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Fibrostenotic
Inammatory Bowel
Disease
Florian Rieder
Editor
123
Fibrostenotic Inammatory Bowel Disease
Florian Rieder
Editor
Fibrostenotic Inammatory
Bowel Disease
Editor
Florian Rieder
Department of Gastroenterology
Hepatology and Nutrition
Digestive Diseases and Surgery Institute
Cleveland Clinic Foundation
Cleveland, OH
USA
ISBN 978-3-319-90577-8 ISBN 978-3-319-90578-5 (eBook)
https://doi.org/10.1007/978-3-319-90578-5
Library of Congress Control Number: 2018950482
© Springer International Publishing AG, part of Springer Nature 2018
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
the material is concerned, specically the rights of translation, reprinting, reuse of illustrations, recitation,
broadcasting, reproduction on microlms 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 specic 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
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in published maps and institutional afliations.
This Springer imprint is published by Springer Nature, under the registered company Springer
International Publishing AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
Foreword
As clinicians, we encounter brosis frequently in practice, nowhere more challenging than in the management of inammatory bowel disease (IBD). Fibrosis, the nal
common pathway of many diseases, causes strictures and obstruction. These conditions cause our patients to have serious clinical problems, signicantly and chronically affecting their health and quality of life. Additionally, brosis in the form of
adhesions causes scarring that complicates the surgical and endoscopic procedures
that are needed to manage their disease.
For many decades, researchers have studied the initiating inammatory causes of
IBD.Surprisingly, the concept of investigating the brosis caused by this inammation has been a relatively recent development. Indeed, there is a paucity of available
data in this young, but critically important eld. This book presents an innovative
and comprehensive review of our current understanding of brosis. In addition, key
international experts discuss the future of the eld.
After an insightful introduction by Dr. Rieder, setting the stage for the remainder
of the work, the early chapters explore the epidemiology, genetics, and biology of
brosis. The next section reviews the clinical consequences of brosis, as well as
exploring developments in detection and imaging. The nal chapters provide an indepth review of current pharmacological and interventional management of IBDrelated brostenotic disease. Especially interesting to clinicians will be the chapters
about endoscopic and surgical management of the clinical consequences of brosis,
written by experienced international leaders in the eld.
This is a fascinating and timely book. It will be enjoyed by scientists and clinicians
who manage this challenging condition and lead to an improved understanding of
both the biology and management of brosis, helping our current and future patients.
ConorP.Delaney
Chairman, Digestive Disease and Surgery Institute, Cleveland Clinic
Cleveland, OH, USA
VictorW.Fazio Endowed Professor of Colorectal Surgery, Cleveland Clinic
Cleveland, OH, USA
v
Foreword
Inammation is a fundamental response essential to health and disease. Because of
this biological duality inammation exerts both benecial and harmful effects.
These effects are highly context-dependent and differ with the multiple components
of the inammatory process, including the host, age, cause, time, organ, and tissue.
Each of these components is intrinsically variable, adding to the complexity of the
inammation and its ultimate outcome. The perfect inammatory response is quick,
highly regulated, and totally effective, eliminating the offense agent and restoring
the affected site to a state of pre-inammation anatomical and functional normality.
This ideal series of events seldom occurs and the exact opposite is actually the most
common reality. In clinical practice the majority of inammatory diseases that currently affect humanity are chronic and relapsing, are accompanied by complex and
aberrant immune responses, and inict various degrees of lasting anatomical and
structural damage. One of the most serious consequences is the formation of scar
tissue—brosis—in the affected organ, which can then be translated into altered
function and clinical symptoms. Because the most common diseases of modern era
consist of chronic inammation, brosis is now considered as a major universal
problem with similarities as well as peculiarities that depend on which organ is
being compromised by it.
The simple fact that only recently brosis has been recognized as a major problem in itself implies that until now attention has been almost exclusively devoted to
its cause, i.e., the underlying inammatory process, rather than the ensuing brotic
response. Although this is justiable in rational but simplistic terms, the factual
realization that the available anti-inammatory therapies have limited or no appreciable antibrotic effects has alerted the research community to focus on organ
brosis and its mechanisms as the only way to discover brand new and truly effective antibrotic strategies. Progress in this line of discovery has taken multiple and
diverse paths depending on the frequency and clinical severity of the brotic
response in different organs. For instance, liver brosis has been receiving substantial attention for a much longer time than brosis in other organs, where it may
result in just as much morbidity and clinical suffering. The best example of the latter
vii
viii
Foreword
situation is inammatory bowel disease (IBD)-driven intestinal brosis, the subject
of this much needed and timely publication.
In the various sections of this book the individual pathogenic and clinical components of IBD-associated brosis are sequentially introduced and dissected allowing the reader to gain a comprehensive overview on the mechanisms, consequences,
and possible solutions to brostenotic IBD.
Introductory chapters discuss the poorly appreciated history of intestinal brosis
in IBD, the still widely accepted notion that gut brosis develops inexorably, and
the acceptance that there is nothing much to do about it. This reects a defeating
mentality that is about to change based on advances in the understanding of the biology of brosis and where, when, and how to intervene, as discussed in subsequent
chapters. The fact that intestinal brosis develops not only in Crohn’s disease, where
its most orid clinical manifestations are more easily detected, but in all forms of
chronic intestinal inammation, including ulcerative colitis and diverticulitis,
receives needed attention.
Where and when brostenosis emerges in the evolution of IBD, how it evolves,
and what genetic, epigenetic, and environmental factors may contribute to it also
receive proper consideration and discussion. Importantly, how brostenotic IBD
may eventually evolve independently of inammation in the late stages of disease is
also discussed, as this unique aspect of the biology of intestinal brosis has crucial
pathogenic and therapeutic implications.
Some of the scientic biological bases of intestinal brosis are included to
inform the reader about the numerous and intertwined cellular components of brogenesis. It is now clear that these are not restricted to the response of classical mesenchymal cells such as broblasts, myobroblasts, and muscle cells, but also the
response of the extracellular matrix and nonimmune cells, such as epithelial and
endothelial cells, that transform into collagen-producing cells in response to persistent inammatory pressure. Particularly innovative is the inclusion of fat cells as
possible contributors to brostenotic IBD, as it may be the case for the creeping fat
classically observed in long-standing Crohn’s disease. Part of the biological bases
of intestinal brosis also includes a discussion of animal models, still relatively
underutilized but holding a great potential for unraveling the intimate molecular
events responsible for brogenesis in specic situations.
A major unmet need in clinical practice is the early detection of brosis in IBD,
which would obviously be of paramount importance and extremely valuable to
allow early clinical interventions aimed at preventing or limiting scar tissue formation and narrowing of the intestinal lumen. To this end, clinical, cellular, and serologic biomarkers of intestinal brosis are elaborated upon, and their potential value
and limitations are objectively assessed. Complementing these clinically valuable
areas is a discussion on imaging of intestinal brosis, a particularly challenging area
under active investigation with the help of numerous novel imaging techniques. The
challenge here resides in the practically inseparable existence of the immune inammatory response and the temporally concomitant brogenic response, both of which
differ in relative proportions but not in qualitative (yes or no) terms.
Foreword
ix
The chapters on management of brostenotic IBD cover all necessary clinical,
endoscopic, and surgical aspects. They offer a valuable state-of-the-art update that
lets the reader have a comprehensive and objective understanding of what can be
practically done in daily clinical practice to alleviate the suffering resulting from the
various forms of intestinal architectural modications in different clinical settings.
The concluding chapters of this book examine the current medical approaches to
brostenotic IBD and look at what has been and is being done in brotic conditions
of other organs that could be applied to combat brogenesis in the intestine. What
can be expected from neutralizing factors known to be involved in brogenesis,
such as TGF-β1, IL-4 or IL-13, or blocking signaling pathways and integrin receptors, inhibiting certain enzymes or components of the extracellular matrix, is presented in a comprehensive fashion and realistic expectations proposed.
In summary, this is a timely and unique publication that truly represents a rst of
its kind in the area of intestinal brosis. It is hoped that the broad and well- integrated
components of this book will entice a new generation of basic, translational, and
clinical investigators to make intestinal brosis the focus of their study because only
cohesive information and novel approaches can offer real solutions to the challenges
posed by brostenotic IBD.
ClaudioFiocchi
Department of Pathobiology
Lerner Research Institute, Cleveland Clinic
Cleveland, OH, USA
Department of Gastroenterology and Hepatology
Digestive Disease and Surgery Institute, Cleveland Clinic
Cleveland, OH, USA
Contents
1 Fibrostenotic Inflammatory Bowel Disease: ACinderella Story . . . . 1
Florian Rieder
2 Epidemiology andNatural History ofFibrostenosing
Inflammatory Bowel Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Wee Khoon Ng and Siew C. Ng
3 Genetic Influences ontheDevelopment ofFibrosis
inInflammatory Bowel Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Bram Verstockt, Sare Verstockt, and Isabelle Cleynen
4 Epigenetic Regulation ofIntestinal Fibrosis . . . . . . . . . . . . . . . . . . . . . 39
Chao Li and John F. Kuemmerle
5 Cytokine andAnti-Cytokine Agents asFuture
Therapeutics forFibrostenosing IBD . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Noam Jacob, Stephan R. Targan, and David Q. Shih
6 Inflammation-Independent Mechanisms ofIntestinal
Fibrosis: TheRole oftheExtracellular Matrix . . . . . . . . . . . . . . . . . . 77
Debby Laukens
7 Fat andFibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
Ren Mao and J. CalvinCoffey
8 Environmental Factors andTheir Influence
onIntestinal Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
Claudio Bernardazzi, Fernando Castro, and Heitor S. de Souza
9 Animal Models andSources ofMesenchymal Cells
inIntestinal Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Dominik Bettenworth
10 Fibrosis inUlcerative Colitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Fernando Magro and Tatiana António
xi
xii
Contents
11 Histopathology ofIntestinal Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Ilyssa O. Gordon
12 Clinical, Cellular andSerologic Biomarkers
ofIntestinal Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
Antonio Di Sabatino and Paolo Giuffrida
13 Imaging inIntestinal Fibrosis. What Is State oftheArt? . . . . . . . . . . 183
Jordi Rimola
14 The Future ofIntestinal Fibrosis Imaging . . . . . . . . . . . . . . . . . . . . . . 193
Ryan W. Stidham and Mahmoud Al-Hawary
15 Medical Therapy inStricturing Inflammatory Bowel Diseases . . . . . 209
Damien Soudan and Yoram Bouhnik
16 Endoscopic Therapy ofIntestinal Strictures:
What Is State oftheArt? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
Talat Bessissow and Gert Van Assche
17 Resectional Surgery forIntestinal Strictures:
What Is State oftheArt? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
Karin A. T. G. M. Wasmann, Christianne J. Buskens,
Pieter J. Tanis, and Willem A. Bemelman
18 Management ofIleal Pouch Strictures
andAnal Stricturing Disease: AClinical Challenge . . . . . . . . . . . . . . 253
Jean H. Ashburn and Tracy L. Hull
19 Stricturing Crohn’s Disease: Strictureplasty . . . . . . . . . . . . . . . . . . . . 267
Gabriele Bislenghi and Andre D’Hoore
20 Challenges ofTranslation ofAnti-Fibrotic Therapies
into Clinical Practice inIBD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
Gerhard Rogler
21 What Distinguishes Mechanisms ofFistula
andStricture Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
Michael Scharl
22 The Pathogenesis ofIntraabdominal Adhesions:
Similarities andDifferences toLuminal Fibrosis . . . . . . . . . . . . . . . . . 319
Edward Macarak and Joel Rosenbloom
23 Anti-Fibrotic Therapies fromOther Organs:
What theGut Can Learn fromtheLiver, Skin, Lung andHeart . . . . 347
Calen A. Steiner and Peter D. R. Higgins
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387