Contents

Cover

Title Page

Copyright

Contributors

Preface

Part I: Genes and Phenotype in IBD

Chapter 1: Which will take us further in IBD—study of coding variation or epigenetics?

Gene expression: sequence variation versus epigenetic factors

Genetic variation in IBD

Regulation of gene expression in IBD

Limitations of current studies of epigenetic mechanisms in IBD

Conclusions

Chapter 2: IBD in different ethnic groups: same or different?

Introduction

Genotype

Phenotype

Dysplasia in UC

Extraintestinal Manifestations

Conclusions

Part II: Bugs and IBD—Good, Bad, or Indifferent?

Chapter 3: How does the risk of infection influence management of IBD around the world?

Introduction

Acute bacterial and parasitic infections mimicking IBD flare

Influence of IBD therapies on the risk of infection

Conclusion

Chapter 4: Traveling with IBD

Introduction

IBD, infections, and vaccination

Pretravel preparation

Chapter 5: What to do about hepatitis B and hepatitis C in patients with IBD

Introduction

IBD and chronic viral hepatitis

Effect of treatment for IBD on viral hepatitis

Treatment of IBD in patients with HBV

Treatment of IBD in patients with HCV

Treatment of viral hepatitis—effect of interferon on IBD

Conclusions

Chapter 6: CMV in IBD—passenger or pathogen?

Introduction

Diagnosis of CMV infection

Conclusions and recommendations

Chapter 7: Clostridium difficile in IBD: impact, prevention, and treatment

Introduction

Prevalence and impact

Presentation and assessment

Diagnosis

Prognosis

Treatment

Prevention

Conclusions

Chapter 8: Prebiotics and synbiotics: panacea or placebo

Introduction: the pathogenesis of inflammatory bowel disease (IBD)

The microbiota in IBD

Probiotics in IBD

Prebiotics and synbiotics: introduction

Conclusions

Chapter 9: Worms: light at the end of their burrow

Introduction

Hygiene hypothesis/rational for helminthic therapy

Conclusion

Chapter 10: Do we really need to vaccinate all patients with IBD?

What constitutes immunocompromised status?

Conclusion

Part III: Investigating IBD

Chapter 11: Biomarkers in IBD: myth or marvel?

Introduction

Classical biomarkers

Fecal biomarkers

Emerging serological biomarkers

Conclusions

Chapter 12: Radiation exposure in IBD: how do we minimize the dangers?

Introduction

Radiation exposure in IBD

Radiation exposure and CT

Alternative imaging strategies for minimizing radiation exposure

Improving referral practices

Conclusion

Chapter 13: Surveillance colonoscopy in UC: what is the best way to do it?

Introduction

Risk stratification

Surveillance colonoscopy

Dysplasia management

Conclusion

Part IV: Medical Therapy

5-ASA

Chapter 14: New 5-ASAs for ulcerative colitis: a tiny step or giant stride forward?

Introduction

Mechanism of action and pharmacology of different formulations

Efficacy and safety of aminosalicylates for UC

Conclusion

Chapter 15: Do 5-ASAs prevent cancer?

Introduction

How might 5-ASAs protect against CRC in UC?

What is the clinical and observational evidence?

Might other drugs be chemopreventive?

Conclusion

Chapter 16: Why do we still use 5-ASAs in Crohn's disease?

Introduction

Role in inducing remission

Role in maintaining remission

Role in maintaining remission in postoperative patients

Role in chemoprevention for colorectal cancer (CRC) prevention

Conclusions

Steroids

Chapter 17: Steroids in Crohn's disease: do the benefits outweigh the dangers?

Introduction

Benefits of steroids

Limitations of therapeutic effects of steroids

Adverse effects of steroids

Co-administration of immunomodulators with steroids

Role of anti-TNF therapies

The place of steroids in treatment of Crohn's disease

Immunomodulators

Chapter 18: Thioguanine nucleotide measurement: nonadherent, underdosed, shunter, or refractory?

Introduction

Thiopurine metabolism and the role of metabolite monitoring

Indications for the measurement of thiopurine metabolites

Conclusions

Chapter 19: Thiopurines and the sun: what should be done?

Introduction

Thiopurines and the sun: what is the risk?

Molecular mechanisms of thiopurine-associated skin cancer

What should be done?

Conclusions

Acknowledgements

Chapter 20: Do thiopurines worsen risk and prognosis of cervical neoplasia?

Introduction

Thiopurines and cancer risk

The risk of cervical cancer in thiopurine-treated IBD

The prognosis of cervical cancer in thiopurine-treated IBD

AZA in patients with a history of cervical cancer

Conclusion

Minimizing risks

Chapter 21: Optimizing use of methotrexate

Introduction

Lessons from pharmacology of methotrexate [1,2]

Efficacy in IBD

Adverse effects

Conclusions (Table 21.1)

Chapter 22: Which calcineurin inhibitor and when?

Introduction

Cyclosporine in UC

Tacrolimus in UC

Pharmacology

Toxicity

When to start a calcineurin inhibitor

Conclusions

Biologics

Chapter 23: Are all anti-TNF agents the same?

Introduction

Structure and function

Pharmacokinetic properties

Immunogenicity

Clinical efficacy

Conclusions

Chapter 24: One drug or two: do patients on biologics need concurrent immunomodulation?

Introduction

Efficacy of combination therapy

Conclusion

Chapter 25: How do we identify patients needing early aggressive therapy and what should we use?

Introduction

Clinical factors identifying complicated disease

Biomarkers for predicting complicated disease

Genetic markers of complicated disease

What should we use in patients identified as requiring early aggressive therapy?

Conclusion

Chapter 26: What is the role of biologics in UC?

Introduction

When to initiate a biologic for UC

Which drug(s) to initiate

The use of biologics around the time of surgery

Conclusions

Chapter 27: What can we do with Crohn's patients who fail or lose response to anti-TNF therapy?

Treat the patient earlier in their disease course

Use concomitant immune modulation and commit to maintenance therapy

Confirm active inflammation

Defining primary nonresponse to anti-TNF therapy

Management of the Patient with Primary Nonresponse to TNF inhibitors

Management of the patient with secondary loss of response or simple relapse

Conclusions

Chapter 28: Which extraintestinal manifestations of IBD respond to biologics?

Musculoskeletal EIMs

Skin manifestations

Oral manifestations

Ocular complications of IBD

Hepatobiliary complications of IBD

Conclusion

Chapter 29: Use and abuse of biologics in pregnancy

Use of biologics during pregnancy

Use of biologics and breastfeeding (see Chapter 20)

Use of biologics and newborn management

Conclusions

Chapter 30: Is anti-TNF therapy safe to use in people with a history of malignancy?

Introduction

What is the risk of malignancy in patients treated with anti-TNF antibodies?

What is the risk of cancer recurrence or progression after anti-TNF therapy?

Should patients with previous malignancy be treated with anti-TNF therapy?

Chapter 31: The risks of immunomodulators and biologics: what should we tell patients?

Introduction

What to tell patients about possible side effects

How to tell patients about the risk of side effects

Conclusion

Chapter 32: When, how, and in whom should we stop biologics?

Introduction

Reasons for stopping anti-TNF

Available studies on anti-TNF treatment cessation in IBD

Practical considerations when stopping anti-TNF treatment in CD

Conclusions

Part V: Other Treatments

Chapter 33: Avoiding drug interactions

Introduction

Drug interactions

Warfarin

Smoking cessation

Conclusion

Chapter 34: Is there still a role for ursodeoxycholic acid treatment in patients with inflammatory bowel disease associated with primary sclerosing cholangitis?

Introduction

The PSC–IBD relationship

Effectiveness of UDCA in PSC

Chemopreventive effect of UDCA

Conclusions

Chapter 35: Stem cell transplantation for Crohn’s: will it fulfill its promise?

Introduction

What are stem cells?

Rationale for stem cell transplantation in Crohn's disease

Hematopoietic stem cell transplantation

Safety of HSCT in Crohn's disease

Mesenchymal stem cell transplantation

Conclusions

Chapter 36: Complementary therapy: is there a needle in the haystack?

How often and why is CAM used in IBD?

Conclusions

Part VI: Surgical Dilemmas in IBD

Chapter 37: Optimizing IBD patients for surgery and recovery

Introduction

Preoperative care

Operative care

Postoperative care

Chapter 38: Is surgery the best initial treatment for limited ileocecal Crohn's disease?

Introduction

Conclusion

Chapter 39: Laparoscopic or open surgery for IBD?

Introduction

Laparoscopy for Crohn's disease

Conclusion

Chapter 40: Optimizing management of perianal Crohn's disease

Introduction

Skin tags and hemorrhoids

Strictures

Fissures

Perianal abscesses

Fistulizing disease

Conclusions

Chapter 41: Does anti-TNF therapy increase the risk of complications of surgery?

Introduction

Crohn's Disease

Combined cohorts

Conclusion

Chapter 42: Pouches for indeterminate colitis and Crohn's disease: act now, pay later?

Indeterminate colitis

Crohn's disease

Conclusion

Chapter 43: Dealing with pouchitis

Introduction

Investigation

Treatment (see Figure 43.1 [3])

Preventing initial onset of pouchitis

Implications of use of antibiotics in patients with pouchitis

Part VII: Unsolved Issues in IBD

Chapter 44: Mucosal healing in IBD: does it matter?

Crohn's disease

Ulcerative colitis

Conclusions

Chapter 45: Vitamin D in IBD: from genetics to bone health via cancer and immunology

Vitamin D In IBD: from genetics to bone health via cancer and immunology

Conclusion

Chapter 46: Got milk? Medication use and nursing in women with IBD

Introduction

Effect of nursing on course of IBD

Problems and unresolved issues

Chapter 47: Does stress matter?

Introduction

Plausible mechanisms by which stress can increase gut inflammation

Conclusion

Chapter 48: IBS is common in IBD: fact or fallacy?

Introduction

What is IBS?

Chapter 49: So where is all the cancer?

Colorectal cancer in IBD remains an unsolved issue

Conclusion

A glance into the future

Part VIII: Nutrition in IBD

Chapter 50: What should patients with IBD eat?

Intervention studies

Malnutrition in IBD

“Best current advice”

Need for future work

Chapter 51: Enteral nutrition in Crohn’s—who for, when, how and which formula?

Diet and risk of IBD

Conclusions

Chapter 52: Optimizing treatment of iron deficiency anemia

Introduction

Anemia in IBD

Screening

Diagnostics

Therapy

Intravenous iron supplementation

Further therapy options

Conclusion

Part IX: Management Process

Chapter 53: IBD Standards: will they enhance patient care?

Quality of care: an overview

Quality of IBD care

Defining IBD standards: structure, process, and outcomes

Current efforts to define IBD standards

Future directions: using quality measures to enhance care

Chapter 54: Your treatment will not work if the patient does not take it

Introduction

Nonadherence to maintenance treatment in IBD

The perceptions and practicalities approach (PPA) [9]

Implications for practice

Conclusion

Chapter 55: Inflammatory bowel disease: what to tell your emergency department (ED) team

Introduction

The scale of the problem

Reasons for ER attendance

Approach to the patient with IBD presenting as an emergency

Non-IBD related attendances to ER

How to improve emergency care for patients with IBD

Chapter 56: Transitioning from pediatric to adult care

Introduction

Barriers

The transition process

Conclusion

Chapter 57: Medicolegal pitfalls in inflammatory bowel disease care

Introduction

Conclusions

Index

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Library of Congress Cataloging-in-Publication Data

Clinical dilemmas in inflammatory bowel disease : new challenges / edited by
Peter Irving ... [et al.]. – 2nd ed.
p. ; cm.
Includes bibliographical references and index.
ISBN-13: 978-1-4443-3454-8 (pbk. : alk. paper)
ISBN-10: 1-4443-3454-9 (pbk. : alk. paper)
ISBN-13: 978-1-4443-4254-3 (ePDF)
ISBN-13: 978-1-4443-4257-4 (e-ISBN-10: : Wiley Online Library) [etc.]
1. Inflammatory bowel diseases. 2. Inflammatory bowel diseases–Decision making.
I. Irving, Peter, 1970-
[DNLM: 1. Inflammatory Bowel Diseases. WI 420]
RC862.I53C553 2011
616.3′44–dc22
2011007515

A catalogue record for this book is available from the British Library.

This book is published in the following electronic formats: ePDF 9781444342543; Wiley Online Library 9781444342574; ePub 9781444342550; Mobi 9781444342567

Contributors

Ashwin N. Ananthakrishnan MD, MPH
Instructor in Medicine
Harvard Medical School
Gastrointestinal Unit
Massachusetts General Hospital
Boston, MA, USA

Donna Appleton MD, MRCS
Specialist Registrar
Department of General and Colorectal Surgery
Stafford General Hospital
Stafford, UK

Judith E. Baars MSc, PhD Medical Student
Erasmus University
Rotterdam, The Netherlands
Department of Gastroenterology and Hepatology
Erasmus MC Hospital
Rotterdam, The Netherlands

Jacques Belaiche PhD
Professor of Gastroenterology
Department of gastroenterology
CHU Liège and GIGA Research University of Liège
Liège, Belgium

David G. Binion MD
Visiting Professor of Medicine
Division of Gastroenterology, Hepatology, and Nutrition
University of Pittsburgh School of Medicine
Pittsburgh, PA, USA

Wojciech Blonski MD, PhD
Research Scholar
Division of Gastroenterology
University of Pennsylvania
Philadelphia, PA, USA;
Department of Gastroenterology
Medical University
Wroclaw, Poland

Brian Bressler MD, MS, FRCPC
Clinical Assistant Professor of Medicine
Division of Gastroenterology
University of British Columbia
Vancouver, BC, Canada

Emma Calabrese MD, PhD
University of Rome “Tor Vergata”
Rome, Italy

Adam S. Cheifetz MD
Assistant Professor of Medicine;
Clinical Director, Center for Inflammatory Bowel Disease
Division of Gastroenterology
Beth Israel Deaconess Medical Center and Harvard Medical School
Boston, MA, USA

Dorothy K.L. Chow MBChB, MD, MRCP
Clinical Assistant Professor (Honorary)
Department of Medicine and Therapeutics
Prince of Wales Hospital
The Chinese University of Hong Kong
Hong Kong SAR, China

Miranda Clark BSc(Hons)
Clinical Trials Coordinator
University Hospital
Queen’s Medical Centre
Nottingham, UK

Norman R. Clark III MD
Division of Gastroenterology
Vanderbilt University Medical Center
Nashville, TN, USA

Morven Cunningham MA(Hons), MBBS, MRCP
Clinical Research Fellow
Blizard Institute of Cell and Molecular Science
Barts and The London School of Medicine and Dentistry
Queen Mary, University of London
UK

Andrew S. Day MB,ChB, MD, FRACP, AGAF
Associate Professor
Department of Paediatrics
University of Otago
Dunedin, Otago, New Zealand;
Pediatric Gastroenterology
Christchurch Hospital
Christchurch, New Zealand

Alan N. Desmond MB, BCh, BAO, BMedSc, MRCPI
Specialist Registrar
Department of Gastroenterology and General Internal Medicine
Cork University Hospital
Wilton, Cork, Ireland

Shane M. Devlin MD, FRCPC
Clinical Assistant Professor
Division of Gastroenterology
Inflammatory Bowel Disease Clinic
The University of Calgary
Calgary, AB, Canada

Geert D’Haens MD, PhD
Professor of Medicine
Academic Medical Centre
Amsterdam, The Netherlands

Axel Dignass MD, PhD, FEBG, AGAF
Professor of Medicine
Head, Department of Medicine I
Markus Hospital
Frankfurt/Main, Germany

Glen A. Doherty MB, PhD, MRCPI
Consultant Gastroenterologist
Centre for Colorectal Disease
St Vincent’s University Hospital/University College Dublin
Dublin, Ireland

Marla C. Dubinsky MD
Associate Professor of Pediatrics
Director, Pediatric IBD Center
Cedars Sinai Medical Center
Los Angeles, CA, USA

Tim Elliott MBBS, FRACP
Specialist Registrar
Department of Gastroenterology
Guys and St Thomas’ Hospitals
London, UK

Marc Ferrante MD, PhD
Consultant Gastroenterologist
Department of Gastroenterology
University Hospital Gasthuisberg
Leuven, Belgium

Laurie N. Fishman MD
Assistant Professor of Pediatrics
Center for Inflammatory Bowel Disease
Division of Gastroenterology and Nutrition
Children’s Hospital Boston
Harvard Medical School
Boston, MA, USA

Phillip Fleshner MD, FACS, FASCRS
Program Director, Colorectal Surgery Residency
Los Angeles, CA, USA;
Clinical Professor of Surgery
UCLA School of Medicine
Los Angeles, CA, USA

Anna Foley MBBS(Hons), FRACP
Consultant Gastroenterologist
Department of Gastroenterology and Hepatology
Box Hill Hospital
Melbourne, VIC, Australia

Graham R. Foster FRCP, PhD
Professor of Hepatology
Blizard Institute of Cell and Molecular Science
Barts and The London School of Medicine and Dentistry
Queen Mary, University of London
London, UK

Richard B. Gearry MB, ChB, PhD, FRACP
Associate Professor of Medicine
Consultant Gastroenterologist
Department of Medicine
University of Otago
Dunedin, Otago, New Zealand;
Department of Gastroenterology
Christchurch Hospital
Christchurch, New Zealand

Peter Gibson MD, FRACP
Professor of Medicine and Consultant Gastroenterologist
Department of Gastroenterology and Hepatology
Eastern Health Clinical School
Monash University, Melbourne
VIC, Australia

James Goodhand BSc(Hons), MBBS, MRCP
Clinical Research Fellow
Barts and the London School of Medicine and Dentistry
Queen Mary’s University of London
London, UK

Richard J. Grand MD
Professor of Pediatrics
Harvard Medical School
Director Emeritus, Center for Inflammatory Bowel Diseases
Division of Gastroenterology and Nutrition
Children’s Hospital Boston
Boston, MA, USA

Gauree Gupta MD
Staff Physician
Department of Medicine
Cedars Sinai Medical Center and David Geffen School of Medicine at UCLA
Los Angeles, CA, USA

Elizabeth J. Hait MD, MPH
Center for Inflammatory Bowel Disease
Division of Gastroenterology and Nutrition
Children’s Hospital Boston
Harvard Medical School
Boston, MA, USA

Stephen B. Hanauer MD
Professor of Medicine and Clinical Pharmacology
Section of Gastroenterology, Hepatology, and Nutrition
University of Chicago Medical Center
Chicago, IL, USA;
Chief, Section of Gastroenterology, Hepatology, and Nutrition
University of Chicago Medical Center
Chicago, IL, USA

Catherine A. Harwood
Centre for Cutaneous Research
Blizard Institute of Cell and Molecular Science
Barts and The London School of Medicine and Dentistry
Queen Mary University of London
London, UK

Christopher J. Hawkey DM, FRCP
Professor of Gastroenterology
University Hospital
Queen’s Medical Centre
Nottingham University Hospitals NHS Trust
Nottingham, UK

A. Barney Hawthorne DM, FRCP
Consultant Gastroenterologist
Department of Medicine
University Hospital of Wales
Cardiff, UK

Michael Hershman DHMSA, MSc(Hons), MS(Hons), FRCS (Eng, Ed, Glas & Irel), FICS
Consultant Surgeon
Department of General Surgery
Stafford Hospital
Stafford, UK

Rob Horne
Professor of Behavioural Medicine
Director, Centre for Behavioural Medicine
The School of Pharmacy
University of London
London, UK

Peter M. Irving MD, MRCP
Consultant Gastroenterologist
Department of Gastroenterology
Guy’s and St Thomas’ Hospitals
London, UK

Jennifer L. Jones MD, MSc, FRCPC
Director, MDIBD Clinic and IBD Clinical Trials
Assistant Professor
Departments of Medicine and Community Health Sciences and Epidemiology
University of Saskatchewan
Royal University Hospital
Saskatoon, SK, Canada

Ahmed Kandiel MD, MPH
Staff Gastroenterologist
Department of Gastroenterology and Hepatology
Digestive Disease Institute
Cleveland Clinic
Cleveland, OH, USA

Sunanda Kane MD, MSPH
Professor of Medicine
Mayo Clinic College of Medicine
Rochester, MN, USA

Gilaad Kaplan MD, MPH, FRCPC
Assistant Professor
Departments of Medicine and Community Health Sciences
Teaching Research and Wellness Center
University of Calgary
Calgary, AB, Canada

Michael D. Kappelman MD, MPH
Assistant Professor
Division of Pediatric Gastroenterology
Department of Pediatrics
University of North Carolina Chapel Hill
Chapel Hill, NC, USA

Louise Langmead BSc(Hons), MD
Consultant Gastroenterologist
Endoscopy Unit
Barts and the London NHS Trust
The Royal London Hospital
London, UK

Bret Lashner MD, MPH
Professor of Medicine
Department of Gastroenterology and Hepatology
Digestive Disease Institute
Cleveland Clinic
Cleveland, OH, USA

Joanna K. Law MD, MA [Ed], FRCP(C)
Clinical Instructor, Division of Gastroenterology
University of British Columbia
Vancouver, BC, Canada

Ian Craig Lawrance MBBS(Hons), PhD, FRACP
Professor, School of Medicine and Pharmacology
University of Western Australia
Perth, WA, Australia;
Director, Centre for Inflammatory Bowel Diseases
Fremantle Hospital
Fremantle, WA, Australia

Keith Leiper MD, FRCP
Consultant Gastroenterologist
Royal Liverpool University Hospital
Liverpool, UK

Rupert W.L. Leong MBBS, MD, FRACP
Associate Professor of Medicine (Conjoint)
The University of New South Wales
Sydney, NSW, Australia;
Director of Endoscopy
Department of Gastroenterology and Liver Services
Sydney South West Area Health Service
Concord and Bankstown Hospitals
Sydney, NSW, Australia

John Leung MD
Instructor
Division of Gastroenterology
Tufts Medical Center
Boston, MA, USA

L. Campbell Levy MD
Assistant Professor of Medicine
Dartmouth Medical School
Section of Gastroenterology and Hepatology
Dartmouth–Hitchcock Medical Center
Lebanon, NH, USA

Gary R. Lichtenstein MD
Professor of Medicine
Division of Gastroenterology
University of Pennsylvania
Philadelphia, PA, USA

Ming Valerie Lin MD
Department of Internal Medicine
Pennsylvania Hospital
University of Pennsylvania Health System
Philadelphia, PA, USA

Keith D. Lindor MD
Professor of Medicine
Division of Gastroenterology and Hepatology
Mayo Clinic
Rochester, MN, USA;
Dean, Mayo Medical School
Mayo Clinic
Rochester, MN, USA

James O. Lindsay PhD, FRCP
Consultant and Senior Lecturer in Gastroenterology,
Digestive Diseases Clinical Academic Unit
Barts and the London NHS Trust
The Royal London Hospital
Whitechapel, London, UK

Richard Logan, MB, ChB, MSc, FFPH, FRCP
Professor of Clinical Epidemiology/Consultant Gastroenterologist
Division of Epidemiology and Public Health
Queens Medical Centre
Nottingham University Hospitals
Nottingham, UK

Edouard Louis MD, PhD
Professor of Gastroenterology
Department of Gastroenterology
CHU Liège and GIGA Research University of Liège
Liège, Belgium

Mark Lust MBBS, FRACP, PhD
Senior Clinical Fellow in Gastroenterology
Translational Gastroenterology Unit
John Radcliffe Hospital
Oxford, UK

Michael M. Maher MD
Professor
Department of Radiology
Alimentary Pharmabiotic Centre
University College Cork
National University of Ireland
Cork, Ireland

Robert G. Maunder MD
Associate Professor and Staff Psychiatrist
Mount Sinai Hospital and University of Toronto
Toronto, ON, Canada

Jane M. McGregor MA, MB BChir, FRCP, MD
Senior Lecturer and Honorary Consultant Dermatologist
Barts and the London NHS Trust
London, UK;
Centre for Cutaneous Research
Blizard Institute of Cell and Molecular Science
Barts and The London School of Medicine and Dentistry
Queen Mary University of London, London, UK

Simon D. McLaughlin MD, MRCP
Consultant Gastroenterologist
Department of Gastroenterology
Royal Bournemouth Hospital
Bournemouth, UK

Tina A. Mehta
Department of Gastroenterology
Bristol Royal Infirmary
Bristol, Avon, UK

Gil Y. Melmed MD, MS
Assistant Clinical Professor of Medicine
Cedars Sinai Medical Center and David Geffen School of Medicine at UCLA
Los Angeles, CA, USA

Owen J. O’Connor MD, FFR(RCSI), MRCSI
Radiology Lecturer
Department of Radiology
University College Cork
National University of Ireland
Cork, Ireland

Tom resland MD, PhD
Professor
Department of GI Surgery
Akershus University Hospital
University of Oslo
Lrenskog, Norway

Helen M. Pappa MD, MPH
Instructor in Pediatrics
Harvard Medical School
Staff, Center for Inflammatory Bowel Diseases
Division of Gastroenterology and Nutrition
Children’s Hospital Boston
Boston, MA, USA

Miles Parkes MA, DM, FRCP
Consultant Gastroenterologist
Addenbrooke’s Hospital and University of Cambridge
Cambridge, UK

Kiran K. Peddi MBBS, MRCP (UK)
Department of Gastroenterology
Specialist Registrar and Fellow in Gastroenterology
Fremantle Hospital
Fremantle, WA, Australia

Conal M. Perrett MB, ChB, MRCP(UK), PhD
Consultant Dermatologist and Honorary Senior Lecturer
University College London Hospitals
London, UK

Chris S.J. Probert MD, FRCP, FHEA
Professor of Gastroenterology
Bristol Royal Infirmary
Bristol, UK

David S. Rampton DPhil, FRCP
Professor of Clinical Gastroenterology
Centre for Digestive Diseases
Barts and The London School of Medicine and Dentistry
London, UK

Catherine Reenaers MD, PhD
Department of Gastroenterology
CHU Liège and GIGA Research University of Liège
Liège, Belgium

Jonathan M. Rhodes MD, FRCP, FMedSci
Division of Gastroenterology
School of Clinical Sciences
University of Liverpool and Royal Liverpool University Hospital
Liverpool, UK

Emile Richman BSc(Hons), MSc, PGCE
Specialist Gastroenterology Dietitian
Department of Nutrition and Dietetics
Royal Liverpool University Hospital
Liverpool, UK

David T. Rubin MD
Associate Professor of Medicine
Codirector, Inflammatory Bowel Disease Center
Program Director, Fellowship in Gastroenterology, Hepatology, and Nutrition
University of Chicago Medical Center
Chicago, IL, USA

Matthew D. Rutter MBBS, MD, FRCP
Consultant Gastroenterologist and Trust Endoscopy Lead
University Hospital of North Tees
Stockton-on-Tees, Cleveland, UK;
Clinical Director, Tees Bowel Cancer Screening Centre
University Hospital of North Tees
Stockton-on-Tees, Cleveland, UK

Jeremy D. Sanderson MBBS, MD, FRCP
Consultant Gastroenterologist
Department of Gastroenterology
St Thomas’ Hospital
London, UK;
Senior Clinical Research Fellow
Nutritional Sciences Research
Kings College London
London, UK

Hermann Schulze Dr.med.
Frankfurter Diakonie-Kliniken
Markus-Krankenhaus
Frankfurt, Germany

David A. Schwartz MD
Associate Professor of Medicine
Director, IBD Center
Division of Gastroenterology
Vanderbilt University Medical Center
Nashville, TN, USA

Ernest G. Seidman MDCM, FRCPC, FACG
Professor of Medicine and Pediatrics
Division of Gastroenterology
McGill University Health Center
Faculty of Medicine
McGill University
Montreal, QC, Canada

Christian P. Selinger MRCP
Salford Royal Hospital
Department of Gastroenterology
Salford, UK

Raanan Shamir MD
Chairman, Institute of Gastroenterology, Nutrition, and Liver Diseases
Schneider Children’s Medical Center
Petach-Tikva, Israel;
Professor of Pediatrics
Sackler Faculty of Medicine
Tel-Aviv University
Tel-Aviv, Israel

Fergus Shanahan MD
Professor and Chair
Department of Medicine
Director, Alimentary Pharmabiotic Centre
University College Cork
National University of Ireland
Cork, Ireland

Bo Shen MD
Professor of Medicine
Department of Gastroenterology
Cleveland Clinic Lerner College of Medicine
Case Western Reserve University
Cleveland, OH, USA;
Staff Gastroenterologist
Department of Gastroenterology
Cleveland ClinicCleveland, OH, USA

Corey A. Siegel MD, MS
Assistant Professor of Medicine and The Dartmouth Institute for Health Policy and Clinical Practice;
Dartmouth Medical School
Director, Inflammatory Bowel Disease Center
Dartmouth–Hitchcock Medical Center
Section of Gastroenterology and Hepatology
Lebanon, NH, USA

Emmanouil Sinakos MD
Research Fellow
Division of Gastroenterology and Hepatology
Mayo Clinic
Rochester, MN, USA

Melissa A. Smith BSc(Hons), MB, ChB, MA, MRCP
Specialist Registrar
Department of Gastroenterology
St Thomas’ Hospital
Guy’s and St Thomas’ NHS Foundation Trust
London, UK

Ing Shian Soon MD
Resident
Division of Gastroenterology
Department of Pediatrics and Community Health Sciences
University of Calgary
Calgary, AB, Canada

Miles Sparrow MBBS, FRACP
Consultant Gastroenterologist
Department of Gastroenterology
The Alfred Hospital
Melbourne, VIC, Australia

A. Hillary Steinhart MD, FRCP(C)
Inflammatory Bowel Disease Centre
Mount Sinai Hospital
Toronto, ON, Canada;
Associate Professor of Medicine
University of Toronto
Toronto, ON, Canada

Venkataraman Subramanian MD, DM, MRCP (UK)
Academic Clinical Lecturer (Gastroenterology)
Nottingham Digestive Diseases Centre
Queens Medical Centre
Nottingham University Hospitals NHS Trust
Nottingham, UK

Simon Travis DPhil, FRCP
Consultant Gastroenterologist
Translational Gastroenterology Unit
John Radcliffe hospital
Oxford, UK

William J. Tremaine MD
Maxine and Jack Zarrow Professor
Division of Gastroenterology and Hepatology
Mayo Clinic
Rochester, MN, USA

C. Janneke van der Woude MD, PhD
Gastroenterologist Department of Gastroenterology and Hepatology
Erasmus MC Hospital
Rotterdam, The Netherlands

Séverine Vermeire MD, PhD
Assistant Professor
Department of Gastroenterology
University Hospital Gasthuisberg
Leuven, Belgium

Joel V. Weinstock MD
Professor in Gastroenterology
Division of Gastroenterology
Tufts Medical Center
Boston, MA, USA

Jonathan M. Wilson MBCh B, FRCS(Edin), PhD
Specialist Registrar in Colorectal Surgery
Department of Colorectal Surgery
University College London Hospitals
London, UK

Alastair Windsor MD, FRCS, FRCS (Ed), FRCS (Glas)
Consultant SurgeonUniversity College London Hospitals
London, UK

Henit Yanai MD
University of Chicago Medical Center
Chicago, IL, USA

Preface

In 2006, three of us published a short book containing about 60 pithy and sometimes provocative chapters on controversial topics in IBD. These were selected with the aim of covering areas that commonly cause clinicians difficulties in decision-making. The book was well received but because of its subject matter has inevitably, at least in some chapters, become a bit out of date. Therefore, we have now produced a new book guided by the same principles as the first. A few of the chapters in this book are updates of their predecessors, but most are entirely new, reflecting the changing challenges faced by gastroenterologists at the beginning of the millennium’s second decade. Our authors are almost all acknowledged experts in their fields and work wherever IBD is common in the world. To help widen the appeal of the book, for this edition we have engaged both a US coeditor (CS) and more US-based contributors than previously.

As before, we have deliberately chosen some tricky topics, and should point out that as editors we do not necessarily agree with all that is written here; if we did the book might be dull. Again, we hope the book will appeal both to senior and trainee gastroenterologists, as well as other members of the IBD team, and that readers will find that it provides a useful distillation and analysis of a wide range of current management dilemmas.

We are very grateful to all our coauthors, almost all of whom delivered their chapters on time and with minimal hassling. We are particularly grateful too to the team at Blackwell’s, especially Oliver Walter for his support for the project and Jennifer Seward for her editorial work.

PMI, CS, DSR, FS July 2011

Part I

Genes and Phenotype in IBD

1

Which will take us further in IBD—study of coding variation or epigenetics?

Miles Parkes

Department of Gastroenterology, Addenbrooke's Hospital and University of Cambridge, Cambridge, UK

Genetic susceptibility to inflammatory bowel disease (IBD) is complex. While genome-wide association scans (GWAS) have pushed Crohn's disease (CD) to the front of the field of complex disease genetics, the recognition that only 20% of the variance in heritability has so far been accounted for provides a salutary reminder of the challenges ahead [1]. The main achievement of GWAS has been to highlight a number of previously unsuspected pathogenic pathways for IBD and to provide a stable base-camp from which to explore the genetic higher ground—defining causal variants at each of the loci identified, accounting for the remaining 80% of heritability and exploring functional implications.

This chapter discusses what is understood regarding causal mechanisms in IBD genetics, particularly the relative contributions of simple variation in DNA coding sequence and epigenetic regulation of gene transcription. For some readers, epigenetic regulation of gene transcription may be an unfamiliar concept: it involves changes in gene expression resulting from mechanisms such as chromatin packaging, histone acetylation (affecting electrostatic charge and hence DNA binding), and DNA methylation.

Gene expression: sequence variation versus epigenetic factors

The human genome is thought to encode some 23,000 protein-coding genes, comprising just 1.5% of the total of 3 billion base pairs. Sequence variation can take many forms from single nucleotide polymorphisms (SNPs) to indels (insertion–deletion polymorphisms) to copy number variants, where segments up to thousands of base pairs long can be deleted or duplicated. SNPs are the commonest variant. They occur approximately every 200 base pairs, but less frequently in coding sequence because of potential for adversely affecting protein function and hence incurring negative selection pressure.

Genes comprise exons (the coding sequence) and introns, which are removed prior to mRNA being translated to protein. Gene density varies considerably, with lengthy tracts of noncoding sequence, formerly and erroneously referred to as “junk DNA,” being interposed. Increasingly, it is recognized that much of the complexity of human biology derives not from the coding sequence, but from the complex, networked regulation of gene transcription by a host of epigenetic mechanisms. These include alternative exon splicing and control of mRNA stability by microRNAs, as well as DNA methylation and histone binding. These mechanisms (reviewed in [2]) allow dynamic activation or silencing of genes, and are heritable in being transmissible at mitosis, for example, to maintain tissue-specificity of gene expression, but they are not related to changes in DNA sequence.

Genetic variation in IBD

What forms of genetic variation contribute to IBD? The answer is likely to be “all of them,” to a greater or lesser extent, perhaps including mechanisms yet to be characterized. Extrapolation from monogenic disease initially suggested that coding variation was likely to be most relevant, and its obvious impact on protein structure and function supported this intuition. Further, the three relatively common causal variants in NOD2, the first IBD gene to be identified, were all coding variants [3]. Thus, early genome-wide genotyping arrays, which could accommodate relatively few SNPs, focussed only on “nonsynonymous” SNPs. Although some interesting results were obtained, particularly in identifying the importance of ATG16L1 and autophagy in CD, the yield was unimpressive [4].

Truly hypothesis-free GWAS studies have followed, interrogating most if not all common variations (allele frequency >5%) genome-wide. Interestingly, the yield from these “proper” GWAS studies has been much greater than from nonsynonymous SNP scans and many lessons have been learned.

One remarkably consistent feature of GWAS studies has been the number of “gene deserts” showing association across a range of complex diseases. The supposition is that these loci contain elements that regulate transcription, and there is now evidence that sequence variation influences transcription for many genes. Thus, epigenetic regulation is itself a heritable trait and may be the key factor contributing to phenotypic variation in humans [5].

Several “gene desert” associations have been seen in IBD: indeed in the first meta-analysis plus replication of CD GWAS studies from the international IBD genetics consortium, 6 out of the 32 confirmed loci mapped to gene deserts. More than this, our now detailed knowledge of all common sequence variations genome-wide allowed us to identify how many of the CD susceptibility loci correlated with any known coding variation. The answer, rather startlingly, was just 9 [1]. To emphasize this point, coding variation has to date been confirmed as causal for just two loci—NOD2 and ATG16L1, with one other at IL23R strongly implicated.

Regulation of gene expression in IBD

Accepting the indirect evidence that regulatory effects are important, is there any direct evidence? The answer is emphatically yes. In the Belgian CD GWAS, the strongest association was seen with a 1.25-Mb gene desert on chromosome 5. Using publicly available expression quantitative trait loci (eQTL) data, Libioulle et al. showed that these same SNPs that showed association with CD also correlated strongly with expression of the prostaglandin receptor gene EP4 270 Kb away [6]. The international CD meta-analysis study identified a number of other such correlations [1], and in its most recent analysis identified association at a DNA methyltransferase gene, emphasizing the importance of epigenetic regulation and its interrelationship with sequence variation in CD susceptibility.

Evidence from basic research corroborates the importance and potential complexity of epigenetic effects. Thus, the toll-like receptor-induced inflammatory response in mouse macrophages is regulated at a gene-specific level by transient chromatin modification, with Th2 “bias” being conferred by a transcriptional regulator of IL-4 called Mina. Highlighting the interplay of sequence variation with epigenetics, production of Mina is itself strongly correlated with SNP haplotypes in its promoter [7].

Identifying correlation between IBD association signals and gene expression hints at functional regulatory elements, but usually does not explain the mechanism. The expectation is that genome-wide assays for DNA methylation, ChIP seq, histone binding, and DNA tertiary structure (e.g., chromatin conformation capture or 3C), will provide some answers over the next few years [8]. They should allow both a better understanding of the mechanisms underlying current GWAS signals and also permit de novo genome-wide studies.

Limitations of current studies of epigenetic mechanisms in IBD

At present, difficulties in defining which cell type to target for expression analyses are limiting. The relevance of this comes from the recognition that many gene regulatory effects are cell-type specific—as seen for the CD-associated allele of IRGM which affects expression in opposite directions in different cell types [9]. Further concerns relate to the confounding effects of inflammation and drug therapy. Nonetheless, the evidence that epigenetic mechanisms are crucial in regulating gene transcription and thereby affecting susceptibility to disease will drive development of the appropriate resources to tackle these questions.

Epigenetic regulation is also significantly influenced by environmental factors, including diet, smoking, and infection—all of which are implicated in IBD pathogenesis. For example, aryl hydrocarbon receptor (AhR) agonists, which are present in substances as varied as cigarette smoke and Brassica vegetables, can strongly influence COX-2 expression. The effect may be related to AhR acting directly as a transcriptional regulator and also by regulating histone acetylation and hence chromatin structure [10]. The AhR also plays a key role in modulating Th17 lymphocyte development through epigenetic mechanisms [11]. The suggestion that some epigenetic regulatory influences may be transmissible through meiosis to the next generation adds particular interest to this story [12].

Conclusions

At present, GWAS studies are being widely deployed not because they provide all the answers, but rather because they are technologically tractable and provide robust and reproducible data. More technologically challenging and complex studies will follow to advance our knowledge of the epigenetic regulation of gene transcription and its contribution to inflammatory disease [13].

The suspicion is that many of the pathways highlighted by GWAS studies will also be flagged as important for IBD pathogenesis by other techniques. A case in point might come from the confirmed association of noncoding SNPs adjacent to IL-10 with IBD [14], plus the recent observation that IL-10 gene expression in antigen-presenting cells is strongly regulated by the histone deacetylase HDAC11 [15]. Perhaps these findings are directly correlated, or maybe the GWAS signal is flagging a pathway influenced by many epigenetic and other mechanisms that themselves regulate IL-10 transcription and thereby influence IBD susceptibility.

All of these studies represent work in progress, and despite recent exciting developments this remains a field in its infancy. Nonetheless, current evidence suggests that for most individuals with IBD, coding variation is likely to have made only a modest contribution to their disease risk, while epigenetic regulation of gene transcription, perhaps influenced by environmental factors such as smoking, bacteria, and diet, play a much more important role.

References

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