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Daniel C. Baumgart
Editor

Crohn’s Disease and

Ulcerative Colitis
From Epidemiology and
Immunobiology to a
Rational Diagnostic and
Therapeutic Approach

Second Edition

13
Crohn’s Disease and Ulcerative Colitis
Daniel C. Baumgart
Editor

Crohn’s Disease
and Ulcerative Colitis
From Epidemiology and Immunobiology
to a Rational Diagnostic and Therapeutic
Approach

Second Edition
Editor
Daniel C. Baumgart
Inflammatory Bowel Disease Center
Department of Gastroenterology and Hepatology
Charité Medical School—Humboldt-University of Berlin
Berlin, Germany

ISBN 978-3-319-33701-2    ISBN 978-3-319-33703-6 (eBook)

DOI 10.1007/978-3-319-33703-6

Library of Congress Control Number: 2016959449

© Springer International Publishing AG 2017

This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is
concerned, specifically the rights of translation, reprinting, reuse of illustra-tions, recitation, broadcasting, reproduction
on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation,
computer software, or by similar or dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not
imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and
regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed
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Printed on acid-free paper

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The registered company is Springer International Publishing AG Switzerland
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Foreword

The clinical features of the major forms of Inflammatory Bowel Disease, Crohn’s disease and
ulcerative colitis, have been generally well known for decades. After a long period in which
advances in our understanding of the causation and pathogenesis of inflammatory bowel dis-
eases remained painfully slow and, in parallel, improvements in management were at best
incremental, the momentum of progress has accelerated over the past several years, making a
textbook that draws together the full continuum of these advances timely.
The recent pace of progress in understanding the underlying pathogenesis has been espe-
cially remarkable. This has been possible because of more powerful methodological approaches
as well as a growing community of investigators focused on these disorders and the basic
processes associated with them. Progress in recent years has been rapid along a number of
fronts, and a general paradigm has emerged to suggest that these disorders result from altera-
tions in the host response to the microflora present within the GI tract. These host responses
comprise the collective functional integrity of the mucosal epithelium and the complex set of
innate and adaptive immune responses. While many details remain to be fleshed out, molecular
pathways intrinsic to the interactions and functional regulation of these responses have been
identified and it is clear that for many the “set point” is determined by the genotypic variations
at dozens of susceptibility genes. Undoubtedly surprises remain. History suggests the skeptic
of any entrenched dogma has a good likelihood of eventually being proven right. However, this
paradigm or model has proven a powerful context to ask better questions that should eventuate
in more complete answers about the causation and pathogenesis of inflammatory bowel dis-
eases. Progress in understanding of the basic processes underlying the development of inflam-
matory bowel diseases should be an engine for still more effective therapies as well as
diagnostic tools to facilitate management.
On the clinical front, the global epidemiology of inflammatory bowel diseases continues to
evolve. While incidence and prevalence plateaued after a long period of steady rise in those
regions that remain highest, Europe and North America, other areas of the world are seeing a
characteristic pattern of increases in the frequency of ulcerative colitis followed pari passu by
increases in Crohn’s disease. Clinicians caring for these patients cannot be complacent. There
is more information that needs to be incorporated into management decisions and, most impor-
tantly, much more to offer patients. Improvements in management include evolving surgical
approaches and, in some instances, alternative interventions via endoscopy offering efficacy
with less morbidity. Advances in nonsurgical medical therapy have had an even greater impact
on treatment of IBD patients. These include categorically new agents, which have been devel-
oped on the basis of advances in our understanding of mechanisms relevant to the pathogenesis
of these disorders. As exemplified by anti-TNF agents, the age of biologics has arrived. Given
that understanding of pathogenesis is still progressing rapidly, one can anticipate that more and
more effective agents will yet be forthcoming.
These advances have resulted in greater complexity in good decision-making. Those caring
for these patients should welcome this complexity in so far as it reflects the possibility of find-
ing management strategies better tailored to the specific needs of an individual patient. The
opportunities to make more confident management decisions, if not initial diagnosis as well,
have also become both more complicated and more promising with the advent of new imaging

v
vi Foreword

modalities (both “radiologic” and “endoscopic”) as well as various biomarkers. While it is not
yet clear how specific susceptibility genotypes might be best used clinically there is, in con-
cept, the possibility of more definitive diagnosis after decades in which diagnosis has remained,
in the final analysis, an empiric process.
In these general reflections on recent progress are clear indications of the timeliness for a
textbook that endeavors to bring these new advances into better focus. The editors have
embraced this ambitious goal and assembled an outstanding group of authors who have been
at the forefront of much of this progress. This volume provides both the clinician and the
scientist with an understanding of the most recent advances as well as the context for each of
them to be pursuing their mission of caring for patients and advancing our knowledge, respec-
tively. However, these general reflections also come with an embedded caution. Clinicians
will recognize that even with this progress, unmet needs persist and there remain many
patients for whom current approaches are simply not good enough. The scientist will recog-
nize how still incomplete our understanding of these diseases remains. So, this textbook pro-
vides a powerful tool to ensure that clinicians can provide today’s best care and scientists can
pose today’s best questions. One can only hope that within a few years the next volume will
be ready to be written.

Professor of Medicine Daniel K. Podolsky

President of the University of Texas Southwestern Medical Center
Dallas, TX, USA  
Preface to the Second Edition

Crohn’s disease and ulcerative colitis—two chronic inflammatory diseases (IBD) on the rise—
result from an inappropriate immune response, in genetically susceptible individuals, to micro-
bial antigens of commensal microorganisms. This inappropriate response is promoted by
certain environmental factors including Western life style, explaining their globally increasing
incidence. As a systemic disorder of the immune system, IBD manifest itself primarily in the
gastrointestinal tract but can affect all of the organ systems of the human body. Thus, not only
gastroenterologist, but many other clinicians are confronted with IBD.
On the other hand IBD is an excellent example of how the exponential growth of knowledge
in biomedical science can make a remarkable impact on clinical practice and patient’s quality of
life. The number of novel and targeted treatments is growing rapidly. They are continuously
being refined to treat not only the two original conditions of the gut but also the variety of asso-
ciated immune disorders. New therapies are sometimes complex and associated with important
risks requiring a deeper understanding of their molecular principles from clinicians.
This book continues to serve as a unique combined resource for physicians and scientists
addressing the needs of both groups. It is meant to help stimulate exchange and collaboration,
shorten the path between discovery and clinical application, and also help clinicians under-
stand new therapeutic concepts from their origins.
The great success of the first edition confirms our concept. It encouraged us to not only
bring all chapters up to date but also include new scientific and clinical trends in new
chapters.
I’m grateful to my colleagues from all over the world who took out time out of their busy
days to contribute new and updated chapters in their respective fields of expertise to make
accomplishing the goals of this book possible.

Berlin, Germany Daniel C. Baumgart

vii
Preface

Crohn’s disease and ulcerative colitis—two chronic inflammatory diseases (IBD) on the rise—
result from an inappropriate immune response, in genetically susceptible individuals, to micro-
bial antigens of commensal microorganisms. This inappropriate response is promoted by
certain environmental factors including Western life style, explaining their globally increasing
incidence. As a systemic disorder of the immune system, IBD manifest itself primarily in the
gastrointestinal tract but can affect all of the organ systems of the human body. Thus, not only
gastroenterologist, but many other clinicians are confronted with IBD.
On the other hand IBD is an excellent example of how the exponential growth of knowledge
in biomedical science can make a remarkable impact on clinical practice and patient’s quality
of life. It has led to the development of a number of novel targeted and tailored treatments.
These are continuously being refined to treat not only the two original conditions in the gut but
also the variety of associated immune disorders. New therapies are sometimes complex and
associated with important risks requiring a deeper understanding of their molecular principles
from clinicians.
This book is intended to serve as a unique combined resource for physicians and scientists
addressing the needs of both groups. It is meant to help stimulate exchange and collaboration
and shorten the path between discovery and application of new knowledge and also help clini-
cians understand new therapeutic concepts from their origins.
I’m grateful to my colleagues from all over the world who contributed chapters in their
respective fields of expertise and made accomplishing the goals of this book possible.

Berlin, Germany Daniel C. Baumgart

ix
Contents

Part I Epidemiology

1 Environmental Factors in the Epidemiology of Inflammatory

Bowel Disease............................................................................................................ 3
Morten H. Vatn

Part II Immunobiology

2 Role of the Intestinal Immune System in Health................................................... 23

Per Brandtzaeg
3 Understanding the Epithelial Barrier in IBD......................................................... 57
Matthew A. Odenwald and Jerrold R. Turner
4 Intestinal Microbiology and Ecology in Crohn’s Disease
and Ulcerative Colitis............................................................................................... 67
Ludovica F. Buttó and Dirk Haller
5 The Immune System in IBD: Antimicrobial Peptides........................................... 75
Charles L. Bevins
6 Vascular Responses to Intestinal Inflammation..................................................... 87
D. Neil Granger and Norman R. Harris
7 Immunobiology of Human Dendritic Cells in Inflammatory Bowel Disease...... 93
Daniel C. Baumgart
8 Immunobiology of T-cells in Inflammatory Bowel Disease................................... 101
S. Snapper, D. Nguyen, and A. Biswas
9 Immunobiology of B Cells in Inflammatory Bowel Disease.................................. 111
Atsushi Mizoguchi and Atul K. Bhan
10 Immune Cells: Monocytes and Macrophages........................................................ 119
Gerhard Rogler
11 Immune Functions of Epithelial Cells in Inflammatory Bowel Disease.............. 123
Eric L. Campbell and Sean P. Colgan
12 Autophagy and Endoplasmic Reticulum Stress..................................................... 131
Arthur Kaser
13 Matrix Metalloproteinases....................................................................................... 135
Paolo Biancheri and Thomas T. MacDonald
14 Paradigm of T Cell Differentiation in IBD............................................................. 141
Takashi Nagaishi and Mamoru Watanabe

xi
xii Contents

15 Mouse Models of Chronic Intestinal Inflammation:

Characterization and Use in Pharmacological Intervention Studies................... 149
Cynthia Reinoso Webb and Matthew B. Grisham
16 Stem Cells and Organoids to Study Epithelial Cell Biology in IBD..................... 167
Jorge O. Munera and James M. Wells

Part III Diagnostic Approach

17 Enhanced Endoscopy................................................................................................ 175

R. Kiesslich
18 Magnetic Resonance Enterography........................................................................ 185
Patrik Rogalla and Luís Guimarães
19 Computed Tomography Enterography and Inflammatory Bowel Disease......... 205
J.G. Fletcher
20 Ultrasound in Inflammatory Bowel Disease........................................................... 217
A. Potthoff, C. Agne, and M. Gebel
21 Laboratory Evaluation, Including Novel Diagnostic Markers............................. 233
M. Flamant and X. Roblin
22 Pathology of Inflammatory Bowel Disease............................................................. 243
Nora E. Joseph and Christopher R. Weber
23 Objective Assessment of Clinical Disease Activity................................................. 259
Edouard Louis, Catherine Van Kemseke, and Catherine Reenaers
24 Objective Assessment of Endoscopic Disease Activity and Mucosal Healing..... 267
Britt Christensen and David T. Rubin
25 Evaluation of Quality of Life in Crohn’s Disease and Ulcerative Colitis:
What Is Health-Related Quality of Life?................................................................ 279
Katrine Carlsen, Pia Munkholm, and Johan Burisch
26 Evaluation of Health Economics in Inflammatory Bowel Disease....................... 291
Reena Khanna and Brian G. Feagan

Part IV Therapy: Crohn’s Disease

27 The Natural History of Inflammatory Bowel Disease........................................... 301

Charles N. Bernstein
28 Conventional Medical Management of Crohn’s Disease: Sulfasalazine.............. 311
Miquel A. Gassull and Eduard Cabré
29 Steroid Therapy for Crohn’s Disease...................................................................... 315
A. Hillary Steinhart
30 Thiopurines in Crohn’s Disease............................................................................... 321
Adi Lahat and Rami Eliakim
31 Conventional Medical Management of Crohn’s Disease: Methotrexate............. 333
Grace Harkin and Laurence Egan
32 Adalimumab for the Treatment of Crohn’s Disease.............................................. 343
Remo Panaccione
Contents xiii

33 Biologic Therapy of Crohn’s Disease: Certolizumab............................................ 351

Alessandro Armuzzi and Daniela Pugliese
34 Biologic Therapy for Crohn’s Disease: Infliximab................................................ 357
Jan-Michael A. Klapproth and Gary R. Lichtenstein
35 Briakinumab and Ustekinumab: Anti-p40 Antibodies
for Inflammatory Bowel Disease Treatment........................................................... 367
Peter Mannon
36 Biological Therapy of Crohn’s Disease: Natalizumab, Vedolizumab,
and Anti-MadCAM................................................................................................... 375
Pieter Hindryckx and Geert D’Haens
37 Optimal Management of Fistulizing Crohn’s Disease........................................... 381
Farhad Peerani and Bruce E. Sands

Part V Therapy: Ulcerative Colitis

38 Sulfasalazine and 5-aminosalicylates for Ulcerative Colitis.................................. 389

Reena Khanna and John K. Marshall
39 Conventional Therapy of Ulcerative Colitis: Corticosteroids............................... 399
Kirstin Taylor and Peter R. Gibson
40 Medical Management of Ulcerative Colitis: Conventional
Therapy—Azathioprine........................................................................................... 413
Barrett G. Levesque and Edward V. Loftus Jr.
41 Calcineurin Inhibitors in Ulcerative Colitis........................................................... 421
Andreas Fischer and Daniel C. Baumgart
42 Biologic Therapy in Moderate-to-Severe Ulcerative Colitis: Infliximab............. 429
Mindy Lam and Brian Bressler
43 Biologic Therapy of Ulcerative Colitis: Adalimumab........................................... 435
Walter Reinisch
44 Biologic Therapy of Ulcerative Colitis: Golimumab............................................. 441
Mark A. Samaan and Peter M. Irving
45 Biologic Therapy of Ulcerative Colitis: Natalizumab, Vedolizumab,
Etrolizumab (rHUMab beta 7), Anti-MAdCAM................................................... 449
Severine Vermeire
46 Probiotics, Prebiotics, and Antibiotics in IBD........................................................ 455
Paolo Gionchetti, Carlo Calabrese, Andrea Calafiore, and Fernando Rizzello
47 Biosimilars in the Treatment of Inflammatory Bowel Disease............................. 471
Vivian W. Huang and Richard N. Fedorak
48 Step-Up vs. Top-Down Approach in Crohn’s Disease........................................... 481
Christine Y. Yu and Daniel W. Hommes
49 Leukocytapheresis Therapy of Inflammatory Bowel Disease............................... 491
Takanori Kanai
50 Surgical Management of Crohn’s Disease and Ulcerative Colitis........................ 505
Robert R. Cima and John H. Pemberton
xiv Contents

Part VI Extraintestinal Manifestations

51 Extraintestinal Manifestations: Autoimmune Hepatitis....................................... 521

Michael P. Manns and Nora Schweitzer
52 Primary Sclerosing Cholangitis............................................................................... 531
Roger W. Chapman and Kate D. Williamson
53 Autoimmune Pancreatitis and Other Organ Involvement.................................... 549
Go Kuwata and Terumi Kamisawa
54 Cutaneous and Oral Manifestations of Inflammatory Bowel Disease................. 557
Caroline P. Allen and Susan M. Burge
55 Arthritis, Arthropathy, and Osteoporosis in Inflammatory Bowel Disease........ 571
Alistair Tindell, Hanna Johnson, and Iain B. McInnes

Part VII Nutrition

56 Nutrition in Inflammatory Bowel Disease.............................................................. 587

Alan L. Buchman

Part VIII Pregnancy, Family Planning and Pediatric Aspects

57 Pregnancy and Fertility in Inflammatory Bowel Disease...................................... 599

Rebecca Matro and Uma Mahadevan
58 Pediatric Aspects of Inflammatory Bowel Disease................................................. 609
Brendan Boyle and Jeffrey S. Hyams

Part IX Surveillance and Prevention

59 Management and Prevention of Infectious Diseases in IBD Patients.................. 621

Kristine Macartney and Nigel Crawford
60 Incidence of Cancer and Screening in Inflammatory Bowel Disease................... 639
Jimmy K. Limdi and Francis A. Farraye
61 Inflammatory Bowel Diseases: How to Identify High-Risk Patients................... 653
Jacques Cosnes and Harry Sokol

Part X Patient Perspective and Resources

62 Patient Perspective on Inflammatory Bowel Disease............................................. 663

Ayesha Williams and Marjorie Merrick
63 Patient Resources in Inflammatory Bowel Disease................................................ 667
Sanna Lönnfors and Marco Greco

Index................................................................................................................................... 673
Contributors

C. Agné, M.D. Department of Gastroenterology, Hepatology and Endocrinology, Hannover

Medical School, Hannover, Germany
Caroline P. Allen Department of Dermatology, Oxford University Hospitals NHS Trust,
Oxford, UK
Alessandro Armuzzi, M.D., Ph.D. IBD Unit, Complesso Integrato Columbus, Gemelli
Hospital, Catholic University Foundation, Rome, Italy
Daniel C. Baumgart Department of Gastroenterology and Hepatology, Inflammatory Bowel
Disease Center, Charité Medical Center—Virchow Hospital, Medical School of the Humboldt
University of Berlin, Berlin, Germany
Charles N. Bernstein, M.D. University of Manitoba IBD Clinical and Research Centre,
Winnipeg, MB, Canada
Charles L. Bevins, M.D., Ph.D. Department of Microbiology and Immunology, University
of California Davis School of Medicine, Davis, CA, USA
Atul K. Bhan, M.B.B.S., M.D. Department of Pathology, Massachusetts General Hospital,
Harvard Medical School, Boston, MA, USA
Paolo Biancheri, M.D., Ph.D. Centre for Immunobiology, Barts and The London School of
Medicine and Dentistry, Queen Mary University of London, London, UK
A. Biswas Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s
Hospital, Boston, MA, USA
Brendan Boyle Division of Pediatric Gastroenterology, Hepatology, and Nutrition,
Nationwide Children’s Hospital, The Ohio State University, College of Medicine and Public
Health, Columbus, OH, USA
Per Brandtzaeg, M.D., Ph.D. Centre for Immune Regulation (CIR), University of Oslo,
Oslo, Norway
Laboratory for Immunohistochemistry and Immunopathology (LIIPAT), Department of
Pathology, Oslo University Hospital—Rikshospitalet, Nydalen, Oslo, Norway
Brian Bressler Division of Gastroenterology, University of British Columbia, Vancouver,
BC, Canada
Alan L. Buchman, M.D., M.S.P.H. Department of Surgery, University of Illinois at Chicago,
Glencoe, IL, USA
Susan M. Burge, B.Sc., D.M., F.R.C.P. Department of Dermatology, Oxford University
Hospitals NHS Trust, Oxford, UK
Johan Burisch, M.D., Ph.D. Danish Centre for eHealth & Epidemiology, Department of
Gastroenterology, North Zealand Hospital, Frederikssund, Denmark

xv
xvi Contributors

Ludovica F. Buttó, Ph.D. Chair of Nutrition and Immunology, Technische Universität

München, Freising-Weihenstephan, Germany
Eduard Cabré, M.D., Ph.D. IBD/G-I Unit, Department of Gastroenterology, Hospital
Universitari Germans Trias i Pujol, Badalona, Catalonia, Spain
CIBERehd, Barcelona, Catalonia, Spain
Carlo Calabrese Department of Medical and Surgical Sciences (DIMEC), University of
Bologna, Bologna, Italy
Andrea Calafiore Department of Medical and Surgical Sciences (DIMEC), University of
Bologna, Bologna, Italy
Eric L. Campbell, Ph.D. Department of Medicine and the Mucosal Inflammation Program,
University of Colorado School of Medicine, Aurora, CO, USA
Katrine Carlsen Department of Pediatrics, Hvidovre Hospital, Hvidovre, Denmark
Roger W. Chapman Department of Translational Gastroenterology, John Radcliffe, Oxford, UK
Britt Christensen Department of Medicine, University of Chicago Medicine, Inflammatory
Bowel Disease Center, Chicago, IL, USA
Department of Gastroenterology, Alfred Hospital and Monash University, Melbourne, Australia
Robert R. Cima, M.D., M.A. Division of Colon and Rectal Surgery, Mayo Clinic College of
Medicine, Rochester, MN, USA
Sean P. Colgan, Ph.D. Department of Medicine and the Mucosal Inflammation Program,
University of Colorado School of Medicine, Aurora, CO, USA
Jacques Cosnes, M.D. Service de Gastroentérologie et Nutrition, Hôpital St-Antoine (APHP)
and Pierre-et-Marie Curie University (Paris VI), Paris, France
Nigel Crawford Department of General Medicine, Royal Children’s Hospital Melbourne,
Parkville, VIC, Australia
Geert D’Haens Department of Gastroenterology, Academic Medical Centre, Amsterdam,
The Netherlands
Laurence Egan, M.D., F.R.C.P.I. Clinical Science Institute, University Hospital Galway,
Galway, Ireland
Rami Eliakim, M.D. Department of Gastroenterology, Chaim Sheba Medical Center, Sackler
School of Medicine, Tel-Aviv University, Tel Aviv, Israel
Francis A. Farraye, M.D., M.Sc. Department of Gastroenterology, Boston Medical Center,
Boston University School of Medicine, Boston, MA, USA
Brian G. Feagan, M.D. Robarts Clinical Trials, University of Western Ontario, London, ON,
Canada
Division of Gastroenterology, Department of Medicine, University of Western Ontario,
London, ON, Canada
Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON,
Canada
Richard N. Fedorak, M.D., F.R.C.P.C., F.R.S.C. Department of Medicine, Zeidler Ledcor
Centre, University of Alberta, Edmonton, Canada
Andreas Fischer Department of Gastroenterology and Hepatology, Inflammatory Bowel
Disease Center, Charité Medical Center—Virchow Hospital, Medical School of the Humboldt
University of Berlin, Berlin, Germany
Contributors xvii

M. Flamant Institut des Maladies de l’Appareil Digestif (IMAD), Hotel Dieu, Nantes, Cedex,
France
J.G. Fletcher Mayo Clinic, Rochester, MN, USA
Miquel A. Gassull, M.D., Ph.D. Health Science Research Institute, Germans Trias i Pujol
Foundation, Badalona, Catalonia, Spain
Gastroenterology and Hepatology Department, Germans Trias I, Pujol University Hospital,
Badalona, Catalonia, Spain
M. Gebel, M.D. Department of Gastroenterology, Hepatology and Endocrinology, Hannover
Medical School, Hannover, Germany
Peter R. Gibson, M.D., F.R.A.C.P. Department of Gastroenterology, The Alfred Hospital
and Monash University, Melbourne, VIC, Australia
Paolo Gionchetti, M.D. Department of Medical and Surgical Sciences (DIMEC), University
of Bologna, Bologna, Italy
D. Neil Granger, Ph.D. Department of Molecular & Cellular Physiology, Louisiana State
University Health Sciences Center—Shreveport, Shreveport, LA, USA
Marco Greco, Ph.D. European Federation of Crohn’s and Ulcerative Colitis Associations
(EFCCA), Brussels, Belgium
European Patients’ Forum (EPF), Brussels, Belgium
Matthew B. Grisham, Ph.D. Department of Immunology and Molecular Microbiology,
Texas Tech University Health Sciences Center, Lubbock, TX, USA
Luís Guimarães Department of Medical Imaging, Princess Margaret Hospital, Toronto, ON,
Canada
Dirk Haller, Ph.D. Chair of Nutrition and Immunology, Technische Universität München,
Freising-Weihenstephan, Germany
Grace Harkin, M.B., M.R.C.P.I. Clinical Science Institute, University Hospital Galway,
Galway, Ireland
Norman R. Harris, Ph.D. Department of Molecular & Cellular Physiology, Louisiana State
University Health Sciences Center—Shreveport, Shreveport, LA, USA
Pieter Hindryckx Department of Gastroenterology, University Hospital of Ghent, Ghent,
Belgium
Daniel W. Hommes Division of Medicine, Gastroenterology, Department of Medicine,
Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA
Vivian W. Huang Department of Medicine, Zeidler Ledcor Centre, University of Alberta,
Edmonton, AB, Canada
Jeffrey S. Hyams, M.D. Division of Digestive Diseases, Hepatology, and Nutrition,
Connecticut Children’s Medical Center, Hartford, CT, USA
University of Connecticut School of Medicine, Hartford, CT, USA
Peter M. Irving Department of Gastroenterology, Guy’s and St Thomas’ Hospital, London, UK
Hanna Johnsson Institute of Infection, Immunity and Inflammation, College of MVLS,
University of Glasgow, Glasgow, UK
Nora E. Joseph Department of Pathology and Laboratory Medicine, NorthShore University
Health System, Evanston, IL, USA
xviii Contributors

Terumi Kamisawa, M.D., Ph.D. Department of Internal Medicine, Tokyo Metropolitan

Komagome Hospital, Tokyo, Japan
Takanori Kanai, M.D. Division of Gastroenterology and Hepatology, Department of Internal
Medicine, Keio University School of Medicine, Tokyo, Japan
Arthur Kaser Division of Gastroenterology and Hepatology, Department of Medicine,
Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK
Catherine Van Kemseke Department of Gastroenterology, University Hospital CHU of
Liège, Liège, Belgium
Reena Khanna Robarts Clinical Trials, University of Western Ontario, London, ON, Canada
Department of Medicine, Division of Gastroenterology, University of Western Ontario,
London, ON, Canada
R. Kiesslich Klinik für Innere Medizin II (ZIM II), HELIOS Dr. Horst Schmidt Kliniken
Wiesbaden, Wiesbaden, Germany
Jan-Michael A. Klapproth Division of Gastroenterology, Department of Medicine,
University of Pennsylvania, Philadelphia, PA, USA
Go Kuwata, M.D. Department of Internal Medicine, Tokyo Metropolitan Komagome
Hospital, Tokyo, Japan
Adi Lahat, M.D. Department of Gastroenterology, Chaim Sheba Medical Center, Sackler
School of Medicine, Tel-Aviv University, Tel Aviv, Israel
Mindy Lam Division of Gastroenterology, University of British Columbia, Vancouver, BC,
Canada
Barrett G. Levesque Division of Gastroenterology, University of California San Diego, La
Jolla, CA, USA
Gary R. Lichtenstein, M.D. Division of Gastroenterology, Department of Medicine,
University of Pennsylvania, Philadelphia, PA, USA
Jimmy K. Limdi Division of Gastroenterology, The Pennine Acute Hospitals NHS Trust,
Manchester, UK
Institute of Inflammation and Repair, University of Manchester, Manchester, UK
Edward V. Loftus Jr. , M.D. Division of Gastroenterology & Hepatology, Mayo Clinic,
Rochester, MN, USA
Sanna Lönnfors, M.Sc.P.H., M.A. European Federation of Crohn’s and Ulcerative Colitis
Associations (EFCCA), Brussels, Belgium
Edouard Louis Department of Gastroenterology, University Hospital CHU of Liège, Liège,
Belgium
Kristine Macartney, M.D., F.R.A.C.P. The Children’s Hospital of Westmead, The National
Centre for Immunisation Research and Surveillance, Westmead, NSW, Australia
Thomas T. MacDonald, Ph.D., F.R.C.Path., F.Med.Sci. Centre for Immunobiology, Barts
and The London School of Medicine and Dentistry, Queen Mary University of London,
London, UK
Uma Mahadevan, M.D. UCSF Center for Colitis and Crohn’s Disease, San Francisco,
CA, USA
Peter Mannon Professor of Medicine and Microbiology, University of Alabama at
Birmingham, Birmingham, AL, USA
Contributors xix

Michael P. Manns, M.D. Department of Gastroenterology, Hepatology and Endocrinology,

Hannover Medical School, Hannover, Germany
John K. Marshall, M.D., M.Sc., F.R.C.P.C. Department of Medicine, Farncombe Family
Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
Division of Gastroenterology (2F59), McMaster University Medical Centre, Hamilton,
ON, Canada
Rebecca Matro Oregon Health and Sciences University, Portland, OR, USA
Iain B. McInnes Institute of Infection, Immunity and Inflammation, College of MVLS,
University of Glasgow, Glasgow, UK
Marjorie Merrick, M.A. Research and Scientific Programs, Crohn’s & Colitis Foundation of
America, New York, NY, USA
Atsushi Mizoguchi Department of Immunology, Kurume University School of Medicine,
Fukuoka, Japan
Jorge O. Múnera Division of Developmental Biology, Cincinnati Children’s Hospital
Research Foundation, Cincinnati, OH, USA
Pia Munkholm, M.D. Danish Centre for eHealth & Epidemiology, Department of
Gastroenterology, North Zealand Hospital, Frederikssund, Denmark
Takashi Nagaishi, M.D., Ph.D. Department of Gastroenterology, Tokyo Medical and Dental
University, Tokyo, Japan
D. Nguyen Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s
Hospital, Boston, MA, USA
Matthew A. Odenwald, Ph.D. Department of Pathology, The University of Chicago,
Chicago, IL, USA
Remo Panaccione, M.D., F.R.C.P.C. Inflammatory Bowel Disease Clinic, Professor of
Medicine, University of Calgary, Calgary, Canada
Farhad Peerani Division of Gastroenterology, Department of Medicine, University of
Alberta, Zeidler Ledcor Centre, Edmonton, AB, Canada
John H. Pemberton, M.D. Division of Colon and Rectal Surgery, Mayo Clinic College of
Medicine, Rochester, MN, USA
A. Potthoff, M.D. Department of Gastroenterology, Hepatology and Endocrinology,
Hannover Medical School, Hannover, Germany
Daniela Pugliese IBD Unit, Complesso Integrato Columbus, Gemelli Hospital Catholic
University Foundation, Rome, Italy
Catherine Reenaers Department of Gastroenterology, University Hospital CHU of Liège,
Liège, Belgium
Walter Reinisch Division of Gastroenterology, Department of Medicine, McMaster
University, Hamilton, ON, Canada
Fernando Rizzello Department of Medical and Surgical Sciences (DIMEC), University of
Bologna, Bologna, Italy
X. Roblin Service de Gastroentérologie, CHU de Saint Etienne, Hopital Nord, Saint-Priest-
en-Jarez, France
Patrik Rogalla, BS, MD Department of Medical Imaging, Princess Margaret Hospital,
Toronto, ON, Canada
xx Contributors

Gerhard Rogler Division of Gastroenterology and Hepatology, University Hospital of

Zürich, Zürich, Switzerland
David T. Rubin, M.D. Department of Medicine, University of Chicago Medicine Inflammatory
Bowel Disease Center, Chicago, IL, USA
Mark A. Samaan Department of Gastroenterology, Guy’s and St Thomas’ Hospital, London, UK
Bruce E. Sands, M.D., M.S. Dr. Henry D. Janowitz Division of Gastroenterology and
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Nora Schweitzer, M.D. Department of Gastroenterology, Hepatology and Endocrinology,
Hannover Medical School, Hannover, Germany
S. Snapper Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s
Hospital, Boston, MA, USA
Division of Gastroenterology, Brigham and Women’s Hospital, Boston, MA, USA
Harry Sokol, M.D., Ph.D. Service de Gastroentérologie et Nutrition, Hôpital St-Antoine
(APHP) and Pierre-et-Marie Curie University (Paris VI), Paris, France
A. Hillary Steinhart, M.D., M.Sc., F.R.C.P.(C) IBD Centre, Mount Sinai Hospital and
Department of Medicine, University of Toronto, Toronto, ON, Canada
Kirstin Taylor Department of Gastroenterology, The Alfred Hospital and Monash University,
Melbourne, VIC, Australia
Alistair Tindell Institute of Infection, Immunity and Inflammation, College of MVLS,
University of Glasgow, Glasgow, UK
Jerrold R. Turner, M.D., Ph.D. Department of Pathology, The University of Chicago,
Chicago, IL, USA
Departments of Pathology and Medicine (GI), Brigham and Women’s Hospital and Harvard
Medical School, Boston, MA, USA
Morten H. Vatn, M.D., Ph.D. Section of Gastroenterology, Oslo University Hospital,
Nydalen, Oslo, Norway
Akershus University Hospital, Institute of Clinical Medicine, University of Oslo, Nordbyhagen,
Akershus, Norway
Severine Vermeire, M.D., Ph.D. Department of Gastroenterology, University Hospitals
Leuven, Leuven, Belgium
Mamoru Watanabe, M.D., Ph.D. Department of Gastroenterology, Tokyo Medical and
Dental University, Tokyo, Japan
Cynthia Reinoso Webb, B.S., M(ASCP) Department of Immunology and Molecular
Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX, USA
Christopher R. Weber, M.D., Ph.D. Department of Pathology, The University of Chicago,
Chicago, IL, USA
James M. Wells, Ph.D. Division of Developmental Biology, Cincinnati Children’s Hospital
Research Foundation, Cincinnati, OH, USA
Ayesha Williams IBD Help Center, Crohn’s & Colitis Foundation of America, New York, NY,
USA
Kate D. Williamson Department of Translational Gastroenterology, John Radcliffe, Oxford,
UK
Christine Y. Yu, M.D. GI fellow, University of California, Los Angeles, USA
 Part I
Epidemiology
 Environmental Factors
in the Epidemiology of Inflammatory 1
Bowel Disease

Morten H. Vatn

and between countries, and in how well the patients were

Introduction characterized on the basis of first or later admissions [4, 5].
The centers which have achieved most experience in IBD are
The occurrence of IBD has been increasing in Western second or third line hospitals with large databases, including
Europe and North America [1, 2] over several decades after patients with relatively more complicated disease [6–8].
the Second World War. It has been assumed that socioeco- In population-based studies, in which the cohorts better
nomic factors represent the most important explanation for represent the total number of patients with IBD in an area,
this increase [3]. A part of this increase may have been increased number of patients are recorded with light to mod-
related to more awareness and recognition of the diseases, as erate disease and less complications, and with a relatively
well as generally better registration in all countries. higher age at diagnosis [8–14].
It is important to realize that the general acceptance of In spite of the variation in incidence and prevalence of
endoscopy as the main internationally accepted diagnostic IBD between the Western countries, the recognition of
procedure is quite young, and that we may divide the history increased occurrence has been a common feature (Figs. 1.1
into a pre-endoscopic area before 1970, an early endoscopic and 1.2). Although follow-up studies have given increased
period between 1970 and 1990 characterized by a relatively knowledge of outcome of disease, repeated prospective stud-
large heterogeneity among studies, and a post-endoscopic ies on incidence have only recently been performed [9], and
period from around 1990, whereafter a widespread distribu- mostly in children (Figs. 1.3 and 1.4; Tables 1.2 and 1.3) [15,
tion of equipment and skills of endoscopy enabled all coun- 16]. These studies tend to suggest that the incidence of CD
tries to perform uniform diagnostic procedures (Table 1.1). may still be increasing in the Western world, despite signs of
Moreover, after this point in time, most international studies a stable frequency of UC in the same cohorts [15–17]. In
have been performed according to generally accepted defini- spite of the reported higher incidence rates of CD than of UC
tions and criteria of diagnosis [4]. from Canada and the middle of Europe, UC is the predomi-
However, even if we generally include only endoscopy-­ nant phenotype of IBD in the rest of Europe. Moreover, stud-
based studies, the heterogeneity of even the Western materi- ies from certain areas of Northern [18, 19] and Eastern
als is striking and difficult to compare, regarding incidence, Europe [20], as well as New Zealand [21], may suggest that
prevalence, and subtypes. One important reason for this is UC is still increasing among adults.
the selection of cohorts in the different countries. In most When looking for a cause relationship behind CD and
centers, the registration of IBD has been hospital based, by UC, the environmental factors of importance mainly seem to
which the type of recorded patients were depending on the be related to the Western lifestyle. Nevertheless, the varia-
level of each hospital in the health-care system of each coun- tion in lifestyle, between countries and areas within coun-
try, including access to health care. Additionally, great varia- tries, is great. Additionally, the emerging increase in
tions exist in the recording systems, both between hospitals prevalence reported from outside the Western countries,
makes the focus on environmental factors even more impor-
tant. A burning question is therefore, whether certain specific
M.H. Vatn, M.D., Ph.D. (*)
risk factors for the development of IBD are related to
Section of Gastroenterology, Oslo University Hospital,
Nydalen, P.O. Box 4959, 0424 Oslo, Norway increased socioeconomic status, regardless of geography,
and in addition to public awareness and access to health
Akershus University Hospital, Institute of Clinical Medicine,
University of Oslo, 1474 Nordbyhagen, Akershus, Norway care? Additionally, we have to bear in mind that in diseases
e-mail: m.h.vatn@medisin.uio.no like IBD, with a multifactorial etiology, different risk factors

© Springer International Publishing AG 2017 3

D.C. Baumgart (ed.), Crohn’s Disease and Ulcerative Colitis, DOI 10.1007/978-3-319-33703-6_1
4 M.H. Vatn
Table 1.1 Registration of IBD
Possible causes for change over time
• Before 1970
– Retrospective data
– Hospital based
– Cross-sectional studies
– Unclear definitions
– Pre-endoscopic period
• After 1970
– Early endoscopic period
– Defined populations
– Prospective registration
– GP/hospital based
• After 1990
– Endoscopy-based diagnosis
– International criteria
– Subgroups: proctitis/indeterminate
– Controlled on specialist level
– Follow-up controls
– Possibility for “case–control” studies
may cause imbalance of the environmental–host relationship
in different parts of the world. Suspected consequences of
industrialization might not necessarily be relevant for dis-
ease development in different geographic regions, although
our traditional reductionism of logic thinking tends to look
for a simplified explanation for cause relationships.
In the following, it seems necessary to relate environmen-
tal factors to the reported occurrence of IBD in the different
geographic areas, and thereafter discuss the degree of poten-
tial risk factors of disease present in each specific region, to
the best of our present knowledge.
Geography
Variation Between Countries
The fact that IBD occurs with the highest frequency in the
Western world is undisputable, and the experience is based
on hospital materials from the large centers in Europe and
North America. These areas also have in common that
remarkable increasing prevalence rates have been recorded
during the second half of the twentieth century [1, 2]
(Figs. 1.1 and 1.2).
In addition to that, differences between regions of Europe
and North America have been recorded. In Europe, a North–
South gradient for incidence rate, phenotype, and recurrence,
has been demonstrated [10, 22, 23] based on modern diag-
nostic procedures and prospective follow up.
Interestingly, the highest incidence rates of both the North
and South of Europe have been demonstrated in the islands
of Iceland and Faroe Islands [10], and the islands of Crete
and Sicily and Mallorca [10], respectively (Fig. 1.5). This
might raise interesting questions regarding both genetic and
environmental explanations. Recently, also high incidence
rates of IBD have been reported from New Zealand and
Australia (Wilson J, Hair C, Knight R. High incidence of
inflammatory bowel disease in Australia: a prospective
population-­based Australian incidence study. Inflamm Bowel
Dis 2010;16:1550–6), which may contribute to this discus-
sion. In Japan, most of the experience in IBD is based on the
reports from large hospital-based centers, all reporting on
increased prevalence rates, although definitively much lower
than in the Western world [24]. Some reports have also come
from South America [25].
Racial differences of IBD prevalence rates have been
reported from North America [26], showing much lower
rates among Hispanic and Asian people compared to whites
and African Americans. High prevalence rates for Crohn’s
disease and ulcerative colitis have also been shown for North
American Ashkenazi and Israeli Jews [27, 28]. The sug-
gested effect of ethnicity on disease location, complications,
and anticipation may be partly explained by genetic and
environmental factors [25–27].
Developing regions have traditionally reported lower
prevalence of IBD, which seems to increase, probably as a
consequence of a rising incidence of IBD in many of these
nations, such as India and China, as they have become indus-
trialized [29, 30].
Furthermore, migrant studies have demonstrated that
individuals immigrating from regions with low prevalence to
countries with higher prevalence rates are at an increased
risk for developing IBD, particularly among first and second
generation children [30, 31].
In the USA, also, a North–South gradient has been shown
by hospital-based registrations [6, 32, 33], whereas in
Canada, an East–West gradient has been demonstrated in a
nationwide comparison [13] (Fig. 1.6). Moreover, the
population-­ based registry of Manitoba, Canada [13] has
demonstrated some of the highest incidence rates of IBD in
the world.
In the population based ECCO-Epicom study (Burisch J,
Pedersen N, Cukovic-Lavka S, et al. East-West gradient in
the incidence of inflammatory bowel disease in Europe: the
Ecco-Epicom inception cohort. Gut 2014;63:588–97), an
east–west ratio was demonstrated for Europe, with the high-
est incidence rate in Western Europe. Recent review articles
have reported on global variability in IBD and environmental
risk factors in adults (Ng SC, Bernstein CN, Vatn MH, et al.
Geographic variability and environmental risk factors in
inflammatory bowel disease. Gut 2013;62:630–49;
Moledecky NA, Soon IS, Rabi DM, et al. Increasing inci-
dence and prevalence of inflammatory bowel disease with
time, based on systematic review. Gastroenterology
2012;142:46–54) and children (Benchimol EI, Fortinsky KJ,
Gozdyra P, et al. Epidemiology of pediatric inflammatory
bowel disease: a systematic review of international trends.
Inflamm Bowel Dis 2011;17:423–39).
1 Environmental Factors in the Epidemiology of Inflammatory Bowel Disease 5

Fig. 1.1 Temporal trends in 12

incidence rates (cases per 100,000
Olmsted County, MN
person-years) of Crohn’s disease in

Incidence/100,000 person-years
selected areas (Olmsted County, 10 Cardiff, Wales
Minnesota; Cardiff, Wales, UK; Rochester, New York
Rochester, New York; Iceland;
Aberdeen, Scotland, UK; Helsinki, 8 Iceland

Finland; and Florence, Italy). Aberdeen, Scotland

[Reprinted from Gastroenterology;
6 Helsinki, Finland
126(6). Loftus E. Clinical
epidemiology of inflammatory Florence, Italy
bowel disease: incidence,
4
prevalence, and environmental
influences: 1504–17. ©2004 with
permission from Elsevier] 2

0
1955 1960 1965 1970 1975 1980 1985 1990 1995
Year

Fig. 1.2 Temporal trends in 20

incidence rates (cases per 100,000
person-years) of ulcerative colitis 18 Olmsted County, MN
Incidence/100,000 person-years

in selected geographic regions 16

Rochester, NY
(Olmsted County, Minnesota; Iceland
Rochester, New York; Iceland; 14
Florence, Italy
Florence, Italy; Malmo, Sweden;
Heraklion, Crete, Greece; and 12 Malmo, Sweden
Seoul, South Korea). [Reprinted
10 Heraklion, Crete
from Gastroenterology; 126(6).
Loftus E. Clinical epidemiology of Seoul, South Korea
8
inflammatory bowel disease:
incidence, prevalence, and 6
environmental influences: 1504–17.
©2004 with permission from 4
Elsevier]
2

0
1955 1960 1965 1970 1975 1980 1985 1990 1995
Year

Within Germany, Spain, and the UK, national variations

 ariations Within European Countries:
V based on direct comparisons have not been reported, although
Population-Based Studies (Fig. 1.7)
In Europe, great differences have been reported regarding
variation in frequency of IBD between centers within coun-
tries. In Greece, the island of Crete showed a markedly
higher incidence of IBD compared to Joannina in the North
[10] similar to a higher incidence in Sicily compared to the
North of Italy [10]. Based on comparisons on the Italian
­continent, also a North–South gradient is indicated, similar
to a North–South gradient in Portugal and Spain [10].
In France, a higher incidence and prevalence in the North
compared to the South has been reported, based on a partly
hospital-based Nationwide registry [34].
variations between single center studies are obvious within
countries. High incidence rates have been reported from
Ireland, Scotland, and the Netherlands compared to the UK
and Western Germany [10]. Many of these differences, how-
ever, might be explained by variation in type of cohorts and
organization of health care.
From Denmark and Norway, generally high incidence
rates have been reported in population-based studies [1, 10–
12]. In Norway, similar incidence rates have been shown
between the Northern [35], Western [36], and the South-­
Eastern part [12], whereas great differences were shown
between counties for the two latter areas compared to a more
even distribution within the former [35]. This could be
6 M.H. Vatn

Fig. 1.3 Incidence of CD in children (Table 1.2)

1 Environmental Factors in the Epidemiology of Inflammatory Bowel Disease 7

Fig. 1.4 Incidence of CD in children (Table 1.3)

Table 1.2 Incidence of pediatric IBD in the Nordic countries

Country Year Incidence of CD Incidence of UC N
Norway (IBSEN) 1990–1993 2.7 2.0 29 <16 years
Norway (AHUS) 1993–2004 2.8 3.9 49 <16 years
Norway (IBSEN II) 2005–2007 6.7 3.9 48 <16 years
West Norway 1984–1985 2.5 4.3 27 <16 years
Denmark 1998–2006 3.1 1.6 50 <15 years
Sweden 1990–2001 4.9 2.5 152 <16 years
Finland 1987–2003 1.9 3.9 604 <18 years
8 M.H. Vatn

Table 1.3 Incidence of pediatric IBD in Europe

Country Year Incidence of CD Incidence of UC N
Scotland 1981–1995 2.5 3.8 665 <16 years
1980–1990 2.2 107 <16 years
1990–1999 4.4 107 <16 years
Iceland 1990–1994 8.5
Wales 1996–1997 1.36 2.6 38 <16 years
1996–2003 3.6 5.4 39 <16 years
England 1998–1999 3.1 5.2 739 <16 years
Czechoslovakia 1990–1999 1.25 470 <15 years
1999–2001
North France 1988–1999 2.3 3.1 509 <17 years
Netherlands 1999–2001 2.1 7.3 220 <18 years

Fig. 1.5 Global incidence of IBD

explained by a generally mixed urban rural population in the
North and a better separation between urban and rural areas
in the two others. Both the Western and South-Eastern part
showed a generally higher incidence rate in the scattered
rural populations, opposite to previous international experi-
ence, in which urban areas have been considered to be areas
of increased risk of IBD.
An explanation for this discrepancy within the literature
might be that different risk factors are acting concomitantly
within an area in addition to the existence of different risk
factors between areas. One should not, however rule out the
possibility of variations in efficiency and quality of registra-
tion between areas.
In Norway, the counties with most scattered and rural
populations were also the areas with only one hospital, in
contrast to the many recording hospitals and multidisci-
plinary doctors in the cities. This gave a variation in inci-
dence rate between 17/100,000 in Oslo and 28/100,000 in
the scattered populated area of Aust Agder, with one hospital
in the only city of the county.
These data may provide evidence for the importance of
access to health care and awareness of the population under
examination. To increase the understanding of the complex-
ity of this problem, one might add, that the area with the
highest incidence of IBD, had the highest increase in socio-
economic status during the decade prior to the incidence
1 Environmental Factors in the Epidemiology of Inflammatory Bowel Disease
Fig. 1.6 Incidence of IBD in the USA
study, as measured by the number of individuals obtaining
higher education. Although a much higher level of education
was seen for Oslo, this level had been stable during the previ-
ous decades. With this respect, a factor that might be of
importance in the Western societies is the increasing rate of
immigration. Recent reports from the UK, reported on an
unexpected high prevalence rate of IBD among immigrants
from Southeastern Asia [37].
Relationship Between UC and CD
Although a change in socioeconomic level seems to be a
common risk factor for UC and CD, it is important to
note that these diseases may react quite differently, not
only genetically, but also to environmental risk factors.
A solid background of geographic examinations is therefore
important.
In addition to variations between countries and regions
regarding incidence and prevalence of IBD in general, the
9
ratio between UC and CD has also shown geographic
­variations. A generally higher incidence rate for UC than
for CD has been shown both in the North, East and the
South of Europe, but with a smaller difference in the South
[9]. In Canada and the USA, however, CD seems to occur
with a higher frequency than UC [13], similar to Northern
France [10]. Since this now also seems to be the case for
Southern Germany [38] and parts of Eastern Europe [20]
(Sjucic BM, Vuculic B, Persic M, et al. Incidence of inflam-
matory bowel disease in Primorsko-Gromska county,
Croatia, 2002–2004: a prospective population based study.
Scand J Gastroenterol 2006;41:437–44), we may no longer
describe this as a French enigma, but rather as a tendency
for middle Europe. The variation in ratios of UC/CD
between countries and areas might reflect differences in
environmental risk factors, although genetic predisposi-
tions may occur. It might be interesting to note that in
Europe, the incidence of NOD2 mutations seems to be
highest in the middle part, corresponding to the region with
an increased CD to UC ratio.
10
Fig. 1.7 Incidence of IBD in Europe—adults
Although unsolved questions exist regarding patterns of
IBD in Europe, the risk factors and frequency of IBD in
Eastern Europe must principally be regarded as related to the
same socioeconomic trends as the rest of the continent and
North America, in contrast to the developing countries. It is,
therefore, relevant to discuss the environmental risk factors
of IBD generally for the whole Europe as one area.
The question if the incidence and prevalence rates of IBD
still are increasing is generally an unsolved question in most
parts of the world. The reasons for this are different in the
Western world compared to the developing countries. In the
USA and Europe, few data exist based on comparable pro-
spective studies performed during different time periods
M.H. Vatn
within the same area. A study from Copenhagen may suggest
that the incidence of CD in adults is still increasing during
the last decade [9]. In children, however, studies from several
countries have suggested that the incidence still is increasing
for CD but not for UC [15, 16]. The relationship between this
increase and immigration is unclear, but studies on the risk of
acquiring IBD among first-generation immigrants are under-
way. In a recent study from Oslo [17], the incident cases of
CD representing first-degree immigrants from developing
countries were partly responsible for the 100 % increase in
incidence of CD over the last decade. To what extent the shift
of environment has an impact on the development of IBD
will have to be focused in the future.
1 Environmental Factors in the Epidemiology of Inflammatory Bowel Disease
The geographic difference between the North and South
of Europe was the same for UC as for CD [10, 22, 23], also
with regard to outcome and complications. For the above-
mentioned reasons, it is not quite clear if the incidence of UC
has stabilized or in some areas still is changing. A recent
study from Finland indicates a dramatic increase in UC,
based on partly population-based data from a regional regis-
try. For all registry-derived data, some uncertainty exists,
regarding reliability of the recording system over time. On
the other hand, since recently also an increase of UC has
been suggested in Hungary, a combined causality of environ-
mental factors and ethnicity could explain a parallel increase
in Finland and Hungary.
Reports from developing countries on the incidence and
prevalence of IBD are still missing as regards population-­
based studies. Regional studies from India [24], may, how-
ever, suggest an increase over time in well-defined regions.
Documented increase of incidence or prevalence in Japan
would, however, be of particular interest, since Japan may be
the only country in Asia with stable socioeconomic condi-
tions over several decades. An eventual increase in frequency
of IBD would then have to be related to other than direct
socioeconomic factors, and rather to other changes in the
environment or lifestyle, such as dietary habits.
Environmental Factors
Relationship to Microbiology
Today, the most important environmental factor, with a cause
relationship to the development of IBD, is considered to be
related to an imbalance in the microbial–host relationship
with mucosal barrier dysfunction and reduced microbial
diversity [39]. Resent publications have further developed our
understanding of the changed bacterial composition in IBD
(Manishanh C, Bourruel N, Casellas F, Guarner F. The gut
microbiota in IBD. Nat Rev Gastroenterol Hepatol
2012;9:599–608; Hold GL, Smith M,, Grange C, et al. Role
of gut microbiota in inflammatory bowel disease pathogene-
sis: what have we learned in the past 10 years? World J
Gastroenterol 2014;20:1192–1210; Sartor RB, Mazmanian
SK. Intestinal microbes in inflammatory bowel diseases. Am
J Gastroenterol Suppl 2012;1:15–21; Matsuoka K, Kanai
T. The gut microbiota and inflammatory bowel disease.
Semin Immunopathol 2015;37:47–55) The hygiene hypothe-
sis is an attempt to explain why improvement of hygienic
conditions may result in intestinal dysbiosis as a primary
event, resulting in IBD among genetically predisposed indi-
viduals. This hypothesis implies that the rising frequency of
immunologic disorders can be attributed to lack of childhood
exposure to enteric pathogens. This dysbiosis may on the one
hand be characterized by an imbalance between commensal
11
bacteria, and on the other hand, by secondary development of
pathogens, which by omitting the immunocompromised cells
of the different barrier systems, may lead to chronic inflam-
mation. The suggested “Cold chain hypothesis” represents a
more direct explanation of a cause relationship between spe-
cific bacteria and the immunocompromised host, from a
molecular perspective, postulating that CD is a result of a
defect in the host recognition of pathogenic bacterial compo-
nents that usually escape the immune response (e.g., Yop
molecules), leading to an excessive host response to bacteria,
such as Yersinia spp. and Listeria spp., which can survive
refrigerator temperature [40]. The definition relies on the
introduction of refrigeration in society, which was related to
the time of increased prevalence of CD. A support for this
hypothesis has been reported in case–control studies, partly in
combination with other socioeconomic risk factors [41, 42].
In support of the hygiene hypothesis are the generally
negative association to the epidemiology of Helicobacter
pylori [43] and the inverse association to the prevalence of
helminthic colonization [44, 45].
It is still an issue if primary pathogens like Mycobacterium
avium paraturbeculosis (MAP), Johne’s disease [46], may
be an etiologic factor, but problems related to the biologic
methodology has been a major concern, and further studies
are expected in the years to come. Clinical studies up to now
have been inconclusive with regard to the impact of MAP in
IBD, and a study of seropositivity showed a high prevalence
for IBD, but failed to demonstrate a difference between CD,
UC, and controls [47].
Several studies, however, have detected a high prevalence
rate of MAP in CD patients, and a meta-analysis of 28
case–control studies showed a positive association, both
for enzyme-linked immunosorbent assay (ELISA) and
PCR [48].
A recent examination [49], however, performed with
highly sensitive methods in intestinal mucosa, could not
detect the presence of MAP in newly diagnosed, treatment
naïve cases, in contrast to many affected cases among hospi-
talized CD patients on treatment, in the same catchment area.
MAP was not found among patients with long-standing
UC. According to these results, MAP is probably not an etio-
logic factor, but a bystander appearing during the course of
disease and appearing in patients on treatment. Another
interpretation could be that MAP remains elusive to detec-
tion during the early phase of disease, and that a longer dura-
tion of immune decompensation is needed for diagnosis by
the present methods.
The high prevalence of adherent-invasive Escherichia
coli spp. associated to ileal CD may represent another pri-
mary pathogenic strain of bacteria, which is able to adhere to
intestinal epithelial cells, to invade epithelial cells via a
mechanism involving actin polymerization and microtu-
bules, and to survive and replicate within macrophages [50].
12
Other hospital-based studies have demonstrated a geo-
graphic covariation related to hospitalization and mortality
for IBD and Clostridium difficile [51].
Since IBD is most common in the northern hemisphere,
most studies with regard to microbial risk factors have been
performed in this region. As, on the one hand, one might
speculate that improvement in sanitary conditions is respon-
sible for reduced microbial diversity, industrial pollution in
society might serve as another explanation for changed envi-
ronment. It is probably unlikely that the exogenous predispo-
sition for IBD can be explained by one single environmental
factor. At the moment, our knowledge regarding possible
risk factors derived from industrialization must be divided
mainly into primary direct effects of endogenous dysbiosis
and secondary effects on this microbial imbalance. The latter
explanation will include all the risk factors that will either
increase the microbial instability or increase the vulnerabil-
ity of the host organism.
For testing of dysbiosis, a genetic test applied on human
feces has been published recently, comparing IBD with IBS
and controls. Such comparisons need to be performed glob-
ally to be relevant to all populations (Casén C, Vebo H,
Sekelja M, et al. Deviations in human gut microbiota: deter-
mining dysbiosis in a diagnostic setting in IBS and IBD
patients. Aliment Pharmacol Ther 2015).
 elationship Between Environment
R Several studies have reported on increased incidence of
and Geography
Of factors that may act on the intestinal microbial composi-
tion, geography may represent a risk in addition to socioeco-
nomic development. Living on the northern hemisphere may
therefore explain the increased incidence of IBD, only based
on this single factor, which might be explained by increasing
intestinal dysbiosis. It has been suggested that this risk
increases with increasing latitude from the Equator to the
North Pole [52]. This explanation needs support from more
comparable studies, which need to be performed by standard-
ized examinations on preferentially unselected materials.
Although latitude alone may represent a risk for develop-
ment of IBD, the reports from Canada, showing a marked
East–West gradient, which at least up to now, might have
been the case also for Europe, seems to indicate that contem-
porary differences within a society or within a region over
time, represent the most important risk factors. These two
examples of East–West gradients may therefore strengthen
the argumentation for industrialization as a main causative
factor for IBD. The North–South gradient in Europe does not
necessarily depend on the same differences, because indus-
trialization and socioeconomic growth patterns have in part
ran more parallel in the North and South of Europe.
Other environmental factors, such as water supply, may
act in addition to, or increase, the instability, primarily
M.H. Vatn
caused by the dysbiotic intestine. In a recent study, a strong
association between iron concentration in the sources of
drinking water and the community incidence of IBD, both
CD and UC, was found [53]. Other metals showed no asso-
ciation to IBD, opposed to the proposed focus on aluminum
as a risk factor [54]. One explanation why inorganic iron
might be a risk factor is its known ability to cause oxidative
stress, whereas another might be its effect on bacterial
growth. The results might generally agree with a role for
oxygen radicals in animals and humans [55].
Relationship to latitude might also be explained by
changes in sun exposure and vitamin D [56] Geographic pat-
terns related to IBD seem to involve complex interactions
between genetics and sun exposure, both related to latitude
(Scilagyi A, Leighton H, Burstein B, Xiaoquing Xue.
Latidude, sunshine, human lactase phenotype distributions
may contribute to geographic patterns of modern disease: the
inflammatory bowel disease model. Clinical Epidemiology
2014;6:183–98).
Socioeconomic Factors
One might speculate that the role of latitude is part of the
North–South gradient in Europe, although other environ-
mental factors, such as diet or socioeconomics, may be
responsible for the variation in the occurrence of IBD.
both UC and CD in more densely populated areas [57–61].
Both family size and number of older siblings, as well as
birth order, have been related to increased risk of UC, and
with smaller families and few older siblings related to CD
[62], which might be a sign that UC is more directly affected
by environmental factors than CD. This explanation was also
supported by a shorter interval between first-degree relatives
acquiring UC compared to CD [63]. The relationships
between these diseases and other household-related condi-
tions, such as pets, are unclear [64–67].
It has previously been reported that both UC and CD are
affecting white collar more than blue collar employees [68].
Further studies among German employees suggested that
work in the open air and physical exercise were protective,
while being exposed to air conditioned, artificial working
conditions or extending and irregular shift working increased
the risk of IBD [69]. In population-based studies in Norway,
the incidence of IBD was higher in rural areas with a recent
increase in socioeconomic status, based on years of educa-
tion, compared to urban areas with a stable high socioeco-
nomic level [12, 36].
Other factors which might be related to socioeconomics
are sanitary conditions, which actually formed the basis for
the hygiene hypothesis. In an epidemiological study in the
UK, the availability of a fixed hot water supply in childhood
before the age of 11 was associated with Crohn’s disease [3].
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 CHAPTER IX.
‘those are the killing griefs which dare not speak.’
By slow degrees Beatrix arrived at an understanding of her position.
People in Little Yafford believed her guilty of her father’s murder. The
idea was horrible, and she would have fled, but pride came to her
rescue, and she stayed, defying all the slanderous tongues and cold
cruel eyes in the village, from the judicial discourse and pale gray
orbs of Miss Coyle, to the lively comments and little red-brown rat-
like optics of Mr. Tudway. She met cold looks and averted heads at
the church door, where she had been wont to find herself saluted
with nods and becks, and a world of sympathy and friendliness. Now
and then she encountered a startling glance, as of wonder that she
should dare to enter the church. Even Mrs. Dulcimer was cold, and
seemed embarrassed by Beatrix’s presence, though affecting all the
old cordiality. But the Vicar was full of kindness, and tried to make up
for everybody else’s cruelty. His charity was not of the officious kind
which forces itself upon people who do not want it, but it was that
stronger and wider charity which is inexhaustible for those who do.
He had let Beatrix come and go as she pleased hitherto, and had
never pressed her to remain. Now he took her under his wing,
brought her from the Water House to the Vicarage on his arm, and
let the whole village see that he was not ashamed of his ward.
‘Mr. Dulcimer always cared too much for the fleshpots of Egypt,’
said Mrs. Coyle. ‘Miss Harefield’s money blinds him to her character.
A sad thing to see a minister of the gospel so devoted to worldly
things.’
One day, stung by the disapproving look of a face that passed her
in the village street, Beatrix made a sudden appeal to Miss Scales.
‘What does it all mean?’ she asked, in an agitated voice. ‘Why do
these people give me such horrible looks—or pretend not to see
me? I don’t want their friendship. They are nothing in the world to
me. But I can’t endure to live in an atmosphere of dislike. What does
it mean?’
‘My dear Beatrix, I had rather you did not ask me,’ Miss Scales
answered, stiffly.
Her manner had been gaining stiffness ever since her return from
Devonshire. A deeply bordered letter had come to announce the
aunt’s death, and a week after there had come another letter in a
blue envelope, from a local solicitor who had drawn the old lady’s
will, to inform Miss Scales that her aunt had appointed her sole
executrix and residuary legatee. There was a legacy to the faithful
old servant—a little sum in consols to provide for puss and pug—
ancient favourites who had quarrelled daily for the last fifteen years
—and all the rest went to Miss Scales. She was now a lady of
property like her pupil, with an unencumbered estate of nearly two
hundred a year.
‘It would have been quite two hundred,’ said Miss Scales, ‘if it
hadn’t been for the money in consols left to Martha. I think my aunt
might have left me to provide for Martha and Floss and Fido. I should
have taken care they never wanted anything.’
‘Perhaps they would rather be able to take care of themselves,’
Beatrix had replied, a speech which was not agreeable to Miss
Scales.
‘But I must ask you,’ said Beatrix, as she drove her pony carriage
up the moorland road. ‘Whom else can I ask? Have I so many
friends ready to give me information? You must answer me.’
‘I do not recognise any obligation to do so unless I choose,
Beatrix,’ Miss Scales replied, severely. ‘The question you put is a
very painful one. I cannot deny that there is an unpleasant feeling
about you in people’s minds. Your purchasing laudanum at different
shops—forgive me if I say in an underhand and crafty manner——’
‘They would not have given me enough at one shop,’ interrupted
Beatrix, ‘and I was almost mad for want of sleep.’
‘My dear, I am not finding fault with you. God forbid that I should
judge you. But, altogether, the circumstance was most unfortunate,
and it has had a painful effect upon people’s minds. I am not sure,
Beatrix, that it would not be well for you to leave Little Yafford.’
‘What! run away from these people because they are cruel enough
to believe this hideous thing?’ cried Beatrix, passionately. ‘No, that is
a thing I will never do. I will live here till my hair is gray, rather than
let them think their false judgment has driven me away.’
‘Well, Beatrix, I am very sorry,’ said Miss Scales. ‘I think a tour in
Switzerland—or a residence in Hanover—where you might acquire
the German language with the best accent—would be good for you
in every way. And, perhaps, before you came back something would
transpire to convince people they had misjudged you. However, you
must do as you please, of course. I have no authority. Mr. Dulcimer
is your guardian. So long as he is satisfied I cannot complain. And
now, my dear, with regard to myself, I have been wishing to mention
it for some time, but I did not like to say anything while your papa’s
death was so recent. I am going to leave you, and settle in
Devonshire.’
Beatrix was petrified. She had considered Miss Scales as much a
fixture as the old eight-day clock in the hall—nay, as the Water
House itself, or as the massive old bridge with its single arch, which
had spanned the river ever since the time of the Romans. Miss
Scales was tiresome, and given to much preaching, and to the use
of Johnsonian locutions, without the correctness of Johnson. She
easily degenerated into a nuisance, but Beatrix was used to her, and
regarded her as a part of life. Such fondness as grows out of time
and custom, Beatrix had for Miss Scales, though not the affection
that springs from merit and sweetness in the object of it. That Miss
Scales could wish to remove herself permanently from the Water
House was of all things most startling. It was as if the cedar on the
lawn had uprooted itself and walked away to shade some other
garden.
‘Leave me!’ cried Beatrix, pale with surprise. ‘You can’t really
mean it.’
‘Indeed, my dear, I do. My dearest aunt Judson has left me a nice
little independence—and at my age you would hardly expect a
person to go on working.’
‘There need be no work,’ said Beatrix, eagerly. ‘I need not trouble
you any more with my studies. I can read to myself instead of to you.
It will make no difference. You can have all your mornings free.’
‘You cannot suppose that, so long as I remained with you, I could
neglect the improvement of your mind, Beatrix,’ severely exclaimed
Miss Scales, fully believing in her own style of grinding—quite forty
years behind the spirit of the age—as an improving process. ‘No, my
dear, that is not the consideration. I want to live in my own house.
Dear aunt Judson has left me a bijou cottage at Exmouth, and all her
beautiful furniture, and I feel it a duty I owe to myself, after all these
years of scholastic toil, to settle down. I shall be on the spot to see
after Floss and Fido, whom I should not like to leave to the care of a
hireling, however well provided for.’
This was a stray javelin flung at the faithful servant, to whom Mrs.
Judson had left five hundred pounds in consols.
‘Oh, very well, Miss Scales, if you like Floss and Fido better than
me,’ said Beatrix, proudly, giving the reins a little shake that sent
Puck into a canter.
‘Beatrix, are you trying to murder me?’ cried the terrified Miss
Scales. ‘Stop that pony this instant, or I’ll take the reins out of your
hands.’
‘If you do that we shall certainly be in the ditch. There, Puck is
quiet enough now.’
‘As to my liking Floss and Fido better than you,’ pursued Miss
Scales with her judicial air, when Puck had resumed his accustomed
trot, ‘that is a very unfair way of putting it. I have my own happiness
to consider.’
‘Yes,’ said Beatrix, ‘that seems the first consideration with
everybody.’
‘If we cannot discuss this question without temper, Beatrix——’
remonstrated Miss Scales.
 ‘We cannot. At least, I cannot,’ answered Beatrix, quickly. ‘You
have lived with me ever since I can remember. Yes, one of the first
things I can remember is standing at your knee on a hot summer
morning droning over a selection of the psalms, in words of one
syllable. That psalm about the wicked man and a green bay tree, for
instance. I never see a bay tree without remembering how hard it
was to learn to read. You have lived with me ever since I was in my
cradle, and yet you talk of leaving me as coolly as if it were nothing
to you.’
‘My dear Beatrix, the parting will be very painful to me; but it would
be more painful to remain.’
‘Why?’ asked Beatrix, fiercely.
‘Because I could not bear to see people look coldly upon you. I
could not live in a house under such a cloud as that which
overshadows your house.’
‘I see,’ cried Beatrix, her face hardening. ‘You believe what these
people believe.’
‘I have not said that.’
‘No, you would not dare to say it. But you are wicked enough to
think it—you who have known me all my life. This ends everything
between us.’
‘I should think so,’ said Miss Scales. ‘I shall pack my trunks to-
night, and leave Little Yafford the first thing to-morrow morning.’
‘It will be best so,’ replied Beatrix, and she turned Puck with a
suddenness that swung the chaise round in a manner to make Miss
Scales a second time in fear of her life.
Beatrix drove home in silence, went straight to her own room, and
shut herself in there. Her own maid, Mary, carried her up some tea,
and she sent a message to Miss Scales excusing herself from going
down to dinner on the ground of a headache. Had she said a
heartache it would have been the truth.
Miss Scales ate her dinner in sullen state, meditating her life of
independence with Floss and Fido. She asked Peacock to order a fly
for her at a quarter past seven next morning, in time to catch the
quarter-past eight London train at Great Yafford. She devoted the
evening to packing her trunks, weeding out a few scarecrow odds
and ends of finery from the garden of her wardrobe as a parting
bequest to Mary. She left the Water House in the early winter gray,
without having seen Beatrix. Peacock handed her an envelope at the
last moment, which she opened presently in the fly. It contained no
word of farewell, only bank-notes for the current quarter’s salary.
This was the first absolute desertion. Beatrix felt it heavily. She
had been wounded at Bella Scratchell’s keeping aloof from her, as
she had done since her visit ended. She was more deeply wounded
by Miss Scales’s abandonment.
Before the day was out she was to receive another and much
heavier blow. A letter was brought her, late in the evening, from Cyril
Culverhouse. It was only the second letter she had ever received
from him, but she could have sworn to his handwriting if it had been
shown her among a thousand. There is no expert keener-eyed in
these things than love.
‘At last!’ she said to herself, with a great wave of joy drowning her
heart.
That the letter might bring evil tidings never occurred to her. It was
like the leaflet in the beak of the dove. It meant that the dark days
were ended, and the glad world was beginning to smile upon her
again. The letter was long, but she had not read many lines before
despair seized her. She uttered no cry or groan. She sat with the
letter held tightly in her convulsed hand, devouring the cruel words.
‘My dearest and only Beloved,—Before leaving this
place I write to explain my conduct of the last six weeks,
which must have seemed cold and unworthy, and to
explain my course in the future, which may offend her for
whom I would sacrifice most things rather than offend. I
have made up my mind to leave Little Yafford. I have
made up my mind never to marry. Reasons which I cannot
enter upon have urged me to this resolution. I have loved
you deeply, fondly, with an unmeasured and absorbing
 love, but I have schooled myself to surrender the hope of
a happiness which made life very fair and sweet, and
which I once deemed not incompatible with my calling and
the duties that belong to it.
Forgive me, Beatrix, for the pain this letter may cause
you—forgive me for the part I have had in your life. Had
Providence willed for me to find you unshackled and poor
we might have been happy. As it is, I am assured that only
misery, remorse, and regret would follow our union.
May God bless you. May He pardon and pity you, in all
your need of pardon and pity. The best of us need both at
His hands. I take up my pilgrim’s staff, with a heavy heart,
and go my way, cheered by no promise in the future,
sustained only by the hope of doing some good work
among my fellow-men before I die.
Oh, Beatrix, if you could know how my heart yearns
towards you—how my whole being is rent as I write this
cold farewell—you would pity me as I pity you—for I have
need of all your pity.
I will write no more. Words are no balm for a real and
lasting sorrow.
Farewell, Beatrix, and whatever you may think of me,
believe at least that you are the only woman I have ever
loved—the only woman I can ever love.
Yours in deepest sorrow,
Cyril Culverhouse.’
This ended all. It was very clear to her that her lover thought as
Little Yafford thought. In his eyes too she was a guilty wretch, for
whom he could feel nothing but pity.
‘He was the only creature who ever really loved me since my
mother died,’ she thought, ‘and now he has deserted me.’
 CHAPTER X.
‘alas! i have nor hope nor health.’
Bella Scratchell, tripping to the Park one frosty morning, and
entering Mrs. Piper’s sitting-room, all beaming with smiles, like a
small edition of Aurora, found the invalid in tears, and sniffing feebly
at a bottle of aromatic vinegar.
‘Dear Mrs. Piper, have you had one of your bad headaches?’
‘No, my dear, it is not my bodily health, but my spiritual condition
that affects me. I feel as if I had been holding on by an anchor, and
somebody had taken the anchor away and left me tossing on a
stormy sea. I had such faith in him. He put things in a clearer light
than Mr. Mowler. The Reverend Josiah Mowler is a sainted creature
—and I shall always say so, but he is not equal to Mr. Culverhouse.
He hasn’t the inspiration. Oh, Bella, I am grateful to you for having
brought that good man here, but I feel it hard to lose him, just as I
had pinned my faith upon his teaching.’
Mrs. Piper wiped away her tears with the fine hem-stitched
cambric that befitted her wealth and position, and applied herself
disconsolately to her smelling-bottle.
‘What do you mean?’ asked Bella, all the pinkness fading out of
her cheeks.
‘Why, surely you have heard?’
‘I have heard nothing. Is it about Mr. Culverhouse?’
‘My dear, he has left us. He has gone to Bridford—a horrible place
in Lancashire, where they have small-pox every year. You might
have knocked me down with a feather when Ebenezer came in and
told me about it.’
 Bella sat pale and speechless. Was it for this that she had
schemed? She had slandered her familiar friend, sold herself to
Satan, in the hope of winning this man; and behold! he was gone,
and there was no more chance of winning him than there had been
before she perilled her soul by this sin. For Bella knew that she had
sinned. She was quite capable of doing a wicked thing for her own
advantage, or to gratify her evil temper, but she knew that the act
was wicked, and she had a lurking idea that she would have to pay
for it in some manner in the future. Bella regarded sin as some
people regard going into debt for present gratification; a matter to be
settled in a remote future, and hardly worth thinking about while the
day of reckoning is so far off.
‘Do you mean that he has really gone,’ she faltered presently, ‘for
ever?’
‘Yes, my dear, he has left us for a permanency. I suppose it is to
better himself; but I can’t fancy anybody bettering themselves at
Bridford, where the small-pox has been raging, on and off, ever
since I can remember, and where they have cholera worse than
anywhere in the kingdom.’
‘How did you hear of it?’ asked Bella, with the faint hope that this
piece of information might prove a fable.
‘From himself, dear. He wrote me the sweetest letter, full of
comfort. But I don’t know what I shall do without him. His visits
buoyed me up.’
‘Other people will be sorry,’ said Bella, faintly.
‘Everybody must be sorry. He is a saintly young man.’
‘When did he leave?’
‘Yesterday morning.’
‘And I never heard of it,’ exclaimed Bella.
She was thinking how all things had looked the same, though he
was gone. There had been nothing in earth or sky to tell her that the
light had faded out of her life. The dull village street—with her
mother’s vagabond fowls pecking in the highway—had looked not a
shade duller than usual. She had passed Mrs. Pomfret’s trim garden,
and had looked tenderly at the square unpretending cottage, thinking
that those walls sheltered him; and he was far away. He was gone,
and she had not known it.
‘He might have called to wish me good-bye,’ she complained,
‘after my working for his poor.’
‘It must have been very sudden at the last,’ suggested Mrs. Piper.
Bella went to the schoolroom to grapple with the unruly young
Pipers, sick at heart. All her misery was Mrs. Dulcimer’s fault, she
thought, not taking into consideration her own readiness to lend
herself to Mrs. Dulcimer’s plans.
There was only one ray of comfort, a lurid and unholy light, in the
dark gulf of her thoughts. If Cyril had gone away taking her hopes
with him, he had left Beatrix also hopeless. There was an end of the
tie between those two. If he had meant to marry Miss Harefield he
would not have left Little Yafford.
She dragged herself through the lesson, somehow, beating time to
Elizabeth Fry’s performance of the classic melody of Trab, Trab, with
somebody’s variations—the variations of an ancient and stereotyped
order, first triplets, then little stunted runs, then octaves, then a
dismal minor, all in chords, and then a general banging and flare-up
for a finale. The piece was hideous, and Elizabeth Fry’s playing was
a degree worse than the piece. Bella’s head ached woefully by the
time her pupil had pounded through the brilliant finale, but she bore
up heroically, and heard Horne Tooke read about William the
Conqueror in a drawling voice—with a nasal ad libitum
accompaniment. These children never seemed to get beyond
William the Conqueror and his immediate posterity. Their historical
ideas were strictly feudal, and it must have appeared to them only
yesterday when the curfew was heard from every church tower, and
Peter the Hermit was kindling the souls of Christians with his war-cry
of Deus vult.
Bella stopped to see the little Pipers safely through their early
dinner, the table of these juveniles being as much a scene of strife
and contention as any battle-field in history. It was a hard matter to
preserve some semblance of peace, still harder to inculcate anything
approaching good manners, the young Pipers having entered the
world with an incapacity for using spoons, forks, knives, or other
implements of civilized life in a decent manner. The battle-field was
generally flooded before dinner was over—not with the gore of the
combatants, but with Brougham’s stout, or with Elizabeth’s regulation
glass of old port, or a sauce boat that had capsized in a struggle to
get it ‘first,’ or a mustard-pot turned over in a free fight. Bella had a
little more influence over these barbarians than the servants, who,
coming and going like the wind, were of no authority; but to-day Bella
sat at the head of the table looking straight before her, and allowed
the young Pipers to squabble, snatch, push, and kick one another to
their heart’s content.
She was thinking of that ideal vicarage which might have been
hers in the future if Cyril Culverhouse had only cared for her.
‘He might have chosen me if his heart had been free,’ she
reflected. ‘Everybody tells me I am pretty; even Mr. Piper, coarse and
common as he is, always compliments me about my looks. Why
should not Cyril have liked me?’
It seemed a hard thing to Bella that this gift of prettiness should be
such a barren boon, that it should not bring her exactly what she
wanted. She shed some sullen tears on her way home across the
windy Park, along the bleak high road. There was no one to see her
tears or to pity her. She was angry with fate, angry with life, in which
all things were so unequally meted out. Beatrix was miserable too,
no doubt, in her handsome house yonder, the house whose dulness
Bella had found a shade worse than poverty.
Bella changed her dress and bonnet, and went to make an
afternoon call upon Mrs. Dulcimer, certain of hearing all about Cyril’s
departure from that loquacious lady. The twilight shadows were
falling already, and the half-dozen dingy little shops in the village
street were dimly illuminated with oil or tallow, but an hour or so
before tea was always the best time for finding Mrs. Dulcimer.
 ‘Well, my dear, you have heard the news, I suppose?’ said the
Vicar’s wife, dispensing with the usual ‘how do d’ye do,’ in her
eagerness.
‘I have, dear Mrs. Dulcimer, and I am so surprised.’
‘So is everybody, my dear, Mr. Dulcimer most of all. Such a
sudden desertion—an old pupil too, whom we looked upon almost as
a son. I think it positively unkind. He wants a wider sphere for his
work. Such nonsense. Little Yafford has been wide enough for Mr.
Dulcimer for the last twenty years. But the young men of the present
day are so restless and ambitious. I suppose he thinks Little Yafford
is not the shortest way to a bishopric. And he has taken a charge at
Bridford—a horrible town in Lancashire, where there are nothing but
chemical works, and where the river runs sulphur and asafœtida.’
‘Rather a perverted taste,’ said Bella. ‘I wonder he did not stay
here and try to marry Miss Harefield. She would be a splendid match
for him. And now her father is dead she is free to marry any one she
likes.’
Mrs. Dulcimer shook her head with a dismal air, and gave a
prolonged sigh.
‘Ah, my dear, it is very sad. Those reports!’
Bella echoed the sigh.
‘I was very fond of her—once,’ she said.
‘So was I, Bella. And, even now, I should be the last to condemn
her. God forbid that I should judge anybody. I hope I know the gospel
too well for that. But I confess that I cannot feel the same as I used
about Beatrix Harefield. I can’t get over the strangeness of her
having bought that laudanum in ever so many different shops. There
seems such a low cunning in it—it is like the act of a criminal,’
continued Mrs. Dulcimer, warming as she went on, and forgetting her
protest against judging others. ‘And I am sorry to say,’ she
continued, with increasing solemnity, ‘Rebecca thinks as I do.’
‘And Mr. Dulcimer?’ inquired Bella.
 ‘Oh, Mr. Dulcimer is a very curious man in that respect. He never
thinks the same as other people. He is convinced of Beatrix’s
innocence, and says the Little Yafford people are a set of venomous
idiots for condemning her. But say what he will, he cannot stem the
tide of public opinion. The coroner’s verdict was so unsatisfactory.’
‘What does Sir Kenrick think?’ asked Bella.
‘Oh, he and Mr. Dulcimer are of the same opinion.’
‘Beatrix is too handsome to be condemned by gentlemen,’ said
Bella, with unconscious venom.
‘Oh, my dear, that consideration would not affect Mr. Dulcimer,
however it might influence Kenrick. The best thing she could do
would be to marry Kenrick,’ pursued Mrs. Dulcimer, thoughtfully, ‘but
I could never take the same interest in the match that I should have
done a few months ago. In fact, I would rather not have act or part in
it. If they were to marry, and Kenrick were to die suddenly—or under
mysterious circumstances, and I had been the means of bringing
about the marriage, I should feel myself a murderer.’
Mr. Dulcimer came in from his afternoon round at this moment. He
nodded to Bella, and sank down with a fatigued air in the
comfortable arm-chair that always stood ready for him in the
snuggest corner of the hearth.
‘I have been to the Water House,’ he said, as if taking up the
thread of his wife’s discourse. ‘Beatrix is very ill.’
‘I am sorry to hear that.’
‘I am more than sorry. These wretches will contrive to kill her
before they have done. Namby says that her illness is entirely the
result of mental disturbance. That monster Scales has gone off at a
moment’s notice—after eating Harefield’s bread for fifteen years—
and left that poor child to face this foul-mouthed world alone. She is
ill—and with no one but servants about her. You ought to go and
nurse her, Bella. She has been very good to you. I hope you are not
a fair-weather friend, like the old man in the weather-glass, who only
comes out when the sun is shining.’
 ‘Oh, Mr. Dulcimer, how can you think so badly of me?’
remonstrated Bella.
‘I don’t wish to think badly about you. But you have rather deserted
Beatrix lately, I have noticed.’
‘Mrs. Piper is so exacting, and such an invalid.’
‘Well, Beatrix is also an invalid now, and Mrs. Piper must give way
a little. She has her husband and children to take care of her. Beatrix
has no one. As soon as she is well enough to be moved I shall have
her brought here.’
‘Oh, Clement!’ exclaimed Mrs. Dulcimer, with a troubled look.
‘What do you mean by “Oh, Clement”? We have plenty of spare
bedrooms. Providence, in denying us children, has balanced matters
by giving us spare bedrooms.’
‘Don’t you think people will talk if we have her here?’
‘People will talk whether or no. The business in life of one half of
the world is to criticise and misjudge the conduct of the other half.
But have you ever reflected how little difference all this evil speaking
makes in life? It cannot change a single element in nature. It can
worry us into untimely graves, if we are foolish enough to be worried
by it—it can divide man and wife, or father and son, if man or wife, or
father or son, is idiotic enough to be influenced by the evil tongues of
indifferent lookers on—but scandal cannot, of itself, make the
slightest difference in us or in the world we inhabit. It cannot shorten
our days or prevent the summer sun from shining upon us.’
‘I am sure I don’t know what Miss Coyle will say,’ murmured Mrs.
Dulcimer, plaintively.
‘Miss Coyle is not my bishop,’ retorted her husband, ‘and if she
were I should not consult her as to my choice of guests.’
Bella went to the Water House next day. She found Beatrix
prostrate with some kind of low fever, and light-headed. It was
altogether a piteous spectacle, this lonely sick bed. Mr. Namby came
in three times in the course of the day and evening, and was full of
anxiety about his patient. He found Bella sitting quietly by the
bedside, ready to assist the faithful maid-servant in nursing her
mistress. Mrs. Peters, the fat housekeeper, came in every half-hour,
and was miserable because her beef tea and calves’ foot jelly were
not appreciated by the fever-parched invalid.
Cyril’s name came more than once from those dry pale lips, while
Bella sat by and listened. His desertion was evidently the blow that
had struck home.
‘I’m afraid she’s heard some of the unkind gossip that’s been
about, and that it has preyed upon her mind,’ said Mr. Namby, in a
confidential chat with Miss Scratchell. ‘I can’t account for her illness
in any other way. It’s all the mind. Mr. Dulcimer promises to carry her
off to the Vicarage directly she is well enough to be moved. That will
be a very good thing. Change—change of scene and surroundings
will do a great deal.’
To Mr. Namby, whose horizon had for the last five-and-thirty years
been bounded by the sulky ridge of the moor that shut in Little
Yafford, a change from the Water House to the Vicarage seemed a
grand thing. And if in the summer his patient could be taken to
Scarborough or Harrogate, the cure ought to be complete. Mr.
Namby never thought of prescribing the Tyrol or the Engadine.
Those places had for him little more than a traditionary or
geographical existence, and were only present in his mind as certain
wavy lines upon the map. The days of Cook and Gaze, when even
such persons as Mr. Namby may be personally conducted over the
face of the Continent, were yet to come.
Beatrix mended slowly under Mr. Namby’s care, and with plenty of
nursing from Mrs. Peters, Mary the housemaid, Bella, and Mrs.
Dulcimer; the Vicar’s wife being incapable of remaining long in a
state of even tacit opposition to her dear Clement. She was not quite
comfortable in her own mind about Beatrix, but she tried to be
convinced, and she told herself that such a clever man as Clement,
whose opinions were supported by the finest library of reference that
ever a country parson collected, must be wiser than Miss Coyle.
So one afternoon in windy March, Beatrix was put into the old-
fashioned carriage in which her mother had driven during her brief
wedded life, and was conveyed to the Vicarage, there to remain till
she should be strong enough to travel. She felt a sensation nearer
akin to happiness than she had known for a long time when she
found herself seated in the Vicar’s firelit library, with a little old-
fashioned tea-table by her side, and Rebecca waiting upon her with
a cup of strong tea. Rebecca had been talked to seriously by the
Vicar, and had seceded in a scandalously abrupt manner from the
Coyle faction.
‘Now, Beatrix, this is to be your home as long as you can make
yourself happy in it,’ said the Vicar. ‘The Water House is a very fine
old place, but it is damp and dismal, and I don’t at all wonder that it
made you ill. You are to call this home, and you are to think of me as
your father.’
‘And you do not believe—’ faltered Beatrix, and then burst into
tears.
‘I believe you are a good and noble girl,’ said the Vicar, cheerily,
‘and that a happy and honourable life lies before you.’
‘And after all,’ he reflected, ‘though I detest match-making, it would
be no bad thing for that dog Kenrick if he could win this splendid girl
for his wife.’
That dog Kenrick was still staying, off and on, at the Vicarage. His
leave did not expire till the end of April. He had about six weeks
before him.
He came in presently while Beatrix was sitting in the dimly lighted
room sipping her tea. Mr. Dulcimer had been called out into the hall
to see a parishioner. There was no one else in the room.
‘I am so glad to see you better,’ said Kenrick, heartily, planting
himself in a chair near Miss Harefield.
By that doubtful light he was wonderfully like Cyril. The shock of
his entrance—something in the likeness, as he sat beside her with
the fire-glow flickering upon his face, moved Beatrix painfully. She
could hardly answer him.
‘Thank you. I am much better,’ she murmured, faintly.
 ‘But far from well, I am afraid,’ he said. ‘You seem very weak.’
In the next instant her head fell back upon the cushion of the easy
chair. She had fainted. Kenrick rang the bell violently for Rebecca.
He was not a coxcomb, but he had a very good opinion of himself,
and this fainting fit of Beatrix’s affected himself curiously. He made
up his mind that it was he whom she loved, and not Cyril; and he
made up his mind that he would win her for his wife.
 CHAPTER XI.
‘why was my cressid then so hard to win?’
Slowly and gradually health and strength came back to Beatrix
Harefield. The family life at the Vicarage was a new thing to her. It
was a new thing to live in a house where everybody was cheerful,
and where people seemed fond of her. The library was her favourite
room, and Mr. Dulcimer her chosen companion. Whether he was
silently absorbed in his book, or laid it down, as he did very often, to
talk to her, Beatrix found his society all-sufficient. She read and
studied at a table he had allotted to her, apart from him, and yet near
him. Under his guidance she read the books that filled her mind with
the best material; she climbed from height to height upon the hills of
knowledge. New worlds opened to her that she had never dreamed
of, and she went in and found that there were pleasant regions in
those strange worlds. Science, which she had only known as a
name, opened its treasure-house for her. Art, which she had known
almost as vaguely, was revealed to her, with all its mysteries and
beauties, unknown to the ignorant. And Poetry, best and sweetest of
all, in her mind, opened the door to a fairy-land of inexhaustible
delight. She did not forget Cyril, but she learned to look with a calm
disdain upon her maligners in Little Yafford, and she was almost
happy.
Before the end of March Mrs. Dulcimer had broken altogether with
Miss Coyle, after rebuking that ancient sibyl, in no measured phrase,
for her want of charity.
‘I shall never drop in to tea here again,’ said Mrs. Dulcimer. ‘No,
Miss Coyle, not if we both were to live for a hundred years.’
‘I shall be very sorry for that,’ replied Miss Coyle, sitting very erect
behind her oval tea-tray, and with her gaze fixed upon her silver
teapot, marked with King George’s pigtail, and an heirloom; ‘but I
cannot alter my opinion, even,’ with a tremulous movement of her
cannon curls, ‘for the privilege of retaining Mrs. Dulcimer’s
friendship. I can only say, and I shall say so while the power of
speech is left me, that Miss Harefield is a young person I would
never consent to receive in my house—no, not if her thousands were
millions.’
‘Fortunately Miss Harefield does not want to come into your
house,’ retorted Mrs. Dulcimer, very red and angry, and with all her
frillings and puffings in agitation. ‘Thousands, indeed! Do you
suppose Beatrix Harefield’s fortune has any influence with Mr.
Dulcimer or me?’
‘I don’t presume to speculate upon Mr. Dulcimer’s motives or
yours, but I believe the coroner’s jury would have come to a very
different verdict if Miss Harefield had been poor and a stranger. Look
at the men who were on the jury. Why, there was Haslope the grocer,
who has served the Water House ever since he has been in trade;
and Ridswell the upholsterer, who had the order for the funeral.
Slavish creatures who have fattened upon the Harefield family! Of
course they would not condemn the daughter of their patron.’
‘What proof can you bring against her?’
‘Enough to hang her if she had been anybody else,’ said Miss
Coyle. ‘Why did she buy that laudanum?’
‘For her own use.’
‘Ah!’ said Miss Coyle.
There is a great deal of meaning in the monosyllable ‘Ah!’ if it be
uttered with a grave shake of the head, a tightening of thin lips, and
a prolongation of tone.
‘I don’t think there is any Christian feeling in Little Yafford,’
exclaimed Mrs. Dulcimer, drawing on a tight glove, and bursting it in
a ruinous manner.
‘Except at the Vicarage,’ sneered Miss Coyle.
‘The place is given over to a pack of prying old maids and spiteful
old bachelors.’
 ‘Thank you,’ said Miss Coyle, with withering sarcasm.
She rose to accompany Mrs. Dulcimer to the door. She was not
going to fail in politeness, even to a departing foe.
‘Good afternoon, and good-bye,’ said the Vicar’s wife, walking
along the little garden path with an air of shaking the dust of Miss
Coyle’s tenement from off her shoes.
From this time forward Mrs. Dulcimer took Beatrix under her wing.
She forgot that she too had shared the dark suspicions of Little
Yafford. It was in her mind as if those suspicions had never been.
She was a woman who lived from hand to mouth. Her ideas were the
ideas of to-day; yesterday’s convictions went for nothing. She told
Rebecca that she was disgusted with the people of Little Yafford for
their infamous conduct to Beatrix; and Rebecca, who, though of too
sterling metal to be a time-server, loved to please her mistress, went
over to Miss Harefield’s party, and defended her stoutly at all kitchen
tea parties.
And Sir Kenrick—Sir Kenrick, who had always despised her
slanderers, was now Beatrix Harefield’s most ardent champion. He
had begun by thinking that she would make an admirable mistress of
Culverhouse Castle; he ended by being very sure that she would
make an adorable wife. He left off fishing for sulky pike in the reedy
pools and inlets of the winding river, and spent his days hanging
about the Vicarage, idle and happy, and very much in the way of
other people’s industry. The lynx eyes of Mrs. Dulcimer, trained to
see very far into all budding loves, were quick to perceive the state
of affairs. She was delighted, and forgot that she had ever
abandoned her plans for the union of the impoverished Culverhouse
estate, and the fat fields and rich pastures of the Harefield property.
It seemed to her the realization of her own idea. She took Kenrick’s
young affection under her protection; she smiled fondly upon the
unconscious Beatrix. She was full of Machiavellian schemes for
leaving the two young people in each other’s society. The end of
Kenrick’s leave was drawing near. Things were getting desperate,
Mrs. Dulcimer thought. It must be now or never. She even went so
far as to tell Kenrick so.