Contents
This edition first published 2010, © by Blackwell Publishing Ltd
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Library of Congress Cataloging-in-Publication Data
Inflammatory bowel disease : translating basic science into clinical practice / edited by Stephan R. Targan, Fergus Shanahan, Loren C. Karp.
p.;cm.
Includes bibliographical references.
ISBN 978-1-4051-5725-4
1. Inflammatory bowel diseases. 2. Inflammatory bowel diseases–Pathophysiology.
I. Targan, Stephan R. II. Shanahan, Fergus. III. Karp, Loren C.
[DNLM: 1. Inflammatory Bowel Diseases. WI 420 I4258 2010]
RC862.I53I545 2010 616.3 ′44–dc22
2009029904
ISBN: 978-1-4051-57254
A catalogue record for this book is available from the British Library.
1 2010
Preface
Inflammatory bowel disease research is changing. Progress in defining and treating these diseases is advancing in lock step with the furious pace of technological advances that continue to refine the tools of discovery. With sequencing of the entire genome completed, genetics research is providing direction for molecular and immunological in vivo and in vitro investigation, which in turn directs the development of targeted therapeutics. As translational investigation evolves, what is learned in clinical research is combined with what is learned in basic science research and is leading to a “personalized medicine” approach for managing inflammatory bowel diseases and is bringing the potential of prevention into view.
As Editors, our intention is that this book will provide insight along the entire continuum from basic science to clinical practice. The basic science chapters present findings in the context of what has already been established about the clinicopathological nature of the diseases. The clinical chapters describe the most effective applications of all available diagnostic and therapeutic approaches. This book reflects today’s trends toward globalism and is a truly international effort. We encouraged our contributors to editorialize and provide thought-provoking, progress-stimulating content in their manuscripts. Now, more than ever, is the combination of all disciplines working in concert with the pharmaceutical industry key to the development of better treatments, with fewer side effects, and for predicting patient responses. As drugs become more specialized, it is vitally important to describe carefully patient populations both for study and for treatment. With ever increasing evidence that the inflammatory bowel diseases are heterogeneous disorders, drugs will likely only be effective in certain subpopulations of patients.
Above all, we hope that this book will stimulate future research to the point that achieving a diagnosis and development of a treatment plan will be directed by genetic, immunological and clinical markers of phenotypic distinctions.
We would like to express our sincere gratitude to each of the authors, our colleagues and partners, for nearly three decades of commitment to inflammatory bowel disease, and for their insightful, field-leading contributions. We would also like to acknowledge the commitment, patience and support of our publishers, Wiley-Blackwell, particularly Alison Brown, Adam Gilbert, Gill Whitley, Elisabeth Dodds and Oliver Walter.
Stephan R. Targan
Los Angeles
Fergus Shanahan
Cork
Loren C. Karp
Los Angeles
List of Contributors
Faten N. Aberra
Assistant Professor of Medicine
Division of Gastroenterology
University of Pennsylvania Philadelphia, PA, USA
Maria T. Abreu
Chief, Division of Gastroenterology
Department of Medicine
University of Miami Miller School of Medicine
Miami, FL, USA
David H. Alpers
William B. Kountz Professor of Medicine
Department of Internal Medicine
Division of Gastroenterology
Washington University School of Medicine
St Louis, MO, USA
Raja Atreya
Laboratory of Immunology
Department of Medicine
University of Mainz
Mainz, Germany
Mohammad Azam
Gastroenterology Research Registrar
Department of Gastroenterology
Connolly Hospital
Dublin,Ireland
Charles N. Bernstein
Professor of Medicine
Head, Section of Gastroenterology
Director, University of Manitoba IBD Clinical and
Research Centre
Bingham Chair in Gastroenterology
University of Manitoba
Winnipeg, Manitoba, Canada
David G. Binion
Co-Director, Inflammatory Bowel Disease Center
Director, Translational IBD Research;
Visiting Professor of Medicine
Division of Gastroenterology, Hepatology and Nutrition
University of Pittsburgh School of Medicine
Pittsburgh, PA, USA
Richard S. Blumberg
Chief, Division of Gastroenterology, Hepatology and Endoscopy
Brigham and Women’s Hospital
Professor of Medicine, Harvard Medical School
Boston, MA USA
Leonidas A. Bourikas
Fellow in Gastroenterology
University Hospital of Heraklion
University of Crete Medical School
Heraklion, Crete, Greece
Keith Breglio
Inflammatory Bowel Disease Center
Division of Gastroenterology
Department of Pediatrics
Mount Sinai School of Medicine
New York, NY, USA
Roger Chapman
Gastroenterology Unit
John Radcliffe Hospital
Oxford, UK
Lea Ann Chen
Mount Sinai School of Medicine
New York, NY, USA
Stephen M. Collins
Professor of Medicine
The Farncombe Family Digestive Health Institute
McMaster University Medical Centre
Hamilton, ON, Canada
William Connell
Director, IBD Clinic
Department of Gastroenterology
St Vincent’s Hospital Melbourne
Fitzroy, Victoria, Australia
Ross D. Cranston
Assistant Professor
Division of Infectious Diseases
Department of Medicine
University of Pittsburgh
Pittsburgh, PA, USA
Kenneth Croitoru
Professor of Medicine
Mount Sinai Hospital;
Department of Medicine
University of Toronto
Toronto, ON, Canada
Sue Cullen
Consultant Gastroenterologist
Department of Gastroenterology
Wycombe General Hospital
High Wycombe, Bucks, UK
Sun-Chuan Dai
Department of Medicine
Cedars-Sinai Medical Center
Los Angeles, CA, USA
Lee A. Denson
Division of Gastroenterology, Hepatology, and Nutrition
Cincinnati Children’s Hospital Medical Center
Cincinnati, OH, USA
Shane M. Devlin
Clinical Assistant Professor
Inflammatory Bowel Disease Clinic
Division of Gastroenterology
The University of Calgary
Calgary, Alberta, Canada
Marla C. Dubinsky
Associate Professor of Pediatrics
Director of Pediatric IBD Center
Cedars-Sinai Medical Center
Los Angeles, CA, USA
Laurence J. Egan
Professor of Clinical Pharmacology
Clinical Science Institute
National University of Ireland
Galway, Ireland
Charles O. Elson
Division of Gastroenterology and Hepatology
Department of Medicine
University of Alabama at Birmingham
Birmingham,AL, USA
Sue C. Eng
Clinical Gastroenterologist
Eastside Gastroenterology
Kirkland, WA, USA
Richard J. Farrell
Consultant Gastroenterologist
Department of Gastroenterology
Connolly Hospital
Dublin, Ireland
Michael J.G. Farthing
Vice-Chancellor and Professor of Medicine
University of Sussex
Sussex House
Brighton, Sussex, UK
Victor W. Fazio
Chairman, Digestive Disease Institute
Cleveland Clinic
Cleveland, OH, USA
Masayuki Fukata
Division of Gastroenterology
Department of Medicine
University of Miami Miller School of Medicine
Miami, FL, USA
Marc Girardin
Research Fellow
Division of Gastroenterology
Montreal General Hospital
McGill University
Montreal, QC, Canada
D. Neil Granger
Boyd Professor and Head
Department of Molecular and Cellular Physiology
Louisiana State University Health Sciences Center
Shreveport, LA, USA
Matthew B. Grisham
Boyd Professor
Department of Molecular and Cellular Physiology
Louisiana State University Health Sciences Center
Shreveport, LA, USA
Norman R. Harris
Professor
Department of Molecular and Cellular Physiology
Louisiana State University Health Sciences Center
Shreveport, LA, USA
Steven Itzkowitz
Professor of Medicine
Mount Sinai School of Medicine
New York, NY, USA
Derek P. Jewell
Professor of Gastroenterology
John Radcliffe Hospital
Oxford, UK
Myles R. Joyce
Clinical Associate, Colorectal Surgery
Digestive Disease Institute
Cleveland Clinic Cleveland, OH, USA
Loren C. Karp
Cedars-Sinai Medical Center
Los Angeles, CA, USA
John Keohane
Alimentary Pharmabiotic Centre
Department of Medicine
University College Cork
National University of Ireland
Cork, Ireland
Christopher G. Kevil
Associate Professor Department of Pathology
Louisiana State University Health Sciences Center
Shreveport, LA, USA
Pokala Ravi Kiran
Clinical Fellow
Department of Colorectal Surgery
The Cleveland Clinic Foundation
Cleveland, OH, USA
Louise Langmead
Consultant Physician and Gastroenterologist
Digestive Diseases Clinical Academic Unit
Barts and the London NHS Trust London, UK
Keith Leiper
Consultant Gastroenterologist
Royal Liverpool University Hospital
School of Clinical Sciences
University of Liverpool
Liverpool, UK
William D. Leslie
Department of Medicine, University of Manitoba;
University of Manitoba Inflammatory Bowel Disease
Center;
Manitoba Bone Density Program University of Manitoba Winnipeg, Manitoba, Canada
James D. Lewis
Center for Clinical Epidemiology and Biostatistics
University of Pennsylvania
Philadelphia, PA, USA
Simon K. Lo
Director of Endoscopy
Clinical Professor
David Geffen School of Medicine at UCLA
Cedars-Sinai Medical Center
Los Angeles, CA, USA
Edward V. Loftus Jr
Professor of Medicine
Inflammatory Bowel Disease Clinic
Division of Gastroenterology and Hepatology
Mayo Clinic
Rochester, MN, USA
Thomas T. MacDonald
Dean for Research and Professor of Immunology
Centre for Immunology and Infectious Disease
Blizard Institute of Cell and Molecular Science
Barts and the
London School of Medicine and Dentistry London, UK
Uma Mahadevan
Associate Professor of Medicine
UCSF Center for Colitis and Crohn’s Disease
San Francisco, CA, USA
Michel H. Maillard
Center for the Study of Inflammatory Bowel Diseases
Gastrointestinal Unit
Massachusetts General Hospital
Harvard Medical School
Boston, MA, USA;
Gastroenterology and Hepatology Unit
CHUV-University of Lausanne Lausanne,
Switzerland
Finbar MacCarthy
Department of Pharmacology and Therapeutics
National University of Ireland
Galway, Ireland
Dermot P. McGovern
Immunobiology Research Institute and IBD Center
Cedars-Sinai Medical Center
Los Angeles, CA, USA
Ian McGowan
Professor of Medicine
Division of Gastroenterology, Hepatology and Nutrition
Department of Medicine, University of Pittsburgh
Pittsburgh, PA, USA
Robin S. McLeod
Professor of Surgery and Health Policy, Management
and Evaluation
University of Toronto;
Angelo and Alfredo De Gasperis Families Chair in
Colorectal Cancer and IBD Research
Zane Cohen Digestive Disease Research Unit and Samuel
Lunenfeld Research Institute
Mount Sinai Hospital
Toronto, ON, Canada
Giovanni Monteleone
Professor of Gastroenterology
University of Rome “Tor Vergata”
Rome, Italy
Division of Gastroenterology
University of Washington School of Medicine
Seattle, WA, USA
Markus F. Neurath
Laboratory of Immunology
Department of Medicine
University of Mainz
Mainz, Germany
Diarmuid O’Donoghue
Consultant Physician/Gastroenterologist
Newman Professor of Clinical Research
Centre for Colorectal Disease
St Vincent’s University Hospital
Dublin, Ireland
Seamus O’Mahony
Consultant Physician/Gastroenterologist
Cork University Hospital;
Senior Lecturer in Gastroenterology
University College Cork
Cork, Ireland
Timothy R. Orchard
Department of Gastroenterology and Hepatology
Imperial College London
London, UK
Mark T. Osterman
Assistant Professor
Department of Medicine
University of Pennsylvania
Philadelphia, PA, USA
Konstantinos A. Papadakis
Associate Professor of Medicine
University of Crete Medical School
Division of Gastroenterology
University Hospital of
Heraklion Heraklion, Crete, Greece
Raymond J. Playford
Vice Principal (NHS Liaison) and Vice Principal
(Science and Engineering)
Queen Mary, University of London Barts and the London School of Medicine and Dentistry
London, UK
Daniel K. Podolsky
President
University of Texas Southwestern Medical Center at Dallas
Dallas, TX, USA
Graham L. Radford-Smith
Head, Inflammatory Bowel Disease Unit
Department of Gastroenterology, Royal Brisbane and
Women’s Hospital
Visiting Scientist, Queensland Institute of Medical Research
Associate Professor, Department of Medicine,
University of Queensland
Brisbane, Queensland, Australia
Parvaneh Rafiee
Associate Professor of Surgery
Department of Surgery
Medical College of Wisconsin
Milwaukee, WI, USA
David S. Rampton
Professor of Clinical Gastroenterology
Digestive Diseases Clinical Academic Unit
Institute of Cell and Molecular Science
Barts and the London Queen Mary School of Medicine
and Dentistry
London, UK
Jonathan Rhodes
Professor of Medicine,
School of Clinical Sciences
University of Liverpool
Liverpool, UK
Gerhard Rogler
Division of Gastroenterology and Hepatology
Department of Medicine
University Hospital of Zürich
Zürich, Switzerland
Daniel J. Royston
John Radcliffe Hospital
Headington, Oxford, UK
Sarah Rushworth
Gastroenterology Fellow
School of Clinical Sciences
University of Liverpool
Liverpool, UK
Paul Rutgeerts
Department of Gastroenterology
University Hospital Gasthuisberg
Leuven, Belgium
William J. Sandborn
Inflammatory Bowel Disease Clinic
Division of Gastroenterology and Hepatology
Mayo Clinic and Mayo Clinic College of Medicine
Rochester, MN, USA
Bruce E. Sands
Associate Professor of Medicine
Harvard Medical School
Acting Chief, Gastrointestinal Unit
Medical Co-Director, MGH Crohn’s and Colitis Center Massachusetts General Hospital
Boston, MA, USA
Christine Schlenker
Professor of Medicine
Division of Gastroenterology
Assistant Dean for Faculty of Development
University of Washington
Seattle, WA, USA
Ernest G. Seidman
Professor of Medicine and Pediatrics
Canada Research Chair in Immune Mediated Gastrointestinal
Disorders
Bruce Kaufman Endowed Chair in IBD
McGill University
Montreal, QC, Canada
Fergus Shanahan
Alimentary Pharmabiotic Centre
Department of Medicine
University College Cork
National University of Ireland
Cork, Ireland
Kieran Sheahan
Consultant Histopathologist and Associate Clinical Professor
Centre for Colorectal Disease
St Vincent’s University Hospital and University College Dublin
Dublin, Ireland
Bo Shen
Staff Gastroenterologist
Digestive Disease Institute
Cleveland Clinic
Cleveland, OH, USA
Corey A. Siegel
Assistant Professor of Medicine
Dartmouth Medical School
Director, Dartmouth-Hitchcock IBD Center
Section of Gastroenterology and Hepatology
Lebanon, NH, USA
Scott B Snapper
Associate Chief of Research
Center for the Study of Inflammatory Bowel Diseases
Gastrointestinal Unit
Massachusetts General Hospital
Associate Professor of Medicine
Harvard Medical School
Boston, MA, USA
Christina M. Surawicz
Stephan R. Targan
Cedars-Sinai Medical Center
Los Angeles, CA, USA
Simon Travis
Gastroenterology Unit
John Radcliffe Hospital
Oxford, UK
Gert Van Assche
Associate Professor of Medicine
Department of Gastroenterology
University Hospital Gasthuisberg
Leuven, Belgium
Séverine Vermeire
Department of Gastroenterology
University Hospital Gasthuisberg
Leuven, Belgium
Alissa J. Walsh
Consultant Gastroenterologist
Department of Gastroenterology
St Vincent’s Hospital
Sydney, NSW, Australia
Bryan F. Warren
Honorary Professor Queen Mary College, University of London
Consultant Gastrointestinal Pathologist and Honorary
Senior Lecturer
John Radcliffe Hospital
Headington, Oxford, UK
Casey T. Weaver
Department of Pathology
University of Alabama at Birmingham
Birmingham, AL, USA
Jarrad Wilson
IBD Fellow
Department of Gastroenterology
St Vincent’s Hospital Melbourne
Fitzroy, Victoria, Australia
Sebastian Zeissig
Laboratory of Mucosal Immunology
Brigham and Women’s Hospital
Harvard Medical School
Boston, MA, USA
Renyu Zhang
Clinical Research Fellow
Department of Colorectal Surgery
Cleveland Clinic
Cleveland, OH, USA
Chapter 1
Introduction: the Science and the Art of Inflammatory Bowel Disease
This book is about the science and the art and the science of the art of gastroenterology as it pertains to inflammatory bowel disease. Once described as disabling and under-researched diseases, the inflammatory bowel diseases now attract intense interest from clinical and basic investigators, but remain an important cause of suffering and a major burden on healthcare resources.
Why another textbook, in this era of rapid information access? The answer is simple – there is a continuing need for informed opinion and perspective on the deluge of data generated in recent years spanning a diversity of aspects of inflammatory bowel disease. Many wish for a single repository of information from authoritative sources. With this in mind, the authors for this textbook were selected because they are expert and currently active contributors to their respective areas of the field. Each was charged with delivering a crisp, timely and opinionated account of their area with a futuristic perspective.
A recurring theme within modern biology in general and inflammatory bowel disease, in particular, is the need to think across traditional boundaries of intellectual pursuit and to be aware of research at the interface of disparate disciplines. The convergence of different research avenues in inflammatory bowel disease is represented by the host–microbe interface; other pertinent examples have been variably expressed as the brain–gut axis, immunoepithelial dialogue and neuroimmunology. Each is embraced in this textbook in various chapters dealing with disease mechanisms.
One of the great lessons of the recent past in gastroenterology was the failure of traditional epidemiologic and biologic approaches to identify a transmissible agent as the cause of peptic ulcer disease. A more important lesson was that the solution to some complex diseases may never be found by research focused exclusively on the host, without due regard for host–environment interactions, particularly host–microbe interactions. In the future, investigators involved in epidemiologic, genetic or other areas of research in inflammatory bowel disease will have to approach their challenge with some form of rapprochement with disease mechanisms. It is noteworthy, for example, that the genetic risk factors for inflammatory bowel disease are responsible for sensing and interpreting the microenvironment (e.g. NOD2/CARD15) or are involved in the regulation of the host immune response to that microenvironment (e.g. autophagy, IL23R). The complexity and clinical implications of these interactions are discussed by several authors in this volume.
Advances in technology have greatly facilitated research in inflammatory bowel disease. These include automated approaches to gene sequencing and genotyping large numbers of study subjects and molecular strategies for studying the intestinal microbiota, most of which is still unculturable and, therefore, neglected or considered until recently to be obscure. The human organism is now viewed as a composite of the human genome and its commensal microbial genome (microbiome), both of which interact with environmental and lifestyle modifying factors. As the human microbiome project and other similar metagenomic collaborations around the world deliver new information on the diversity and individual variations in the intestinal microbiota, it is anticipated that some of the heterogeneity of inflammatory bowel disease may be resolved. Thus, genetic risk factors will have to be reconciled with variations in microbial composition and with patterns of immunologic responsiveness to the microbiota. The challenge for epidemiologists and biologists will be to relate the aspects of a modern lifestyle with changes in the microbiota and thence with immunologic behavior and susceptibility to disease. Thus, the elucidation of the “IBD genome” provides the foundation for micro- and macro-environmental epidemiologic investigation. The contributing authors to this text have provided the background to this futuristic scenario.
Has the relentless march of the biotech and genotech era of research delivered for the patient? Unquestionably patients are better off today than they were only a generation ago. A more coherent understanding of fundamental disease mechanisms is being translated into improved patient management with a progressive shift toward evidence-based approaches and away from therapeutic empiricism. This is reflected throughout those chapters of this book dedicated to patient care.
Although not quite at the stage of personalized health-care, the splitters are in the ascendancy over the lumpers in today’s approach to the patient with inflammatory bowel disease. Refinement of clinical phenotypes by fusing genetic variation and the functional consequences thereof will lead to the reclassification of standard clinical phenotypes into physiologically determined subgroups and ultimately to individualized therapeutic targeting. These critical steps will continue to inform the interpretation of data on the genotype. This represents just one of many opportunities for clinicians and basic scientists to engage in a mutually beneficial manner in translating bench-to-bedside research to improved management of inflammatory bowel disease.
But some things never change. Clinical care of chronic disease will always require attention to detail, compassion and a commitment to long-term follow-up. In the face of the extraordinary advances in therapeutics, which continue apace, there is substantial patient dissatisfaction with modern medicine, either because of increasing expectations or reduced tolerance of illness. Most patients place greatest emphasis on the doctor–patient relationship. In this relationship, the attitude and level of interest of the former will always be a major determinant of the outcome of the latter.
Textbooks like this cannot confer attitude, energy or enthusiasm on the reader, but they can sensitize and equip the reader with the necessary background information, opinion and perspective. Therein lies the essence of what is intended with this book – to provide stimulus and steerage for the interested clinician, scientist and clinician–scientist in what is already an intriguing and rewarding field of endeavor.