and suggested screening in Budd Chiari Syndrome. Prevalence (%) Inherited conditions Antithrombin deficiency Protein C deficiency Protein S deficiency Heterozygous factor V Leiden

5 20 7 20

Heterozygous G20210A prothrombin Hyperhomocysteinaemia

7 (?)

Plasma level ATIII if no marked liver dysfunction Plasma level protein C if no marked liver dysfunction Plasma level protein S if no marked liver dysfunction Activated protein C resistance if molecular test reveals Factor V Leiden mutation Molecular test for G20210A prothrombin gene mutation B12 folate, homocysteine level and MTHFR polyporphism

Acquired conditions V617F JAK2 positive MPD V617F JAK2 negative MPD Antiphosholipid syndrome Behcet’s disease PNH Other conditions

40 10 10 5 2 5

V617F JAK2 mutation in peripheral blood granulocytes Bone marrow biopsy looking for clusters of dystrophic megakaryocytes Lupus anticoagulant, anti beta2-glycoprotein-1 antibodies, anticardiolipin antibodies Specific diagnostic criteria Flow cytometry for CD55 and CD59 deficient blood cells Detailed medical history

External factors Oral contraceptives in women Multiple factors including local factors No factor

50 35 5

Medical history Search always for all possible causes Screening for familiar prothrombotic conditions

MPD: Myeloproliferative disorders. PHN: Parosysmal nocturnal hemoglobinuria.

Table 37.2 Clinicopathological factors associated with prognosis of Budd-Chiari syndrome.

Number of patients Histological features Higher serum transaminases Higher Child-Pugh score Ascites Hepatic encephalopathy Worse prothrombin time Higher serum bilirubin Older age at diagnosis Higher serum creatinine

Henderson et al. [30]

Tang et al. [18]

Langlet et al. [17]

Zeitoun et al. [29]

Murad et al. [16]

24a yes ND no ND ND ND ND ND yes

45 no yes yes no no no no yes no

73 yes ND yes no ND yes yes ND no

120 no no yes yes ND no no yes yes

237 no no yes yes yes yes yes no no

a

Patients who had shunt. ND: not determined.

obliterative cavopathy have a 25% mortality rate over 15 years; most die from variceal bleeding, liver failure and hepatocellular carcinoma [10].

Treatment Medical therapy and management of complications All patients should receive anticoagulation, unless contraindicated, starting with intravenous heparin, then warfarin, to maintain the international normalized ratio of at

least 2.5, if not higher. This treatment will control the disease in 10% of cases when the thrombosis is mild and prevent progression, although there are no randomized trials [17, 31, 34]. Fulminant BCS is usually associated with abundant necrosis that ideally requires liver transplantation. Even in the setting of immediate shunting (surgical or TIPS), hepatic regeneration will rarely take place and liver transplantation must be available as the liver failure may worsen [35]. In patients with acute BCS, early thrombolytic therapy 605

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used within 72 hours from diagnosis and infused directly into the thrombosed hepatic vein for 24 hours, has had variable success [36]. Adjunctive angioplasty or stent placement may not be of further therapeutic benefit [37].

Angioplasty Short-segment obstruction or webs in hepatic veins or the IVC are treated successfully by balloon dilatation or intravascular stents. Membranous vena caval obstruction can be relieved initially in 90% of patients, but 20–30% will need additional angioplasty [38, 39]. Eapen et al. reported 94% and 87% survival at one and five years in BCS patients with mild disease, according to the Murad classification, who were treated only by radiological intervention at a single center [40]. Approximately half of all cases of rethrombosis are due to suboptimal anticoagulation therapy. When there is diffuse thrombosis of hepatic veins, angioplasty alone is only successful in 56% of patients, even with additional thrombolytic therapy. On the other hand, stents result in long-term patency rates of 80–90%, requiring further angioplasty in 50% [41]. Failure of thrombolysis or angioplasty and the presence of a diffuse hepatic vein thrombosis are indications for shunting.

Portosystemic shunting The therapeutic principle of portosystemic shunting is the conversion of the portal vein into an outflow tract (reversed portal flow), thus decompressing the sinusoids. Thrombosis or compression of the IVC maintains a high pressure in the infrahepatic IVC. Therefore a portacaval or mesocaval shunt will not provide decompression, whereas a shunt from the portal or mesenteric vein to the suprahepatic IVC or right atrium will be effective. Surgical shunts Patients with a non-fulminant presentation of BCS and those without significant hepatic fibrosis who have a chronic presentation, can be considered for surgical shunting, providing the portal vein is patent. A side-to-side portal caval shunt (or meso-caval shunt) not only decompresses the liver, but also relieves ascites and eliminates the risk of variceal bleeding. A differential of 10 mmHg or more between the portal and intrahepatic IVC is considered essential [32]. A hypertrophied caudate lobe often makes the side-to-side portal caval shunt difficult to construct. Orloff et al. reported no technical failures, one operative death, 95% survival, a complete resolution of ascites and no encephalopathy in 60 patients, followed for a range of 3.5 to 27 years. Normal liver histology was found in 48% of patients, and stable fibrosis in the other patients, but cirrhosis did not regress. All shunts, with the exception of two patients who experienced late thrombosis, remained hemodynamically effective, despite some patients not receiving anticoagulation [42]. Contrary to this study, 606

another series reported a survival rate between 57–75% [35, 43] suggesting Orloff et al. either possessed greater experience or used more favorable selection criteria. If the IVC is patent but severely compressed, a selfexpanding stent can be placed in the intrahepatic IVC, followed by a surgical infrahepatic shunt [44]. Retrospective series have questioned the benefits of surgical shunts due to the lack of a survival advantage, independent of liver disease severity, the type of shunt (including TIPS), and the interval between diagnosis and procedure; an exception was patients with mild hepatic impairment (82% vs 68% survival at five years) [19, 21]. This lack of effect on survival could be explained by the average 25% hospital/perioperative mortality (range 0–30%) [35], and late shunt dysfunction/thrombosis [45]. Increased fibrosis at surgery was associated with higher mortality [32]. Some perioperative mortality can be attributed to acute hepatic decompensation, which is remedied only by emergency salvage liver transplantation. Thus, shunting should be performed in a liver transplantation center where rescue therapy is possible. Moreover a TIPS procedure should be attempted before a surgical one, allowing a trial of shunting; if this fails, a liver transplantation is indicated. B4 Transjugular intrahepatic portosystemic shunts (TIPS) The use of TIPS has improved the management of BCS. TIPS avoids laparotomy, overcomes caudate lobe compression and occlusion of the IVC, with less periprocedure mortality than surgical shunting, particularly in patients with poor liver function. Using TIPS does not preclude subsequent surgical shunting or liver transplantation [14, 46–48]. With TIPS, the porto-caval pressure gradient should be normalized (≤6 mmHg). In three series, mortality rates ranged from 9–30% during a mean follow-up of four years. Among 65 patients, seven died: one with fulminant liver failure (transplantation contraindicated), four with severe liver disease (acute on chronic presentation) and three with underlying hematological disorders. Long-term patency, despite routine anticoagulation therapy, only averaged 50%, with 36–72% of patients needing reintervention. TIPS can be placed even if there is portal vein thrombosis [11]. Polytetrafluoroethylenecovered stents result in patency rates of 67% at one year compared with 19% with uncovered stents, a very low rate compared with other series [46]. A recent cohort study on 124 patients with BCS who underwent TIPS in six centers in Europe showed that TIPS was able to improve survival according to Rotterdam score prediction with five years survival of 71% in high risk patients [49]. TIPS should be considered as first-line therapy, if variceal bleeding occurs, for acute and chronic BCS and also in patients with fulminant BCS if a liver donor is not available within 2–3 days. B4 A recent report demonstrated that

CHAPTER 37

Hepatic outflow syndromes

Table 37.3 Liver transplantation for Budd-Chiari syndrome.

Patients Mean interval from diagnosis to OLT (months) Follow-up (years) Survival Recurrence of disease/thrombosis

Halff et al. [52]

Jamieson et al. [53]

Ringe et al. [35]

Srinivastan et al. [54]

Ulrich et al. [55]

Metha et al. [58]

Segev et al. [57]

17 13 3 88% 17%

12 ND 5 50% 13%

43 ND 10 69% 9%

19 8 10 95% 21%

27 ND 5 87% 15%

248 55.8 10 68% 11%

510 NA 3 80% NA

Legend: ND: not determined.

among five patients with FHF, TIPS allowed resolution of the disease in one, and acted as a bridge to liver transplantation within one month in three patients [50]. TIPS intervention should be managed carefully if the patient’s liver reserve is sub-optimal and rescue liver transplantation should be available. B4

Liver transplantation In the remaining 10% of patients, when percutaneous angioplasty or TIPS fail, liver transplantation should be considered. Emergency liver transplantation is indicated for fulminant BCS, and has been used as a salvage procedure for fulminant liver failure induced by surgical shunting [35, 43, 51]. There are seven major transplant series, with more than ten patients each, totaling 162 patients (see Table 37.3), with survival rates between 50% and 95% with a mean followup of 4.5 years [35, 52–55]. Twenty patients (12%) had acute portal vein or hepatic arterial thrombosis, or late thrombosis, which was fatal in eight and resulted in retransplantation in eight. Despite anticoagulation recurrent BCS occurred in two of seven transplanted patients [56]. Recently a retrospective analysis of series from USA and Europe has shown a five-year survival rate of 80% [57, 58]. However, a TIPS was placed in only 4% of patients before transplant in the European series and anticoagulation was used in less than 60%. Recurrence of venous thrombosis or BCS occurred in about 10% of patients, confirming the need of anticoagulation. Although almost all genetic thrombophilic disorders are cured by transplantation [43, 59], thrombosis still occurs and routine anticoagulation therapy is necessary. Careful monitoring is necessary as complications of anticoagulation were seen in 40% and in 17/197 (11%) after liver transplantation who had bleeding complications due to anticoagulation leading to two deaths in the European series [56]. In patients with myeloproliferative disorders, use of hydroxyurea and aspirin is safe and effective [60]. So far

malignant transformation is anecdotal [54, 58]. A suggested algorithm of treatment for BCS is shown in Figure 37.1.

Portal and splanchnic vein thrombosis Splanchnic thrombotic disease has a wide spectrum of presentation and a wide range of severity. The disorders can be challenging and sometimes overlapping; appropriate management hinges on accurate diagnosis and especially on the broad distinction between cirrhosis-associated thrombotic disease and non-cirrhotic splanchnic venous thrombosis. The complexity of these cases, especially with non-cirrhotic acute PVT or cavernoma, usually warrants a multidisciplinary approach with involvement of both hematology and GI/hepatology, as well as other support services. Below, we have focused on portal vein thrombosis (PVT) and isolated splenic vein thrombosis (SVT), with emphasis on adult disease from a practical clinical perspective. Several recent reviews also offer excellent and comprehensive examination of the disorder [61–63].

Portal vein thrombosis (PVT): epidemiology The exact annual incidence of PVT is not known although it is a common condition in most tertiary care centers. The difficulty in determining clear epidemiology of PVT results in part from its highly variable associations. In an autopsy series, PVT was discovered in 254 of 23,796 autopsies (1%) performed over a 12-year period from Uppsala Sweden [64]. Among those with PVT, 28% had cirrhosis (one-third with and two-thirds without hepatocellular cancer), 23% had primary hepatobiliary cancer (two-thirds hepatocellular cancer and one-third biliary), 44% had metastatic cancer, 10% had intra-abdominal infection or inflammatory conditions, 3% had myeloproliferative disease and 14% were without an apparent association. As discussed below, up to 20% of patients with cirrhosis develop portal thrombosis, which probably constitutes the single most common association encountered in liver centers. However, PVT in 607

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Ultrasound/Doppler Thrombophilia and myeloproliferative disorders screening Anticoagulation

ballooning stent

PV thrombosis

Hepatic venography/IVC venogram caval pressures porta vein (PV) imaging

HV webs

Multiple HV thrombosis

FHF

Failure

IVC compression thrombosis

No IVC compression or thrombosis

Single HV thrombosis

Ballooning stent

No PV thrombosis

Attempt local thrombolysis

Moderate/severe liver function/ascites

Attempt TIPS

Isolated IVC webs

Success

Meso-atrial or infra-hepatic shunt if no IVC thrombosis and liver transplantation available

Stable/minor liver function/ascites

?

Liver transplantation Follow-up, close monitoring of anticoagulation Figure 37.1 Flow chart in and management of Budd-Chiari syndrome.

cirrhosis is frequently discovered incidentally and, while it may result in liver atrophy and warrants a close examination for an associated hepatocellular cancer, it is a less urgent clinical situation than acute PVT in the non-cirrhotic patient in whom the presentation can be dramatic. In all cases, additional diagnostic investigation is warranted and the risk-benefit of anticoagulation therapy needs to be carefully considered. However, as a result of the broad array of presentations and relatively low prevalence, controlled data treatment is limited and much of the literature, including two efforts at consensus or summary statements, are reflections more of experience and expert opinion than evidence-based on randomized trials [65, 66].

Portal vein thrombosis: overview of clinical presentation and evaluation The typical clinical presentation ranges from sudden onset of abdominal pain and ascites with acute PVT, to acute variceal hemorrhage in the setting of chronic PVT, to incidentally discovered cavernoma (cavernous transformation of the portal vein) found, for example, during an evaluation of low platelets due to hypersplenism and splenome608

galy. These clinical situations can present the clinician with diagnostic and therapeutic problems which need to be systematically worked through. For example, the presence of splenomegaly may be both part of PVT secondary to the thrombus and localized portal hypertension and also part of an underlying myeloproliferative disorder. Ascites can be seen even in patients without cirrhosis and its evaluation can be confusing (see below). These studies, especially CT and MR, may also help to establish whether the thrombus is recent (absence of collateralisation) or chronic (presence of cavernous transformation.) Long standing portal vein thrombosis may result in irregularity of the liver outline, probably due to asymmetry of blood flow, resulting in the radiological appearance of cirrhosis-in these instances a biopsy is required, as the prognosis will be significantly altered by the histology. The clinician then needs to exclude the presence of varices by endoscopy which then helps to weigh the riskbenefit of anticoagulation therapy. Laboratory tests should be performed to evaluate for hypercoagulable conditions and the history must be carefully explored to evaluate for any evidence of prior liver abnormalities, use of prothrombotic agents such as estrogen preparations, and prior

CHAPTER 37

thrombotic disease, including family history and prior intra-abdominal inflammation. Detailed questioning is needed regarding any history of neonatal illness which would suggest possible umbilical vein cannulation, and any distant episodes of intra-abdominal illnesses which might suggest prior appendicitis or diverticulitis.

Acute non-cirrhotic PVT Acute, non-cirrhotic PVT is the least common cause of PVT but perhaps the most dramatic. Among 3655 liver disease patients recorded in a University of Virginia liver disease registry kept between approximately 1995 and 2004, 19 patients (0.5%) presented with this condition (unpublished observations). Although these patients have not yet been thoroughly evaluated about one-third of these had an underlying myeloproliferative disorder and another third had an identifiable pro-thrombotic condition. The most common presentation in our patients was abdominal pain and ascites, with intractable variceal bleeding in a minority. Similarly, Condat et al. observed significantly less gastrointestinal bleeding in acute PVT compared to cavernoma (see below) [67]. Bloody diarrhea may also be evident, especially if the thrombosis extends into the superior mesenteric vein distribution. Ascites can also be seen in one-third of patients with non-cirrhotic acute PVT [61]. Opening of portosystemic collaterals dissipates the portal hypertension and thus the ascites, although a transition to chylous ascites indicates rupture of the pressurized lymphatic vessels [68]. The ascites fluid characteristics may be difficult to interpret as the fluid (in non-chylous situations) derives from bowel edema rather than the typical liverderived transudate as in cirrhosis [69]. Although 20–40% of patients have no identifiable underlying thrombophilic risk factors and there is a degree of regional variation, myeloproliferative disorders (polycythemia vera, essential thrombocythemia or myelofibrosis) are the most common identifiable causes of acute PVT, while specific factor abnormalities such as protein C, S or anti-thrombin III deficiency, factor V Leiden or prothrombin mutation, and anti-phospholipid abnormalities are associated risk-factor in the remaining cases [67, 70]. Myeloproliferative disorders underlie PVT more often than previously thought, and it is here that the test for the JAK2 mutation has been particularly eye-opening, as it has provided a non-invasive screening test for bone marrow disorders allowing one to select patients for the more invasive bone marrow biopsy [71]. This test probably should become a part of the routine laboratory evaluation of these patients but this remains to be determined. It should be considered if available. Morbidity in acute PVT can be substantial, but prolonged survival in acute non-cirrhotic PVT is common. Consistent with our own experience, Janssen et al. reported ten-year

Hepatic outflow syndromes

survival of 81% in this group provided that cirrhosis and underlying malignancy were excluded [72]. As discussed further below, long-term morbidity related to recurrent thrombi and/or transformation to cavernoma can be influenced by early anticoagulation, although controlled data is lacking, and the benefits must be weighed against the risk of severe portal hypertensive bleeding and other complications of anticoagulation.

Portal cavernoma This entity was first reporteded in 1869 by Balfour and Stewart to describe the post-thrombotic dilatation of the portal vein, which we now know to be commonly associated with prior and often unrecognized PVT. The term “cavernoma” was subsequently used by Köbrich in 1928 to describe the spongy appearance of the network of blood vessels in the portal vein location related to re-canalization of the thrombosis. Local infections (portal phlebitis, omphalitis), abdominal trauma and a history of prothrombotic disorders are implicated in the development of the PVT, but many cases remain unexplained. Cavernoma develops as the portal vein thrombus undergoes reorganization and remodeling into a network of collateral vessels which overcome the occlusion and restore, to a variable degree, hepatopedal blood flow. Cavernous transformation can occur rapidly even within 6–20 days and thus the presence of cavernoma, while usually suggesting chronicity, does not necessarily indicate a very distant event [73]. Hematemasis and splenomegaly are the most common presenting symptoms occurring in about 50% of these patients [74]. Portal biliopathy (biliary obstruction and stricturing) due to ischemia, duct compression by collateral vessels or possible local infection causes symptomatic disease in 4 to 24%, although abnormal cholestatic liver chemistries and cholangiographic abnormalities are much more common [75]. Treatment options include medical therapy with ursodeoxycholic acid, endoscopic therapy including biliary stenting, and in severe cases surgical or radiological shunting. In chronic cases, pre-operative decompression of the portal cavernoma is being explored to avoid life-threatening hemorrhage and other complications following surgical intervention [76]; decompression can be feasible by the placement of TIPS [77]. Strategies to avoid the complications of portal cavernomas have involved early anticoagulation, in cases with early diagnosis, to promote recanalization [67]. Long-term therapy is essential in those with an identified pre-thrombotic condition such as underlying protein C or S deficiency. However, intervention with anticoagulation requires careful exclusion and management of varices if present. It is also important to recall that portal cavernoma may be stable over many years, even without aggressive intervention, especially among patients presenting with 609

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more indolent symptoms, which is also our experience. In such cases, we have typically used low-dose forms of anticoagulation provided varices have been excluded endoscopically.

PVT in cirrhosis Portal vein thrombosis (PVT) occurs in 10–20% of all cirrhotic patients, and conversely cirrhosis is responsible for about 20% of all cases of PVT [78]. Symptoms of acute abdominal pain, variceal bleeding, and ascites develop in 57% of cirrhotic patients with PVT [79]. Portal vein thrombosis in this setting can develop due to hepatic fibrosis and the resistance to blood flow (stasis), but there can also be many other factors, including a genetic predisposition to prothrombotic disorders, or abdominal infections, or local factors, for example pancreatitis [80]. Thrombosis can extend distally into right and left portal vein branches or proximally into the superior mesenteric vein (see Table 37.4). More often the thrombosis in the portal vein is incomplete and does not result in complete occlusion [81]. Complications of PVT in cirrhosis include splenomegaly, esophageal varices, gastric varices, and portal hypertensive gastropathy. PVT has traditionally been a contraindication to liver transplantation due to technical difficulties in intraoperative anastomases. This situation has led to evaluation of a trial of anticoagulation in patients with cirrhosis and PVT [82]. However, monitoring anticoagulation in cirrhosis with an underlying coagulopathy is a challenge. Traditional measures such as INR (international normalized ratio) are of limited use because it is not only affected by oral anticoagulation medication, such as coumadin, but also factor deficiencies from hepatic dysfunction. Low weight molecular heparins may be safer than oral anticoagulation in cirrhosis. Recently, repermeation was obtained in 50% of 38 patients with cirrhosis and portal vein thrombosis with only one episode of non-severe variceal bleeding [83]. Further study is clearly essential to determine the relative utility and the risk-benefit of this type of intervention. Surgical techniques involving thrombectomy and bypass

Table 37.4 Grades of portal vein thrombosis (PVT). Grade Grade Grade Grade Grade

Description I PVT 2 PVT 3 PVT 4 PVT

Thrombosis of intrahepatic portal vein branches Thrombosis of right or left portal branches Partial obstruction of portal vein trunk Complete obstruction of portal vein trunk

Adapted from Nonami et al. [86].

610

grafts also remain to be fully evaluated but should be used cautiously as these may be associated with high morbidity and mortality [84]. The use of transjugular intrahepatic portosystemic shunt is feasible in patients with portal vein thrombosis given the patency of intrahepatic portal branches, even in the presence of cavernous transformation and allows treatment of portal hypertensive complications when anticoagulation fails to prevent progression of thrombosis. Moreover TIPS allows the undertaking of thrombectomy in 50% of cases [85]. An integrated algorithm of treatment of portal vein thrombosis including easy anticoagulation and radiological treatments when progression of thrombosis or portal hypertensive complications occur could be the best option, but this needs to be prospectively explored. B4

Portal vein thrombosis and hepatocellular cancer (HCC) The incidence of PVT in patients with cirrhosis and hepatocellular carcinoma (HCC) has been found to be as high as 35% [86]. Indeed, the development of PVT in previously stable cirrhosis warrants a close evaluation for neoplasia. Hypercoagulability due to the underlying malignancy can explain the higher rate of PVT, but tumor invasion into the portal vein can also cause mechanical obstruction. Clinically, it can be difficult to discern between thrombosis or tumor invasion using current imaging modalities. The concurrence of PVT and HCC imparts a severe prognosis. HCC without PVT has a median prognosis of 24 months, but when associated with PVT and possible portal vein tumor invasion, this drops to a dismal 2.7 months [87]. This striking difference may relate to tumor aggressiveness or possibly to limitations of therapeutic intervention. Several different techniques for HCC treatment are currently being used: percutaneous ethanol injection, radiofrequency ablation, transcatheter arterial chemoembolization, and glass radioactive microspheres. In the setting of PVT and compromised portal flow, extensive or multiple arterial embolization techniques can increase the risk of liver failure, but radioactive microspheres may offer the best risk-benefit ratio. In experienced centers, super-selective, segmental drug delivery can avoid these complications but still has clinical limitations [88]. In addition, the diagnostic dilemma of thrombus versus tumor invasion, limited by current imaging techniques, usually precludes the possibility of liver transplantation. With tumor invasion into the portal vein, transplantation has limited success and is associated with rapid recurrence [89]. Together, these complex associations are indicative of the need for careful clinical investigation in patients suffering the triad of cirrhosis, HCC and PVT.

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Isolated splenic vein thrombosis Isolated splenic vein thrombosis presents most commonly with abdominal pain and UGI bleeding, frequently due to gastric varices, although there is regional variation in the major clinical manifestations and associated symptoms [70, 90]. Underlying malignancy (50%) and pancreatitis (15%) are the two most common predisposing factors although identifiable hypercoagulable states and myeloproliferative disorders can be present in a small minority (7%) in some series [70]. While intractable gastric variceal bleeding is the most serious complication, a natural history study from North Carolina indicates, surprisingly, that this occurs in only about 4% of SVT patients, in the setting of pancreatitis over a mean follow-up of 40 months [91]. From the perspective of gastric variceal bleeding, SVT is the cause in only about 10% of new onset GVB, with the majority being related to cirrhosis and portal hypertension without associated thrombotic disease [92]. Nonetheless, GV bleeding in the setting of SVT is challenging and associated with a high rate of recurrent bleeding following local therapy such as with cyanoacrylate injection. This may be due to the origin of GV in SVT from the short gastric veins rather than gastro-spleno-renal anastomases as seen in cirrhosis. In our experience, most cases of such non-cirrhotic SVT complicate either local pancreatic or gastric cancer (50%), or chronic pancreatitis (50%) [92]. In the latter case, splenectomy, although lacking controlled data, is the optimal intervention [93]. B4 In the former, palliative measures are more often appropriate. Several unique circumstances can also be seen in this clinical scenario, such as pregnancy-related SVT [96]. Notably, bleeding due to pregnancy related splenic vein thrombosis can be treated with local injection of cyanoacrylate polymers as occurred in one case we have described [92]. Delivery was successful and post-partum endoscopic evaluation revealed no recurrence of the gastric varices.

Anti-coagulation in portal vein thrombosis Patients with a procoagulant disorder should be anticoagulated to prevent thrombus extension, or the development of de-novo thromboses. The concern is that patients with varices may bleed if anticoagulated. Yet the evidence suggests that the lethality of subsequent thrombosis is higher than that of bleeding [94]. Thus pragmatically, the approach should be: if pro-coagulant, and never bled, then anticoagulate. If pro-coagulant and previous variceal bleedingthen balance of risk may favour (brief) variceal obliteration and/or betablockers followed by anticoagulation. The data on thrombolytic therapy in patients with acute portal vein thrombosis is peppered with anecdote and case

Hepatic outflow syndromes

reports. Whilst outstanding results have been documented, catastrophic complications are also recognised (though usually less reported). A recent review suggested this should only be considered in those who are least likely to re-canalise with anticoagulant therapy-patients with ascites, acute splenic and portal vein thrombosis [95]. Current evidence favours early institution of heparin anticoagulation followed by warfarinisation whilst a search for precipitant factors occurs. Patients with an identified prothrombotic tendency, even in the presence of varices, should be anti-coagulated [97].

Veno occlusive disease/sinusoidal obstruction syndrome Introduction Hepatic veno-occlusive/sinusoidal obstruction syndrome (VOD/SOS) disease is a clinical syndrome characterized by hepatomegaly, ascites, weight gain and jaundice [98, 99]. It was first described in a patient who drank an infusion made with pyrrolizidine alkaloids. Early histological abnormalities include sinusoidal congestion associated with centrilobular necrosis, and later fibrous obliterative lesions in the hepatic venules occur with histologic damage located to zone 3 of the acinus. VOD is also associated with other toxins such as alcohol, oral contraceptives, toxic oil, terbinafine, or radiation injury. The first case associated with hematopoietic stem cell transplantation (STC) was reported in 1979 [100]. Since then SCT has become the most important and frequent cause of VOD. In this setting diagnosis is made using the same clinical signs as for other etiologies. Other causes are infrequent but require exclusion. VOD after SCT is a part of the spectrum of multi organ syndromes which include idiopathic pneumonitis, diffuse alveolar hemorrhage, thrombotic microangiopathy and capillary leak syndrome. The incidence of VOD after STC ranges from 0 to 70%, dependent on the particular application of specific diagnostic criteria, the sample size and risk factors which are heterogenous amongst different cohorts [101]. Currently, the incidence and severity of VOD after SCT is decreasing due to earlier timing of SCT in patients with leukemia, the use of non-myeloablative regimens and the decrease of HCV infection amongst transplant candidates [102]. However, the incidence of VOD remains high in patients undergoing aggressive chemotherapy regimens to eradicate cancer. New chemotherapeutic agents, in particular gemtuzumab and ozogamicin have been associated with a frequent occurrence of sinusoidal toxicity. Veno-occlusive disease is also reported after other solid organ transplantation, particularly, kidney transplantation.

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The largest series report an incidence of 2–5% (5/200 kidney transplants), mainly related to azathioprine toxicity. In liver transplant recipients the largest series reported an incidence of 1.9% (19/1023 liver transplants) clinical VOD, related to the number and severity of rejection episodes and azathioprine use. In contrast, reversible hepatic venule stenosis, including cases diagnosed histologically, is reported in 43% after liver transplantation and is mainly related to azathioprine [103].

Pathophysiology and histology After SCT the high dose cytoreductive therapy used in patients who have a particular susceptibility, produces endothelial injury of both sinusoids and small hepatic venules (the latter only if the damage is more severe). Due to the inconspicuous presence of venular damage in patients with less severe VOD/SOS, and evidence from experimental models of the primary target being sinusoidal endothelial cells, the denomination of sinusoidal obstruction syndrome has been proposed to replace the term VOD. The sinusoidal damage leads to activation of the coagulation cascade and clot formation. Fibrin-related plugs, intracellular fluid entrapment and cellular debris progressively occlude sinusoids, causing intrahepatic post-sinusoidal portal hypertension, responsible for the clinical signs of fluid retention (weight increase), hepatomegaly, ascites and jaundice. Usually fibrosis occurs several weeks after the onset of the disease. An early deposition of matrix metalloproteinases-2 has also been reported in the sinusoids. Several factors other than cytoreductive therapy contribute to the damage in VOD. Release of cytokines such as TNF-alfa, IL1 and 2 released due to the endothelial injury, but also due to cyclosporine given to patients with GVHD, have procoagulant activity. Immunological mechanisms have been implicated based on the observation of a lower incidence of VOD following T cell depleted and autologous SCT, and a higher incidence amongst mismatched transplants. All these injuries cause depletion of glutathione from hepatocytes, resulting in increased sensitivity to zone 3 damage due to other compounds, which can further deplete this antioxidant compound, such as cyclophosphamide, busulfan and BCNU. In parallel with the decline in hepatic venous flow, nitric oxide (NO) levels in the hepatic vein decreases [104]. This change suggests that vasoconstriction related to NO depletion occurs, further incrementing the damage.

Clinical presentation and diagnosis The classic presentation of VOD is characterized by the triad of weight gain caused by fluid retention, tender hepatomegaly and hyperbilirubinemia without any known cause [104, 105]. Usually this occurs within 10–20 days after 612

SCT when regimens containing cyclophosphamide have been used. With other regimens it occurs later on [106]. After liver transplantation VOD occurs over a wide interval, with a mean of nine weeks after transplant. Diagnosis is usually based on signs and symptoms, having ruled out other conditions which can mimic the disease, particularly after STC, such as viral infections and graft versus host disease, cholestatic secondary sepsis, heart failure and tumoral infiltration of the liver [107]. Nowadays, clinical criteria have been formalized in the Baltimore and Seattle criteria (see Table 37.5). The Baltimore criteria are more restrictive, and usually patients fulfilling these are diagnosed at a more severe stage of the disease [108]. Endothelial injury can be suspected even before the appearance of the clinical or other laboratory signs by finding elevated serum levels of PAI-1, procollagen III, and its precursor propeptide (P-III-P) [109]. Serum hyaluronic acid, vWF-cleaving protease ADAMTS13 and Ca-125 have also been evaluated as early markers of VOD. Ultrasound of the liver and abdomen with Doppler examination is the first-line imaging investigation. Findings include the presence of ascites, hepatomegaly, attenuated hepatic veins and/or biliary dilatation. However, none of these signs are specific for the diagnosis and must be interpreted within the clinical context [110]. Pulsed Doppler ultrasound can suggest VOD on the basis of a decreased or reversed portal venous flow [111]. Significant elevation of the hepatic artery resistive index in duplex sonography may be a sensitive index of liver

Table 37.5 Diagnostic criteria of veno occlusive disease after SCT. Seattle criteria At least two of the three following criteria: within the first month after stem cell transplantation (SCT): (1) Jaundice (2) Hepatomegaly and right upper quadrant pain (3) Ascites and/or unexplained weight gain Baltimore criteria Elevated total serum bilirubin (≥2 mg/dl) before day 21 after SCT and two of the following three criteria: (1) Tender hepatomegaly (2) Weight gain > 5% from baseline (3) Ascites Modified Seattle criteria Occurrence of two of the following events within 20 days of SCT: (1) Hyperbilirubinaemia (≥2 mg/dl) (2) Hepatomegaly or right upper quadrant pain of liver origin (3) Unexplained weight gain (> 2% of baseline bodyweight) because of fluid accumulation

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damage related to VOD. In infants, a segmental portal flow reversal has also been shown to be strongly associated with early VOD [112].

Hemodynamics and hepatic vein catetherization The transjugular access is a safe route to perform measurement of the hepatic venous pressure gradient (HVPG) and liver biopsy [113]. The absence of a significant gradient ( 2 mg/dl Ascites hepatomegaly

VOD suspected

Timing After SCT before day 20 After LT mean 9 weeks

Diagnosis

Laboratory Imaging Confirm and assess prognosis • AST • US and Doppler • Transjugular liver biopsy • Bilirubin • MRI • HVPG • PAI-1, Procollagen III • HV and IVC pressures if OLT • Ca 125 Medical treatment • Treatment of ascites • tPA + heparin • Defibrotide LT, KTx, alkaloids

TIPS

failed

OLT

STC

No malignancy No MOF

endothelium as well as decreasing thrombin generation and lowering circulating levels of PAI-1. In the largest series published, treatment with 10–60 mg/ kg/day infusion of defibrotide every six hours achieved a response rate of 36% and overall survival rate of 35% at 100 days after SCT, without adverse events [122]. The high mortality rate of VOD after liver transplantation leads to the need of specific therapy. In the only two patients treated with defibrotide for VOD after LT, only one survived [123]. No effective medical therapy has been reported. Decompression of the engorged sinusoids by a transjugular, intrahepatic, portosystemic shunt can relieve portal hypertension and prevent renal failure in patients with VOD. The recent review on clinical practice guidelines for transjugular intrahepatic portosystemic shunt (TIPS) did not recommend TIPS for veno-occlusive disease (VOD). B4 However, it was implied that VOD is only seen after SCT, whereas it can be seen in other settings, in which TIPS may offer a potentially useful treatment. To date, 27 VOD patients treated with TIPS, have survived, 20% of the total. All but three (two with previous liver and one with previous kidney transplantation) had bone marrow transplantation [124, 125]. The most common causes of death usually occurring within one to three weeks following diagnosis were multi-organ failure (MOF), sepsis and hemorrhage, due to underlying hematological disease. The interval could influence the success of TIPS. If MOF is already present, patients are probably being treated too late. Earlier intervention may be worthwhile, but it needs formal assessment. Indeed, the causes of death in patients with VOD are usually renal and cardiopulmonary failure and sepsis, rather than liver 614

Figure 37.2 Flow chart in diagnosis and management of veno-occlusive disease. VOD: veno occlusive disease; SCT: stem cell transplantation; OLT: ortothopic liver transplantation; HVPG: hepatic venous pressure gradient; HV: hepatic vein; IVC: inferior vena cava; KT: kidney transplantation; MOF: multi organ failure; TIPS: transjugula, intrahepatic, portosystemic shunt.

failure per se. In liver transplantation six patients with VOD have been treated with TIPS, one died, one was retransplanted, but information in these two patients about the course or the cause of liver failure or death were not reported. Thus, although TIPS is not recommended for patients with severe VOD, this may apply only to SCT patients in whom MOF conditions the prognosis. If a severe VOD is diagnosed in a liver transplanted patient and if medical therapy fails, a transjugular portosystemic shunt should be considered. Liver transplantation has been reported anedoctically as a rescue therapy in patients with VOD after SCT not responding to medical therapy. Currently, 18 patients have been reported in the literature for transplantation due to VOD/SOS, with 13 deaths (72%), primarily due to infective complications [126]. The presence of malignancies and multiple organ failure (if VOD is advanced) contraindicates OLT. When VOD develops after liver transplantation itself, retransplantation can be performed as a rescue therapy as the liver is the only organ damaged. Previous placement of TIPS allows more time for the clinician to relist the patients for OLT and it does not jeopardize subsequent OLT. A flow-chart for the suggested diagnosis and management of VOD is shown in Figure 37.2.

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38

Ascites, hepatorenal syndrome and spontaneous bacterial peritonitis Pere Ginès, Andrés Cárdenas, Vicente Arroyo and Juan Rodés Liver Unit and GI Unit, Hospital Clínic and University of Barcelona, Institut d’Investigacions Biomèdiques August Pi-Sunyer (IDIBAPS), Ciber de Enfermedades Hepáticas y Digestivas (CIBERHED), Barcelona, Spain

Introduction

Ascites

Patients with cirrhosis frequently develop disturbances in body fluid regulation that result in an increase in the volume of extracellular fluid, which accumulates in the peritoneal cavity as ascites and in the interstitial tissue as edema [1]. Although the pathogenesis of ascites is incompletely understood, most available evidence indicates that fluid retention is the consequence of the homeostatic activation of vasoconstrictor and sodium-retaining systems triggered by marked arterial vasodilation mainly in the splanchnic vascular bed [2]. Marked abnormalities in the splanchnic microcirculation due to portal hypertension facilitate the accumulation of the retained fluid in the peritoneal cavity. Ascites is frequently complicated by abnormalities of renal function such as impaired ability to eliminate solute-free water and vasoconstriction of the renal circulation, which may lead to development of dilutional hyponatremia and hepatorenal syndrome respectively [1, 3]. Finally, coexistence of ascites and abnormalities in the host defense mechanisms against bacterial infection, which occur frequently in patients with advanced cirrhosis, accounts for the spontaneous infection of ascitic fluid, a condition known as spontaneous bacterial peritonitis [4, 5]. The aim of this chapter is to review, on the basis of available evidence, the efficacy of various therapeutic methods in the management of ascites, hepatorenal syndrome and spontaneous bacterial peritonitis in cirrhosis. The pathogenesis of these complications is briefly discussed to provide the reader with an understanding of the pathophysiological basis of the different therapeutic approaches. A comprehensive review of the pathophysiology of these disorders may be found elsewhere [1, 6].

A large body of evidence indicates that in cirrhosis, sodium retention with subsequent ascites and edema formation, results from the action of neurohumoral factors on the kidney, which are activated during the homeostatic response to a disturbed systemic circulation (see Figure 38.1) [1, 2, 6, 7]. The initial abnormality is sinusoidal portal hypertension causing marked arterial vasodilation mainly in the splanchnic circulation. The mechanism of this vasodilation is not known, but may involve the increased synthesis/release of vasodilating substances, including nitric oxide and/or vasodilator peptides [2, 8]. Arterial vasodilation results in an abnormal distribution of blood volume, with reduced effective arterial blood volume (the blood volume in the heart, lungs and central arterial tree), sensed by the arterial receptors with subsequent renal sodium retention due to the activation of vasoconstrictor and sodium-retaining factors.

Evidence-Based Gastroenterology and Hepatology, Third Edition John WD McDonald, Andrew K Burroughs, Brian G Feagan and M Brian Fennerty © 2010 Blackwell Publishing Ltd. ISBN: 978-1-405-18193-8

Sodium restriction In all diseases associated with generalized edema (cirrhosis, heart failure, renal failure), the amount of exogenous fluid retained depends on the balance between sodium intake and the renal excretion of sodium. Because sodium is retained iso-osmotically in the kidney, 1 liter of extracellular fluid is gained for every 130–140 mmol of sodium that is retained. If sodium excretion remains constant, the gain in extracellular fluid volume (and the consequent increase in weight) depends exclusively on sodium intake and increases proportionally to the amount of sodium in the diet. Nevertheless, because sodium excretion may be increased pharmacologically by the administration of diuretics, the sodium balance depends not only on sodium intake but also on the natriuretic response to the diuretics. With this background, it seems reasonable that a reduction in sodium intake (low salt diet) will favor a negative 619

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Liver transplantation

CIRRHOSIS

Surgical portosystemic shunts and TIPS

SINUSOIDAL PORTAL HYPERTENSION

Vasodilator factors (NO, peptides) SPLANCHNIC ARTERIAL VASODILATION

Abnormal distribution of blood volume Peritoneovenous shunting

DECREASED EFFECTIVE ARTERIAL BLOOD VOLUME

Activation of vasoconstrictor and sodium-retaining systems Diuretics

RENAL SODIUM RETENTION

Positive sodium balance Increased splanchnic capillary filtration coefficient Therapeutic paracentesis

ASCITES

Figure 38.1 Proposed pathogenesis of ascites formation in cirrhosis according to the arterial vasodilatation hypothesis and available therapeutic interventions (in bold). TIPS: transjugular intrahepatic portosystemic shunt; NO: nitric oxide.

sodium balance and the elimination of ascites and edema. This was demonstrated in earlier studies and is supported by the common clinical observation that the management of ascites is more difficult in patients who do not comply with a low sodium diet [9, 10]. C5 B4 Non-compliant patients usually require higher doses of diuretics to achieve resolution of ascites and are readmitted more frequently to hospital for recurrence of ascites. Surprisingly, however, an advantage of low sodium diet as compared with an unrestricted sodium diet in the management of ascites has not been demonstrated in randomized controlled trials [11–13]. Ald Nevertheless, it should be pointed out that in these studies most patients had mild sodium retention (urine sodium in the absence of diuretic therapy was close to sodium intake) and showed an excellent response to diuretic therapy (less than 5% of patients did not respond to diuretics). Therefore, on the basis of available evidence, it can be concluded that in patients with mild sodium retention, restriction of dietary sodium is probably not necessary; the hypothetical benefit of low salt diet in the achievement of a negative sodium balance is overridden by the marked natriuretic effect of diuretics. In contrast, in patients with marked sodium retention, who usually have a less intense natriuretic response to diuretics compared with patients with moderate sodium retention, dietary sodium restriction (80 mmol of sodium per day) may facilitate the elimination of ascites and delay the reaccumulation of fluid. A 620

more severe restriction of sodium is not recommended because it is poorly accepted by patients and may impair their nutritional status. C5

Therapeutic paracentesis Therapeutic paracentesis has progressively replaced diuretics as the treatment of choice in the management of patients with cirrhosis and large volume ascites [14, 15]. This change in treatment strategy is based on the results of several randomized controlled trials comparing paracentesis (either removal of all ascitic fluid in a single tap or repeated taps of 4–6 1iters/day) associated with plasma volume expansion versus diuretics [16–20]. Ald Because paracentesis does not affect renal sodium retention, patients should be given diuretics after paracentesis to avoid reaccumulation of fluid [21]. Ald Two aspects concerning the use of therapeutic paracentesis in patients with cirrhosis and ascites deserve to be specifically discussed: (1) the population of patients with cirrhosis in whom therapeutic paracentesis should be used; and (2) the use of plasma expanders to prevent disturbances in circulatory function after paracentesis. While most physicians consider that therapeutic paracentesis is the treatment of choice for all patients with large volume ascites [14, 15], others believe that therapeutic paracentesis should be used only in those patients who show a poor or no response to diuretics [22]. Results of randomized trials indicate that therapeutic paracentesis is faster and in several trials was associated with lower incidence of adverse effects compared with diuretics (see Table 38.1) [16–20]. Ald Moreover, therapeutic paracentesis may have a better cost-effectiveness profile compared with diuretic treatment that can result in prolonged hospitalization. Therefore, on the basis of the available evidence, it seems clear that the use of therapeutic paracentesis should not be restricted to patients failing to respond to diuretics but should be considered the treatment of choice for all patients with large volume ascites (see Box 38.1). The removal of large volumes of ascitic fluid is associated with circulatory dysfunction characterized by a reduction of effective blood volume [23–29]. Several lines of evidence indicate that this circulatory dysfunction and/or the mechanisms activated to maintain circulatory homeostasis have detrimental effects in cirrhotic patients. First, circulatory dysfunction is associated with rapid reaccumulation of ascites [29]. Second, approximately 20% of these patients develop hepatorenal syndrome and/or water retention leading to dilutional hyponatremia [23]. Third, portal pressure increases in patients developing circulatory dysfunction after paracentesis, probably owing to an increased intrahepatic resistance due to the action of vasoconstrictor systems on the hepatic vascular bed [27]. Finally,

CHAPTER 38

Ascites, hepatorenal syndrome, peritonitis

Table 38.1 Adverse effects in randomized trials comparing the efficacy and safety of diuretics versus therapeutic paracentesis and plasma volume expansion in patients with cirrhosis and large volume ascitesa. Adverse effect

No. of patients with adverse effects

P

Type of plasma expander

Diuretics (%)

Paracentesis and plasma volume expansion (%)

Renal impairment Ginès et al. [16] Salerno et al. [17] Hagège et al. [18] Acharya et al. [19] Solà et al. [20]

Albumin Albumin Albumin Dextran-40 Dextran-40

16/59b (27) 1/21 (5) 1/27 (4) 1/20 (5) 5/40 (12)

3/58 1/20 1/26 0/20 1/40

(5) (5) (4) (0) (2)

0.003 NS NS NS NS

Hyponatremia Ginès et al. [16] Salerno et al. [17] Hagège et al. [18] Acharya et al. [19] Solà et al. [20]

Albumin Albumin Albumin Dextran-40 Dextran-40

18/59 (30) — 8/27 (30) 1/20 (5) 8/40 (20)

3/58 — 2/26 3/20 5/40

(5) (8) (15) (12)

0.0009 — 0.07 NS NS

Encephalopathy Ginès et al. [16] Salerno et al. [17] Hagège et al. [18] Acharya et al. [19] Solà et al. [20]

Albumin Albumin Albumin Dextran-40 Dextran-40

17/59 (29) 3/21 (14) 4/27 (15) 1/20 (5) 12/40 (30)

6/58 2/20 1/26 0/20 1/40

(10) (10) (4) (0) (2)

0.02 NS NS NS 0.0015

a b

Differences in the rate of adverse effects among the studies may be due, at least in part, to differences in the populations of patients included. Figures represent the number of patients developing the adverse effects compared with the total number of patients in each treatment group.

BOX 3 8 .1 Recommendations for the management of

patients with cirrhosis and large volume ascites [1] (1) Total paracentesis plus intravenous albumina (8 g/l of ascites removed). Patients can be treated as outpatients. Hospitalization is recommended for patients with associated complications (i.e. encephalopathy, bacterial infection, gastrointestinal bleeding). (2) After removal of ascitic fluid, start with moderate sodium restriction (80 mmol/day) and diuretics, either aldosterone antagonists alone (i.e. spironolactone 50–400 mg/day) or in combination with loop diuretics (i.e. furosemide 20–100 mg/day). If patients were on diuretics before the development of large volume ascites, check compliance with sodium diet and diuretic therapy. Compliant patients should be given doses of diuretics higher than those given before paracentesis in order to prevent the recurrence of ascites. Non-compliant patients should be instructed to comply with therapy. (3) Consider liver transplantation. a

Although a survival benefit of albumin over other plasma expanders has not been demonstrated, albumin is more effective than other plasma expanders in the prevention of paracentesis-induced circulatory dysfunction when more than 5 l of ascitic fluid are removed.

the development of circulatory dysfunction is associated with shortened survival [29]. The most studied effective method to prevent circulatory dysfunction is the administration of plasma expanders. A randomized trial has shown that albumin is more effective than other plasma expanders (dextran-70, polygeline) for the prevention of circulatory dysfunction as estimated by changes in plasma renin activity, probably owing to its persisting longer in the intravascular compartment [29]. Alc When less than five liters of ascites are removed, dextran-70, polygeline or saline show efficacy similar to that of albumin. However, albumin is more effective than these other plasma expanders when more than five liters of ascites are removed [29]. Alc Despite this greater efficacy, randomized trials have not shown differences in survival of patients treated with albumin compared with those treated with other plasma expanders [29–33]. Larger trials would be required to demonstrate a benefit of albumin on survival as well as on renal function. Table 38.2 shows the incidence of adverse effects observed in randomized trials comparing therapeutic paracentesis without plasma volume expansion or with three different plasma expanders in patients with cirrhosis and large ascites. In summary, conclusive results from a randomized trial with adequate power to demonstrate a benefit of albumin 621

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Table 38.2 Adverse effects reported in randomized trials assessing the efficacy and safety of therapeutic paracentesis without plasma volume expansion or with different plasma volume expanders in patients with cirrhosis and large ascites. Adverse effect

Renal impairment Ginès et al. [23] Ginès et al. [29] Planas et al. [30] Salerno et al. [31] Fassio et al. [32] Sola-Vera et al. [33] Hyponatremia Ginès et al. [23] Ginès et al. [29] Planas et al. [30] Salerno et al. [31] Fassio et al. [32] Sola-Vera et al. [33]

No. of patients with adverse effects

p

No plasma expander (%)

Polygeline (%)

Dextran-70 (%)

6/531 (11) — — — — —

— 10/100 (10) — 1/27 (4) — —

— 8/93 (9) 1/42 (2) — 1/20 (5)

9/53 (17) — — — —

— 19/100 (19) — 5/27 (18) —

— 23/93 (25) 4/45 (9) — 3/20 (15)

Saline (%)

Albumin (%)

3/21 (14)

0/52 7/97 1/43 1/27 1/21 1/21

4/21 (19)

1/52 (2) 14/97 (14) 3/43 (7) 4/27 (15) 4/21 (19) 0/21 (0)

(0) (7) (2) (4) (5) (5)

0.03 NS NS NS NS 0.02

0.02 NS NS NS NS 0.02

Figures represent the number of patients developing the adverse effect compared with the total number of patients in each treatment group.

administration after therapeutic paracentesis on mortality are not available. However, the currently available data indicate that circulatory dysfunction after removal of large amounts of ascitic fluid is potentially harmful to patients with cirrhosis. Albumin appears to be the plasma expander of choice when more than five liters of ascites are removed.

Diuretics Diuretics eliminate the excess extracellular fluid presenting as ascites and edema by increasing renal sodium excretion, thus achieving a negative sodium balance. The diuretics most frequently used in patients with cirrhosis and ascites are aldosterone antagonists, mainly spironolactone and potassium canrenoate, drugs that selectively antagonize the sodium-retaining effects of aldosterone in the renal collecting tubules, and loop diuretics, especially furosemide, that inhibit the Na+-K+–2Cl− co-transporter in the loop of Henle [34]. Despite the use of diuretics in clinical practice for more than 30 years, few randomized trials have been reported comparing the efficacy of different diuretic agents in the treatment of ascites [34–36]. In patients without renal failure, the aldosterone antagonist spironolactone at a dose of 150 mg/day (increased to 300 mg/day if there was no response) was shown in one randomized trial to be more effective than the loop diuretic furosemide at a dose of 80 mg/day (increased to 160 mg/day if there was no response) [35]. A1d This increased efficacy of aldosterone 622

antagonists has also been suggested in several studies [13, 37–40]. Based on these findings, aldosterone antagonists are considered the diuretics of choice in the management of cirrhotic ascites. In clinical practice, aldosterone antagonists are frequently given in combination with loop diuretics. Theoretical advantages of this combination include greater natriuretic potency, earlier onset of diuresis, and reduced tendency to induce hyperkalemia. Two different regimens of diuretic administration have been proposed. In the first, the dose of aldosterone antagonists is increased progressively (usually up to 400 mg/day of spironolactone) and loop diuretics (furosemide up to 160 mg/day) are added only if no response is achieved with the highest dose of spironolactone. In the second, the two drugs are given in combination from the start of therapy. Both regimens are similar with respect to efficacy and incidence of complications. The only difference is that when the combination of spironolactone and furosemide is used from the beginning of therapy there is a more frequent need to reduce the dose of the drugs in responsive patients compared with the other stepwise regimen [41]. Ald Diuretic therapy is effective in the elimination of ascites in 80–90% of all patients, a percentage that may increase to 95% when only patients without renal failure are considered [13, 16–20, 35–40]. Ald B4 The remaining patients either do not respond to diuretic therapy or develop diuretic-induced adverse effects that prevent the use of high doses of these drugs. This condition is known as refractory ascites [42]. These adverse effects

CHAPTER 38

include hepatic encephalopathy, hyponatremia, renal impairment, potassium disturbances, gynecomastia and muscle cramps [34, 40–43]. The incidence of renal and electrolyte disorders and encephalopathy vary depending on the population of patients studied, and is higher in patients with marked sodium retention and renal failure (who require higher doses of diuretics) and lower in patients with moderate sodium retention and without renal failure. Although some of these complications may be unrelated to diuretic therapy and due to the existence of advanced liver disease [44], there is no doubt that diuretics are a major cause of these complications because their frequency is markedly lower if ascites is removed by therapeutic paracentesis (see Table 38.1). Spironolactone-induced gynecomastia is common and may be important enough to lead to the discontinuation of the drug in some patients. An alternative treatment for these patients is amiloride, although its potency is much lower than that of spironolactone [36]. Ald Eplerenone, a new aldosterone antagonist has fewer endocrine adverse effects compared with spironolactone and could be a good alternative to spironolactone in patients with spironolactone-induced gynecomastia [45]. However, its effectiveness in patients with cirrhosis and ascites has not been assessed. Finally, muscle cramps of variable intensity, sometimes severe, may also occur as an adverse effect of diuretics. Effective therapies for muscle cramps include quinidine (300 mg/day) [46], or albumin (25 g/week) [43]. Zinc sulfate (440 mg/day) also appeared effective in an uncontrolled study including a small number of patients [47]. B4 Because therapeutic paracentesis has replaced diuretics as the treatment of choice for hospitalized cirrhotic patients with large volume ascites in most centers, at present the main indications for use of diuretics in cirrhosis are as follows [15]: • Treatment of patients with mild or moderate ascites or those with large volume ascites in whom paracentesis is not effective because of compartmentalization of ascitic fluid due to peritoneal adhesions. • Treatment of patients with edema without ascites. • Prevention of recurrence of ascites after therapeutic paracentesis.

Peritoneovenous shunt A peritoneovenous shunt is a device designed to transfer ascitic fluid from the abdominal cavity to the systemic circulation via an abdominal tube and a thoracic tube ending in the superior vena cava connected through a one-way valve. This device was used extensively in the 1970s and 1980s for the treatment of refractory ascites in cirrhosis. Although the system was pathophysiologically sound, its use declined progressively during the 1990s due to a high incidence of severe adverse effects, a high rate of obstruc-

Ascites, hepatorenal syndrome, peritonitis

tion, lack of demonstration of a significant survival benefit, and development of new procedures, such as the transjugular intrahepatic portosystemic shunt (TIPS) [48–54]. For all these reasons, this procedure is rarely used nowadays.

Transjugular intrahepatic portosystemic shunt TIPS was introduced in clinical practice in the 1990s for the management of refractory variceal bleeding, with the objective of creating a portosystemic shunt, without the need of surgery. The procedure consists of the placement of an intrahepatic stent between one hepatic vein and the portal vein using a transjugular approach [55]. It soon became evident that in patients with variceal bleeding and ascites treated with TIPS there was an increased natriuretic effect of diuretics, leading to the reduction or elimination of ascites in most patients. These beneficial effects of TIPS on ascites are similar to those reported in earlier studies in patients treated with surgical portosystemic shunts, especially side-to-side portacaval shunts. A large number of uncontrolled studies have shown that TIPS is effective in preventing recurrence of ascites in patients with refractory ascites. This effect is due to reduction in the activity of sodium-retaining mechanisms and amelioration of renal function, which lead to an improvement of the renal response to diuretics [56–61]. B4 The main disadvantages of TIPS include shunt stenosis or obstruction (up to 75% of patients develop stenosis within 6–12 months, leading to reaccumulation of ascites in most cases), but this has been reduced with covered stents. In addition, there is a high rate of encephalopathy due to the shunting of blood from the splanchnic to the systemic circulation [62, 63]. Other adverse effects include impairment in liver function, which is usually transient, hemolytic anemia and heart failure [55, 64]. Because of its efficacy and the paucity of good alternative therapies (except for that of repeated large-volume paracentesis with concomitant administration of intravenous albumin), TIPS became a widely used treatment for patients with refractory ascites during the 1990s despite the initial lack of randomized controlled trials comparing it with medical therapy. Five randomized trials comparing uncovered TIPS versus repeated large volume paracentesis with concomitant intravenous albumin in patients with cirrhosis and refractory ascites have been published [65–69]. Alc The trials demonstrate that TIPS controls ascites effectively and is associated with a lower rate of ascites recurrence. The main results of these trials are summarized in Table 38.3. Although there are some discrepancies between the results of the trials these studies demonstrate the following: • TIPS is clearly more effective than large volume paracentesis in the prevention of recurrence of ascites [65–69]. However, normalization of renal sodium homeostasis is 623

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Table 38.3 Complications and survival in randomized trials comparing transjugular intrahepatic portosystemic shunt (TIPS) and large volume paracentesis in patients with cirrhosis and refractory ascites. Study

TIPS

Paracentesisa

p

Recurrent ascites Lebrec et al. [65] Rössle et al. [66] Ginès et al. [67] Sanyal et al. [68] Salerno et al. [69]

5/10 (50)b 3/23 (13) 17/35 (49) 22/52 (42) 13/33 (39)

12/12 15/22 29/35 48/57 32/33

< < < <
1.5 mg/dl (133 μmol/l). (3) No improvement of serum creatinine (decrease to a level lower than 1.5 mg/dl–133 μmol/l– after at least two days off diuretics and volume expansion with albumin (1 g/kg body weight up to a maximum of 100 g/day). (4) Absence of shock. (5) No current or recent treatment with nephrotoxic drugs. (6) Absence of signs of parenchymal renal disease, as suggested by proteinuria (>500 mg/day) or hematuria ( 1.5 mg/dl in the absence of diuretic therapy) and the exclusion of other causes of renal failure that may occur in patients with cirrhosis (see Box 38.3) [42, 78]. For many years, no effective therapy existed for patients with hepatorenal syndrome, except for liver transplantation. Recently, several effective, new interventions have been introduced.

Vasoconstrictors A number of observational studies published in the 1990s showed that the administration of vasoconstrictor drugs to patients with cirrhosis and hepatorenal syndrome causes a marked improvement of renal function in a large proportion of patients [80–92]. B4, C5 The rationale for the use of vasoconstrictors in patients with hepatorenal syndrome is to improve effective arterial blood volume by causing a vasoconstriction of the extremely dilated splanchnic vascular bed. The improvement in the arterial circulatory function leads to a suppression in the activity of vasoconstrictor systems and a subsequent increase in renal perfusion and glomerular filtration rate. Two types of vasoconstrictor drugs have been used in patients with hepatorenal syndrome: vasopressin ana626

logues (terlipressin and ornipressin) andα-adrenergic agonists (norepinephrine, noradrenaline and midodrine), which act on V1 vasopressin receptors and α1-adrenergic receptors, respectively, present in the smooth muscle cells of the vessel wall. The drug most frequently used in published studies is terlipressin, which is marketed in many countries for the indication of acute variceal bleeding in cirrhosis. In most studies terlipressin has been combined with intravenous albumin to further improve the arterial underfilling. Ornipressin is no longer available and there is limited information on the efficacy of α-adrenergic agonists [89-92]. There are four randomized placebo controlled trials investigating the efficacy and safety of terlipressin and albumin in patients with hepatorenal syndrome [93– 96]. Alc The information currently available on terlipressin can be summarized as follows: (1) In uncontrolled trials, the administration of terlipressin improves renal function in 50–75% of patients [82–88]. Although there are no dose-efficacy studies, treatment is usually started with 1 mg/4–6 h IV, and the dose is increased up to a maximum of 2 mg/4–6 h after two days if there is no response to therapy as defined by a reduction of serum creatinine > 25% of pre-treatment values. (2) Results from two large randomized placebo controlled studies indicate that treatment with terlipressin together with albumin is associated with marked improvement of renal function in approximately 40% of patients [93, 94]. A1c The overall population of patients treated with terlipressin and albumin in these two studies did not have an improved survival compared to that of patients treated with albumin alone. However, both studies showed that responders in terms of improvement of renal function after therapy had a significant (but moderate) increase in survival compared to non-responders [93, 94]. A1c A summary of the results of the four randomized studies are shown in Table 38.4 [93–96]. (3) In most studies, treatment with terlipressin is usually maintained until serum creatinine decreases below 1.5 mg/ dl or for a maximum of 15 days. It is unknown whether the continued administration of the drug after the endpoint of 1.5 mg/dl of serum creatinine has been reached may cause a further improvement of renal function. (4) The incidence of ischemic side effects requiring the discontinuation of treatment is approximately 10%. Some patients may develop myocardial ischemia, arrhythmia, intestinal ischemia or transient pulmonary edema during the first few days of therapy [82–88, 93–96]. Therefore, patients with HRS treated with terlipressin should be closely followed with cardiac monitoring, ideally in semiintensive or intensive care unit, and if signs of cardiovascular disturbances develop, terlipressin should be discontinued promptly. (5) A consistent finding in all studies is that the recurrence of hepatorenal syndrome after treatment withdrawal is

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Table 38.4 Response rate, survival, recurrence, and adverse effects in patients with cirrhosis and hepatorenal syndrome treated with terlipressin and albumin in randomized controlled trials. Response (ref)

Terlipressin/ Albumin (%)

Response Sanyal et al. [93] Martin-Llahi et al. [94] Solanki et al. [95] Neri et al. [96]

19/56(34) 10/23 (44) 5/12 (42) 21/26(80)

Survival Sanyal et al. [93]a Martin-Llahi et al. [94]b Solanki et al. [95]c Neri et al. [96]b

24/56 6/23 5/12 14/26

Recurrence Sanyal et al. [93] Martin-Llahi et al. [94] Solanki et al. [95]c Neri et al. [96]b Adverse effects Sanyal et al. [93] Martin-Llahi et al. [94]d Solanki et al. [95] Neri et al. [96]

Placebo/ Albumin (%)

p

7/56 (12.5) 2/23(9) 0/12 5/26(19)

0.08 0.01 0.001 0.001

21/56 (37.5) 4/23 (19) 0/15 4/26 (18)

0.84 0.7 NR NR

1/19 (5) 1/10 (10) NR NR

1/5(14) NR NR NR

NR — — —

18/56 (32) 10/23 (43) 2/12 (16) 9/26

12/56 (22) 4/23 (17) 0/12 0/26

NR 0.10 NR NR

(43) (27) (41) (54)

a

Survival at 180 days. Survival at 90 days. c Survival at 15 days. d Myocardial ischemia, arrhythmia, intestinal ischemia, circulatory overload. NR: not reported. b

uncommon (approximately 5–15% of patients) (Table 38.4). The explanation for this low recurrence rate is unknown. Treatment of recurrence is usually effective. (6) The above observations refer mainly to type 1 hepatorenal syndrome, as the majority of patients included in the published studies were in this category. Although some reports suggest that vasoconstrictors also improve renal function in patients with type 2 hepatorenal syndrome, their efficacy in this setting remains to be confirmed [94].

Transjugular intrahepatic portosystemic shunt There is limited information on the effects of TIPS in patients with type 1 hepatorenal syndrome. Two uncontrolled studies reported that TIPS improves renal function in patients with this syndrome [97, 98]. B4 Improvement in renal function after TIPS placement alone is slow and successful in approximately 60% of patients. Median survival after TIPS in patients with type 1 HRS ranges between

Ascites, hepatorenal syndrome, peritonitis

two and four months. Studies assessing TIPS for type 1 HRS have included patients with preserved liver function and excluded those with a history of hepatic encephalopathy, Child-Pugh scores ≥ 12 or serum bilirubin > 5 mg/dl. The applicability of TIPS in patients with type 1 HRS is low because TIPS is considered contraindicated in patients with severe liver failure (high serum bilirubin levels and/or Child-Pugh score greater than 12) and hepatic encephalopathy, which are common findings in the setting of type 1 HRS. No studies have been reported that compared TIPS with vasoconstrictor drugs in patients with type 1 hepatorenal syndrome. There have been no specific studies assessing the efficacy of TIPS in type 2 hepatorenal syndrome. However, in a subgroup analysis of patients with refractory ascites and type 2 hepatorenal syndrome included in one randomized trial, TIPS reduced the recurrence rate of ascites and the risk of progression from type 2 to type 1 hepatorenal syndrome, but did not improve survival compared to control patients treated with repeated therapeutic paracentesis with intravenous albumin [67]. Ald

Other therapeutic methods Hemodialysis or continuous hemodiafiltration are frequently used in the management of type 1 hepatorenal syndrome in many centers, particularly in patients who are candidates for liver transplantation, with the aim of preventing the complications associated with acute renal failure and maintaining patients alive until transplantation is done [99]. Complications during hemodialysis in these patients are common and include arterial hypotension, bleeding and infections. On the other hand, clinical or biochemical features indicating the need for renal replacement therapy, such as heart or respiratory failure, severe acidosis or severe hyperkalemia are uncommon, at least in early stages of type 1 hepatorenal syndrome. In contrast, these features are usually seen in patients with cirrhosis and acute renal failure caused by conditions other than hepatorenal syndrome, especially acute tubular necrosis due to septic or hemorrhagic shock and acute glomerulonephritis. Considering all these facts and the efficacy of measures aimed at improving circulatory function (especially vasoconstrictors), the use of hemodialysis or continuous hemodiafiltration in the management of patients with hepatorenal syndrome needs to be re-evaluated and perhaps used as a second-line therapy for those patients not responding to vasoconstrictors. Recently, a new method of dialysis, the extracorporeal albumin dialysis or molecular adsorbent recirculating system (MARS), a system that uses an albumin-containing dialysate that is used to remove albuminbound and water-soluble toxic metabolites, has been reported to improve renal function and survival in a small uncontrolled study in patients with hepatorenal syndrome 627

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[100]. B4 These promising results, however, require confirmation.

Liver transplantation Liver transplantation is the only definitive treatment for patients with hepatorenal syndrome without contraindications to the procedure [101]. Even patients showing a complete response to vasoconstrictors or TIPS with normalization of serum creatinine have a poor prognosis if not transplanted [85, 86, 93, 94]. B4 A1c Main causes of death in these patients include liver failure and/or bacterial infections [85, 86]. Ideally, patients with hepatorenal syndrome should be prioritized for liver transplantation due to the high mortality rate; otherwise, most patients may die while awaiting liver transplantation. The implemented system of organ allocation in the USA based on the MELD score may be useful in this respect, because it includes serum creatinine in addition to parameters of liver function (bilirubin and INR) [75, 102]. Therefore, patients with hepatorenal syndrome usually achieve high values in the MELD score and may receive transplants within a short period of time. In addition to prioritization, these patients should probably be treated with vasoconstrictors, whenever possible, while awaiting transplantation in order to improve renal function and maintain life while they are on the waiting list. The reversal of HRS before transplantation may help patients not only reach transplantation, but also reduce the relatively high morbidity and mortality after liver transplantation characteristic of HRS [103, 104]. A small study indicates that patients with hepatorenal syndrome treated with vasopressin analogues before transplantation have a complication rate and short-term and long-term survival which are not different from those observed in transplant patients without hepatorenal syndrome [105].

Dilutional hyponatremia Patients with advanced cirrhosis often develop spontaneous dilutional hyponatremia due to impairment of the renal excretion of free water. This disorder always occurs in the setting of ascites with severe sodium retention, and most patients have poor or no response to diuretics [106]. In this condition, renal retention of solute-free water is disproportionate to that of sodium retained and serum sodium levels decrease despite the existence of increased total body sodium. Dilutional hyponatremia in cirrhosis is defined as a reduction in serum sodium concentration below 130 mEq/l in the setting of ascites and/or edema [106]. C5 The impaired solute-free water excretion is due to high circulating levels of vasopressin (antidiuretic hormone) secondary to a hypersecretion of the hormone from the neurohypophysis triggered by a non-osmotic (vasoactive) stimulus [107, 108]. The clinical consequences of dilutional hyponatremia are incompletely understood, 628

but it has been linked to some neurological and non-neurological symptoms seen frequently in patients with advanced cirrhosis. Dilutional hyponatremia impairs the quality of life of patients with cirrhosis because it requires the restriction of fluid intake to a level similar to that of urine output in order to prevent a positive fluid balance that would lead to a further increase in total body water and impairment of hyponatremia. There is no effective therapy currently available in clinical practice to treat spontaneous dilutional hyponatremia. Fluid restriction is effective in preventing further reduction of serum sodium concentration but usually is not followed by an increase in serum sodium. The administration of hypertonic saline solutions does not make much sense from a pathophysiological perspective, because total body sodium and extracellular fluid volume are increased in patients with dilutional hyponatremia. It invariably leads to marked increase in ascites and edema and has only modest effects on serum sodium concentration and therefore is not recommended. There are anecdotal reports of the efficacy of albumin infusions, but this remains to be proved in larger series [109]. B4 In recent years, several orally active drugs, the so-called vaptans, that selectively antagonize the vasopressin V2 receptor (the receptor present in collecting duct cells in the kidney responsible for water reabsorption in the distal parts of the nephron), have been developed [108, 110]. C5 The rationale behind the use of these drugs in patients with cirrhosis and dilutional hyponatremia is to selectively antagonize the effects of vasopressin in the kidney so that solute-free water excretion is increased, the abnormal water balance restored, the increased body water reduced, and serum sodium concentration normalized [108]. C5 So far, the results of a few phase II and III studies in patients with cirrhosis have confirmed the beneficial effects of these drugs. Two multicenter, randomized, placebo-controlled trials evaluated the use of lixivaptan in cirrhotic patients with dilutional hyponatremia [111, 112] A1c In these two studies this agent caused a dose-related increase in serum sodium levels and solute-free water clearance. Unfortunately, the drug caused significant dehydration in some patients at the effective doses in one study [111]. In the other study, which evaluated two doses of the drug versus placebo, a small amount of patients in each group was included and the effects of lixivaptan were only evaluated until serum sodium normalized, without information on long-term response [112]. A large multicenter randomized controlled study evaluating the use of tolvaptan in patients with euvolemic or hypervolemic hyponatremia (SIADH, congestive heart failure and cirrhosis) indicates that this agent is effective in raising serum sodium concentration when used for 30 days [113]. A1c In this study, a subgroup of patients with cirrhosis and dilutional hyponatremia were assigned tolvaptan or placebo in ascending doses according to response [113].

CHAPTER 38

A1c There were no significant side effects compared to placebo. Tolvaptan rapidly improved serum sodium, fluid balance and caused significant weight loss in patients with cirrhosis and hyponatremia compared to placebo and markedly increased solute-free water clearance without adversely affecting renal function. In patients with cirrhosis and dilutional hyponatremia, normalization of sodium levels (>135 mEq/l) occurred in 30% and 22% of subjects at days 4 and 30 respectively [113]. This agent therefore seems to be safe, effective and is likely to be promising in the treatment of dilutional hyponatremia. Another multicenter randomized study evaluated short- term use (14 days) of satavaptan at doses of 5 mg, 12.5 mg, 25 mg once daily in 110 patients with cirrhosis and hyponatremia receiving 100 mg of spironolactone [114]. A1c Satavaptan treatment was associated with improved control of ascites (measured by a reduction in body weight) and a reduction in abdominal girth. This beneficial effect on ascites was associated with improvements in serum sodium in all patients. A major side effect was thirst in the satavaptan group, and in a few patients a large volume diuresis of 5 liters or more in less than 24 hours. V2 receptor antagonists seem to not only improve ascites control, but also increase serum sodium in patients with cirrhosis, ascites and hyponatremia on diuretics. Although a number of issues remain to be answered about the efficacy, clinical usefulness, tolerability, drug interactions and adverse effects of vaptans, they represent a powerful pharmacological tool for the management of patients with advanced cirrhosis and dilutional hyponatremia.

Spontaneous bacterial peritonitis Spontaneous bacterial peritonitis is a common and severe complication in cirrhotic patients with ascites characterized by infection of ascitic fluid with no apparent intra-abdominal source of infection [4, 5]. Spontaneous bacterial peritonitis is generally caused by Gram-negative bacteria from the intestinal flora, especially Escherichia coli. However, Gram-positive cocci, particularly Staphylococcus aureus, are being isolated with increasing frequency, mainly in hospitalized patients [115–117]. The diagnosis of spontaneous bacterial peritonitis is based on the demonstration of an absolute number of polymorphonuclear cells in ascitic fluid greater than 250/mm3 [5]. C5 The clinical spectrum is very variable and ranges from complete absence of symptoms to a classic clinical picture of peritonitis [4, 5, 118]. For this reason and because of its high prevalence, spontaneous bacterial peritonitis should be ruled out in patients with cirrhosis admitted to hospital with ascites, outpatients undergoing large volume paracentesis, and hospitalized patients who develop signs and/or symptoms suggestive

Ascites, hepatorenal syndrome, peritonitis

of peritoneal or systemic infection (i.e. abdominal pain, rebound tenderness, ileus, fever, leukocytosis, shock), hepatic encephalopathy or impairment in renal function [5, 118]. Cirrhotic patients with hydrothorax may also develop a spontaneous infection of pleural fluid that is pathogenically similar to spontaneous bacterial peritonitis and should be managed in a similar fashion [119].

Therapy Antibiotic therapy should be started whenever the polymorphonuclear count in ascitic fluid is greater than 250/ mm3 and before obtaining microbiological culture results [5]. C5 Third-generation cephalosporins are the antibiotics of choice as initial empiric treatment for spontaneous bacterial peritonitis, because of their broad antibacterial spectrum, high efficacy and safety [5, 120–123]. Alc Resolution of infection occurs in up to 90% of patients. Cefotaxime (2 g/8–12 hours) has been the drug most commonly used in randomized trials, but other third-generation cephalosporins have similar efficacy [124]. Alc Cefotaxime has been shown to be more effective than other antibiotics, such as aztreonam or the combination of aminoglycosides plus ampicillin [120–125]. Amoxicillin-clavulinic acid is as effective as third-generation cephalosporins [126]. Quinolones (ofloxacin, ciprofloxacin) administered orally are also effective and may be an alternative to third-generation cephalosporins or amoxicillinclavulanic acid except in patients who are severely ill (i.e. septic shock, severe renal failure) or with complications that may impair the absorption of the drug (gastrointestinal hemorrhage or ileus) [127]. Alc Given the increased frequency of Grampositive cocci isolates in nosocomial spontaneous bacterial peritonitis, the empiric antibiotic treatment for this condition should probably include an antibiotic active against these bacteria, particularly S. aureus, until the results of ascitic fluid or blood cultures are available [115–117]. C5 Antibiotic therapy is maintained until the complete disappearance of all signs of infection and decrease of polymorphonuclear count in ascitic fluid below the threshold value of 250/mm3. In most patients, resolution is achieved in a short period of time, usually less than six days. The development of hepatorenal syndrome, which is one of the most common and severe complications of spontaneous bacterial peritonitis can be effectively prevented by the administration of albumin together with the antibiotic therapy [79, 128]. B4 The incidence of hepatorenal syndrome is markedly lower in patients receiving albumin plus antibiotics compared with patients receiving antibiotics alone. The prevention of hepatorenal syndrome achieved by administration of albumin improves survival of these patients [128]. B4 This may be particularly important for liver transplant candidates. The beneficial effect of albumin is probably related to its capacity to prevent the 629

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BOX 38. 4 Recommendations for the management of

spontaneous bacterial peritonitis (1) After diagnosis of peritonitis has been made (>250 polymorphonuclear cells/mm3 in ascitic fluid), start with third-generation cephalosporins (i.e. cefotaxime 2 g/8–12 hourly intravenously or ceftriaxone 1 g/24 hours intravenously) or amoxicillin-clavulinic acid (500 mg/125 mg/8 hourly intravenously). In patients on antibiotic prophylaxis, third-generation cephalosporins are the treatment of choice. In nosocomial spontaneous bacterial peritonitis, consider the addition of an antibiotic active against Gram-positive cocci. (2) Give albumin 1.5 g/kg intravenously at the time of diagnosis of the infection and 1 g/kg 48 hours later. (3) Maintain antibiotic therapy until disappearance of signs of infection and reduction of polymorphonuclear cells in ascitic fluid below 250/mm3. (4) After resolution of infection, start long-term norfloxacin 400 mg/day per os (orally).

reduction in the effective arterial blood volume and subsequent activation of vasoconstrictor systems that occurs during the infection. Recommendations for the management of spontaneous bacterial peritonitis are summarized in Box 38.4. Hospital mortality in patients with spontaneous bacterial peritonitis was around 30% in most series published during the 1980s and 1990s. In the series that included patients treated with intravenous albumin, hospital mortality has decreased to 10–15% [128]. Advanced liver failure and associated complications (i.e. gastrointestinal hemorrhage, hepatorenal syndrome) are the main causes of death in these patients. As previously discussed, the most important predictor of survival in patients with spontaneous bacterial peritonitis is the development of hepatorenal syndrome during the infection [79, 128]. Long-term prognosis of patients who have recovered from an episode of spontaneous bacterial peritonitis is poor, and patients should be evaluated for liver transplantation. Recurrent spontaneous bacterial peritonitis is very common in these patients and constitutes a major cause of death [4].

Prophylaxis The identification of subsets of patients with an increased risk of developing spontaneous bacterial peritonitis has stimulated the search for interventions to prevent the development of this complication. Conditions associated with an increased risk of spontaneous bacterial peritonitis include: gastrointestinal bleeding, low protein concentration in ascitic fluid, advanced liver failure (high serum bilirubin and/or markedly prolonged prothrombin time), and past history of spontaneous bacterial peritonitis [4, 5]. Because 630

most episodes are caused by Gram-negative bacteria present in the normal intestinal flora, the rationale for the prophylaxis of spontaneous bacterial peritonitis has been based mainly on the administration of antibiotics that produce a selective decontamination of the gastrointestinal tract, with elimination of aerobic Gram-negative bacteria without affecting aerobic Gram-positive bacteria and anaerobes. The efficacy of this approach has been demonstrated in patients with gastrointestinal hemorrhage and in patients who have recovered from the first spontaneous bacterial peritonitis episode (see Table 38.5) [129–136]. Alc In patients with gastrointestinal hemorrhage, the short-term administration of norfloxacin markedly reduces the incidence of spontaneous bacterial peritonitis or bacteremia as compared with patients not receiving prophylactic antibiotics [130]. In patients with advanced liver disease who are actively bleeding, intravenous ceftriaxone (1 g/day for seven days) is the preferred dose due to problems with oral absorption in this setting [133]. A1c Other effective approaches consist of the administration of parenteral antibiotics, such as ofloxacin or the combination of ciprofloxacin and amoxicillin-clavulinic acid [131, 132]. B4 The absolute risk reduction in four trials of antibiotic prophylaxis in patients with gastrointestinal hemorrhage ranges from 9% to 23%. The results of a meta-analysis indicate that antibiotic prophylaxis in patients with gastrointestinal bleeding not only prevents infection but also improves survival [134, 135] Alc Long-term norfloxacin administration is very effective in the prevention of spontaneous bacterial peritonitis recurrence (Table 38.5) [136]. This approach is effective and is recommended to prevent recurrence in patients who have recovered from an initial episode [5, 136]. Ald Antibiotic prophylaxis (norfloxacin, ciprofloxacin, or trimethoprimsulfamethoxazole) also appears to be effective in the prevention of the first episode of spontaneous bacterial peritonitis (primary prophylaxis) in patients with low ascitic fluid protein (90 >90

a All patients were on neomycin. HR, hepatorenal syndrome; RF, respiratory failure; MOF, multiorgan failure; BCAA, branched chain amino acids; MHE, minimal hepatic encephalopathy.

function than either conventional clinical assessment or the EEG [16]. However, the tests are cumbersome, and when applied repeatedly the reliability of most of them is adversely affected by the learning effect. Few are useful in routine practice. The most frequently applied test is the number connection test [14, 16]. This test is easily administered and the results can be quickly quantified. One important consequence of the application of psychometric tests in cirrhotic patients was the finding that even patients with apparently normal mental status have a measurable deficit in their intellectual performance [13]. These patients are usually referred to as suffering from “minimal HE” or 638

“stage 0 HE”. However, psychometric tests may overdiagnose minimal HE, because scores are usually not corrected for age [14, 18]. Furthermore, it is unknown whether abnormalities of test results correlate with impaired quality of life or performance in daily life [18]. On the contrary, the driving ability of patients with test results classifying them as “unable to drive a car” [15] was not different from that of healthy controls. A quality-of-life questionnaire (sickness impact profile (SIP)) detects the extent and frequency of deficits in daily functioning in patients without clinically apparent HE. From the 136 statements, five were selected as predictive of minimal HE [18].

CHAPTER 39

A standardized prospectively developed test battery that includes the NCT A and B, the line tracing test, the serial dotting test and the digit symbol test was recommended by the working party to be used in future studies [2]. This test (PHES) can be applied at the bedside and performed within 10–20 minutes and examines visual perception, visuo-spatial orientation, visual construction, motor speed and accuracy, and is also sensitive against disturbances of concentration, attention and working memory. Each individual test and the whole battery has been standardized in a large group of healthy controls (including all ages). A composite score of the single test results was calculated. Each of the individual test results was scored 0 points in the ± 1 SD range from the mean. Thereby, subjects can achieve between +6 and −18 points. When a cutoff between normal and pathological results was set at −4 points, only 1 (0.9%) of the controls, 25% of cirrhotic patients without clinical evidence of HE, but all patients with grade I HE achieved pathological results. B2 The test has a high specificity for HE as compared with other metabolic encephalopathies [19, 20].

Electrophysiological tests The simplest EEG assessment of HE is to grade the degree of abnormality of the conventional EEG trace. A more refined assessment by computer assisted techniques allows variables in the EEG such as the mean dominant EEG frequency and the power of a particular EEG rhythm to be quantified. Evoked responses (by visual, somatosensory, or acoustic stimuli) or event related responses, like the P300 peak after auditory stimuli, are sensitive to detect subtle changes of brain function and can be used for diagnosis of minimal HE [20].

Critical flicker frequency Retinal glial cells are involved in ammonia detoxification by glutamine synthesis. In patients with liver failure, they exhibit morphological changes similar to those observed in brain astrocytes, suggesting that retinal gliopathy could serve as a marker of cerebral gliopathy in patients with hepatic encephalopathy. These observations provided the rationale for the development of a visual test (the critical flicker/fusion frequency) for determining whether hepatic encephalopathy is present. Initial experience suggests that the critical flicker/fusion frequency may be a highly objective and sensitive measure of minimal hepatic encephalopathy [21, 22, 23].

Diagnosis of minimal hepatic encephalopathy One important consequence of the application of psychometric tests in patients with cirrhosis was the finding that even patients with apparently normal mental status have

Hepatic encephalopathy

some form of a measurable deficit in their intellectual performance, long-term memory, and learning capability [15, 24]. These patients are usually referred to as “minimal HE” or “stage 0 HE”. Up to 15% of patients with cirrhosis have minimal HE when defined by the presence of a prolonged NCT or an abnormal EEG [25]. Several approaches are being studied to evaluate for minimal hepatic encephalopathy. At present, none is used routinely in clinical practice. One study comparing the Psychometric Hepatic Encephalopathy Score (PHES) with an EEG in 100 patients with cirrhosis found agreement in detection of MHE in only 73% [26]. The poor correlation may reflect differences in how these tests detect various features of MHE. The Inhibitory Control Test (ICT) is a computerized test of attention and response inhibition that has been used to characterize attention deficit disorder, schizophrenia and traumatic brain injury. The subject is instructed only to respond to two alternating letters (X/Y) (called “targets”) and not to respond when they are not alternating (called “lures”). Lower lure responses, higher target responses, and shorter lure and target reaction times indicate good psychometric performance. A study comparing ICT to a psychometric battery of tests for MHE diagnosis in 136 patients estimated sensitivity for MHE to be 88% [27]. Patients with MHE had significantly higher ICT lures and lower targets compared to patients without MHE. The PHES was compared with a comprehensive computerized assessment (Cognitive Drug Research [CDR]) of cognitive function in 89 patients with cirrhosis [28]. There was a high correlation between the two assessment methods. The MELD score correlated with PHES. In contrast, the CDR domains Continuity of Attention and Quality of Episodic Memory were significantly related to venous blood ammonia levels. There were marked deteriorations in the CDR composite scores representing Accuracy of Working and Episodic Memory after amino acid challenge to increase blood ammonia. Both PHES and CDRS returned to the control range after liver transplantation. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) measures a wide range of neurocognitive functions relevant to MHE. The test has been used in multiple clinical trials in the USA for a variety of neurologic disorders and in patients with advanced cirrhosis [29]. The RBANS has not yet been compared directly with the PHES, and its responsiveness to hepatic encephalopathy treatment is unknown. A concern in patients with minimal hepatic encephalopathy is whether they are at increased risk for driving accidents. Studies evaluating this question have produced disparate conclusions. At least three reports concluded that 44–60% of patients with advanced liver disease (but without overt clinical signs of HE) were unfit to drive based upon the results of extensive batteries of neuropsychologic tests 639

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[1, 21, 22]. In one study, for example, 40 patients with chronic liver disease and portal hypertension without clinical signs of portasystemic encephalopathy were given the same extensive psychometric tests typically used for expert reports on driving capacity [15]. Sixty percent of patients were considered to be unfit to drive, and 25% were considered to be questionable. The total driving score of patients with minimal hepatic encephalopathy was significantly reduced compared with controls or cirrhotic patients without minimal hepatic encephalopathy [30]. A later report found that patients with minimal hepatic encephalopathy had poor insight into their driving skills [31].

tinal bleeding, increased protein intake, hypokalemic alkalosis, infection, and constipation (all of which increase arterial ammonia levels), hypoxia, and the use of sedatives and tranquilizers. Patients with advanced cirrhosis may be particularly sensitive to benzodiazepines. Treatment of these precipitating events is typically associated with a prompt and permanent improvement of HE. As a result, every attempt should be made to identify and to treat such precipitating events. This approach has never been tested formally but is based on common clinical experience. As judged from the outcomes observed in placebo groups of controlled studies (see Table 39.3) standard medical care is highly effective.

Evidence-based medicine and hepatic encephalopathy

Enemas

Evidence based medicine is a process of systematically finding, appraising, and using research findings as the basis for clinical decisions [32] based on the formulation of relevant questions concerning a patient’s problem. The answer to the question “Does treatment with specific drugs, compared to placebo, improve HE?” should be addressed separately for overt and subclinical HE. In the following sections we have identified the studies that attempt to answer this question and we have critically appraised the evidence for the most important treatment regimens. The magnitude of the treatment effect of various interventions has been assessed. This assessment is difficult in HE because of the use of different methods which are not readily comparable for quantifying the severity of this disease. The question of the clinical applicability and generalizability of the findings of randomized controlled studies in HE must be addressed in the context of the treatment and the grade of encephalopathy studied. To identify all randomized controlled trials in HE, a Medline search was conducted using several terms. A total of 50 randomized trials had the endpoint “improvement of HE” and included more than ten patients per study group (see Table 39.5). In addition, two meta-analyses have been published [33, 34].

Treatment of hepatic encephalopathy Clinically overt he (grade I–IV) in patients with cirrhosis Supportive care and treatment of precipitating causes of HE It is important to recognize that HE, acute and chronic, is reversible and that a precipitating cause rather than worsening of hepatocellular function can be identified in the majority of patients [1, 2].These causes include gastrointes640

Cleansing of the colon by enemas is a rapid and effective procedure to remove ammoniagenic substrates. The efficacy of enemas of 1–3 liters of 20% lactulose or lactitol solutions was proven in randomized controlled trials; a favorable response was noted in 78–86% of patients (ARR 0.4%, NNT = 2.5) [35, 36]. A1d Interestingly, enemas with tap water were ineffective, raising the possibility that colonic acidification rather than bowel cleansing was the effective therapeutic mechanism.

Nutrition Patients with grade III–IV HE usually do not receive oral nutrition. In general, there is no need for parenteral nutrition if patients improve within two days. Based on the “false neurotransmitter hypothesis”, total parenteral nutrition with specific amino acid solutions has been proposed. A number of randomized controlled studies have evaluated the use of solutions with a high content of branched chain amino acids (BCAA) and a low content of aromatic amino acids (AAA). These studies differ with respect to the amino acid solutions used, the study protocols, patient selection and the duration of treatment, and are difficult to compare. The results have been conflicting, but most studies did not find any improvement in HE or any reduction in mortality in patients treated with BCAA [37, 38]. Although a meta-analysis revealed a significant trend toward improvement in these outcomes, it was concluded that further randomized controlled trials are needed [34]. At present, infusions of modified amino acid solutions should not be used in the standard treatment of patients with HE. A1c There is no proven need for a specific diet for patients with HE. Although mentioned in all textbooks, the recommendation of a low protein diet in patients with advanced liver disease is not supported by good clinical or experimental evidence. On the contrary, in patients with alcoholic hepatitis, low protein intake is associated with worsening HE, while a higher protein intake correlates with improvement in HE [39]. The recommendations of the

CHAPTER 39

Hepatic encephalopathy

Table 39.5 Randomized trials with endpoint “improvement of HE”. Test drug

Flumazenil BCAA IV BCAA oral Lactulose Lactitol Neomycin Lactulose + neomycin Lactulose/lactose enemas LOLA Zinc Benzoate L-Dopa Rifaximine SF-68 Acarbose L-Carnitin Probiotics Total a

Control

Total

Placebo

Standard therapya

Lactulose/lactitol

Neomycin

7 4 2 5 — 1 1 1 2 — — 1 — — 1 1 1 27

— 2 — 1 — — — — — 2 — — — — — 1 1 7

— — — — — — — — 1 — 1 — 2 1 — 1 — 6

— — — 3 3 — — 1 — — — 2 — —

9

7 6 2 9 3 1 1 2 3 2 1 1 4 + 1 dose finding study 1 1 3 2 49 + 1

Usually includes lactulose or neomycin.

European Society of Parenteral and Enteral Nutrition (ESPEN) are that oral protein intake should not exceed 70 g/day in a patient with a history of HE; a level below 70 g/day is rarely necessary and minimum intake should not be lower than 40 g/day to avoid negative nitrogen balance [40]. C5

Pharmacotherapy Flumazenil Based upon the GABA-benzodiazepine hypothesis of the pathogenesis of HE, the benzodiazepine receptor antagonist flumazenil has been tested for treatment of HE in five randomized placebo controlled trials involving over 600 patients. Four were crossover trials, and one used a parallel group design. Flumazenil was superior to placebo in four of these studies (Table 39.5). In the only large double-blind, placebo controlled crossover trial 537 cirrhotic patients with grade III (265 patients) or IVa (262 patients) hepatic encephalopathy were randomized to receive intravenous flumazenil or a placebo over a 3–5 minute period [3]. Patients subsequently received the other study medication if they were still in grade III or IVa encephalopathy after the first study period. Treatment was begun within 15 minutes of randomization. Outcome measures included both a neurological score and a grading derived from con-

tinuous EEG recordings. Table 39.6 shows the results obtained by combining the scores from the initial and crossover period. Improvement of the neurological score was documented in 46 of grade III and in 39 of grade IVa patients during the combined flumazenil treatment periods and in 10 (Grade III) and 3 (Grade IVa) of the patients during placebo treatment periods. Improvement of the EEG score occurred in 73 (Grade III) and 57 (Grade IVa) patients during flumazenil treatment and 13 (Grade III) and 9 (Grade IVa) patients during placebo treatment. The effects of flumazenil were statistically significant (p < 0.01). A1d In the second study [41], 24 of 49 randomized patients were excluded from the final analysis, mainly due to inadequate benzodiazepine screening. However, flumazenil was superior to placebo even when the data were evaluated by intention-to-treat analysis; among the 25 patients who were not excluded, clinically relevant improvement was seen in 35% compared to 0% in patients given placebo. A1d In the Canadian trial, very strict exclusion criteria resulted in the rejection of 56 of 77 potential patients [42]. Improvement in neurological symptoms was observed in 6 of 11 flumazenil treatment periods compared to 0 of 10 placebo periods; a few patients showed improvement in the EEG during both treatments. The beneficial effect of flumazenil was not related to the presence of identifiable benzodiazepines in the blood. A1d In the fourth positive study, drug effects were evaluated on continuous EEG recordings obtained before, during and ten minutes after a 641

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Table 39.6 Randomized controlled trials of flumazenil for hepatic encephalopathy. Study design

No. of pats.

Dose (mg)

Outcome measure

HE grade

Number improved/number of treatment periods (%) Flumazenil

Barbaro [3]

Crossover RCT

527

1

Placebo

clinical

EEG

clinical

EEG

Neurological EEG and

3

46/262f (17.6)

73/262f (27.9)

10/262 (3.8)

13/262 (5)

Score

4

39/265f (14.7)

57/265f (21.5)

3/265 (1.1)

9/265 (3.4)

2/13 (15)

Gyr [41]

RCT

49a

1/hr ×3hr

PSE score dependent on neurologic symptoms

2–4

5/14f (35) (28)bf

0/11 (0) (0)

PomierLayrargues [42]

Crossover RCT

21

2

HE grade EEG

2–4

6/13f (46)

4/12 (33)

0/15 (0)

Cadranel [43]

Crossover RCT

14c

1

HE grade EEG

2–4

d

12/18f (67)

0/8 (17)

Van der Rijt [44]

Crossover RCT

18

0.25/h for 3 d

HE grade EEG

0–4

6/18g (35)

0/18

2/18 (12)

Lacetti [45]

RCTe

54

2

Glasgow coma scale

3–4

22/28f (79)

0/18

16/26 (61)

a

24 Patients excluded from analysis (see text). Intent to treat analysis. c 18 episodes of HE in 14 patients. d “Modest improvement”. e All patients received BCAA, IV fluids and lactulose. f p < 0.05. g p = 0.06. b

bolus dose of the drug [43]. No patient improved on placebo; on flumazenil the EEG recording improved in 12 out of 18 cases (66%) and was associated with a shortlasting modest clinical improvement. A1d In the fifth study the response rate with flumazenil was greater than that observed with placebo, but the result was not statistically significant [44]. A meta-analysis of all published trials involving a total of 641 patients showed that flumazenil induces clinical and electroencephalographic improvement of HE in patients with cirrhosis [46]. Taken together, these studies suggest that some patients with severe HE will experience clinical improvement when flumazenil is added to standard treatment. A1c

Antibiotics Neomycin has been used as standard treatment of HE for almost 40 years. Surprisingly, there is no evidence that 642

neomycin is effective. The only randomized placebo controlled study found no benefit of neomycin compared to standard treatment alone [12]. Based on this negative study and the potential for serious adverse effects of this drug, neomycin should not be prescribed for this condition. A1d The combination of neomycin with lactulose was not superior to placebo [33]. A1d Other antibiotics including paromomycin, metronidazole, vancomycin [47] but there is no evidence supporting their efficacy but are better tolerated. Rifaximin was introduced for treatment of HE about 15 years ago [48, 49]. In a prospective randomized controlled trial two doses of rifaximin were compared for treatment of HE, but this prospective trial unfortunately did not include a control group. A dose of 1200 mg/d appeared to be most effective [50]. Rifaximin was than compared to lactitol in a prospective randomized, double-blind, doubledummy, controlled trial. The overall efficacy of both drugs in episodic HE type was similar (81.6 and 80.4% improved on rifaximin and lactitol, respectively) but rifaximin was

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associated with a more profound decrease of serum ammonia levels [51]. In a metaanalyis rifaximin was at least equally effective as and in some studies superior to nonabsorbable disaccharides and antimicrobials in relieving signs or symptoms observed in patients with mild-to-moderately severe hepatic encephalopathy [52]. A recently published randomized controlled trial showed rifaximin 550 mg tablets significantly reduced the risk of overt hepatic encephalopathy (HE) recurrence over a six month period, maintaining remission more effectively than placebo [53]. Additionally in this study, treatment significantly reduced the risk of hospitalization for HE. Future clinical trials should focus on using standardized methods of evaluating mental status and limiting enrollment to patients with mild-to-moderate, episodic, persistent, or minimal hepatic encephalopathy. A1c Well-designed studies are needed to fully delineate the efficacy of rifaximin and other pharmacologic treatments for patients with hepatic encephalopathy.

Disaccharides Synthetic disaccharides (lactulose, lactitol, lactose in lactase deficiency) are currently the mainstay of therapy of HE. The dose of lactulose (45–90 g/day) should be titrated in every patient to achieve two to three soft stools with a pH below 6 per day. Lactitol has been evaluated in a number of clinical trials. It appears to be as effective as lactulose, is more palatable, and may have fewer adverse effects [33, 54]. A1d In patients with lactase deficiency, lactose has

Hepatic encephalopathy

most of the same effects as the synthetic disaccharides in the colon [55, 56]. The efficacy of these disaccharides is considered to be beyond doubt, although only one a properly conducted placebo controlled trial has been performed [12, 55]. Approximately 70–80% of patients with HE improve on lactulose treatment, a response rate comparable to that observed in patients treated with neomycin [10, 11]. Treatment is usually well tolerated, and the principal toxicity is abdominal cramping, diarrhea, and flatulence. Nevertheless, in view of the questionable efficacy of neomycin, the efficacy of oral lactulose or lactitol for treatment of clinically overt HE has to be questioned. The first placebo controlled trial (with a crossover design) involved just seven patients, of whom [57] only two had clinical symptoms. One patient improved on lactulose. This result is clearly not significant, and the trial lacked adequate power. The second trial reported only the outcome of 14 of the 26 randomized patients [58]. In another prospective trial 90 patients with cirrhosis and minimal hepatic encephalopathy (MHE) were randomly assigned in a 1:1 ratio to receive treatment (lactulose) for 3 months (n = 31) or no treatment (n = 30) in a nonblinded design. Psychometric performance by number and figure connection tests parts A and B, picture completion, and block design tests and HRQOL by the Sickness Impact Profile (SIP). The mean number of abnormal neuropsychological tests decreased significantly in patients in the treated group compared with patients in the untreated group (multivariate analysis of variance for time and treatment, P = 0.001). The mean total SIP score improved among patients

Table 39.7 Randomized controlled trials of lactulose for hepatic encephalopathy. N

design

Lactulose (g/day)

Control

standard Tx

Outcome measures

Baseline characteristics

result

crossover

67

sorbitol

40 g protein

NH3,PSE, EEG

not given, 2 pts. overt HE

no difference

40 g protein

HE grade

not given, all overt HE

? no difference, data of 12 pats not given

N abnormal ψ-tests

Only MHE control group worse

L better than control group, no difference to baseline!

Elkington [56]

7

Simmons [57]

26

RCT

60

glucose

Dhiman [59]

26

RCT

30–60

—

Watanabe [60]

36

RCT

27

—

40 g protein

N abnormal ψ-tests

Only MHE

?

Horsmans [61]

14

RCT

60

lactose

60 g protein

N abnormal ψ-tests

Only MHE control group worse

L better than control group, no difference to baseline!

Sharma [72]

140

RCT

30–60

Recurrent HE

Pts-recovered from HE

L better than no Tx

Prasad [58]

90

RCT

90

N abnormal ψ-tests

Only MHE

L better than no Tx

MHE: minimal HE; ψ-tests: psychometric tests.

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in the treated group compared with patients in the untreated group. [59] The interpretation of the three new studies [60, 90, 91] performed within the last five years is difficult due to the definitions used to document the effect of therapy. A recent trial studied consecutive cirrhotic patients who recovered from HE. Patients were randomized to receive lactulose or placebo [61]. Of 300 patients with HE who recovered, 140 (46.6%) met the inclusion criteria and were included. Primary end point was development of overt HE. All patients were assessed by psychometry (number connection test A and B, figure connection test if illiterate, digit symbol test, and object assembly test), critical flicker frequency test, and blood ammonia level at inclusion. Twelve (19.6%) of 61 patients in the lactulose group and 30 (46.8%) of 64 in the placebo group (P < 0.001) developed HE over a median follow-up of 14 months (range, 1–20 months). Readmission rate due to causes other than HE (lactulose vs placebo: 9 vs 6) and deaths (5 vs 11) in 2 groups were similar. This is the first RCT which proves that lactulose is more effective than placebo. In contrast to oral lactulose administration, the efficacy of lactulose or lactose enemas is beyond any doubt (see above).

L-ornithine-L-aspartate Ornithine and aspartate increase ammonia removal. In cirrhotics, ornithine aspartate infusions prevented hyperammonemia after an oral protein load in a dose-dependent fashion [62]. In a randomized, placebo-controlled trial of patients with HE, ornithine aspartate (20 g/day given intravenously over four hours for seven days) improved fasting and postprandial blood ammonia levels compared to placebo treated patients [4]. There was also symptomatic improvement (assessed by psychometric tests and the PSE index) in patients with grade I or II HE, but no effect was observed in those with minimal HE. A smaller placebo-controlled study also found benefits of oral ornithine-aspartate (18 g/day) with no adverse effects [63]. In a randomized controlled study from Mexico oral administration of lactulose or L-ornithine-L-aspartate to Mexican patients with cirrhosis and hyperammonemic encephalopathy significantly reduced serum ammonia levels in study groups and additionally improved mental status parameters, number connection test, asterixis scores, and EEG activity in the group receiving L-ornithine-Laspartate [64].The results of this study are encouraging, and a confirmatory trial is needed. A recent meta-analysis came to the same conclusions [65]. A1c In patients with acute liver failure, L-ornithine-L-aspartate was ineffective [66].

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L-Carnitine L-carnitine is a natural substance involved in regulating substrate flux and energy balance across cell membranes. Carnitine has beneficial effects in different pathologies and prevents acute ammonia toxicity [67–69]. Several mechanisms have been suggested to explain its efficacy on ammonia toxicity, most importantly the interaction with NMDA-receptors [70]. A recent randomized, placebo-controlled trial in 150 patients with minimal to mild HE showed that on a 90-d treatment with 2 g L-carnitine/BID fasting serum ammonia levels decreased and psychometric tests improved with a significant difference to patients receiving placebo [71]. In a continuation of their studies arandomized, double-blind, placebo-controlled study administering Acetyl-L-carnitine (ALC) in 125 cirrhotic patients with MHE was conducted [72]. Patients in group A were treated with ALC and in group B with placebo for 90 days. Minimal hepatic encephalopathy was diagnosed with the Trail Making Test (TMT), Symbol Digit Modalities Test (SDMT) and Auditory Verbal Learning Test (AVL) and cognitive function with the Mini Mental State Examination (MMSE). After 90 days in group A treated with ALC, there were decreases in prothrombin time, bilirubin serum levels, AST, fasting, and psychometric tests improved. No significant differences were observed in EEG in either group of patients treated with ALC or placebo. The benefits of ALC in comparison with placebo are demonstrated in greater reductions in serum ammonia levels, as well as in improvements of neuropsychological functioning. A systematic review of the literature assessing the use of carnitine in the treatment of HE identified three high-quality human trials for review. Analysis of the selected carnitine trials compared to currently accepted therapies suggests that L-acyl-carnitine is promising as a safe and effective treatment for HE, and further trials of this drug are warranted [73]. A1c

Benzoate A different approach to elimination of ammonia is the use of benzoate. Benzoate reacts with glycine to form hippurate. For each mole of benzoate, one mole of waste nitrogen is excreted into the urine. In a prospective, randomized double-blind study of 74 patients with acute HE, sodium benzoate (5 g bid) was compared with lactulose [74]. Treatment effects were evaluated using the PSE index, visual, auditory and somatosensory evoked potentials, and a battery of psychometric tests. The improvement in encephalopathy parameters and the incidence of adverse effects were similar in the two treatment groups. A1d In view of the unknown efficacy of lactulose, a confirmatory placebo controlled trial is needed.

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Acarbose Theoretically, the inhibition of intestinal disaccharidases should induce malabsorption of disaccharides and increase delivery of undigested carbohydrates to the colon. Acarbose (AO-128, an inhibitor of alpha glycosidase that is approved for treatment of diabetes mellitus) inhibits alpha-glucosidases that convert carbohydrates into monosaccharides. It also promotes the proliferation of intestinal saccharolytic bacterial flora at the expense of proteolytic bacterial flora producing mercaptans, benzodiazepine-like substances and ammonia. Their reduction could improve HE. A double-blind, randomized, controlled trial was performed in 35 cirrhotic patients with PSE. Patients were given a two-week treatment consisting of AO-128 (2 mg three times daily) or an identical placebo. Efficacy of treatment was assessed by the PSE index (PSEI) in weekly intervals. More patients receiving AO-128 than patients receiving placebo showed >40% improvement in the PSEI (83% vs 35%; p < 0.05). The mean stool pH decreased from 5.8+/−0.3 to 5.5+/−0.3 (p < 0.004) after AO-128 treatment, whereas no changes were observed in the placebo group. The EEG and nitrogen balance did not show changes in any of the two groups. An improvement was seen in the NCT performance after AO128 (from grade 2.0+/−1.04 to grade 1.25+/−0.87; p < 0.05). Seven patients treated with AO-128 developed diarrhea, as compared with none in the placebo group (p < 0.05) [75]. To further test this hypothesis a randomized controlled crossover trial involving 107 cirrhotic patients with diabetes mellitus and grade 1 to 2 HE was performed [76]. Treatment was associated with a reduction in blood ammonia blood levels and improvement in HE. A1d

Modification of colonic flora (probiotics and prebiotics) Alteration of gut flora (either with probiotics or with prebiotics such as fermentable fiber) has been associated with improvement in HE in pilot studies [77–79]. Such therapy appears to lower blood ammonia concentrations possibly by favoring colonization with acid-resistant, non-urease producing bacteria associated with MHE in 50% of patients [78]. Treatment with fermentable fibres alone was also of benefit in a substantial proportion of patients. A small trial demonstrated a significant rate of MHE reversal and excellent adherence in cirrhotics after probiotic yogurt supplementation with potential for long-term adherence [80]. In an open label randomized controlled study in patients with MHE, probiotics and lactulose were equally effective to improve the test employed to measure MHE [81]. A1d In a further study in 125 patients with cirrhosis and HE were randomized either to a treatment with Bifidobacterium+ fructo-oligosaccharides (FOS) or lactulose for 60 days.

Hepatic encephalopathy

Bifidobacterium+FOS-treated patients compared with lactulose-treated patients showed a significant improvement of psychometric tests and a decrease of fasting ammonia levels at end of the study (82).

Molecular adsorbent recirculating system (MARS) Extracorporeal albumin dialysis (ECAD) using molecular adsorbent recirculating system (MARS) may improve severe HE in patients with advanced cirrhosis via the removal of protein or non-protein-bound toxins. A prospective, randomized, controlled, multicenter trial of the efficacy, safety and tolerability of ECAD was conducted in such patients [83]. Patients were randomized to ECAD and standard medical therapy (SMT) or SMT alone. ECAD was provided daily for six hours for five days or until the patient had a two-grade improvement in HE. HE grades (West Haven criteria) were evaluated every 12 hours using a scoring algorithm. The primary endpoint was the difference in improvement proportion of HE between the two groups. A total of 70 subjects (median age, 53; 56% male; 56% HE grade III; 44% HE grade IV; median model for end-stage liver disease (MELD) 32 (11–50) and CPT 13 (10–15)) were enrolled in eight tertiary centers. Patients were randomized to ECAD + SMT (n = 39) or SMT alone (n = 31). Groups were matched in demographics and clinical variables. The improvement proportion of HE was higher in ECAD (mean, 34%; median, 30%) versus the SMT group (mean, 18.9%; median, 0%) (p = 0.044) and was reached faster and more frequently than in the SMT group (p = 0.045). Subjects receiving ECAD tolerated treatment well, with no unexpected adverse events. The conclusion was that the use of ECAD may be associated with an earlier and more frequent improvement of HE (grade III/IV). Because this five-day study was not designed to examine the impact of MARS on survival, a full assessment of the role of albumin dialysis awaits the results of additional controlled trials. The shortcomings of this trial do not allow us to recommend its general use [84].

Persistent HE type C Patients with HE that is refractory to standard therapy are rare. Most have surgical shunts or a large diameter transjugular intrahepatic portosystemic shunt (TIPS). Due to the small number of such patients, there are no controlled studies. Case reports on individual patients describe successful approaches by narrowing or closure of the shunt, protein restriction together with BCAA supplementation, supplementation of zinc and thiamin, and the use of bro-

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mocriptin and oral flumazenil. The only controlled study was performed in 37 hospitalized patients with documented severe protein intolerance [85]. Addition of BCAA to the diet enabled the daily protein intake to be increased to up to 80 g without worsening of cerebral function. B4 Many control patients who received casein as a protein source deteriorated after increasing dietary protein intake. No benefit of BCAA supplementation was observed in protein-tolerant patients. In protein-intolerant patients vegetable proteins appear to be better tolerated than proteins derived from fish, milk or meat. In three controlled studies a vegetable diet was better tolerated than a diet which also included meat [86, 87]. A1d Other studies did not show these favorable effects [88]. B4 The beneficial effects of a vegetable diet on the protein tolerance of patients with HE cannot be explained by the amino acid compositions of the proteins alone [89].

Minimal HE Although the number of patients with minimal HE is large, good clinical studies are rare. Even among experts, there is no agreement on how to define minimal HE or whether minimal HE even exists. Efficacy of treatment is judged by the improvement of psychometric tests or of electrophysiological measurements (see Table 39.6). The clinical relevance of these outcomes is uncertain. Substances that improved responses in psychometric tests in randomized trials include lactulose [59, 90, 91], modification of colonic flora to increase lactobacilli [79, 80], ornithin aspartate [5], and oral BCAA [92, 93].

Prevention of HE The occurrence of HE is a problem after TIPS insertion [94]. Although most clinicians administer prophylactic treatments after TIPS placement, the frequency of episodes of overt HE was about 10% per month. B4 The manifestation of HE before TIPS and/or reduced liver function were identified as independent risk factors.

Summary of recommended treatment of hepatic encephalopathy in clinical practice Treatment of episodic he type C Treatment of episodic HE type C involves two steps. The first is to identify and to correct precipitating causes: • gastrointestinal bleeding • sedatives or tranquilizers • infections 646

• hypovolemia, hypoxia, electrolyte imbalance, hypoglycemia The second step is initiation of measures to lower blood ammonia concentrations using: • lactulose enemas • ornithine aspartate IV • parenteral or enteral nutrition, if patient is unable to eat • flumazenil if the patient has been given benzodiazepines

Chronic therapy Chronic management of the patient with recurrent episodic HE type C requires individual adjustment of treatment. The titration of protein tolerance after an episode of HE should permit the design of an individual diet for each patient. Limitation of protein intake is reasonable in some patients, but protein restriction should be avoided if possible, since it will lead to negative nitrogen balance. In protein-intolerant patients, vegetable proteins are better tolerated than proteins derived from fish, milk, or meat. The supplementation of a low protein diet with branched chain amino acids should be considered. Additionally, patients may benefit from zinc and thiamin supplementation. The long-term benefit of all other treatments (including lactulose and neomycin) is uncertain. The need for treatment of minimal HE is not established and unproven therapy should be administered in the context of randomized controlled clinical trials.

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59 Prasad S, Dhiman RK, Duseja A, Chawla YK, Sharma A, Agarwal R. Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy. Hepatology 2007; 45: 549–559. 60 Dhiman RK, Sawhney MS, Chawla YK, Das G, Ram S, Dilawari JB. Efficacy of lactulose in cirrhotic patients with subclinical hepatic encephalopathy. Dig Dis Sci 2000; 45: 1549–1552. 61 Sharma BC, Sharma P, Agrawal A, et al. Secondary prophylaxis of hepatic encephalopathy: an open-label randomized controlled trial of lactulose versus placebo. Gastroenterology 2009; 137: 885. 62 Staedt U, Leweling H, Gladisch R et al. Effects of ornithine aspartate on plasma ammonia and plasma amino acids in patients with cirrhosis. A double-blind, randomized study using a fourfold crossover design. J Hepatol 1993; 19: 424–430. 63 Stauch, S, Kircheis, G, Adler, G et al. Oral L-ornithine L-aspartate therapy of chronic hepatic encephalopathy: Results of a placebocontrolled double-blind study. J Hepatol 1998; 28: 856. 64 Poo JL, Góngora J, Sánchez-Avila F et al. Efficacy of oral L-ornithine-L-aspartate in cirrhotic patients with hyperammonemic hepatic encephalopathy. Results of a randomized, lactulose-controlled study. Ann Hepatol 2006; 5: 281–288. 65 Jiang Q, Jiang XH, Zheng MH, Chen YP. L-Ornithine-l-aspartate in the management of hepatic encephalopathy: a meta-analysis. J Gastroenterol Hepatol 2008 (epub). 66 Acharya SK, Bhatia V, Sreenivas V, et al. Efficacy of L-Ornithine L-aspartate in acute liver failure: a double-blind, randomized, placebo-controlled study. Gastroenterology 2009; 136: 2159. 67 Therrien G, Rose C, Butterworth J, Butterworth RF. Protective effect of L-carnitine in ammonia-precipitated encephalopathy in the portacaval shunted rat. Hepatology 1997; 25: 551–556. 68 Matsuoka M, Igisu H, Kohriyama K, Inoue N. Suppression of neurotoxicity of ammonia by L-carnitine. Brain Res 1991; 567: 328–331. 69 Siciliano M, Annicchiarico BE, Lucchese F, Bombardieri G. Effects of a single, short intravenous dose of acetyl-L-carnitine on pattern-reversal visual-evoked potentials in cirrhotic patients with hepatic encephalopathy. Clin Exp Pharmacol Physiol 2006; 33: 76–80. 70 Llansola M, Erceg S, Hernandez-Viadel M, Felipo V. Prevention of ammonia and glutamate neurotoxicity by carnitine: molecular mechanisms. Metab Brain Dis 2002; 17: 389–397. 71 Malaguarnera M, Pistone G, Elvira R, Leotta C, Scarpello L, Liborio R. Effects of L-carnitine in patients with hepatic encephalopathy. World J Gastroenterol 2005; 11: 7197–7202. 72 Malaguarnera M, Gargante MP, Cristaldi E et al. Acetyl-Lcarnitine treatment in minimal hepatic encephalopathy. Dig Dis Sci 2008; 53: 3018–3025. 73 Shores NJ, Keeffe EB. Is oral L-acyl-carnitine an effective therapy for hepatic encephalopathy? Review of the literature. Dig Dis Sci 2008; 53: 2330–2333. 74 Sushma S, Dasarathy S, Tandon RK et al. Sodium benzoate in the treatment of acute hepatic encephalopathy: a double-blind randomized trial. Hepatology 1992; 16: 138–144. 75 Uribe M, Moran S, Poo JL, Mendez-Sanchez N, Guevara L, Garcia-Ramos G. Beneficial effect of carbohydrate maldigestion induced by a disaccharidase inhibitor (AO-128) in the treatment of chronic portal-systemic encephalopathy. A double-blind, randomized, controlled trial. Scand J Gastroenterol 1998; 33: 1099–1106.

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76 Gentile S, Guarino G, Romano M et al. A randomized controlled trial of acarbose in hepatic encephalopathy. Clin Gastroenterol Hepatol 2005; 3: 184. 77 Macbeth WA, Kass EH, Mcdermott WV Jr. Treatment of hepatic encephalopathy by alteration of intestinal flora with lactobacillus acidophilus. Lancet 1965; 191: 399. 78 Liu Q, Duan ZP, Ha da K et al. Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology 2004; 39: 1441. 79 Loguercio C, Abbiati R, Rinaldi M et al. Long-term effects of enterococcus faecium SF68 versus lactulose in the treatment of patients with cirrhosis and grade 1–2 hepatic encephalopathy. J Hepatol 1995; 23: 39. 80 Bajaj JS, Saeian K, Christensen KM et al. Probiotic yogurt for the treatment of minimal hepatic encephalopathy. Am J Gastroenterol 2008; 103: 1707–1715. 81 Sharma P, Sharma BC, Puri V, Sarin SK. An open-label randomized controlled trial of lactulose and probiotics in the treatment of minimal hepatic encephalopathy. Eur J Gastroenterol Hepatol 2008; 20: 506–511. 82 Malaguarnera M, Gargante MP, Malaguarnera G et al. Bifidobacterium combined with fructo-oligosaccharide versus lactulose in the treatment of patients with hepatic encephalopathy. Eur J Gastroenterol Hepatol. 2010; 22: 199–206. 83 Hassanein TI, Tofteng F, Brown RS Jr et al. Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis. Hepatology 2007; 46: 1853–1862. 84 Ferenci P, Kramer L. MARS and the failing liver – any help from the outer space? Hepatology 2007; 46: 1682–1684. 85 Horst D, Grace ND, Conn HO et al. Comparison of dietary protein with an oral, branched chain-enriched amino acid supplement in chronic portal-systemic encephalopathy: a randomized controlled trial. Hepatology 1984; 4: 279–287.

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86 Uribe M, Marquez MA, Ramos GG et al. Treatment of chronic portal-systemic encephalopathy with vegetable and animal protein diets. Dig Dis Sci 1982; 27: 1109–1116. 87 Bianchi GP, Marchesini G, Fabbri A et al. Vegetable versus animal protein diet in cirrhotic patients with chronic encephalopathy. A randomized cross-over comparison. J Intern Med 1993; 233: 385–392. 88 Greenberger NJ, Carley J, Schenker S et al. Effect of vegetable and animal protein diets in chronic hepatic encephalopathy. Dig Dis 1977; 22: 845–855. 89 Keshavarzian A, Meek J, Sutton C et al. Dietary protein supplementation from vegetable sources in the management of chronic portal systemic encephalopathy. Am J Gastroenterol 1984; 79: 945–949. 90 Watanabe A, Sakai T, Sato S et al. Clinical efficacy of lactulose in cirrhotic patients with and without subclinical hepatic encephalopathy. Hepatology 1997; 26: 1410–1414. 91 Horsmans Y, Solbreux PM, Daenens C et al. Lactulose improves psychometric testing in cirrhotic patients with subclinical encephalopathy. Aliment Pharmacol Ther 1997; 11: 165–170. 92 Egberts EH, Schomerus H, Hamster W et al. Branched chain amino acids in the treatment of latent portosystemic encephalopathy. A double-blind placebo-controlled crossover study. Gastroenterology 1985; 88: 887–895. 93 Plauth M, Egberts EH, Hamster W et al. Long-term treatment of latent portosystemic encephalopathy with branched-chain amino acids. A double-blind placebo-controlled crossover study. J Hepatol 1993; 17: 308–314. 94 Nolte W, Wiltfang J, Schindler C et al. Portosystemic hepatic encephalopathy after transjugular intrahepatic portosystemic shunt in patients with cirrhosis: clinical, laboratory, psychometric, and electroencephalographic investigations. Hepatology 1998; 28: 1215–1225.

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40

Hepatocellular carcinoma Massimo Colombo and Massimo Iavarone Department of Medicine, First Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy

Introduction Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most common cause of cancer mortality, with an estimated worldwide prevalence of 632,000 cases [1]. Accounting for about 90% of all primary liver cancers, HCC is unique in that it develops in the background of well-recognized risk factors that are responsible for marked variations of the tumor prevalence and clinical presentation, worldwide. Sequential scrutiny of the cancer registries has demonstrated important variations in the temporal trends of HCC incidence, with some evidence for an increase in incidence in resource-rich countries [1]. In these regions molecular epidemiology investigations have predicted a further rise in HCC incidence and mortality rates in the next decades due to the accumulation of patients with chronic liver diseases who are expected to develop HCC.

Early diagnosis Early diagnosis of HCC is feasible through surveillance of patients at risk, who are readily identifiable. Surveillance is feasible since the test adopted, abdominal ultrasound (US), is user friendly and acceptable to the population, while it has high diagnostic accuracy. Moreover, the diagnostic tests and recall procedures have been standardized, while early cancer definition also incorporates suitability for potentially curative treatments [2, 3]. The term “very early tumor” has been recently defined to indicate a 30 years and those 13 pg/ml than in those with undetectable (103 HBV-DNA, following the demonstration of the pathogenetic importance of HBV replication in HCC. Patients with porphyria cutanea tarda, genetic hemochromatosis, α-1-antitrypsin deficiency, tyrosinemia and hypercitrullinemia are also at high risk for HCC. Patients with glycogenosis types I and III, Wilson’s disease and hereditary fructose intolerance may also develop HCC, but are at substantially lower risk [24]. HCC has also developed in patients with autoimmune hepatitis and primary biliary cirrhosis, probably reflecting treatment-related improvement in patient survival. HCC was also found in 64% of 160 Japanese patients and in 48% of 101 South African black people with Budd-Chiari syndrome [25, 26]. However, in these studies the possible role of other unidentified carcinogens could not be excluded.

Screening tests Ultrasound is the method of choice for screening, since it has adequate sensitivity, specificity, positive and negative predictive values [3]. Based upon studies of tumor volume doubling time, six months has been selected by most experts in the West as the ideal interval of screening with US, whereas in the Far East, the three-month interval for screening is largely adopted. In Italy, a study in hemophiliacs chronically infected with hepatitis C virus demonstrated similar efficacy of 6-month and 12-month intervals of screening in the identification of potentially curable HCC [27]. In France, a multicenter study in patients with compensated cirrhosis showed that increasing the frequency of US examinations every three months did not increase the accuracy of screening whereas it resulted in increased costs to treat patients with false-positive results [28]. The serum assay AFP is no longer considered for screening by AASLD and EASL due to the high rates of false positive and false negative results in patients with chronic liver disease. Whether other serum markers like desgamma carboxy-prothrombin (DCP) and fucosylated AFP (AFP-L3) should be incorporated into surveillance for HCC, is debatable [2]. A DCP value of 150 mAU/ml had a better positive predictive value for differentiating early HCC from cirrhosis than an AFP value of 13 ng/ml (92% vs 54%) [29]. The AFP-L3 variant with high affinity to lensculinaris, is more specific for HCC than total AFP too, but differences among studies in assay methods, cutoff values chosen as diagnostic for HCC, and case mix with respect 652

to early tumors, do not allow for a definitive evaluation of the accuracy of this marker [29].

The recall policy An abnormal screening test needs to be confirmed by either a US-guided liver biopsy or imaging-studies [3]. In patients with cirrhosis and a liver nodule detected during screening/surveillance, HCC can be diagnosed by imaging techniques without the need for a histological examination (see Table 40.2) [30]. CT scan, MRI and contrast-enhanced US serve the purpose whenever arterial enhancement of the nodule is demonstrated and followed by wash-out of contrast in the delayed venous phase [31]. The accuracy of radiological diagnosis, however, is tumor size dependent: the diagnosis is attained in all nodules >2 cm in diameter with one imaging technique only, whereas nodules between 5 and 20 mm in size escape diagnosis in two-thirds of the cases despite application of two imaging techniques [30]. Liver nodules not accurately diagnosed by imaging will require histological examination with a liver biopsy or close monitoring with US carried out at three-month intervals (enhanced follow-up). The risk of seeding should be considered as a complication of biopsy: in 41 papers specifying the total number of patients biopsied, the median risk of seeding was 2.9% (range 0–11%) for biopsy group, being lower (0.61–1.4%) in therapeutic percutaneous procedures [32]. The radiological diagnosis of HCC is complicated by false positive results in the presence of artero-venous shunts and macroregenerative nodules with dysplastic liver cells. Currently, dysplastic macronodules can be discriminated from early tumors by morphological criteria based on exclusion of microscopic stromal invasion [33].

Table 40.2 Radiological diagnosis of hepatocellular carcinoma in patients with cirrhosis according to the guidelines of EASL and AASLD [2, 3, 29]. Imaging techniques

Contrast-enhanced US, contrast-enhanced spiral CT and gadolinium-enhanced MRI

1–2 cm nodule

Two imaging techniques showing hyperenhanced nodule in the arterial phase and hypoenhanced nodule in the portal phase (wash-out) one imaging technique

>2 cm nodule Prospective validation Sensitivity Specificity Pos Pred Value Neg Pred Value

89 patients with a 5–20 mm nodule 33% 100% 100% 42%

CHAPTER 40

Immunostaining for GPC-3, and structural and functional analysis of the genetic profile of the nodules may also distinguish between macronodules and tumors [4, 34]. Falsely negative nodules at contrast imaging are also a problem when searching for very early tumors, accounting for approximately 20% of all 1–2 cm in size HCCs [33].

Is liver-related mortality reduced by screening? In the last decade, more than 50% of all patients in Japan have been diagnosed with a TNM I/II tumor compared to the 1980s, when only a minority of the patients with a HCC were diagnosed in the early stage [35]. In a national survey of 554 members of the AASLD, the vast majority of responders indicated that patients with cirrhosis were routinely screened using US [36]. A surveillance program of semi-annual determinations of AFP in HBV carriers in Alaska led to the identification of curable HCC in 40% of the affected patients, a fact that was perceived as beneficial since prior to AFP screening programs the case-fatality rate for HCC in Alaskan natives was 100%, with an average survival of three months [37]. B4 A randomized controlled study conducted in Shanghai area using abdominal US and serum AFP every six months among individuals with chronic hepatitis and other risks for HCC, showed a reduction in the mortality rates in the screened versus unscreened population (83.2 vs 131.5 per 100,000 inhabitants) [38]. A1d The study, however, has limitations in the design and conduct, because the proportion of patients with cirrhosis is unknown, transplantation was not included among the radical therapies and the compliance of the population to the program was suboptimal (58%) (see Table 40.3). Notwithstanding all these limitations, the RCT in Shanghai confirms the importance of

Hepatocellular carcinoma

early diagnosis for improving HCC-related mortality in the community. In cirrhotic patients attending hospital facilities, the HCC-specific mortality rates were reduced in patients with HCC detected during surveillance, most likely due to improvements in both detection and treatment. In a reanalysis of 112 cirrhotic patients with HCC detected during a hospital-based surveillance program, the survival rates were improved in patients who were treated for a liver cancer which had developed during the previous five years of surveillance compared to previous intervals (90% vs 55%, p = 0.0009) (see Table 40.4) [7]. B3 Increased survival was attributed to a significant reduction in the mortality rates of treated patients (from 34% to 5%, p = 0.003), due to wider application of curative treatments and improved selection of patients undergoing surgical or ablative treatments. In Taiwan between 1989 and 1998, there was a significant increase in survival among 3345 patients with a HCC during the previous five years (from 29% to 35%), that was only in part (34%) due to advancement in medical care, but mostly (66%) attributable to early detection [39]. B4

Is surveillance in patients with cirrhosis cost-effective? The economic consequences of HCC surveillance strategy are poorly appreciated, due to the lack of randomized trials evaluating moderators of treatment outcome, like compliance, heterogeneity and etiology of liver disease and treatment effectiveness that may impact on cost-effectiveness of surveillance. Patient compliance is an important variable of surveillance, as 1–15% of all patients failed to comply with clinic-based surveillance programs in Europe and

Table 40.3 A population-based screening for HCC: the importance of early diagnosis for improving HCC-related mortality[38].

Table 40.4 A clinic-based surveillance of 447 cirrhotics: the importance of treatment refinement for improving HCC-related mortality[7].

Findings

Outcomes

1987–91

HCC, No.

52

HCC size, cm

3.7 (1.5–8)

Radical treatments

28%

Mortality in treated

HCC occurrence Cases Early cancer Total incidence (per 100,000) Rate ratio (95% CI) Deaths from HCC Deaths Total mortality (per 100,000) Rate ratio (95% CI)

Screened group (pp x yr = 38,444)

86 39 223.7 1.37 (0.99, 1.89)

32 83.2 0.63 (0.41, 0.98)

Control group (pp x yr = 41,077)

67 0 163.1 reference

54 131.5 reference

1992–96 37 3.0 (1.5–6)

1997–2001

p

23 2.2 (1.4–3.1)

0.02

38%

43%

0.02

34%

28%

5%

0.024

Mortality in untreated

69%

100%

92%

ns

Overall mortality

45%

37%

10%

0.0009

653

PA RT I I

Liver disease

Japan (reviewed by Thompson Coon 2007 et al.) [40], compared to the 42% of the population enrolled in a study in Shanghai [38]. Cost-effectiveness of screening is largely influenced also by the heterogeneity of the natural history of tumor disease, the annual risk of HCC ranging from 1% in HBV patients to 5–8% in some patients with compensated cirrhosis due to HCV [5]. Since the cost for tumor detected is inversely proportional to the tumor incidence, screening is considered worthwhile in populations with equal or greater than 1.5% incidence of HCC. In population-based screening programs with HCC incidence lower than 1.5%, the low cost-effectiveness of surveillance is counterbalanced by the high numbers of targeted individuals with a preserved liver function, who have more chances of receiving curative treatments compared to patients enrolled in clinic-based surveillance programs. Finally, since cost-effectiveness of surveillance largely depends upon the outcome of treatments, studies like the Shanghai program which lack access to liver transplantation, do not inform about cost-effectiveness of surveillance in the West, where liver transplantation is a first option for selected patients with cirrhosis and a small tumor. In the absence of randomized trials, decision analysis (Markov modeling) has provided the best means to estimate cost-effectiveness of HCC surveillance in this patient population. A costeffectiveness ratio represents the cost for life-year saved compared to a cost-utility ratio, which describes the cost per quality-adjusted life-year (QALY) saved. Surveillance programs in which cost-utility ratios are measured at less than US$ 50,000 x QALY are thought to be cost-effective (see Table 40.5) [41].

Treatment of patients with cirrhosis and HCC The success of HCC treatment largely depends on staging accuracy, that is, the clinical classification of disease severity aimed to establish prognosis and select the adequate treatment for the best candidates. The Barcelona Clinic Liver Center (BCLC) classification for HCC has been endorsed by EASL and AASLD as standard of care for patients with cirrhosis, since it links tumor stage with treatment strategies (see Table 40.6). The compelling evidence that surveillance improves treatment of HCC is due to its ability to improve detection of small, treatable tumors.

Early HCC Survival of patients with compensated cirrhosis and an early HCC reaches up to 70–75% at five years after resection, transplantation or percutaneous interstitial treatments in carefully selected candidates (see Tables 40.7, 40.8, 40.9). Patients with a very early tumor, that is, well differenti654

Table 40.5 Markov decision models to simulate cost-utility ratio of surveillance according to AASLD/EASL guidelines [40, 41]. Study

Etiology of cirrhosis

Sarasin et al. 1996a

Mixed

48,293

60 % survival 3-yr after resection

Everson et al. 2000a

Mixed

35,000

2.5% HCC x year

Saab et al. 2003a

Wait list

74,000

Arguedas et al. 2003a

HCV

26,689

Lin et al. 2004 a

HCV

73,789

Patel et al. 2005a

HCV

26,100 46,700 50,400

Thompson Coon 2007

Mixed

£ 31,900

Anderson et al. 2008

Mixed

30,700

a

Incremental cost utility ratio (US$/ QALY)

Prerequisite

50-yr old eligible to OLT

Hepatic resection Cadaveric liver transplant Living donor liver transplant Most alcohol-related

US alone

Referenced by Thompson Coon 2007 [40].

ated, less than 2 cm in size with an ill-defined nodular pattern at US, show the best survival rates and the lowest recurrence rates after either resection or percutaneous ablation [51]. While percutaneous ablation of HCC with alcohol (PEI) or radiofrequency (RF) likely are equally effective for treating ≤2 cm tumors, patients with 3–4 cm tumors, who are at increased risk of local recurrence, benefit more from RF than from PEI [47–53]. A1d However, most studies comparing RF to PEI are underpowered, lack estimates of overall survival at five years and do not account for patients unfit for RF who could receive PEI only. Further, RF had greater reported mortality (0.5%) and complication rates (8.9%) than PEI. Overall, limited hepatic resection is superior to local ablative therapies in cirrhotic patients with 2–5 cm HCC who have moderate portal hypertension ( 50 seconds (INR > 3.5) Bilirubin > 300 μmol/l In paracetamol induced FHF pH < 7.3 (following fluid resuscitation) Or the coexistence of: Prothrombin time > 100 (INR > 6.5), creatinine > 300 μmol/l and grade III or worse encephalopathy

CHAPTER 41

highly specific for a poor outcome in paracetamol poisoning. A serum pH persistently less than 7.3 has become an independent transplant criterion regardless of grade of encephalopathy [156]. B4 The metabolic acidosis seen in FHF is often associated with a raised whole blood lactate concentration. This hyperlactatemia is caused by both an increased production, but also by decreased clearance by the liver [174, 175]. Prolonged high blood lactate concentration in critical illness other than FHF is associated with poor prognosis. The relationship between whole blood lactate and prognosis in FHF has been investigated recently. Bernal and colleagues showed that a post-resuscitation lactate concentration of greater than 3.0 mmol/l can predict death with similar accuracy to the King’s criteria, but earlier in the course of the illness. The addition of postresuscitation lactate concentration to the KCH criteria increased sensitivity from 76% to 91% and lowered the negative likelihood ratio from 0.25 to 0.10 [176]. B4 The importance of lactate in the prognosis of ALF secondary to paracetamol overdose has been reflected by its inclusion as a criteria for registration on the UK superurgent liver transplant scheme. Other recent variations to the classic King’s criteria have recently been adopted in the UK. Patients who are deteriorating in terms of mean arterial pressure, ICP or oxygenation can be listed for urgent liver transplantation if they fulfill two out of the three classical criteria in an attempt to increase the sensitivity of the King’s criteria. The level of pH as the sole criteria at which a patient can be listed has been reduced to 7.25, reflecting improved and earlier renal support, whilst at the same time a lactate of greater than 3.5 mmol/l has become a single criterion for urgent registration. A French group performed multivariate analysis of data from 115 patients with fulminant hepatitis B and found that a low factor V following the onset of grade III encephalopathy was the strongest predictor of a poor outcome (see Box 41.3) [177]. Both the King’s and the Clichy criteria are in common use around the world. Following the publication of the King’s College Hospital data the criteria were evaluated retrospectively in a French liver unit. Eighty-one non-transplanted patients with non-paracetamol induced acute liver failure were studied. The mortality rate was 0.81. The predictive accuracies, respectively on admission and 48 hours

BOX 4 1 .3 The Clichy criteria in viral FHF

Coma or confusion and Factor V < 20% if under 30 years of age or Factor V < 30% if over 30 years of age

Fulminant hepatic failure

before death, were 0.80 and 0.79 for the King’s criteria and 0.60 and 0.73 for the Clichy criteria. The positive and negative predictive values, 48 hours before death, were 0.89 and 0.47 for the King’s criteria and 0.89 and 0.36 for the Clichy criteria respectively. The low negative predictive values (0.36 and 0.47) indicated that neither of these could identify a subgroup with a low risk of death [178]. The additions to the King’s criteria have yet to be subjected to external validation but these studies are ongoing. While the above study compared prognostic criteria in non-paracetamol induced FHF, two recent studies compared general ICU scoring systems, the Acute Physiology and Chronic Health Evaluation (APACHE) scores, and the King’s criteria for urgent liver transplantation [16, 179]. Mitchell et al. prospectively evaluated the APACHE II system in patients with FHF due to paracetamol poisoning. The study aimed to see whether the APACHE system is able to provide an accurate risk of hospital death in patients with paracetamol induced FHF or identify those patients needing transfer for possible hepatic transplantation and compared this to the King’s College Hospital transplant criteria. A total of 102 patients were studied. An APACHE II score of >15 had the ability to predict death, which was similar to that of the King’s criteria (sensitivity 82% and 65% respectively; specificity 98% and 99% respectively) when evaluating those patients who were transplanted as “deaths”. An APACHE II score of >15 was able to identify four more patients than the King’s criteria on the first day of admission. The calculated risk of death according to the APACHE II score, using the original drug overdose coefficient, was poorly calibrated. This is probably due to the lower incidence of potentially life-threatening drug overdoses in the original calibration population. From these data the crude APACHE II score may be able to identify non-survivors at an earlier stage than the King’s College Hospital criteria. Delays in listing patients for transplantation and in organ procurement result in further patient deterioration. This altered status results in the withdrawal of patients from the urgent list. Withdrawal of patients is based on clinical experience. However, several authors have analyzed the outcome from transplantation in FHF to help define contraindications to transplantation on the basis of poor outcome after transplantation. Devlin et al. used APACHE III data to look at 100 patients transplanted for FHF [16]. They found that in the paracetamol group at the time of transplantation, APACHE III score and serum bilirubin were significantly higher in the non-survivors. In the non-paracetamol group, serum creatinine, organ system failure scores, and APACHE III scores were significantly higher in the non-survivors. Bernal et al. studied the use of liver transplantation and the application of King’s College Hospital transplant criteria in 548 patients presenting to the liver failure unit with severe paracetamol poi677

PA RT I I

Liver disease

soning [180]. Of 424 patients who did not fulfill criteria, 28 (7%) died. Of 124 who fulfilled the criteria, 68 (55%) were listed for transplant, and 44 underwent transplantation. Thirty-three of the transplanted patients left hospital. Of the 80 patients who satisfied criteria but were not transplanted, nine survived to leave hospital. The reasons why patients who satisfied criteria were not listed were multiple organ failure and cerebral edema. These reasons also applied to the patients listed but withdrawn before a graft was available. In contrast to the report of Devlin et al., the authors were unable to identify any preoperative factors predictive of death in the transplanted group. This suggests that patients unlikely to survive with a transplant are recognized and subsequently removed from the list. However, graft factors (identified by early markers of graft function, INR and AST) were also significantly worse in the non-survivors.

Auxiliary OLT and regeneration Auxiliary partial orthotopic liver transplantation holds potential advantages over conventional orthotopic liver transplantation in the setting of FHF. It has been known for many years that survivors from FHF often return to full health with normal or only slightly abnormal livers. The liver has great powers of regeneration and this has led to the introduction of partial liver transplantation in the hope of native liver regeneration and the eventual withdrawal of immunosuppression. A multicenter European study reported the results of 30 patients who underwent auxiliary transplantation for FHF [181]. After 3 months, 19 of the 30 patients survived; 13 had resumed normal native liver function with interruption of immunosuppression. The indications are not well defined, but the survivors of immunosuppression were aged less than 40 years and had FHF secondary to viral hepatitis and paracetamol poisoning. A more recent study reported the outcomes of patients who underwent auxiliary grafting for FHF at a single center, 49 patients received an auxiliary graft, overall survival was 77% and over 50% of patients were able to be weaned from immunosuppression. Sequential post-transplant biopsies of native livers showed excellent regeneration, especially in patients transplanted for acteminophen hepatotoxicity, where 100% native liver recovery was noted in survivors [182].

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renal failure: a prospective randomised trial. Lancet 2000; 356(9223): 26–30. Braun MC, Welch TR. Continuous venovenous hemodiafiltration in the treatment of acute hyperammonemia. American Journal of Nephrology 1998; 18(6): 531–533. Lai YC, Huang HP, Tsai IJ, Tsau YK. High-volume continuous venovenous hemofiltration as an effective therapy for acute management of inborn errors of metabolism in young children. Blood Purification 2007; 25(4): 303–308. Marik PE. Critical illness-related corticosteroid insufficiency. Chest 2009; 135(1): 181–193. Confalonieri M, Urbino R, Potena A et al. Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study. American Journal of Respiratory and Critical Care Medicine 2005; 171(3): 242–248. Meduri GU, Tolley EA, Chrousos GP, Stentz F. Prolonged methylprednisolone treatment suppresses systemic inflammation in patients with unresolving acute respiratory distress syndrome: evidence for inadequate endogenous glucocorticoid secretion and inflammation-induced immune cell resistance to glucocorticoids. American Journal of Respiratory and Critical Care Medicine 2002; 165(7): 983–991. Sprung CL, Annane D, Keh D et al. Hydrocortisone therapy for patients with septic shock. The New England Journal of Medicine 2008; 358(2): 111–124. Harry R, Auzinger G, Wendon J. The clinical importance of adrenal insufficiency in acute hepatic dysfunction. Hepatology (Baltimore, Md) 2002; 36(2): 395–402. Harry R, Auzinger G, Wendon J. The effects of supraphysiological doses of corticosteroids in hypotensive liver failure. Liver Int 2003; 23(2): 71–77. O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989; 97(2): 439–445. Harrison PM, O’Grady JG, Keays RT, Alexander GJ, Williams R. Serial prothrombin time as prognostic indicator in paracetamol induced fulminant hepatic failure. BMJ (Clinical research ed.) 1990; 301(6758): 964–966. Harrison PM, Wendon JA, Gimson AE, Alexander GJ, Williams R. Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure. The New England Journal of Medicine 1991; 324(26): 1852–1857. Walsh TS, Hopton P, Philips BJ, Mackenzie SJ, Lee A. The effect of N-acetylcysteine on oxygen transport and uptake in patients with fulminant hepatic failure. Hepatology (Baltimore, Md) 1998; 27(5): 1332–1340. Harrison P, Wendon J, Williams R. Evidence of increased guanylate cyclase activation by acetylcysteine in fulminant hepatic failure. Hepatology (Baltimore, Md) 1996; 23(5): 1067–1072. Lee WM, Hynan LS, Rossaro L et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage nonacetaminophen acute liver failure. Gastroenterology 2009; 137: 856–864. Stange J, Hassanein TI, Mehta R, Mitzner SR, Bartlett RH. The molecular adsorbents recycling system as a liver support system based on albumin dialysis: a summary of preclinical investigations, prospective, randomized, controlled clinical trial, and clinical experience from 19 centers. Artificial Organs 2002; 26(2): 103–110.

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163 Logsen Hea. Correction of Increased Plasma Amino Acid Levels by Dialysis with Amino-Acid-Electrolyte Glucose Solutions. SpringerVerlag, New York, 1981. 164 Gimson AE, Braude S, Mellon PJ, Canalese J, Williams R. Earlier charcoal haemoperfusion in fulminant hepatic failure. Lancet 1982; 2(8300): 681–683. 165 Tygstrup NLF, Hansen BA. Treatment of acute liver failure by high volume plasmapheresis. Cambridge University Press, Cambridge, 1997. 166 Novelli G, Rossi M, Pretagostini R et al. MARS (Molecular Adsorbent Recirculating System): experience in 34 cases of acute liver failure. Liver 2002; 22(Suppl. 2): 43–47. 167 Kantola T, Koivusalo AM, Hockerstedt K, Isoniemi H. The effect of molecular adsorbent recirculating system treatment on survival, native liver recovery, and need for liver transplantation in acute liver failure patients. Transpl Int 2008; 21(9): 857–866. 168 Wai CT, Lim SG, Aung MO et al. MARS: a futile tool in centres without active liver transplant support. Liver Int 2007; 27(1): 69–75. 169 Ellis AJ, Hughes RD, Wendon JA et al. Pilot-controlled trial of the extracorporeal liver assist device in acute liver failure. Hepatology (Baltimore, Md) 1996; 24(6): 1446–1451. 170 Demetriou AA, Brown RS, Jr., Busuttil RW et al. Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure. Annals of Surgery 2004; 239(5): 660–667; discussion 667–670. 171 Ringe B, Lubbe N, Kuse E, Frei U, Pichlmayr R. Management of emergencies before and after liver transplantation by early total hepatectomy. Transplantation Proceedings 1993; 25(1 Pt 2): 1090. 172 Benhamou JP. Fulminant and Sub-Fulminant Hepatic Failure – Definitions and Causes. Mitre Press, London, 1991. 173 O’Grady JG, Wendon J, Tan KC et al. Liver transplantation after paracetamol overdose. BMJ (Clinical research ed.) 1991; 303(6796): 221–223. 174 Walsh TS, McLellan S, Mackenzie SJ, Lee A. Hyperlactatemia and pulmonary lactate production in patients with fulminant hepatic failure. Chest 1999; 116(2): 471–476. 175 Murphy ND, Kodakat SK, Wendon JA et al. Liver and intestinal lactate metabolism in patients with acute hepatic failure undergoing liver transplantation. Critical Care Medicine 2001; 29(11): 2111–2118. 176 Bernal W, Donaldson N, Wyncoll D, Wendon J. Blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure: a cohort study. Lancet 2002; 359(9306): 558–563. 177 Bernuau J, Goudeau A, Poynard T et al. Multivariate analysis of prognostic factors in fulminant hepatitis B. Hepatology (Baltimore, Md) 1986; 6(4): 648–651. 178 Pauwels A, Mostefa-Kara N, Florent C, Levy VG. Emergency liver transplantation for acute liver failure. Evaluation of London and Clichy criteria. Journal of Hepatology 1993; 17(1): 124–127. 179 Mitchell I, Bihari D, Chang R, Wendon J, Williams R. Earlier identification of patients at risk from acetaminopheninduced acute liver failure. Critical Care Medicine 1998; 26(2): 279–284. 180 Bernal W, Wendon J, Rela M, Heaton N, Williams R. Use and outcome of liver transplantation in acetaminophen-induced

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acute liver failure. Hepatology (Baltimore, Md) 1998; 27(4): 1050–1055. 181 Chenard-Neu MP, Boudjema K, Bernuau J et al. Auxiliary liver transplantation: regeneration of the native liver and outcome in 30 patients with fulminant hepatic failure – a multicenter

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42

Liver transplantation: Prevention and treatment of rejection Maria Pleguezuelo, Giacomo Germani and Andrew K Burroughs The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital and University College London, London, UK

Introduction Liver transplantation (LT) has evolved rapidly over the past four decades. It may seem logical to consider LT recipients as a homogeneous group of patients who should be managed using universally applicable protocols, but they are a heterogeneous group of individuals, with different predisposing factors and co-factors for the development of rejection [1]. However, appropriate therapeutic approaches should be generated on the basis of evidence. In this chapter we attempt to elucidate the following: • Do the severity, timing and number of episodes of acute cellular rejection affect prognosis? • Is it possible to predict which patients will develop clinically significant acute rejection? • Can immunosuppression be tailored to the individual patient? • What is the evidence from randomized controlled trials that supports the choice of an immunosuppressive agent? • Is it possible to withdraw immunosuppression or to change to less toxic immunosuppression? • What is the influence of immunosuppression on HCV (hepatitis C virus) recurrence after LT? • Does immunnosuppression have a role in preventing HCC recurrence after LT? During the past 25 years LT has become the standard therapy for acute and chronic liver failure of all etiologies. Nowadays most patients and liver grafts survive beyond the perioperative period, achieving one-year and ten-year survival rates of 90% and 65–80% respectively [2, 3]. In addition to longer survival, most LT recipients experience improved quality of life, including resumption of active

Evidence-Based Gastroenterology and Hepatology, Third Edition John WD McDonald, Andrew K Burroughs, Brian G Feagan and M Brian Fennerty © 2010 Blackwell Publishing Ltd. ISBN: 978-1-405-18193-8

employment and reproductive capacity [4–8]. Despite these advances, LT faces several major challenges. Longterm outcome of patients is becoming the main concern for clinicians who have to deal with the side effects of immunosuppressant drugs in the long term. These include opportunistic infections that affect up to 50% of recipients, contributing to mortality in approximately 10%, and an increased incidence of de novo malignancy as a consequence of immunosuppression. In addition, complications arise from direct drug toxicity such as hypertension, renal dysfunction, induction of diabetes and dyslipidemias and rarely nodular regenerative hyperplasia of the liver, in patients receiving azathioprine [9–12]. The most important complication is the development of nephrotoxicity due to calcineurin inhibitors. In a series from Birmingham, 4% of patients surviving one year or more developed severe chronic renal failure, with a mortality of 44% in this group [13]. In a study on 36,849 LT recipients the cumulative incidence of chronic renal failure after LT at 12, 36 and 60 months was 8.0 ± 0.1, 13.9 ± 0.2 and 18.1 ± 0.2 percent respectively [14]. In another series 6.9% had renal dysfunction within one year and 4.7% after one year, defined as a creatinine >1.8 mg/dl for two weeks or more [15]. Moreover, the nephrotoxic effects, hypertension and hyperlipidemia of some immunosuppressive agents have been implicated in the pathogenesis of chronic allograft loss [16]. These problems have stimulated the re-evaluation of the ability of some patients to tolerate their liver graft without the need for long-term immunosuppression (operational tolerance), or with greatly reduced immunosuppression (prope tolerance) with the benefits derived from the return of natural immunity and reduction in drug-related toxicity [17–22]. However, at present the “manipulation” of the immune system to induce tolerance and thus significantly reduce or eliminate immunosuppression is not yet clinically viable [23–25]. Therefore, the vast majority of LT recipients need to take lifelong immunosuppressive therapy and this situation will not change until more reliable methods for 685

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predicting and monitoring tolerance in individual patients are developed [21, 22].

Acute allograft rejection Definition of rejection Viewed from a biological perspective, the recipient’s immune system is activated after transplantation but, because of the baseline immunosuppressive therapy, only some recipients will have clinical manifestations of this [26]. An important distinction has to be made between histological changes of cellular rejection, which may be seen in the absence of any significant clinical or biochemical abnormalities (biological rejection), and those accompanied by clinical signs of graft dysfunction (clinical rejection). However, abnormalities of liver function tests are almost universally present, and symptoms absent, so in the vast majority of the cases, the distinction between clinical and biological rejection, as defined above, can rarely be made in clinical practice.

Acute cellular rejection Cellular rejection was defined in 1995, by an international panel of experts, as “inflammation of the allograft elicited by genetic disparity between the donor and recipient, primarily affecting interlobular bile ducts and vascular endothelia, including portal veins and hepatic venules and occasionally the hepatic artery and its branches” [26].

fusion injury) and none of these markers has been adopted into routine clinical practice. Graft eosinophilia has been identified as an independently associated feature of acute cellular rejection in LT [31]. The absence of peripheral eosinophilia predicted the absence of moderate/severe histological rejection in one study [32]. However, as yet this has not been validated in other centers. Eosinophilia cannot be used to predict or to assess the response to corticosteroids for the treatment of acute rejection [32]. Therefore, liver histology remains the gold standard for the diagnosis of acute rejection [33–35].

Histopathological features The three main histopathological features are: • A predominantly mononuclear but mixed portal inflammation, containing blast-like or activated lymphocytes, neutrophils and eosinophils (graded 1 to 3). • Subendothelial inflammation of portal or terminal hepatic veins (or both) (graded 1 to 3). • Bile duct inflammation and damage (graded 1 to 3). In general, at least two of the above histopathological findings and biochemical evidence of liver damage constitutes the minimal diagnostic criteria for hepatic rejection. The diagnosis is strengthened if >50% of the ducts are damaged or if unequivocal endothelitis of the portal vein branches or terminal hepatic venules can be identified (see Table 42.1). Early studies of the liver allograft rejection were focused mainly on inflammatory changes occurring in portal tracts,

Clinical and laboratory findings Most cases occur in the early postoperative period within 30 days. Late cases are usually associated with non-compliance of immunosuppressive therapy. A major problem is that the incidence varies according to whether rejection is defined on the basis of clinically significant rejection or simply on the basis of histological abnormalities or a combination of the two. Clinically significant rejection occurs in approximately 50% of patients, whereas histological abnormalities can be seen in up to 80% of protocol biopsies performed at the end of the first week following transplantation [27]. Several reports have clearly indicated that standard liver tests, when elevated, have a low sensitivity and specificity for rejection and show only a weak correlation with the severity of histopathological findings [28, 29]. Various markers have been studied in an attempt to seek a specific indicator of graft rejection [30]. However, although markers of immune activation, such as peripheral eosinophilia, serum intercellular adhesion molecule (ICAM)-1 and interleukin (IL)-2 receptor are elevated, there is considerable overlap with other conditions (including sepsis and reper686

Table 42.1 Banff schema for grading of acute liver allograft rejection. Overall gradea

Criterion

Indeterminate

Portal inflammatory infiltrate that fails to meet the criteria for the diagnosis of acute rejection

Mild

Rejection infiltrate in a minority of the triads that is generally mild and confined within the portal spaces

Moderate

Rejection infiltrate that expands most or all of the triads

Severe

As for “moderate” but with spillover into periportal areas and moderate to severe perivenular inflammation that extends into the hepatic parenchyma and is associated with perivenular hepatocyte necrosis

a

Verbal descriptions of mild, moderate and severe acute rejection could also be labeled as grades 1, 2 and 3 respectively.

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but also recognized the presence of inflammation involving hepatic venous endothelium and surrounding liver parenchyma [36–38]. During the Eighth Banff Conference on Allograft Pathology in 2005, the term central perivenulitis emerged to describe a spectrum of inflammatory regions of the liver that are in most cases thought to be a manifestation of liver allograft rejection. In cases in which perivenular inflammation occurrs within the first weeks of LT and is associated with characteristic portal tract changes, the diagnosis of rejection is straightforward [39]. However in cases where portal inflammation lacks typical features of ACR the term isolated central perivenulitis should be used [40]. Krasinkas et al. demonstrated that isolated central perivenulitis is a common finding in late post-transplant biopsies and that most cases are probably related to rejection and are associated with a worse outcome compared to cases of purely portal-based rejection [40]. In 2004 Lovell et al. found that patients with centrilobular alterations in their first post-transplant biopsy (n = 15) developed chronic rejection more frequently (60% vs 30%; p < 0.04) and subsequent episodes of acute rejection (53% vs 25%; p < 0.04) when compared to patients who did not have centrilobular alterations (n = 20) [41].

Grading and staging In 1997, an international consensus on a common grading system for acute allograft rejection was achieved and subsequently it has been prospectively tested and proved to be simple, reliable and clinically relevant [42–44]. According to this Banff schema, which represents a merger and simplification of many previously published studies (see Table 42.1), there are two main components: the first is a global assessment of the overall rejection grade (indeterminate, mild, moderate, severe), the second involves scoring the three specific features of rejection semiquantitatively to produce an overall Rejection Activity Index (RAI) [45]. Datta-Gupta et al. showed that graft eosinophilia was an independent diagnostic marker of acute cellular rejection and it was included in the scoring system developed at the Royal Free Hospital [31].

Role of liver biopsy and indication for treatment The use of liver biopsy in the early post-transplant setting depends on each center ’s policy. Nowadays there is less uniformity regarding the use of protocol liver biopsies. This is mainly for two reasons: risks associated with the procedure and doubts about the usefulness of these biopsies to guide therapy, particularly amongst patients with normalizing transaminase values and other biochemical values [46]. However, to date, no large series has described a substantial risk associated with percutaneous liver biop-

LT: prevention and treatment of rejection

sies in transplant recipients [46–48], and greater use of transjugular liver biopsies improves the applicability and does not increase the complication rate compared to percutaneous biopsies [49, 50]. Although it is accepted that liver histology is the gold standard and is essential for the diagnosis of acute cellular rejection, controversy continues to arise over the indications for treatment of rejection. The implication of this is that if treatment is not going to be given, why do a liver biopsy? Specifically, there is the question of the patient who has histological features of acute cellular rejection on protocol liver biopsy, with static or improving graft dysfunction. Some studies suggest that there is spontaneous resolution of mild rejection without biochemical dysfunction [51, 52]. However, abnormal liver function is more usual, and liver function tests are seldom normal at 5–7 days post-transplantation when protocol biopsies are usually done. Bartlett et al. reviewed the literature concerning the natural history of acute cellular rejection, comprising 1566 patients, all of whom had protocol biopsies: 331 (21%) patients had evidence of acute histologic rejection with “normal or normalizing liver function tests” [53]. The majority (91%) of these patients did not receive adjuvant immunosuppression, and only 4% developed chronic rejection. B3 Given these results, the authors concluded that withholding adjuvant immunosuppression from patients with histologic acute cellular rejection with “normal or normalizing liver function tests” is safe, thus not supporting the practice of protocol liver biopsies. However, the study has several limitations: the retrospective nature of the analysis of a heterogeneous group of studies, the lack of definition of “normal or normalizing liver function tests” and the lack of evaluation of histological severity of acute cellular rejection in patients without “biochemical graft dysfunction”. Before abandoning protocol biopsies, a hard look needs to be given to the evidence supporting this approach, and well designed prospective studies are necessary [54]. A further issue is that even severe histological rejection, and not only mild rejection, may resolve spontaneously and only rarely does this lead to graft loss [1, 55]. There is now evidence that the development of early rejection which responds to treatment has no negative long-term effects and may even be associated with lower risk for later immunological complications [44, 56]. Thus, the more fundamental question is how much rejection is not harmful, and therefore complete suppression of rejection is not a goal in managing immunosuppression.

Prognostic factors Do the severity, timing and number of episodes of acute cellular rejection affect prognosis? 687

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Number of episodes In an abstract, Wiesner et al. evaluating a LT database with 870 patients followed for a median of three years, showed that the number of episodes of acute rejection and the histological severity were significantly associated with chronic rejection (p < 0.001) [57]. Dousset et al. prospectively evaluated 170 LT patients and showed that there was no difference in graft function between patients with a single episode of acute rejection (n = 56) and those without rejection (n = 84) [58]. Among patients treated for a single episode of acute rejection, late hepatic function was not influenced by the severity of acute rejection, or by the response to corticosteroids. In contrast, patients with more than one acute rejection episode (n = 30) had significant impairment of liver function tests (aspartate aminotransferase (AST) p < 0.05; alanine aminotransferase (ALT), p < 0.001; alkaline phosphatase, p < 0.01), lower dye clearances (p < 0.01), and more severe histological damage (p < 0.001). The authors concluded that a single episode of acute rejection does not impair long-term hepatic function, whereas recurrent episodes can lead to damage to the liver allograft.

were similar to those of Fisher et al. who analyzed nine studies (comprising a total of 1473 patients), and found that there was no correlation between mortality and incidence of treated acute cellular rejection [60]. B4 These findings in LT are in contrast to renal transplantation in which acute rejection is significantly associated with decreased patient and graft survival. Why acute cellular rejection in LT recipients is not associated with decreased patient and graft survival remains unexplained. It is possible that acute rejection in the setting of controlled alloreactivity exerts a tolerizing effect, making the graft less susceptible to further immunological attack. However, it should be noted that successful treatment for cellular rejection occurs in nearly all cases. Thus, the correct interpretation of the finding reported above is that the occurrence and successful treatment of acute cellular rejection does not influence survival in LT patients, but it does imply that abolishing early cellular rejection need not, and indeed, should not be a goal of initial immunosuppression. This may eliminate the WOFIE period to provide some tolerance to the graft [17, 21, 22].

Timing Severity McVicar et al. described a group of patients who had focal rejection in the hepatic allograft biopsy defined as lymphocytic infiltration involving less than 20% of portal tracts [59]. In the follow-up of patients showing focal or mild rejection, only six (15%) patients subsequently developed abnormal liver function tests and required treatment with additional immunosuppression for acute cellular rejection, suggesting additional immunosuppression is not needed in these patients, and close follow-up would identify the small number requiring therapy [56]. B4 In Birmingham, during follow-up of 151 patients to assess the effect of not treating mild acute rejection (protocol seven-day biopsies), 97 had histologically mild rejection, 50 had biochemical dysfunction and received prednisone for three days, while the remaining 47 cases with stable biochemistry had no additional treatment. Fifty-four patients with no rejection were included for comparison. The outcome at three months in all three groups was similar [27]. B4 Wiesner et al., using the Liver Transplantation Database in a cohort study of 762 consecutive adult LT recipients, examined the association of histological severity of acute rejection and overall patient outcome [44]. They showed, using univariate analysis, that acute rejection overall, including mostly the milder grades, was significantly associated with an increased patient survival (relative risk (RR) 0.71, p = 0.05) and a trend toward improved graft survival. Moreover, adjusting for other risk factors such as age and renal insufficiency revealed no significant decrease in survival among patients who had rejection. These findings 688

As regards timing of acute cellular rejection, there is no firm consensus to define what is early or late rejection. In three different studies the timing and the outcome varied according to the definition of each center. In a retrospective multi-center analysis of 623 LT, the cumulative incidence of biopsy proved rejection was 59% for early episodes (15 ng/ml) are associated with renal dysfunction in the long-term, so that the cost-benefit of this strategy versus steroid therapy requires evaluation [105]. In summary, CNI-based immunosuppression, particularly Tac, improves the long-term graft survival in post-LT patients but renal dysfunction is frequent (9.5%) and this can worsen survival and lead to renal transplantation [13]. Reduction in CNI dosage often does not resolve this problem and suspension of CNI is often associated with increased rejection. Better use of CNI, and/or substitution with effective immunosuppressive agents without nephrotoxicity is required. The use of AZA, mycophenolate mofetil (MMF) and sirolimus with lower doses of CsA or Tac is the most commonly used strategy, as use of these agents as single drugs increases rates of rejection and graft loss [112].

Dosage of tacrolimus A multicenter four-period crossover study showed that conversion from Tac twice a day to a

Antimetabolites: azathioprine and mycophenolate mofetil Azathioprine is a prodrug form of 6-mercaptopurine which inhibits T cell activation, reduces antibody synthesis and decreases the circulating monocytes and granulocytes [113]. AZA alone is relatively effective in the prevention of rejection but has very little effect upon an established immune response [114]. Mycophenolate mofetil is a selective inhibitor of the de novo pathway of purine biosynthesis, thereby providing more specific and potent inhibition of T cell and B cell proliferation than AZA. It has been used for both treatment and prevention of rejection in combination with CNI (see Table 42.3) [115]. 693

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Table 42.3 Randomized trials on MMF in liver transplanted patients. Author

Year

Groups

Immunosuppression

n

Dose MMF

Interval since LT

Other agents

BPACR (%)

Fischer

2000

MMF AZA

1 g bid

No interval

CsA + Ster + ATG CsA + Ster + ATG

19.4 40.6

31 32

Wiesner

2001

MMF AZA

1.5 g bid

No interval

CsA + Ster CsA + Ster

38.5 47.7

278 287

Schlitt

2001

MMF + CNI withdrawal CNI

1 g bid

76 m (median) 90 m (median)

± Ster ± Ster

21.4 0

14 14

Reich

2005

MMF + CNI discontinuation MMF + reduction 50% CNI dose

1.5 g/d

16.5 m (mean) 12.9 m (mean)

Ster Ster

30.0 11.1

20 18

Reggiani

2005

MMF MMF + steroids

0.75 g/d followed by 0.5 mg/d

No interval

Tac Tac

75a 16.7

12 7

Pageaux

2006

MMF + reduction ≥50% CNI dose MMF + standard CNI

2–3 g/d

62.4 m (median) 68.4 m (median)

± Ster ± Ster ± AZA

0 3.4

27 29

Ciccinati (Beckebaum)

2007 (2004)

MMF + low dose CNI MMF + full dose CNI

1 g bid

67.2 (mean) 64.8 (mean)

± Ster

0 0

21 11

a

Only trial in which protocol biopsies were performed (at day 7 after transplantation). This trial was stopped due to a high incidence of acute rejection in the study group. MMF: mycophenolate mofetil; Ster: steroids; CNI: calcineurin inhibitors; Tac: tacrolimus; CsA: cyclosporin; AZA: azathioprine; ATG: antithimocyte globulin; BPACR: biopsy proven acute cellular rejection; LT: liver transplantation.

MMF (1–1.5 g twice daily) was superior to AZA (1–2 mg/kg/d) in preventing biopsy proven acute rejection in the first six months post-LT in two RCTs, but patient and graft overall was not improved [115, 116]. Ald Compared with AZA, MMF has fewer myelotoxic and hepatotoxic adverse effects, but has more gastrointestinal upset including diarrhea, which affects 30% of patients but usually resolves with reducing the dose [117]. The two agents should never be used together. MMF is teratogenetic and 3% of patients develop neutropenia [114]. Opportunistic infections are not significantly increased in comparison to AZA treatment. Monitoring of blood levels is not usually required. Retrospective analysis of large series of liver recipients (n = 15,133) reported better patient and graft survival, as well reduced late acute rejection rates in patients treated with MMF in addition to Tac and steroids, compared with Tac and steroids alone, again just showing that increased immunopotency results in less rejection [118, 119]. An enteric-coated formulation of mycophenolate sodium (EC-MPS) has been developed to reduce the gastrointestinal side effects by delaying mycophenolic acid (MPA, the active metabolite of MMF) release until the small intestine. Bioequivalence has been shown in renal transplantation for both pharmacokinetics [120–122], and RCT [123]. In LT EC-MPS use is limited [124, 125]. 694

MMF has been successfully used as rescue therapy in 38 of 47 (80.9%) liver recipients with acute steroid resistant rejection, in 5 of 8 (62.5%) patients with chronic rejection, in 52 of 60 (86.7%) patients with chronic graft dysfunction and in 46 of 59 (77.9%) patients with CNI-related nephrotoxicity [126]. An RCT including 30 liver recipients who received Tac plus MMF vs Tac plus MMF plus steroids (MMF 750 mg bd for all), showed a higher rate of biopsy proven acute rejection in the former group (75% vs 17%, p < 0.002), with similar toxicity [127]. However early acute rejection did not affect graft or patient survival. As previously mentioned, this study unfortunately did not evaluate equipotent regimes in terms of immunosuppression and just showed that more immunosuppression results in less rejection. To date there is no clear evidence that combination of MMF with CNI improves graft or patient survival compared to CNI and steroids or AZA. Its role may be more as a renal-sparing agent. When administered to reduce the CNI dose in patients with impaired renal function or as monotherapy, acute rejection episodes occurred in 9–38% of cases after CNI withdrawal [128–130], which was more frequent when withdrawal occurred within six months [131] or 12 months [132] after LT in two RCTs, with rates of 50% [131] and 60% [132]. Later withdrawal was safe in

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a retrospective review of 45 patients with renal dysfunction, treated at a median of 45 months after LT, either with MMF as monotherapy (n = 16), or in combination with low dose of CNI [133]. Therapeutic trough levels were deliberately kept < 5 ng/ml or CsA < 50 ng/ml. Acute cellular rejection was documented in only 6% with MMF monotherapy, and serum creatinine values decreased, more so in the monotherapy group compared to the combination group. Similarly, another non-controlled but prospective study introduced MMF 7.7 ± 4.3 years after LT in 49 patients with CNI-associated chronic renal failure (14 Tac, 35 CsA) [134]. Creatinine clearance increased significantly after CNI reduction (from the baseline level of 42.9 ± 14 ml/min to 48.8 ± 17 ml/min after one year and 58.4 ± 20 ml/minute after three years, p < 0.0001). No acute or chronic rejection was reported. B4 A trial randomized 28 post-LT patients on CNI treatment (CsA or Tac) with impaired renal function (defined as >20% decline in renal function with creatinine level 1.8–4 mg/dl and/or creatinine clearance 20–60 ml/min) either to discontinuation or 50% reduction of CNI dose [129]. Both groups received MMF 1.5 g twice daily and steroids. Improvement of 15% or more in glomerular filtration rate (GFR) occurred in 64% of patients with CNI suspension and in 50% of patients with CNI dose reduction, and GFR remained stable in 36% and 37% respectively in a per protocol analysis. Mild or moderate rejection occurred in 30% with CNI discontinuation and in 11% with CNI dose reduction. However, no comparison was made with full dose of CNI. The same strategy was evaluated in an RCT in 32 post-LT patients who received MMF followed by stepwise reduction of CNI (n = 21) or continued CNI therapy (n = 11) [135]. Serum creatinine levels and BUN decreased significantly with MMF at three months (p < 0.01) and GFR increased (p < 0.001), and the lipid profile, blood pressure and transaminase levels also improved after introduction of MMF. No rejection episodes were observed. Ald However, the follow-up for some patients was very short. Pharmacokinetic data have shown that peak concentrations and bioavailability with IV MMF are more than twice those of oral MMF, which may provide immunological advantage, but this has not been evaluated [136, 137]. Therapeutic drug monitoring of MMF is effective in preventing acute rejection in kidney and heart transplantation [138, 139]. Some evidence suggests that MPA concentrations (its active metabolite) could be used for predicting acute rejection in LT recipients [140]. However, routine monitoring of MMF has not been widely performed and dose adjustments are usually performed based on adverse effects. It is common practice to use 2 g/day or less in some LT studies rather than the 3 g/day in the renal transplant registration studies. There is great inter-individual variability of MPA pharmacokinetics, and as in the case of CsA and Tac, measurement after dosing of MMF may have a

LT: prevention and treatment of rejection

stronger correlation with AUC, than C0 monitoring [141– 144]. Subtherapeutic values of MPA measured as C0 and AUC have been found in approximately two-thirds of patients during the first days after LT and in one-third at months 3 and 6 post-LT, but the clinical associations with this are unclear [145].

mTOR inhibitors: sirolimus and everolimus These are inhibitors of the mammalian target of rapamycin (mTOR). Their immunosuppressive activity is primarily related to the blockade of interleukin-2 and interleukin-15 induction of proliferation of T and B cells, and their synergism with other drugs such as CsA, Tac or MMF allows new combinations of therapy (see Table 42.4). Cell growth and angiogenesis are also linked with mTOR activity; mTOR inhibition decreases HCC growth [146]. Recurrence of HCC after LT has become an important problem due to a longer recipient survival under chronic immunosuppression. Data from uncontrolled clinical studies and case reports suggest mTOR inhibitors may delay onset or reduce recurrent HCC [147–149]. A large randomized trial is taking place to clarify this issue (clinicaltrials.gov identifier NCT 00328770). Sirolimus Sirolimus (rapamycin) is a macrocyclic lactone with similar structure to Tac, but its mechanism of action and adverse effect profiles are quite different. Sirolimus (SRL) blocks signal transduction in T-lymphocytes and inhibits cell-cycle progression from G1 to S phase, but does not inhibit calcineurin [150, 151]. While AZA and MMF often are used in conjunction with CNI inhibitors, since their use as single agents increases rates of rejection and graft loss [112], SRL is a promising alternative that may be equivalent to CNI in preventing graft rejection [152–154]. The adverse effects of SRL include dose-dependent hyperlipidemia, thrombocytopenia, anemia, leukopenia, with the absence of neurotoxicity, nephrotoxicity and diabetogenesis, but it has adverse effects on wound healing [155]. Risk of oligospermia in young male patients has also been reported [156]. Sirolimus as primary immunosuppression An international trial comparing SRL with Tac and steroids (n = 110) vs Tac and steroids alone (n = 112) in LT patients was suspended in phase II due to an increase of hepatic artery thrombosis in the SRL group (5.5% vs 0.9%) [157]. This has not been seen in non-randomized studies, but a formal warning remains on the drug information sheet [158, 159]. The first report only comprised 15 patients treated with SRL alone, or SRL plus CsA-ME, or SRL plus CsA-ME plus steroids [160]. Patients on triple therapy had no rejection, while 28% and 75% of those with dual and monotherapy, respectively had rejection. A retrospective study compared three groups: SRL alone (n = 28), SRL plus CIN (n = 56) 695

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Table 42.4 RCT on mTOR inhibitors in liver recipients. Author

Year

Groups

n

mTOR inhibitor

Other agents

Dose

Blood levels at 12 months

Time from LT (months)

ACR (%)

Shenoy

2007

SRL conversion Continued CIN

20 20

3 mg/d (5 mg load)

6.7 ± 3 mg/dL (mean ± SD)

6–132 12–144 (range)

± AZA ± MMF ± Ster ± AZA ± MMF ± Ster

Watson

2007

SRL conversion Continued CIN

13 14

2 mg/d (no loading dose)

7.3 (3.8–9.9) ng/mL (median – range)

36 60 (median)

± AZA ± Ster ± AZA ± Ster

15.4 0

Levy

2006

Everol 1 g Everol 2 g/d Everol 4 g/d Placebo

28 30 31 30

CsA CsA CsA CsA

32.1 26.7 25.8 40.0

N/A

+ + + +

Ster Ster Ster Ster

5 5

Protocol biopsies were not performed in any of the three trials. In the Levy et al. trial, histological diagnosis of rejection was required, but not in the Shenoy et al. trial. The definition of ACR was not stated in the Watson et al. trial. SRL: sirolimus; Everol: everolimus; MMF: mycophenolate mofetil; Ster: steroids; CNI: calcineurin inhibitors; CsA: cyclosporin; AZA: azathioprine; ACR: acute cellular rejection; LT: liver transplantation.

and CNI alone (n = 101) [161]. One-year patient and graft survival rates and histologically proven acute cellular rejection rates (no protocol liver biopsies) were not significantly different. The mean creatinine at one month was similar despite being higher in the SRL group at the time of transplantation. Trotter et al. reported that low dose SRL plus CNI and minimal dose of steroids (three-day taper), resulted in less acute rejection rates than historical controls (treated with CNI plus 14-day tapered prednisone (30% vs 70%; p < 0.01) [162]. Steroid-resistant rejection decreased by 90%. B4 However, as in many studies the interpretation of these data is difficult as no protocol biopsies were done. McAlister et al. reported 56 patients who received low-dose Tac and SRL (target: trough levels, 5 and 7 ng/ml respectively) with prednisone up to six months after transplantation [159]. The biopsy proven acute cellular rejection rate was 14%, approximately 50% lower than historical controls. No patient had steroid-resistant rejection. Pridohl et al. reported patients transplanted for acute liver failure with triple immunosuppression (SRL, Tac and steroids); acute rejection and steroid-resistant rates were 14% and 0% respectively [163]. Some authors have suggested that SRL should be used in combination with low dose Tac to minimize adverse effects from either drug, whilst avoiding an increased risk of rejection [164, 165]. Dunkelberg et al. reported 170 LT recipients treated with SRL (2 mg/day) as part of primary immunosuppression [158]. One-year patient (93%) and graft survival rates (92%) were not different from historical controls (95% and 89% 696

respectively). The acute rejection rate and use of OKT3 (monoclonal antibody against CD3, muromonabCD3) was significantly lower in SRL-treated patients (14%) versus controls (39%), similar to a previous report [162]. However, the proportion of patients needing OKT3 was very high, both in the controls and SRL-treated groups, so that the precise immunosuppressive endpoints are difficult to compare with other publications. Hepatic artery and wound complications in SRL-treated patients were similar to historical controls. Further studies are needed to assess the value of SRL as primary immunosuppression after LT, either as a single agent or in combination with other agents. Conversion from CNI to sirolimus Chronic renal dysfunction occurs in approximately 18% of LT recipients by five-year post-LT and several patients develop end-stage renal disease which shortens patient survival [14]. In contrast to CNI, neither nephrotoxicity nor neurotoxicity has been described with SRL [155], so that it has been used in liver recipients with renal dysfunction, in order reduce or stop CNI, as well as for neurotoxicity or chronic rejection. The first RCT assessing CNI withdrawal and replacement with SRL allocated 40 liver recipients with CrCl between 40–80 ml/min, to receive either SRL or continued CNI [166]. The mean SRL concentrations at one, three and twelve months were 9 ± 3.1; 7.7 ± 1.9 and 6.7 ± 3 mg/dl respectively, with a mean dose throughout of 3 mg/day. Early improvement in CrCl was seen at one and three months in SRL patients: 75 ml/min SRL vs 61 ml/min con-

CHAPTER 42

trols, p = 0.024 at one month and 75 ml/min SRL vs 56 ml/min controls, p = 0.012 at three months. However, at 12 months the difference was not significant: 72 ml/min SRL vs 58 ml/min controls, p = 0.09. Ald This could be because the conversion was too late, at a mean of 4.4 years after LT. The incidence of acute rejection was 5% in both groups and there was no significant difference in lipid profile. Similarly, another RCT allocated 27 liver recipients with GFR < 65 ml/min, to remain on CNI therapy (86% Tac, 14% CsA) or to switch to SRL based immunosuppression [94]. Renal function was measured by the change in 51Crethylenediaminetetraaceticacid GFR (delta GFR). The median time from LT to randomization was three years (0.88–7.4). The median whole blood SRL concentrations were 6.3 ng/ml at three months and 7.3 ng/ml at 12 months. Tac median 12-hour trough concentrations were 7.7 at three months and 7 ng/ml at 12 months. Mean CsA concentrations at three and twelve months were 86 and 107 and 147 ng/ml. Conversion to SRL led to a modest but significant improvement in renal function at three months after conversion, but the difference was not significant at one year. Ala No significant differences in serum creatinine were found. No acute rejection was diagnosed in patients with CNI, while it occurred in two patients (15%) on SRL. Adverse effects were similar except for rash and hypercholesterolemia requiring new statin therapy in the SRL group. These data suggest that conversion to SRL can be done safely and provide adequate immunosuppression without increased incidence of rejection, graft loss or infection in LT recipients. However, there is no evidence as yet for long-lasting renal improvement. Moreover it is not clear if Tac dosing was reduced to a minimum as therapeutic concentrations could still be measured in blood. Multicenter randomized trials including larger groups, in particular, with much earlier conversion intervals, minimal Tac dosing, as well as longer follow-up, are needed to address the benefit of conversion to SRL. Lastly, the hypercholesterolemia induced by SRL may affect cardiovascular risk despite use of statin agents. Everolimus Everolimus is a rapamycin derived compound with improved bioavailability and shorter half-life than SRL (18–35 hours vs 60 hours). Experience with everolimus in liver recipients is more limited than that with SRL. It has lower rates of acute rejection than those seen with AZA in heart transplants and similar to MMF in kidney transplants and may result in less cytomegalovirus infection [167, 168]. It inhibits the growth of human Epstein-Barr virus-transformed B lymphocytes in vitro and in vivo, so it may be optimal when treating post-transplant lymphoproliferative diseases or for prevention [169]. CsA increases exposure to everolimus.

LT: prevention and treatment of rejection

Levy et al. performed a randomized placebo-controlled trial evaluating everolimus combined with CsA (target trough level of 150–400 ng/ml) and prednisone in liver recipients [170]. Three different doses of everolimus were compared: 0.5 mg bid (n = 28) vs 1 mg bid (n = 30) vs 2 mg bid (n = 31) vs placebo (n = 30). Biopsy proven acute rejection episodes were: 39.3% (0.5 mg); 30% (1.0 mg); 29% (2 mg) vs 40% placebo, all non-significant. Rejection was three-fold higher when levels were = 3 ng/ml. Overall graft and patient survival rates and renal dysfunction and its severity were similar across groups. However, the small sample size and high drop-out rates prevent robust conclusions. Larger RCTs are required.

Anti-CD3 pan-T cell (orthoclone OKT3) Muromonab–CD3 (OKT3) is a monoclonal antibody with defined specificity to the CD3 receptor of T cells, thus inactivating both naive and activated cytotoxic T cells. It has been used to prevent acute rejection and to reduce CNI dosage [171, 172]. It was the first monoclonal antibody preventing liver graft rejection. Re-exposure to OKT3 can result in lower efficacy due to the development of antimurine antibodies. There is increased risk of developing post-LT lymphoproliferative disorders and its use is associated with worse recurrence of HCV. Randomization of 52 LT patients to receive either CsA + AZA + steroids or AZA + steroids + OKT3 followed by conversion to CsA at 14 days, showed lower incidence of acute rejection within two weeks after LT (41% vs 72%, p < 0.02) as well as better renal function in the OKT3 group [173]. Nevertheless, long-term follow-up showed similar rejection rates at 30 days post-LT and similar renal function at 6, 12 and 24 months [174]. Ald A trial comparing OKT3 (n = 44) vs a IL-2 receptor antibody (LO-Tact-1) (n = 43) vs no induction (n = 42) in liver recipients on treatment with CsA, AZA and steroids, showed that both agents significantly reduced acute rejection with fewer CMV infections in the LO-Tact-1 group [175]. These results, as well as improved use of current immunosuppressives, make OKT3 less likely to be used as induction therapy.

Interleukin-2 receptor blockers: daclizumab and basiliximab T-lymphocytes play a central role in the initiation and progression of the rejection response. Activated T-lymphocytes secrete IL-2 that acts in an autocrine and paracrine fashion to drive the response forward, and produces more IL-2 receptors (IL-2R). As only activated T-lymphocytes express IL-2R, blocking this receptor with a monoclonal antibody provides a highly selective approach to prevent rejection [176]. Daclizumab and basiliximab are chimeric and humanized antibodies that act on a receptorial subunit, which is expressed only on activated T-lymphocytes, thus selectively inhibiting their proliferation. However, due to 697

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Table 42.5 Randomized trials on IL-2 blocker in liver transplanted patients. Author

Year

Groups

n

Dose IL-2 blocker

BPACR (%)

Boillot

2005

Daclizumab + Tac Tac + Ster

351 347

2 × 2 mg/kg IV pre-reperfusion – 1 mg/kg between day 7–10

25.4 26.5

Yoshida

2005

Daclizumab + Low Tac + MMF + Ster

72

2 mg/kg IV 4 h post-LT – 1 mg/kg IV day 4

Full Tac + MMF + Ster

76

23.2 27.7

188 193

40 mg IV day 0 and 4

35.1 43.5

84 90

20 mg IV day 0 and 4

24.4a 38.1

96 102

20 mg IV day 0 and 4

18 13

Neuhaus

2002

Basiliximab + CsA + Ster Placebo + CsA + Ster

Pageaux

2004

Basiliximab + CsA + Placebo Basiliximab + CsA + Ster

Llado

2006

Basiliximab + CsA Basiliximab + CsA + Ster

a Only trial in which protocol biopsies were performed (at month 12 after transplatation). MMF: mycophenolate mofetil; Ster: steroids; CsA: cyclosporin; AZA: azathioprine; BPACR: biopsy proven acute cellular rejection; LT: liver transplantation.

some redundancy within the IL-2R complex, which permits the IL-2R signalling despite the use of these antibodies, they have to be used together with other agents, such as CNI (see Table 42.5). A pilot study evaluated the daclizumab (1 mg/kg IV, immediately pre- and post-operatively and four more doses at two-week intervals), combined with MMF and steroids, without use of CNI [177]. The study was stopped after the first seven liver recipients due to a 100% incidence of acute rejection, with 57% being steroid resistant. In contrast, retrospective analysis of 25 patients receiving the same therapy but with CNI had a rejection rate of 36% [24]. Considering the sequence of events in graft rejection in LT [24], immunosuppression with IL-2R blockers could play a role at the very beginning, leaving the introduction of CNI to a point when these agents can be introduced without excessive risk of infection or renal dysfunction, that is, monotherapy with IL-2R blockade for the first to second week and then monotherapy with CNI or other drugs. Daclizumab A multicenter randomized trial assessed daclizumab as a steroid avoiding agent in 347 patients receiving Tac plus steroids against 351 patients on steroidfree regimen with Tac following daclizumab induction (follow-up three months) [178]. Acute rejection proven by biopsy that required treatment was similar, as well as graft and patient survival. The daclizumab group had less corticosteroid-resistant acute rejection (6.3 vs 2.8% respectively, p = 0.027), less diabetes mellitus and CMV infection, without increased renal toxicity. Ald In a multicenter, pilot study, 102 liver recipients were treated with daclizumab (2 mg/kg within six hours follow698

ing transplant and 1 mg/kg on day 7), MMF and Tac [179]. Acute rejection proven by biopsy was 9.8% at six months (none graded as severe) and 11.8% after 12 months. Patient and graft survival rates at six months were 96% and 95% respectively. Infections, hypertension, diabetes mellitus and hypercholesterolemia occurred in 22%, 37%, 14% and 2% of patients respectively. B4 Thus, a steroid-free regimen using daclizumab, MMF, and Tac may prevent the occurrence of acute rejection without decreasing safety. An RCT compared renal function in liver recipients treated with daclizumab (2 mg/kg IV within four hours postoperatively and 1 mg/kg IV on day 4 postLT) and delayed low-dose Tac (starting day 4–6) (n = 72), vs those treated with standard Tac regimen without induction (n = 76) [180]. Both groups also received MMF and tapering steroids. The GFR was significantly better in the daclizumab group during the first week after LT, but this was not maintained during the 12 months follow-up. Ald Patient survival and acute rejection rates were similar. Therapy with daclizumab and delayed CNI may not have long-term benefits. A large series of 209 LT patients receiving daclizumab induction (2 mg/kg intraoperatively and 1 mg/kg on day 5 post-LT) was compared with 115 patients without induction therapy [181]. Despite the delayed initiation of CNI in the daclizumab group, there was less acute rejection within six months (25% vs 39%; p = 0.01). Moreover, patients on daclizumab with pre-LT creatinine levels >1.5 mg/dl showed sustained improvement of renal function, while it worsened in those without daclizumab. However patient and graft survival and the chronic rejection rates were not significantly different, again questioning whether long-

CHAPTER 42

term benefit accrues. B4 Currently, daclizumab has been withdrawn from the market. Basiliximab Calmus et al. evaluated 101 patients treated with basiliximab (20 mg dose on day 0 and 4) in conjunction with CsA (adjusted according to therapeutic levels), AZA (1.5 mg/kg per day), and steroids (tapering from 200 mg/day to 5 mg/day) [182], and compared these with a historical cohort derived from Multicentre International Study in Liver Transplantation of Neoral (MILTON) [183]. One-year patient and graft survival rates were 90.1% and 88.1% respectively. Biopsy-confirmed ACR with basiliximab was 22.8% and none was severe. Malignancies, infections or other adverse effects were not increased. Rejection episodes were more frequent in HCV positive compared to HCV negative patients (29% vs 20%, p = ns). B3 Basiliximab in association with Tac and steroids similarly prevented ACR in live donor liver recipients, with a rejection-free probability of 93.5% within three months and 93.8% patient survival rate at three years [184, 185]. Neuhaus et al. reported an RCT comparing basiliximab (n = 188) or placebo (n = 193) in addition to CsA and steroids [186]. There were no protocol biopsies, but clinically suspected rejection was confirmed by liver biopsy. Within six months, acute rejection rates were 35.1% basiliximab and 43.5% placebo (p = ns). Rejection rates in HCV positive patients were slightly more in basiliximab treated patients (39.1% vs 36.2%, p = ns). Complications including infections were similar. Ald The greater rejection rates in HCV positive patients might result from false positive reporting linked to histological similarities between recurrent hepatitis C and acute rejection [187]. However, caution is needed in HCV infection, as adjuvant IL-2R antibodies combined with MMF in the early peritransplantation period was associated with early recurrence of hepatitis C and more rapid histological progression of disease in another study [188]. An RCT evaluated 198 liver recipients (45% HCVpositive) treated with basiliximab as induction therapy with CsA as maintenance immunosuppression, 102 of whom received steroids and 96 were steroid-free [189]. Biopsy-proven ACR, patient and graft survival, and infection rates were similar, including in HCV versus non-HCV subgroups. Diabetic patients in the steroid group had significantly more bacterial infections. The incidence of de novo hypertension and hypercholesterolemia was comparable at six months. Ald In another multicenter trial treated initially with basiliximab, CsA and steroids were allocated to receive maintenance therapy either with CsA and steroids (n = 90) or steroid withdrawal at day 14 (n = 84) [190]. Biopsyconfirmed rejection and treated acute rejection by six months was higher in the steroid-free group (38.1% vs 24.4%, p = 0.03). Metabolic complications were similar.

LT: prevention and treatment of rejection

These results were also similar at 12 months follow-up. Acute rejection was easily controlled in most patients and did not affect graft survival. Ald Non-randomized studies suggest basiliximab induction may allow delay in introducing CNI and reduced CNI dosage, thus improving renal function as well as reducing acute rejection. A prospective study included adult living donor LT (LDLT) recipients assigned to either basiliximab induction (Tac delayed until renal function improved; n = 27) or conventional immunosuppression without basiliximab (Tac started on the first day post-LT; n = 18) [191]. Patients in the induction group were in worse condition pre-LT and had a higher blood loss and transfusion. The serum creatinine levels at the second and third months post-LT were lower in the induction group (p < 0.05). Renal insufficiency (an increase of = 0.5 mg/dl in serum creatinine over the baseline value, or an increase of >50% over baseline, or a reduction of 50% in calculated creatinine clearance, or need for dialysis) at the third month post-LT was lower in the induction group (26% vs 67%, p = 0.007). Acute rejection at six months, as well as infections and diabetes mellitus were similar, and the median cholesterol level was lower in the induction group (152 mg/dl vs 196 mg/dl, p = 0.03). B3 However, the lack of randomization, the small number of patients and the short follow-up, negate robust conclusions. The same considerations pertain to 31 patients (94% chronic hepatitis B carriers) treated with basiliximab with steroid withdrawal 24 hours after LT and reduction of Tac dosage, which showed similar findings compared to historical controls [192].

Anti-thymocyte globulin Anti-thymocyte globulins are heterologous preparations consisting of polyclonal anti-lymphocyte antibodies. A rabbit derived polyclonal antibody (RATG) was shown to be an effective immunosuppressive agent in LT [193]. The role of RATG in LT has been evaluated as a CNI sparing agent [194], or to delay CNI administration in patients with renal dysfunction [195], to reduce or eliminate steroid use [196], or to avoid maintenance immunosuppression [197]. Moreover, its ability to selectively deplete T cells has been used for both prophylaxis and treatment of acute cellular rejection per se. In conjunction with steroids, RATG reduced rejection without increasing infectious complications or malignancy [193, 198]. Eason and colleagues randomized 71 liver recipients to induction therapy with either RATG (n = 36) or steroids (n = 3 5) with maintenance Tac and MMF, with or without prednisone [196]. The rate of biopsy proven rejection was not significantly different: 20.5% RATG vs 32% steroids. However, the RATG group had less rejection needing steroids (p = 0.01), without increased complications, in particular cytomegalovirus infection, diabetes and HCV recurrence. A follow-up of these patients and data on 699

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additional patients undergoing steroid-free OLT confirmed these results [199]. Ald Starzl et al. reported using RATG (5 mg/kg) as pretreatment therapy in 82 solid organ transplant recipients (17 LT) followed by minimum use of post-transplant immunosuppression (Tac monotherapy during the first four months, then spaced Tac therapy) [198]. Graft survival rates were 89% at one year and 88% at 13–18 months. RATG enabled 57.5% of recipients with surviving grafts to be maintained with spaced doses of Tac monotherapy from four months. B4 A retrospective analysis of 198 liver recipients, 118 receiving RATG and delayed initiation of CNI, and 80 receiving no antibody and early initiation of CNI, showed that delayed CNI initiation with RATG significantly improved serum creatinine levels and GFR, with similar patient and graft survival [200]. Overall infection and cytomegalovirus infection rates were significantly lower with RATG, with less early biopsy-proven acute rejection (16% vs 26%, p = 0.08). Another comparison between 129 liver recipients with CNI immediately after LT vs 262 with CNI after initial short-term RATG induction, showed that by one year acute rejection rates were significantly lower in RATG treated patients (14.5% vs 31.8%, p = 0.0008) [201]. Again, serum creatinine levels and GFR were better in the RATG group, with no additional harmful effects. Undesired side effects occurred at a similar rate in both groups. B3 Use of a three-day ATG induction therapy regimen after LT has been promoted as it results in no more rejection than a ten-day course, while reducing the adverse effects, especially lethal infection [202].

Anti-CD52 (alemtuzumab) New protocols of tolerogenic preconditioning have been developed using alentuzumab (Campath-1H) and low doses of CNI. Alentuzumab is a humanized monoclonal antibody directed against the CD52 antigen, a pan T, B and natural killer cell, and monocyte markers [203]. It rapidly depletes lymphocytes, monocytes and other cells without affecting neutrophils and hematopoietic stem cells. The depleted cells begin to re-emerge gradually during a period of six months without returning to baseline levels. This activity is believed to prevent an aggressive lymphocytic immune response after transplantation and allow a more gradual engagement of the host immune system under low conventional immunosuppression. This regimen of host conditioning prior to transplantation, followed by minimum post-transplant immunosuppression could increase the chance of developing tolerance [21, 22, 204–207]. The most extensive experience with the use of alemtuzumab in solid organ transplantation has been done in kidney transplantation [17, 208], as well as intestinal and multivisceral transplantation [209], in which treatment with 700

Campath-1H and low dose of CNI has shown encouraging results. The outcome of 77 liver recipients treated with Campath1H and low dose Tac, with steroid-free maintenance, compared with 50 patients treated with Tac and steroids (HCV patients excluded), showed no differences in patient and graft survival, while rejection-free survival was higher in the Campath-1 group: 51% vs 65% at 12 months, p = 0.009 [23, 210]. Tac-related nephrotoxicity and mean creatinine levels were higher in the control group (p = 0.0001 and p < 0.05 respectively). B3 No differences in viral infection rates were found. Thus, Campath-1 may be at least as effective, as Tac and steroid regimens, with less renal toxicity, but long-term follow-up is needed, especially with regard to risk of malignancy. A similar study evaluated 76 liver recipients (50% HCV positive) treated with Campath-1 induction and low-dose Tac compared to 84 patients (31% HCV positive) receiving standard immunosuppression [211]. No differences in rejection or patient and graft survival were found at one year. However, HCV positive patients did significantly worse than those who were HCV negative, both in the induction and the control group. Moreover increased HCV viral replication was worse with Campath-1. B3 Until now, optimal dose of Campath-1 and ideal combinations of maintenance immunosuppression remain to be determined and the effect on HCV recurrence documented. Its use as a primary treatment for rejection has not been studied. Randomized-controlled trials addressing these issues need to be performed.

Ursodeoxycolic acid Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid which may improve parenchymal function in cholestatic states and possibly slow the progression of primary biliary cirrhosis [212, 213]. Additionally, UDCA reduces the expression of major histocompatibility complex (MHC) class I antigens in patients with primary biliary cirrhosis and therefore may have immunomodulatory effects on T cell-dependent liver damage [212–214]. During acute cellular rejection, MHC class I and II antigens are expressed on hepatocytes, although these are not primary target cells. Cholestasis itself may induce an increased expression of MHC class I antigens on hepatocytes, which can lead to lymphocyte CD8+-dependent cytotoxicity [215]. Based on these theoretical considerations, UDCA might decrease acute cellular rejection episodes in LT patients. There are seven randomized controlled trials involving 335 liver recipients which evaluated UDCA or tauro-UDCA for prevention of acute allograft rejection (see Table 42.6) [216–222]. All seven trials failed to demonstrate that UDCA prevented the occurrence of acute rejection, confirmed by a

CHAPTER 42

LT: prevention and treatment of rejection

Table 42.6 Randomized trials on ursodeoxycholic acid in liver transplanted patients included in the meta-analysis. Author

Year

Groups

n

Immunosuppression

Results

Dose UDCA

Duration UDCA (First dose- Maintenance)

Other agents

ACR (%)

Patient Mortality (%)

Sama

1991

UDCA No treatment

20 20

600 mg/kg

5–7 d after LT – 6 months

Steroids + CsA Steroids + CsA

65.0 65.0

25.0 30.0

Koneru

1993

UDCA No treatment

16 16

900 mg/d

3–5 d after LT – 3 months

Steroids + AZA + CNI Steroids + AZA + CNI

18.7 56.2

N/A

Pageaux

1995

UDCA Placebo

26 24

600 mg/d

3–5 d after LT – 2 months

Steroids + AZA + CNI Steroids + AZA + CNI

34.6 37.5

N/A

Keiding

1997

UDCA Placebo

54 48

15 mg/kg

3–5 d after LT – 3 months

Steroids + AZA + CNI Steroids + AZA + CNI

64.8a 66.7

25.9 20.8

Barnes

1997

UDCA Placebo

28 24

10–15 mg/kg

3–5 d after LT – 3 months

Steroids + AZA + CNI Steroids + AZA + CNI

60.7a 70.8

7.1 29.2

Fleckenstein

1998

UDCA Placebo

14 16

15 mg/kg

3–5 d after LT – 3 months

Steroids + AZA + CNI Steroids + AZA + CNI

57.1 56.3

14.3 25.0

Angelico

1999

TUDCA No treatment

14 15

500 mg/d

3–5 d after LT – 12 months

Steroids + AZA + CNI Steroids + AZA + CNI

50.0 58.8

18.7 11.8

a

Trials in which protocol biopsies were performed after liver transplantation: Keiding et al.: days 7–21–90–365; Barnes et al.: day 7 and month 3. UDCA: ursodeoxycholic acid; TUDCA: tauro-ursodeoxycholic acid; CNI: calcineurin inhibitors; CsA: cyclosporin; AZA: azathioprine; ACR: acute cellular rejection.

meta-analysis of six trials [223]: acute cellular rejection (RR 0.89; 95% CI: 0.74–1.08), mortality, re-transplantation or steroid-resistant rejection were not improved. Ala Assy et al. [224] performed a further RCT evaluating whether UDCA decreased rejection after total immunosuppressant withdrawal, in 26 liver recipients, free of rejection while on immunosuppressive agents for a minimum of two years after LT. They were randomized to UDCA (15 mg/kg) (n = 14) or placebo (n = 12) followed by sequential withdrawal of their immunosuppression over several months. Rejection and its severity were no different: UDCA 43% vs control 75% (p = 0.09) nor in the severity of the rejection. Ald

Granulocyte-colony stimulating factor Studies in animal models as well as clinical trials have demonstrated significant benefits of human recombinant granulocyte-colony stimulating factor (G-CSF) for the treatment of infections in bone marrow recipients, while the experience in solid organ transplantation is more limited. G-CSF used for the first 7–10 days resulted in less acute rejection in 37 liver transplant recipients, compared with historical controls (n = 49) receiving the same immunosuppressive protocol (22% vs 51%). This could be related to a significant reduction in serum TNF levels, which may

be a key player in allograft rejection [225, 226]. However, a subsequent multicenter randomized placebo-controlled trial comprising 194 patients did not confirm reduced infection rates and biopsy proven rejection was more common in the G-CSF treated group compared with placebo (30% vs 19%) [227]. Ald

New immunosuppressive agents Leflunomide is a member of malononitrilamide family which targets the de novo pathway of pyrimidine biosynthesis and thus inhibits T and B cell proliferation. A retrospective review of the use of leflunomide was carried out in 8 liver and 45 kidney transplant recipients [228]. CNI were stopped completely in four liver recipients and reduced by 65% in another patient. No evidence of acute rejection developed in any of these liver (or kidney) transplant patients. FK778, a synthetic derived from leflunomide, has been developed to reduce the extended half-life of leflunomide (6–45 hours vs 15–18 days) [229]. Studies in LT are awaited. FTY 720 is a unique immunosuppressive agent that not only inhibits lymphocyte proliferation, but also results in a redistribution of lymphocytes into lymph nodes and out of circulation. This ability of FTY 720 to impair effector T cell homing is achieved without affecting induction or 701

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expansion of memory responses, suggesting that it may leave tolerizing interactions intact [230]. Studies in human LT are awaited. Janus kinases (JAK) are intermediaries between cytokine receptors and STAT, which result in activation of the immune cells. JAK-3 may be an excellent target for clinical immunosuppression due to its requirement for signaling by multiple cytokines. JAK3/STAT inhibitors in animal models lead to immunosuppression to prevent rejection, without inducing many of the side effects observed with other current therapies [231]. Human studies are awaited.

ity of protocols utilize regimens based on MMF in conjunction with Tac and the proportion of studies using CsA is lower compared to those using Tac. However, many protocols utilize antibody induction agents such as daclizumab, basiliximab and rabbit-derived antithymocyte globulin, thus increasing immunopotency.

Steroid withdrawal and steroid avoidance

Steroid withdrawal Steroid withdrawal based on Taccontaining regimens showed comparable patient and graft survival to protocols using maintenance immunosuppression with steroids; one study found that histology-proven acute rejection was less with steroid withdrawal compared to a steroid regimen (6% vs 27%; p = 0.001) [192, 233, 234]. Infection was less amongst patients who underwent steroid withdrawal (0% vs 18%; p = 0.001) and two studies showed significant reduction in the onset of diabetes mellitus amongst patients who stopped steroids (Table 42.7) [192, 234]. B3 Pageaux et al. evaluated the impact of steroid withdrawal based on a CsA-based regimen in 174 patients, randomized to receive CsA and prednisolone (n = 90) or CsA and placebo (n = 84) [190]. Histologically proven acute rejection at six months was significantly more frequent among patients without steroids than patients on prednisolone (38.1% vs 24.4%; p = 0.03). However, patient and graft survival were similar between the two group, as well as infection rate, diabetes and hypertension. Ald Greig et al. evaluated the safety and efficacy of early steroid withdrawal, comparing 71 patients treated with Tac to 72 patients treated with CsA-ME. They found that patients on Tac had a statistically significant better patient and graft survival (97% and 97%) compared to patients on micro-CsA (89% and 86% respectively) [86]. Acute rejection occurring during the first year was similar (35% with Tac and 43% with micro-CsA), and no chronic rejection developed during this period, presumably because of the short follow-up. B4

Steroids have been the cornerstone of immunosuppressive regimens since the inception of solid organ transplantation. In the past two decades immunosuppressive protocols have evolved driven by a deeper understanding of immunological events after transplantation, and more focus has been placed on minimizing the multitude of side effects and toxicities associated with a long-term therapy with steroids (renal function, infectious risk, loss of bone density, diabetes, hypertension, hyperlipidemia, etc.). The trend has been to use fewer steroids for maintenance therapy. In 2000, a series showed safe withdrawal from the third postoperative month, but the duration of steroid use after LT and the potential role of complete steroid avoidance remain uncertain [232]. Studies evaluating steroid-withdrawal and steroid avoidance in LT are heterogeneous, especially with regards to the interval at withdrawal (1 day–9 months). The major-

Steroid avoidance Several studies have evaluated the safety and efficacy of steroid avoidance in liver transplanted patients (see Table 42.8) [127, 178, 189, 196, 235–247]. No study found statistically significant differences in patient and graft survival comparing steroid-free and steroid inclusive regimens, but these studies are heterogeneous with a range of evaluation time between three months and five years, and often evaluated increased immunosuppression in the steroid free groups. B4 Two studies found statistical differences in biopsyconfirmed acute rejection rates [127, 235]: 24.3% with steroids vs 39.4% without (p = 0.04) [235], and 16.7% steroids vs 75% no steroids (p = 0.002) by Reggiani et al. [127]. In contrast, Varo et al. reported patients on steroids having a higher acute rejection rate compared to patients on steroidfree regimen (11.5% vs 26.6%; p = 0.01) [240].

The future immunosuppression in liver transplantation Future immunosuppressive strategies will be designed to help the development of tolerance of the allograft, selectively stimulating and/or minimally suppressing the recipient’s immune reaction. Studies of the current immunosuppressive agents suggest two ways in which this goal might be attained. First, CNI dosage minimization or even avoidance will continue to be the focus of future studies, to avoid adverse effects and too much rejection. Second, use of new selective immunosuppresive agents which do not depress tolerizing mechanisms or even enhance them, while avoiding side effects, need to be developed [21, 22]. Both approaches need an easy method to assess immunopotency of the immunosuppressive agents and/or a measure of tolerance. The surrogate markers of blood concentrations of immunosuppressives in current use relate more to avoiding toxicity than to issues of rejection or tolerance. These new assays would allow personalized medicine, by individual tailoring doses of immunosuppressive therapy, depending on “day-to-day” immune status.

Weaning immunosuppression

702

2003

2004

2004

2005

2007

Greig

Pageaux

Liu

Junge

Moench

54 56

14 16

31 49

Tac + steroids Tac + (steroids)

Tac + steroids Tac + MMF + (steroids)

Bas + Tac + MMF + (steroids) Tac + steroids

Bas + CsA + steroids Bas + CsA + (steroids)

CsA + AZA + (steroids)

90 84

Tac + AZA + (steroids)

72

IS regimens

Immunosuppression

71

No. of patients

14 days

3 months

1 day

14 days

4–9 months

Interval at withdrawal

12

24

10.8 21.6

12

12

Mean follow-up (months)

94 94

NSa

NS NS

93b 100b 88.8c 85.7c

100 98.8

97 86 p = 0.01

Graft (%)

94 96

97.8 91.7

97 89 p = 0.05

Patient (%)

Survival

35.2 48.2

NSa

6 27 p = 0.001

24.4 38.1 p = 0.03

35 43

Acute (%)

Rejectiona

b

Data non specified, but no difference between the two group was reported. Two-year survival. c One-year survival. All studies considered biopsy-proven acute rejection except from Junge et al. and Moench et al. in which this data is not specified.

a

Year

Author

Table 42.7 Steroid withdrawal in clinical trial (RCT and non-RCT) in the last five years.

0/54 2/56

NS NS

NS NS

NS NS

0 0

Chronic (%)

33 25

NSa

0 18 p = 0.001

13.3 8.3

NS

Infections (%)

53 30 p = 0.02

42.8 12.5

0 28 p = 0.001

22 14.3

NS

Diabetes (%)

Complications

52 39

NS

NS

33.3 28.6

NS

Hypertension (%)

CHAPTER 42

LT: prevention and treatment of rejection

703

704 Year

2003 2004 2004

2005

2005 2005 2005

2005 2005

2006 2006

Author

Eason

Mogl

Filipponi

Reggiani

Boillot

Margarit

Kato

Studenik

Varo

Jensen

Pelletier

Bas/Tac + MMF + steroids Bas/Tac + MMF

Tac + MMF + steroids Tac + Dac + MMF

Tac + steroids Dac + Tac + MMF

Dac + Tac + MMF + steroids Dac + Tac + MMF

Tac + MMF + steroids Dac + Tac + MMF

Tac + steroids Tac

Tac + steroids Dac + Tac

Tac + MMF + steroids Tac + MMF

Bas + CsA + AZA + steroids Bas + CsA + AZA

Tac + steroids Tac + MMF

Tac + MMF + steroids Tac + MMF + RATG

IS regimens

36 36

15 15

79 78

19 20

20 19

32 28

347 351

18 12

74 66

27 26

59 60

No. of patients

13.7

67

NS (0–12)

13

15 8

44

3

31

12

28

18.5

Mean follow-up (months)

Table 42.8 Steroid avoidance in clinical trials (RCT and non-RCT) in the last five years.

78.5 91.6 81c 90c

83c 90c

NSh

NSh

85.7 91.6

NSh

NSh

75–60–60d 84–78–73d

84–78–73d 85–81–66d NS

92.2a 90.5a

94.5a 93.7a

NS

88.9 91.7

84.8c 89c

72.9c 81.5c 100 91.7

NS

80c 82c

85c 85c 78.8 85.7

acute (%)

Graft (%)

patient (%)

14 25

20 13.3

26.6 11.5 p = 0.01

28 52 p = 0.03

NS

NSh

20 5

37 14

28–6–20e 0–0–13e 16 35

30g 26g 32.3 39

11.5 5.1

27.8 50

16.7e 75e p = 0.002 26.5 25.4

86.5 81.8

NS

25 22

infections (%)

Complications

23 39 p = 0.002

30 31

31 25

Rejectionj

Survival

NS

13.3 13.3

NSh

11 5

43 7 p = 0.02

18.7 7.1

15.3 5.7

27.8 16.7

NS NS

NS

14 2

Diabetes (%)

NS

NS

37 15

58 36

9.6 3.5

14.4 12.8

27.8 16.7

NS NS

NS

NS NS

Hypertension (%)

PA RT I I

Liver disease

2006

2006

2006 2008

2008

Fasola

Lladò

Samonakis

Lerut

i

Tac + steroids Bas + Tac

Tac

Tac + steroids

Tac + AZA + steroids Tac

Bas + CsA + MMF + steroids Bas + Csa + MMF

Tac + steroids Tac + MMF + steroids Dac + Tac + MMF

IS regimens

34 50

156 (total)

29 27

102 96

80 79 153

No. of patients

36

12

21.7

6

NS (0–12)

Mean follow-up (months)

91 96

85.9

93.6

88 94

83.3

92.3

89.7 88.9

88b 90b

89b 94b 93.2 77.8

84.8 88.1 89.9

89.5 89.4 92.5

NS

19.2f

53 26

NS

NS

86f 70f

23f

51 47

NS

infections (%)

Complications

13 18

18 13 7

acute (%)

patient (%)

Graft (%)

Rejectionj

Survival

e

Patient and graft survival: a 3 months, b 6 months, c 1 year, d 1, 3 and 5 years. Acute rejection at these interval times: 0–3 months, 3–6 months and 6–12 months; f treated acute rejection. g Infection episodes. h Data non-specified, but no difference between the two group was reported. i Study on pediatric patients. j All studies considered biopsy-proven acute rejection except from Mogl et al., Varo et al. and Gras et al. in which this data is not specified.

Gras

Year

Author

NS

NS

NSh

29 18

NS

Diabetes (%)

NS

NS

NS

44 25 p = 0.006

NS

Hypertension (%)

CHAPTER 42

LT: prevention and treatment of rejection

705

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Liver disease

Patients following regimens without steroids experienced a lower incidence of infections (28% vs 52%; p = 0.03) [242], a lower diabetes mellitus rate (7% vs 43%; p = 0.02) [237], and a lower incidence of hypertension (25% vs 44%; p = 0.006) [189] after LT compared to those using steroids. B4 Segev et al. performed a systematic review of 19 individual studies and 11 updates of these, comparing steroidfree to steroids-based protocols in liver transplanted recipients [248]. There was no difference in survival, graft loss or infection rates. There was a significant reduction in serum cholesterol, risk of CMV infection and HCV recurrence in the steroid-free group. However, the heterogeneity, short-term follow-up and relatively small size of many randomized controlled trials included in this meta-analysis and the lack of evaluating steroid dosage make the conclusions less robust. Alc Moreover, since in 19 individual studies, nine had replaced steroids with another immunosuppressive agent (one basiliximab, five daclizumab, one thymoglobulin and two MMF) and six studies had administered perioperative steroids (one or two doses) to the steroid-free arm, the real impact of steroid-free regimens on outcome after LT has not been evaluated properly. However the data available on steroid withdrawal and/ or steroid avoidance in LT recipients, do show at least comparable results to maintenance immunosuppressive protocols including steroids. B3 Thus, steroids can be either avoided completely or withdrawn without significant sequelae. However, the long-term consequences of steroid avoidance remain unclear. Long-term follow-up studies are needed to explore more fully the benefits of steroid withdrawal and/or steroid avoidance in liver transplanted patients, particularly those transplanted for HCV related cirrhosis.

Total withdrawal of immunosuppression The main aspiration of transplant clinicians is the acceptance of the graft by the recipient without any long-term pharmacological help [17, 21, 22]. Long-term survivors following LT recipients are often systematically and excessively immunosuppressed. Consequently, drug weaning is an important management strategy, providing it is done gradually under careful physician surveillance. Only a few studies have reported cohorts with total withdrawal (see Table 42.9). In 1998 Devlin et al. evaluated 18 adults with uneventful post-LT follow-up and showed that it was possible to either completely withdraw (5/18 patients) or significantly reduce (9/18 patients) maintenance immunosuppression to levels previously considered subtherapeutic [18]. Parameters associated with successful drug withdrawal were transplantation for non-immune-mediated liver disorders, fewer donor-recipient HLA A, B and DR mismatches, and low incidence of early rejection. In 13/18 immunosuppression was recommenced due to elevated 706

liver function tests, but only 4 out of these 13 patents had a histologically proven acute rejection. In a recent update of this study one patient out of the five successfully withdrawn from immunosuppression, developed chronic rejection and required re-transplantation, while in another patient immunosuppression was restarted due to low-grade rejection [249]. B4 Takatsuki et al. described 63 living donor LT recipients receiving Tac: 26 were entered in an elective program of withdrawal, while in the remaining 37 withdrawal was due to serious complications of immunosuppression [250]. In 24 patients, 6 from the elective cohort, Tac was stopped with a median drug-free period of 23.5 months. Rejection occurred in 16 patients (25.4%) after a median interval of 9.5 months, but all episodes were treated by reintroducing Tac or with short courses of steroids. In a later update of this study, the number of patients included in elective weaning increased to 67, with almost similar results (23.8% success and 12% acute rejetion) [251]. B4 Contrasting with previous results, Eason et al. only achieved immunosuppression withdrawal in 1 of 18 patients (5.5%) but 11 of 18 (61%) had rejection [252]. These poor results were probably due to weaning immunossuppression just six months after transplantation, much earlier than in other studies. B4 UDCA did not prevent rejection after total immunosuppression withdrawal [224]. The role of liver cell chimersim and the role of donor bone marrow cell (DBMC) infusion were evaluated in immunosuppression withdrawal programs [253, 254]. Pons et al. achieved complete immunosuppression withdrawal in 3 out of 9 (33%) liver recipient patients [253]. Liver endothelial cell chimerism was studied in five patients and it was not associated with immunosuppression withdrawal. Tryphonopoulos et al. reported similar patient and graft survival, comparing patients who received DBMC and patients who did not [254]. Rejection episodes were significantly lower in the DBMC group in the first two years, but overall there was no significant difference. Successful weaning was achieved in 20 patients out of 104 (19%), without difference between groups. B4 Two patients developed chronic rejection and one required re-transplantation. These data confirmed previous results by Rolles et al., who showed, in a randomized controlled study, that donorspecific bone marrow infusion has no benefit in inducing tolerance in patients undergoing LT [255]. Ald Tisone et al. evaluated weaning immunosuppression in 34 HCV positive patients with recurrent allograft disease [256]. Complete and permanent immunossuppression withdrawal was achieved in 23.5%, with 35.2% rejecting during tapering, and another 41.2% developed rejection within eight months. Weaned patients showed stabilization or improvement of histological fibrosis, lower necroin-

HCV-RNA positive No rejection or cirrhosis on basal biopsy >2 years rejection free History of compliance

>12

>24

2006

2007

Tisone

Assy

26

34

104

CsA + AZA (54%) CsA + steroids (19%) CsA (27%)

CsA

Tac (85%) CsA (14%)

>2

Mean: 5.25

Mean: 4 Range: 3.6–4.6

Median: 7 Range: 5–11

>0.5

Median: 5.2 Range: 2–8.8

>2

Time between LT and weaning (years)

12

Mean: 45.5 Range: 15–44

Mean: 25.8 Range: 11–36

120

12

Range: 17–24

Median: 21.9 Range: 3–69

Follow-up after IS withdrawal (months)

b

LDLT recipients. Treated acute rejection. c All studies considered biopsy-proven acute rejection except from Takatsuki et al. and Oike et al. in which this data is not specified. Table modified by Lerut J, Sanchez-Fueyo A. An appraisal of tolerance in liver transplantation. Am J Transplatation 2006; 6(8): 1774–1780.

a

>1 year rejection-free No autoimmune disease

>36

2005

Tryphonopoulos

CsA + AZA

Side effects of IS

>60

1998/2005

Devlin/Girlanda

Tac

18

9

Normal LFTs

2005

Eason

>1 year rejection-free Normal LFTs

>24 Tac

Maintenance IS

Other

Months after LT

>6

2003

Pons

26a

Immunosuppression

Selection criteria

CsA

2001/2002

Takatsuki/Oike

No. of patients

> 24

Year

Author

Table 42.9 Complete elective imunosuppression withdrawal in liver transplantation.

8

23.4

19

16.7

5.6

33

23.8

Complete withdrawal (%)

58

76.4

67b

28

61

22

12

Acute

0

0

1.9

5.6

0

0

0

Chronic

0

0

0.96

5.6

0

0

0

Graft loss due to rejection

Rejectionc / Graft loss

CHAPTER 42

LT: prevention and treatment of rejection

707

PA RT I I

Liver disease

flammation and improved liver function after a mean follow-up of 45 months. Low blood CSA trough levels during the first post-transplant week and initial steroidfree immunosuppression were found to be independent predictors of sustained weaning, suggesting this subgroup had less propensity for rejection. B4

Immunosuppression in recipients with HCV related cirrhosis Hepatitis C (HCV)-induced cirrhosis is a leading indication for LT [257]. HCV re-infection after LT occurs in virtually all patients transplanted for HCV-related liver disease [258, 259]. Histological evidence of chronic HCV infection develops in 50% to 90% of patients by 12 months after LT [260], and cirrhosis occurs in about 20% of patients within five years after transplant [257, 258, 261]. Several studies have evaluated host and viral factors that might be associated with the severity of HCV recurrence. Among host factors, immunosuppression is one of the major factors that accounts for accelerated HCV recurrence and it has been an area of extensive research and controversy [262]. In a recent multi-center international survey, the prevalent immunosuppressive strategies in LT for hepatitis C were evaluated among 81 LT programs worldwide. The most common regimen used (41%) was based on triple therapy (Tac, MMF and steroids). Concerning the use of steroids, 7.4% of programs used steroid-free protocols, 11% discontinued steroids within a week, 56% within three months and 98% within the first year. When US-programs and non-US programs were compared, CsA was used significantly more among non-US programs (35.6% vs 2.8%) and the duration of steroid therapy was significantly shorter in US programs (10.8 vs 29.4 weeks) [263].

Steroids Although the data on increase of HCV viral loads due to steroid boluses are convincing, the effects of steroid maintenance are still controversial [264, 265]. The link between steroid therapy and viral replication after LT in HCV recipients prompted many centres to advocate steroid therapy withdrawal. However, robust data are limited as to the efficacy of this approach. A rapid reduction in steroid dosage may be harmful for HCV recurrence [266]. B4 The direct effect of dexamethasone and prednisolone on HCV replication has been investigated using an in vitro replicon model. At clinically relevant concentrations (1–10 nM) treatment with both dexamethasone and prednisolone did not enhance, but resulted in a slight reduction of HCV replication. This minor reduction of HCV replication was confirmed by RT-PCR, showing more than 41% reduction in HCV-RNA levels [267]. In a recent study HCV patients transplanted between 2001 and 2004 (n = 90) were compared to a historical group 708

of HCV patients transplanted before the introduction of dual initial immunosuppression (CsA or Tac plus steroids) and slow steroid tapering (1999–2000) (n = 52) [266]. The historical cohort showed a significantly higher rate of severe disease (48%) compared to patients transplanted between 2001 and 2004 (29%). Among patients more recently transplanted the proportion on triple or quadruple regimens (10% vs 25%; p = 0.001) and the number of boluses of methyl-prednisolone were less (4 vs 11; p = 0.002) and the duration of maintenance prednisone was longer (350 days vs 249 days; p < 0.0001) [266]. B4 These data confirm a previous study by Samonakis et al., who found that shortterm maintenance steroids (≤6 months) and AZA were associated with less fibrosis progression [268]. B4 This was further suggested by Vivarelli et al., who compared rapid tapering of steroid (from 25 mg (day 6 to day 30 post-LT) to 15 mg (day 31 to 45), 10 mg (day 46 to 60) 5 mg (day 61 to 75), 2.5 mg (day 76 to 90)) and withdrawal at day 91 after LT (group A) to slow tapering (from 25 mg (day 6 to day 30 post-LT) to 15 mg (day 31 to 90), 10 mg (day 91 to 180), 7.5 mg (day 181 to 270), 5 mg (day 271 to the end of first year), 2.5 mg) and withdrawal 25 months after LT (group B) [269]. At 12 months after LT the rate of advanced fibrosis was higher in the group A compared to group B (42.1% vs 7.6%). Moreover, one and two-year advanced fibrosis-free survivals were 65.2% and 60.8% in group A and 93.7% in group B (p = 0.03 and p = 0.02 respectively). B4 In a recent randomized trial 103 liver transplanted patients for HCV cirrhosis were randomized to Tac (0.1 mg/kg/day) either alone or with AZA (1 mg/kg) and prednisolone (20 mg daily tailing off to zero by 3–6 months) [270]. There were no differences in short-term or overall survival between the two treatment arms and, despite more rejection episodes, the group that had maintenance low dose steroids for between three and six months had slower progression to Ishak stage 4 (23% vs 44%; p = 0.044). Ald Filipponi et al. compared patients on steroid maintenance versus steroid-free regimens in HCV liver transplanted patients [235]. At 12 months after LT there was no significant difference with regard to liver fibrosis and viral loads. However, in patients treated with steroids the antiviral treatment failure rate was significantly higher, but the biopsy proven acute rejection rate was significantly lower. B4 Steroid avoidance was also evaluated in a prospective, randomized, multicenter trial comparing 312 patients randomized to three arms: (1) Tac and steroids; (2) Tac, steroids and MMF; and (3) daclizumab induction, Tac and MMF. Patient and graft survival did not differ significantly among treatment arms; freedom from HCV recurrence at one year was 62%, 60% and 67% in the three groups respectively; freedom from rejection was significantly higher in patients treated with corticosteroid-free immunosuppression compared to those exposed to steroids. Long-term

CHAPTER 42

follow-up is not yet available [271]. Kato et al. randomized HCV positive liver transplanted patients to receive Tac and daclizumab, or Tac and steroids during 1999–2001 and Tac plus MMF and daclizumab or Tac plus MMF and steroids during 2002–2005 [272]. No statistically significant difference was found in mean fibrosis stage between the various treatment arms, either averaging across the two time periods or during these periods themselves. Patients on steroid free-regimens experienced a lower rate of diabetes mellitus (10% vs 45%; p = 0.01) and wound infections (6% vs 31%; p = 0.01). In a recent meta-analysis on steroid avoidance in LT, HCV recurrence was assessed heterogeneously (biopsy-proven (Ishak score) n = 1; biopsy-proven (Ishak ≥ 8) n = 1; biopsy proven (fibrosis, score NS) n = 2; biopsy-proven reinfection n = 2; biopsyproven n = 2; biopsy-proven and biochemical abnormalities n = 1; biopsy-proven with high LFTs and HCV-RNA n = 1; biopsy-proven and HCV-RNA n = 1; not specified n = 1), HCV recurrence was lower with steroid avoidance and although no individual trial reached statistical significance, meta-analysis demonstrated this effect (RR 0.90; 95% CI: 0.82–0.99, p = 0.03). However, there was considerable clinical heterogeneity. Data on fibrosis progression and on steroid dose and withdrawal were not reported [248].

Calcineurine inhibitors In a recent meta-analysis by Berenguer et al. including five randomized control trials (1995–2006) comparing Tac based vs CsA-based immunosuppression in HCV-infected liver transplant recipients, no statistically significant differences for mortality, graft survival, biopsy proven acute rejection, corticoresistant acute rejection or fibrosis cholestatic hepatitis were found [273]. These data confirm previous single center evaluations of differences between CsA and Tac showing no histological differences in HCV recurrence at 12 months nor overall survival rates (90) and no differences in HCV-RNA levels, serum transaminases, histological grading of portal inflammation and fibrosis [274]. Ala CsA has recently been found to have an antiviral effect on HCV [275–281]. CsA has been shown to have a suppressive effect on the HCV replicon RNA level and HCV protein expression in an HCV sub-genomic replicon cell culture system. CsA also inhibited multiplication of HCV genome in a cultured human hepatocyte cell line infected with HCV [275]. This anti-HCV activity is independent of its immunosuppressive and cytotoxic function. Moreover Nakagawa et al. found that Tac does not suppress HCV replication [276]. However, despite the clear antiviral effect of CsA in vitro, there is still controversy about the effect of CsA on HCV-replication in vivo, in the setting of clinical organ transplantation. In a study, ten patients with chronic hepatitis C who did not respond to IFN therapy and who had elevated serum ALT values for at least six months

LT: prevention and treatment of rejection

were treated with CsA for three months (dose increased at one month intervals from 1.5–2 to 2–3 and 3–4 mg/kg/ day). Serum ALT levels gradually decreased in all but one patient; however, serum HCV-RNA titers did not change in any patient throughout the study period [282]. On the basis of current data, it is not possible to conclude that CsA by itself has a profound effect on viral replication or on the course of HCV recurrence after transplantation [283]. In contrast, there are also cohort studies that show advantages using CsA-based regimen compared to Tacbased ones [98, 266, 277, 284–286]. Berenguer et al. found that the interval from LT to acute hepatitis was shorter in patients on Tac regimen compared to those on CsA (59 days vs 92 days; p = 0.02) [266], and that one of the variables associated with a higher probability of developing cirrhosis was induction therapy with Tac [284]. Levy et al. found that the mean time to histological diagnosis of hepatitis C recurrence was significantly longer with CsA-based regimen (100 ± 50 days) than with Tac (70 ± 40 days) even if the rate of histologically-proven HCV recurrence rate was similar between the two groups [98]. In an update study based on the same cohort of patients Shenoy et al. confirmed earlier recurrence in the Tac group (72 ± 42 days vs 145 ± 43 days, p = 0.006) but found that recurrent HCV occurred less frequently in Tac treated patients than in CsA-ME treated ones (21% vs 61%; p = 0.04) [99]. Median time from LT to initiation of antiviral therapy was longer in CsA group compared to Tac group (4.9 ± 1.1 year vs 2.6 ± 1.2 years) [277]. In another study, three-year actuarial risk of fibrosis stage 2 (METAVIR scoring system) was 66% with CsA and 90% with Tac [285]. The relationship between progression of liver fibrosis and histological necroinflammation in HCV recipients was evaluated in 55 patients transplanted for HCV liver disease between 1993 and 2002, retrospectively stratified in three different 40-month periods of transplantation. In a multiregression analysis, Tac at dose to maintain serum concentration of 5–10 ng/ml) was a major factor associated with three-year fibrosis progression rate in HCV-transplanted patients [286]. However this was based on only ten patients. A more interesting set of data is the potential influence of CsA on the efficacy of antiviral therapy in transplant recipients. Firpi et al. reported 115 patients in whom cotreatment of CsA with low-dose IFNα resulted in greater inhibition of HCV replication in comparison with the effects of CsA or IFNα alone [277]. A higher SVR rate was achieved in CsA based immunosuppression compared to Tac based regimens (46% vs 27%; p = 0.03) when evaluated retrospectively. Inoue et al. observed higher SVR rate among patients with chronic HCV treated with IFN-α2b in combination with CsA compared to the group with IFN alone (55% vs 32%; p = 0.01) [287]. B4 709

PA RT I I

Liver disease

CsA taper in association with MMF compared to unchanged immunosuppression with CsA was associated with a marked progression of allograft fibrosis (66% vs 0%), a slight increase of aminotranferases and HCV viral loads (372 ± 280 × 103 IU/ml vs 124 ± 245 × 103 IU/ml). On the other hand renal function improved significantly in the group with MMF and CsA taper [288]. Margarit et al. randomized 35 HCV-positive liver transplanted patients to Tac monotherapy (n = 20) and dual therapy (Tac and steroids) (n = 15) [238]. HCV recurrence, diagnosed as elevation of liver enzymes together with histologic confirmation from liver biopsy, was seen in 17/20 (85%) patients on Tac-monotherapy and in 14/15 (93%). No difference in fibrosis score (Ishak classification) (2.77 ± 2 vs 3.27 ± 1.8) and survival rate at one, three and five years after LT (89%, 83% and 61% vs 81%, 61% and 61%) was seen between the two groups. A comparison was also made between the 12 HCV patients who received no steroids at all (only-Tac) and the 23 patients who received steroids either from the beginning or to treat rejection (only-TacSter). Fibrosis score (Ishak classification) was significantly lower in only-Tac group compared to the only-Tac-steroid group (1.78 ± 1 vs 3.73 ± 1.94; p = 0.005). Patient survival rate at one, three and five years after LT was no different between groups (92%, 92% and 73% only-Tac vs 78%, 61% and 51% only-Tac-steroids). Ald Tac monotherapy (n = 27) in a randomized comparison with triple therapy (Tac, AZA and steroids tapered with six months) (n = 29), resulted in less severe graft hepatitis C with Tac triple therapy (p = 0.0044), despite a higher histological rejection rate (70% vs 86%) and more steroid resistant rejection episodes (10% vs 18.5%) [245, 270]. Ald

Azathioprine and mycophenolate mofetil Antimetabolite immunosuppressants such as AZA and MMF have some common features with ribavirin, an antiviral drug which has been shown to enhance the activity of interferon in the treatment of HCV. Both ribavirin and MMF inhibit the inosine monophosphate deydrogenase that has been shown to have in vitro antiviral properties against flaviviruses [289]. Moreover, ribavirin and three metabolites of AZA are processed to monophosphate nucleotides by inosine monophosphate deydrogenase [290]. These data suggested the possibility that these immunosuppressive agents might also inhibit the hepatitis C virus replication. However, potential beneficial effects of MMF and AZA on HCV recurrence have not been documented in the literature [291]. Azathioprine Stangl et al. used the Bovine viral diarrhea virus (BDVD), a Flaviviridae virus closely related to HCV, to test the potential antiviral effects of AZA andMMF [292]. At doses that achieved similar cytotoxicity, AZA decreased BVDV replication ten times more than MMF. The inhibi710

tion of BVDV by AZA was not related to its cytotoxicity and the effect of AZA on a HCV replicon was at least as large as that of ribavirine. Several studies (1996–2008) have reported on the impact of AZA on the severity of HCV recurrence [268, 284, 286, 293–299]. Most (70%) found that severity of HCV recurrence was decreased using AZA [268, 284, 294–296, 298, 299], whereas three studies showed similar severity in HCV recurrence whether AZA was used or not [286, 293, 297]. B4 However, no study showed that AZA was associated with increased severity of recurrent HCV. Patients treated with AZA containing immunosuppressive regimens reported by Hunt et al. experienced less recurrence (35.2% vs 77%; p < 0.005) and fibrosis progression (5.8% vs 37.5%; p = 0.014) than those without AZA [294]. Berenguer et al. evaluating pre-transplantation and early post-transplantation variables associated with a high risk for severe HCV related disease post-transplantation, found that one of the risk factors associated with severe disease was a short duration induction (50% of triads. NIDDK, National Institute of Diabetes, Digestive and Kidney disease.

Neff et al. in a retrospective review of 21 transplant recipients with clinical and histological diagnosis of chronic rejection treated with sirolimus (0.07 mg/kg) and Tac (serum level 8–14 ng/dl), showed an improvement in the bile duct to hepatic artery ratio and total bilirubin levels. However, a large number of patients experienced drugrelated side effects and were unable to tolerate therapy [321]. B4 Re-transplantation remains the best treatment for chronic rejection associated with severe biochemical cholestasis and advanced bile duct loss, which is usually unresponsive to immunosuppression. The recurrence rate of chronic rejection is as high as 90%, although it is not clear if some characteristics, for example early re-transplantation, are predictive factors for recurrence [322]. Recently it has been recognized that some cases of advanced chronic rejection have recovered spontaneously, or with the use of additional immunosuppression. In some of these cases, follow-up liver biopsies have shown a per-

LT: prevention and treatment of rejection

sistent paucity of bile ducts without other histological features of chronic rejection. Ductopenia has also been noted as an incidental finding in protocol biopsies taken at annual review from patients who are clinically well, with no previous biopsies suggesting chronic rejection. These findings suggest that some patients may suffer permanent duct loss as a result of rejection, but that sufficient ducts remain to allow the graft to function normally. Because of these observations and the risks associated and logistical difficulties with a second transplantation, the decision to retransplant should only be made when a confident diagnosis of irreversible and progressive graft damage is established.

Acknowledgements Dr Maria Pleguezuelo is supported by the Liver Research Unit, University Hospital Reina Sofia, Cordoba, Spain; Dr Giacomo Germani is supported by University Hospital of Padua, Department of Surgical and Gastroenterological Sciences, Gastroenterology Section, University of Padua, Italy.

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269 Vivarelli M, Burra P, La Barba G et al. Influence of steroids on HCV recurrence after liver transplantation: A prospective study. J Hepatol 2007; 47(6): 793–798. 270 Manousou P, Samonakis D, Cholongitas E et al. Outcome od recurrent HCV after liver transplantation in a randomized trial of tacrolimus monotherapy versus triple therapy. Liver Transpl 2009; 15(12): 1783–1791. 271 Klintmalm GB, Washburn WK, Rudich SM et al. Corticosteroidfree immunosuppression with daclizumab in HCV(+) liver transplant recipients: 1-year interim results of the HCV-3 study. Liver Transpl 2007; 13(11): 1521–1531. 272 Kato T, Gaynor JJ, Yoshida H et al. Randomized trial of steroidfree induction versus corticosteroid maintenance among orthotopic liver transplant recipients with hepatitis C virus: impact on hepatic fibrosis progression at one year. Transplantation 2007; 84(7): 829–835. 273 Berenguer M, Royuela A, Zamora J. Immunosuppression with calcineurin inhibitors with respect to the outcome of HCV recurrence after liver transplantation: results of a meta-analysis. Liver Transpl 2007; 13(1): 21–29. 274 Hilgard P, Kahraman A, Lehmann N et al. Cyclosporine versus tacrolimus in patients with HCV infection after liver transplantation: effects on virus replication and recurrent hepatitis. World J Gastroenterol 2006; 12(5): 697–702. 275 Watashi K, Hijikata M, Hosaka M, Yamaji M, Shimotohno K. Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes. Hepatology 2003; 38(5): 1282–1288. 276 Nakagawa M, Sakamoto N, Enomoto N et al. Specific inhibition of hepatitis C virus replication by cyclosporin A. Biochem Biophys Res Commun 2004; 313(1): 42–47. 277 Firpi RJ, Zhu H, Morelli G et al. Cyclosporine suppresses hepatitis C virus in vitro and increases the chance of a sustained virological response after liver transplantation. Liver Transpl 2006; 12(1): 51–57. 278 Goto K, Watashi K, Murata T, Hishiki T, Hijikata M, Shimotohno K. Evaluation of the anti-hepatitis C virus effects of cyclophilin inhibitors, cyclosporin A, and NIM811. Biochem Biophys Res Commun 2006; 343(3): 879–884. 279 Henry SD, Metselaar HJ, Lonsdale RC et al. Mycophenolic acid inhibits hepatitis C virus replication and acts in synergy with cyclosporin A and interferon-alpha. Gastroenterology 2006; 131(5): 1452–1462. 280 Ishii N, Watashi K, Hishiki T et al. Diverse effects of cyclosporine on hepatitis C virus strain replication. J Virol 2006; 80(9): 4510–4520. 281 Paeshuyse J, Kaul A, De Clercq E et al. The nonimmunosuppressive cyclosporin DEBIO-025 is a potent inhibitor of hepatitis C virus replication in vitro. Hepatology 2006; 43(4): 761–770. 282 Kakumu S, Takayanagi M, Iwata K et al. Cyclosporine therapy affects aminotransferase activity but not hepatitis C virus RNA levels in chronic hepatitis C. J Gastroenterol Hepatol 1997; 12(1): 62–66. 283 Watashi K, Metselaar HJ, Van Der Laan LJ. Interfering with interferon: re-igniting the debate on calcineurin inhibitor choice and antiviral therapy for hepatitis C virus recurrence. Liver Transpl 2008; 14(3): 265–267.

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284 Berenguer M, Prieto M, San JF et al. Contribution of donor age to the recent decrease in patient survival among HCV-infected liver transplant recipients. Hepatology 2002; 36(1): 202–210. 285 Villamil F, Levy G, Grazi GL et al. Long-term outcomes in liver transplant patients with hepatic C infection receiving tacrolimus or cyclosporine. Transplant Proc 2006; 38(9): 2964–2967. 286 Baiocchi L, Angelico M, Petrolati A et al. Correlation between liver fibrosis and inflammation in patients transplanted for HCV liver disease. Am J Transplant 2008; 8(3): 673–678. 287 Inoue K, Sekiyama K, Yamada M, Watanabe T, Yasuda H, Yoshiba M. Combined interferon alpha2b and cyclosporin A in the treatment of chronic hepatitis C: controlled trial. J Gastroenterol 2003; 38(6): 567–572. 288 Kornberg A, Kupper B, Wilberg J et al. Conversion to mycophenolate mofetil for modulating recurrent hepatitis C in liver transplant recipients. Transpl Infect Dis 2007; 9(4): 295–301. 289 Neyts J, Meerbach A, McKenna P, De CE. Use of the yellow fever virus vaccine strain 17D for the study of strategies for the treatment of yellow fever virus infections. Antiviral Res 1996; 30(2–3): 125–132. 290 Nelson JA, Carpenter JW, Rose LM, Adamson DJ. Mechanisms of action of 6-thioguanine, 6-mercaptopurine, and 8-azaguanine. Cancer Res 1975; 35(10): 2872–2878. 291 Firpi RJ, Nelson DR, Davis GL. Lack of antiviral effect of a short course of mycophenolate mofetil in patients with chronic hepatitis C virus infection. Liver Transpl 2003; 9(1): 57–61. 292 Stangl JR, Carroll KL, Illichmann M, Striker R. Effect of antimetabolite immunosuppressants on Flaviviridae, including hepatitis C virus. Transplantation 2004; 77(4): 562–567. 293 Singh N, Gayowski T, Ndimbie OK, Nedjar S, Wagener MM, Yu VL. Recurrent hepatitis C virus hepatitis in liver transplant recipients receiving tacrolimus: association with rejection and increased immunosuppression after transplantation. Surgery 1996; 119(4): 452–456. 294 Hunt J, Gordon FD, Lewis WD et al. Histological recurrence and progression of hepatitis C after orthotopic liver transplantation: influence of immunosuppressive regimens. Liver Transpl 2001; 7(12): 1056–1063. 295 Berenguer M, Crippin J, Gish R et al. A model to predict severe HCV-related disease following liver transplantation. Hepatology 2003; 38(1): 34–41. 296 Bahra M, Neumann UI, Jacob D et al. MMF and calcineurin taper in recurrent hepatitis C after liver transplantation: impact on histological course. Am J Transplant 2005; 5(2): 406–411. 297 Belli LS, Burroughs AK, Burra P et al. Liver transplantation for HCV cirrhosis: improved survival in recent years and increased severity of recurrent disease in female recipients: results of a long term retrospective study. Liver Transpl 2007; 13(5): 733–740. 298 Eid AJ, Brown RA, Paya CV, Razonable RR. Association between toll-like receptor polymorphisms and the outcome of liver transplantation for chronic hepatitis C virus. Transplantation 2007; 84(4): 511–516. 299 Walter T, Dumortier J, Guillaud O et al. Rejection under alpha interferon therapy in liver transplant recipients. Am J Transplant 2007; 7(1): 177–184. 300 Gonzalez MG, Madrazo CP, Rodriguez AB et al. An open, randomized, multicenter clinical trial of oral tacrolimus in liver

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310 311

allograft transplantation: a comparison of dual vs. triple drug therapy. Liver Transpl 2005; 11(5): 515–524. Zekry A, Gleeson M, Guney S, McCaughan GW. A prospective cross-over study comparing the effect of mycophenolate versus azathioprine on allograft function and viral load in liver transplant recipients with recurrent chronic HCV infection. Liver Transpl 2004; 10(1): 52–57. Kornberg A, Kupper B, Tannapfel A, Hommann M, Scheele J. Impact of mycophenolate mofetil versus azathioprine on early recurrence of hepatitis C after liver transplantation. Int Immunopharmacol 2005; 5(1): 107–115. Papatheodoridis GV, Davies S, Dhillon AP et al. The role of different immunosuppression in the long-term histological outcome of HCV reinfection after liver transplantation for HCV cirrhosis. Transplantation 2001; 72(3): 412–418. McCaughan GW, Zekry A. Impact of immunosuppression on immunopathogenesis of liver damage in hepatitis C virusinfected recipients following liver transplantation. Liver Transpl 2003; 9(11): S21–S27. McCaughan GW, Zekry A. Mechanisms of HCV reinfection and allograft damage after liver transplantation. J Hepatol 2004; 40(3): 368–374. Berenguer M, Aguilera V, Prieto M et al. Effect of calcineurin inhibitors on survival and histologic disease severity in HCVinfected liver transplant recipients. Liver Transpl 2006; 12(5): 762–767. De Ruvo N, Cucchetti A, Lauro A et al. Preliminary results of a “prope” tolerogenic regimen with thymoglobulin pretreatment and hepatitis C virus recurrence in liver transplantation. Transplantation 2005; 80(1): 8–12. Kamar N, Borde JS, Sandres-Saune K et al. Induction therapy with either anti-CD25 monoclonal antibodies or rabbit antithymocyte globulins in liver transplantation for hepatitis C. Clin Transplant 2005; 19(1): 83–89. Ramirez CB, Doria C, di Francesco F, Iaria M, Kang Y, Marino IR. Basiliximab induction in adult liver transplant recipients with 93% rejection-free patient and graft survival at 24 months. Transplant Proc 2006; 38(10): 3633–3635. Lake JR. The role of immunosuppression in recurrence of hepatitis C. Liver Transpl 2003; 9(11): S63–S66. O’Keeffe C, Baird AW, Nolan N, McCormick PA. Mast cell hyperplasia in chronic rejection after liver transplantation. Liver Transpl 2002; 8(1): 50–57.

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312 Demetris AJ, Murase N, Lee RG et al. Chronic rejection. A general overview of histopathology and pathophysiology with emphasis on liver, heart and intestinal allografts. Ann Transplant 1997; 2(2): 27–44. 313 Lowes JR, Hubscher SG, Neuberger JM. Chronic rejection of the liver allograft. Gastroenterol Clin North Am 1993; 22(2): 401–420. 314 Kemnitz J, Gubernatis G, Bunzendahl H, Ringe B, Pichlmayr R, Georgii A. Criteria for the histopathological classification of liver allograft rejection and their clinical relevance. Transplant Proc 1989; 21(1 Pt 2): 2208–2210. 315 Blakolmer K, Seaberg EC, Batts K et al. Analysis of the reversibility of chronic liver allograft rejection implications for a staging schema. Am J Surg Pathol 1999; 23(11): 1328–1339. 316 Theruyath TP, Neumann UP, Langrehr JM et al. Risk factors for chronic rejection after liver transplantation. Liver transpl 2003; 9(6): C4 [abstract]. 317 Quaglia AF, Del Vecchio BG, Greaves R, Burroughs AK, Dhillon AP. Development of ductopaenic liver allograft rejection includes a “hepatitic” phase prior to duct loss. J Hepatol 2000; 33(5): 773–780. 318 Demetris AJ, Seaberg EC, Batts KP et al. Reliability and predictive value of the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database nomenclature and grading system for cellular rejection of liver allografts. Hepatology 1995; 21(2): 408–416. 319 Sher LS, Cosenza CA, Michel J et al. Efficacy of tacrolimus as rescue therapy for chronic rejection in orthotopic liver transplantation: a report of the U.S. Multicenter Liver Study Group. Transplantation 1997; 64(2): 258–263. 320 Gregory CR, Huang X, Pratt RE et al. Treatment with rapamycin and mycophenolic acid reduces arterial intimal thickening produced by mechanical injury and allows endothelial replacement. Transplantation 1995; 59(5): 655–661. 321 Neff GW, Montalbano M, Slapak-Green G et al. A retrospective review of sirolimus (Rapamune) therapy in orthotopic liver transplant recipients diagnosed with chronic rejection. Liver Transpl 2003; 9(5): 477–483. 322 van Hoek B, Wiesner RH, Ludwig J, Gores GJ, Moore B, Krom RA. Combination immunosuppression with azathioprine reduces the incidence of ductopenic rejection and vanishing bile duct syndrome after liver transplantation. Transplant Proc 1991; 23(1 Pt 2): 1403–1405.

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Liver transplantation: Prevention and treatment of infection Antoni Rimola and Miquel Navasa Liver Unit, Institut de Malalties Digestives i Metaboliques, Hospital Clinic, IDIBAPS, CIBEREHD, Barcelona, Spain

Early studies reported that 50–80% of patients developed infection after liver transplantation and that this complication was a major cause of death, especially during the first postoperative year, with a rate of infection-related mortality of around 20% [1–6]. Little information is available on the incidence of infection after liver transplantation in more recent years. However, due to progressively implemented preventive strategies against infection, especially opportunistic infections, it is likely that infectious complications have become less frequent. As an example, in our institution the incidence of infection decreased from 83% in the period 1988–1990 to 42% in the period 2001–2003 [7]. This, coupled with the improvement in the diagnosis of infection, has reduced the mortality secondary to infection, as shown in several recent prospective clinical trials on the efficacy and safety of different immunosuppressive regimens in which the short and mid-term infection-related mortality was less than 10% [8–10]. Nonetheless, infection remains a common and relevant complication in liver transplantation, requiring appropriate prophylactic and therapeutic measures, as summarized in this chapter. Since the rationale for these measures not only arises from the particular characteristics of each infection but also from the risk factors for and the time of occurrence of the different types of infection, these two aspects are also addressed in this chapter. As the spectrum of infection and its prevention and treatment have experienced important changes over time, this chapter is mainly focused on current practice.

Risk factors for infection All liver transplant recipients have two risk factors for infection: the major abdominal surgical procedure of transEvidence-Based Gastroenterology and Hepatology, Third Edition John WD McDonald, Andrew K Burroughs, Brian G Feagan and M Brian Fennerty © 2010 Blackwell Publishing Ltd. ISBN: 978-1-405-18193-8

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plantation and the administration of immunosuppressive treatment. In most cases powerful immunosuppression is administered during the early postoperative period, the phase with the greatest risk of rejection. Subsequently, immunosuppression is gradually reduced until the end of the first or second postoperative year, when immunosuppression is stabilized at a low grade of immune suppression. Other circumstances common in liver transplant recipients are also risk factors for infection by increasing the so-called “net state of immunosuppression” [11]. The most relevant of these circumstances are listed in Table 43.1. Apart from these general risk factors, there are also specific risk factors for the different types of infection, which will be addressed in the sections dealing with these infections.

Time of infection occurrence Classically, three different periods have been defined according to the predominant types of infection in each period: the first postoperative month, from month two to month six, and beyond six months (see Figure 43.1) [11–15]. During the first postoperative month, the most frequent infectious complications are bacteremia, pneumonia and surgical site infection, predominantly caused by nosocomial bacteria and recipient colonizing bacteria. Fungal infections are also relatively common. Despite the high grade of immunosuppression during this period, opportunistic infections are infrequent, with the exception of herpes simplex, probably because immunosuppression requires some time to promote the clinical expression of most opportunistic infections. Infections derived from the graft donor, although potentially serious, are also uncommon [16]. Characteristically, opportunistic infections and reactivated latent infections emerge during the intermediate period, from months two to six. Classical pathogens in this

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LT: prevention and treatment of infection

RISK FACTORS FOR INFECTION: INFECTION Immunosuppression

Powerful

Moderate

Mild

Pre-operative Surgical-related, , g invasive maneuvers Immunomodulatory events PERIOD Figure 43.1 Occurrence of the most frequent infections in liver transplant recipients according to time after transplantation and to the main risk factors for infection. Continuous or broken lines indicate the relative importance (strong or less intense, respectively) of the different risk factors in each period.

INFECTION

Table 43.1 Circumstances affecting the net state of immunosuppression in liver transplant recipients (adapted from reference 11). Pharmacological immunosuppression Invasive manoeuvres compromising muco-cutaneous barrier integrity: Intravenous lines Tracheal intubation Reoperation Bladder catheterization Underlying immunomodulatory conditions (pre- and/or post-operative): Very advanced liver disease Metabolic: Renal failure Diabetes mellitus Malnutrition Multiple organ failure Viral infection: Cytomegalovirus Epstein-Barr virus Hepatitis C virus

EARLY (< 1 month)

INTERMEDIATE (2 - 6 months)

LATE (> 6 months)

Bacterial: - Nosocomial - Recipient colonizing

Opportunistic and latent reactivated: - CMV - EBV - P. jirovecci - Tuberculosis - Toxoplasma

Community-acquired infections (similar to general population)

Fungal: - Candida - Filamentous

Opportunistic and latent reactivated (less frequent)

and little requirement of re-hospitalization, the risk of infection drastically decreases, becoming similar to that in the general population. During this late period, most infections are community acquired, although opportunistic infections can also occur. This spectrum of infection occurrence can be altered due to a variety of reasons, with important overlap between the periods. For example, biliary and graft vascular problems can persist beyond the early postoperative period, with the subsequently prolonged risk of infection related to these surgical complications. The need to maintain long-term immunosuppression due to late-onset or persisting rejection is associated with an increased risk of opportunistic infections and latent infection reactivation throughout the time under potent pharmacological immunosuppression. Finally, the persistence or de novo appearance of immunomodulatory events, such as chronic renal failure or severe recurrence of pre-transplant liver disease (particularly, hepatitis C), can modify the risk of infection during the intermediate and late post-transplant periods.

Bacterial infection period include cytomegalovirus (CMV) and other herpes group viruses, Pneumocystis jirovecii (formerly, P. carinii), other fungi (variable according to fungal geographical distribution), and protozoa (mainly Toxoplasma and Leishmania). Infections caused by mycobacteria, Listeria spp. and Nocardia spp. can also be observed. Although beyond the scope of this chapter, recurrence of hepatitis C virus should also be mentioned because this complication represents a major problem in liver transplantation. Beyond month six post-transplantation, and coincidentally with a progressive reduction of immunosuppression

Incidence and special risk factors Bacterial infections are the most frequent infectious complications in liver transplant recipients and predominantly occur during the early postoperative period. The commonest bacterial infections in this period are surgical site infection, bacteremia and pneumonia. In most studies, the development of bacteremia and pneumonia has been associated with increased risk of mortality [17–22]. Surgical site infection, although not greatly influencing survival, increases hospital resource utilization and cost [23, 24]. In 725

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recent reports, the mean incidence of surgical site infection, involving the incision wound and intra-abdominal organspace infections (namely, localized or diffuse peritonitis, cholangitis, infected biloma and hepatic abscess), is approximately 25%, ranging from 5% to 40% [23–33]. Bacteremia has also been reported with variable frequency, between 9% and 36% [19, 28–30, 33–36]. In a recent prospective, multicenter study involving 16 Spanish centers and including 1012 liver transplantations followed up to two years, the incidence of the bloodstream infections (caused by bacteria in 96% of the cases) was 10% [22]. In this study, most bloodstream infection episodes were catheter-related (30%), secondary to surgical site infection (24%) and, to a lesser extent, to pneumonia (6%), whereas the primary source of bacteremia was not identified in 34% of cases. Similar sources of bacteremia have been found by other authors [18, 36, 37]. A 7–28% incidence of pulmonary infections has been reported in recent series [17, 19, 21, 28–30, 33, 35, 38–42]. Other types of infection, such as urinary tract or central nervous system infections, are much less frequently observed [13]. Aside from the general risk factors for infection previously mentioned, other factors specifically favor bacterial infection in liver transplant recipients. Prolonged surgery or reoperation, increased perioperative transfusion, living donor liver transplantation and biliary anastomosis with choledochojejunostomy predispose to surgical site infections [25, 26, 43, 44]. Specific risk factors for bacterial pneumonia are prolonged mechanical ventilation, persistent non-infectious pulmonary alterations and living donor transplantation [19–20, 39]. Rejection and prolonged hospital stay are risk factors for bacterial infections in general [35, 37, 40, 45]. In children, low weight and low age have been associated with increased risk of bacterial infection

[30]. The type and intensity of pharmacological immunosuppression does not clearly influence the risk of bacterial infection, although mTOR inhibitors (sirolimus and everolimus; also called proliferation signal inhibitors, PSIs) may favor surgical-site infections by impairing wound healing [46]. In later post-transplant periods, bacterial infections are much less frequent and are mainly limited to communityacquired infections, especially pneumonia and urinary tract infections [16, 47–49], and to infections related to persisting biliary and arterial complications [32, 33, 50, 51]. Liver transplant patients are slightly more susceptible to some intracellular bacteria, such as Listeria spp., Legionella spp., and Nocardia spp. [47, 52]. The negative impact of late bacterial complications on the survival of liver transplant patients is low or very modest [53–58].

Causative organisms Organisms causing bacterial infections in liver transplant patients during the early postoperative period correspond to environmental bacteria (transmitted from contaminated persons or equipment) and recipient endogenous bacteria [2, 3, 12, 13, 15, 17, 19–22, 24–28, 34, 36, 45, 59–61], summarized in Table 43.2. Occasionally, other pathogens, such as Legionella spp., can transiently acquire special relevance [62–64]. Anaerobes are a rare cause of infection in liver transplant patients [35, 29, 30, 61], although Clostridium difficile colitis has been reported as being relatively prevalent in some centers [2, 43]. A substantial proportion of surgical-site and, to a lesser extent, pulmonary infections are polymicrobial. In pneumonia, the isolation of different organisms can correspond to either true polymicrobial infections or subsequent super-

Table 43.2 The commonest microorganisms responsible for major bacterial infections in the early postoperative period following liver transplantation. Only data from recent studies (published from 2000 onwards) are included [17, 19–22, 24–26, 28, 34, 36, 59–61]. Surgical-site infections

Bacteremia

Pulmonary infections

General type

Most frequent

Enterococcus spp. Staph. aureus CN staphylococcus

Gram+ cocci: 32–75%

E. coli Klebsiella spp. Pseudomonas spp.

Aerobic Gram− bacilli: 25–59%

General type

Most frequent

Gram+ cocci: 40–56%

Aerobic Gram− bacilli: 44–53%

Polymicrobial: 17–48%

a

Polymicrobial: 4%

a

General type

Most frequent

CN staphylococcus Enterococcus spp. Staph. aureus

Gram+ cocci: 0–42%

Staph. aureus Streptococcus spp.

E. coli Klebsiella spp Pseudomonas spp.

Aerobic Gram− bacilli: 48–100%

Pseudomonas spp. Klebsiella spp. S. maltophilia

Polymicrobial: 10% Unidentified: 30%

a

In some institutions, Acinetobacter baumanii is also very prevalent. CN: coagulase-negative.

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infections by pathogens resistant to the current antibiotic therapy [17, 20]. As expected, causative organisms in pneumonia cannot be identified in a significant percentage of cases because the microbiological diagnosis frequently requires bronchoscopy with bronchoalveolar lavage, which is not always performed before starting antibiotic therapy [20, 38, 40, 62]. In late periods of liver transplantation, the most frequent bacterial complications are community-acquired pneumonia, mainly caused by Streptococcus. pneumoniae, Haemophilus influenza and Mycoplasma, and urinary tract infections, mainly caused by Gram-negative bacilli [47, 13, 35, 49]. Other late bacterial infections are cholangitis related to persistent biliary complications, mainly caused by enterobacteria and Pseudomonas spp. [33], and hepatic abscess secondary to vascular complications, caused by a variety of organisms including Gram-positive cocci, Gram-negative bacilli and anaerobes [51]. Liver transplant patients can also develop tuberculosis. However, since this complication has special characteristics, its prevention and treatment will be addressed separately at the end of this section.

LT: prevention and treatment of infection

most European countries [29, 74, 75]. Bowel colonization, acquired pre- or post-transplant, is the major source of VRE infection [71, 76]. Linezolid and daptomycin are active against most VRE [77, 78]. Among the enteric Gram-negative bacilli, Escherichia coli and Klebsiella pneumoniae are the organisms most commonly producing extended-spectrum beta-lactamase (ESBL), although other enterobacteriaceae strains can also express ESBL [79]. In general, ESBL-producing enterobacteria are susceptible to carbapenems (imipenem, meropenem and ertapenem) [80, 81]. Pseudomonas spp. are the most relevant multi-resistant non-fermentative Gram-negative bacilli in liver transplant patients. Other multi-resistant members of this family with increasing importance for liver transplant patients are Acinetobacter baumanii and Stenotrophomonas maltophilia. Tigecycline is habitually active against A. baumanii and S. maltophilia [82]. S. maltophilia is also highly susceptible to cotrimoxazole [83]. Several authors have found a direct association between mortality and VRE colonization and infection by some multi-resistant organisms [22, 65, 71, 76].

Multi-drug resistant bacteria A world-wide problem during the last decades has been the progressive emergence of bacteria resistant to multiple antibiotics. The most relevant multi-resistant bacteria in liver transplant patients are shown in Table 43.3 [19, 22, 24, 26, 29, 33, 59, 60, 65–67]. Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of early postoperative infection following liver transplantation. Nasal carriage of MRSA (acquired pre- or postoperatively) is associated with an increased risk of MRSA infection [68–72]. MRSA strains are usually susceptible to the glycopeptide antibiotics vancomycin and teicoplanin. The prevalence of vancomycin-resistant enterococci (VRE) follows a variable geographical distribution, being high in most centers from the USA [65, 71, 73], and low in

Prevention In theory, infection can be prevented by strategies reducing risk factors for infection and those reducing the infective capacity of potentially pathogenic organisms. However, risk factors for infection are either not susceptible to improvement (i.e. the severity of pre-transplant liver disease) or have experienced little change over the last years. Only two surgical and anesthetic approaches should be mentioned. One is the attempt to decrease the operative hemorrhage, an important risk factor for early bacterial complications, by the use of temporary portocaval shunting [84], the reduction of both central venous pressure and plasma transfusion [85], or the administration of aprotinin [86]. The other is the immediate tracheal extubation after

Table 43.3 Multi-resistant bacteria in liver transplant patients with bacterial infections. Bacteria

Mechanisms of multi-resistance

Percentage of multi-resistant organisms (average and range)

References

Staphylococcus aureus Enterococcus spp. Enteric Gram-negative bacilli Nonfermentative Gram-negative bacilli

Methicillin resistance Vancomycin resistance ESBL productiona Multiple mechanismsb

67% 10% 27% 15%

19, 26, 22, 22,

(16–100%) (0–50%) (9–60%) (10–47%)

22, 26, 33, 60, 65, 66 29, 33, 60, 65, 67 24, 33, 60, 65, 67 65

a

ESBL (extended-spectrum beta-lactamase) producing organisms resistant to penicillins, cephalosporins and aztreonam. Pseudomonas spp. (the most representative organisms of this group) resistant to at least three of the following antibiotics: beta-lactams, carbapenems, aminoglycosides, or quinolones. Other relevant pathogens are Acinetobacter baumanii and Stenotrophomonas maltophilia. b

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surgery (“fast track” policy) to reduce the risk for pneumonia [87]. Nevertheless, the impact of these strategies on the incidence of bacterial infection is uncertain. At present, therefore, prevention of bacterial complications in liver transplant patients is almost exclusively based on interventions on the microbial flora.

Peri-operative antibiotic prophylaxis Although controlled studies on this topic are lacking (namely, prophylaxis versus no prophylaxis), perioperative antibiotic prophylaxis is the standard practice to prevent surgical-site infections as well as other bacterial infections during the very early post-operative period. However, due to the marked differences from one center to another regarding the predominant causative organisms, no specific prophylaxis can be universally recommended. Furthermore, the paucity of prospective, comparative studies on different antibiotic regimens adds important difficulties. The only exception is a study comparing cefazolin and amoxicillin-clavulanate, in which no difference in the rate of surgical-site infection was observed between the two regimes [24]. Unfortunately, these two antibiotic regimes were suboptimal because around 40% of isolated organisms were resistant to the administered agents. A1d Thus, only general rules for peri-operative antibacterial prophylaxis can be made. The appropriate antibiotic agents must be selected according to the local microbial epidemiology and the susceptibility of the most prevalent organisms at each center [88]. The most currently used antibiotics are third and fourth generation cephalosporins, frequently administered in association with other agents, especially those active against Enterococcus spp., such as ampicillin or amoxicillin (with or without clavulanate) [20, 25, 33, 65, 70, 75, 89, 90]. Other antibiotic combinations involve quinolones, antipseudomonal penicillins, or aztreonam [25]. One dilemma is the prophylactic use of antibiotics active against multiresistant bacteria, because it seems judicious to reserve these often last-line antimicrobial agents for treatment [91]. In this setting, only the prophylactic administration of vancomycin or teicoplanin could be reasonable in centers with a high prevalence of MRSA [70, 91–93]. In contrast, the prophylactic administration of antibiotics active against VRE, such as linezolid, or ESBL-producing enterobacteria, such as carbepenems, is uncommon even at institutions with a high prevalence of these microorganisms. Peri-operative antibiotic prophylaxis is routinely initiated immediately prior to transplantation and prolonged throughout the operation, although in some centers prophylaxis is extended to the first postoperative 24 hours or longer [33, 65, 70, 88, 89, 93]. Although the risk of donor-derived bacterial infection is low and the impact on patient and graft survival is usually negligible, the antibiotic prophylaxis in the recipient is 728

usually adapted to the organisms responsible for the donor infection and its duration prolonged for five to ten days [17, 94–96].

Selective bowel decontamination and administration of probiotics and prebiotics Since a high proportion of early infections are caused by bacteria of intestinal origin, selective decontamination of the digestive tract with nonabsorbable antibiotics has been used in different centers. However, few randomized, prospective, controlled trials have properly assessed the efficacy of this strategy [97–101]. Decontaminating regimens in these studies included gentamicin or tobramycin, polymyxin or colistin, and amphotericin or nystatin, administered orally for a variable period of time. In one study an oral paste with antimicrobial agents was also administered [100]. A reduction of infections caused by Gram-negative bacilli was attained in most treated groups, although the global rate of early bacterial infection was not significantly different, as emphasized in a recent meta-analysis [102]. A1a Survival was not influenced by the use of selective digestive decontamination. Therefore, the potential benefit of this type of prophylaxis is uncertain and it cannot be routinely recommended [45]. A1a In two randomized trials, a marked reduction was achieved in the incidence of early infection caused by enteric bacteria with the prophylactic administration of a combination of living lactic acid bacteria (probiotics) and bioactive fibers (prebiotics), but clinical outcomes were not significantly different [103, 104]. A1d

Prophylactic measures for multi-drug resistant bacteria General measures include hand hygiene and barrier precautions, which are applicable for all these organisms [45, 105, 106]. Based on the association of nasal carriage of MRSA with infection by this organism [68–72], periodical pre- and post-operative screening for MRSA and nares decolonization with mupirocin application have been proposed in liver transplant candidates and recipients [69–71, 107]. Unfortunately, one study showed that this policy was not effective as it did not prevent postoperative MRSA infection and was followed by a frequent recurrence of nasal MRSA colonization [108]. B4 Since other sites of colonization may be important, skin cleansing with chlorhexidine has also been postulated for a better control of MRSA [109, 110], as well as for VRE [111], but no study has evaluated these measures in liver transplant patients.

Antibiotic prophylaxis for invasive procedures The diagnosis and treatment of biliary complications, especially stenosis, frequently require endoscopic cholangiography. Bactobilia, that is, the bacterial colonization of bile, has been found with a very high incidence in liver

CHAPTER 43

transplant patients with biliary stenosis, stents or previous papillotomy [112]. B4 On the other hand, in a large series of patients undergoing ERCP, the only factor predisposing to cholangitis was liver transplantation [113]. Based on these data, antibiotic prophylaxis for ERCP is recommended in liver transplant patients [114]. Piperacillintazobactam and impenem provide adequate coverage [112]. Although, to the knowledge of the authors of this chapter, there are no studies on the risk of cholangitis in patients undergoing percutaneous cholangiography, it seems advisable to follow the same recommendation as for ERCP. In one study, liver biopsy was associated with sepsis when this procedure was performed in liver transplant patients with choledochojejunostomy [115]. For the authors of this study, antibiotic prophylaxis at the time of liver biopsy may be appropriate in this high-risk subgroup of patients, but biliary obstruction was not categorically excluded at the time of biopsy. For surgical re-intervention very early after transplantation, the same peri-operative antibiotic prophylaxis as for liver transplantation appears adequate. For surgical interventions in later periods, the general guidelines for non-transplant patients undergoing surgery [116] seem sufficient, although the type of antibiotics to be administered should be adapted to the liver transplant patient condition (i.e. grade of immunosuppression) and local microbial epidemiology. B4

Treatment Antibiotic treatment should be started whenever a liver transplant patient develops either signs strongly suggesting infection (mainly significant fever), signs of sepsis or a well documented localized infection. Nevertheless, it is important to note that not all febrile episodes in liver transplant recipients correspond to infection [18]. When the need for treatment is defined, and after blood and other relevant site cultures are taken, antibiotic therapy is empirically initiated, without knowledge of the causative organisms and their in vitro susceptibility. Empirical therapy should be selected on the basis of different factors, particularly the site of the suspected infection and the local predominant pathogens and their susceptibility patterns. Other important factors are the time since transplantation, recent antibiotic administration, and the colonization status of the patient, if known. At each institution, protocols for empirical treatment of bacterial complications should be periodically revised and adapted to the changes in epidemiology and in vitro susceptibility of predominant organisms. According to the commonest pathogens during the early period after transplantation (see Table 43.2), the most frequently used agents in the empiric therapy are third and fourth-generation cephalosporins, piperacilli-tazo-

LT: prevention and treatment of infection

bactam and quinolones [13, 117–119]. The administration of glycopeptides (vancomycin or teicoplanin) and carbapenems (imipenem, meropenem or ertapenem) can be justified in patients with sepsis and hospitalized in centers with a high incidence of MRSA and ESLB-producing Gramnegative bacilli, respectively [66, 118]. Once the responsible bacteria are identified and susceptibility tests are available, further adjustments may be required, consisting of either the withdrawal of superfluous antibiotics or the adequate antimicrobial changes if resistant organisms are isolated. Information on the adequacy of the initial empirical treatment is scarce in liver transplant patients with bacterial infection, although some authors have reported around 20% of failure [20, 61, 117]. However, the effectiveness of the initial empiric therapy does not seem to influence the final outcome provided the antibiotic therapy is rapidly modified according to the microbiological results, as also described in non-transplant populations [120–122]. B4 In later periods after transplantation, communityacquired pnemonia and urinary tract infection, the commonest bacterial infections in this postoperative phase [16, 47–49], are treated according to standard protocols in each center for immunosuppressed patients. Specific antibiotic therapy is administered for infections caused by infrequent but characteristic organisms, such as Listeria spp. and Nocardia spp. [47, 52].

Special considerations Surgical or percutaneous drainage is often required for the treatment of infections arising in devitalized anatomic sites, such as infected abdominal cavity collections or hepatic abscess [32, 36, 51]. Treatment of cholangitis secondary to biliary stenosis must include the endoscopic, radiological or surgical resolution of the stenosis [50]. The removal of IV lines is mandatory in catheter-related bacteremia [66]. Antibiotic treatment of pneumonia, especially in early stages following liver transplantation and in patients with mechanical ventilation, can be difficult because the responsible organisms are not identified in approximately 50% of episodes [20, 38]. Polymicrobial pneumonia, caused by more than one bacteria or bacteria combined with nonbacterial microbes, such as fungi, cytomegalovirus or P. jirovecii may represent an added difficulty for treatment [17, 20]. Although the empiric treatment of pneumonia attains a positive response in a relatively high proportion of patients, in patients who impair regardless of this therapy, invasive diagnostic procedures, such as fiberoptic bronchoscopy with bronchoalvelar lavage or lung biopsy, must be performed [20, 38, 62]. B4 In spite of an aggressive diagnostic approach, the etiology of pneumonia can only be established on necropsy basis in some patients. Since most liver transplant patients receive calcineurin inhibitors (tacrolimus or cyclosporine) as immunosuppres729

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sive drugs, the potential capacity of different antibiotics to increase the risk of toxicity of calcineurin inhibitors must be taken into consideration [14]. Aminoglycosides can increase the risk of nephrotoxicity, and they should be avoided if possible [123]. Since imipenem may enhance the risk of seizures, particularly in patients with renal function or neurological impairment [124], the administration of other carbapenems (meropenem or ertapenem) may be more appropriate in patients treated with calcineurin inhibitors. Pharmacokinetic interactions of several antibiotics with calcineurin inhibitors metabolized by the hepatic cytochrome P-450 have been described [125, 126]. Rifampicin and nafcillin induce the metabolism of calcineurin inhibitors, with risk of rejection due to low levels of these immunosuppressants, whereas macrolides reduce their metabolism, with the consequent increased risk of toxicity. In patients who necessarily have to receive these antibiotics, a careful monitoring of blood levels of calcineurin inhibitors is mandatory. Since proliferation signal inhibitors (PSIs, also named mTOR inhibitors: sirolimus and everolimus) are also metabolized by the cytochrome P-450 [127, 128], it is likely that similar drug interactions can also occur.

Tuberculosis The incidence of tuberculosis in liver transplant recipients is around 1–2% in developed countries and 10–15% in endemic regions, which is much higher than that in the general population in the respective countries [129]. Reactivation of latent tuberculosis is considered the main mechanism for active tuberculosis in transplant recipients, which predominantly occurs within the first postoperative year [130, 131]. Approximately half of the patients have pulmonary disease, whereas the other half present with extrapulmonary or disseminated tuberculosis [130, 131]. Aggressive investigations are often required for the diagnosis, and, in some patients, the definitive diagnosis can only be established after a positive response to empiric treatment.

Prevention In patients receiving kidney transplantation, and, by extension, in patients with extra-renal transplantation, there is the general recommendation to administer antituberculous chemoprophylaxis with isoniazid for the first 9–12 postoperative months in transplant recipients with a past history of tuberculosis and/or pre-operative positive tuberculin test [88, 132–134]. B4 However, regardless of the excellent efficacy of this strategy [130], prophylaxis with isoniazid in liver transplant patients with a positive tuberculin test is challenging for two reasons. First, a positive skin test without other additional risk factors is rarely associated 730

with latent infection reactivation [88]. As an example, in a study by our group, none of 73 patients with a pre-transplant positive tuberculin test developed post-transplant tuberculosis regardless of not receiving isoniazid prophylaxis [135]. In contrast, in the same study, tuberculosis was diagnosed in 2% of 279 patients with a negative tuberculin test; the incidence was especially high (10%) in patients with a past history of tuberculosis and untreated with isoniazid prophylaxis, thus suggesting that anergic patients with possible latent tuberculosis were very prone to develop latent infection reactivation. Second, an important concern for generalized isoniazid prophylaxis in liver transplant recipients with a pre-transplant tuberculin skin positive test is the high incidence of isoniazid hepatotoxicity, ranging from 17% to 41%, which can outweigh the possible benefit of this strategy [130, 135]. For these reasons, although there are no controlled studies on this issue, the general feeling is to limit isoniazid prophylaxis to patients with a history or chest X-ray evidence of past tuberculosis, particularly if it has been inadequately treated, or to patients with a positive skin test and additional risk factors (recent tuberculin conversion, non-Caucasian ethnicity or regional endemicity, and excessive immunosuppression) [88, 134]. B4 In the remaining cases, surveillance and treatment of active tuberculosis, if it develops, seem sufficient. Alternative prophylactic regimes, particularly the combination of a quinolone and ethambutol, can be administered in the case of previous isoniazid administration forming part of inadequate antituberculous therapies or in the case of liver graft alterations precluding isoniazid treatment or making it hazardous. Another possibility is to administer prophylaxis while patients are on the waiting list for liver transplantation, although this strategy has been rarely explored [136].

Treatment The most recommended standard treatment for active tuberculosis in the general population is the combination of rifampicin, isoniazid, pyrazinamid and ethambutol for two months, followed by an additional four-month therapy with rifampicin and isoniazid [137, 138]. In transplant recipients, the length of treatment is extended up to 12 months in pulmonary disease and up to 18 months in extrapulmonary disease [139–143]. B4 However, this therapeutic regime cannot be accomplished in a substantial proportion of patients due to hepatotoxicity, with an average incidence of around 30–40% [131, 130, 141, 144]. In patients with hepatoxicity or significant liver graft alterations, the most hepatotoxic combination of rifampicin with isoniazid and/or pyrazinamide is usually withdrawn or avoided, and non-hepatotoxic or less hepatotoxic regimes, including ethambutol, quinolones, and rifabutin combined with isoniazid or pyrazinamide, are administered with satisfactory results [140, 142, 145].

CHAPTER 43

Viral infections Cytomegalovirus Cytomegalovirus (CMV) belongs to the human herpesvirus family and is a significant opportunistic pathogen in liver transplantation. Infection by CMV is defined as the isolation of CMV or the detection of viral proteins or nuclear acids in whatever fluid or tissue of the organism [146, 147]. The clinical spectrum of CMV infection is very wide, from an asymptomatic infection to a lethal disease [147, 148]. Infection with CMV is classified as asymptomatic or symptomatic. An asymptomatic infection is defined by the detection of either the antigen pp65 of CMV in the leucocytes or the DNA of CMV in plasma, blood or leucocytes by PCR, without symptoms of the infection and without affecting organs [143, 149]. Symptomatic infection or CMV disease may manifest as a febrile viremic illness often associated with leukopenia and thrombocytopenia (CMV syndrome) or as an organ-specific disease, such as colitis, hepatitis and pneumonia. In case of organ involvement, the diagnosis can be established by histopathologic or cytological changes suggestive of CMV disease, particularly intranuclear inclusions and positive immunohistochemistry. In most cases, CMV disease occurs at weeks four to six after transplantation.

Risk factors CMV infection can be primarily acquired from the graft or from transfused blood products in patients lacking preexistent CMV-specific immunity or can result from reactivation of latent virus or superinfection with a new strain [146, 150–152]. The risk of developing CMV infection and disease after liver transplantation is related to the donor and recipient CMV serostatus. Seronegative recipients of grafts from seropositive donors (D+/R−) are at the highest risk, with an incidence of infection of up to 80% and an incidence of disease of up to 60% in the absence of antiCMV prophylaxis [151]. Seronegative patients who receive an organ from a seronegative donor (D−/R−) are considered at the lowest risk, although CMV infection can still develop from blood products, particularly if they receive unscreened pool of platelets [150]. Seropositive recipients have an intermediate risk, with an incidence of CMV disease of approximately 20% when the donor is also seropositive (D+/R+) and 10% when the donor is seronegative (D−/R+) [151]. Re-transplantation, antilymphocytic antibodies, and high levels of immunosuppressants are also risk factors for CMV infection.

Prophylaxis Prophylaxis of CMV infection is the administration of antiCMV treatment prior to the detection of active CMV repli-

LT: prevention and treatment of infection

cation, usually for the first three post-operative months. There are two strategies of prophylaxis: universal prophylaxis, when it is administered to all transplant recipients, and targeted prophylaxis, when it is only administered to high-risk patients [153]. Oral valganciclovir is the most commonly used antiviral agent for prophylaxis of CMV in liver transplant patients. A number of reports have documented the efficacy of this strategy [153–159], with CMV disease development in only 15–30% of the D+/R− patients who received valganciclovir prophylaxis [160, 161]. B4 The other potential benefit is the reduction of the indirect effects of CMV infection, including graft loss, fungal infection and even bacterial infection [160–163]. Potential risks are cost, toxicity, CMV resistance to ganciclovir, and the possible development of late onset CMV disease [164]. These risks have questioned universal prophylaxis and even targeted prophylaxis in favour of pre-emptive therapy. Prolonged prophylaxis beyond the month three and CMV infection monitoring after prophylaxis cessation have been proposed [162].

Preemptive therapy Preemptive therapy is the administration of anti-CMV treatment after the detection of active CMV infection but prior to the development of symptomatic disease. With this strategy, transplant recipients are carefully monitored for early evidence of viral replication by using CMV antigenemia assay or PCR for detection of viral DNA, followed by preemptive therapy at the first positive result. Some authors use a specific quantitative threshold value as an indicator for the initiation of antiviral medication in seropositive transplant recipients, but begin treatment in high risk recipients whenever any level of CMV antigenemia or viral DNA becomes detectable [159]. Valganciclovir is also the drug of choice for preemptive therapy. Recent studies have shown its efficacy in D+/R−, pointing again to the advantages of preemptive therapy over targeted prophylaxis [161, 162, 164]. B4 However, more studies are needed to validate these findings.

Therapy The recommended treatment of a proven or suspected CMV infection is the IV administration of ganciclovir, an inhibitor of the CMV DNA polymerase [165]. In mild to moderate CMV disease, the duration of treatment is usually 14–21 days, although the best strategy is to stop the therapy when two weekly negative CMV tests (antigenemia or PCR) are achieved [151]. In many cases, oral valganciclovir can be used to complete the treatment after an initial period of IV administration of ganciclovir and when clinical symptoms have resolved. In a recent trial, oral valganciclovir has been as effective as IV ganciclovir in the treatment of non-severe CMV disease [166]. A1d The duration of the treatment in compartmentalized disease, that is, organ 731

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involvement with minimally detectable or undetectable viremia, is more challenging. The most important adverse effect of ganciclovir and valganciclovir is bone marrow suppression. In case of severe bone marrow toxicity or ganciclovir resistance (very rare in liver transplant recipients), foscarnet is the best alternative treatment. Nephrotoxicity is the most important adverse effect of foscarnet [165].

Other herpesvirus Herpes simplex virus Herpes simplex virus (HSV) infection, commonly caused by reactivation of a latent infection, predominantly involves mucosal surfaces [13]. Disseminated forms are rare. Treatment and prophylaxis is based on the administration of acyclovir or valacyclovir.

Varicella zoster virus

Epstein-Barr (EBV) virus In liver transplantation, EBV infection is usually primary in children, whereas reactivation is the predominant mechanism for infection in adults [167]. Symtomatic EBV infection mainly consists of fever, leukopenia, lymphomonocytosis or thrombocytopenia, although approximately the half of patients present with atypical symptoms and signs [146]. However, the most important consequence of EBV infection in solid organ transplant recipients is its association with the development of post-transplantation lymphoproliferative disease.

Post-transplantation lymphoproliferative disease The association between EBV and post-transplant lymphoproliferative disease (PTLD) has been recognized since the early days of transplantation, although not all cases can be attributed to EBV [168–171]. The major pathogenic mechanism for PTLD is the insufficient EBV-specific cytotoxic T-cell control on EBV-driven B-cell proliferation [171]. PTLD, a systemic process involving both nodal and extranodal tissues, ranges from an infectious mononucleosislike reactive plasmacytic hyperplasia to a lymphoma [172]. The incidence of PTLD in liver transplant recipients is around 2%, although children are particularly exposed, with an incidence approximately three times as high [173]. Poly- and monoclonal anti-lymphocyte antibodies and maintenance immunosuppression with azathioprine are major risk factors for PTLD, although doses of maintenance azathioprine used in liver transplantation are lower than in other solid organ transplants [174]. High EBV load may also be a risk factor, and this has led some authors to postulate that preemptive antiviral therapy and reduction of immunosuppression on the basis of viral load monitoring could be indicated to prevent EBV-associated PTLD [174, 175]. However, the efficacy of such a prophylaxis strategy is uncertain. Treatment of PTLD includes reduction of immunosuppression if possible, chemotherapy and anti-Bcell antibodies (rituximab) when PTLD has evolved to lymphoma, and surgical resection and radiotherapy in patients with tumor masses. Administration of interferon, immune globulin and anti-EBV treatment with acyclovir or ganciclovir are other potential therapies, although their efficacy is unproven [143, 174]. 732

Localized cutaneous zoster, secondary to a reactivation of latent varicella zoster virus infection, occurs with an incidence of approximately 5–10% in solid-organ transplant recipients [143]. Primary infection, although very rare in adults, can be more aggressive with severe organ involvement. Acyclovir and valacyclovir are the most used agents for treatment of varicella zoster virus infection [143].

Human herpesvirus 6 and 7 After the primary infection, human herpesvirus (HHV) type 6 and type 7 remain latent in the host and can reactivate after transplantation and cause varied clinical manifestations, such as fever, cutaneous rash, pneumonitis, encephalitis, hepatitis and myelosuppression [176]. Although the incidence of HHV 6 and 7 infection is low [177], the interest for these pathogens or copathogens in transplant recipients is increasing due to the possibility of indirect effects: association with CMV disease, increased risk of opportunistic infections, and graft dysfunction and rejection [171, 176, 178]. Antiviral agents active against CMV are also active against HHV-6.

Human herpesvirus 8 Human herpesvirus 8 (HHV-8) causes Kaposi’s sarcoma, as well as primary effusion lymphoma (PEL) and many cases of multicentric Castleman disease (MCD) [179, 180]. Other co-factors, mainly immunosuppression, are also necessary. Current treatment options of Kaposi’s sarcoma are limited to reduction in immunosuppression and chemotherapy [146]. Although an important reduction in HHV-8 replication by valganciclovir has been recently reported in non-transplanted patients [181], antiviral medication in combination with chemotherapy has been rarely investigated in the setting of organ transplantation [180, 182]. Interestingly, the conversion to PSI immunosuppressive drugs has been followed by regression of Kaposi’s sarcoma in kidney transplant patients [183, 184]. B4 Therefore, PSIs provide a potential treatment option in the management of post-transplant Kaposi’s sarcoma.

Fungal infections Systemic fungal infections are a significant cause of morbidity and mortality in solid organ transplant recipients.

CHAPTER 43

Table 43.4 Specific risk factors for fungal infections (in addition to the general factors for infection shown in Table 43.1). Pre-transplant period: Steroid therapy Hemodyalisis, hemofiltration Fungal colonization (Aspergillus) Re-transplantation Intra-operative period: Prolonged and difficult surgical intervention Important blood product transfusion Combined liver-kidney transplantation Early post-operative period (40 yrs Prolonged cold ischemia time Female sex Living donor liver transplant experience (2 log drop in HCV RNA at 12 weeks), infection with genotype 2, adherence to therapy and baseline viremia [18]. Primary treatment endpoints include histological response, graft survival and patient survival. While typically the major indication for treatment is driven largely by allograft damage, significant psychological and social factors of the patient play a role in withholding antiviral therapy in some cases.

Pre-transplant antiviral therapy Pre-transplant antiviral therapy is an attractive approach in which those with undetectable HCV RNA going into transplant may eliminate the risk of developing recurrent HCV. In some cases when patients achieve SVR from this regimen, they may completely avoid transplantation altogether. A recent review shows that up to two-thirds of patients who obtain SVR prior to liver transplantation will remain free of HCV in the post-transplant setting. This rate is lower for patients without achievement of SVR [21].

Table 44.3 Contributing factors leading to lower response rates to antiviral therapy in liver transplant patients. • High HCV RNA levels post-LT • High prevalence of genotype 1, previous non-responders to antiviral therapy • Presence of immunosuppression • Poor clinical status and tolerability, especially early post-LT • Cytopenias as result of immunosuppression requiring dose reduction and use of growth factors • Renal insufficiency limiting dose of ribavirin on account of its associated risk of hemolytic anemia

Table 44.2 Antiviral treatment strategies for recurrent HCV. Treatment strategy

Timing of antiviral therapy

Advantage

Disadvantage

Pre-transplant

Prior to LT

Eliminate or reduce risk of recurrent HCV Potential to avoid LT

Low virological response Limited tolerability and potential for serious adverse effects

Preemptive

Early post-LT

Relatively low HCV RNA levels Minimal or no histological disease

Maximal immunosuppression Higher risk of rejection and infection

Established disease

Diagnosis of acute hepatitis or established and/or severe disease

Lower immunosuppression Improved clinical status and better tolerance Lower risk of rejection

High HCV RNA levels More advanced fibrosis

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Unfortunately, this is a difficult group to treat given low response rates due to the high prevalence of genotype 1 and underlying cirrhosis and its associated side effects (e.g. leukopenia, thrombocytopenia). One of the largest studies of pre-transplant antiviral therapy by Everson et al. described their experience with a low accelerating dose regimen (LADR) of primarily nonpegylated interferon and ribavirin and its efficacy for HCV clearance prior to transplant [22]. A total of 124 patients (70% genotype 1 and 63% having Child-Pugh class B or C) were treated, with 24% achieving SVR (13% genotype 1 and 50% non-genotype 1). Twelve out of 15 (80%) of patients who were HCV RNA negative going into transplant remained HCV RNA negative at least six months after LT. Three comparative studies of peginterferon in liver transplant candidates (although included patients were not necessarily already considered or placed on transplant listing) have been reported [23–25]. DiMarco et al. reported results of 102 patients (67% treatment naive) randomized to receive peginterferon α-2b monotherapy or peginterferon plus ribavirin (800 mg) for up to 52 weeks (treatment was stopped if HCV RNA was not undetectable at 24 weeks) [23]. Overall, SVR was 19.6% in the peginterferon and ribavirin group and 9.8% in peginterferon monotherapy group (p = 0.06). Not surprising, response rates for non-genotype 1 were higher than for genotype 1 (66% vs 11%, p = 0.001). Discontinuation was 27% in the peginterferon and ribavirin group and 41% in the peginterferon group. Helbling et al. randomized 124 naive patients to either peginterferon α-2a plus standard dose ribavirin (1000–1200 mg) or peginterferon plus low dose ribavirin (600–800 mg) for 48 weeks [24]. SVR was 50% with the standard dose ribavirin group compared to 38% for the lower dose group (p = 0.153). Both groups had similar rates of treatment discontinuation. Finally, in a nonrandomized controlled trial, the first to specifically assess the effect of antiviral therapy on liver function in patients with decompensated HCV cirrhosis, Iacobellis et al. compared 66 patients treated with peginterferon α-2b and ribavirin (800–1000 mg) to 63 controls (no treatment). Twenty percent of the treatment group achieved SVR [25]. The study had similar discontinuation rates for the treatment group as observed in prior studies and survival was not different between the two groups, but a post hoc analysis showed a survival benefit in the treated group. An important finding in this study was a decreased incidence of decompensation (ascites, hepatic encephalopathy) in the treated group compared to the controls during follow-up. However it did not translate into increased survival in the treated patients. In summary, pre-transplant antiviral therapy should be strongly considered in patients with cirrhosis who have Child-Pugh scores ≤ 7 or Model for End-Stage Liver Disease (MELD) scores ≤ 18 [8]. (MELD score = 10 [0.957 Ln (serum creatinine) + 0.378 Ln (total bilirubin) + 1.12 Ln 742

(INR) + 0.643].) B2 A special group that should be strongly considered for antiviral therapy while awaiting transplantation are patients with well compensated liver disease upgraded on the transplant list solely for an indication of hepatocellular carcinoma, especially if they are non-genotype 1. B4 Our program attempts to make these patients HCV RNA negative on treatment for at least two months before proceeding with either cadaveric or living donor transplantation. However, it is important to emphasize that the majority of HCV-infected patients without hepatocellular carcinoma will not be optimal candidates for antiviral therapy by the time they have moved up on the transplant list, due to their disease severity.

Preemptive antiviral treatment Preemptive treatment refers to early antiviral therapy days to weeks after LT, before the development of histological recurrence. A number of theoretical advantages exist with this approach in that patients have lower HCV RNA levels and lack histological disease. However, from a clinical standpoint, treatment at this time is most challenging due to poor clinical status, cytopenias from maximal immunosuppression, and higher rates of rejection and infection in the early transplant period. Only about 60% of LT recipients are eligible for preemptive therapy, with the need for dose reduction occurring in up to 50% of treated patients [26]. A recent meta-analysis found no studies of preemptive therapy that satisfied inclusion for analysis [19]. In summary, the efficacy of preemptive anti-viral therapy remains to be defined and should only be considered in patients undergoing retransplantation for rapidly progressive HCV recurrence [8].

Treatment of established disease Given the lack of efficacy and limitations of preemptive therapy, many transplant centers have opted to delay treatment until significant recurrent disease is verified. By taking this approach, treatment is focused on those likely to achieve benefit with antiviral therapy, avoiding unnecessary toxicity and side effects in those without significant disease recurrence. Two general approaches have been used to treat established disease. One approach initiates antiviral treatment at the diagnosis of acute recurrent hepatitis utilizing liver biopsy to exclude other causes for elevated liver enzymes, such as rejection. The second approach followed by most transplant centers is to initiate antiviral therapy when clinically significant evidence of recurrence exists. This latter approach utilizes protocol and/or clinically indicated liver biopsies reporting both the grade and stage of recurrent disease.

CHAPTER 44

HCV infection and liver transplantation

Table 44.4 Published of controlled trials utilizing peginterferon and ribavlrin for treating recurrent HCV vs no treatment. Author year

Type of Study

# of Patients

Antiviral Regimen

Duration (weeks)

SVR

Histological Responsea

Genotype 1 (%)

Castells, 2005

NRT

48

(1) PEG-IFN (1.5 mcg/kg/wk) + Riba (600–800 mg/d) for 24 wks + 24 wks if RNA neg (2) No treatment

24–48

(1) 33%

NR

100

(1) PEG-IFN (1.5 mcg/kg/wk) + Riba (800–1000 mg/d) (2) No treatment

48

(1) PEG-IFN (1.5 mcg/kg/wk) + Riba (800–1200 mg/d) (2) No treatment

48

Bizollon, 2007

Carrion, 2007

NRT

RCT

48

54

(2) 0% (1) 30%

(1) 100%

(2) 0%

(2) 24%

(1) 48%

(1) 74%

(2) 0%

(2) 30%

85

79

NRT: nonrandomized trial; RCT: randomized controlled trial; Riba: ribavirin; SVR: sustained virological response; NR: not reported. Defined as fibrosis stabilization (same fibrosis stage) or fibrosis improvement (reduction of >/= 1 fibrosis stage).

a

Protocol liver biopsies in patients transplanted for HCV may be useful given the potential for significant fibrosis progression and has largely become standard of care [8]. Since fibrosis progression is not linear over time, possibly progressing more rapidly in the first post-LT year, the 12-month liver biopsy has the ability to stratify fibrosis progression. Those developing severe disease recurrence within the first transplant year are at a high likelihood of progressing to cirrhosis and should be considered for antiviral therapy [14, 27]. Furthermore, the absence of fibrosis 12 months post-LT is associated with excellent cirrhosisfree survival [14]. The measurement of hepatic venous pressure gradients (HVPG; wedged hepatic vein pressure minus free hepatic vein pressure) appears to be a useful tool in assessing disease severity in recurrent HCV [28]. HVPG measurements ≥6 mm Hg in one study [29], or ≥10 mm Hg in another study [5], at one year post-LT have been shown to be extremely accurate in predicting clinical decompensation over liver biopsy. The same group has also shown good correlation between HVPG measurements and histological response with antiviral therapy [30]. In summary, patients with fibrosis stage ≥ 2 out of 4, severe inflammation (grade 3 or 4), evidence of significant hepatic dysfunction (elevated bilirubin, prolonged prothrombin time), or HPVG gradients ≥6 should be strongly considered for antiviral therapy [5, 8] B4

Controlled trials of peginterferon and ribavirin The current standard of care for treating established recurrent HCV is pegylated interferon and ribavirin therapy. Multiple studies using various study designs and endpoints have been performed to evaluate the efficacy of established disease therapy after transplantation, with end-

points consisting of SVR, histological improvement, and allograft and patient survival. It appears that there is no significant correlation between success of antiviral therapy and the interval of time from transplant and start of antiviral therapy. There are only three comparative studies of peginterferon and ribavirin in treatment of established recurrent HCV (see Table 44.4 and Figure 44.1) with only one randomized study [30–32]. Castells et al. studied 24 patients receiving peginterferon α2b (1.5 mcg/kg/wk) and ribavirin (600–800 mg/day) for 48 weeks (if HCV RNA undetectable at 24 weeks) and 24 consecutive untreated controls [30]. All patients were genotype 1 and treatment was initiated for acute recurrent HCV confirmed on biopsy (mean four months after LT). Growth factors (filgrastim and darbepoetin alpha) were given and anemia and leukopenia occurred in 71% and 96% of cases respectively. Overall SVR was 33% in the treatment group and 0% in controls. One patient developed acute cellular rejection in the treatment group (two in the control group) that resolved with adjusting immunosuppression. No histological follow-up was reported in this study. On univariate analysis, SVR was associated with absence of corticosteroid administration to treat rejection (p = 0.01), presence of early virological response (EVR > 2 log drop in HCV RNA at week 12) (p = 0.002) and absence of cytomegalovirus infection (p = 0.001). B2 Bizollon et al. studied 27 patients with established recurrent HCV (median ten months after LT) receiving peginterferon α2b (1.5 mg/kg/wk) and ribavirin (800–1000 mg/d) for 48 weeks and compared them to 21 consecutive untreated controls [31]. Seventy nine percent were genotype 1 and some had previous treatment post-LT with non-pegylated interferon and ribavirin. Filgrastim was not used, but erythropoietin alpha was given. SVR was 30% in 743

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Liver disease –75.00 Author Year Tx Castells 2005 8/24 Bizollon 2007 8/27 Carrion 2007 13/27

No Tx 0/24 0/21 0/27

–50.00 –25.00

0.00

25.00

50.00

75.00

Sustained virological response

Histological response Bizollon 2007 25/27 5/21 Carrion 2007 20/27 8/27 Treatment group better

No treatment group better

Figure 44.1 Forest Plot of sustained virological response and histological response rates in comparative studies of pegylated interferon and ribavirin versus no therapy in patients transplanted for HCV related cirrhosis with recurrent disease. Tx: treatment. Adapted from Xirouchakis E et al. Pegylated-interferon and ribavirin in transplant candidates and recipients with HCV cirrhosis: systemic review and meta-analysis of prospective controlled studies. J Viral Hep 2008; 15: 699–709.

treatment group and 0% in controls. Two patients in the treatment group and one in the control group had acute cellular rejection. Patients completing treatment had improvement (65%) or stabilization (35%) of fibrosis 24 weeks after completing treatment. All eight patients achieving SVR had improvement in histology. Based on univariate analysis, the use of cyclosporine (p = 0.03) and early virological response (p = 0.02) were associated with SVR. B2

Carrion et al. have published the only randomized study to date [32]. In this study, 54 patients with mild HCV recurrence (F0-F2) at least six months post-LT were randomized to either peginterferon α2b (1.5 mcg/kg/wk) and ribavirin (800–1200 mg/day) for 48 weeks or no treatment. Filgrastim and darbepoetin were used to treat neutropenia and anemia respectively. Eighty-five percent were genotype 1 and treatment was initiated a mean of 16 months post-LT. Overall SVR in the treatment group was 48%. Histological response (improvement or stabilization six months after completing antiviral therapy) was seen in 74% of the treated compared to 30% of controls with all patients achieving SVR having a histological response. Biochemical response (normalization of ALT) on multivariate analysis independently predicted fibrosis improvement or stabilization. Hepatic venous pressure gradient also correlated with progression of fibrosis. A1d

Graft survival Bizollon et al. in a retrospective study analyzed the effect of SVR on graft survival in 80 patients treated for recurrent HCV at least six months after transplant with nonpegylated interferon and ribavirin [33]. Erythropoietin was utilized. Overall SVR was 42%. In those achieving SVR, 82% had either stabilization or improvement in fibrosis compared to 744

26% in those not achieving SVR (p < 0.001). Among responders without cirrhosis at inclusion, none developed cirrhosis at the end of follow-up. In the one patient with cirrhosis at inclusion, no decompensation or hepatocellular carcinoma occurred. In nonresponders, 9 of 48 (19%) developed cirrhosis after a mean of 32 months. Four of the nine developed decompensation, with three being retransplanted a mean of seven months following diagnosis of cirrhosis. Veldt et al. performed a larger study to investigate treatment benefits on graft survival [34]. In this retrospective cohort study, 78 patients treated predominately with peginterferon (n = 61) in combination with ribavirin (n = 69) were compared to 81 contemporary untreated patients, to assess graft survival. As treated patients may have been selected on the basis of medical compliance, mean immunosuppression levels were compared during the first month after transplant, between treated and untreated patients, as a measure for previous treatment compliance; no statistical differences were seen. Patients with severe recurrence resulting in graft failure or death within six months of transplant were not evaluated. Erythropoietin was utilized in this study. Seventy-four percent of treated patients had stage 60–65% at the end of fourth year of lamivudine therapy [9]. Breakthroughs during lamivudine therapy have a risk for severe exacerbation of liver disease, which may result in rapid development of liver failure and patient death [10]. Moreover, pre-transplant HBV viremia even when due to YMDD mutants has been associated with increased probability of post-transplant HBV recurrence [11, 12], poorer outcome after LT and lower hepatocellular carcinoma (HCC) recurrence-free post-transplant survival in patients with HCC before LT [13]. Thus, transplant centers may be reluctant to perform LT in HBV cirrhotics with viremia irrespective of the type of HBV strains [14]. Another important issue is that the emergence of lamivudine resistance may have a negative impact on the efficacy of and the probability of resistance to other anti-HBV agents [9]. For all these reasons, lamivudine monotherapy is no longer considered an appropriate first-line therapy for pre-transplant HBV patients. B4

Adefovir The availability of adefovir, an acyclic nucleotide analogue of adenosine esterified with two pivalic acid molecules that is effective against both wild and lamivudine resistant HBV strains, was initially used in order to ameliorate the consequences of lamivudine resistance [9]. The use of adefovir monotherapy as first-line treatment in HBVpretransplant patients has not been adequately evaluated. In CHB, adefovir monotherapy is associated with lower rates of resistance compared to lamivudine, but resistance may emerge in the second year and develop in up to 30% of cases treated with adefovir for five years [15]. Adefovir resistance is related to the emergence of a mutation at position 236 (substitution of asparagine with threonine, (rtN236T)) and/or at position 181 (substitution of alanine with valine or threonine (rtA181V or rtA181T)) of the HBV polymerase gene [16]. Another issue with adefovir monotherapy is that this agent, at least in the licensed 10 mg daily dose, is not very potent, resulting in residual viremia in approximately 80% of HBeAg-positive and 50% of HBeAgnegative CHB patients [9]. In addition, it may have some potential for nephrotoxicity. For these reasons, adefovir monotherapy was not considered as an attractive option for patients with HBV decompensated cirrhosis, in whom complete inhibition of viral replication should be achieved [17]. Because of the suboptimal profile of both lamivudine and adefovir monotherapy in HBV pre-transplant patients, ab initio use of lamivudine and adefovir combination has been recommended for such cases in several guidelines, despite the lack of strong data on efficacy and safety for such a strategy [18]. B4

HBV infection and liver transplantation

Entecavir Entecavir, a carboxylic analogue of guanosine, is a potent and selective anti-HBV agent that has been approved relatively recently for the treatment of CHB [9]. In nucleos(t) ide naive patients with HBeAg-positive or HBeAg-negative CHB, entecavir (0.5 mg daily) has greater potency than lamivudine and adefovir and a very good resistance profile with 50% of cases had HBV-DNA detectable by hybridization assays) and achieved low HBV reinfection rates at a reduced cost. Moreover, a relatively low HBIG dosage [12, 33, 34, 58, 63, 66, 67], similar to the recommended dosage for non-viremic HBV transplant patients [31], and/or intramuscular HBIG 751

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Table 45.1 Published studies using combination of hepatitis B immune globulin (HBIG) and lamivudine (LAM) for prevention of hepatitis B virus (HBV) recurrence after liver transplantation (LT) for HBV related chronic liver disease. Study First author, year Markowitz, 1998 [66] Yao, 1999 [33]

Patients, n

Post-LT HBIG dose (IU), (cumulative within first month (mo)) − after the first mo

Mean followup, mos

HBV recurrence, n (%)

14

(80,000) − 10,000/mo IV

13

0

93

10

(15,555 ) − 1111/3 weeks (wks) IM

16

1 (10)

90

a

Survival (%)

Yoshida, 1999 [34]

7

(34,720) − 2170/1–4 wks IM

18

1 (14)

86

McCaughan, 1999 [65]

9

Low dose (no details)

17

0

89

Roche, 1999 [64]

15

No details-anti-HBs > 500 iu/l

16

1 (7)

93

Angus, 2000 [63]

32

(3200–6400) − 400 or 800/mo IM

18

1 (3)

100b

Han, 2000 [62]

59

(80,000) − 10,000/mo IV

15

0

98

5

(26,000) − 2000/mo IV

11

0

80

Andreone, 2000 [60]

19

(45,000) − 5000/mo IV

17

1 (5)

95

Rosenau, 2001 [12]

21

(40,000-anti-HBs > 500 iu/l) − anti-HBs > 100 iu/l IV

20

2 (10)

90

Machicao, 2001 [59]

30

High dose

22

0

97

Choi, 2002 [58]

56

(10,000) − 10,000/mo IV x mos − 2000/2 mos IM

26

4 (7)

Kim, 2002 [57]

51

(80,000) − 10,000/mo IV x 6/12 mos

21

4 (8)

Chu, 2002 [56]

8

(10,000) − 10,000/mo IV x 43 mos − 1000/mo IM x 12 mos

16e

0

100

Honaker, 2002 [55]

9

(80,000–100,000 IV) − 10,000–40,000/1 − 2 mos IV

50

0

100

Anselmo, 2002 [54]

89

(80,000 IV) − 10000/mo IV after 1998: (22,000 IV) − 1560 iu IM − anti-HBs

NA

10 (11)

94 (1 year)

Sousa, 2003 [53]

10

(70,000 IV) − 10,000/mo IV first year (10,000 IV every 2 mos second to third year, then 10,000 IV every 3–4 mos)

30.1

0

100

Dumortier, 2003 [52]

17

(100,000 IV) − 10,000 IM/1 − 2 mos − anti-HBs

30

0

80 (5 years)

Ferretti, 2004 [51]

28

(40,000–80,000 IV) − 1200 IM/2–6 wks

20

1 (3.5)

Karasu, 2004 [50]

80

(4000 IV − 2000–8000 IM) − IM (anti-HBs)

21

3 (4%)

Neff , 2004 [32]

41

(130,000 IV) − 10,000 IV/mo x 6 mos

49f

5 (12)f

80f

Marzano, 2005 [67]

77

(50,000 IV) − 6000 IV/mo

39

4 (5)

96

(7200 IM) − 800 IM/mo

54

16 (14)

95

Lee, 2000 [61]

Zheng, 2006 [48]

114

c

d

NA NA.

83 85 (1 year)

Karaderim, 2006 [68]

35

(4000 IV + 2000 IM/day for anti-HBs > 200–100 iu/ml)

15

2 (20)

86

Nath, 2006 [69]

14

(80,000 IV (within first 7 days))

14

1 (7)g

100

Gane, 2006 [70]

147h

(5600 IM within first wk) − 800 IM/mo

62

5 (4)

92 (1 year)

Yoshida, 2007 [71]

34

(120,000 IV) − 10,000 IV/mo x ≥ 6 mos

54

3 (9)

68

Jiao, 2007 [72]

56

(10,000 IM) − 400–1200/1–4 wks IM

32

3 (5)

91

Neff, 2007 [73]

10

(140,000 IV) − 10,000 IV/mo x ≥ 6 mos

Zimmerman, 2007 [13]

77

Before 1998: (80,000 IV (within 7 days)) − 10,000 IV/mo After 1998: (22,000 IV (within 6 days)) − IM (anti-HBs)

48

12 (15)

75

(8000–36,000 IV/IM) − anti-HBs

18

11 (5)

100

Akyildiz, 2007 [74]

752

209

6.5

0

100

CHAPTER 45

HBV infection and liver transplantation

Table 45.1 Continued Study First author, year

Patients, n

Post-LT HBIG dose (IU), (cumulative within first month (mo)) − after the first mo

Mean followup, mos

HBV recurrence, n (%)

Survival (%)

Buti, 2007 [75]

29

(62,000 IV) − 2000/mo IV (x1 mo)/IM

83

4 (13)

Takaki, 2007 [76]

23

(10,500 IV within first wk) − anti-HBs > 100 iu/ml for first 6 mos − anti-HBs > 10 iu/l

30

0i

NA

Freshwater, 2008 [77]

24

(25,000 IV (within 3 days)) − 5000 IV for anti-HBs > 100 IU/ml

32

0j

NA

Yilmaz, 2008 [78]

16

(17,500–20,500 IV (within 5–7 days) − 1500 IM/3–5 wks

96

0

85

Angus, 2008 [79]

18

(2100–5600 IM) − 400 or 800/mo IM

21.8

0

100

90

NA: not available. Plus 70,000 IV during the first seven days in two HBV-DNA positive patients. b Five patients, who died within one month after LT from unrelated to HBV causes, were not included in this survival estimation. c One patient received 80,000 IU of HBIG during the first month, while another patient received only 2000 IU of HBIG during the anhepatic phase and four IM injections of 650 iu each within the first six months after LT. d Thirteen patients received higher HBIG dosage (10,000 IU IV daily for seven days, 10,000 IU IV weekly for one month, and then 10,000 iu IV monthly for several years before conversion to IM HBIG. e Post-transplant LAM was added when HBIG administration changed from IV to IM (16 months median follow-up after the onset of LAM). f No HBV recurrence in 18 patients with undetectable pre-LT HBV-DNA during 70 months of follow-up. g All patients received LAM plus adefovir (10 mg/day) from day 8. h No patient with YMDD mutants. I Two patients had transiently positive HBsAg (one was under adefovir due to LAM resistance pre-LT). j One patient had detectable HBV-DNA (YMDD mutants), but none had clinical HBV recurrence. a

preparations were usually used [13, 33, 34, 48, 50, 51, 58, 70, 72, 75, 79], or HBIG was even discontinued after a certain period [56, 57, 69, 73]. Therefore, the prophylactic post-transplant combination of HBIG and lamivudine preceded by short-term pre-transplant anti-HBV therapy is the currently recommended approach [5]. B4 In the near future, the newer nucleos(t)ides analogues are expected to replace lamivudine in the post-transplant prophylaxis as well, probably leading to use even less HBIG. The optimal post-transplant prophylaxis for patients who develop YMDD mutants in the pre-transplant period might be different than that for patients without such HBV strains. In total, seven studies have focused on patients with YMDD mutans pre-LT showing that only 4.2% (6/143) of patients developed post-OLT HBV recurrence during a mean follow-up of 19–36 months (see Table 45.2) [27, 67, 77, 80–83]. B4 The triple combination of HBIG, lamivudine and adefovir was used in most patients (55% of 134 cases) with available data [73], while fewer (45%) were treated with HBIG plus lamivudine or HBIG plus adefovir or adefovir plus lamivudine. Of the six cases with post-LT HBV recurrence, two developed in patients under HBIG plus lamivudine and adefovir and four in patients under HBIG plus lamivudine (two had stopped HBIG and two did not receive adefovir pre-transplant and transplanted with

HBV-DNA > 5 log10 copies/ml) [27, 67]. Tenofovir instead of adefovir is expected to offer better results in this setting. The ab initio use of potent antivirals with a high genetic barrier is definitely preferred in the transplant setting and particularly in cases with pre-existing evidence of viral resistance, as the risk of multi-drug resistance is higher than in non-transplant cases [84]. One relatively recent strategy of the prophylactic combined approach has been the withdrawal of HBIG administration after a certain period followed by maintenance lamivudine alone [85]. The first results of two small randomized trials were encouraging, with no HBV recurrence after 12–17 months under lamivudine monoprophylaxis [86, 87]. However, longer follow-up showed that 20% of patients eventually experienced recurrence of HBV at seven years [75], which might have been related to poor compliance [75], or premature discontinuation of HBIG [86]. B4 Indeed, HBV recurrence was not observed in any of 16 patients who continuously received HBIG for two years and then switched over to lamivudine monotherapy for an additional period of up to 27 months [88]. The latter findings were confirmed by a more recent retrospective study with median follow-up of 40 months after HBIG discontinuation [89]. These data suggest that the combination of HBIG plus lamivudine might be replaced by 753

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Liver disease

Table 45.2 Published studies using combination of adefovir (ADV) and lamivudine (LAM) and hepatitis B immune globulin (HBIG) for prevention of hepatitis B virus (HBV) recurrence after liver transplantation (LT) for HBV related chronic liver disease in patients who had developed lamivudine resistance pre-LT. Study First author, year

Patients, n

Patients under HBIG, n

Patients under LAM/ LAM+ADV, n/n

Mean follow-up, months (mos)

HBV recurrence, n (%)

Survival (%)

Marzano, 2005 [67] Lo, 2005 [80] Caccamo, 2005 [81] Schiff, 2007 [27] Yang, 2007 [82] Osborn, 2007 [83] Freshwater, 2008 [77]

22 16 17 57 16 9 6

22a 8d 17 34 16 9 6

11/11b 0/16 17/0 0/57 0/16 NA/NA 0/6

35 21 32 9 19 25 7

4 (18)c 0 0 2 (3.5)e 0f 0 0

96 94 91 (1 year) 87 94 78 NA

NA: not available. Two patients discontinued HBIG. b HBIG+ADV+LAM in 11/13 patients with phenotypic LAM-resistance (HBV-DNA > 105 copies/ml) and HBIG+LAM in 9/9 with genotypic LAM resistance (detected retrospectively) and 2/13 with phenotypic LAM-resistance. c 2/13 patients under HBIG+LAM (transplanted with HBV-DNA > 105 copies/ml and without ADV pre-LT) and 2/9 patients under HBIG+LAM (the two cases who discontinued HBIG). d HBIG for 9–59 mos post-LT. e 2/34 patients under HBIG+LAM+ADV. f One patient had detectable HBV-DNA but negative HBsAg at six months post-LT. not available. a

lamivudine monotherapy after ≥ 24 months post-transplant in selected HBV transplant patients with low risk of HBV recurrence, although stronger data are needed before the wide use of such a strategy. B4 Given the poor resistance profile of lamivudine monotherapy, the replacement of HBIG and lamivudine combination with lamivudine and adefovir combination after the first few post-OLT months was also evaluated [73, 79, 90]. In the first relevant randomized study, 34 patients under low-dose intramuscular HBIG plus lamivudine for ≥12 months were randomized to continue the same treatment or switch to adefovir plus lamivudine [79]. At a median of 21 months post-switch, there was no case of disease recurrence (one patient in the switch group became HBsAg positive but remained HBV-DNA negative), while the switch approach was associated with substantially lower cost and better patient quality of life [79]. Ald In another recent study, 19 patients who were under adefovir plus lamivudine before LT, received low dose intramuscular HBIG, lamivudine and adefovir for only one week post-LT, followed by adefovir plus lamivudine without any case of HBV recurrence after 12 months of follow-up [90]. However, larger studies with longer follow-up are needed for definitive conclusions about this approach. Finally, the use of newer, more potent antivirals, such as entecavir or tenofovir, in order to early and safely discontinue HBIG certainly deserves to be evaluated. 754

Therapeutic post-transplant approach Therapeutic post-transplant approach is used in cases with HBV recurrence despite previous post-transplant prophylaxis. Given the immunosuppressive therapy taken by all post-transplant patients, the high levels of HBV replication and the risk for rapid progression of liver disease in such cases, the primary targets of treatment of post-transplant HBV recurrence are the control of liver disease and stabilization of graft function [5]. Generally, the principles of treatment in post-transplant HBV recurrence resemble those in the pre-transplant setting. In the pre-lamivudine era, interferon-alfa was a common option, but now its role has almost disappeared due to both low efficacy and low but possible theoretic risk of graft rejection [5]. Lamivudine has been frequently used in cases with recurrence despite HBIG prophylaxis, but it will be inactive in cases with lamivudine resistance [5]. Again, the main disadvantage of long-term lamivudine monotherapy is the progressively increasing rates of resistance exceeding 50% at three-years of therapy in transplant patients [91–95]. The emergence of such HBV mutants is associated with rapid development of advanced histologic lesions and even liver failure and death in some HBV transplant patients [94, 96, 97]. Thus, lamivudine is not an appropriate option for the treatment of HBV transplant patients. B4

CHAPTER 45

HBV infection and liver transplantation

Table 45.3 Published studies of adefovir (ADV) therapy for hepatitis B virus (HBV) recurrence HBV infection after liver transplantation (LT) in patients who developed LAM resistance post-LT. Study First author, year

Patients, n

Baseline serum HBV-DNA (+), n (%)

Baseline HBeAg (+), n (%)

Mean duration of ADV (mos)

Clearance of serum HBV-DNA, n (%) Hybridization-PCR

Clearance of HBeAg, n (%)

Clearance of HBsAg, n (%)

Beckebaum, 2003 [98] Chan, 2004 [47] Akay, 2004 [99] Neff, 2004 [32] Wai, 2004 [100] Toniutto, 2004 [101] Bacerna, 2005 [102] Akyildiz, 2006 [74] Schiff, 2007 [27]

1 6 2 9 4 1 42 11 241

1 (100) 6 (100) 2 (100) 9 (100) 4 (100) 1 (100) 42 (100) 9 (81) NA

1 (100) NA NA 7 (77) NA 0 30 (71.4) NA 132 (69)

15a 20b 4a 30.8a 24c 2a 21.5 14c 36a

0 NA 2 (100) 3 (33) 0. 1 27 (64) 7 (77) 35/45 (78)

0 NA NA 4 (44) NA NA 6 (14) NA 29/50 (58) (8 months)

0 NA 1 (50) 3 (33) NA NA 4 (9.5) NA NA

NA: not available. LAM plus ADV. b ADV plus LAM in 1, LAM plus famiciclovir followed by ADV in one, LAM plus famiciclovir in one and LAM alone in three patients. c ADV monotherapy. a

Adefovir added to ongoing lamivudine therapy has been shown to be effective in transplant patients with lamivudine resistance, achieving significant improvements of serum HBV-DNA and transaminases levels (see Table 45.3) [27, 32, 47, 74, 98–102]. In the largest study, including 241 patients with lamivudine-resistant recurrent HBV infection, the addition of adefovir achieved HBV-DNA undetectability in >95% of cases (94% with HBIG and 100% without HBIG administration) with a cumulative resistance probability of 2% at 144 weeks (see Table 45.3) [27]. B4 Tenofovir has also been reported to be effective in patients with posttransplant HBV re-infection and lamivudine resistance [32]. Since tenofovir is more potent and has a better therapeutic ratio compared to adefovir, it is expected to become the nucleotide of choice for such post-transplant patients. Entecavir might be also used in patients with posttransplant HBV re-infection because of its great potency, high genetic barrier and absence of nephrotoxicity, particularly in cases without lamivudine resistance. Entecavir has been tried in some transplant patients with adefovir [103] and lamivudine resistance [104], but the high probability of resistance with long-term entecavir in non-transplant patients with lamivudine resistance discourages its use in similar post-transplant cases [19].

Anti-HBc positive donors The current efforts to overcome the organ shortage include the use of marginal liver grafts, such as those from anti-

HBc positive donors. Unfortunately, the “occult” HBV infection in the donor liver may be reactivated in the recipient due to post-LT immunosuppressive therapy leading to de novo HBV infection. The most reasonable approach is to direct anti-HBc positive grafts to recipients with HBV related liver disease, as they will require life-long anti-HBV prophylaxis anyway. However, due to organ shortage, HBsAg-negative patients may also receive these grafts. The post-LT outcome of HBsAg-negative recipients of grafts from anti-HBc donors has been evaluated in 30 studies published as full papers (see Table 45.4) [105–134]. De novo HBV infection developed in 27% (82/300) of HBsAgnegative recipients who received no anti-HBV prophylaxis, this being significantly more frequent in HBV naive than anti-HBc positive recepients (12/123 or 10% vs 70/177 or 40%, p < 0.001). In the anti-HBc positive group, de novo infection developed less frequently in cases with anti-HBs positivity compared to no anti-HBs positivity (1/67 or 1% vs 5/37 or 14%, p = 0.021) [105, 106, 109–111, 113, 114, 121, 124–128, 130, 132, 133]. Anti-HBV prophylaxis reduced de novo HBV infection rates in both anti-HBc positive (4%) and HBV naive recipients (9%) [108, 112, 114–116, 118–125, 127, 128, 130, 131, 134]. In particular, de novo HBV infection rate was 23%, 5% and 0% in HBsAg-negative recipients under HBIG, lamivudine and their combination, respectively [105, 108, 112, 114–116, 120, 121, 124, 125, 128, 130, 131, 134]. Whether HBIG may be safely discontinued after a certain period or monoprophylaxis with a new nucleos(t)ide analogue with low resistance rates, are effective strategies in 755

756 None LAM HBIG

3 4 2

17 31

40

44 39 NA

0 0

0

0 0 NA 4 6 5 3 5

3 NA

LAM: 3, None: 1 None LAM+Vaccination LAM HBIG

NA HBIG

None HBIG+LAM: 7, None: 6

19 23

19 45 57 28 31

39 NA

NA 21

26

0 0 0 0 1

0 NA

0 0

0

1 0 NA 0

0

2 12 64 8

3 25 5 8

4 9

3

LAM HBIG

HBIG+LAM: 2, LAM: 6 HBIG (bolus)+ LAM+Vaccination HBIG+LAM None HBIG+LAM HBIG+LAM: 1, HBIG: 6, None: 4 LAM: 1, None: 2

HBIG None: 4, HBIG: 8

None None None None None HBIG+LAM: 7, HBIG: 1 None None LAM LAM or HBIG+LAM

Anti-HBV prophylaxis

23 31

30

23 63 39 57

33

26 22 NA 37

51 29 17 19

22 NA 22 56 51 46

F-up, months

0 1

0

0 2 0 7

0

2 5 10 1

1 15 0 0

7 3 15 16 2 1

De novo HBV, n

F-up: follow-up; HBIG: hepatitis B immunoglobulin; LAM: lamivudine, NA: not available. * Six studies with insufficient data on the serological HBV status of donors and/or recipients are not included [107, 116–118, 122, 129]. De novo HBV infection developed in (1) one case under no anti-HBV prophylaxis among 18 recipients with past HBV infection or HBV naive under HBIG±LAM or no prophylaxis [122]; (2) 0/1 anti-HBc positive recipient (unknown anti-HBs status) under HBIG+LAM [116]; (3) 2/12 recipients with past HBV infection or HBV naive under no anti-HBV prophylaxis [107]; (4) 15/16 anti-HBc positive recipients (unknown anti-HBs status) under no anti-HBV prophylaxis during 12 (5–26) months of follow-up [129]; (5) 3/28 recipients with unknown HBV status under HBIG+LAM [117]; (6) 2/14 recipients with unknown HBV status under HBIG plus vaccination [118]. De novo HBV infection also developed in (1) 0/3 anti-HBc positive recipients (unknown anti-HBs status) under LAM during 20 months of follow-upa [134]; (2) 0/1 anti-HBc positive recipient (unknown anti-HBs status) under HBIG during 11 months of follow-upb [114]; (3) 1/25 anti-HBc negative and anti-HBs positive recipients under LAM plus vaccination during 57 (33–85) months of follow-upc [119].

Pracoso, 2006 [125] Bacerna, 2006 [105] Lin, 2007c [119] Celebi-Kobak, 2007 [108] Takemura, 2007 [131]

None HBIG+LAM HBIG

1

13

11 29 NA 23

56

8 6 18 25 2 8

Patients, N

6 8 15 11

2 4 NA

22

2 0

HBIG: 1 None: 2 None LAM None or HBIG+LAM None

None

3 2 NA NA

7

De novo HBV, n

Fabrega, 2003 [115] Villamil, 2004 [132] Suehiro, 2005 [130] Donataccio, 2006b [114]

13

26 26

1 0 NA 0

0

0 2

F-up, months

11

HBIG+LAM:4, LAM: 9

11 4

Manzabeita, 2002 [121] Roque-Afonso, 2002 [128] Bacerna 2002 [106] Nery, 2003 [124]

15 29 NA 23

46

22 56

Anti-HBV prophylaxis

HBV naive recipients

Loss, 2003 [120]

None None LAM None or HBIG+LAM None HBIG

HBIG+LAM

None None

1 3 NA NA

8

2 15

De novo HBV, n

Patients, N

F-up, months

Patients, N

Anti-HBV prophylaxis

anti-HBc (+), anti-HBs (+) recipients

anti-HBc (+), anti-HBs (−) recipients

Rokuhara, 2000 [127] Prietro, 2001 [126] Yu, 2001a [134] Nerry, 2001 [123]

Chazouilleres, 1994 [109] Wachs, 1995 [133] Dickson, 1997 [111] Dodson, 1997 [113] Crespo, 1999 [110] Dodson, 1999 [112]

First author, year

Table 45.4 Published studies* with liver transplantation from anti-HBc positive donors to HBsAg negative recipients.

CHAPTER 45

all, or in subsets, of such transplant patients remains to be determined. Pre- and post-transplant HBV vaccination has also been evaluated in this setting [105, 106, 108, 114–116, 118–121, 124, 125, 128, 131, 134], but further studies are required before safe conclusions can be drawn. For now, successful pre-LT vaccination does not appear to provide satisfactory protection from de novo post-LT HBV infection [105, 106, 108, 114–116, 121, 124, 125, 128, 131, 134]. However, HBV vaccination should be offered to all naive HBV LT candidates, even though additional anti-HBV prophylaxis might be required in cases of LT with anti-HBc positive grafts. If de novo post-LT HBV infection develops, antiviral treatment (see therapeutic post-transplant approach) is mandatory.

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129

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liver grafts from anti-HBC positive donors. Gut 2002; 50: 95–99. Shinji U, Kohachiro S, Hiroyuki M et al. Transmission of hepatitis B virus from hepatitis B core antibody-positive donors in living related liver transplants. Transplantation 1998; 65: 494–499. Suehiro T, Shimada M, Kishikawa K et al. Prevention of hepatitis B virus infection from hepatitis B core antibody-positive donor graft using hepatitis B immune globulin and lamivudine in living donor liver transplantation. Liver International 2005; 25: 1169–1174. Takemura N, Sugawara Y, Tamura S et al. Liver transplantation using hepatitis B core antibody-positive grafts: review and university of Tokyo experience. Dig Dis Sci 2007; 52: 2472–2477. Villamil I, Gonzalez-Quintela A, Aguilera A et al. Truly de novo HBV infection after liver transplantation. Am J Gastroenterol 2004; 99: 767–768. Wachs ME, Amend WJ, Ascher NL et al. The risk of transmission of hepatitis B from HBsAg(−), HBcAb(+), HBIgM(−) organ donors. Transplantation 1995; 59: 230–234. Yu AS, Vierling JM, Colquhoun SD et al. Transmission of hepatitis B infection from hepatitis B core antibody-positive liver allografts is prevented by lamivudine therapy. Liver Transplant 2001; 7: 513–517.

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Liver biopsy Evangelos Cholongitas1, Andrew K Burroughs1 and Amar P Dhillon2 1 2

The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital, and University College London, London, UK Histopathology Department, Royal Free Hospital, London, UK

Introduction Since the introduction of the 1-sec Menghini needle technique in the early 1950s, liver biopsy (LB) has become the commonest procedure performed in clinical hepatology and remains an important tool in the differential diagnosis and therapeutic decision-making in patients with clinically diagnosed acute and chronic liver disease. Other indications include the evaluation of cholestatic liver disease (primary biliary cirrhosis, primary sclerosing cholangitis), the diagnosis and follow-up of treatment of heritable disorders (hemochromatosis, Wilson’s disease), and LB may be helpful in identification of systemic inflammatory or granulomatous disorders [1–5]. LB is useful in evaluating otherwise unexplained abnormalities of liver function tests, particularly in patients with fever of unknown origin [1–5]. In patients with non-alcoholic fatty liver disease (NAFLD), imaging techniques are sensitive for detecting fatty liver (especially moderate to severe steatosis) [6–9], but they cannot distinguish simple steatosis from steatohepatitis and they cannot measure the degree of fibrosis [8, 10–12]. Thus, LB can confirm the diagnosis of NAFLD and identify the severity and the extent of fibrosis. Other indications for LB include the diagnosis of drug-induced liver damage and the diagnosis of neoplastic and other mass lesions, as well as conditions such as sarcoidosis and hematologic diseases. Finally, in the liver transplantation setting, LB is essential for diagnosis of acute or chronic rejection, recurrence of the primary disease, and characterization of additional intercurrent disease. However, LB only represents approximately 1/50000 of the total liver mass [13] and several studies have stressed this limitation, evaluating the optimal size of a liver speci-

Evidence-Based Gastroenterology and Hepatology, Third Edition John WD McDonald, Andrew K Burroughs, Brian G Feagan and M Brian Fennerty © 2010 Blackwell Publishing Ltd. ISBN: 978-1-405-18193-8

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men and the impact of heterogeneity and intra- and interobserver variation on the histopathological interpretation of LB. The status of LB is being challenged by non-invasive markers for the evaluation of fibrosis, both serum markers and types of transient elastography [14], but in reality LB and non-invasive surrogates are complementary investigations [15]. Furthermore, recent studies have tried to determine optimal standards for length and number of complete portal tracts for accurate evaluation of grading and staging in chronic viral hepatitis [16, 17]. Percutaneous (PLB) and transjugular (TJLB) liver biopsy are the two main techniques. Laparoscopic LB is more invasive [18]. The needles used can be considered large, that is, an external diameter ≥1.0 mm (14–19 G) and thin when 1.6. Patients with chronic renal insufficiency (serum creatinine greater than 1.5 mg/dl) are also considered at high risk: they usually receive desmopressin 15–30 minutes prior to the procedure [42]. Pre-liver biopsy US helps to detect focal hepatic tumors (benign or malignant), cysts, ascites, intrahepatic biliary dilatation or hepatic anatomical variation. Regarding the impact of US guidance on complication rate, recent evidence suggests that real time US guidance, compared to US guidance in order only to identify the puncture site, does not give any advantage regarding safety or size of liver specimen [55]. Both approaches decrease minor and major complications [47–49], particularly the risk of hemorrhage [56], but there is no clear evidence of this benefit [57, 58], compared to the blind approach, where the liver is percussed. Routine use of US for diffuse liver disease is still 763

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debated and has not been established to be cost-effective related to time in hospital [48, 56, 59]. The lower bleeding rate under US guidance may be related to the use of fewer passes used to obtain an adequate sample [46, 51]. US does help the operator to avoid puncture of adjacent important structures [60, 61]; US changed the biopsy site in 21 (12.7%) of 165 patients in a prospective study [60]. The use of US may be especially important in obese patients, those with cirrhosis and patients with chronic obstructive pulmonary disease [56]. Although blind PLB is more commonly performed, it was found that US guidance was used by 56% of gastroenterologists and hepatologists in France [53]. In addition, Angtuaco et al. randomly sent questionnaires involving 260 members of the American Association for the Study of Liver Diseases and found that 75% had performed liver biopsies under US guidance [62]. Post-biopsy US is not routinely needed; usually it is performed in the presence of possible complications. Although fine-needle PLB should be avoided for grading and staging in chronic viral hepatitis patients, guidance fine-needle PLB (via US or computed tomography) is considered particularly useful for diagnosis of hepatocellular carcinoma (HCC) [18, 54]. Indeed, histopathology is often the only way to establish or exclude HCC and to differentiate malignant from dysplastic or benign (degenerative) lesions arising from a background of cirrhosis [63, 64]. Using current guidelines for diagnosis of HCC [65], biopsy is limited to tumors between 1–2 cm diameter [66, 67], which do not have both arterial hypervascularity and portal venous washout. However, there is the risk of malignant seeding [68]. A recent review showed the median seeding rate to be 2.29% for biopsy alone and 0.95% when associated with ablation techniques [69]. B4 This was confirmed by another review, where the risk of malignant seeding with biopsy alone was estimated at up to 2.7% [70]. B4

Plugged PLB is performed through a sheath following embolization of the biopsy track and it is used in patients with impaired blood coagulation. Plugged PLB is easier and quicker than TJLB (15 min vs 41 min respectively) and thus, it is recommended in cases of coagulopathy when TJLB approach is not available or has been performed unsuccessfully [71].

Menghini versus Tru-cut technique in PLB It is considered that the Tru-cut needle produces larger and less fragmented samples compared to the suction needle [4, 47, 54], particularly in patients with advanced fibrosis or cirrhosis [72], but in our recent systematic review on the quality of PLB, we found that the Menghini technique yielded significantly longer samples (19.9 ± 6.6 mm) compared to Tru-cut (14.3 ± 3.2 mm, p = 0.016), but without a significant difference in the mean number of complete portal tracts (CPT) (7.3 vs 6.9, p = 0.8). B4 This could be 764

explained by the fact that the Tru-cut needle provides a maximum length of sample determined by the notch in the needle shaft (usually 20–25 mm) whereas with Menghini needle the length depends on the force of aspiration and operator experience. Finally, there are conflicting results regarding the relative safety of these two techniques: a retrospective study reported a higher rate of major complications with the Tru-cut needle as a result of its longer intrahepatic phase [18, 54], but another prospective study found no significant difference in complication rates related to the type of needle used [73]. B4

Quality of PLB for accurate histological interpretation Diagnostically, PLB of ≥15 mm length has been considered necessary for accurate diagnosis in chronic liver disease [74]; a review also concluded that six to eight complete portal tracts (CPT) should be present for precise diagnosis [13]. However, with the increasing need to assess fibrosis in chronic viral hepatitis, larger liver samples are needed to reliably assess grading and staging. Holund et al. [75] were the first to study the optimal specimen size for accurate assessment of necroinflammation and fibrosis. The studies of Colloredo et al. [16] and Bedossa et al. [17] established the minimum size for reliable scoring of LB for chronic viral hepatitis. In the first study 161 LB from CHC and CHB patients were evaluated, finding that a specimen of at least 20 mm long (of a 1.4 mm diameter, that is, 17 gauge biopsy) and/or containing ≥11 CPT was necessary for reliable assessment of grading and staging in chronic viral hepatitis [16]. Inadequate small samples tend to underestimate the degree of disease grade and stage. B2 In the second study the adequacy of LB samples was assessed using image analysis in 17 surgical specimens taken from CHC patients [17]. A 25 mm long specimen (of a “virtual” 1 mm diameter biopsy) was the minimum length for reliable staging [17]. B4 Indeed, the CPT number is the most suitable parameter to compare different kinds of liver biopsy specimens (e.g. percutaneous versus transjugular, or Menghini versus Tru-cut, or using different needle sizes) [76]. Although the recommendation that an adequate LB should have 11 or more CPT, or be longer than 20–25 mm for the assessment of chronic viral hepatitis, has been accepted rapidly as the optimal standard, there are several additional considerations. An important implication of these studies is that more than one pass is likely for most PLB, in order to achieve an adequate liver sample size [16, 17]. Indeed, the mean length and number of CPT in series of PLB reported in the literature was 17.7 ± 5.8 mm and 7.5 ± 3.4 respectively, which are less than the optimal standard [76]. Interestingly, in the same review, US guidance and more experienced operators were important factors for the length of PLB, but not for the number of CPT [76]. Thus,

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based on documented series of PLB in the literature, the average length and number of CPT of PLB are both below the current optimal criteria for accurate histological interpretation [16, 17]. Therefore, more than one pass is likely to be needed, but this increases the risk of complications with PLB, making the minimum requirement for optimal PLB unrealistic and potentially more dangerous for the patient [46, 50, 51, 53]. B4

Evaluation of heterogeneity and inter-observer variation in histopathological hepatitis scores in PLB using the new sampling standard The minimum requirements for a LB reported above in relation to sampling heterogeneity in diffuse liver disease and inter-observer variability, are very important [16, 17]. Interestingly, there was no significant sample variability (that is, no there was significant difference in stage or grade between synchronous R and L lobe samples) in only one study in which the liver samples were on average >20 mm long and thus adequate [77]. Conversely, Siddique et al. found a ≥2 point difference in Knodell scores of paired (two separate R lobe samples, via the same puncture site, with 4–5 portal tracts in each) HCV liver biopsies in 69% (total necroinflammatory score) and 21% (fibrosis score) of the pairs of biopsies [78]. Clearly inadequate samples are likely to give variable results, while adequate samples will give more reproducible results. Regarding intra- and inter-observer variability, Rousselet et al. confirmed the influence of length and number of portal tracts on inter-observer agreement, at least between academic versus non-academic histopathologists and the available data from the literature shows that the agreement between histopathologists increases with the length and number of portal tracts in PLB [79]. B2

Transjugular liver biopsy Transjugular liver biopsy (TJLB) was first described experimentally in 1964 and it has been used in clinical practice since 1970. TJLB is usually used when there are contraindications to PLB, that is, in patients with massive obesity, gross ascites and severe coagulopathy [13, 45, 80]. However, in recent years, the use of TJLB has expanded to other patient groups, such as liver transplant recipients in the early post transplantation period [81, 82], patients with acute liver failure [83, 84], and those with congenital clotting disorders [85, 86]. The main advantage of TJLB is that there is no penetration of Glisson’s capsule and, therefore, bleeding is extremely rare [13, 18, 45, 87]. Moreover, hepatic venography, hepatic venous pressure gradient (HVPG) measurements and portography with CO2 can be performed concomitantly [18, 45]. Interestingly, HVPG might be a better endpoint than histology for the assessment of

Liver biopsy

therapeutic benefit of antiviral therapy and thus the transjugular approach may be the first choice in these cases [88]. The mean procedure time of TJLB is estimated to be 40.6 (15.5–48) minutes [80]. Initially, TJLB was performed by aspiration technique (Menghini); this resulted in excessive fragmentation and small specimens making diagnosis difficult [89, 90]. The development of a standard and, later, automated Tru-cut needle improved its effectiveness without increasing complications [91, 92]. At our center we use a quick-core 19 G Tru-cut needle. Indeed, minor complications may be more frequent with Menghini TJLB needle, possibly related to the difficulty in controlling the depth of puncture [80]. B2 Tru-cut needles give better samples (longer and more adequate for histological diagnosis) than Menghini needles (median length: 14.5 mm vs 9.5 mm respectively, p = 0.008) [80]. B2 The total complication rate is 7.1% [80]. Minor complications are reported in 6.6% and include abdominal pain, supraventricular arrhythmias and complications from the neck. The latter are significantly less under ultrasound guidance [80]. Major complications occurred in 0.6% and include hepatic hematoma and intra-peritoneal hemorrhage. The latter is the most common major complication (0.2%) as a result of capsular perforation. This occurs particularly in patients with small livers, but it can be detected and treated during the procedure by injecting gelatin or coils at the site of leakage [93]. Death occurred in 0.09% of TJLBs due to intraperitoneal hemorrhage (0.06%) or ventricular arrhythmia (0.03%). Pediatric compared to adult series showed significantly higher total complication rates [81]. B4

Quality of TJLB for accurate histological interpretation Adequate biopsy specimens are crucial for accurate histological interpretation [16, 17], but TJLB specimens have been said to give smaller and more fragmented specimens, compared to PLB [13, 94]. However, a review of TJLB series reported in the literature showed that the mean length and number of CPT with TJLB after an average 2.5 passes were 12.8 ± 4.5 mm and 6.8 ± 2.3 respectively [80]. B2 In addition, TJLB with three passes using Tru-cut needle gives comparable liver biopsy specimens to PLB (mean length and number of CPT were 22 ± 7 mm and 8.7 ± 5 respectively) without any serious complications [82]. B2 TJLB with four passes provided liver specimens with a significantly greater number of CPT, compared to three passes TJLB (median: 9 vs 8, p = 0.04) [95], without an increase in complications compared to a previous series [93]. B2 In addition, four passes, compared to three passes, more often produced specimens of adequate length (≥25 mm: 50% vs 35%, p = 0.026) with more CPT (≥11: 40% vs 26%, p = 0.027) [95]. B2 Thus, at least four passes with TJLB should be 765

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performed when liver specimens are needed for histopathological hepatitis grading and staging. These data showed that TJLB gives comparable specimens to PLB, but as for PLB, optimal quality criteria for grading and staging are not universally obtained. However, in contrast to the risks of percutaneous biopsy with multiple passes, TJLB allows multiple passes (to obtain adequate samples) [46, 50, 51, 96], with far less likelihood of increasing complications [93, 97]. Therefore, TJLB could be an alternative and safe approach to obtain an adequate size of samples for reliable assessment of liver histology. Heterogeneity of liver disease and inter- or intra-observer variation have been evaluated in only one study [98]: three cores of TJLB allowed a more accurate histological interpretation, compared to one or two cores of TJLB. A1d Another advantage of TJLB is the opportunity to measure hepatic venous pressure gradient. This is particularly useful if the patient has cirrhosis, as it has prognostic significance [99], but it can also be used as an indirect marker of fibrosis [81, 88, 100].

Laparoscopic and endoscopic liver biopsy Diagnostic laparoscopy with LB is a safe and very efficient procedure, which can be performed under local anesthesia with conscious sedation and allows the visualization of the liver surface and can yield a larger amount of tissue (wedge biopsy) compared to the other techniques [18]. However, wedge biopsy in patients with diffuse liver disease, may overestimate the extent of fibrosis (staging) because of the exaggerated tissue changes that are observed in subcapsular tissue [101]. Therefore, during laparoscopy, needle biopsy samples of deeper tissue should be obtained for accurate staging. Laparoscopic LB should also be considered when both coagulation abnormalities and focal liver lesions are present [45], as well as for tumor staging and diagnosis of peritoneal disease. Laparotomy has the same advantages with laparoscopy, but is a more invasive procedure and with a higher rate of complications. In fact, the surgical approach is usually performed after accidental discovery of a focal or diffuse liver lesion during routine surgery [46]. Finally, in a recent study, De Witt et al. have proposed the endoscopic US-guided fine needle biopsy as an alternative, safe and sensitive procedure for the diagnosis and staging of liver metastases and mass lesions, since it was able to detect the presence of liver malignancy in 41% of patients with a previously negative evaluation [102].

“Histological” assessment without liver biopsy LB is an invasive procedure, requires hospitalization for at least a few hours and it is associated with low but signifi766

cant morbidity and mortality rates. Thus, it is not suitable for repeat testing to assess progression of liver disease. In addition, to achieve the new standards for optimal LB (20–25 mm length and 11 CPT) the patients will require more than one pass using a standard PLB, increasing the risk of complications. The question has been asked as to whether LB can be regarded as “the gold standard” for staging and grading of diffuse liver diseases when risks of biopsy, inadequate sampling, intra- and inter-observer error are taken into account [103]. Many studies have evaluated non-invasive markers (NIM). There are two types of NIM [104]. The first is based on serum markers: direct and indirect [105]. The indirect NIM may be simple, such as Fibroindex (AST, platelet count, gamma globulin) [106], and APRI index (AST/platelet count) [107], or more complex and expensive such as Fibrotest (a2-macroglobulin, haptoglobin, gamma globulin, apolipoprotein, bilirubin) [108], and PGAA index (a2macroglobulin, γGT, apolipoprotein A1, prothrombin time) [109]. Direct NIM are more expensive and are based on measurement of extracellular matrix in serum [110]. The second category of NIM are methodologies related to liver imaging techniques [105], such as transient elastography (FibroScan), which is based on ultrasound technology [111]. Some scores combine direct and indirect NIM (e.g. Fibrometer), while the accuracy of single NIM has been increased using them in algorithms (e.g. Fibrotest with Fibroscan) [110, 112]. Unfortunately, all these non-invasive tests are currently unable to distinguish different stages of fibrosis and are considered less reliable, compared to LB [113, 114]. The non-invasive tests are not measurements of fibrosis, and the studies that attempt to validate non-invasive tests generally compare them to histopathological stage scores, which are not liver fibrosis measurements either. Initially, studies had compared NIM with sub-optimal LB ( C (V444A), which is associated with decreased hepatic BSEP expression, was significantly more frequent in drug-induced cholestasis than in hepatocellular injury, or in the control population [80]. In contrast, carriers of the ABCB11, 1331T > C polymorphism were found to have a two-fold increased risk of developing toxic hepatocellular damage in a cohort of 188 Spanish DILI patients [81]. With the availability of increasing information on new polymorphisms and their functional significance, it is currently feasible in some cases to perform genotyping for different polymorphisms concomitantly. A study involving 24 patients with diclofenac-induced liver injury showed that simultaneous possession of variant of UDPglucuronosyl-transferase (that mediates the glucuronoconjugation of diclofenac to a paradoxically reactive metabolite acyl-glucuronide) the UGT2B7*2 allele (associated with increased activity), and the ABCC2 (that transports the glucuronide to the biliary canaliculus), C-24T variant (associated with reduced activity) was more common in DILI patients compared with controls. Haplotype distributions for CYP2C8 (which plays a role in the metabolism of diclofenac to 5-hydroxydiclofenac) were also significantly different in patients with hepatotoxicity [36]. Interestingly, in this study, 21% of the community control population was positive for both the “at-risk” UGT2B7 and ABCC2 genotypes [36]. It is clear that the incidence of serious hepatotoxicity is much lower than these figures. Indeed, genetic polymorphisms of drug metabolism, although increasing the risk of DILI, do not explain why all patients with a given polymorphism do not develop DILI when treated with the relevant drug.

Immunological factors Once hepatic cells become stressed by the toxic insult, the response of the innate and acquired immune system

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(downstream events), appear to determine whether liver injury subsides or progresses to clinical disease (see Figure 47.1) [27]. Variations in the production of immunoregulatory cytokines (genetic polymorphisms) such as IL-10 and IL-4 have also been reported to contribute to the susceptibility to diclofenac hepatotoxicity [82]. The observed polymorphisms, resulting in low IL-10 and high IL-4 gene transcription, could favour a Th-2 mediated antibody response to neoantigenic stimulation associated with disease susceptibility. As the increased susceptibility related to these downstream events may be less drug-specific than those involved in the accumulation of reactive metabolites, it might be possible to group cases of DILI associated with a heterogeneous group of drugs. In a cohort of 146 patients with DILI the analysis of three polymorphisms: −1082G/A, −819C/T, and −592C/A in the IL-10 gene promoter, did not reveal any association with the predisposition to develop hepatotoxicity. However, the low IL-10 producing haplotype was more prevalent in DILI patients coupled with the absence of peripheral blood eosinophilia [83]. All cases with serious DILI outcome carried low or intermediate IL-10 producing haplotypes and had normal or low eosinophil counts. [83] Indeed, low IL-10 producing haplotype, leading to a reduced or absent rise in peripheral eosinophil count, could be a marker of an unfavorable outcome of DILI, supporting the concept of accelerated Th1 T-cytotoxic response.

HLA genotyping Major histocompatibility complex molecules (i.e. class I and II HLA molecules) participate in antigen presentation to immunocompetent cells and in the regulation of the immune response. Significant association has been reported between DRB1*1501-DRB5*0101-DQB1*0602 haplotype and cholestatic hepatitis related to amoxicillin-clavulanate [84]. Also a genome-wide association study using 866,399 markers in 51 cases of flucloxacillin DILI and 282 controls matched for sex and ancestry showed an association peak in the major histocompatibility complex (MHC) region with the strongest association (P = 8.7 × 10(−33)) seen for rs2395029[G], and other SNPs all of which are a part of an extended MHC 57.1 haplotype present in 3N ALT or when R ≥ 5 Cholestatic: Increase >2N AP or when R ≤ 2 Mixed: Increase >2N ALT and AP or 2 < R > 5 ALTxN R= APxN N: Upper limit of normal; BC: Conjugated bilirubin; BT: Total bilirubin; ALT: Alanin-aminotransferase; AP: Alkaline phosphatase.

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Table 47.4 Drugs and compounds predominantly associated with hepatocellular or cholestatic damage. Hepatocelullar damage

Cholestatic damage

Acarbose Allopurinol Amiodarone Amoxicillin, Ampicillin Anti-HIV: (didanosine, zidovudine, protease inhibitors) Non-steroidal anti-inflammatory drugs (ibuprofen, diclofenac, piroxicam,indometacin) Asparaginase Bentazepam Bromfenac Chlormethiazole Cocaine, Ecstasy and amphetamine derivatives Diphenytoin Disulfiram Ebrotidine Fluoxetine, paroxetine Flutamide Halothane Herbal remedies ((Chaso and Onshido, Herbalife® Germander (Teucrium chamaedrys), senna Pennyroyal oil, kava-kava (Piper Methysticum), Camellia sinnensis (green tea), Chinese herbal medicines)) Leflunomide Lipid lowering drugs: (lovastatin, pravastatin) Isoniazid Ketoconazole Mebendazole, albendazole, pentamidine Mesalazine Methotrexate Minocycline Nitrofurantoin Nefazodone Omeprazole Pemoline Pyrazinamide Risperidone Ritodrine Sulfasalazine Telithromycin Terbinafine Tetracycline Tolcapone Topiramate Trazodone Troglitazone Trovafloxacin Valproic acid Venlafaxine Verapamil Vitamin A Ximelagatran

Amoxicillin clavulanic acid Azathioprine Captopril, enalapril, fosinopril Benoxaprofen Bupropion Carbamazepine Carbimazole Cloxacillin, dicloxacillin Clindamycin Ciprofloxacin, norfloxacin Contraceptive steroids Cyproheptadine Diazepam, Nitrazepam Erythromycins Estrogens Gold compounds,penicillamine Herbal remedies: (Chaparral leaf (Larrea tridentate), Glycyrrhizin, Greater celandine (Chelidonium majus)) Irbesartan Lipid lowering drugs: (atorvastatin, fluvastatin) Macrolide antibiotics Mirtazapine Penicillin G Phenotiazines (chlorpromazine) Raloxifen Rofecoxib, Celecoxib Rosiglitazone, pioglitazone Sulfamethoxazole-trimethoprim Sulfonylureas: (Glibenclamide,Chlorpropamide) Sulindac Terbinafine Tamoxifen Tetracycline Ticlopidine, Clopidogrel Thiabendazole Tricyclic antidepressants: (Amitriptyline, Imipramine)

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female gender and AST levels were independently associated with a poor outcome [21, 38]. B4 Further analysis of the Swedish database, has found that there was also a significant linear relationship between daily dose and the outcome of death/liver transplantation (2%, 9.4% and 13.2% in 50 mg/day groups respectively, p = 0.03) [24]. B4 On the contrary, it has recently been suggested that eosinophilia accompanying DILI may be associated with a better short-term prognosis [91, 92]. Actually, none of the patients included in the Spanish Registry with idiosyncratic DILI who died, evolved to liver failure, or required a liver transplantation had eosinophilia, whereas this feature was found in the 23% of the patients with milder outcomes [21]. B4 Of note is that the height of transaminases in acute hepatocellular DILI lacks prognosis significance. Indeed, a decrease in liver enzymes after drug withdrawal in patients with severe DILI may reflect rather than a clinical improvement, a limited hepatic reserve associated with impending liver failure [90]. Moreover, if acute injury is superimposed on underlying liver disease, monitoring liver function tests may be difficult to interpret. For example, if advanced cirrhosis is present, the severity of liver injury may be underestimated by the height of the serum ALT measurements [93]. Acute cholestatic injury is caused by many drugs, including anabolic and contraceptive steroids, which characteristically produce DILI with minimal or absent accompanying inflammation. Other medications, which include amoxicillin-clavulanate, macrolide antibiotics and phenothiazine neuroleptics, typically cause variable degrees of portal inflammation and hepatocyte necrosis, in addition to marked cholestasis, which is predominantly centrilobular (see Table 47.4) [42, 47]. In mixed hepatic injury, the clinical and biological picture is intermediate between the hepatocellular and the cholestatic patterns, and features of either type may predominate. By definition, the ALT/AP ratio is between 2 and 5 (see Table 47.3). When faced clinically with a mixed hepatitis picture, the gastroenterologist should always suspect and seek a potentially hepatotoxic medication, since this type of injury is far more characteristic of drug-induced hepatotoxicity than of viral hepatitis [47]. Almost all drugs that produce cholestatic injury are also capable of inducing a mixed pattern. Drug-induced acute cholestatic and mixed lesions progress less frequently to acute liver failure than the hepatocellular type. However, their resolution is generally slower, with a higher likelihood towards chronicity in one study (9% vs 4% respectively; p < 0.031) [94]. In contrast, in the hepatocellular pattern with jaundice at presentation, the severity of chronic lesions was greater (higher incidence of cirrhosis and chronic hepatitis) [94, 95]. Cardiovascular and central nervous system drugs are the main groups leading to chronic liver damage [94]. Of the

Drug induced liver disease

whole population included in the Spanish Registry, 5.6% of patients had biochemical evidence of chronicity [94], a figure similar to that reported in the Swedish population (6%), even though the majority of the patients included in this latter study were identified in an outpatient basis and had mild to moderate DILI [96]. A higher prevalence of chronicity (14%) has been reported in the analysis of the first 300 patients enrolled in the cooperative group Drug Induced Liver Injury Network in USA [22]. Further studies on the natural history of DILI are ongoing. The diagnosis of DILI remains a challenge because, except for the very rare circumstance in which an unintentional positive re-challenge may confirm the putative involvement of a drug, the evidence that is usually collected is often circumstantial. It is often based on subjective impressions from previous experiences, and can lead to inaccurate diagnosis [97]. At present, the diagnosis of DILI is complex and not standardized, and is made with varying levels of confidence, relying largely on exclusion of other causes of liver disease and identification of a signature pattern of disease manifestations, in relation to starting and stopping of the suspected drug or herbal medication [98]. The process is time-consuming and delays clinical diagnosis; at least until other possible causes of liver disease have been excluded. It has been considered as the Achilles heel in the field of hepatotoxicity. Confounding features include multiple drugs prescribed, lack of information on doses consumed, as well as the stop and start dates [99]. A careful “step-by-step” approach is outlined in Figure 47.2 [100]. This issue has important implications not only for practicing clinicians, but also for conducting research into the risk factors, mechanisms and natural history of DILI, and from a medico-legal and drug regulation/development standpoint [101]. The use of causality assessment methods does add some consistency to the diagnostic process, by translating the suspicion into a quantitative score and by providing a framework that emphasizes the features that merit attention in cases of suspected hepatic adverse reaction (see Table 47.2) [102]. A controversial issue is the role of liver biopsy in the diagnosis of DILI. Indeed, since there are no histological findings specific for toxic damage, liver biopsy should not be performed routinely for this indication [103]. Furthermore, a liver biopsy specimen which is often taken several days after the clinical presentation of the symptoms, when the pathological features are beginning to wane, may generate perplexity and confusion in cases in which chronological sequence criteria are critical and when exclusion of alternative causes appear to incriminate the drug [104]. Currently, a reasonable approach for performing a liver biopsy in patients with suspected DILI is restricted to some specific situations: (1) the patient may have an underlying liver disease and, hence, it is difficult to ascribe the picture to the candidate drug or to a 779

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LIVER DISEASE

Check for

Suspicion

• Viral hepatitis, A (IgM-Anti VHA), B (IgM-AntiHBc), C (Anti-VHC, RNA-VHC) • Autoimmune hepatitis (ANA, ASMA) • Alcoholic liver disease (AST/ALT > 2) • Biliary tract disease (dilated bile ducts in ultrasonography)

Drug exposure data and chronology

• Pre-existent liver disease (baseline liver tests) • Drug addiction • Alcohol abuse • Blood transfusions • Hypotension, cardiac failure Not compatible

If compatible assess Hepatotoxic potential

Search for an alternative diagnosis

Found

Not found: Assess features suggesting drug-toxicity Allergic manifestations

Specific therapy

Course on de-challenge Look for possible unintentional re-challenge data Liver biopsy findings (if performed) and biochemical “signature”

Figure 47.2 Algorithm for step-by-step approach to a suspected case of drug-induced liver disease.

recrudescence of the disease [104]; (2) to characterize the pattern of injury with those drugs that had not been previously incriminated in hepatotoxicity [1, 3, 105]; and (3) for identifying more severe or residual lesions (e.g. fibrosis) which could have prognostic significance. For instance, in some chronic variants of hepatotoxicity, clinical and laboratory features poorly reflect the severity of the liver injury [105], and a liver biopsy may clarify its true magnitude. Furthermore, severe bile duct injury during cholestatic hepatitis has been shown to be predictive of clinical evolution into chronic cholestasis [106], and, in a retrospective study, the presence of fibrosis in the index liver biopsy was related to the development of chronic liver disease [107]. Prompt recognition of potentially hepatotoxic drugs as the cause of liver injury is the most important aspect in the management of hepatotoxicity. It is of paramount importance as immediate stoppage appears to decrease the risk of progression to acute liver failure or chronic liver injury [94, 95]. The fact that the diagnosis of hepatotoxicity still relies upon careful history taking (completeness of data and accuracy) and a correct interpretation of the patient’s clinical manifestations and laboratory data, should not be underestimated. An approach to diagnosis following clinical judgment, that closely depends on physician’s skill, and that is not standardized, results in categories of causation that can be defined as drug-related (e.g. acetaminophen 780

over dosage, cases of positive re-challenge), clearly nondrug related (an alternative explanation found, negative de-challenge) or possibly drug-related (temporal sequence, possible competing cause, de-challenge positive) [104]. This last judgment in which subjectivity prevails and in which there is no strong argument for confirming or ruling out drug causality represents the majority of situations in clinical practice. Consequently, agreement among physicians who evaluate a given case of drug-suspected hepatotoxicity may differ strongly, and indeed has been shown to lead to inaccurate diagnosis [97]. To ascertain the putative role of a drug on the basis of quantitative criteria, clinical and laboratory data are assessed with probabilistic approaches (based on Bayesian statistics) and algorithms or clinical scales. The qualities usually required for a diagnosis scale are reproducibility and validity. Reproducibility ensures an identical result regardless of who the user is, and when the scale is used. Validity means the method is able to distinguish between cases where the drug is responsible and cases where it is not [104]. It is worth noting that none of the things that are currently measured have proven to be reliable in assessing causality for drug-induced liver injury. Therefore, more convincing evidence of validity is difficult to obtain in the absence of a unanimously accepted “gold standard” defining “truth” (see Table 47.2).

CHAPTER 47

The first method developed in the area of DILI and, at present, the most prominent adjudication system in use by experts/researchers/sanitary authorities is CIOMS or RUCAM (Roussel Uclaf Causality Assessment Method) scale, which provides a standardized scoring system, in which the limits and content of most criteria were decided by consensus, among experts, on the basis of organ-oriented characteristics [50]. The parameters are outlined in Table 47.5. The time to onset and course criteria vary according to whether cases present with hepatocellular or cholestatic/mixed liver injury, since the latter may occur after a longer post-cessation interval and resolve much more slowly. The CIOMS/RUCAM scale provides a scoring system for seven axes in the decision strategy in which the answers correspond to weighted numeric values that are summed to give a total score. The scores are translated into categories of suspicion: definite or highly probable (score >8), probable (score 6–8), possible (score 3–5), unlikely (score 1–2) and excluded (score (17, relationship definite; 14–17, probable; 10–13, possible; 6–9, unlikely; 8 highly probable or definite. With Maria & Vitorino/CDS, score > 17, definite; 14–17, probable; 10–13, possible; 6–9, unlikely;