Encyclopedia of Gastroenterology (4-Volume Set) [2 ed.] 0128124601, 9780128124604

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Volume 1
Volume 2
Volume 3
Volume 4

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ENCYCLOPEDIA OF GASTROENTEROLOGY SECOND EDITION VOLUME 1

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ENCYCLOPEDIA OF GASTROENTEROLOGY Second Edition EDITOR IN CHIEF

ERNST J. KUIPERS Erasmus University Medical Center, Rotterdam, The Netherlands VOLUME 1

Academic Press is an imprint of Elsevier 125 London Wall, London, EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright © 2020 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers may always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN 978-0-12-812460-4

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Publisher: Oliver Walter Acquisition Editor: Blerina Osmanaj Content Project Manager: Kate Miklaszewska Designer: Miles Hitchen

EDITOR IN CHIEF

Ernst Kuipers (MD, PhD) trained in Internal Medicine and Gastroenterology in The Netherlands. He worked as postdoctoral researcher at Vanderbilt University Medical Center, Nashville, TN, United States. He became Professor of Medicine and Chair of the Departments of Gastroenterology and Hepatology (2000), Internal Medicine (2006), and Surgery (2012) of Erasmus MC University Medical Center in Rotterdam, the Netherlands. His clinical and research interests include early neoplastic gastrointestinal conditions, with focus among others on colorectal cancer screening. He is fellow of the American Gastroenterology Association and a member of the Clinical Practice Committee of this Association. He serves as the World Endoscopy Organization’s Regional Lead on colorectal cancer screening for Europe and the Middle East. He co-organized and contributed to various international guidelines on gastrointestinal neoplasia. He has been a member of the editorial boards of various journals including Gastroenterology, Gut, American Journal of Gastroenterology, APT, Cancer Prevention Research, and the Cochrane group for upper GI and pancreatic disorders, as well as associate editor of Gut, and Editor in Chief of Best Practice and Research in Clinical Gastroenterology. He was a member of the WHO committee on H. pylori and gastric cancer, member of the European Committee on Quality Assurance in Colorectal Cancer Screening, president of the European Helicobacter Study Group, and member of the research audit committee of the Australian Commonwealth for Scientific and Industrial Research Organization CSIRO. He was a member of the Advisory Council of the European Society of Digestive Oncology, and member of the General Council of the European Gastroenterology Federation. He was President of the European Helicobacter & Microbiota Study Group. In the Netherlands, he was president of the Dutch Society of Gastroenterologists, chair, and is a member of the Dutch National Health Council. He serves since 2013 as CEO of Erasmus MC, a university medical institute that includes a medical school, research facilities and hospitals. In addition, he chaired the board of the Dutch Federation of University Medical Centers. He also chairs the Dutch national emergency medicine network, as well as the national oncology taskforce. He received the Dutch Ministry of Health Pearl award (2013), the Ismar Boas Medal of the German Society of Gastroenterology and Liver Disease (2015), the United European Gastroenterology Research Prize (2016), the Innovation Award of the German Felix Burda Society (2017), a Clinical Mentorship award by the American Gastroenterology Association (2017), and the Dutch Hospital Manager of the Year award (2017).

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EDITORIAL BOARD Marco J Bruno Department Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands

Simon Law Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong

Francis K. L. Chan Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong

Philip M. Sherman Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

Catherine Dubé Department of Medicine, Division of Gastroenterology, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada

Magnus Simrén University of Gothenburg, Gothenburg, Sweden; Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden; and University of North Carolina (UNC) School of Medicine, Chapel Hill, NC, United States

Emad El-Omar St George and Sutherland Clinical School, University of New South Wales, Sydney, NSW, Australia; Microbiome Research Centre, St George Hospital, Sydney, NSW, Australia Alexander Gerbes Department of Medicine II, University Hospital, LMU Munich, Munich, Germany

Christina Surawicz Division of Gastroenterology, Department of Medicine, University of Washington School of Medicine, Seattle, WA, United States

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SECTION EDITORS

Prof. Dr. Marco J. Bruno (1963) is a full professor of Gastroenterology and Hepatology and chief of the department of Gastroenterology and Hepatology at the Erasmus Medical Centre in Rotterdam, the Netherlands. His clinical and research activities span more than two decades and focus on gastrointestinal oncology, hepato-pancreato-biliary diseases, and interventional endoscopy, including endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS). He is (co)-author of over 350 peer reviewed articles in high ranking journals including the New England Journal of Medicine, The Lancet, Gastroenterology, Gut, Endoscopy, and Gastrointestinal Endoscopy. He is a recognized international authority on the diagnosis and treatment of biliary and pancreatic diseases and has served as invited faculty at many international conferences and live endoscopy workshops. He is also the initiator and leading author of international guidelines on chronic pancreatic, pancreatic cyst surveillance, and pancreatic cancer surveillance in high risk individuals based on a hereditary predisposition. He is council member and treasurer of the European Association of Gastroenterology, Endoscopy and Nutrition (EAGEN), council member of the Dutch Pancreatic Cancer Study Group, member of the Scientific Committee of United European Gastroenterology (UEG), past council member of UEG, and past chairman of the Education Committee of UEG and the Dutch Pancreatitis Study Group. Prof. Francis K. L. Chan obtained his MB ChB, MD and DSc from the Chinese University of Hong Kong (CUHK), Hong Kong. After completing postgraduate training as Croucher Foundation research fellow in Canada, he joined CUHK in 1997 and rose through the ranks to become Professor of Medicine in 2005 and Director of Institute of Digestive Disease and Associate Dean (Clinical) in 2010. From 2013, he has been appointed Dean of Faculty of Medicine and Choh-ming Li Professor of Medicine and Therapeutics of CUHK. He is a member of the Board of the Hong Kong Hospital Authority. His research interests include peptic ulcer bleeding, helicobacter pylori, endoscopic therapy, and colorectal cancer. His research on the prevention of nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin-related gastrointestinal bleeding has led to major revisions to clinical practice guidelines in the United States, Europe, and the Asia Pacific region. He has published over 500 full scientific articles in high impact international journals and his h-index is 94. His contributions to medical research have been recognized worldwide with many national and international honors and awards, such as The David Y. Graham Lecturer, The Andy Martynoga Memorial Lecturer, and 2018 International International Leadership Award of American College of Gastroenterology. Since 2016, he has been a Councillor of Esophageal, Gastric and Duodenal Disorders section of the American Gastroenterological Association and has been appointed by Asian Pacific Association of Gastroenterology and the Asian Pacific Society of Digestive Endoscopy to be the leader of a Task Force for Developing Clinical Practice Guidelines for Clinicians in Asia Pacific Countries. In 2019 ExpertScape named him a world expert in aspirin. ix

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Section Editors

He was the Associate Editor of The American Journal of Gastroenterology, Clinical Gastroenterology and Hepatology, and was on editorial board of Digestive Endoscopy, Digestive and Liver Diseases, Journal of Digestive Diseases, and Gastroenterology Clinics of North America. He was the editor of a 2012 textbook titled Gastroenterology and Hepatology and the section editor of the Encyclopedia of Gastroenterology from 2016 to 2018. Catherine Dubé obtained her Medical Degree from the University of Montréal, Canada, in 1989, where she also completed a Master’s degree in Pharmacology in 1990. She completed her training in Internal Medicine and in Gastroenterology at the University of Ottawa, Canada, in 1993 and 1995, respectively, and is a Fellow of the Royal College of Physicians and Surgeons of Canada in Internal Medicine and in Gastroenterology. She completed a Master’s degree in Clinical Epidemiology at the University of Ottawa in 1999. She held the positions of Assistant Professor of Medicine at the University of Ottawa (1999-2006); Associate Clinical Professor of Medicine at the University of Calgary (2006-2013) and is currently Associate Professor of Medicine at the University of Ottawa. Dr Dubé was on the Editorial Boards of the Canadian Journal of Gastroenterology (2010-2013) and Best Practice & Research Clinical Gastroenterology (2015-2018). She has co-authored and published several large systematic reviews for the US Preventative Task Force on celiac disease and on the roles of ASA and NSAIDs in colorectal cancer prevention, as well as numerous original papers on colonoscopy quality, post-polypectomy surveillance, and colorectal cancer screening. She was Medical Lead for the Alberta Colorectal Cancer Screening program, AB, Canada, from 2011 until 2013 and has since been the Clinical Lead for Cancer Care Ontario’s ColonCancerCheck, Ontario’s colorectal cancer screening program. She has chaired and delivered several workshops on quality and patient-centered care in endoscopy and on the use of the Endoscopy Global Rating Scale (GRS), and has led the development of several clinical practice guidelines for gastrointestinal endoscopy. Emad El-Omar graduated in Medicine from Glasgow University, Scotland, and trained as a gastroenterologist. He worked as a Visiting Scholar/Scientist at Vanderbilt University, TN, and National Cancer Institute, MD, United States, and was Professor of Gastroenterology at Aberdeen University, Scotland, for 16 years before taking up the Chair of Medicine at St George and Sutherland Clinical School, University of New South Wales, Sydney, Australia. He is a Fellow of the Royal Society of Edinburgh, Scotland. Prof. El-Omar is the Editor in Chief of the journal Gut. His research interests include the gut microbiome, inflammation driven gastrointestinal cancer, and inflammatory bowel disease. He is the Director of the Microbiome Research Centre at St George Hospital, Sydney, Australia.

Alexander Gerbes completed his medical studies at the universities of Munich, Germany, Sheffield, United Kingdom, and San Francisco, United States. Following a research fellow stay at University of Montreal, Canada (1991-1992), Prof. Gerbes was granted lifetime full professorship (C3) in 1995. Currently he is Vice Director of the Department of Gastroenterology and Hepatology and Head of the Liver Center Munich at the LMU Hospital. His research has focused on pathophysiology, diagnosis, and treatment of liver diseases, with emphasis on complications of cirrhosis. In recent years he has had an increasing interest in acute-on-chronic liver failure and in druginduced liver injury. In 2014 Prof. Gerbes was winner of the m4 Award for Research Innovation in Personalized Medicine. Since 2019 he is the LMU PI in the EU Horizon 2020 IMI Consortium TransBioLine. Alexander Gerbes has authored about 250 articles in acknowledged journals including Nature

Section Editors

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Medicine, New England Journal of Medicine, The Lancet, Gastroenterology, Gut, Hepatology, and Journal of Hepatology, with a lifetime citation of 55 (Hirsch Index). Alexander Gerbes has been honored with the GASL award of the German Association for the Study of the Liver and the Rudolf-Pichlmayr award of the German Transplant Society, and with Honorary Clinical Professorship of the Chinese University of Hong Kong. He is a Fellow of the European Board of Gastroenterology, Fellow of the AGA, and Inaugural Fellow of AASLD. Since 2010 he has served as deputy editor of the journal Gut. In 2017-2018 Prof. Gerbes served as President of the Bavarian Gastroenterology Association. Since 2017 he represents the LMU Faculty of Medicine in the Global Alliance of Medical Excellence. Simon Law graduated from the University of Cambridge, United Kingdom, with First Class Honors. He received his post-graduate training at the Department of Surgery at The University of Hong Kong. He is currently Cheung Kung-Hai Professor in Gastrointestinal Surgery, and Chair Professor and Chief of Esophageal and Upper Gastrointestinal Surgery at The University of Hong Kong. Professor Law is a council member of the College of Surgeons of Hong Kong. He served as the Chairman of the General Surgery Board and the Chief Examiner of the Joint Fellowship Examination of the Royal College of Surgeons of Edinburgh and The College of Surgeons of Hong Kong. He is past president of the Hong Kong Society of Upper Gastrointestinal Surgeons and was a member of the Education and Accreditation Committee of the Medical Council of Hong Kong. He has been playing an active role in many international societies, such as Asia Representative of the Member Services Committee of the Society for Surgeons of the Alimentary Tract (SSAT) and National Delegate for the International Society of Digestive Surgery (ISDS). He is the current Secretary of the Hong Kong China Chapter of the American College of Surgeons. Notably for international collaborations, he is a member of the Worldwide Esophageal Cancer Collaboration, and the Esophagectomy Complications Consensus Group. He is a member of the Research and Database Committee, as well as the Education Committee of the International Society of Diseases of the Esophagus. He is Honorary Fellow of the American Surgical Association as well as the European Surgical Association. He has concentrated his experience and research in both benign and malignant upper gastrointestinal tract disorders. He has published over 260 articles, including those in Annals of Surgery, Gut, and Nature Genetics. He has 37 book chapters under his authorship, many of which are in “classics” in surgery, such as Mastery of Surgery, Maingot’s abdominal operations, Pearson’s thoracic and esophageal surgery, and Shakelford’s surgery of the alimentary tract. He is/has been Associate Editor of Diseases of the Esophagus, and member of the editorial board in 15 other journals, including Annals of Surgery, JAMA Surgery, Surgery, World Journal of Surgery, and Annals of Surgical Oncology. He has been invited to speak nationally and internationally on over 320 occasions. Philip M. Sherman is Professor of Pediatrics, Microbiology, Nutritional Sciences, and Dentistry at the Hospital for Sick Children, University of Toronto, Canada, where he has been on faculty since 1984. Dr. Sherman obtained his medical degree at the University of Calgary, Canada, and completed training in Pediatrics at the University of California, San Francisco, United States. His research training in Gastroenterology was completed in the Research Institute at the Hospital for Sick Children in Toronto and at the Walter Reed Army Institute of Research in Washington, DC. Dr. Sherman is Past-President of the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition and Past-President of the Canadian Association of Gastroenterology. Dr. Sherman was Scientific Director of the Canadian Institutes of Health Research Institute of Nutrition, Metabolism and Diabetes (2009-2017). He is the recipient of a tier 1 Canada Research Chair in Gastrointestinal Disease (2001-2022). His research interests focus on the role of prebiotics and probiotics in altering epithelial cell signaling responses in settings of intestinal injury and inflammation. The research is supported by the Canadian Institutes of Health Research and, previously, by Crohn’s and Colitis Canada. Dr. Sherman has authored more than 300 peer reviewed articles and edited 6 other textbooks.

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Section Editors

Magnus Simrén graduated from medical school, University of Gothenburg, Sweden, in 1991, and afterwards completed his internship and fellowship in internal medicine at the County Hospital of Lidköping, Sweden. From 1998 to 1999, Dr. Simrén completed his fellowship in gastroenterology at Sahlgrenska University Hospital, Sweden, and has been working as a specialist physician in gastroenterology at Sahlgrenska University Hospital since 1999. He defended his thesis entitled Irritable Bowel Syndrome. Pathophysiological and clinical aspects in 2001. He was a post-doctoral research fellow at the University of Leuven, Belgium, in 2002. Between 2011 and 2016, Dr Simrén held a Senior Research position at the Swedish Research Council and the University of Gothenburg in Molecular Gastroenterology. He was visiting research scientist at the Center for Functional GI and Motility Disorders, University of North Carolina (UNC), Chapel Hill, NC, United States (2015-2016), and currently holds a position as Adjunct Professor of Medicine at UNC School of Medicine (2017-). Since 2013 he has a combined position as Professor of Gastroenterology at the University of Gothenburg, and Senior Consultant at the Sahlgrenska University Hospital in Gothenburg, Sweden. Dr. Simrén is head of the Neurogastroenterology Unit at Sahlgrenska University Hospital. His main research areas are the pathogenesis and pathophysiology of functional GI disorders, as well as the treatment of these. He has published more than 270 original articles and written several book chapters on GI motility diseases and functional GI disorders, and is currently supervisor for 18 PhD students and 3 post-docs. Doctor Simrén has been the President of the Scandinavian Association for Gastrointestinal Motility (SAGIM) and Scientific Secretary to the Swedish Society of Gastroenterology, and served as council member for several international organizations. He has been the chair of the United European Gastroenterology (UEG) Scientific Committee (2013-2017) and is currently the UEG Secretary General (2018-2021), and a member of the UEG council (2013-2021). Dr. Simrén has also been working as Deputy Editor and Associate Editor of Gut, and as the Clinical Editor of Neurogastroenterology and Motility. He is also on the Rome Foundation Board of Directors since 2011. In 2010-2012 he led the Rome Foundation Working Team, “Intestinal Microbiota in Functional Bowel Disorders”, and was on the Rome IV committees for Functional Bowel Disorders and Centrally Mediated Disorders of GI Pain. Dr Simrén is the Research Director of the Rome Foundation Research Institute (RFRI) (2017). Christina M. Surawicz is Professor Emerita of Medicine in the Department of Medicine, University of Washington School of Medicine in Seattle, United States. She graduated with honors from the University of Kentucky College of Medicine in 1973. She completed Internal Medicine residency and a Gastroenterology fellowship at the University of Washington School of Medicine, following which she joined the faculty as the first woman faculty member in the Gastroenterology Division in 1981, based at Harborview Medical Center, one of the University’s teaching hospitals, where she was section chief for 20 years until July 2013 and an attending gastroenterologist for 35.5 years. She was the inaugural assistant (then associate) dean for faculty development, a position created in 2002 and which she held until 2018 when she retired. Dr Surawicz’s research has included the role of colorectal biopsy in differential diagnosis of colitis, clinical research on Clostridium difficile infection (CDI), and the role of probiotics and fecal microbiota transplant in treatment of recurrent CDI infection. She has 118 peer reviewed publications, 82 book chapters and 3 books. Among other leadership positions, she was President of the Western Association of Physicians and served as President (first woman) of the American College of Gastroenterology (1998-1999). She was a Senior Associate Editor of the American Journal of Gastroenterology from 2015 to 2018.

LIST OF CONTRIBUTORS Haider Abdalah China Medical University Hospital, Taichung City, Taiwan

Somaya Albhaisi VCU School of Medicine, Richmond, VA, United States

Mona Abdel-Hady Birmingham Women's and Children's Hospital, Birmingham, United Kingdom

Charles D Anderson Jr. Virginia Commonwealth University, Richmond, VA, United States

Thomas Abrahamsson Linköping University; Crown Princess Victoria Children's Hospital, Linköping, Sweden

Gregory J Anderson QIMR Berghofer Medical Research Institute; University of Queensland, Brisbane, QLD, Australia

Phillipe Abreu University of Toronto, Toronto, ON, Canada

Xavier Ariza University of Barcelona, Barcelona, Spain

Julie Absil Université Libre de Bruxelles, Bruxelles, Belgium

David Armstrong Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada

Rodney D Adam Aga Khan University, Nairobi, Kenya; University of Arizona, Tucson, AZ, United States RJM Ader Medisch Spectrum Twente, Enschede, The Netherlands K Adeli University of Toronto; The Hospital for Sick Children, Toronto, ON, Canada Ali Aghdassi University Medicine Greifswald, Greifswald, Germany Abrar Ahmed Presbyterian Hospital of Dallas, Dallas, TX, United States Aysegül Aksan Interdisciplinary Crohn Colitis Center Rhein-Main; Goethe University, Frankfurt am Main, Germany Ahmad Al-Taee Saint Louis University School of Medicine, St. Louis, MO, United States Hussam Alamri McGill University, Montreal General Hospital, Montreal, QC, Canada

Viridiana Arreola CIBERehd CSdM-Autonomous University of Barcelona, Hospital de Mataró, Barcelona, Spain Vicente Arroyo European Foundation for Study of Chronic Liver Failure, Barcelona, Spain Kara Asbury Mayo Clinic, Phoenix, AZ, United States Timothy Asmis University of Ottawa, Ottawa, ON, Canada Volker Aßfalg Technical University Munich, Munich, Germany Rebecca Auer University of Ottawa, The Ottawa Hospital, Ottawa, ON, Canada Y Avitzur University of Toronto, Toronto, ON, Canada Zoya Awan Heart of England Foundation Trust, Birmingham, United Kingdom

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List of Contributors

Sabrina Ayoub-Charette University of Toronto, St. Michael’s Hospital, Toronto, ON, Canada Imran Aziz University of Sheffield, Sheffield, United Kingdom; University of Gothenburg, Gothenburg, Sweden Qasim Aziz The Wingate Institute of Neurogastroenterology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom Fernando Azpiroz University Hospital Vall d'Hebron, Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid; Universitat Autònoma de Barcelona, Bellaterra, Spain Jane PF Bai U.S. Food and Drug Administration, Silver Spring, MD, United States Jasmohan S Bajaj Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, United States Ludovica Baldari Department of Surgery, Fondazione IRCCS Ca' Granda; Ospedale Maggiore Policlinico, University of Milan, Milan, Italy Manuel Barberio IHU-Strasbourg Institute of Image-Guided Surgery; Institute for Research against Cancer of the Digestive System (IRCAD), Strasbourg, France

Peter Bauerfeind City of Zurich – Triemli Hospital, Zurich, Switzerland Jean-François Beaulieu University of Sherbrooke, Sherbrooke, QC, Canada Mirza Arshad Beg China Medical University Hospital, Taichung City, Taiwan Patrick Behrendt Hannover Medical School, Hannover, Germany Kevin Behrns Saint Louis University, St. Louis, MO, United States Davide Bellini Department of Radiological Sciences, Oncology and Pathology, “Sapienza” - University of Rome Diagnostic Imaging Unit - I.C.O.T. Hospital, Latina, Italy Marc A Benninga Emma Children's Hospital/Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Karen Bensted University of New South Wales, Sydney; St George Hospital, Kogarah, NSW, Australia Patrick Berg University of Nevada—Las Vegas, Las Vegas, NV, United States Michael Berger Dr. von Hauner Children's Hospital, Ludwig-MaximiliansUniversity, Munich, Germany M Cecilia Berin Icahn School of Medicine at Mount Sinai, New York, NY, United States

Marc Bardou CIC INSERM 1432 and Gastroenterology Department, CHU Dijon-Bourgogne, Dijon, France

Barbara Bielawska University of Ottawa and The Ottawa Hospital, Ottawa, ON, Canada

Ryan D Baron The Royal Liverpool University Hospital, Liverpool, United Kingdom

Samuel Bitton Donald and Barbara Zucker School of Medicine at Hofstra/ Northwell, New Hyde Park, NY, United States

Diane Barsky Children's Hospital of Philadelphia, Philadelphia, PA, United States

Cyrille Blondet University Hospitals of Strasbourg; University of Strasbourg, Strasbourg, France

Luther A Bartelt University of North Carolina School of Medicine, Chapel Hill, NC, United States

Niviann M Blondet University of Washington School of Medicine and Seattle Children's Hospital, Seattle, WA, United States

Omer Basar Massachusetts General Hospital, Boston, MA, United States

Joseph R Bloomer University of Alabama at Birmingham, Birmingham, AL, United States

Ramon Bataller University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

Michael Boeckh Fred Hutchinson Cancer Research Center; University of Washington, Seattle, WA, United States

List of Contributors

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Guy E Boeckxstaens KU Leuven, Leuven, Belgium

Markus W Büchler University of Heidelberg, Heidelberg, Germany

Mireia Bolívar-Prados CIBERehd CSdM-Autonomous University of Barcelona, Hospital de Mataró, Barcelona, Spain

Daniel C Buckles University of Kansas Medical Center, Kansas City, KS, United States

Luigi Bonavina University of Milan, Milan, Italy

J Steven Burdick University of Texas Southwestern Medical Center, Dallas, TX, United States

Luigi Boni Department of Surgery, Fondazione IRCCS Ca' Granda; Ospedale Maggiore Policlinico, University of Milan, Milan, Italy Mariël Maria Helena Borgerink University Medical Center Groningen, Groningen, The Netherlands Jan Bornschein Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford University Hospitals, Oxford, United Kingdom Julia M Boster University of Colorado School of Medicine, Aurora, CO, United States Gaëlle Boudry McMaster University, Hamilton, ON, Canada Michael J Bourke Westmead Hospital; University of Sydney, Sydney, NSW, Australia Cecilia Bove Penn State University-College of Medicine, Hershey, PA, United States Lawrence J Brandt Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, United States Joan Brennan Mount Sinai Hospital, Toronto, ON, Canada Stuart M Brierley Flinders University, Bedford Park; South Australian Health and Medical Research Institute (SAHMRI); University of Adelaide, Adelaide, SA, Australia William R Brugge Mt. Auburn Hospital, Cambridge, MA, United States Jordi Bruix Hospital Clinic of Barcelona, University of Barcelona, Barcelona; Biomedical Network for the Research of Liver and Digestive Diseases (CIBERehd), Madrid, Spain Marco J Bruno Department Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands

Caitlin J Burke The University of Chicago, Chicago, IL, United States Nicole E Burma University of Calgary, Calgary, AB, Canada Marco Bustamante-Bernal Texas Tech University Health Sciences Center, El Paso, TX, United States Mohsin F Butt The Wingate Institute of Neurogastroenterology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom Giacomo Caio University of Ferrara, Ferrara, Italy Michael Camilleri Mayo Clinic, Rochester, MN, United States Stephanie D Canning The Ottawa Hospital and University of Ottawa, Ottawa, ON, Canada Sandra-Maria Capraru Bürgerspital Solothurn, Solothurn, Switzerland Francesca Carestiato University of Verona, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy Dustin A Carlson Northwestern University’s Feinberg School of Medicine, Chicago, IL, United States Fátima Carneiro Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) and Medical Faculty of the University of Porto/Centro Hospitalar São João, Porto, Portugal Adria Carpio Hospital Clinic, Barcelona, Spain Silvia Carrión-Bolorino CIBERehd CSdM-Autonomous University of Barcelona, Hospital de Mataró, Barcelona, Spain Jennifer A Cartwright University of Edinburgh, Edinburgh, United Kingdom

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List of Contributors

Damiano Caruso Department of Radiological Sciences, Oncology and Pathology, “Sapienza” - University of Rome Diagnostic Imaging Unit - I.C.O.T. Hospital, Latina, Italy Elisa Cassinotti Department of Surgery, Fondazione IRCCS Ca' Granda; Ospedale Maggiore Policlinico, University of Milan, Milan, Italy Laurent Castera Department of Hepatology, Beaujon Hospital; INSERM UMR 1149-CRI, Denis Diderot Paris University, Paris, France Carlo Catassi Marche Polytechnic University, Ancona, Italy

Giuseppe Chiarioni University of Verona, Integrated University Hospital of Verona, Verona, Italy; UNC Center for Functional GI and Motility Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States Prianka Chilukuri Saint Louis University School of Medicine, St. Louis, MO, United States Peter V Chin-Hong University of California San Francisco, San Francisco, CA, United States Judy Di Chiou St George Public Hospital, Sydney, NSW, Australia

Arthur I Cederbaum Icahn School of Medicine at Mount Sinai, New York, NY, United States

Wan Hang Keith Chiu Department of Diagnostic Radiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong

Albert Chan The University of Hong Kong, Pok Fu Lam, Hong Kong

Lennart Choo St George Hospital, Kogarah, NSW, Australia

Anthony WH Chan Department of Anatomical and Cellular Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China

Quyen M Chu Louisiana State University Health Sciences Center and Overton Brooks Veterans Affairs Medical Center, Shreveport, LA, United States

JH Chan Prince of Wales Hospital, Shatin, Hong Kong, China

Phillip Y Chung University of Chicago, Chicago, IL, United States

Jimmy Yu Wai Chan Division of Head and Neck Surgery, Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Pok Fu Lam, Hong Kong

Vincent CH Chung The Chinese University of Hong Kong, Hong Kong

Man-Pan Chan China Medical University Hospital, Taichung City, Taiwan Melissa M Chan University of Ottawa, Ottawa, ON, Canada Nicolas Chapelle Institute for Diseases of the Digestive System, University Hospital of Nantes, Nantes, France Christophe Chardot Necker - Enfants Malades Hospital, Paris Descartes University, Paris, France Jacob Charette University of Calgary, Calgary, AB, Canada Victor Chedid Mayo Clinic, Rochester, MN, United States Yao-Wen Cheng Indiana University School of Medicine, Indianapolis, IN, United States

Nicola Cillara Santissima Trinità Hospital, Cagliari, Italy Roberto Civitelli Division of Bone and Mineral Diseases, Washington University in St. Louis, St. Louis, MO, United States Joan Clària European Foundation for Study of Chronic Liver Failure; Biochemistry and Molecular Genetics Service, Hospital Clí nic-IDIBAPS, Barcelona, Spain Kindra D Clark-Snustad University of Washington Medical Center, Seattle, WA, United States Pere Clavé CIBERehd CSdM-Autonomous University of Barcelona; Center for Biomedical Research in the Liver and Digestive Diseases Network (CIBERehd), Carlos III Health Institute, Barcelona, Spain Daniel R Clayburgh University of Chicago, Chicago, IL, United States

List of Contributors

Fiona Clegg University of Aberdeen, Aberdeen, United Kingdom

David J Culp University of Rochester, New York, NY, United States

Jordan M Cloyd The Ohio State University Wexner Medical Center, Columbus, OH, United States

Álvaro Díaz-González Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain

Kenneth Coenegrachts AZ Sint-Jan Brugge—Oostende AV, Brugge, Belgium

Boushra Dalile KU Leuven, Leuven, Belgium

Michael J Coffey University of New South Wales, Sydney, NSW, Australia

Bernard Dallemagne IHU-Strasbourg Institute of Image-Guided Surgery; Institute for Research against Cancer of the Digestive System (IRCAD), Strasbourg, France

Robert J Coffey Vanderbilt University, Nashville, TN, United States Stanley Martin Cohen University of Chicago, Chicago, IL, United States

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ThucNhi T Dang University of Alberta, Edmonton, AB, Canada

James F Collins University of Florida, Gainesville, FL, United States

Rene Davila University of Tennessee Health Science Center, Memphis, TN, United States

Massimo Colombo Center for Translational Research in Hepatology, Humanitas Clinical and Research Center IRCCS, Milan, Italy

Bassel Dawod Dalhousie University, Halifax, NS, Canada

Elena M Comelli University of Toronto; St. Michael’s Hospital, Toronto, ON, Canada

Andrew S Day University of Otago (Christchurch), Christchurch, New Zealand

John Gerard Coneys University of Toronto, Toronto, ON, Canada

Uma Debi Postgraduate Institute of Medical Education and Research, Chandigarh, India

Bradley A Connor Weill Cornell Medicine; The New York Center for Travel and Tropical Medicine, New York, NY, United States

Sara de Campos Hospital Garcia de Orta, Almada, Portugal; Erasmus University Medical Center, Rotterdam, The Netherlands

Emmanuel Coppens Université Libre de Bruxelles, Bruxelles, Belgium

Roberto De Giorgio University of Ferrara, Ferrara, Italy

Gino Roberto Corazza San Matteo Hospital Foundation, University of Pavia, Pavia, Italy

Wouter W de Herder Erasmus University Medical Center, Rotterdam, The Netherlands

Maura Corsetti NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and the University of Nottingham; Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, United Kingdom

Steven Jakob de Jongh University Medical Center Groningen, Groningen, The Netherlands Barbara AE de Koning Sophia Children's Hospital, Erasmus Medical Center, Rotterdam, The Netherlands

Alicia Costa CIBERehd CSdM-Autonomous University of Barcelona, Hospital de Mataró, Barcelona, Spain

Edgard Delvin Research Centre, CHU Ste-Justine and University of Montreal, QC, Canada

Philip I Craig St George Hospital; University of New South Wales, Sydney, NSW, Australia

Nicholas D Demers University of Toronto; Hospital for Sick Children, Toronto, ON, Canada

Eileen Crowley Hospital for Sick Children, Toronto, ON, Canada

Louis de Mestier Beaujon University Hospital (APHP), Clichy; Paris-Diderot University, Paris, France

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List of Contributors

Gerald Denk Department of Medicine II, University Hospital, LMU Munich, Munich, Germany

J Enrique Domínguez-Muñoz University Hospital of Santiago de Compostela, Santiago de Compostela, Spain

Margo A Denke University of Texas Southwestern Medical Center, Dallas, TX, United States

Michael K Dougherty University of North Carolina School of Medicine, Chapel Hill, NC, United States

Emmanuelle de Raucourt Beaujon Hospital, Clichy, France

Vicky Drapeau Laval University; Research Center of the Quebec Institute of Cardiology and Pulmonology, Québec, QC, Canada

Terry GJ Derks University Medical Center of Groningen, Groningen, The Netherlands Lacey DeVreese University of Ottawa, Ottawa, ON, Canada AC de Vries Department Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, The Netherlands Marco Di Corpo University of North Carolina at Chapel Hill, Chapel Hill, NC, United States Matteo Di Giuseppe Department of Surgery, Ospedale Regionale di Bellinzona e Valli, Bellinzona, Switzerland Antonio Di Sabatino San Matteo Hospital Foundation, University of Pavia, Pavia, Italy Salomone Di Saverio Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom WA Dik Erasmus University Medical Center, Rotterdam, The Netherlands Brittany Dingley University of Ottawa, The Ottawa Hospital, Ottawa, ON, Canada Mario Dinis-Ribeiro Gastroenterology Department, Portuguese Oncology Institute of Porto; Center for Research in Health Technologies and Information Systems (CINTESIS), Faculty of Medicine, University of Porto, Porto, Portugal Wouter Dinkelaar Erasmus University Medical Center, Rotterdam, The Netherlands Phil G Dinning Flinders Medical Centre; Flinders University, Bedford Park, SA, Australia

Catherine Dubé Department of Medicine, Division of Gastroenterology, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada Steven L Due Flinders University, Bedford Park, SA, Australia Donald Duerksen University of Manitoba, Winnipeg, MB, Canada Christopher P Duggan Boston Children's Hospital, Boston, MA, United States Elizabeth R Duke Fred Hutchinson Cancer Research Center; University of Washington, Seattle, WA, United States Simon Eaton UCL Great Ormond Street Institute of Child Health, London, United Kingdom Tracy R Ediger The Ohio State University College of Medicine, Columbus, OH, United States Yousef El-Gohary St. Jude Children's Research Hospital, Memphis, TN, United States Emad El-Omar St George and Sutherland Clinical School, University of New South Wales; Microbiome Research Centre, St George Hospital, Sydney, NSW, Australia Christian Ell Horst-Schmidt-Kliniken,Wiesbaden, Germany Abdelbaset A Elzagallaai Schulich School of Medicine and Dentistry, Western University, London, ON, Canada Robert Enns The University of British Columbia, Vancouver, BC, Canada Emeka K Enwere University of Calgary, Calgary, AB, Canada

List of Contributors

Eren Esen NYU Langone Health, New York, NY, United States

Jakub Fichna Medical University of Lodz, Lodz, Poland

Gianluca Esposito Department of Medical-Surgical Sciences and Translational Medicine, Sant’Andrea Hospital, Sapienza University of Rome, Rome, Italy

Rafik Filobbos Department of Radiology, Manchester Royal Infirmary, Manchester, United Kingdom

B Mark Evers University of Kentucky, Lexington, KY, United States Jehovan Fairclough University of Ottawa, Ottawa, ON, Canada Sepideh Fallah University of Sherbrooke, Sherbrooke, QC, Canada Karima Farrag Interdisciplinary Crohn Colitis Center Rhein-Main; Gastroenterology and Clinical Nutrition, DGD Clinics Sachsenhausen, Frankfurt am Main, Germany James J Farrell Yale University School of Medicine; Yale School of Medicine, New Haven, CT, United States Ronnie Fass Case Western Reserve University, Cleveland, OH, United States Matteo Fassan Surgical Pathology and Cytopathology Unit, University of Padua, Padua, Italy Evgeny Fedorov N.I.Pirogov Russian National Research Medical University, University Hospital N31, Moscow, Russia Peter Ferenci Medical University of Vienna, Vienna, Austria Mark K Ferguson The University of Chicago, Chicago, IL, United States Guylaine Ferland University of Montréal, Montréal, QC, Canada Javier Fernández EASL-CLIF Consortium and Grifols Chair; Hospital Clí nic, IDIBAPS and CIBERehd, Barcelona, Spain Lorenzo Ferri McGill University, Montreal General Hospital, Montreal, QC, Canada Paul Feuerstadt Yale University School of Medicine, Hamden, CT, United States

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Monika Fischer Indiana University School of Medicine, Indianapolis, IN, United States Alexander Charles Ford University of Leeds, St James's University Hospital, Leeds, United Kingdom Alejandro Forner Hospital Clinic of Barcelona, University of Barcelona, Barcelona; Biomedical Network for the Research of Liver and Digestive Diseases (CIBERehd), Madrid, Spain Reidar Fossmark Norwegian University of Science and Technology; St.Olav's Hospital, Trondheim, Norway Adam J Frankel University of Queensland, Woolloongabba, QLD, Australia David M Frazer QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia Leonardo Frazzoni University of Bologna, Bologna, Italy John Freiman St George Hospital, Kogarah, NSW, Australia Carl H Freyer St George Hospital, Sydney, NSW, Australia Peter J Friend University of Oxford, Oxford, United Kingdom Helmut Friess Technical University Munich, Munich, Germany Candice Fung University of Leuven, Leuven, Belgium Adam P Geballe Fred Hutchinson Cancer Research Center; University of Washington, Seattle, WA, United States Andreas Geier University Hospital Würzburg, Würzburg, Germany Juan Reyes Genere Mayo Clinic, Rochester, MN, United States Joe Geraghty Department of Gastroenterology, Manchester Royal Infirmary, Manchester, United Kingdom

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List of Contributors

Christopher J Gill Boston University School of Public Health, Boston, MA, United States Pere Ginès University of Barcelona, Barcelona, Spain Vi Goh Children's Hospital of Philadelphia, Philadelphia, PA, United States Lan Gong Microbiome Research Centre, University of New South Wales, Sydney, NSW, Australia Gregory J Gores Mayo Clinic, Rochester, MN, United States Andre Gorgen University of Toronto, Toronto, ON, Canada Joanna Gotfrit University of Ottawa, Ottawa, ON, Canada Leah Gramlich Division of Gastroenterology, Royal Alexandra Hospital, University of Alberta, Edmonton, AB, Canada Anna Granato Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy Matthew T Grant Washington University School of Medicine, St. Louis, MO, United States Thomas Greuter University Hospital Zurich, Zurich, Switzerland; Mayo Clinic, Rochester, MN, United States John R Grider Virginia Commonwealth University, Richmond, VA, United States Christopher Griffiths McMaster University, Hamilton, ON, Canada Michael Grimm St George and Sutherland Clinical School; St George Hospital, Kogarah, NSW, Australia Silviu Grisaru University of Calgary, Calgary, AB, Canada David Grundy University of Sheffield, Sheffield, United Kingdom Luke Grundy Flinders University, Bedford Park; South Australian Health and Medical Research Institute (SAHMRI); University of Adelaide, Adelaide, SA, Australia

Francisco Guarner University Hospital Vall d'Hebron, Barcelona, Spain Maha Guindi Cedars-Sinai Medical Center, Los Angeles, CA, United States David Gunn NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and the University of Nottingham; Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, United Kingdom Abra Guo University of Virginia School of Medicine, Charlottesville, VA, United States Ellen Guo University of Illinois at Chicago College of Pharmacy, Chicago, IL, United States Sanjeev Gupta Departments of Medicine, Pathology and Molecular Genetics, Marion Bessin Liver Research Center, Diabetes Center, Irwin S. and Sylvia Chanin Institute for Cancer Research, Global Health Center, and Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY, United States Vikas Gupta University of Toronto, Toronto, ON, Canada Stefan Gutknecht City of Zurich – Triemli Hospital, Zurich, Switzerland Anat Guz-Mark Schneider Children's Medical Center of Israel, Petach Tikva; Tel-Aviv University, Tel-Aviv, Israel Christine Hachem Saint Louis University School of Medicine, St. Louis, MO, United States Nigel J Hall Southampton Children's Hospital, University of Southampton, Southampton, United Kingdom Magnus Halland Mayo Clinic, Rochester, MN, United States S Hamdy University of Manchester, Manchester, United Kingdom Davidson H Hamer Boston University School of Public Health; Boston Medical Center; Tufts University Friedman School of Nutrition Science and Policy, Boston, MA, United States

List of Contributors

Won Ho Han Center for Gastric Cancer, National Cancer Center, Goyang, South Korea Thuy-Van Pham Hang Emory University School of Medicine, Atlanta, GA, United States Megan Hansen University of Calgary, Calgary, AB, Canada J Harold Harrison Augusta University, Augusta, Georgia Daniel Hartmann Technical University Munich, Munich, Germany William L Hasler University of Michigan, Ann Arbor, MI, United States Cesare Hassan Nuovo Regina Margherita Hospital, Rome, Italy J Eileen Hay Mayo Clinic, Rochester, MN, United States Péter Hegyi University of Szeged, Szeged; University of Pécs, Pécs, Hungary Rachel Heise-Ginsburg Evangelisches Krankenhaus Düsseldorf, Düsseldorf, Germany Steven J Heitman University of Calgary, Calgary, AB, Canada Navid Hejazifar McMaster University, Hamilton, ON, Canada Olivia Hentic Beaujon University Hospital (APHP), Clichy; Paris-Diderot University, Paris, France Gustaf Herlenius Sahlgrenska University Hospital, Gothenburg, Sweden María Hernández-Tejero Hospital Clinic, Barcelona, Spain Claudia Herrera de Guise University Hospital Vall d'Hebron, Barcelona, Spain Hiroki Higashiyama The University of Tokyo, Tokyo, Japan V Higgins University of Toronto; The Hospital for Sick Children, Toronto, ON, Canada Ivor D Hill The Ohio State University College of Medicine, Columbus, OH, United States

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Moira B Hilscher Mayo Clinic, Rochester, MN, United States Ryan Himes Baylor College of Medicine, Houston, TX, United States Alan F Hofmann University of California San Diego, San Diego, CA, United States Wayne L Hofstetter University of Texas, MD Anderson Cancer Center, Houston, TX, United States Simon Hohenester Department of Medicine II, University Hospital, LMU Munich, Munich, Germany Lori R Holtz Washington University in St. Louis School of Medicine, St. Louis, MO, United States Michael Horowitz The University of Adelaide; Royal Adelaide Hospital, Adelaide, SA, Australia Lesley Anne Houghton University of Leeds, St James’s University Hospital, Leeds, United Kingdom Eddy Hsueh Saint Louis University, St. Louis, MO, United States Chih-Kun Huang China Medical University Hospital, Taichung City, Taiwan Emily Huang Ohio State University, Columbus, OH, United States Fabrice Hubelé University Hospitals of Strasbourg; University of Strasbourg, Strasbourg, France Norbert Hüser Technical University Munich, Munich, Germany Neil Hyman University of Chicago, Chicago, IL, United States Jong Jin Hyun Korea University College of Medicine, Seoul, South Korea; Virginia Mason Medical Center, Seattle, WA, United States Alessio Imperiale University Hospitals of Strasbourg; University of Strasbourg, Strasbourg, France Daniela Migliarese Isaac University of Alberta, Edmonton, AB, Canada

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List of Contributors

Hiroshi Ishiguro Nagoya University Graduate School of Medicine, Nagoya, Japan Farhad Islami American Cancer Society, Atlanta, GA, United States Raphaëlle Jacob Laval University; Research Center of the Quebec Institute of Cardiology and Pulmonology, Québec, QC, Canada Hartmut Jaeschke University of Kansas Medical Center, Kansas City, KS, United States Rajeev Jain Presbyterian Hospital of Dallas, Dallas, TX, United States Bhairvi Jani Saint Louis University School of Medicine, St. Louis, MO, United States

Farin Kamangar Morgan State University, Baltimore, MD, United States Patrick S Kamath Mayo Clinic, Rochester, MN, United States Amrit K Kamboj Mayo Clinic, Rochester, MN, United States EJCA Kamp Department Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands Yoshiakira Kanai The University of Tokyo, Tokyo, Japan Dina Kao University of Alberta, Edmonton, AB, Canada Vinay K Kapoor SGPGIMS, Lucknow, India David A Katzka Mayo Clinic, Rochester, MN, United States

Mehul P Jariwala University of Saskatchewan, Saskatoon, SK, Canada

Laurie Keefer Icahn School of Medicine at Mount Sinai, New York, NY, United States

Saumya Jayakumar University of California San Diego, San Diego, CA, United States

Paul Kefalides University of California San Diego, San Diego, CA, United States

Asad Jehangir Temple University School of Medicine, Philadelphia; Reading Hospital—Tower Health, Reading, PA, United States

Arun Kelay Southampton Children's Hospital, Southampton, United Kingdom

Nestor N Jimenez-Vargas Queen's University, Kingston, ON, Canada Jennifer Jin Division of Gastroenterology, Royal Alexandra Hospital, University of Alberta, Edmonton, AB, Canada Kathene C Johnson-Henry University of Toronto, Toronto, ON, Canada Lester W Johnson Louisiana State University Health Sciences Center and Overton Brooks Veterans Affairs Medical Center, Shreveport, LA, United States Karen L Jones The University of Adelaide; Royal Adelaide Hospital, Adelaide, Australia Nicola L Jones Research Institute, SickKids; University of Toronto, Toronto, ON, Canada Bellal Jubran University of Calgary, Calgary, AB, Canada

Jennifer Keller Saint Louis University, St. Louis, MO, United States Deidre A Kelly Birmingham Women's and Children's Hospital, Birmingham, United Kingdom Gyanprakash A Ketwaroo Baylor College of Medicine, Houston, TX, United States Jason Keune Saint Louis University, St. Louis, MO, United States Tauseef A Khan University of Toronto; St. Michael’s Hospital, Toronto, ON, Canada Sahil Khanna Mayo Clinic, Rochester, MN, United States Ilze Kikuste Institute of Clinical and Preventive Medicine, University of Latvia; Digestive Diseases Centre GASTRO, Riga, Latvia Peter K Kim University of Toronto; Hospital for Sick Children, Toronto, ON, Canada

List of Contributors

xxiii

Stacey A Kim Cedars-Sinai Medical Center, Los Angeles, CA, United States

Vinod Kumar Indiana University Health Methodist Hospital, Indianapolis, IN, United States

Young-Woo Kim National Cancer Center Graduate School of Cancer Science and Policy, Goyang, South Korea

Andrea Laghi Department of Surgical and Medical Sciences and Translational Medicine School of Medicine and Psychology, “Sapienza” - University of Rome Chairman of Radiology Unit - Sant'Andrea University Hospital Via di Grottarossa, Rome, Italy

Charles W Kimbrough The Ohio State University Wexner Medical Center, Columbus, OH, United States Sarah Kinsinger Loyola University Medical Center, Maywood, IL, United States

Sundeep Lakhtakia Asian Institute of Gastroenterology, Hyderabad, India

Hasan T Kirat NYU Langone Health, New York, NY, United States

Aitor Lanas-Gimeno Hospital Universitario de la Princesa, Madrid, Spain

Yuko Kitagawa Keio University, Tokyo, Japan

Angel Lanas University of Saragossa, Saragossa, Spain

Jörg Kleeff Martin-Luther-University Halle-Wittenberg, Halle, Germany Chih-Wei Ko University of Cincinnati, Cincinnati, OH, United States Kenneth L Koch Wake Forest School of Medicine and Wake Forest Baptist Medical Center, Winston-Salem, NC, United States Jeroen J Kolkman Medisch Spectrum Twente, Enschede and University of Groningen, Groningen, The Netherlands Ilan JN Koppen Emma Children's Hospital/Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Heather Mary-Kathleen Kosick University of Toronto, Toronto, ON, Canada Wei Chieh Alfred Kow National University Health System; Lin School of Medicine, National University of Singapore, Singapore, Singapore Richard A Kozarek Virginia Mason Medical Center, Seattle, WA, United States Mary Lee Krinsky University of California San Diego, San Diego, CA, United States Ernst J Kuipers Erasmus University Medical Center, Rotterdam, The Netherlands

Alfonso Lapergola Nouvel Hôpital Civil, Strasbourg University Hospital, Strasbourg, France; “SS. Annunziata” Hospital, G. D’Annunzio University of Chieti-Pescara, Chieti, Italy Jacqueline M Lauer Boston Children's Hospital, Boston, MA, United States Simon Law Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong Ronald M Laxer University of Toronto; The Hospital for Sick Children, Toronto, ON, Canada Allen A Lee University of Michigan, Ann Arbor, MI, United States Ashley Lee Saint Louis University, St. Louis, MO, United States Makau Lee University of Mississippi Medical Center, Jackson, MS, United States Scott D Lee University of Washington, Seattle, WA, United States Philippe Lehours University of Bordeaux; Pellegrin Hospital, Bordeaux, France Marcis Leja Institute of Clinical and Preventive Medicine, University of Latvia; Digestive Diseases Centre GASTRO; Riga East University Hospital, Riga, Latvia

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List of Contributors

Marco Vincenzo Lenti San Matteo Hospital Foundation, University of Pavia, Pavia, Italy

Ana Lleo Humanitas University, Milan, Italy; Humanitas Clinical and Research Center IRCCS, Milan, Italy

Markus M Lerch University Medicine Greifswald, Greifswald, Germany

Paul Lochhead Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States

Howard HW Leung Department of Anatomical and Cellular Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China

Ansgar W Lohse University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

IJM Levink Erasmus University Medical Center, Rotterdam, The Netherlands

Davide Lomanto National University Hospital; National University of Singapore, Singapore

Emile Levy Research Centre, CHU Ste-Justine and Departments of Nutrition & Pediatrics, University of Montreal, QC, Canada

Alan Lomax Queen's University, Kingston, ON, Canada

Philippe Lévy DHU UITY, University of Paris 7, Beaujon Hospital, APHP, Clichy, France

Lorena López-Domínguez University of Toronto, Toronto, ON, Canada Monica E Lopez Baylor College of Medicine; Texas Children’s Hospital, Houston, TX, United States

Xiaoxue Li University of Maryland School of Medicine; Baltimore Veterans Affairs Medical Center, Baltimore, MD, United States

Alan Lozano-Ruf Research Institute, SickKids; University of Toronto, Toronto, ON, Canada

Zhiling Li University of Leuven, Leuven, Belgium

Yan Lu QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia

Greger Lindberg Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden Andreas Linder University Hospital, LMU Munich, Munich, Germany Simon C Ling The Hospital for Sick Children; University of Toronto, Toronto, ON, Canada Elena Lionetti Marche Polytechnic University, Ancona, Italy Fritz W Lischka Center for Neuroscience and Regenerative Medicine/ Uniformed Services University of the Health Sciences, Bethesda, MD, United States Andy Liu University of Calgary, Calgary, AB, Canada Chia-Chia Liu China Medical University Hospital, Taichung City, Taiwan Louis WC Liu University of Toronto, Toronto, ON, Canada Olle Ljungqvist Örebro University, Örebro, Sweden

Gordon D Luk Digestive Health Associates of Texas, Bedford, TX, United States Eberhard Lurz Ludwig Maximilian University Munich, Munich, Germany Michael X Ma Fiona Stanley Hospital, Perth, WA, Australia Cara L Mack University of Colorado School of Medicine, Aurora, CO, United States Neema Mafi Mayo Clinic in Arizona, Phoenix, AZ, United States Carolina Malagelada Digestive System Research Unit, University Hospital Vall d’Hebron, Barcelona, Spain József Maléth University of Szeged, Szeged, Hungary Ronit Mandal The University of British Columbia, Vancouver, BC, Canada

List of Contributors

xxv

Harshal S Mandavdhare Postgraduate Institute of Medical Education and Research, Chandigarh, India

Paul N Maton Digestive Disease Specialists Incorporated, Oklahoma City, OK, United States

Roberto Manfredini University of Ferrara, Ferrara, Italy

Tamara Matysiak-Budnik IMAD, Hepato-Gastroenterology & Digestive Oncology, University Hospital of Nantes, Nantes, France

Ramandeep Mangat Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada Carl Manzo Penn State Health Milton S. Hershey Medical Center, Hershey, PA, United States Jennifer Maranki Penn State Health Milton S. Hershey Medical Center, Hershey, PA, United States Chinmay S Marathe The University of Adelaide; Royal Adelaide Hospital, Adelaide, Australia Valérie Marcil Research Centre, CHU Ste-Justine and Department of Nutrition, University of Montreal, QC, Canada James F Markowitz Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New Hyde Park, NY, United States

Alan H Maurer Temple University School of Medicine, Philadelphia, PA, United States Julia Mayerle University Hospital, LMU Munich, Munich, Germany Matthew S Mazurek University of Calgary, Calgary, AB, Canada Richard W McCallum Texas Tech University Health Sciences Center, El Paso, TX, United States; University of Kansas Medical Center, Kansas City, KS, United States Francis Megraud University of Bordeaux; Pellegrin Hospital, Bordeaux, France James E Melvin University of Rochester, New York, NY, United States Thierry Metens Université Libre de Bruxelles, Bruxelles, Belgium

Jean S Marshall Dalhousie University, Halifax, NS, Canada

Sonia Michail The University of Southern California and Children's Hospital of Los Angeles, Los Angeles, CA, United States

Elizabeth Marsicano Saint Louis University School of Medicine, St. Louis, MO, United States

Fabrizio Michelassi Weill Cornell Medicine, New York, NY, United States

Alberto Martin University of Toronto, Toronto, ON, Canada

E Michou TEI Western Greece, Patras, Greece

Colin A Martin University of Alabama at Birmingham, Birmingham, AL, United States

Adriaan Moelker Erasmus University Medical Center, Rotterdam, The Netherlands

Victoria Mackenzie Martin Harvard Medical School; Food Allergy Center, MassGeneral Hospital for Children, Boston, MA, United States

Sonmoon Mohapatra Saint Peter's University Hospital—Rutgers Robert Wood Johnson School of Medicine, New Brunswick, NJ, United States

MG Martinez Cancer Research Center of Lyon (CRCL); INSERM, U1052, Lyon, France Miguel Martínez-Guillén CIBERehd CSdM-Autonomous University of Barcelona, Hospital de Mataró, Barcelona, Spain Abraham Mathew Penn State Health Milton S. Hershey Medical Center, Hershey, PA, United States

Michiel C Mommersteeg Erasmus University Medical Center, Rotterdam, The Netherlands Louise Montalva Division of General and Thoracic Surgery, The Hospital for Sick Children, Toronto, ON, Canada Marshall H Montrose Indiana University, Indianapolis, IN, United States

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List of Contributors

Allison Moore Liddell Presbyterian Hospital of Dallas, Dallas, TX, United States

Gregg Nelson University of Calgary, Calgary, AB, Canada

Conor Moran Mater Misericordiae University Hospital, Dublin, Ireland

John P Neoptolemos University of Heidelberg, Heidelberg, Germany

Jeffrey D Mosko University of Toronto, Toronto, ON, Canada

Joshua Nero University of Manitoba, Winnipeg, MB, Canada

Marialena Mouzaki University of Cincinnati College of Medicine, Cincinnati, OH, United States

James Neuberger Queen Elizabeth Hospital, Birmingham, United Kingdom

Steffen Muehldorfer University of Erlangen, Nuremberg, Germany Aleixo M Muise Hospital for Sick Children; University of Toronto, Toronto, ON, Canada Andrew J Murphy St. Jude Children's Research Hospital; University of Tennessee Health Sciences Center, Memphis, TN, United States Karen F Murray University of Washington School of Medicine and Seattle Children's Hospital, Seattle, WA, United States Karnam S Murthy Virginia Commonwealth University, Richmond, VA, United States Sanjay K Murthy University of Ottawa, Ottawa, ON, Canada Reilly P Musselman University of Ottawa, Ottawa, ON, Canada Wouter Bastiaan Nagengast University Medical Center Groningen, Groningen, The Netherlands Rishi D Naik Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, United States

Horst Neuhaus Evangelisches Krankenhaus Düsseldorf, Düsseldorf, Germany Claus Niederau St. Josef-Hospital, Oberhausen, Germany Stella AV Nieuwenburg Erasmus University Medical Center, Rotterdam, The Netherlands Jan-Erick Nilsson University of Alberta, Edmonton, AB, Canada Carol S North University of Texas Southwestern Medical Center, Dallas, TX, United States Greg O’Grady University of Auckland, Auckland, New Zealand Derek A O’Reilly Department of Hepatopancreatobiliary Surgery, Manchester Royal Infirmary; University of Manchester, Manchester, United Kingdom Svein Ødegaard Haukeland University Hospital and University of Bergen, Bergen, Norway Robert D Odze Brigham and Women's Hospital, Boston, MA, United States Mihai Oltean Sahlgrenska University Hospital, Gothenburg, Sweden

Mey Narayanan Saint Louis University School of Medicine, St. Louis, MO, United States

Chee Y Ooi University of New South Wales, Sydney; Sydney Children's Hospital, Randwick, NSW, Australia

Yasmin Nasser University of Calgary, Calgary, AB, Canada

Magdalena EM Oremek University of Edinburgh, Edinburgh, United Kingdom

Russell J Nauta Harvard University; Mount Auburn Hospital, Cambridge, MA, United States

Robert Orenstein Mayo Clinic in Arizona, Phoenix, AZ, United States

Patrick J Navin Mayo Clinic, Rochester, MN, United States

Perry Orthey Temple University School of Medicine, Philadelphia, PA, United States

List of Contributors

George Ou The University of British Columbia, Vancouver, BC, Canada Robert L Owen University of California San Francisco, San Francisco, CA, United States Chinnusamy Palanivelu Gem Hospital and Research Centre, Chennai, India Olafur S Palsson University of North Carolina at Chapel Hill, Chapel Hill, NC, United States Vanessa N Palter St. Michael's Hospital, Toronto, ON, Canada Shirin Panahi Laval University, Québec, QC, Canada John E Pandolfino Northwestern University's Feinberg School of Medicine, Chicago, IL, United States Darrell S Pardi Mayo Clinic, Rochester, MN, United States Colleen H Parker University of Toronto, Toronto, ON, Canada Henry P Parkman Temple University School of Medicine, Philadelphia, PA, United States Sunil V Patel Queen's University, Kingston General Hospital, Kingston, ON, Canada Deepa T Patil Brigham and Women's Hospital, Boston, MA, United States Roberto Patron Mayo Clinic, Phoenix, AZ, United States Marco G Patti University of North Carolina, Chapel Hill, NC, United States

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Silvana Perretta Nouvel Hôpital Civil, Strasbourg University, Hospital; IHU-Strasbourg, Institute of Image-Guided Surgery; Institut de Recherche contre les Cancers de l’Appareil Digestif (IRCAD), IHU-Mix Surg, Strasbourg, France Martina Pezzullo Université Libre de Bruxelles, Bruxelles, Belgium Sheryl A Pfeil The Ohio State University Wexner Medical Center, Columbus, OH, United States Kristopher Philogene Mt. Auburn Hospital, Cambridge, MA, United States Stefania Piccirelli Poliambulanza Hospital, Brescia; Catholic University, Rome, Italy Pedro Pimentel-Nunes Gastroenterology Department, Portuguese Oncology Institute of Porto; Center for Research in Health Technologies and Information Systems (CINTESIS), Faculty of Medicine; Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal Capecomorin S Pitchumoni Saint Peter's University Hospital—Rutgers Robert Wood Johnson School of Medicine, New Brunswick, NJ, United States Mauro Podda San Francesco Hospital, Nuoro, Italy Stephanie D Pointer The Ohio State University Wexner Medical Center, Columbus, OH, United States Jan-Werner Poley Erasmus University Medical Center, Rotterdam, The Netherlands Michael K Porayko Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, United States

Sanjeev S Pattni University Hospitals of Leicester, Leicester, United Kingdom

Massimiliano Della Porta Department of Surgery, Fondazione IRCCS Ca' Granda; Ospedale Maggiore Policlinico, University of Milan, Milan, Italy

Gokulan Pavendranathan St George Hospital, Kogarah, NSW, Australia

Liliana Portales-Cervantes Dalhousie University, Halifax, NS, Canada

Timothy M Pawlik The Ohio State University Wexner Medical Center, Columbus, OH, United States

Piero Portincasa University of Bari Medical School, Bari, Italy

Mary H Perdue McMaster University, Hamilton, ON, Canada

Kaushal K Prasad Postgraduate Institute of Medical Education and Research, Chandigarh, India

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List of Contributors

Akriti Prashar Research Institute, SickKids; University of Toronto, Toronto, ON, Canada

Vinciane Rebours DHU UITY, University of Paris 7, Beaujon Hospital, APHP, Clichy, France

Anubhav Pratap Singh The University of British Columbia, Vancouver, BC, Canada

Kavya M Reddy Saint Louis University School of Medicine, St. Louis, MO, United States

Michael Quante Department of Internal Medicine II, Technical University Munich, Munich, Germany

María Reig Hospital Clinic of Barcelona, University of Barcelona, Barcelona; Biomedical Network for the Research of Liver and Digestive Diseases (CIBERehd), Madrid, Spain

James Quinlan University of Ottawa, Ottawa, ON, Canada Linda Rabeneck University of Toronto; Cancer Care Ontario, Toronto, ON, Canada Vikrant Rachakonda University of North Carolina at Chapel Hill, Chapel Hill, NC, United States Vikram K Raghu UPMC—Children’s Hospital of Pittsburgh, Pittsburgh, PA, United States Anup Ramachandran University of Kansas Medical Center, Kansas City, KS, United States Natalie Ramsy The University of Southern California and Children's Hospital of Los Angeles, Los Angeles, CA, United States Purnika Damindi Ranasinghe Linköping University, Linköping, Sweden Jaladanki N Rao University of Maryland School of Medicine; Baltimore Veterans Affairs Medical Center, Baltimore, MD, United States

Feza H Remzi NYU Langone Health, New York, NY, United States Michael J Rieder Schulich School of Medicine and Dentistry, Western University, London, ON, Canada Edmond HHM Rings Sophia Children's Hospital, Erasmus University Medical Center, Rotterdam; Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, The Netherlands Udo Rolle University Hospital Frankfurt, Frankfurt, Germany Sabine Roman Edouard Herriot Hospital and Lyon University, Lyon, France Rachel R Rosen Children's Hospital Boston, Boston, MA, United States Eric Rosenthal University of California San Diego, San Diego, CA, United States

Mrinalini C Rao University of Illinois at Chicago, Chicago, IL, United States

Adriano G Rossi University of Edinburgh, Edinburgh, United Kingdom

Satish Rao Augusta University, Augusta, GA, United States

Deborah C Rubin Washington University School of Medicine, Saint Louis, MO, United States

Monika Rau University Hospital Würzburg, Würzburg, Germany Pierre-Emmanuel Rautou University of Paris, Paris; Beaujon Hospital, Clichy; French Network for Rare Liver Diseases (FILFOIE), European Reference Network (ERN) 'Rare-Liver', Paris, France Jennifer Ray Saint Louis University, School of Medicine, St. Louis, MO, United States Christopher K Rayner The University of Adelaide; Royal Adelaide Hospital, Adelaide, Australia

Maria Rubino Division of Gastroenterology, Royal Alexandra Hospital, University of Alberta, Edmonton, AB, Canada Luis I Ruffolo University of Rochester Medical Center, Rochester, NY, United States Abbas H Rupawala Brown University, Providence, RI, United States Philippe Ruszniewski Beaujon University Hospital (APHP), Clichy; Paris-Diderot University, Paris, France

List of Contributors

John D Ryan UCL Institute for Liver and Digestive Health, London, United Kingdom

Stefan Seewald Hirslanden Medical Center, Zurich, Switzerland

Srishti Saha Mayo Clinic, Rochester, MN, United States

Carol E Semrad The University of Chicago, Chicago, IL, United States

Maciej Salaga Medical University of Lodz, Lodz, Poland

Blanche Sénicourt University of Sherbrooke, Sherbrooke, QC, Canada

Hrishikesh P Salgaonkar National University Hospital; National University of Singapore, Singapore

Stephen H Settle Vanderbilt University, Nashville, TN, United States

Arun J Sanyal VCU School of Medicine, Richmond, VA, United States Gonzalo Sapisochin University of Toronto, Toronto, ON, Canada A Sasegbon University of Manchester, Manchester, United Kingdom Tilman Sauerbruch University of Bonn, Bonn, Germany Thomas Savides University of California San Diego, San Diego, CA, United States Nina A Saxena Kaiser Permanente, Seattle, WA, United States Marc Schiesser Hirslanden Medical Center, Zurich, Switzerland Lawrence R Schiller Baylor University Medical Center; Texas A&M College of Medicine, Dallas, TX, United States Francisco Schlottmann University of North Carolina, Chapel Hill, NC, United States Paul M Schneider Hirslanden Medical Center; City of Zurich – Triemli Hospital, Zurich, Switzerland Lisa Schulz University Medical Center Hamburg-Eppendorf, Hamburg, Germany David M Schwartzberg NYU Langone Health, New York, NY, United States S Mark Scott Queen Mary University, London, United Kingdom Barbara Seeliger IHU-Strasbourg Institute of Image-Guided Surgery; Institute for Research against Cancer of the Digestive System (IRCAD), Strasbourg, France

xxix

Maria T Seville Mayo Clinic, Phoenix, AZ, United States Seth Shaffer University of Chicago, Chicago, IL, United States Vijay H Shah Mayo Clinic, Rochester, MN, United States Nikrad Shahnavaz Emory University School of Medicine, Atlanta, GA, United States Raanan Shamir Schneider Children's Medical Center of Israel, Petach Tikva; Tel-Aviv University, Tel-Aviv, Israel Ala I Sharara American University of Beirut School of Medicine, Beirut, Lebanon; Duke University Medical Center, Durham, NC, United States Amol Sharma Augusta University, Augusta, GA, United States Vishal Sharma Postgraduate Institute of Medical Education and Research, Chandigarh, India Yogesh M Shastri NMC Specialty Hospital, Abu Dhabi, United Arab Emirates Andrea RG Sheel The Royal Liverpool University Hospital, Liverpool, United Kingdom Vishal G Shelat Tan Tock Seng Hospital, Singapore Philip M Sherman Hospital for Sick Children; University of Toronto, Toronto, ON, Canada Yuan Shi The University of British Columbia, Vancouver, BC, Canada Henry Shiau Baylor College of Medicine, Houston, TX, United States

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List of Contributors

Vivek Shrivastava Hull University Teaching Hospitals NHS Trust, Hull, United Kingdom

Cristiano Spada Poliambulanza Hospital, Brescia; Catholic University, Rome, Italy

Parul J Shukla Weill Cornell Medicine, New York, NY, United States

Ulrich Spengler Department of Internal Medicine 1, University of Bonn, Bonn, Germany

Eric Sibley Stanford University School of Medicine, Palo Alto, CA, United States John L Sievenpiper University of Toronto; St. Michael’s Hospital, Toronto, ON, Canada Magnus Simrén University of Gothenburg, Gothenburg, Sweden; Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden; University of North Carolina (UNC) School of Medicine, Chapel Hill, NC, United States Maartje MJ Singendonk Emma Children’s Hospital/Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Anika Singh The University of British Columbia, Vancouver, BC, Canada Harveen Singh Sydney Children's Hospital, Randwick, NSW, Australia Heather F Sinner University of Kentucky, Lexington, KY, United States Armands Sivins Institute of Clinical and Preventive Medicine, University of Latvia; Riga East University hospital, Riga, Latvia Mordechai Slae Hadassah University Hospital, Jerusalem, Israel Corinna GV Slawinski Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom Michele I Slogoff University of Kentucky, Lexington, KY, United States B Mark Smithers University of Queensland, Woolloongabba, QLD, Australia Nicha Somlaw King Chulalongkorn Memorial Hospital and Chulalongkorn University, Bangkok, Thailand Manon CW Spaander Erasmus University Medical Center, Rotterdam, The Netherlands

Andrew I Spielman New York University College of Dentistry, New York, NY, United States Robert H Squires University of Pittsburgh School of Medicine; UPMC—Children's Hospital of Pittsburgh, Pittsburgh, PA, United States Shanthi Srinivasan Emory University School of Medicine and Atlanta Veterans Affairs Medical Center, Decatur, GA, United States Jürgen Stein Interdisciplinary Crohn Colitis Center Rhein-Main; Goethe University; Gastroenterology and Clinical Nutrition, DGD Clinics Sachsenhausen, Frankfurt am Main, Germany Martin C Steward University of Manchester, Manchester, United Kingdom Manfred Stolte Institute of Pathology, Bayreuth, Germany Rishi Sud Gosford Hospital, Gosford, NSW, Australia Koichi Suda Fujita Health University, Toyoake, Japan Nikie HY Sun University of Hong Kong, Queen Mary Hospital, Hong Kong, China Andrea Superti-Furga Lausanne University Hospital (CHUV), Lausanne, Switzerland Christina Surawicz Division of Gastroenterology, Department of Medicine, University of Washington School of Medicine, Seattle, WA, United States Richmond Sy University of Ottawa, Ottawa, ON, Canada Merit M Tabbers University of Amsterdam, Amsterdam, The Netherlands Frank Tacke RWTH University Hospital Aachen, Aachen, Germany

List of Contributors

Aleksandra Tarasiuk Medical University of Lodz, Lodz, Poland Laura Ellyn Targownik University of Manitoba, Winnipeg, MB, Canada Phillip I Tarr Washington University in St. Louis School of Medicine, St. Louis, MO, United States Sarah A Taylor Ann & Robert H. Lurie Children's Hospital of Chicago; Northwestern University Feinberg School of Medicine, Chicago, IL, United States AY Teoh Prince of Wales Hospital, Shatin, Hong Kong, China Christopher Teshima University of Toronto, Toronto, ON, Canada B Testoni Cancer Research Center of Lyon (CRCL); INSERM, U1052, Lyon, France Bhupesh Kumar Thakur University of Toronto, Toronto, ON, Canada Till-Martin Theilen University Hospital Frankfurt, Frankfurt, Germany Rory K Thompson University of the West Indies, Kingston, Jamaica Iain Thomson Princess Alexandra Hospital; The University of Queensland, Brisbane, QLD, Australia Hans L Tillmann Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, United States Claudio R Tombazzi University of Tennessee Health Science Center, Memphis, TN, United States Leticia Tordesillas Icahn School of Medicine at Mount Sinai, New York, NY, United States Natalie J Török Mayo, Clinic, Rochester, MN, United States Hans Törnblom Gothenburg University, Gothenburg, Sweden Christel Tran Lausanne University Hospital (CHUV), Lausanne, Switzerland

xxxi

R Alberto Travagli Penn State University-College of Medicine, Hershey, PA, United States Jonel Trebicka European Foundation for Study of Chronic Liver Failure, Barcelona, Spain; Internal medicine I, Goethe University Clinic Frankfurt, Frankfurt am Main, Germany Angelo Tremblay Laval University; Research Center of the Quebec Institute of Cardiology and Pulmonology, Québec, QC, Canada Stephen W Trenkner Mayo Clinic, Rochester, MN, United States Joseph R Triggs Northwestern University's Feinberg School of Medicine, Chicago, IL, United States Andrea Tringali Policlinico Agostino Gemelli Foundation IRCCS; Catholic University of the Sacred Heart; Centre for Endoscopic Research Therapeutics and Training – CERTT, Rome, Italy Martin Trippler Essen University Hospital, University of Duisburg-Essen, Essen, Germany Raymond KY Tsang University of Hong Kong, Queen Mary Hospital, Hong Kong, China George SW Tsao School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pok Fu Lam, Hong Kong Donald Man Lap Tse Department of Radiology, Queen Mary Hospital, Pok Fu Lam, Hong Kong Stacy S Tse Icahn School of Medicine at Mount Sinai, New York, NY, United States Cynthia Tsien University of Ottawa, Ottawa, ON, Canada Patrick Tso University of Cincinnati, Cincinnati, OH, United States Emmanuel A Tsochatzis UCL Institute for Liver and Digestive Health, London, United Kingdom Richard H Turnage Louisiana State University Health Sciences Center and Overton Brooks Veterans Affairs Medical Center, Shreveport, LA, United States

xxxii

List of Contributors

Alice Turner University of Birmingham, Birmingham, United Kingdom

Sudhakar K Venkatesh Mayo Clinic, Rochester, MN, United States

Jerrold R Turner University of Chicago, Chicago, IL, United States

Meritxell Ventura-Cots University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

Radu Tutuian Bürgerspital Solothurn, Solothurn, Switzerland Stefan J Urbanski University of Calgary, Calgary, AB, Canada Francesco Ursini University of Catanzaro “Magna Graecia”, Catanzaro, Italy Dominique Valla University of Paris, Paris; Beaujon Hospital, Clichy; French Network for Rare Liver Diseases (FILFOIE), European Reference Network (ERN) ‘Rare-Liver’, Paris, France

Hence JM Verhagen Erasmus University Medical Center, Rotterdam, The Netherlands Robin Visser University of Toronto, Toronto, ON, Canada Stacey R Vlahakis Mayo, Clinic, Rochester, MN, United States Adam M Vogel Baylor College of Medicine; Texas Children's Hospital, Houston, TX, United States

K van Bilsen Nordlands Hospital HF, Lofoten, Norway; Erasmus University Medical Center, Rotterdam, The Netherlands

Theodor Voiosu Colentina Clinical Hospital; Carol Davila School of Medicine, Bucharest, Romania

Louisa JD van Dijk Erasmus University Medical Center, Rotterdam, The Netherlands

Umberto Volta University of Bologna, Bologna, Italy

PM van Hagen Erasmus University Medical Center, Rotterdam, The Netherlands Monique E van Leerdam Department of Gastroenterology and Hepatology, Netherlands Cancer Institute Amsterdam and Leiden University Medical Center, Leiden, The Netherlands Lukas Van Oudenhove KU Leuven, Leuven, Belgium Géraldine Van Winckel Lausanne University Hospital (CHUV), Lausanne, Switzerland Pieter Vanden Berghe University of Leuven, Leuven, Belgium

Pierre-Yves von der Weid University of Calgary, Calgary, AB, Canada Dietrich von Schweinitz Dr. von Hauner Children's Hospital, LudwigMaximilians-University, Munich, Germany Jesse D Vrecenak Washington University School of Medicine, St. Louis, MO, United States Kena Vyas Saint Louis University, St. Louis, MO, United States Derek S Wakeman University of Rochester Medical Center, Rochester, NY, United States

Stephen Vanner Queen's University, Kingston, ON, Canada

Arnold Wald University of Wisconsin School of Medicine and Public Health, Madison, WI, United States

Shyam Vardarajulu Center for Interventional Endoscopy, Florida Hospital, Orlando, FL, United States

Helge L Waldum Norwegian University of Science and Technology; St. Olav’s Hospital,Trondheim, Norway

Jonas Varkey University of Gothenburg, Gothenburg, Sweden; Addenbrooke's Hospital, Cambridge, United Kingdom

PW Wales University of Toronto, Toronto, ON, Canada

Andrew Veitch New Cross Hospital, Wolverhampton, United Kingdom

MB Wallace Mayo Clinic Jacksonville, Jacksonville, FL, United States

List of Contributors

xxxiii

Julian RF Walters Imperial College London and Imperial College Healthcare NHS Trust, London, United Kingdom

David Westrich Saint Louis University School of Medicine, St. Louis, MO, United States

David Q-H Wang Departments of Medicine, Pathology and Molecular Genetics, Marion Bessin Liver Research Center, Diabetes Center, Irwin S. and Sylvia Chanin Institute for Cancer Research, Global Health Center, and Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY, United States

William E Whitehead The University of North Carolina Chapel Hill, Center for Functional GI and Motility Disorders, Chapel Hill, NC, United States

Helen H Wang Albert Einstein College of Medicine, Bronx, NY, United States

C Mel Wilcox University of Alabama at Birmingham, Birmingham, AL, United States

Jian-Ying Wang University of Maryland School of Medicine; Baltimore Veterans Affairs Medical Center, Baltimore, MD, United States

Nadia P Williams University of the West Indies, Kingston, Jamaica

Kenneth K Wang Mayo Clinic, Rochester, MN, United States

Chelsea A Wiltjer Emory University School of Medicine, Atlanta, GA, United States

Wendy E Ward Department of Kinesiology, Faculty of Applied Health Sciences, Brock University, St. Catharines, ON, Canada Kevin M Waters Cedars-Sinai Medical Center, Los Angeles, CA, United States David I Watson Flinders University, Bedford Park, SA, Australia Heiner Wedemeyer Essen University Hospital, University of Duisburg-Essen, Essen, Germany David A Weinstein University of Connecticut, Hartford, CT, United States Ralf Weiskirchen RWTH University Hospital Aachen, Aachen, Germany Christopher L Welle Mayo Clinic, Rochester, MN, United States Cameron Iain Wells University of Auckland, Auckland, New Zealand Michael L Wells Mayo Clinic, Rochester, MN, United States Nathalie Weltens KU Leuven, Leuven, Belgium David E Wesson Baylor College of Medicine; Texas Children’s Hospital, Houston, TX, United States

Sujith Wijerathne National University Hospital; National University of Singapore, Singapore

Michael Wilschanski Hadassah University Hospital, Jerusalem, Israel

Eytan Wine University of Alberta, Edmonton, AB, Canada Clarence K Wong University of Alberta, Edmonton, AB, Canada Florence Wong University of Toronto, Toronto, ON, Canada May YW Wong Royal Melbourne Hospital, Melbourne, VIC, Australia Matthew Woo University of Calgary, Calgary, AB, Canada Jackie D Wood The Ohio State University College of Medicine, Columbus, OH, United States Irene XY Wu The Chinese University of Hong Kong, Hong Kong, Hong Kong Justin CY Wu The Chinese University of Hong Kong, Hong Kong, Hong Kong Nan Wu Microbiome Research Centre, St. George and Sutherland Clinical School, Kogarah; University of New South Wales, Kensington; Department of Gastroenterology, St George Hospital, Kogarah, NSW, Australia Richard Y Wu University of Toronto, Toronto, ON, Canada

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List of Contributors

Tongzhi Wu The University of Adelaide; Royal Adelaide Hospital, Adelaide, SA, Australia Stavra A Xanthakos University of Cincinnati College of Medicine, Cincinnati, OH, United States Rickey Y Yada The University of British Columbia, Vancouver, BC, Canada Akiko Yamamoto Nagoya University Graduate School of Medicine, Nagoya, Japan

Amany Zekry Microbiome Research Centre—University of New South Wales; St George and Sutherland Clinical School—University of New South Wales, Sydney, NSW, Australia Frank Zerbib Bordeaux University Hospital, Bordeaux University, Bordeaux, France Marta Zerunian Department of Radiological Sciences, Oncology and Pathology, “Sapienza” - University of Rome Diagnostic Imaging Unit - I.C.O.T. Hospital, Latina, Italy

Ping-Chang Yang McMaster University, Hamilton, ON, Canada

Gus Q Zhang University of Texas Southwestern Medical Center, Dallas, TX, United States

Yunsheng Yang Chinese PLA General Hospital, Chinese PLA Medical Academy, Beijing, China

Linda Zhang St George Hospital, Kogarah, NSW, Australia

Howard Chi Ho Yim Microbiome Research Centre, St George and Sutherland Clinical School, University of New South Wales, Sydney, NSW, Australia Jin Woo Yoo Yale University School of Medicine, New Haven, CT, United States Augusto Zani Division of General and Thoracic Surgery, The Hospital for Sick Children, Toronto, ON, Canada Judith Zeevenhooven Emma Children's Hospital/Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Lisa Zhang Queen's University, Kingston General Hospital, Kingston, ON, Canada Konstantinos Ziambaras Division of Endocrinology, Washington University in St. Louis, St. Louis, MO, United States Wang Zikai Chinese PLA General Hospital, Chinese PLA Medical Academy, Beijing, China F Zoulim Cancer Research Center of Lyon (CRCL); INSERM, U1052; Hospices Civils de Lyon (HCL); University of Lyon, UMR_S1052, UCBL, Lyon, France

HOW TO USE THE ENCYCLOPEDIA Structure of the Encyclopedia All articles in the encyclopedia are arranged alphabetically as a series of entries. There are four features to help you easily find the topic you are interested in: an alphabetical contents list, cross references, a full subject index, and contributors. 1. Alphabetical contents list: The alphabetical contents list, which appears at the front of each volume, lists the entries in the order that they appear in the encyclopedia. So that they can be easily located, entry titles generally begin with the key word or phrase indicating the topic, with any generic terms following. For example, “Small Intestine, Benign and Malignant Neoplasms of the” is the entry title rather than “Benign and Malignant Neoplasms of the Small Intestine”. 2. Cross references: Virtually all the entries in the encyclopedia have been extensively cross-referenced. The cross references which appear at the end of an entry, serve three different functions: i. To draw the reader’s attention to related material on other entries ii. To indicate material that broadens and extends the scope of the article iii. To indicate material that covers a topic in more depth Example The following list of cross-references appears at the end of the entry “Short Bowel Syndrome”. See also: Short Bowel Syndrome and Intestinal Transplantation, Pediatric. Small Intestine; Absorption and Secretion. Visceral Transplantation.

3. Index: The index appears at the end of volume 4 and includes page numbers for quick reference to the information you are looking for. The index entries differentiate between references to a whole entry, a part of an entry, and a table or figure. 4. Contributors: At the start of each volume there is a list of the authors who contributed to all volumes.

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PREFACE The gastrointestinal tract with its various organs is characterized by great length and surface. The tract is a major player in our body homeostasis and interaction with the external world. It does so by means of a range of intricate processes including motility, secretion, digestion and uptake, immunology, para- and endocrinology. It closely interacts with the gut microbiome, the importance of which we have slowly come to understand. With all these characteristics, it is not surprising that the gastrointestinal tract also gives rise to a significant burden of disease. This can affect all age groups and populations. Disease may present acutely, but also with slow-onset, or chronic character. Conditions of the gastrointestinal tract range broadly in etiology. This includes congenital, infectious, inflammatory, autoimmune, metabolic, neurologic, toxic, and neoplastic processes. In many cases, combinations of these may play a role. For example, many cancers of the tract arise as a result of long-lasting inflammation, which may result from infection, as well as autoimmune and/or toxic factors. The surface area involved, the high cell turnover, and the constant exposure to these external factors together explain that almost one quarter of all human cancers arise in the GI tract. Most GI cancers arise as end-stage of a lengthy cascade characterized by progressive precursors. This rather unique feature makes that GI neoplasias tend to be much more amenable to prevention, early detection, surveillance and intervention than other neoplastic lesions. This all may have marked impact on the epidemiology of certain GI cancers. Similar changes in epidemiology also affect other conditions of the tract, such as certain infectious diseases, inflammatory bowel disease, and metabolic conditions. Our understanding of the etiology and pathogenesis of GI disease, as well as our diagnostic and therapeutic armamentarium have greatly expanded over the past 30 years. This started with the rapid evolution of endoscopy and radiological visualization techniques, the discovery of important infectious agents such as Helicobacter pylori and hepatitis C, followed by the introduction of a range of new drugs as well as other therapies such as new surgical techniques. It is difficult for students as well as clinicians to keep an overview of all these developments. The same pertains to those who are not engaged in daily management of patients with GI conditions, but are in need of information. This led to the first edition of the Encyclopedia of Gastroenterology, edited by professor Leonard Johnson and published by Elsevier in 2003. The major progression in the field urged us to update this significant work and come forward with this second edition as a four-volume Encyclopedia. Other than regular textbooks, this encyclopedia provides an alphabetically organized compendium. It covers the anatomy and physiology of the GI tract, and simultaneously provides a comprehensive overview of the full range of GI disease. In addition, it contains chapters on the main diagnostic and therapeutic options, such as endoscopy, radiology and surgery of the tract. The entries are arranged in alphabetical order based on their main keyword. Entries are cross-referenced to allow the user to obtain specific information in a targeted approach, from broad to specific, from basic to advanced, from symptom to disease and management, and back. The entries at the same time have some deliberate overlap to help the reader to easily gain the intended information and to avoid unnecessary switching between entries. For those readers who wish to obtain more information, entries contain suggestions for further reading. This Encyclopedia could only be produced and reach its high standard with the help of many. I am extremely grateful to the Associate Editors Marco Bruno, Francis Chan, Catherine Dubé, Emad El-Omar, Alexander Gerbes, Simon Law, Philip Sherman, Magnus Simrén, and Christina Surawicz. I firstly thank them for their long-lasting friendship. These friendships make working in academia stimulating and rewarding. Further, I thank them for their willingness to dedicate their expertise and time to collaboratively produce this Encyclopedia. Their expertise, time, and effort are reflected throughout the book, starting as a team with the selection of the entry

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Preface

topics, then each selecting authors for individual entries, and finally reviewing the submitted manuscripts. Secondly, I am grateful to all the authors, all experts in their field and willing to spend time and effort to produce the individual entries. A major textbook like this fully depends on each author to present the best of their knowledge and do so within timelines. I am also very grateful to the Elsevier staff for the continuous help and support. This started with Will Smaldon, Associate Acquisitions Editor, and Becky Gelson as Content Project Manager for Major Reference Works. They organized for the whole team to convene in Oxford to discuss and produce a comprehensive entry list and assign entries to individual associate editors. Kate Miklaszewska later took over from Becky as Content Project Manager. With humor, efficiency, patience, and endurance, she managed the complexities of interaction with many authors, Associate Editors and myself. I much enjoyed the regular telephone and videoconferences for updates and next steps. They were crucial for the quality, the balance, and progress of the overall project. In Rotterdam, the continuous support from my secretary Wendy Holleman was as ever crucial to make things work. Ernst J. Kuipers Rotterdam, The Netherlands

CONTENTS OF ALL VOLUMES Editor in Chief

v

Editorial Board

vii

Section Editors

ix

List of Contributors How to use the Encyclopedia Preface

xiii xxxv xxxvii

VOLUME 1 A Absorption and Secretion, General Symptoms, and Pharmacology

1

Richmond Sy and Melissa M Chan

Achalasia

7

Guy E Boeckxstaens

Acid Suppressive Therapy

18

Andy Liu, Bellal Jubran, Emeka K Enwere, Megan Hansen, Nicole E Burma, and Yasmin Nasser

Aerophagia

32

Louis WC Liu and Colleen H Parker

Aging

35

Makau Lee

AIDS Cholangiopathy

38

Carl H Freyer and Philip I Craig

AIDS-Related Gastrointestinal Cancers

42

Carl H Freyer and Philip I Craig

Alcohol Metabolism

47

Arthur I Cederbaum

Alcoholic Liver Disease, Management of

56

Meritxell Ventura-Cots, Vikrant Rachakonda, and Ramon Bataller

Alpha-1-Antitrypsin (a1AT) Deficiency

64

Rishi D Naik and Michael K Porayko

Amebiasis: E. histolytica

72

Kara Asbury, Roberto Patron, and Maria T Seville

Amyloidosis

78

Rishi Sud and Gokulan Pavendranathan

Anal Cancer

87

Brittany Dingley and Rebecca Auer

xxxix

xl

Contents of All Volumes

Anorectal Function

99

Amol Sharma, Satish Rao, and J Harold Harrison

Anorectal Manometry

105

S Mark Scott

Anorectal Pain

128

Giuseppe Chiarioni and Anna Granato

Antithrombotics and Gastrointestinal Endoscopy

141

Andrew Veitch

Antroduodenojenunal Manometry

149

Carolina Malagelada

Appendicitis

164

Mauro Podda, Nicola Cillara, and Salomone Di Saverio

Appetite

177

Margo A Denke

Ascites

179

John D Ryan and Emmanuel A Tsochatzis

Aspirin and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

186

Aitor Lanas-Gimeno and Angel Lanas

Autonomic Nervous System

192

Jackie D Wood

Autonomic Nervous System Dysfunction and the Gastrointestinal Tract

197

Victor Chedid and Michael Camilleri

B Barium Radiography

213

Stephen W Trenkner and David A Katzka

Barostat Measurement and Other Tests of Gastrointestinal Sensitivity

244

Fernando Azpiroz

Barrett's Esophagus

248

IJM Levink and MB Wallace

Behçet's Disease

261

Kavya M Reddy and Christine Hachem

Belching

266

Daniel C Buckles and Richard W McCallum

Benign Biliary Strictures

268

Andrea Tringali and Theodor Voiosu

Bile Acid Diarrhea

279

Sanjeev S Pattni and Julian RF Walters

Bile Formation and Pathophysiology of Gallstones

287

David Q-H Wang, Piero Portincasa, and Helen H Wang

Biliary Fistulas and Leaks

307

Jan-Erick Nilsson and Marco J Bruno

Biliary System; Anatomy and Development

314

Hiroki Higashiyama and Yoshiakira Kanai

Bleeding, Lower Gastrointestinal and Severe Hematochezia

325

Matthew S Mazurek and Steven J Heitman

Bleeding, Mid-Gastrointestinal George Ou, Carol E Semrad, and Robert Enns

335

Contents of All Volumes

Bleeding, Nonvariceal Upper Gastrointestinal; Risk Stratification and Endoscopy

xli 349

Vikas Gupta, John Gerard Coneys, Heather Mary-Kathleen Kosick, and Christopher Teshima

Bleeding, Upper Gastrointestinal; Clinical Management

363

Nicolas Chapelle and Marc Bardou

Bleeding, Variceal

372

Ala I Sharara

Bloating and Abdominal Distention

380

Lesley Anne Houghton and Alexander Charles Ford

Boerhaave's Syndrome and Esophageal Perforations

386

Paul M Schneider, Stefan Seewald, Marc Schiesser, Stefan Gutknecht, and Peter Bauerfeind

Brain–Gut Axis

394

Nathalie Weltens, Boushra Dalile, and Lukas Van Oudenhove

Breath Tests

401

Alan F Hofmann

C C. difficile Infection and Antibiotic Associated Diarrhea

404

Srishti Saha and Sahil Khanna

Calcium, Magnesium, and Vitamin D Absorption; Metabolim and Deficiency

418

Roberto Civitelli, Konstantinos Ziambaras, and Wendy E Ward

Campylobacter

424

Yao-Wen Cheng and Monika Fischer

Capsule Endoscopy

428

Cristiano Spada and Stefania Piccirelli

Carbohydrate Digestion and Absorption, and Malabsorption

438

Barbara AE de Koning, Eric Sibley, and Edmond HHM Rings

Celiac Disease

447

Carlo Catassi and Elena Lionetti

Celiac Disease; Pediatric

453

Tracy R Ediger and Ivor D Hill

Centrally Mediated Abdominal Pain Syndrome

460

Stacy S Tse and Laurie Keefer

Chagas' Disease

468

Jackie D Wood

Cholangiocarcinoma

470

Saumya Jayakumar and Mary Lee Krinsky

Cholecystectomy

476

Wei Chieh Alfred Kow

Cholera and Noncholera Vibrios

493

Ahmad Al-Taee, Jennifer Ray, and Christine Hachem

Cholestatic Diseases, Chronic

497

Simon Hohenester and Gerald Denk

Cholesterol Absorption

503

Higgins V and Adeli K

Cirrhosis; Acute Kidney Injury

514

Florence Wong

Cirrhosis; Management of Spontaneous Bacterial Peritonitis and Other Infections Marí a Hernández-Tejero, Adria Carpio, and Javier Fernández

526

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Contents of All Volumes

Colitis, Non IBD

538

Deepa T Patil and Robert D Odze

Colitis, Ulcerative

552

Scott D Lee and Kindra D Clark-Snustad

Colitis, Ulcerative (Pediatric)

575

Samuel Bitton and James F Markowitz

Colon and Rectum; Anatomy and Development

587

Kevin M Waters, Stacey A Kim, and Maha Guindi

Colonic Fluid and Electrolytes Absorption and Secretion

594

Mrinalini C Rao

Colonic Ischemia

606

Paul Feuerstadt and Lawrence J Brandt

Colonic Manometry

618

Phil G Dinning and Greg O’Grady

Colonic Motility

627

David Gunn and Maura Corsetti

Colonic Obstruction

634

Lisa Zhang and Sunil V Patel

Colonic Transit

638

Victor Chedid and Michael Camilleri

Colonoscopy

649

Cesare Hassan and Leonardo Frazzoni

Colorectal Cancer

661

Jehovan Fairclough and Catherine Dubé

Colorectal Cancer Screening

673

Catherine Dubé and Linda Rabeneck

Colorectal Polyps

679

James Quinlan and Catherine Dubé

Colostomy

686

Parul J Shukla and Fabrizio Michelassi

Complementary and Alternative Medicine

691

Irene XY Wu, Vincent CH Chung, and Justin CY Wu

Computed Tomography (CT)

701

Patrick J Navin, Christopher L Welle, Michael L Wells, and Sudhakar K Venkatesh

Connective Tissue Disorders, Gastrointestinal Tract Manifestations of

727

May YW Wong and Emad El-Omar

Constipation

734

Arnold Wald

Crohn's Disease

739

Nina A Saxena and Scott D Lee

Crohn's Disease, Pediatric

754

Daniela Migliarese Isaac and Eytan Wine

Crohn's Disease, Pediatric, Management of

761

Daniela Migliarese Isaac and Eytan Wine

Cystic Fibrosis—Liver

772

Simon C Ling

Cystic Fibrosis—Pancreas and Intestine Chee Y Ooi and Harveen Singh

780

Contents of All Volumes

Cystic Neoplasms of the Pancreas

xliii 790

Philippe Lévy and Vinciane Rebours

Cytochrome P450

799

Abdelbaset A Elzagallaai and Michael J Rieder

Cytomegalovirus

807

Elizabeth R Duke, Michael Boeckh, and Adam P Geballe

VOLUME 2 D Defecation; Normal Physiology and Defecatory Disorders

1

Giuseppe Chiarioni and Francesca Carestiato

Diabetes and the Gastrointestinal Tract

9

Chinmay S Marathe, Christopher K Rayner, Tongzhi Wu, Karen L Jones, and Michael Horowitz

Diarrhea; Anti-Diarrheal Drugs

13

Matthew Woo and Seth Shaffer

Diarrhea; Overview

19

Lawrence R Schiller

Diet and Environment in Colorectal Cancer Development, Roles of

33

Alberto Martin and Bhupesh Kumar Thakur

Diet and the Gut Microbiome in Early Life

51

Purnika Damindi Ranasinghe and Thomas Abrahamsson

Dietary Emulsifiers and their Effects on the Gut Microbiome: Insights from Pre-Clinical Studies

60

Sabrina Ayoub-Charette, Lorena López-Domí nguez, Tauseef A Khan, John L Sievenpiper, and Elena M Comelli

Diverticulosis and Diverticular Disease of the Colon

68

Stephanie D Pointer and Sheryl A Pfeil

Dumping Syndrome

73

Marco Bustamante-Bernal, Patrick Berg, and Richard W McCallum

Duodenal Atresia

82

Philip M Sherman

Duodenal Obstruction

86

Jeffrey D Mosko and Gyanprakash A Ketwaroo

Duodenal Ulcer

90

Ramandeep Mangat and David Armstrong

Duodenitis

103

Catherine Dubé

Duodenum Anatomy and Small Intestinal Development

109

Catherine Dubé

Dyspepsia, Functional (Non-Ulcer)

117

Henry P Parkman

E Ehlers–Danlos Syndrome

121

Mohsin F Butt and Qasim Aziz

Electric Activity and Neuronal Components in the Gut Wall

133

Zhiling Li, Candice Fung, and Pieter Vanden Berghe

Electrogastrography Kenneth L Koch

146

xliv

Contents of All Volumes

Endocannabinoid System

159

Aleksandra Tarasiuk, Maciej Salaga, and Jakub Fichna

Endoscopic Imaging Enhancement Techniques

167

Steven Jakob de Jongh, Mariël Maria Helena Borgerink, and Wouter Bastiaan Nagengast

Endoscopic Resection Techniques

182

Michael X Ma and Michael J Bourke

Endoscopic Retrograde Cholangiopancreatography (ERCP)

196

Rachel Heise-Ginsburg and Horst Neuhaus

Endoscopic Staging and Treatment of Ampullary Tumors

210

Sara de Campos and Jan-Werner Poley

Endoscopic Ultrasonography

224

Sundeep Lakhtakia and Shyam Vardarajulu

Enhanced Recovery After Surgery (ERAS)

238

Gregg Nelson and Olle Ljungqvist

Enteral Nutrition

243

Vi Goh and Diane Barsky

Enteric Dysfunction, Environmental

248

Jacqueline M Lauer and Christopher P Duggan

Enteric Nervous System

254

Jackie D Wood

Enterochromaffin-Like (ECL) Cells

265

Helge L Waldum and Reidar Fossmark

Enterocolitis, Necrotizing

273

Simon Eaton and Nigel J Hall

Eosinophilic Enteritis and Colitis

280

Prianka Chilukuri and Christine Hachem

Eosinophilic Esophagitis

285

David A Katzka

Epithelial Barrier Function

300

Nan Wu, Howard Chi Ho Yim, Michael Grimm, and Emad El-Omar

Epithelium; Repair of

314

Magdalena EM Oremek, Jennifer A Cartwright, and Adriano G Rossi

Esophageal Cancer

321

Wayne L Hofstetter

Esophageal Cancer Surgery

328

Simon Law

Esophageal Cancer Surveillance and Screening: Barrett's Esophagus and GERD

337

Marco G Patti, Marco Di Corpo, and Francisco Schlottmann

Esophageal Disorders, Functional

341

Ronnie Fass

Esophageal Manometry

357

Dustin A Carlson and John E Pandolfino

Esophageal Motor Disorders

368

Frank Zerbib and Sabine Roman

Esophageal pH and Impedance Testing

378

Sandra-Maria Capraru and Radu Tutuian

Esophageal Strictures Joseph R Triggs and John E Pandolfino

386

Contents of All Volumes

Esophageal Trauma

xlv 396

Iain Thomson

Esophageal Ulcers

400

Adam J Frankel and B Mark Smithers

Esophagus; Anatomy and Development

404

George SW Tsao

F Familial Adenomatous Polyposis (FAP)

408

Monique E van Leerdam

Fat Digestion, Absorption, and Malabsorption

413

Barbara Bielawska and Nicha Somlaw

Fecal Incontinence

427

William E Whitehead

Fecal Microbiota Transplant

431

Dina Kao and Christina Surawicz

Fistula

436

Emily Huang and Neil Hyman

Food Allergy

443

M Cecilia Berin and Leticia Tordesillas

Food Allergy—Clinical Perspectives

450

Victoria Mackenzie Martin

Food Intolerance and Non-Celiac Gluten Sensitivity

453

Victoria Mackenzie Martin

Food Poisoning Due to Ex Vivo Toxins

456

Christopher J Gill and Davidson H Hamer

Food Safety and Preservation

467

Ronit Mandal, Yuan Shi, Anika Singh, Rickey Y Yada, and Anubhav Pratap Singh

Foreign Bodies

480

Hussam Alamri and Lorenzo Ferri

Fructose Intolerance, Hereditary

487

Géraldine Van Winckel, Andrea Superti-Furga, and Christel Tran

Functional Gastrointestinal Disorders in Neonates and Toddlers

492

Judith Zeevenhooven, Maartje MJ Singendonk, Ilan JN Koppen, and Marc A Benninga

Fungal (Mycotic) Infections of the Gastrointestinal Tract

502

Vinod Kumar and Monika Fischer

G Gallbladder Cancer

521

Charles W Kimbrough, Jordan M Cloyd, and Timothy M Pawlik

Gallbladder; Pediatric

534

Christophe Chardot

Gallstones

541

AY Teoh

Gastrectomy (for Cancer)

547

Koichi Suda and Yuko Kitagawa

Gastric Cancer; Epidemiology and Diagnosis Jan Bornschein, Michael Quante, and Matteo Fassan

553

xlvi

Contents of All Volumes

Gastric Cancer; Prevention and Treatment

565

Marcis Leja, Nicolas Chapelle, Ilze Kikuste, Evgeny Fedorov, Armands Sivins, Fátima Carneiro, and Tamara Matysiak-Budnik

Gastric Cancer; Surveillance

581

Gianluca Esposito, Pedro Pimentel-Nunes, and Mario Dinis-Ribeiro

Gastric Infection (Non-H. pylori)

588

Allison Moore Liddell

Gastric Microbiome

591

Wang Zikai and Yang Yunsheng

Gastric Motility

598

Henry P Parkman, Perry Orthey, and Alan H Maurer

Gastric Outlet Obstruction

613

Richard H Turnage, Lester W Johnson, and Quyen M Chu

Gastric Polyps

615

Steffen Muehldorfer, Christian Ell, and Manfred Stolte

Gastric Premalignant Lesions

620

Stella AV Nieuwenburg, Michiel C Mommersteeg, Manon CW Spaander, and Ernst J Kuipers

Gastric Volvulus

629

Philip M Sherman

Gastrinoma

632

Paul N Maton

Gastritis, Erosive and Hemorrhagic (Gastropathy)

639

Rajeev Jain

Gastroduodenal Surgery for Benign Disease

641

Jennifer Keller, Kena Vyas, Ashley Lee, Jason Keune, Eddy Hsueh, and Kevin Behrns

Gastroenteritis, Viral

652

Robert Orenstein

Gastroenteropancreatic Neuroendocrine Neoplasms

658

Joanna Gotfrit and Timothy Asmis

Gastroenterostomy, Pyloroplasty, and Gastrostomy

667

Young-Woo Kim and Won Ho Han

Gastroesophageal Reflux Disease (GERD)

672

Kenneth K Wang and Juan Reyes Genere

Gastroesophageal Reflux Disease (GERD) in Children

682

Maartje MJ Singendonk, Rachel R Rosen, and Merit M Tabbers

Gastrointestinal Motility; General Principles

692

Nikrad Shahnavaz, Chelsea A Wiltjer, Thuy-Van Pham Hang, and Shanthi Srinivasan

Gastrointestinal Sensation; General Principles

701

Stuart M Brierley, David Grundy, and Luke Grundy

Gastrointestinal Stromal Tumors

711

JH Chan and AY Teoh

Gastroparesis

720

Asad Jehangir and Henry P Parkman

Genetic Counseling and Testing

731

Eric Rosenthal

Giardia, Cryptosporidium, and Other Intestinal Protozoa

734

Luther A Bartelt and Michael K Dougherty

Glycogen Storage Liver Diseases David A Weinstein and Terry GJ Derks

749

Contents of All Volumes

Growth Factors, Gastrointestinal

xlvii 755

Heather F Sinner and B Mark Evers

Gut Microbiome

763

Francisco Guarner and Claudia Herrera de Guise

VOLUME 3 H Halitosis

1

Jacob Charette and Yasmin Nasser

Hamartomatous Polyposis Syndromes

6

Catherine Dubé

Helicobacter pylori

12

Francis Megraud and Philippe Lehours

Helicobacter pylori Infection

24

Akriti Prashar, Alan Lozano-Ruf, and Nicola L Jones

Helminthic Infections

32

Sonmoon Mohapatra and Capecomorin S Pitchumoni

Hemochromatosis

46

Claus Niederau

Henoch–Schönlein Purpura and Other Vasculitides

58

Mehul P Jariwala and Ronald M Laxer

Hepatic Circulation

72

Thomas Greuter and Vijay H Shah

Hepatic Encephalopathy

81

Navid Hejazifar and Jasmohan S Bajaj

Hepatic Fibrogenesis

89

Ralf Weiskirchen and Frank Tacke

Hepatic Granulomas

96

Stacey R Vlahakis

Hepatic Resections

98

Albert Chan

Hepatitis A

107

Patrick Behrendt

Hepatitis B and C in Children

113

Mona Abdel-Hady and Deidre A Kelly

Hepatitis B, New Antiviral Targets

122

MG Martinez, B Testoni, and F Zoulim

Hepatitis C

128

Peter Ferenci

Hepatitis D

133

Heiner Wedemeyer and Martin Trippler

Hepatoblastoma

138

Michael Berger and Dietrich von Schweinitz

Hepatocellular Carcinoma

151

Álvaro Dí az-González, Alejandro Forner, Marí a Reig, and Jordi Bruix

Hepatocytes and Bile Formation Sanjeev Gupta and David Q-H Wang

163

xlviii

Contents of All Volumes

Hepatorenal Syndrome

174

Pere Ginès and Xavier Ariza

Hepatotoxicity; Drug-Induced Liver Injury

183

Hans L Tillmann

Hepatotoxins

204

Anup Ramachandran and Hartmut Jaeschke

Hiatal Hernias

209

Barbara Seeliger, Manuel Barberio, and Bernard Dallemagne

Hirschsprung's Disease

218

Philip M Sherman

Hyperthyroidism

222

Linda Zhang and John Freiman

Hypertrophic Gastropathy (Ménétrier Disease)

225

Howard HW Leung and Anthony WH Chan

I IgG4 Disease

228

Judy Di Chiou and Philip I Craig

Ileoanal Pouch

235

David M Schwartzberg and Feza H Remzi

Ileus

241

Reilly P Musselman

Immunodeficiency

244

Fiona Clegg

Immunosuppressants

248

Lacey DeVreese, Cynthia Tsien, and Sanjay K Murthy

Interstitial Cells of Cajal

267

Cameron Iain Wells and Greg O’Grady

Intestinal Ischemia and Infarction

275

Ludovica Baldari, Matteo Di Giuseppe, Massimiliano Della Porta, Luigi Boni, and Elisa Cassinotti

Intestinal Pseudoobstruction

284

Greger Lindberg

Intussusception in Children

287

Till-Martin Theilen and Udo Rolle

Iron; Intestinal Absorption

301

Gregory J Anderson, Yan Lu, David M Frazer, and James F Collins

Irritable Bowel Syndrome

312

Imran Aziz and Magnus Simrén

L Laparoscopy

324

Davide Lomanto, Hrishikesh P Salgaonkar, and Sujith Wijerathne

Laxatives and Other Drugs for Constipation

333

Stephanie D Canning

Listeriosis

338

Abbas H Rupawala

Liver Abscess Natalie J Török and Gregory J Gores

346

Contents of All Volumes

Liver Biopsy

xlix 349

Somaya Albhaisi and Arun J Sanyal

Liver Cysts

355

Stanley Martin Cohen and Phillip Y Chung

Liver Disease Associated with Non-Hepatitis Viruses

363

Ulrich Spengler

Liver Disease in Alpha-1-Antitrypsin Deficiency

377

Zoya Awan and Alice Turner

Liver Disease, Autoimmune

390

Lisa Schulz and Ansgar W Lohse

Liver Disease, Metabolic

397

Niviann M Blondet and Karen F Murray

Liver Disease, Nonalcoholic Fatty

408

Monika Rau and Andreas Geier

Liver Disease, Pregnancy and

414

J Eileen Hay

Liver Disease; Hemostasis and Coagulation Disorders

418

Emmanuelle de Raucourt, Dominique Valla, and Pierre-Emmanuel Rautou

Liver Diseases, Noninvasive Diagnosis and Staging of

429

Laurent Castera

Liver Failure, Acute-on-Chronic

436

Vicente Arroyo, Joan Clària, and Jonel Trebicka

Liver Failure, Pediatric

444

Vikram K Raghu and Robert H Squires

Liver Transplantation, Longterm Management After

455

James Neuberger

Liver Tumors, Benign

464

Massimo Colombo and Ana Lleo

Lupus Erythematosus

472

PM van Hagen, WA Dik, and K van Bilsen

Lymph, Lymphatics, and Lymph Flow

477

Patrick Tso and Chih-Wei Ko

Lymphoma, Primary Extranodal of Gastrointestinal Tract

481

Stefan J Urbanski

Lynch Syndrome

490

Vanessa N Palter

M Magnetic Resonance Imaging (MRI)

495

Thierry Metens, Martina Pezzullo, Emmanuel Coppens, Julie Absil, and Kenneth Coenegrachts

Malrotation

509

Jesse D Vrecenak and Matthew T Grant

Mast Cells

521

Jean S Marshall, Liliana Portales-Cervantes, and Bassel Dawod

Mastocytosis, Gastrointestinal Manifestations of

533

Paul Lochhead

Meckel's Diverticulum Luis I Ruffolo and Derek S Wakeman

538

l

Contents of All Volumes

Megacolon, Toxic

544

Joshua Nero and Laura Ellyn Targownik

Ménétrier's Disease

549

J Steven Burdick, Stephen H Settle, and Robert J Coffey

Mesenteric Vascular Disease

552

Louisa JD van Dijk and Hence JM Verhagen

Microscopic Colitis, Collagenous and Lymphocytic

567

Amrit K Kamboj and Darrell S Pardi

Minimally Invasive Surgery

575

Chinnusamy Palanivelu

Mucosal Immunology; Immunoglobulins, Lymphocytes and TH1, TH2 Responses

586

Karen Bensted and Michael Grimm

Multiple Endocrine Neoplasia (MEN)

595

Wouter W de Herder

N Natural Orifice Transluminal Endoscopic Surgery

600

Abraham Mathew, Jennifer Maranki, and Carl Manzo

Nausea and Vomiting Disorders

616

Hans Törnblom

Neonatal Acute Liver Failure, Including Gestational Alloimmune Liver Disease

623

Sarah A Taylor

Neonatal Cholestasis and Biliary Atresia

632

Julia M Boster and Cara L Mack

Neonatal Intestinal Obstruction

644

Augusto Zani and Louise Montalva

Neurohumoral Control of Gut Motility and Secretions

652

John R Grider, Charles D Anderson Jr., and Karnam S Murthy

Neurohumoral Control of Gut Mucosal Defense

662

Antonio Di Sabatino, Marco Vincenzo Lenti, and Gino Roberto Corazza

Neuroimmune Signaling in the Gastrointestinal Tract

665

Stephen Vanner, Alan Lomax, and Nestor N Jimenez-Vargas

Non-Nutritive Sweeteners and their Effects on Human Health and the Gut Microbiome

676

Tauseef A Khan, Sabrina Ayoub-Charette, John L Sievenpiper, and Elena M Comelli

Nuclear Medicine Imaging

685

Fabrice Hubelé, Cyrille Blondet, and Alessio Imperiale

Nutrient Transport, Regulation of

695

Jane PF Bai, Abra Guo, and Ellen Guo

Nutrition in Aging

701

Guylaine Ferland

Nutritional Assessment in Adults

709

Maria Rubino, Jennifer Jin, and Leah Gramlich

O Obesity and Bariatric Surgery

717

Chih-Kun Huang, Chia-Chia Liu, Man-Pan Chan, Haider Abdalah, and Mirza Arshad Beg

Obesity, Pediatric Stavra A Xanthakos

728

Contents of All Volumes

Obesity, Treatment of

li 737

Shirin Panahi, Vicky Drapeau, Raphaëlle Jacob, and Angelo Tremblay

Oropharinx Anatomy and Physiology of Swallowing

748

Nikie HY Sun and Raymond KY Tsang

Oropharyngeal Dysphagia

757

Miguel Martí nez-Guillén, Silvia Carrión-Bolorino, Mireia Bolí var-Prados, Viridiana Arreola, Alicia Costa, and Pere Clavé

VOLUME 4 P Pancreas Transplantation

1

Peter J Friend

Pancreas; Anatomy and Development

7

Shelat Vishal G and Kapoor Vinay K

Pancreas; Endocrine Tumors

10

Louis de Mestier, Olivia Hentic, and Philippe Ruszniewski

Pancreatic Bicarbonate Secretion

24

Hiroshi Ishiguro, Akiko Yamamoto, and Martin C Steward

Pancreatic Cancer; Biomolecular and Genetic Aspects

30

Jin Woo Yoo and James J Farrell

Pancreatic Disease, Pediatric

39

Michael J Coffey and Chee Y Ooi

Pancreatic Ductal Adenocarinoma

55

Norbert Hüser, Volker Aßfalg, Daniel Hartmann, and Helmut Friess

Pancreatic Ductal Cell Function

71

József Maléth and Péter Hegyi

Pancreatic Insufficiency, Exocrine

79

J Enrique Domí nguez-Muñoz

Pancreatitis, Acute

88

Ali Aghdassi and Markus M Lerch

Pancreatitis, Autoimmune

98

Kristopher Philogene, Omer Basar, and William R Brugge

Pancreatitis, Chronic

108

Julia Mayerle and Andreas Linder

Pancreatitis, Pediatric

117

Mordechai Slae and Michael Wilschanski

Paraneoplastic Syndrome

122

Francesco Ursini, Giacomo Caio, Umberto Volta, Roberto Manfredini, and Roberto De Giorgio

Parasitic Diseases; Overview

127

Rodney D Adam

Parenteral Nutrition

135

Marialena Mouzaki and Joan Brennan

Pediatric Diarrheal Disorders

143

Eileen Crowley and Aleixo M Muise

Pediatric Lymphatic Development and Intestinal Lymphangiectasia

158

Pierre-Yves von der Weid and Andrew S Day

Pediatric Primary and Secondary Hyperlipidemias Emile Levy, Valérie Marcil, and Edgard Delvin

170

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Contents of All Volumes

Pediatric Vascular Abnormalities

180

Henry Shiau and Ryan Himes

Peptic and Marginal Ulcer Disease

191

C Mel Wilcox

Percutaneous Drainage

195

Wan Hang Keith Chiu, Donald Man Lap Tse, and Vivek Shrivastava

Percutaneous Endoscopic Gastrostomy (PEG)

208

Aysegül Aksan, Karima Farrag, Yogesh M Shastri, and Jürgen Stein

Peritoneum; Anatomy and Development

217

Michele I Slogoff and B Mark Evers

Pernicious Anemia

219

Eberhard Lurz

Peroxisome Biogenesis Disorders

221

Nicholas D Demers and Peter K Kim

Porphyria

234

Joseph R Bloomer

Portal Hypertension and Esophageal Varices

237

Tilman Sauerbruch

Posttranscriptional Regulation of Gut Epithelium Homeostasis by RNA-Binding Proteins and Long Noncoding RNAs

247

Xiaoxue Li, Jaladanki N Rao, and Jian-Ying Wang

Pouchitis

257

Bo Shen

Prader–Willi Syndrome

273

Linda Zhang and Lennart Choo

Prebiotics and Human Milk Oligosaccharides

278

Richard Y Wu, Kathene C Johnson-Henry, and Philip M Sherman

Pregnancy and Gastrointestinal Disease

287

Rene Davila and Claudio R Tombazzi

Probiotic Use

289

Natalie Ramsy and Sonia Michail

Proctitis, Infectious

299

C Mel Wilcox

Proliferation in the Gastrointestinal Epithelium

304

Sepideh Fallah, Blanche Sénicourt, and Jean-François Beaulieu

Protein Digestion and Absorption

311

Donald Duerksen

Psychiatric Issues; Overview

315

Gus Q Zhang and Carol S North

Psychological Treatments for Gastrointestinal Diseases

323

Olafur S Palsson, Sarah Kinsinger, and Laurie Keefer

Pyloric Stenosis

331

Arun Kelay and Nigel J Hall

Pylorus; Anatomy and Development Anomalies Yousef El-Gohary and Andrew J Murphy

338

Contents of All Volumes

liii

R Radiology, Interventional

343

Adriaan Moelker and Wouter Dinkelaar

Rumination Syndrome

367

Magnus Halland

S Salivary Glands; Anatomy and Histology

373

Chan Yu Wai Jimmy

Salivary Glands; Physiology

378

James E Melvin and David J Culp

Salmonellosis

384

Neema Mafi and Robert Orenstein

Sclerosing Cholangitis

392

EJCA Kamp, AC de Vries, and Marco J Bruno

Sexually Transmitted Diseases

406

Peter V Chin-Hong and Robert L Owen

Shiga toxin E. coli

411

Lori R Holtz, Silviu Grisaru, and Phillip I Tarr

Shigella

429

Kara Asbury, Maria T Seville, and Conor Moran

Short Bowel Syndrome

435

Jennifer Jin and Leah Gramlich

Short Bowel Syndrome and Intestine Transplantation, Pediatric

442

PW Wales and Y Avitzur

Small Intestinal Bacterial Overgrowth

454

Imran Aziz and Magnus Simrén

Small Intestinal Motility

459

Allen A Lee and William L Hasler

Small Intestine, Benign and Malignant Neoplasms of the

472

ThucNhi T Dang and Clarence K Wong

Small Intestine, Absorption and Secretion

477

Marshall H Montrose

Small intestine; Anatomy

482

Gaëlle Boudry, Ping-Chang Yang, and Mary H Perdue

Small Intestine; Development

487

Deborah C Rubin

Smoking, Implications of

492

Farin Kamangar and Farhad Islami

Sphincter of Oddi Dysfunction

499

Jong Jin Hyun and Richard A Kozarek

Splenectomy

510

Russell J Nauta

Stomach, Adenomas and Carcinomas of the Gordon D Luk

513

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Contents of All Volumes

Stomach; Anatomy

518

Daniel R Clayburgh and Jerrold R Turner

Stress Ulceration

522

Rajeev Jain and Abrar Ahmed

Submucosal Tumors of the Gastrointestinal Tract

526

Thomas Savides and Paul Kefalides

Surgery for Benign Esophageal Disorders

532

Caitlin J Burke and Mark K Ferguson

Surgery for Biliary Cancer

545

Andre Gorgen, Christopher Griffiths, Phillipe Abreu, Robin Visser, and Gonzalo Sapisochin

Surgery for Gastroesophageal Reflux Disease

554

Luigi Bonavina

Surgery for Necrotizing Pancreatitis

561

Corinna GV Slawinski, Joe Geraghty, Rafik Filobbos, and Derek A O’Reilly

Surgery for Pancreatic Cancer

576

Ryan D Baron, Andrea RG Sheel, Jörg Kleeff, Markus W Büchler, and John P Neoptolemos

Surgery in Inflammatory Bowel Disease

587

Eren Esen, Hasan T Kirat, and Feza H Remzi

Surgical Aspects of Inflammatory Bowel Disease in Children

593

David E Wesson, Monica E Lopez, and Adam M Vogel

Swallowing

602

A Sasegbon, E Michou, and S Hamdy

T Taste and Smell

612

Andrew I Spielman and Fritz W Lischka

Tracheal Esophageal Fistula

620

Colin A Martin

Transplantation Immunology

624

Lan Gong and Amany Zekry

Travelers’ Diarrhea

629

Bradley A Connor

Tropical Sprue

640

Rory K Thompson and Nadia P Williams

Tuberculosis and Other Mycobacterial Infections of the Abdomen

646

Vishal Sharma, Uma Debi, Harshal S Mandavdhare, and Kaushal K Prasad

U Ultrasonography in Gastroenterology

660

Svein Ødegaard

V Vagus Nerve

676

Cecilia Bove and R Alberto Travagli

Vascular Abnormalities

683

Jeroen J Kolkman and RJM Ader

Vascular Diseases of the Liver Moira B Hilscher and Patrick S Kamath

693

Contents of All Volumes

Vasculitis, Gastrointestinal Manifestations of

lv 700

May YW Wong and Emad El-Omar

Virtual Colonoscopy

707

Davide Bellini, Marta Zerunian, Damiano Caruso, and Andrea Laghi

Visceral Transplantation

715

Gustaf Herlenius, Mihai Oltean, and Jonas Varkey

Vitamin A

724

Philip M Sherman

Vitamin B12; Absorption, Metabolism, and Deficiency

727

Eberhard Lurz

Vitamin E

734

Anat Guz-Mark and Raanan Shamir

W Webs

737

Steven L Due and David I Watson

Wilson Disease

742

Peter Ferenci

Y Yersinia enterocolitica

746

Elizabeth Marsicano, Bhairvi Jani, Mey Narayanan, and David Westrich

Z Zenker's Diverticulum

750

Alfonso Lapergola and Silvana Perretta

Index

759

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PERMISSION ACKNOWLEDGEMENT The following material is reproduced with kind permission of Oxford University press Figure 2 of Growth Factors, Gastrointestinal Table 1 of Non-Nutritive Sweeteners and their Effects on Human Health and the Gut Microbiome Table 2 of Non-Nutritive Sweeteners and their Effects on Human Health and the Gut Microbiome The following material is reproduced with kind permission of Nature Publishing Group Figure 3 of Gut Microbiome Figure 4 of Gut Microbiome Table 1 of Gut Microbiome Table 2 of Gut Microbiome Figure 2 of Achalasia Figure 4 of Colonoscopy Table 13 of Colitis, Ulcerative Figure 1 of Irritable Bowel Syndrome Table 8 of Complementary and Alternative Medicine Figure 1 of Complementary and Alternative Medicine Figure 4 of Small Intestinal Motility Figure 2 of Neuroimmune Signaling in the Gastrointestinal Tract Table 1 of Pancreatic Cancer; Biomolecular and Genetic Aspects Figure 7 of Oropharyngeal Dysphagia

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A Absorption and Secretion, General Symptoms, and Pharmacology Richmond Sy and Melissa M Chan, University of Ottawa, Ottawa, ON, Canada © 2020 Elsevier Inc. All rights reserved.

Introduction The introduction of biologic agents over 20 years ago has revolutionized the management of inflammatory bowel disease (IBD). The pathogenesis of IBD is generally agreed upon to be a result of the interaction between genetic predisposition, environmental triggers and a dysfunctional immune system. Biologics are large proteins derived from living biologic sources. Typically, recombinant DNA technology is used to create monoclonal antibodies that allow for specific targeting of various molecules that play critical roles in the inflammatory pathway. Monoclonal antibodies targeting can result in potent regulation of immune pathways with the potential for improved safety given their high selectivity. The clinical decision to start biologic agents typically occurs after the failure of conventional therapy (mesalamine, glucocorticoids or immunosuppressive agents). There are now several biologic treatments available and choosing among the different agents can be challenging as our understanding of the efficacy and safety of each biologic agent expands. There are three main classes of biologic agents approved so far: anti-tumor necrosis factor (anti-TNF) agents, anti integrin receptor agonists and antiinterleukin 12 and 23 agents. In the near future, there will be other agents with different mechanisms of actions available to further expand our therapeutic options. Biologic agents are administered via intravenous (IV) or subcutaneously (SC) routes. To date, there are no simple oral form of biologic products available. Biologic therapy has been used to both induce and maintain remission in Crohn’s disease and ulcerative colitis. Here we will review the efficacy and safety of each biologic class separately.

Anti-TNF Agents Tumor necrosis factor-alpha (TNF–a) is a pro-inflammatory cytokine that has an important role in the pathogenesis of inflammation in IBD and other inflammatory conditions such as rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis and uveitis. Anti-TNF agents target TNF–a and block its action by preventing it from binding to the cell surface receptors. Anti-TNF agents were first used in the treatment of arthritis in the early 1990s and its use expanded to IBD in 1995 when van Dullemen et al. found that a single dose of anti-TNF was associated with improvement in Crohn’s symptoms in 4 weeks (Van Dullemen et al., 1995). Currently, anti-TNF agents continue to be the first line biologic agents as they have proven rapid onset of action, are highly effective in gastrointestinal and extra intestinal manifestations of disease, and carry the most experience of all the biologic classes. The approved anti-TNF agents available so far include infliximab, adalimumab, golimumab and certolizumab. Furthermore, biosimilars for Infliximab are now available with biosimilars for adalimumab arriving in the near future.

Infliximab (RemicadeW) Infliximab is a chimeric IgG monoclonal antibody made of 75% human (constant region of the antibody) and 25% mouse origins (variable region) that bind to TNF–a receptor. It was first approved in 1998 by the US FDA for use in Crohn’s disease, and then for ulcerative colitis in 2005. The recommended dosing of Infliximab is 5 mg/kg IV at weeks 0, 2 and 6 as the initial loading dose followed with every 8 weeks maintenance dosing thereafter. The first randomized clinical trial for the use of Infliximab in moderate to severe Crohn’s disease was initially published in 1997 when Targan et al. demonstrated that a significant proportion of patients achieved clinical response compared to placebo after 1 single infusion of Infliximab (Targan et al., 1997). 108 patients with active Crohn’s disease were randomized in a 12 week trial to receive 5 mg/kg IV of infliximab infusion, 10 mg/kg IV infusion, 20 mg/kg IV infusion or placebo. The proportion of patients that responded to 5 mg/kg IV was 81%, 10 mg/kg IV at 50% and 20 mg/kg IV at 64% compared to placebo at 17%. The P value was 15 mmHg), 100% failed peristalsis and absence of esophageal pressurization, in type II there is pressurization of the esophagus, while in type III premature spastic contractions are recorded in 20% or more % of the swallows (Kahrilas et al., 2015) (Fig. 2). To what extent these different manometric patterns are associated with a different underlying mechanism remains unclear. Goldblum et al. reported that three out of three specimens taken from patients with “vigorous” achalasia had myenteric

Encyclopedia of Gastroenterology, 2nd Edition

https://doi.org/10.1016/B978-0-12-801238-3.65880-4

7

8

Achalasia

Initial insult viral, toxin, ?

Immunogenetics

Chronic infection

Aberrant autoimmune response

HLA DQA1*0103 HLA DQB1*0603

Cytotoxic T cells Auto-immune antibodies

Ganglionitis / loss of neurons

ACHALASIA Fig. 1 Schematic representation of the pathogenesis of achalasia. Reprinted with permission from Boeckxstaens, G. E., Zaninotto, G., and Richter, J. E. (2014). Achalasia. Lancet 383, 83–93.

Fig. 2 Manometric subtypes of achalasia. Reprinted with permission from Kahrilas P.J., et al. (2017). Expert consensus document: Advances in the management of oesophageal motility disorders in the era of high-resolution manometry: A focus on achalasia syndromes. Nature Reviews. Gastroenterology & Hepatology 14 (11), 677–688.

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inflammation, but a normal number of ganglion cells (20–22 ganglion cells per section) (Goldblum et al., 1996). The remaining eight patients with “classical” achalasia had low to no ganglion cells. This led those investigators to propose that “vigorous” achalasia may be the earliest phase of achalasia with preservation of the motor response of the esophageal body, thereafter progressing to more typical achalasia. However, there are several arguments against that hypothesis, the most obvious being that one of these “vigorous” achalasia patients had symptoms for 15 years without obvious progression prior to treatment. Similarly, when subtyped according to the Chicago Classification, type III (spastic) patients enrolled in the recent European Achalasia Trial all had persistent esophageal spasm at follow up (Rohof et al., 2012a). Hence, although prospective studies would be required to definitively address this question, neither the available published data nor the bulk of clinical experience suggests progression from type III to type I or II achalasia. If not representative of an early stage in disease progression, type III achalasia patients likely represent a distinct entity characterized by a less “aggressive” immune response impacting on neuronal function, but not causing apoptosis (Kahrilas and Boeckxstaens, 2013). Supportive of that hypothesis, incubation of resected human gastric fundus tissue with serum of achalasia patients induced down-regulation of NO synthase expression and increased cholinergic sensitivity, without affecting neuron number. Circulating cytokines such as IL-8 may mediate this response suggesting that local cytokine release could induce an imbalance between inhibitory and excitatory postganglionic neuronal function, thereby explaining the preserved neuron number but reduced inhibition and enhanced excitation observed in type III patients. In contrast to type III, type I and type II achalasia likely both result from a cytotoxic immune attack leading to progressive myenteric plexus neuronal apoptosis without selectivity among subsets of myenteric plexus neurons. Rather, variability among patients is reflective of the rapidity with which this occurs. Demonstrative of this variability, Goldblum et al. reported that patients with no myenteric plexus infiltrate had a shorter duration of symptoms and more severe loss of nerve fibers compared to patients with myenteric infiltrate; they even observed complete aganglionosis in some patients who were symptomatic for less than a year (Goldblum et al., 1996). These findings suggest that the type of immune response and the intensity of the cytotoxic T cell attack are the most relevant determinants of the clinical presentation of the disease. Of interest, clinical practice and some reports show that peristalsis returns to some extent after treatment in patients with type II. In the small intestine, chronic obstruction inhibits motility most likely by loss of interstitial cells of Cajal, a phenomenon that is reversible given that neurons are still present. One might speculate that return of peristalsis in these type II achalasics indicates that some neurons are still present, and regain normal function following removal of the obstruction. With time, these neurons will further disappear finally giving rise to type I achalasia. Based on the above, one could forward the hypothesis that depending on immunogenetic background, prior exposure to HSV-1, and the associated immune response, patients may alternatively present with chronic inflammation in the absence of neuronal loss (Chicago Classification type III) or a predominantly cytotoxic immune response with progressive loss of enteric neurons (Chicago Classification type I and II). The time course of progression that may ultimately lead to aganglionosis and fibrosis in these patients depends on the intensity of the initial and sustained immune response and localization of the inflammatory response may determine the specific manometric abnormalities.

Clinical Manifestations The diagnosis of achalasia should be suspected in any patient complaining of dysphagia for solids and liquids with regurgitation of undigested food and saliva. Dysphagia and regurgitation are the most common symptoms occurring in more than 90% and 76%–91% of patients respectively. Other frequent symptoms are respiratory complications (nocturnal cough (30%) and aspiration), mostly observed in patients with significant esophageal stasis, heartburn (18%–52%) and weight loss (35%–91%). Chest pain which is seen in 25%–64% of patients, is predominantly present in type III achalasia and responds less to treatment compared to dysphagia and regurgitation. However, none of these symptoms are specific, explaining the long delay between onset of symptoms and the final diagnosis, in some studies even lasting up to 5 years (Eckardt et al., 1997). A similar clinical picture as in achalasia can be seen in patients with pseudoachalasia, a syndrome most commonly caused by malignant infiltration of the gastroesophageal junction. Approximately 2%–4% of patients suspected of achalasia suffer from pseudoachalasia. In general patients with pseudoachalasia are older, have a shorter history of symptoms and weight loss is more prominent.

Diagnosis The first diagnostic step is to rule out anatomical lesions using radiologic and/or endoscopic evaluation, especially in case of suspicion of pseudoachalasia. As pointed out earlier, this should particularly be suspected in case of rapidly progressing dysphagia, significant weight loss and older age and should be excluded by endoscopic ultrasound and/or CT scan. These investigations will reveal eccentric thickening of the esophageal wall, mass lesions or even an infiltrating pancreatic carcinoma. The most sensitive diagnostic tool to diagnose achalasia is without any doubt manometry. Both endoscopy and radiology are less sensitive than manometry and will only identify approximately half of the patients (Howard et al., 1992). In early stages of achalasia, both endoscopy and radiology may be even completely normal. In a later stage of the disease, endoscopy may show a dilated esophagus with stasis of food and saliva while some resistance can be experienced to pass the gastroesophageal junction. Barium swallow typically reveals a “bird beak” image at the junction, with a dilated esophageal body and an air-fluid level in the absence of an intragastric air bubble or even a sigmoid-like appearance of esophagus in advanced cases (Fig. 3). Barium swallow is of key importance in defining the morphology of the esophagus (diameter and axis) and associated conditions, such as epiphrenic

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Achalasia

Fig. 3 Typical radiological image of bird beak (A) and endstage “sigmoid-like” esophagus (B) in achalasia. Reprinted with permission from Boeckxstaens, G. E., Zaninotto, G., and Richter, J. E. (2014). Achalasia. Lancet 383, 83–93.

diverticulae. To assess emptying of the esophagus, a timed barium swallow can be performed, in which the height of the barium column 5 min after ingestion of diluted barium is a measure for emptying (de Oliveira et al., 1997). Manometry is the gold standard for the diagnosis of achalasia and will provide diagnostic certainty in approximately 90% of the cases. To date, high resolution manometry (HRM) is recognized as the gold standard (Kahrilas et al., 2017). Using catheters incorporating 36 or more pressure sensors spaced only 1 cm apart, high resolution manometry allows in detail pressure recording of the entire esophagus. In essence, achalasia is manometrically characterized by reduced to absent relaxation after swallowing combined with absence of peristalsis in the esophageal body. Evaluation of a manometric tracing therefore will specifically comprise of assessment of the completeness of the LES relaxation and the contractile activity of the esophageal body. With the introduction of high resolution manometry, new criteria have been introduced to define esophageal peristalsis and LES function and to identify achalasia, summarized in the Chicago Classification. To date, LES relaxation is assessed using the integrated relaxation pressure or IRP. This parameter calculates the lowest mean postswallow LES pressure for four contiguous or noncontiguous seconds. The upper limit of normal for the IRP is 15 mmHg. Based on the pressure patterns in the esophageal body, three different subtypes can be identified: type I—classic achalasia with no evidence of pressurization; type II—pan-esophageal pressurization and type III—vigorous achalasia or two or more spastic contractions of the distal esophageal segment (Fig. 2). In some cases, patients present with a clinical picture very suspicious for achalasia, yet not all criteria are fulfilled on manometry. For example, IRP is above the normal limit but some degree of peristalsis can be observed. This entity is referred to as esophagogastric junction outflow obstruction (EGJOO) (Fig. 2) and can in some cases be an early presentation of achalasia. Alternatively, the manometric picture can be secondary to esophageal wall stiffness from an infiltrative disease or cancer, eosinophilic esophagitis, vascular obstruction, sliding or paraesophageal hiatal hernia, abdominal obesity or intake of opiates (Kahrilas et al., 2017). The natural history of EGJOO is somewhat heterogeneous with spontaneous resolution of symptoms in 20%–40% of patients, while the cause of dysphagia is related to a mechanical cause (mostly related to gastroesophageal reflux disease or eosinophilic esophagitis) in approximately half of the patients. In only 12%–40% of patients, EGJOO is considered as an early stage of achalasia and treated as such. A second group of patients with an atypical manometric pattern present with aperistalsis but with an IRP within normal limits. In these patients, the disease may be in a rather early stage in which the innervation of the LES may still be able to induce relaxation in response to a single swallow, but when challenged during multiple swallowing or ingestion of a meal becomes “exhausted” and fails. This reasoning has led to the introduction of new manometric protocols in which patients are asked to have multiple rapid swallows or to undergo manometry during meal intake. These alternative study protocols indeed increase the diagnostic yield and may change the diagnosis in particular from EGJOO into achalasia (Ang et al., 2017). In addition to manometry, a timed barium esophagram is indicated in these patients to have an objective assessment of esophageal emptying, to further illustrate that although IRP is normal, emptying is indeed hampered. It is important to emphasize that emptying of the esophagus not only depends on the completeness of LES relaxation, but is largely determined by the capability of the LES (or esophagogastric junction (EGJ)) to be distended, thereby creating a large enough diameter for the ingested bolus to pass. Distensibility of the EGJ is indeed significantly impaired in achalasia compared to healthy controls. It can be assessed by a new technique, in which the diameter of the EGJ is measured at several levels using impedance planimetry. The catheter used, that is, the endoluminal functional lumen imaging probe or EndoFLIP, is positioned across the EGJ and gradually inflated. Calculation of the diameter and measurement of intra-balloon

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pressure allows calculation of the ease of the EGJ to be distended (distensibility index), which has proven to be very useful in the work-up and follow-up of patients with achalasia (Rohof et al., 2012b).

Treatment Accepting that the loss of neurons (type I and II) or imbalance in nitrergic and cholinergic innervation (type III) is immunemediated, the ideal treatment should aim to stop this process. This will only be effective if a substantial number of neurons is still present, and thus may only apply for type III and some patients with type II achalasia. In case of total loss of neurons, as in type I, neuronal or stem cell transplantation would be the ideal therapeutic approach. Unfortunately, no studies using immunesuppressants have been performed and stem cell transplantation still requires further optimization and validation. So anno 2018, treatment is mainly restricted to reduction of the resistance at the level of the LES by “destruction” of the LES, that is, by forced distension (pneumatic dilation or pneumodilation) or sectioning (laparoscopic Heller myotomy, peroral endoscopic myotomy).

Pharmacological Treatment Smooth muscle relaxants The two most commonly used pharmacological agents are nitrates and calcium channel blockers. Both classes of drugs relax the smooth muscle cells leading to a reduction on LES tone. When administered prior to the meal, this temporary drop in LES pressure may improve bolus passage however clinical results are rather disappointing, and no well-designed randomized studies evaluating the clinical success of nitrates in achalasia are available. Moreover, a significant drawback of these compounds is the occurrence of side effects such as hypotension, headache and dizziness, reported by up to 30% of patients. Moreover, drug tolerance develops with time.

Botulinum toxin A A more commonly used pharmacologic treatment is botulinum toxin A, a neurotoxin which blocks the release of acetylcholine from the nerve terminals. It is directly injected at LOS level through a sclerotherapy needle during upper GI endoscopy, administering 80–100 units in four quadrants. Botulinum toxin is a safe and effective treatment with few side effects. It results in a reduction of LES pressure, most likely explaining its efficacy in achalasia. Clinical improvement at 1 month is reported in over 80% of cases, but fades rapidly with 100 different allelic variants (protease inhibitor or PI types) identified to date (Thun et al., 2013). Each inherited parental allele is co-dominantly expressed. Therefore, the quantity of circulating a1AT represents the combined product of the independent expression of each allele (Table 2). In order to separate these variant glycoproteins into clinically recognizable “phenotypes,” a classification system has been devised, making use of distinctive patterns of bands on polyacrylamide gel electrophoresis using a special technique called isoelectric focusing. Phenotypic variants are assigned letters from the alphabet based on the locations of these bands on gel slabs. During the process, faster moving molecules travel further along the gel strip and are assigned letters at the beginning of the alphabet, whereas slower moving variants are assigned letters near the end of the alphabet. It is important to note that the electrophoretic mobility does not indicate specific function or the capacity to be secreted from the hepatocyte. A majority of individuals (>95%) produce a normal M variety of a1AT, whereas several of the more common “deficiency mutants” have been assigned letters such as S and Z. Homozygotes for the Z allele make up 95% of all deficiency phenotypes in patients with a1ATD and they are readily identifiable using isoelectric focusing (Crystal, 1990). At times, variant molecules associated with a1ATD have patterns that are not easily detected by isoelectric focusing techniques but may be suspected by physicians because of characteristic clinical presentation, recognition of afflicted family members, detection of low circulating levels of a1AT, or detection of typical globules of mutant proteins on liver biopsy. In these instances, the specific mutations can be isolated by DNA sequencing (expanded genotyping). When determining an individual’s phenotype/genotype, the laboratory will provide a letter for each of the two proteins representing the products of each allele (e.g., MM, MZ, ZZ).

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Alpha-1-Antitrypsin (a1AT) Deficiency

Fig. 1 a1-Antitrypsin protein folding in the endoplasmic reticulum.

Table 2

Serum concentrations of a1AT depending on phenotype

Phenotype

Concentration (% of normal)

MM MS SS MZ SZ ZZ Mduarte (homozygote) Mmalton (homozygote) QOQO (null)

100 80 60 55–60 35–40 10–15 0.025 ng/L, and a N-terminal probrain natriuretic peptide  1800 ng/L. Median survival is 94 months, 40 months, 14 months, and 6 months for scores of 0, 1, 2, and 3 respectively. An excess of early deaths also occurs in patients with  10% plasma cells in the bone marrow at diagnosis. Treatment is tailored to the individual patients in terms of their age, comorbidities, staging, extent of organ involvement, and the goal of chemotherapy is normalization of the involved FLC whilst minimizing treatment-related toxicity. The first step in assessing therapy for a patient with AL amyloidosis is determining their eligibility for high dose melphalan followed by autologous stem-cell transplantation (SCT). If there are more than 10% plasma cells on bone marrow, induction therapy with bortezomib-dexamethasone is often given prior to SCT. Unfortunately, no more than 25% of newly diagnosed patients are eligible for SCT due to their age, comorbidities, performance status, renal function, and extent of cardiac failure. In patients undergoing SCT, the overall 10 year survival is 25% and is increased to 53% if there is a complete response to treatment (which occurs in 39% of SCT patients). The remaining patients should be considered for chemotherapy with a bortezomib-based triplet regimen such as cyclophosphamide, bortezomib and dexamethasone (CyBorD), or bortezomib, melphalan, and dexamethasone. These combinations have a very high response rates of greater than 90% for patients treated up front, with 60% achieving complete response (Gertz, 2018). It is important to recognize a subgroup of patients that are likely tolerate chemotherapy very poorly and may not benefit from treatment. These ‘high risk’ groups are defined by the presence of one or more of the following: poor Eastern Cooperative Oncology Group performance status (ECOG PS 3 or 4), severe cardiac disease, severe salt and water retention despite aggressive diuretic therapy, severe amyloid-related autonomic neuropathy causing marked symptomatic impairment in normal activities of daily living and liver involvement by amyloid causing bilirubin >2 times upper limit of normal. During treatment, the disease is assessed in terms of response of (i) clonal response (after each cycle of chemotherapy) (ii) amyloid deposits (every 6–12 months) and (iii) organ function (every 3–6 months). Measurement of free light chains (FLC) is the most effective method for monitoring the clonal disease in the majority of patients. The use of dFLC, has recently been recommended for disease monitoring. Monitoring of the intact paraprotein is often difficult in patients with amyloidosis because of a low concentration at baseline in the majority of patients, and is usually reserved for those 15% of patients with minimally abnormal FLC. Assessment of response of amyloid deposits is via serum amyloid P component (SAP) scintigraphy and assessment of organ size clinically or by imaging techniques (Wechalekar et al., 2015).

AA Amyloidosis Treatment of amyloidosis is control of the underlying inflammatory disease to maintain circulating SAA concentrations in the normal range. Survival in AA amyloidosis has dramatically improved due to more effective treatments of the underlying inflammatory diseases. Patients in whom the underlying inflammatory disorder is difficult to characterize may benefit from specific inhibition of the pro-inflammatory cytokines TNF-a, IL-1, or IL-6. Colchicine has been shown to prevent amyloid deposition and further deterioration of renal function in AA amyloidosis associated with FMF.

Hereditary Amyloidosis In hereditary amyloidosis due to TTR, more than 95% of the mutant transthyretin is produced by the liver. A liver transplant replaces mutated TTR with the normal (wild-type) molecule and thereby stop amyloid formation. In the case of patients with V30M

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mutation in the TTR gene causing autosomal dominant familial polyneuropathy, the overall 5-year survival rate after orthotopic liver transplant is 100% and with improvements in peripheral and autonomic neuropathy. Factors associated with a favorable outcome after liver transplantation include the presence of the TTR Val30Met mutation, symptomatic disease duration of less than 7 years, good nutritional status and lack of severe autonomic impairment. However, prognosis without liver transplant is dismal, with fatal progression occurring within 10–15 years from disease onset. Small molecule compounds to stabilize TTR and prevent its misfolding and amyloid aggregation, as well as RNA-targeted therapies that interfere with hepatic TTR synthesis, have been shown to reduce the progression of neuropathy in patients with familial amyloid polyneuropathy (Berk et al., 2013).

Elimination of Amyloid Deposits Treatments for amyloidosis are aimed at reducing production of the amyloid fibril precursor protein, but do not eliminate amyloid already deposited in tissues. Therapies that can eliminate amyloid deposits in tissues to maintain or restore vital organ function are desperately needed. SAP is a therapeutic target because it is always present in all types of amyloid deposits, and it is the binding of SAP to amyloid fibrils that stabilizes them and promotes the formation and persistence of amyloid. A small molecule drug, miridesap, [(R)-1-[(R)2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC) has been shown to deplete circulating SAP but leaves some SAP in amyloid deposits (Gillmore et al., 2010). Sequential treatment with dezamizumab, a fully humanized monoclonal antibody to SAP, targets the residual SAP in amyloid deposits and triggers immunotherapeutic clearance of amyloid. Pretreatment with miridesap is necessary to deplete circulating SAP so that the antibody dezamizumab can access amyloid in tissues (Richards et al., 2015). In an open-label phase 1 trial of 15 patients with systemic amyloidosis, this approach has been shown to decrease liver stiffness, as measured by the use of transient elastography. These patients also had improvements in liver function in association with a substantial reduction in hepatic amyloid load, as shown my means of SAP scintigraphy and MRI (Richards et al., 2018). Trials of other monoclonal antibodies against amyloid deposits are also underway.

References Berk JL, Suhr OB, et al. (2013) Repurposing diflunisal for familial amyloid polyneuropathy: A randomized clinical trial. JAMA 310(24): 2658–2667. Biewend ML, Menke DM, et al. (2006) The spectrum of localized amyloidosis: A case series of 20 patients and review of the literature. Amyloid 13(3): 135–142. Charidimou A, Gang Q, et al. (2011) Sporadic cerebral amyloid angiopathy revisited: Recent insights into pathophysiology and clinical spectrum. Journal of Neurology, Neurosurgery, and Psychiatry jnnp-2011-301308. Chiti F and Dobson CM (2017) Protein misfolding, amyloid formation, and human disease: A summary of progress over the last decade. Annual Review of Biochemistry 86: 27–68. Dulgheru EC, Balos LL, et al. (2005) Gastrointestinal complications of b2-microglobulin amyloidosis: A case report and review of the literature. Arthritis Care & Research 53(1): 142–145. Dungu JN, Anderson LJ, et al. (2012) Cardiac transthyretin amyloidosis. Heart heartjnl-2012-301924. Gal R, Korzets A, et al. (1994) Systemic distribution of beta 2-microglobulin-derived amyloidosis in patients who undergo long-term hemodialysis. Report of seven cases and review of the literature. Archives of Pathology & Laboratory Medicine 118(7): 718–721. Gameren IIV, Hazenberg BP, et al. (2006) Diagnostic accuracy of subcutaneous abdominal fat tissue aspiration for detecting systemic amyloidosis and its utility in clinical practice. Arthritis and Rheumatism 54(6): 2015–2021. Gertz MA (2018) Immunoglobulin light chain amyloidosis diagnosis and treatment algorithm 2018. Blood Cancer Journal 8(5). Gertz MA, Comenzo R, et al. (2005) Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): A consensus opinion from the 10th international symposium on amyloid and amyloidosis. American Journal of Hematology 79(4): 319–328. Gillmore JD and Hawkins PN (2013) Pathophysiology and treatment of systemic amyloidosis. Nature Reviews Nephrology 9(10): 574. Gillmore JD, Lovat LB, et al. (2001) Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein. The Lancet 358(9275): 24–29. Gillmore JD, Tennent GA, et al. (2010) Sustained pharmacological depletion of serum amyloid P component in patients with systemic amyloidosis. British Journal of Haematology 148(5): 760–767. Gillmore JD, Maurer MS, et al. (2016) Nonbiopsy diagnosis of cardiac transthyretin amyloidosis clinical perspective. Circulation 133(24): 2404–2412. Greenstein AJ, Sachar DB, et al. (1992) Amyloidosis and inflammatory bowel disease. A 50-year experience with 25 patients. Medicine 71(5): 261–270. Hazenberg BP, van Rijswijk MH, et al. (2006) Diagnostic performance of 123I-labeled serum amyloid P component scintigraphy in patients with amyloidosis. The American Journal of Medicine 119(4): 355. e15-355. e24. Liapis K, Michelis FV, et al. (2011) Intestinal pseudo-obstruction associated with amyloidosis. Amyloid 18(2): 76–78. Mollee P, Renaut P, et al. (2014) How to diagnose amyloidosis. Internal Medicine Journal 44(1): 7–17. Pepys-Vered ME and Pepys MB (2014) Targeted treatment for amyloidosis. The Israel Medical Association journal: IMAJ 16(5): 277. Richards DB, Cookson LM, et al. (2015) Therapeutic clearance of amyloid by antibodies to serum amyloid P component. New England Journal of Medicine 373(12): 1106–1114. Richards DB, Cookson LM, et al. (2018) Repeat doses of antibody to serum amyloid P component clear amyloid deposits in patients with systemic amyloidosis. Science Translational Medicine 10(422): eaan3128. Said SM, Grogg KL, et al. (2015) Gastric amyloidosis: Clinicopathological correlations in 79 cases from a single institution. Human Pathology 46(4): 491–498. Tosca Cuquerella J, Bosca-Watts MM, et al. (2016) Amyloidosis in inflammatory bowel disease: A systematic review of epidemiology, clinical features, and treatment. Journal of Crohn’s and Colitis 10(10): 1245–1253. Wechalekar AD, Gillmore JD, et al. (2015) Guidelines on the management of AL amyloidosis. British Journal of Haematology 168(2): 186–206.

Anal Cancer☆ Brittany Dingley and Rebecca Auer, University of Ottawa, The Ottawa Hospital, Ottawa, ON, Canada © 2020 Elsevier Inc. All rights reserved.

Background Anal cancer is an uncommon disease yet, globally, the incidence has been increasing over the last 30 years (Howlader et al., 2017; Johnson et al., 2004). In the United States, the incidence has been increasing by 2.9% per year (Shiels et al., 2015). The vast majority of cases of anal cancer are anal squamous cell carcinoma (SCC). Known risk factors include female gender, infection with human papillomavirus (HPV) or human immunodeficiency virus (HIV), immunosuppression, a high number of sexual partners, anal receptive intercourse, social deprivation, and smoking (Glynne-Jones et al., 2014). In part, the increased incidence may be explained by sexual practice changes, the growing prevalence of anal HPV infection and a growing population living with HIV infection (Shiels et al., 2012). As such, anal cancer has provided a model to study the role of viral infection and immunodeficiency in the development of cancers (Gervaz, 2004). Beyond this, anal cancer has served as a means of better understanding the role of chemoradiation as a definitive treatment modality. There has been a paradigm shift in the understanding of pathophysiology and treatment of anal cancer over the last 40 years. The unimodality treatment of anal cancer with surgery has given way to multimodality therapy, favoring chemotherapy and radiation. In the 1960s it was believed that chronic inflammation was a major causative factor in the development of anal cancer and that it was best treated with an abdominal perineal resection (APR) with a permanent colostomy (Kheir et al., 1972). We now understand that HPV plays a causative role in the development of anal cancer. The seminal paper by Nigro in 1974 began to challenge our assumptions when he reported complete pathologic response following pre-operative chemoradiation, found at the time of APR, marking a change in treatment patterns of anal cancer (Nigro et al., 1974). A variety of studies have been published with variations on the originally proposed protocol but chemoradiation has remained the mainstay of treatment for anal cancer since the 1970s. Given the immunological basis for the HPV associated anal cancer, it is also a model disease to study the role of prophylactic vaccination in reducing disease incidence, much like HPV vaccination in the prevention of cervical cancer. Finally, immunotherapeutics, such as checkpoint inhibitors, are being actively explored both in the metastatic and adjuvant setting because of the clear association between HPV, HIV or transplant-mediated immune suppression and anal cancer development. In summary, while anal cancer may be considered an orphan disease, its biology, epidemiology and treatment methodology make it an important disease for the medical community.

Epidemiology and Risk Factors In the United States, the annual incidence of anal cancer is 1.8 per 100,000 persons or 8600 new cases (Siegel et al., 2018). This represents 0.5% of all new cancer cases and 0.2% of cancer deaths (Howlader et al., 2017). The 5-year relative survival of those presenting with localized disease is 81.3%, 62.1% for regional disease, and 29.6% for distant disease (Howlader et al., 2017). Most individuals are diagnosed between 45 and 65, with women slightly more at risk than men (Shiels et al., 2015; Howlader et al., 2017). The risk of anal cancer is as high as double in women for cloacogenic anal carcinoma and if over the age of 50 (Shiels et al., 2015). There is some evidence to suggest that HPV prevalence in anal carcinoma is associated with female gender, while other studies have failed to demonstrate any impact (Frisch et al., 1997; Alemany et al., 2015). HPV is the most significant risk factor for anal cancer (see “Etiology” Section). Oncogenic forms of HPV, particularly HPV 16, are detected in up to 90% of anal cancer pathological specimens (Frisch et al., 1997; Alemany et al., 2015). HPV has been implicated in anal intraepithelial neoplasia (AIN), a precursor lesion to anal cancer and the presence of HPV 16 can be predictive for both the precursor lesions and for invasive anal cancer (Serup-Hansen et al., 2014). While anal cancer is not an AIDS-defining illness, the incidence of anal cancer is much higher in those with HIV, likely attributable to the higher rates of HPV infection in the immunosuppressed (Frisch et al., 2000). In a large meta-analysis comparing the immunosuppressed following organ transplantation and those with HIV, similar patterns of increased risk for a variety of cancers were found (Grulich et al., 2007). Cancers related to HPV infection, including anal cancer were found at a higher rate in both immunosuppressed patients and those with HIV (Grulich et al., 2007). HIV infected individuals are around 30 times more likely to develop anal canal carcinoma while transplant patients are approximately five times more likely (Tong et al., 2014; Grulich et al., 2007). The adoption of highly active antiretroviral therapy (HAART) in the HIV positive population has failed to yield a decrease in ☆

Change History: November 2018. B Dingley and R Auer updated the sections Anatomy and Histology, Epidemiology and Etiology, Clinical Features and Treatment. The Figs. 1 and 2 remain from the previous version of the chapter. B Dingley and R Auer created and introduced Tables 1–5. The chapter sections Background, Diagnosis and Staging, Prognostic Factors, Surveillance and Screening and Prevention were added by B Dingley and R Auer. Change History: The Author has made minor changes to the References and Text. This is an update of Pascal Gervaz, Anal Cancer, In Encyclopedia of Gastroenterology, edited by Leonard R. Johnson, Elsevier, New York, 2004, Pages 76–78.

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the incidence of anal cancer. Indeed, the increased incidence of anal cancer in the post HAART era may reflect the improved survival of HIV patients allowing an increased number of years in which this patient population is susceptible to developing anal cancer (Diamond et al., 2005). Men with a history of anal intercourse have a relative risk of developing anal cancer that is much higher than that of women engaging in receptive anal intercourse when compared to the general population. The relative risk for men that have sex with men (MSM) is 33.1 times higher compared to the general population whereas for women the relative risk is 1.8 times higher compared to the general population (Daling et al., 1987). In both men and women, sexual promiscuity is associated with a higher risk of anal cancer (Frisch et al., 1997). Engaging in anal receptive intercourse with two partners before the age of 30 placed women at a significantly higher risk for anal cancer. For heterosexual men, an increased risk was found with 10 or more sexual partners over their lifetime (Frisch et al., 1997). Sexually transmitted disease rates increase with an increased number of sexual partners. Individuals with anal cancers have a higher rate of infection with gonorrhea, chlamydia and genital warts (Daling et al., 1987). In a retrospective study of patients diagnosed with anal squamous cell cancer, 47% of homosexual men, 28% of heterosexual men and 28.3% of women reported having genital warts (Daling et al., 1987). In comparison, only 1%–2% of the control group reported the same. Heterosexual men are 17 times more likely to develop anal cancer if they have a history of gonorrhea (Daling et al., 1987). In women, it was found that seropositivity for herpes simplex type 2 resulted in a fourfold greater risk of anal cancer, while women with a chlamydia trachomatis infection had a 2.3-fold greater risk of developing anal cancer (Daling et al., 1987). In both women and men, cigarette smoking results in 7–9 times greater risk of anal cancer. It is believed that cigarette smoking may lead to persistence of HPV infection and therefore have an impact on cancer development and treatment outcome (GlynneJones et al., 2016).

Etiology It has now been established that HPV infection is causative in the development of anal squamous cell carcinoma, as well as its precursor lesion, anal intraepithelial neoplasia (AIN). HPV infection causes microabrasions in the basal keratinocytes and, through dysregulated expression of viral oncogenes, results in disorganized proliferation of the lower epithelial cell layers. The viral oncogenes also cause dysregulation of DNA apoptotic pathways and, through activation of telomerase, lead to cell transformation and immortalization (Tong et al., 2014). There is a viral sequence integrated in to the genome of HPV associated cancer cells. Specifically, E6 and E7 are early structural genes that function as these oncogenes, promoting malignant transformation and tumor growth (Serup-Hansen et al., 2014). These oncogenes inactivate p53 and retinoblastoma protein (pRb) (Serup-Hansen et al., 2014). Because the cyclin-dependent kinase inhibitor p16 is down regulated by pRb, the inactivation of pRb leads to upregulation of p16. p16, therefore, functions as a surrogate marker for HPV infection (Serup-Hansen et al., 2014). AIN can be classified as low-grade squamous intraepithelial lesions (LSIL), which is also known as AIN1, and high-grade squamous intraepithelial lesions (HSIL) or AIN 2/3. The p16 status influences the classification of AIN 2 lesions as follows: a negative p16 status downgrades AIN 2 to LSIL while a positive p16 status upgrades AIN 2 to HSIL (Darragh et al., 2013). There are many factors associated with the progression of AIN to invasive anal SCC including HIV seropositivity, a lower CD4 count, subtype of HPV infection, and higher viral load of oncogenic HPV subtypes in the anal canal (Palefsky et al., 1998). For example, high-grade anal pathology in HIV positive men has been associated with multiple HPV genotypes and high oncogenic HPV 16 viral loads (Salit et al., 2009). In a study of homosexual men, it was found that 62% of HIV positive men progressed from LSIL to HSIL whereas only 36% of HIV negative men experienced progression (Palefsky et al., 1998). While LSIL has been found to spontaneously regress, it is much less likely for HSIL to demonstrate regression and as such current recommendations would still include treatment of these lesions. Despite this, we do not have randomized control trial data demonstrating reduction in anal cancer incidence with the treatment of HSIL. Almost 90% of patients with invasive squamous cell carcinoma test positive for HPV DNA (Alemany et al., 2015). In an international study of HPV distribution in anal carcinoma, HPV DNA was highest amongst young patients, basaloid-type carcinomas and in North America (Alemany et al., 2015). The surrogate cellular marker for HPV-associated transformation, p16, has been detected in 95% of anal carcinoma’s that are HPV DNA positive (Alemany et al., 2015). Of the multiple subtypes of HPV, HPV 16 is by far the most commonly found in anal carcinoma at around 80% while HPV 18 is the next most common at 3%–4% (Alemany et al., 2015). In MSM, those with HIV have far more anal HPV subtypes identified and this seems to relate to low CD4 counts (Klencke and Palefsky, 2003). It is likely that other risk factors such as anal receptive intercourse and HIV, relate to HPV infection rates and the causal relationship that exists with anal SCC.

Anatomy Anal cancers arise 85% of the time, from the anal canal while 15% of anal cancers arise from the anal margin (Gervaz, 2004). The anal canal is about 3.5 cm long and extends from the upper to the lower border of the anal sphincter, at the intersphincteric groove (Gervaz, 2004). The anal canal starts at the intersection of the rectum and the puborectalis sling and extends to

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Column of morgagni Anal canal

Transitional zone

Dentate line Anal crypt Anal gland Anoderm

Fig. 1 Anatomy of the anal canal. Adapted from: Gervaz, P. (2004). Anal cancer. In: Johnson, L. R. (ed.) Encyclopedia of Gastroenterology. New York: Elsevier.

where the squamous mucosa meets the epithelium of the perianal skin. Within the canal itself, the dentate line marks a clinically visible transition from glandular to squamous mucosa. Just proximal to the dentate line is a very narrow region of transitional mucosa. The anal margin corresponds to a 5-cm area of perianal skin, measured from the anal verge (Fig. 1) (Gervaz, 2004). The anal verge is a visible landmark, which delineates the junction between the skin epithelium, or true epidermis, and the squamous mucosa of the anal canal. The perianal region is defined as the 5 cm from the verge that can be visualized when pulling apart the buttocks. Tumors arising within the anal canal tend to be characterized by aggressive local growth, including extension to the sphincter muscles whereas perianal skin cancers have a more favorable prognosis (Gervaz, 2004). Because of this, the anal verge is an important anatomical landmark, separating two histologically distinct epithelial structures that give rise to two types of cancers with different natural histories, prognoses, and treatment (Gervaz, 2004). Cancers arising from the more proximal anal canal drain predominantly into the perirectal lymph nodes along the inferior mesenteric artery, whereas tumors within the distal canal and the anal margin drain into inguinal, femoral and external iliac nodes (Gervaz, 2004). Internal pudendal nodes and the internal iliac nodes provide a drainage pathway for lesions immediately above the dentate line.

Histology The anal mucosa is composed of glandular, nonkeratinizing squamous and transitional histological tissue types. The squamous mucosa is characterized by the lack of epidermal appendages, such as hair follicles and glands. In North America, over 80% of anal carcinoma’s are squamous cell carcinoma with around 12% adenocarcinoma (Shiels et al., 2015). Basaloid is a more contemporary term for what was previously referred to as cloacogenic carcinoma, which arises from the transitional mucosa. It is now known that this is a subtype of anal carcinoma arising from the nonkeratinizing squamous mucosa. The dentate line distinguishes the more proximal nonkeratinizing SCCs from the more distal keratinizing SCCs. Glandular mucosa gives rise to adenocarcinomas within the anal canal. While rare these are best thought of as rectal adenocarcinomas in terms of treatment and prognosis. While anal squamous cell carcinomas may originate from transitional mucosa, nonkeratinizing or keratinizing squamous mucosa, all are treated in the same manner (Glynne-Jones et al., 2014).

Clinical Features Tumors from the anal area typically present as a mass associated with bleeding and pain (Fig. 2). Unfortunately, these symptoms are often erroneously attributed to hemorrhoids, with a subsequent delay in the diagnosis and treatment (Gervaz, 2004). Other symptoms that may lead to diagnosis include a palpable mass, non-healing ulcer, itching, discharge, fecal incontinence, and fistula formation. These symptoms should prompt careful examination, under anesthesia if required, and biopsy. Definitive diagnosis comes with pathologic confirmation of the histology. Occasionally, the diagnosis is made at the time of biopsy or minor procedure for other reasons, such as excision of perianal skin tags or condyloma. Untreated anal cancer spreads by local extension to adjacent tissues and organs of the pelvic floor, including sphincter muscles, vagina, or prostate (Gervaz, 2004). When present, tenesmus, the painful urgency to defecate, suggests that the tumor is involving the sphincter muscles. Roughly 90% of anal tumors present with locoregionally confined disease, whereas 10% have distant metastases at the time of diagnosis (Gervaz, 2004). While up to 30% of patients may have nodal involvement at the time of diagnosis, it is rare that patients present with palpable lymphadenopathy (Glynne-Jones et al., 2014).

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Fig. 2 Anal cancer. Adapted from: Gervaz, P. (2004). Anal cancer. In: Johnson, L. R. (ed.) Encyclopedia of Gastroenterology. New York: Elsevier.

Diagnosis and Staging When anal cancer is suspected, workup should first begin with a thorough history and physical examination. The clinical history should focus on symptoms and associated risk factors. This includes a thorough sexual history, including anal intercourse, inquiring about smoking status, known HPV related disease status, HPV vaccination status, and causes for immunosuppression. On physical examination, the perineum should be carefully examined, paying attention to tumor size and location relative to the anal canal/margin as well as the extent of the circumference of the anus that the tumor is involving. A digital rectal examination should be performed taking note of the extent of disease in the anal canal, and how fixed the tumor feels to surrounding structures. In women, a bimanual pelvic examination should be performed (with digital examination of the anus and vagina concurrently), as well as a pap smear to assess for cervical HPV related disease. Inguinal nodal basins should be examined bilaterally. Investigations should include CT scans of the chest, abdomen and pelvis, and MRI of the pelvis. Proctoscopy should be performed either in the clinic setting or under anesthesia. This will also facilitate proper biopsy, which should be done to confirm histological diagnosis. There is no need to perform a colonoscopy outside of the standard risk screening recommendations, as synchronous lesions are not a major concern with squamous cell carcinoma of the anus (Glynne-Jones et al., 2014). There is increasing data to suggest that PET scan should be routinely performed in the staging and work up of anal cancer patients. ESMO guidelines recommend the use of PET/CT given the high sensitivity, which alters staging in up to 20% of cases. This translates into a change in treatment intent in up to 5% of patients (Glynne-Jones et al., 2014). USA National Comprehensive Cancer Network (NCCN) has supported the same recommendation in the United States (Network, 2018). NCCN excludes the use of PET scan in the workup of anal margin cancers, as these tend to have a lower risk of node positivity when compared to anal canal carcinomas. Abnormal nodes palpated clinically or found on imaging should undergo biopsy to ensure positive nodes are treated fully. HIV testing should be performed in those for whom the status is not known. Tables 1–4 reflects the newest AJCC Guidelines, 8th Edition (Welton et al., 2017). Major changes include the treatment of anal margin cancers in the same manner as anal canal cancers and the removal of N2 and N3 as distinct entities with the incorporation of N1a-c. The most recent NCCN Guidelines still distinguish well-differentiated T1N0 anal margin cancers in regards to treatment (Network, 2018).

Table 1

T staging of anal cancer

T stage

Criteria

Tx T0 Tis

Primary tumor not assess No evidence of primary tumor High-grade squamous intraepithelial lesion (previously termed carcinoma in situ, Bowen disease, anal intraepithelial neoplasia II-III, high-grade anal intraepithelial neoplasia) Tumor
2 cm Tumor >2 cm and 5 cm is independently associated with worse disease-free survival, colostomy rate and overall survival (Ajani et al., 2008; Glynne-Jones et al., 2016). Node-positive disease lends itself to a worse prognosis, and in particular, clinically positive nodes have been found to be a negative prognosticator for disease-free survival (Serup-Hansen et al., 2014; Ajani et al., 2008). Independently, tumor location has not been found to be prognostic, though it may be that anal canal carcinomas present at a higher T stage and therefore overall may do worse (Ajani et al., 2008). Despite the knowledge that women are overall at a slightly higher risk of anal carcinoma, the disease-specific mortality rates remain higher in men than in women (Wan et al., 2017). Male sex was found to be an independent negative prognosticator with respect to disease-free survival (Ajani et al., 2008). Patients that were p16 positive had a significantly better overall survival and disease-specific survival than did negative patients, possibly reflecting a difference in tumor biology. These findings were more dramatic than comparing HPV positivity directly. For example, the overall survival of p16 positive patients was found to be 76% at 5 years compared to 30% in the p16 negative patients. When HPV status was analyzed, the overall survival of HPV positive patients at 5 years was 74% while for HPV negative patients was 52% (Serup-Hansen et al., 2014). This suggests a different etiology and pathophysiology driving the disease when HPV is not playing a causative role. Beyond the prognostic value of p16, it may also play a role as a predictive biomarker, although it has not been validated prospectively. There is an association with greater radiosensitivity in the tumor and favorable inflammatory responses with p16 expression (Glynne-Jones et al., 2016). These HPV positive SCC patients have been found to have a higher number of tumor infiltrating lymphocytes (TIL). An association has been noted between high levels of TIL and well-differentiated histology, early stage, and a better prognosis for anal SCCs (Hu et al., 2015). In patients with high levels of TIL, significantly better disease-free survival rates and overall survival has been demonstrated (Hu et al., 2015). TIL levels have been used to stratify p16 positive patients, and it was found that tumors with absent or low levels of TIL had a relapse-free rate of only 63% compared to 92% when the TIL level was found to be high (Gilbert et al., 2016). This once again supports the role of the immune system in anal cancer biology.

Prognostic and Predictive Biomarkers A variety of biomarkers have been investigated such as squamous cell carcinoma antigen, HPV E6 antibodies, as well as markers belonging to the following classes: tumor suppressors, epidermal growth factor receptors (EGFR), apoptosis regulation, proliferation index, angiogenesis, tumor-specific markers, Hedgehog signaling, and telomerase (Glynne-Jones et al., 2016). The only markers that have more consistently demonstrated a prognostic value are p53 and p21 (Glynne-Jones et al., 2016). The ACT I trial demonstrated that mutated p53 had a negative prognostic value (UKCCCR Anal Cancer Trial Working Party, 1996; Glynne-Jones et al., 2016). In regards to predictive factors, a small study demonstrated that Ki67, nuclear factor kappa B, sonic hedgehog, and nuclear Gli-1 are potentially associated with disease-free survival and may relate to chemoradiation resistance (Ajani et al., 2010; (Glynne-Jones et al., 2016). In another study that analyzed anal squamous cell carcinoma specimens using gene sequencing, gene amplification and immunohistochemistry, multi-drug resistance-associated protein 1 (MRP1) and excision repair cross complimenting gene 1 (ERCC1) were found to be associated with resistance to platinum-based chemotherapy whereas thymidylate synthase (TS) was associated with fluoropyrimidine resistance (Smaglo et al., 2015). These are not routinely tested in all centers.

Treatment The treatment of choice for anal squamous cell carcinoma has shifted from surgical resection with an APR to primary treatment with chemoradiation. This paradigm shift began with Nigro’s discovery of complete pathologic response at the time of APR for anal cancer after being treated with pre-operative chemoradiation (Nigro et al., 1974). These patients received 30 Gy over 3 weeks while receiving 5-FU and mitomycin C, before undergoing an APR at 6 weeks. In a small follow up study of radical chemoradiation using 50 Gy over 4 weeks along with 5-FU and mitomycin C, a complete clinical response was attained in all patients, and there was no evidence of local recurrence up to 20 months out (Cummings et al., 1980).

Evolution of Chemoradiation Systemic chemotherapy The question was then asked whether it was the chemotherapy or the radiation alone contributing most significantly to the complete pathologic and clinical responses. The UKCCCR Anal Cancer Trial (ACT I) compared radiation therapy alone to chemoradiation with 5-FU and mitomycin C and found that local failure rates reached 59% in the radiation alone group compared to 36% in the

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chemoradiation group. Disease-specific rate of death was decreased significantly by the addition of chemotherapy to radiation, however, the overall survival remained the same. While late morbidities between treatments were found to be equal, there was an increased risk of treatment-related morbidity in the short term in the chemoradiation group (UKCCCR Anal Cancer Trial Working Party, 1996). In the 13-year update on this study, it was found that for every 100 patients treated with chemoradiation, there are an expected 25.3 fewer patients with locoregional relapse and 12.5 fewer anal cancer deaths than when compared to radiation alone (Northover et al., 2010). The non-anal cancer death rate was about 10% higher in the first 5 years following chemoradiation compared to radiation alone, however, after ten years of follow up, this was no longer the case (Northover et al., 2010). The superiority of chemoradiation over radiation alone was further demonstrated by the EORTC who found that the addition of mitomycin C and 5-FU to radiation treatment resulted in a complete remission rate of 80% compared to 54% with radiation alone, leading to a significant improvement of locoregional control and colostomy-free interval. Despite this, overall survival remained similar between groups (Bartelink et al., 1997). With the benefits of multimodal treatment clear, the question of the optimal chemotherapy strategy still remained. THE RTOG/ ECOG group investigated the role of mitomycin C in the therapeutic regimen in a phase III randomized trial. Patients received either radiation with 5-FU alone or radiation with 5-FU and mitomycin C. At 5 years the disease-free survival was higher in the group receiving mitomycin C, at 73% versus 59% in the group that received only RT and 5-FU. This also translated to a lower colostomy rate in the mitomycin C group at 9% compared to 22%. However, there was no overall survival benefit between groups and the mitomycin C group experienced a 23% rate of grade 4 and 5 toxicities compared to 7% in the 5-FU alone group (Flam et al., 1996). The US Gastrointestinal Intergroup Trial/RTOG 98-11 conducted a multi-center, phase III randomized controlled trial looking at 5-FU with mitomycin and radiotherapy compared to 5-FU with cisplatin and radiotherapy in patients with anal carcinoma of the anal canal (Ajani et al., 2008). Cisplatin-based therapy failed to demonstrate an improvement in disease-free survival or overall survival. However, there was a significantly worse colostomy-free survival rate amongst those that had cisplatin-based therapy compared to mitomycin-based (Ajani et al., 2008). While the trial did not reach statistical significance in regard to overall, diseasefree survival, or local-regional treatment failure, there was a non-statistically significant trend favoring mitomycin-based therapy over cisplatin-therapy with more cancer-related deaths in the cisplatin group (Ajani et al., 2008). By the time the 5-year update was published, it was found that disease-free survival was significantly better in the mitomycin-based group compared to the cisplatin group at 67.8% compared to 57.8%. Similarly, the 5-year overall survival was 78.3% in the mitomycin group compared to 70.7% in the cisplatin group (Gunderson et al., 2012). A four-armed trial, ACT II, compared 5-FU combined with either mitomycin or cisplatin in the context of chemoradiation and the utility of maintenance chemotherapy compared to no maintenance chemotherapy. The final conclusion of the trial was that fluorouracil and mitomycin C with 50.4 Gy radiotherapy in 28 daily fractions should remain standard practice (James et al., 2013). There was no difference in the complete response rates between the mitomycin group and the cisplatin group. The addition of maintenance chemotherapy did not result in a difference in 3-year progression-free survival or in overall survival (James et al., 2013). Phase II trials have demonstrated comparable results with capecitabine as to infusional 5-FU, with complete response rates of up to 86% by 6 months, allowing consideration for an oral agent in the primary treatment pathway for anal cancer (Oliveira et al., 2016). Currently, 5-FU (or capecitabine) and mitomycin C remain the recommended chemotherapy strategy in conjunction with radiotherapy.

Radiation therapy Standard radiation consists of 30–36 Gy delivered from the pelvis to S1/S2 and includes the inguinal nodes and anus. At this point, there is a dose volume reduction and the primary tumor receives a total dose to 45–50 Gy in daily 2 Gy fractions. A radiation boost is suggested for clinically involved nodal disease (Network, 2018). Regardless of nodal status, it has been demonstrated that omission of inguinal node irradiation results in a higher inguinal recurrence rate. RTOG 98-11 and the ACCORD-03 phase III trials failed to show any benefit to dose escalation. Intensity-modulated radiotherapy (IMRT) is considered the preferable strategy for delivery of radiotherapy. RTOG-0529 reported on T2-4N0-3M0 anal cancer patients who received 5-FU and mitomycin C and compared dose-painted IMRT radiotherapy delivery to the standard radiotherapy protocol from RTOG 98-11. It was found that the grade 3 adverse events were less in the IMRT group. The study also highlighted the need for radiotherapy planning revision in the IMRT group, with 81% of the IMRT group pretreatment plans requiring revision (Kachnic et al., 2013). An ongoing study is evaluating whether reduced radiation dose for early or intermediate risk anal cancers can maintain excellent local control and survival rates while reducing treatment-related toxicities (Registry, 2017). The PLATO-ACT4 study is a U.K. based randomized phase II trial comparing standard-dose chemoradiotherapy (50.4 Gy in 28 fractions) with reduced dose chemoradiotherapy (41.4 Gy in 23 fractions) in patients with T1-2 (100 healthy subjects) (Chaliha et al., 2007; Gundling et al., 2010). For HR-ARM (Carrington et al., 2014; Oblizajek et al., 2019; Wang et al., 2017) and 3D HD-ARM (Li et al., 2013; Wickramasinghe et al., 2015) however, there are already five studies in the published literature of cohort sizes ranging from 101 to 163 (Tables 2 and 3). These studies have shown that biological factors such as age, ethnicity, gender, parity in females, and body mass index may all impact on recorded values (e.g., age is associated with lower resting pressures (Li et al., 2013; Oblizajek et al., 2019), and males have higher squeeze pressures than females (Li et al., 2013)). This is true also for test equipment. For example, a study in Korean subjects using the Diversatek™ manometry system (Lee et al., 2014), coupled to a Laborie/Unisensor catheter with four radially-arranged sensors at each recording level, reports consistently lower test values compared to any other published normative dataset, in which alternative test equipment has been employed. In addition, studies directly comparing solid-state catheters to water-perfused catheters show that pressure measurements during dynamic maneuvers (e.g., squeeze or cough) are significantly lower when recorded with the latter (Rasijeff et al., 2017). Consequently, further (likely collaborative) studies may be necessary to better define normal range for anorectal pressures stratified on the basis of many of these factors.

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Table 2

Normative values from HR-ARM studies of >100 subjects.

Authors

Carrington et al., 2014 n ¼ 115 F 45 (18–68) { 96 Western Laborie 65  19 3.5  0.8 203  74 134  62 12  10 66  38 47  19 27  25 – – – –

Gender Age Number Ethnicity Equipment Mean resting pressure (mmHg) Functional anal canal length (cm) Maximum squeeze pressure (mmHg) Maximum squeeze increment (mmHg) Duration of endurance squeeze Rectal propulsion pressure Residual anal pressure (mmHg) Anal relaxation (%) RAPG FCSV (mL) DDV (mL) MTV (mL)

M 32 (21–72) { 19 73  23 3.9  0.8 215  118 144  116 16  11 71  33 57  23 16  33 – – – –

Wang et al., 2017 n ¼ 126 F/M 38  15 50/76 Asian Unknown 72  17 3.4  0.6 179  53 – – – 64  21 – – 47  10 126  29 176  36

Oblizajek et al., 2019 n ¼ 143a F M 41  16 45  16 96 47 Western Medtronic 78  25 83  25 3.4  0.8 3.9  0.8 201  61 257  78 124  56 174  81 13  7 14  7 30  21 47  36 63  21 105  44 20  35 5  29 34  26 58  53 37  14 44  26 63  22 74  34 102  31 123  53

Values are mean  SD, except { Median (min–max). a 20 subjects (17 female, 3 male) not included who could not expel a rectal balloon during the balloon expulsion test.

Table 3

Normative values from 3D HD-ARM studies of >100 subjects.

Authors Gender Age Number Ethnicity Equipment Mean resting pressure (mmHg) Functional anal canal length (cm) Maximum squeeze pressure (mmHg) Maximum squeeze increment (mmHg) Duration of endurance squeeze Rectal propulsion pressure Residual anal pressure (mmHg) Anal relaxation (%) RAPG FCSV (mL) DDV (mL) MTV (mL) a b

Li et al., 2013a n ¼ 110 F 45 (18–68) 46 Asian Medtronic 60  2 3.5  0.1 167  8 – 15  0.8 46  7 65  7 27  3 13  9 40  2 93  4 145  5

M 32 (21–72) 64 61  2 3.6  0.1 195  7 – 12  0.7 72  9 81  4 23  3 13  8 44  2 103  4 155  4

Wickramasinghe et al., 2015b n ¼ 101 F 25  5 101 Asian Medtronic 87  18 3.7  0.5 179  53 – – – – – – 50  26 77  35 143  66

Values are meanSEM. Values are meanSD.

It is also important to note that when each functional parameter is considered independently, subjects with single values outside the normal range may not have clinical symptoms and, vice versa, patients with clinical problems may exhibit normal values. Due to the capability of the anorectal unit for functional compensation, an isolated dysfunction may not have clinical relevance; symptoms may only occur when multiple parameters are affected (Azpiroz et al., 2002).

Diagnostic Utility in Clinical Practice Due to the often multiple and interrelated factors contributing to the pathophysiology of both FI and constipation/ED (indeed a common pathophysiology likely explains their frequent coexistence) (Nurko and Scott, 2011), no single test can fully characterize relevant function and structure. Hence a battery of complementary tests is typically performed to provide a clear diagnosis; manometry, therefore, can only be expected to yield contributory diagnostic information in an individual patient (Carrington

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et al., 2018; Scott and Williams, 2018). Considering each manometric maneuver separately, several clinically relevant features have been observed, which are incorporated within the London Classification (Carrington et al., 2019b). For some other features, clinical utility remains unclear. All are outlined below.

Clinical Interpretation and Utility of ARM as a Test of Sphincter Function With regard to anal sphincter function, a number of conventional ARM studies and also contemporary HR-ARM/3D HD-ARM studies have demonstrated differences in manometric findings between healthy volunteers and patients.

Anal hypotonia Reduced anal resting pressure is considered a major finding in the London Classification (Table 1 and Fig. 5). Though of low sensitivity (30–35%) (Bharucha et al., 2005; Carrington et al., 2019a; Sun et al., 1992), it is pathophysiologically important in patients with FI, particularly in those with passive or postdefecation-related symptoms. Anal hypotonia primarily reflects a structurally compromised internal anal sphincter, and is often seen in patients with rectal prolapse, a patulous anal canal, or cauda equina injury (Azpiroz et al., 2002). It may be considered a contraindication to reconstructive pouch surgery or stoma reversal in patients who have undergone colorectal resection, and may also be a contraindication for future vaginal deliveries in women with a history of previous 3rd or 4th degree perineal lacerations.

Anal hypertonia Elevated anal resting pressure is considered a minor finding in the London Classification. Anal hypertonia occurs in some patients with anal fissure or anal pain (Opazo et al., 2013), and may suggest smooth muscle or striated muscle spasm (Azpiroz et al., 2002) (see Fig. 5C). Ultra-slow wave pressure activity is often associated with a hypertonic anal canal (Opazo et al., 2013) (see Fig. 5D).

Anal hypocontractility Reduced anal squeeze pressure is considered a major finding in the London Classification (Fig. 6). Of all standard manometric measures of anorectal function, anal squeeze pressure has been shown to have the greatest sensitivity and specificity for discriminating patients with FI from continent patients and controls (Felt-Bersma et al., 1990; Sun et al., 1992). The squeeze increment is essentially contributed by the external anal sphincter (EAS), and also by contraction of the puborectalis sling. Anal hypocontractility thus implies EAS/puborectalis weakness, though ARM cannot differentiate between compromised muscle integrity, impaired innervation, or both as a cause of that weakness. Alternatively, anal hypocontractility may be due to poor patient compliance. A recent study showed that maximum squeeze pressure (as well as rectal propulsive pressure and the RAPG during the push maneuver) was significantly increased when “enhanced” verbal feedback was given to patients, compared to results from the same individuals when only “standard” instructions were provided (Heinrich et al., 2013). Such verbal intervention was able to change manometric findings from locally validated “pathological” to “normal” values in 14/31 patients (45%) with FI (Heinrich et al., 2013). Conversely, refining the analysis metric can improve diagnostic utility. Compared to the conventional ARM measure of maximum anal squeeze increment, a novel HR-ARM parameter, the “contractile integral” (integrating the product of mean pressure increase, sphincter length, and voluntary contraction duration) improved sensitivity of detection of anal hypocontractility from 32% to 55% (Carrington et al., 2019a).

Functional anal canal length An abnormal FACL is not considered in the current iteration of the London Classification. Intuitively, the shorter the anal canal, the less effective the continence mechanism, and indeed FACL has been shown to be reduced in patients with FI compared to controls (Vollebregt et al., 2019). However, an abnormally short FACL in isolation was only found in 1/190 FI patients (0.5%); all other patients had other abnormal manometric findings (e.g., anal hypotonia, hypocontractility, etc.) (Vollebregt et al., 2019). Conversely, an abnormally long FACL may predispose to evacuatory difficulties. Likewise, FACL has been shown to be longer in female patients with constipation than healthy controls, but only 2/201 (1%) patients had this manometric finding in isolation. This severely questions its clinical utility. Nevertheless, FACL might be a useful parameter in predicting the clinical outcome of surgical interventions that may have impact on the anal canal length; prospective studies are required.

Endurance squeeze pressure A poor ability to sustain voluntary squeeze of the anal canal is not considered in the current iteration of the London Classification, as clinical significance is unclear. Although squeeze duration is reduced (Chiarioni et al., 1993) and “fatigability” is greater (Telford et al., 2004) in incontinent patients as a group compared to controls, discriminatory ability to distinguish individuals with normal continence from those with FI may be poor (Rosier et al., 2010). This is, in part, related to the current measure of endurance squeeze (duration of time a subject can sustain an increase in anal pressure >50% of the maximum incremental squeeze pressure), which has a lower limit of normal of only 2 s (Carrington et al., 2014); clearly this metric requires refinement.

Anorectal pressures during cough An abnormal anorectal pressure response to coughing is not considered in the London Classification. Impairment of the cough reflex response likely reflects neural damage within the reflex circuitry (Azpiroz et al., 2002), and manifests as a reversal of the

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Fig. 5 Anal resting tone. The first three traces are 60 s recordings during the rest maneuver: (A) normal anal resting tone (mean 65 mmHg); (B) anal hypotonia (mean 17 mmHg); (C) anal hypertonia (mean 127 mmHg). Trace D is a 5 min recording at rest, showing cyclical high-pressure activity, “ultra-slow waves,” occurring at 0.75 cycles/min. Trace E is also a 5 min recording incorporating rest, short squeeze, endurance squeeze and cough maneuvers. Striking anal hypotonia is evidenced (mean 8 mmHg), though anal response to dynamic maneuvers shows “reserve” in the system, with normal anal contractility.

normal recto-anal pressure gradient, in that a positive anal to rectal pressure differential is not maintained (i.e., rectal pressure exceeds anal pressure) (see Fig. 7). Intuitively, this indicates compromised sphincter barrier function that may be of pathological importance in FI. Despite a paucity of data attesting to its clinical utility, most centers recently surveyed still incorporate the cough maneuver within a routine manometry investigation (Carrington et al., 2017). This may be because it (at least anecdotally) provides for further evaluation of EAS function, especially in those patients with anal hypocontractility on squeezing, in whom poor compliance is suspected (Azpiroz et al., 2002). If a normal cough response is recorded, this suggests there is “functional reserve”

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Fig. 6 Anal squeeze pressure. (A) Series of three normal short squeeze maneuvers; a clear increase in pressure can be observed during each voluntary squeeze, with pressure morphology very similar between attempts. (B) Marked anal hypocontractility, with virtually no observable increase in pressure during the three short squeeze maneuvers.

that may be a target for biofeedback therapy. Conversely, an abnormal cough response in the presence of reduced squeeze pressures indicates a defect in the sacral reflex arc, and may reflect a more severe phenotype of hypocontractility (Lee and Bharucha, 2016).

Functional anal anatomy using 3D HD-ARM One advantage of 3D HD-ARM over other manometric methods, is its ability to define functional anatomy of the anal canal. Recent studies have illustrated a high degree of pressures asymmetry within the anal canal in health (Raizada et al., 2011). With 3D reconstruction of pressures, the sphincter at rest shows a dumbbell shape, with a high-pressure ring in the middle and low-pressure areas at both ends (Fig. 8A). During the squeeze maneuver, an “hourglass” appearance occurs on 3-dimensions, with “tightening” of the central high pressure ring, while the 2-D map shows a “l” shape (Fig. 8B). The greatest contribution during squeeze is from the distal anterior canal, while the posterior peak pressure moves cranially in relation to the anterior peak pressure; this is due to the differential contribution of the puborectalis muscle and EAS to proximal and distal anal canal pressures, respectively. Deviation from this normal manometric anatomy may be suggestive of pathology, though studies only demonstrate slight concordance with anal sphincter defects detected by endo-anal ultrasound (Rezaie et al., 2017).

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Fig. 7 Anorectal pressures during cough. (A) The upper panel shows a normal cough response; peak rectal and anal pressures occur simultaneously, but the anal response shows a characteristic “teardrop” appearance, with prolongation of the pressure increase compared to rectal. In the middle panel, the same trace has been rendered to a composite line tracing (maximum pressure recorded in the rectum [upper trace] and anal canal e-sleeve [lower trace]), which shows peak anal pressure greatly exceeding peak rectal pressure (349 mmHg vs. 99 mmHg), i.e. a “protective” positive anorectal pressure gradient is maintained. In the lower panel, all anal pressures have been referenced to corresponding rectal pressures at the same time instant; this clearly shows that at all time points, anal pressure exceeds rectal pressure. (B) In a patient with fecal incontinence, the characteristic teardrop appearance is lost (upper panel). When quantified (middle panel), peak rectal pressure is seen to exceed anal pressure (113 mmHg vs. 99 mmHg). i.e., there is a reversal of the recto-anal pressure gradient. When referenced to rectal pressure (lower panel), the anal canal displays a line of negative pressure (“cold” blue color), confirming anal pressure has been exceeded by rectal pressure at this point.

Clinical Interpretation and Utility of ARM as a Test of Evacuation Perhaps the most controversial area regarding ARM is its use in assessing defecatory ability in patients presenting with symptoms of constipation/ED (with or without FI) (Scott and Williams, 2018). De facto, manometry does not test evacuation of rectal content (as do defecography and the BET), but rather it is used to test the assumption that during a normal simulated defecation maneuver (“push”), a coordinated anorectal response will occur, comprising an increase in intrarectal pressure (rectal “propulsion”) caused by the Valsalva maneuver, concomitant with a decrease in intraanal pressure, caused by relaxation of the anal sphincters (see Fig. 9). This is postulated to reverse the normal RAPG, such that rectal pressure exceeds anal pressure, theoretically allowing expulsion of rectal content to occur. An inability to perform this coordinated movement, due to an inadequate RAPG resulting from paradoxical

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Fig. 8 High-definition anorectal manometry images. 2D HD-ARM (right panel) and 3D HD-ARM (left panel) representation of pressures at rest (A) and during squeeze (B), as recorded using a 3D HD-ARM probe. In 2D images, the circular anal canal is split at the posterior midline to show a surface plot view of anal canal pressures. Note the asymmetry of pressures along the axial and circumferential directions. Post, posterior; R, right lateral; Ant, anterior; L, left lateral. Adapted from Lee, T.H. and Bharucha, A.E. (2016). How to perform and interpret a high-resolution anorectal manometry test. Journal of Neurogastroenterology and Motility 22, 46–59.

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Fig. 9 Anorectal pressures during push. (A) Good rectal propulsion during the push maneuver seen in the upper panel. Change in anal pressure is difficult to appreciate qualitatively, but when referenced to rectal pressure (lower panel), rectal pressure is always seen to exceed anal pressure during the maneuver, i.e., a positive recto-anal pressure gradient. (B) Almost absent rectal propulsion during push, with some anal contractility (upper panel). When referenced to rectal pressure, anal pressure is higher at all-time points during the maneuver (lower panel), i.e., the recto-anal pressure gradient is negative. (C) Another example of very poor rectal propulsion, with no obvious change in anal pressure. (D) Good anal propulsion, but clear anal dyssynergia (marked increase in pressure). (E) Excessively high rectal propulsive pressure during push (133 mmHg), with concomitant anal dyssynergia. (F) High rectal propulsive pressure, with likely puborectalis dyssynergia (contractile band above the proximal border of the anal canal).

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contraction or inadequate relaxation of the pelvic floor (including anal) muscles and/or to inadequate rectal propulsive forces during defecation, has been proposed to represent the principal pathophysiological mechanism in patients with a “functional” ED, most commonly termed “dyssynergic defecation,” but previously termed anismus, pelvic floor dyssynergia, outlet dysfunction or functional outlet obstruction. With conventional ARM, a normal manometric response to the “push” maneuver has been defined as an “adequate” increase in rectal pressure ( 40 mmHg), accompanied by a simultaneous reduction in anal pressure (>20% from preceding resting baseline). Four dyssynergic patterns of defecation have been proposed (Rao, 2008), characterized by a paradoxical increase in anal pressure, with (type I) or without (type II) adequate rectal propulsion, and failure of reduction in anal pressure with (type III) or without (type IV) adequate rectal propulsion. However, use of this classification has recently been criticized on several fronts: (1) a diagnostic accuracy study (Grossi et al., 2016), with three observers blinded to subject status (healthy volunteer or constipated patient: n ¼ 170), showed that nearly 90% of control subjects had a manometric pattern of defecation during “push” that would be considered abnormal (i.e., “conventional” types I to IV dyssynergia), and that there was very limited ability of the ARM push maneuver to discriminate between heath and disease; only type IV dyssynergia had a positive predictive value of 70%, and a positive likelihood ratio of 2.3. Newer HR-ARM methods show a similar level of “abnormality” in health when the RAPG is considered (i.e., the RAPG is negative in the majority, in that anal pressure exceeds rectal pressure) (Coss-Adame et al., 2015; Grossi et al., 2016; Noelting et al., 2012). (2) The “push” maneuver is usually conducted in the left-lateral position, and thus expulsion efforts do not mimic normal defecation. Even in healthy volunteers, a dyssynergic pattern of defecation is found considerably more frequently in the left-lateral position compared to the sitting position (Rao et al., 2006). (3) There is marked disagreement between the results of tests of defecatory function. When comparing ARM to barium defecography and the BET for diagnosing ED, agreement was poor with the former and there was no agreement with the latter. For the specific diagnosis of dyssynergic defecation, agreement was only fair (Palit et al., 2016). Overall, recent meta-analyses have shown that the median positive yield for dyssynergia using conventional ARM is 48% (95% CI: 40–56%) (Videlock et al., 2013), compared to a median of only 24% (95% CI: 18–31%) with barium defecography (Grossi et al., 2018). Taken together, these findings reinforce the need to reevaluate the role of ARM for diagnosing ED; undoubtedly, reappraisal of both diagnostic criteria and what represents the “gold standard” investigation is required. Nevertheless, in spite of test limitations, identification of the specific manometric abnormality during the ARM “push” maneuver may be useful in identifying patients who are amenable to biofeedback treatment, and may help direct the therapeutic approach (i.e., to improve rectal propulsive ability, or correct anal “dyssynergia”). For example, a very recent study has shown that poor rectal propulsion is predictive of success (OR ¼ 5.03 [1.02; 24.92]) and failure (OR ¼ 0.41 [0.17; 0.99]) of biofeedback therapy, respectively (Andrianjafy et al., 2019). Nevertheless, because of uncertainty regarding the clinical utility of ARM for diagnosing disorders of anorectal co-ordination, the current London Classification requires the results of the ARM study to be considered in conjunction with those of either a balloon expulsion test or defecography, and not in isolation. If the result of either of these “direct” tests of evacuation is abnormal, then any abnormal pattern of recto-anal coordination (either due to poor rectal propulsive pressure, impaired anal relaxation, or both) is considered to be a minor finding. However, if manometric patterns are abnormal in the presence of a normal “direct” test of evacuation, then this is considered to be an inconclusive finding. Conversely, in patients with an abnormal “direct” test of evacuation, if manometric patterns are normal, then this is also considered to be an inconclusive finding. Recent studies, using either HR-ARM or 3D HD-ARM, have attempted to identify other manometric parameters that may be useful in better discriminating patients who have a prolonged balloon expulsion time. Ratuapli et al. (2013) used a principal components analysis of HR-ARM-derived rectoanal pressures, which demonstrated three phenotypes (characterized by: [i] high anal pressure at rest and during evacuation (“high anal”); [ii] low rectal pressure alone (“low rectal”), and [iii] low rectal pressure with impaired anal relaxation during evacuation (“hybrid”)) that could distinguish between patients with a normal and abnormal BET with a sensitivity of 75% (when specificity was set at 75%). Another HR-ARM study has applied the concept of an “integrated pressurized volume” (IPV) calculation to describe recto-anal coordination during simulated defecation. IPV pressure ratio between the upper 1 cm and lower 4 cm of the anal canal during push was found to be significantly more effective in predicting the results of BET than conventional measures (RAPG) (receiver operator curve area under curve, 0.74, 95% CI: 0.67–0.80; vs. 0.60, 95% CI: 0.52–0.67) (Seo et al., 2018). However, such complex analyses may not be readily transferable to routine clinical practice. Finally, a small subset of patients with symptoms of ED are found to have a very high intrarectal pressure during straining (Fig. 9E), that is frequently associated with impaired anal relaxation (Mazor et al., 2017). This likely reflects an extra effort to attempt expulsion. In some cases, this may compensate for the inadequate anal relaxation, but in other cases the compression may still be insufficient, allied to impaired expulsion (Azpiroz et al., 2002).

Functional anal anatomy during the push maneuver using 3D HD-ARM

During normal “push,” increased intrarectal pressure and anal relaxation generate a tubular “trumpet” shape on 3D HD-ARM mapping that tapers proximally (Li et al., 2013). In patients with paradoxical puborectalis contraction confirmed on defecography and digital rectal examination, 3-D mapping during “push” has shown a characteristic high-pressure area in the posterior wall of the 3-D pressure cylinder, almost certainly representing the nonrelaxing or contracting puborectalis muscle; this is absent in healthy controls (Xu et al., 2014).

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Clinical Interpretation and Utility of the Recto-Anal Inhibitory Reflex (RAIR) Recto-anal areflexia Absence of the recto-anal inhibitory reflex (rectoanal areflexia) is considered a major finding in the London Classification. Classically, the RAIR is absent in patients with Hirschsprung disease (though full-thickness biopsy is required to confirm aganglionosis); however, the clinical utility of this observation is minimal in adult practice, where undiagnosed Hirschsprung disease is exceptionally rare (Azpiroz et al., 2002). In health, the reflex is an integral part of normal defecation. Amplitude and duration of anal relaxation are correlated with the distending volume, i.e., the greater the volume, the greater the fall in anal pressure, and the more sustained the response (Cheeney et al., 2012). A recent 3D HD-ARM study has shown that the RAIR is characterized by differential anal relaxation along the anterior-posterior axis, with maximal relaxation seen posteriorly in the middle and upper portions of anal canal (Cheeney et al., 2012). In constipated patients, an “absence” of the RAIR is usually due to a technical issue (Azpiroz et al., 2002); either resting tone is too low, or, in cases where the rectum is enlarged (e.g., megarectum), greater distension volumes will be required to elicit the response. In patients with FI, differences in reflex parameters have been shown compared to healthy controls (Kaur et al., 2002), but the clinical significance of these findings is unclear.

Clinical Interpretation and Utility of ARM as a Test of Rectal Sensation Awareness of rectal filling is critical to normal bowel function, i.e., the process of defecation and the maintenance of continence. Abnormal visceral sensitivity is accepted as important in the development of functional bowel disorders, including FI and ED, and disturbances of rectal sensation (and also biomechanical function, most commonly described by evaluation of rectal compliance) are common in these conditions, providing the rationale for measurement (Scott and Williams, 2018). There are some significant limitations to the use of “simple” volumetric balloon distension however (Scott and Williams, 2018). Abnormal sensory threshold volumes may not accurately reflect the function of visceral afferents in the presence of increased rectal size and/or compliance. Under such circumstances, greater volumes will be required to distend and thus stimulate the rectum; hence threshold volumes recorded may simply reflect increased rectal capacity and inadequate stimulation, rather than dysfunction of the rectal afferent pathway itself (Gladman et al., 2006). Accordingly, in selected patients with alterations of rectal sensation on balloon distension, or in whom there is a high index of suspicion of abnormal rectal capacity/compliance, further assessment using the computerized electromechanical barostat (considered the “gold standard” investigation) may be indicated. Nevertheless, simple balloon distension, as part of a manometric investigation, is acknowledged to serve as an adequate screening test for sensory dysfunction in routine clinical practice (Scott and Gladman, 2008).

Rectal hypersensitivity

Rectal hypersensitivity, defined as  1 sensory parameter(s) below the lower limit(s) of normal (to include MTV) is considered a major finding in the London Classification. In patients with FI, thresholds for rectal sensation may be normal, reduced or increased. In those complaining particularly of fecal urgency or urge FI, rectal sensation is frequently heightened, often allied to rectal hypocompliance, reduced rectal capacity, or rectal hypermotility (Andrews et al., 2007; Chan et al., 2005), which may impact symptom severity and also defecation frequency. These factors may also cause symptoms of urgency and frequent defecation in ulcerative colitis, radiation injury and in patients with symptoms after a variety of surgical procedures (Bharucha, 2006). Additionally, hypersensitivity is recognized as a hallmark of diarrhea-predominant irritable bowel syndrome (Simren et al., 2018), although rectal hyposensitivity is present in a minority (Gladman et al., 2006).

Rectal hyposensitivity

Rectal hyposensitivity, defined as  2 sensory parameter(s) above the lower limit(s) of normal is considered a major finding in the London Classification. If only 1 sensory parameter is abnormal, this is considered an inconclusive finding. In chronic constipation, 18–66% of patients have rectal hyposensitivity, often allied to an attenuated or absent call to stool (Gladman et al., 2006); this may be “primary” (due to direct impairment of afferent pathway function), “secondary” (due to altered biomechanical properties, e.g., megarectum, or rectal hypercompliance), or both (Gladman et al., 2009). Patients with FI, in whom hyposensitivity is present, tend to have passive (overflow) incontinence (i.e., hyposensitivity provides a common pathophysiological mechanism for those with coexistent FI and constipation) (Nurko and Scott, 2011). It is assumed that stool is involuntarily expelled before the individual is alerted to the need to respond (i.e., lack of “early warning,” and compensatory EAS contraction) (Sun et al., 1990a). In such patients, sensory retraining has been shown to facilitate timely contraction of the EAS and improve continence (Buser and Miner Jr., 1986). Indeed, some studies suggest that the single most important component of biofeedback training for FI is an improved ability to detect rectal distention (Miner et al., 1990).

Limitations of ARM Aside from those already addressed, anorectal manometry has other recognized limitations: 1. interpretation of findings can be difficult due to the wide variability (and overlap) of manometric measurements in health and disease. For example, patients with marked anal hypotonia may be fully continent, and conversely, those with “normal” resting tone may be incontinent (Bharucha et al., 2005), which emphasizes the multifactorial nature of FI;

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2. it is well appreciated that study set-up, equipment, as well as patient position and compliance all have a significant impact on absolute values reported; 3. the selection of test maneuvers (rest, squeeze, cough, push, etc.) is long-standing (all have been employed for several decades), yet they may not appropriately test certain aspects of anorectal function. For example, the push maneuver does not evaluate evacuation per se, as has already been discussed. Likewise, there is little evidence to support the enduring assumption that individuals voluntarily squeeze their anal canal during normal deferral of defecation, nor evidence to support that this behavior is altered in incontinence (Carrington et al., 2019b). Voluntary anal squeeze is measured over a period of 5–30 s; however, continent individuals are able to overcome the urge to defecate for much longer than this. Refinement of some existing maneuvers or the development of novel metrics are required to improve diagnostic utility; 4. although HR-ARM and 3D HD-ARAM are superseding conventional manometric techniques, and despite some promising data emerging as to the possible benefits of these technologies (Carrington et al., 2019a; Lee, 2018), there remains precious little information supporting superiority over conventional techniques with regard to prognostic, diagnostic or interventional benefit.

Conclusions In patients with refractory symptoms of fecal incontinence and/or an evacuation disorder, anorectal manometry is indicated as one of a series of complementary tests to provide important diagnostic information on anal sphincter function, recto-anal coordination, and rectal sensation, with proven clinical utility. Accurate and objective measurements can identify disease phenotypes, allowing definitive diagnoses that can have a direct impact on treatment decisions in clinical practice. The recent shift to high-resolution or high-definition technologies has prompted a collaborative consensus process amongst experts in the field to provide a standardized test protocol (the IAPWG protocol) and also the first manometric classification system for disorders of anorectal function (the London Classification) (Carrington et al., 2019b). Adoption of this much-needed framework for those performing and interpreting anorectal manometry studies will undoubtedly offer harmonization of testing and a common language that has been lacking until now. Nevertheless, this is an ongoing process, and future iterations will evolve as experience with this technology increases, and data from physiological and clinical studies emerge to address knowledge gaps.

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(2018) Visceral hypersensitivity is associated with GI symptom severity in functional GI disorders: Consistent findings from five different patient cohorts. Gut 67: 255–262. Sun WM and Rao SS (2001) Manometric assessment of anorectal function. Gastroenterology Clinics of North America 30: 15–32. Sun WM, Read NW, and Miner PB (1990a) Relation between rectal sensation and anal function in normal subjects and patients with faecal incontinence. Gut 31: 1056–1061. Sun WM, Read NW, Miner PB, Kerrigan DD, and Donnelly TC (1990b) The role of transient internal sphincter relaxation in faecal incontinence? International Journal of Colorectal Disease 5: 31–36. Sun WM, Donnelly TC, and Read NW (1992) Utility of a combined test of anorectal manometry, electromyography, and sensation in determining the mechanism of “idiopathic” faecal incontinence. Gut 33: 807–813. Telford KJ, Ali AS, Lymer K, et al. (2004) Fatigability of the external anal sphincter in anal incontinence. 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(2017) Normal values for solid state high resolution anorectal manometry in healthy adult volunteers. Chinese Journal of Internal Medicine 56: 572–576. Wickramasinghe DP, Perera CS, Senanayake H, and Samarasekera DN (2015) Three-dimensional anorectal manometry findings in primigravida. Digestive Diseases and Sciences 60: 3764–3770. Wu GJ, Xu F, Lin L, Pasricha PJ, and Chen JD (2017) Anorectal manometry: Should it be performed in a seated position? Neurogastroenterology and Motility 29: e12997. Xu C, Zhao R, Conklin JL, et al. (2014) Three-dimensional high-resolution anorectal manometry in the diagnosis of paradoxical puborectalis syndrome compared with healthy adults: A retrospective study in 79 cases. European Journal of Gastroenterology & Hepatology 26: 621–629.

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Further Reading Azpiroz F, Enck P, and Whitehead WE (2002) Anorectal functional testing: Review of collective experience. The American Journal of Gastroenterology 97: 232–240. Bharucha AE (2006) Update of tests of colon and rectal structure and function. Journal of Clinical Gastroenterology 40: 96–103. Carrington EV, Heinrich H, Knowles CH, et al. (2017) Methods of anorectal manometry vary widely in clinical practice: Results from an international survey. Neurogastroenterology and Motility 29: e13016. Carrington EV, Scott SM, Bharucha A, et al. (2018) Expert consensus document. Advances in the evaluation of anorectal function. Nature Reviews. Gastroenterology & Hepatology 15: 309–323. Carrington EV, Heinrich H, Knowles CH, et al. (2019) The International Anorectal Physiology Working Group (IAPWG) recommendations: Standardized testing protocol and the London classification for disorders of anorectal function. Neurogastroenterology and Motility 15(5): 309–323. Diamant NE, Kamm MA, Wald A, and Whitehead WE (1999) AGA technical review on anorectal testing techniques. Gastroenterology 116: 735–760. Fox M, Kahrilas PJ, Roman S, et al. (2018) Clinical measurement of gastrointestinal motility and function: Who and when to refer, and for which test? Nature Reviews. Gastroenterology & Hepatology 15: 568–579. Gladman MA, Lunniss PJ, Scott SM, and Swash M (2006) Rectal hyposensitivity. The American Journal of Gastroenterology 101: 1140–1151. Grossi U, Carrington EV, Bharucha AE, et al. (2016) Diagnostic accuracy study of anorectal manometry for diagnosis of dyssynergic defecation. Gut 65: 447–455. Lee TH and Bharucha AE (2016) How to perform and interpret a high-resolution anorectal manometry test. Journal of Neurogastroenterology and Motility 22: 46–59. Nurko S and Scott SM (2011) Coexistence of constipation and incontinence in children and adults. Best Practice & Research. Clinical Gastroenterology 25: 29–42. Rao SS, Azpiroz F, Diamant N, et al. (2002) Minimum standards of anorectal manometry. Neurogastroenterology and Motility 14: 553–559. Ratuapli SK, Bharucha AE, Noelting J, Harvey DM, and Zinsmeister AR (2013) Phenotypic identification and classification of functional defecatory disorders using high-resolution anorectal manometry. Gastroenterology 144: 314–322. e2. Scott SM and Williams AB (2018) Specialist investigation of anorectal and colonic structure and functions. In: Keighley MR, Williams NS, and Knowles CH (eds.) Surgery of the anus, rectum and colon, 2nd edn., pp. 271–304. Boca Raton, Florida: CRC Press/Taylor Francis Group. Sun WM, Donnelly TC, and Read NW (1992) Utility of a combined test of anorectal manometry, electromyography, and sensation in determining the mechanism of “idiopathic” fecal incontinence. Gut 33: 807–813.

Anorectal Pain Giuseppe Chiarioni, University of Verona, Integrated University Hospital of Verona, Verona, Italy; UNC Center for Functional GI and Motility Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States Anna Granato, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy © 2020 Elsevier Inc. All rights reserved.

Glossary

Anal endosonography Ultrasonography testing done by placing the transducer/probe into the anal canal and imaging the internal and external anal sphincters. Anal fissure Crack in the skin or mucosa in or adjacent to the anal canal commonly, causing symptoms of pain or itching during defecation. Anoscopy Examination of the anus and lower rectum with a rigid, cone or tube. Biofeedback The use of electronic or mechanical devices to provide visual and/or auditory information (feedback) on a biological process for the purpose of teaching an individual to control the biological process. Coccygodynia Pain arising in or around the coccyx which is usually triggered by prolonged sitting on hard surfaces. Previous back trauma is commonly reported by those affected. Defecography Radiographic assessment of the shape of the anorectum during resting, squeezing, and attempted defecation. A mixture of barium sulfate and a thickening agent is inserted into the rectum to perform the investigation. Prior to attempted defecation. Oral contrast should be swallowed in advance to visualize the small bowel and the vagina may be marked with a contrast soaked tampon. Dyssynergic defecation: (also pelvic floor dyssynergia, anismus, spastic pelvic floor syndrome) Chronic disorder of defecation due to functional outlet obstruction by paradoxical contraction or failure to relax the pelvic floor muscles with secondary rectal evacuation impairment. Electrogalvanic stimulation of the pelvic floor Transrectal low frequency electrical stimulation, used to treat rectal pain by relaxing skeletal muscles in the pelvic floor. Functional defecation disorder Difficulty to empty the rectum due to impaired defecation dynamics not related to structural alterations of the pelvic floor. Functional constipation and/or irritable bowel syndrome with constipation are required comorbidities. Levator ani syndrome Chronic or recurring dull aching pain in the rectum or anal canal with tenderness on palpation of the puborectalis muscle., with episodes lasting 30 min or longer, in the absence of organic etiologies. Manometry Device developed to pressure measurements within the gut lumen in the actual context. Outlet obstruction Inability or difficulty to void the rectum due to functional defecation disorders or structural alterations of the pelvic floor that become apparent upon straining. Paradoxical sphincter contraction Contraction of the external anal sphincter and/or the puborectalis muscle upon straining, thus impeding stool passage. Causes are painful anal disorders (fissures, perianal thrombosis, abscess) or pelvic floor dyssynergia. It might be relevant etiology to levator ani syndrome. Pelvic magnetic resonance imaging Imaging modality that can visualize both anal sphincters anatomy and global pelvic floor motion in real-time without radiation exposure. Dynamic images in the mid-sagittal plane are acquired at rest, during squeeze, and rectal evacuation. Proctalgia fugax Fleeting (only a few minutes in duration) sharp pains in the rectum or anal canal, in the absence of known organic etiology. Puborectalis muscle A sling muscle which anchors to the symphysis pubis anteriorly and loops around the rectum to form the anorectal angle. Pudendal neuralgia Chronic perineal pain syndrome due to entrapment and injury of the pudendal nerve in the absence of organic diseases that may explain symptom Rectal prolapse Protrusion of the mucosal lining of the rectum through the anus Rectocoele Weakness in the tissues surrounding the rectum which permits it to bulge abnormally. The most common rectocele is one affecting the rectovaginal septum in women. Solitary rectal ulcer Rectal disorder presenting with rectal bleeding and inability to void the rectum. Proctoscopy findings can range from mucosal erythema to ulcers and polypoid lesions with suggestive histology.

Introduction Chronic anorectal pain syndromes are commonly neglected, but disabling functional pain syndromes which have no underlying pelvic organic disease. There are often veiling psychiatric and emotional factors, which complicate management. These syndromes

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are a challenge for a number of specialists: surgeons, orthopedic surgeons, urologists, gynecologists, gastroenterologists, and pain specialists. Patients usually consult to exclude minor anal pathology such as hemorrhoids and fissures. However, any effort to rule out anorectal and pelvic organic disease have to be considered for labeling the pain as functional without thoroughly excluding a malignancy is a major danger. Etiology is obscure for most of these pain syndromes, but tense or overly contracted pelvic floor muscles have been historically rated as causative and focused intervention to achieve pain relief is common treatment approach (Andromanakos et al., 2011). The lack of understanding is mirrored by the number of synonyms used to describe these pain syndromes such as: chronic idiopathic anal pain, anorectal neuralgia, spastic pelvic floor syndromes, levator ani syndrome, etc. (Andromanakos et al., 2011). A basic knowledge of the pelvic floor anatomy and physiology is important to improve the understanding of the chronic anorectal pain syndromes (Chiarioni et al., 2011). The pelvic floor is a muscle diaphragm that supports the pelvic organs leaving a hollow for rectum, vagina, and urethra to pass into the perineum. The levator ani muscle is composed of three distinct parts: iliococcygeus, pubococcygeus, and puborectalis. Ileococcygeus and pubococcygeus insert on both anterior and posterior sides of the pelvic bones, while the puborectalis muscle winds around the recto-anal junction before inserting into the pubis. The puborectalis is easily palpated by digital rectal exam (DRE) at the anorectal junction. A peculiarity of these striated muscles is the condition of continuous tonic activity that decreases during defecation and micturition (Chiarioni et al., 2011). A volitional or reflex increment in muscle activity is also possible to prevent fecal and urinary incontinence. The normal activity of the pelvic floor muscles is not entirely defined, but it is assumed that a number of neuromuscular and ligament disorders may affect its performance (Chiarioni et al., 2011). Simpson in 1859 first described the association between coccyx trauma and coccygodynia. Thaysen in 1935 introduced the term proctalgia fugax to describe a fleeting, spontaneously remitting severe anal pain without organic etiology. Unfortunately, the term coccygodynia was adopted by Thiele in 1936 to label a chronic perineal pain syndrome of apparently distinct etiology. He perceived that the pain was not in the coccyx, but in the overly contracted pelvic floor muscles which partially inserted into the coccyx. The term levator spasm syndrome was first used by Smith in 1959. His thorough clinical description of the syndrome follows that of Thiele’s, and preserves its relevance up to the present days. Eventually, in 1965 McGivney and Cleveland published a report on effective myorelaxant treatment (Diazepam) of the levator syndrome emphasizing the muscle spasm etiology of the disorder (Chiarioni et al., 2011). The definition of pudendal neuralgia, a perineal pain syndrome secondary to pudendal nerve entrapment into the Alcock canal, was even more controversial until the Nantes Criteria were recently issued (2008) (Labat et al., 2008). The aims of this article are to address the epidemiology, etiology, diagnosis, and management of these chronic functional anorectal pain syndromes. To ease the differential diagnosis, we will also describe chronic perineal pain syndromes such as coccygodynia and pudendal neuralgia that produce similar rectal pain symptoms but have a partly structural etiology with some hints on minor rectoanal disease such as thrombosed hemorrhoids, solitary rectal ulcer, and anal fissure that may likewise give rise to chronic or recurring anorectal pain symptoms. Since diagnosis and management of anorectal pain syndromes can be complex and somehow frustrating for both patients and physicians an empathetic, reassuring and conservative physician’s attitude is mostly suggested.

Functional Anorectal Pain Syndromes Chronic Proctalgia: Levator Ani Syndrome and Unspecified Functional Anorectal Pain Chronic proctalgia was a general term used to define a chronic or recurring pain in the anal canal and/or rectum (Chiarioni et al., 2011). Other names considered synonymous with chronic proctalgia were levator ani syndrome, puborectalis syndrome, chronic idiopathic perineal pain, piriformis syndrome, and pelvic tension myalgia (Chiarioni et al., 2011). In addition, Thiele called it coccygodynia, although he acknowledged that the pain was not in the coccyx. To provide greater consistency in the diagnosis and labeling of functional anorectal pain syndromes, the Rome IV criteria define levator ani syndrome and unspecified functional anorectal pain as chronic or recurrent rectal pain or aching lasting at least 30 min, without evidence of structural or systemic disease explanations for these symptoms (Rao et al., 2016). Pain duration of at least 30 min is key to diagnosis since shorter episodes of pain are suggestive of proctalgia fugax, an acute, spontaneously remitting functional pain syndrome (Rao et al., 2016). The Rome IV criteria distinguish levator ani syndrome (LAS) from unspecified functional anorectal pain relying on the presence or absence of tenderness on palpation of the levator ani muscle during digital rectal exam (DRE) (Rao et al., 2016). This classification updates the previous, rather cumbersome Rome classification in which LAS was designated as “highly likely” if traction on the pelvic floor produced a report of tenderness and only “possible LAS” if no tenderness was elicited (Rao et al., 2016). According to recent epidemiology reports, Rome IV changed the minimum duration of pain required for a diagnosis of levator ani and unspecified functional anorectal pain from 20 to 30 min. Subgrouping patients with functional anorectal pain into levator ani syndrome (LAS) unspecified functional anorectal pain, and proctalgia fugax is consistent with clinical experience of different responses to treatment, but distinct epidemiology and pathophysiology data are lacking (Table 1).

Epidemiology Chronic or frequently recurring pain in the anal canal, rectum, or pelvis is a prevalent symptom that may affect up to 6.6% of the population according to a US householder survey run in 1993 (Drossman et al., 1993). These prevalence rates were confirmed by a population survey of 6931 adults using the Rome IV diagnostic criteria: prevalence of proctalgia fugax was estimated to be 5.4% and prevalence of chronic proctalgia was 1.7% (Rao et al., 2016). In the Householder Survey, pain was more commonly reported by

130 Table 1

Anorectal Pain Anorectal pain syndromes.

Syndrome

Assumed etiology

Symptoms

Digital rectal exam

Levator ani syndrome Unspecified functional anorectal pain Proctalgia fugax Coccygodynia Pudendal neuralgia

Pelvic floor muscle spasm Psychosomatic Increased anal tone Coccyx trauma Pudendal nerve entrapment

Chronic dull rectal ache or pressure sensation Chronic dull rectal ache or pressure sensation Short-lasting rectal cramping Perineal pain triggered by sitting Perineal pain with paresthesia

Tender puborectalis, replicates pain Uneventful Uneventful Tender puborectalis, no pain replication Uneventful

middle aged women. Although only 1/3 of anorectal pain patients consulted a physician, they nevertheless reported significant quality of life burden, work absenteeism, and psychological distress (Drossman et al., 1993). No additional study has attempted to replicate these data in the gastroenterology setting. However, a recent study reported on the prevalence and clinical burden of levator myalgia in a large sample of referrals for any pelvic symptoms to both a urogynecology private practice and an academic tertiary referral Centre (946 patients) (Andromanakos et al., 2011). Levator myalgia is a functional disorder that may be represented by an array of symptoms, including pelvic pressure, dyspareunia, rectal discomfort, and urinary symptoms such as frequency, and urgency (Andromanakos et al., 2011). It is characterized by the presence of tight, band-like pelvic muscles that reproduce the patient’s pain when palpated, thus resembling levator ani syndrome. A diagnosis of levator myalgia was made in up to 25% of academic referrals and 9% of private practice referrals (Andromanakos et al., 2011). Most of the patients reported a history of defecatory dysfunction, depression, opioid medication use and fibromyalgia comorbidity.

Pathophysiology Chronic tension or spasm of the pelvic floor muscles is commonly assumed to be the pathophysiological basis for levator ani syndrome and unspecified functional anorectal pain, although there is no definitive evidence for this hypothesis (Wald, 2001). Inflammation of the levator or arcus tendon of the levator ani muscle has also been suggested as a potential cause of chronic proctalgia. This tendinitis hypothesis is favored by the finding of tenderness on palpation on the left side of the levator ani where the muscle inserts into the pubic ramus of the pelvis (Wald, 2001). However, local steroid injection has been shown to be of no benefit for chronic proctalgia in randomized controlled trials (RCTs) (Chiarioni et al., 2011). More recently, discrepancies in lower limb length, chronic straining, and inflammation due to pelvic tilting have been reported to be relevant comorbid conditions in chronic proctalgia. Patients often report prior pelvic surgery, anal surgery and even spinal surgery as well as childbirth as significant etiology of their chronic pain syndrome (Wald, 2001). In addition, many of these patients are emotionally labile, or psychologically disturbed and stressful life events may be regarded as pain precipitating factors by some. When searched for, psychiatric advice is usually unrewarding for pain benefit (Chiarioni et al., 2011). Anorectal imaging and physiology testing have been traditionally considered to be of little help in chronic proctalgia (Wald, 2001). Increased anal canal resting pressures on perfused catheter anorectal manometry (ARM) were inconsistently reported in small sample studies and not confirmed in large case series. On the contrary, Ger et al. reported in 1993 that LAS was associated with paradoxical contraction of the pelvic floor muscles on straining as evidenced by anal electromyography and/or defecography (Ger et al., 1993). Ultrasonography reports of anal sphincter disruption in idiopathic anal pain have prompted ultrasound guided biopsy of the sphincter in small case series. Fibrosis of the anal sphincter has been evidenced in few patients with no correlation with treatment outcome casting doubts on the relevance of the findings (Andromanakos et al., 2011). A number of structural disorders of the pelvic floor (descending perineum, rectocele, mucosal prolapse) have also been reported in small studies addressing chronic proctalgia patients (Andromanakos et al., 2011). In a recent study, Hompes reported on 59 patients referred to a Pelvic Floor Clinic for chronic functional anorectal pain who were tested by means of an extensive diagnostic protocol including: defecating proctography, ARM, anal ultrasound, and rectal examination under anesthesia in selected cases (Chiarioni et al., 2011). By comparison, same procedures were applied to diagnose 543 rectal prolapse patients complaining either of obstructed defecation or fecal incontinence. Rectal morphology examinations demonstrated high grade internal rectal prolapse in the majority (59%) of pain patients, which was often associated with symptoms of obstructed defecation. However, severity grading of prolapse did not correlate with pain intensity, leaving pain pathophysiology unsolved (Chiarioni et al., 2011). An innovative pathophysiology explanation for chronic proctalgia was recently reported by our group in a prospective, RCT comparing biofeedback, electrogalvanic stimulation (EGS), and digital massage of the levator muscles for the treatment of chronic proctalgia (Chiarioni et al., 2010). A sample of 157 chronic proctalgia patients were studied by ARM and balloon evacuation test (BET) at baseline and after 3 months of treatment (Chiarioni et al., 2010). Patients reporting symptoms consistent with either irritable bowel syndrome or functional constipation were excluded. Physiology features of dyssynergic defecation (i.e. paradoxical contraction or failure to relax the pelvic floor on straining at ARM) were seen in approximately 85% of subjects reporting tenderness on palpation of the levator muscles (Rome II: highly likely LAS, Rome III and Rome IV: LAS). Conversely, in patients who denied tenderness during DRE, inability to relax pelvic floor muscles on straining was rarely found (19%). Dyssynergic defecation was a strong predictor of positive outcome (Chiarioni et al., 2010). These observations led us to conclude that the physiologic mechanisms responsible for LAS and dyssynergic defecation are similar. Factors that interact with pelvic floor physiology to determine the prevalent symptom were left unclear by our study and deserve further investigation. No physiological explanation could be provided for unspecified functional anorectal pain suggesting diverse etiology.

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Clinical picture Levator ani syndrome is often described by patients as a dull ache or pressure sensation in the rectum which is exacerbated by prolonged sitting and relieved by standing or lying down (Wald, 2001). The pain commonly lasts for hours, but it might be continuous with sudden aggravation (Wald, 2001). It usually begins in the morning and increases in severity throughout the day with rare excruciating night exceptions. The common belief of the night prevalence of the pain is due to the nightmare remembering of an actually rare symptom. Pain might radiate into the vagina, the gluteal area or the thigh (Wald, 2001). In its original contribution, Thiele has suggested that the pain irradiation may be determined by a spastic piriformis muscle exerting pressure on the sciatic nerve, as it passes through the sciatic foramen, and on the superior gluteal nerve between the upper border of this muscle and the lower border of the gluteus muscle (Chiarioni et al., 2011). The pain may be precipitated by a number of apparently unrelated factors such as long-distance car traveling, stress, sexual intercourse and even normal defecation potentially leading to stool withholding and symptom aggravation (Andromanakos et al., 2011). In retrospective studies, childbirth, pelvic surgery, anal surgery and even spinal surgery are regarded by the patients as significant determinants of chronic proctalgia (Wald, 2001). In addition, the report of numerous surgical procedures (e.g. sphincterotomy, hemorrhoidectomy) being carried out in the unsuccessful attempt to alleviate the pain is dreadfully common (Chiarioni et al., 2011). In some case series, approximately a third of patients report symptoms of psychological disturbance and stress may act as a significant precipitating factor (Wald, 2001).

Diagnosis The diagnosis of levator ani syndrome relies on the clinical report of recurring/chronic pain or aching in the anal canal or rectum with episodes lasting 30 min or longer, and exclusion of alternative disease explanations for these symptoms by multiple diagnostic tests and optional consultations by other specialists (Rao et al., 2016). Digital rectal examination (DRE) should be performed in any patient consulting for chronic anorectal pain to exclude minor anal pathology (e.g. fissure) and to ascertain whether the patient reports tenderness when traction is applied to the levator ani muscles because this diagnostic sign is a strong predictor of whether the patient is likely to benefit from treatments directed at relaxing pelvic floor muscles (e.g. biofeedback) (Andromanakos et al., 2011). For unexplained reasons, tenderness is often nonsymmetric, being greater on the left side than on the right (Wald, 2001). When performing DRE, the examiner should pause after inserting their finger into the rectum before applying traction on the levator muscles to avoid false positive results. Repeating the posterior traction on the levator muscle on the same exam is also useful to check for reproducibility. In the absence of tenderness a diagnosis of unspecified functional anorectal pain should be entertained. However, most of these patients will undergo a complex diagnostic protocol even in the presence of a typical history and positive DRE findings (Chiarioni et al., 2010). In a recent randomized study considering 227 patients referred for chronic, unremitting rectal pain to a referral Centre, diagnostic evaluation included DRE, colonoscopy, pelvic ultrasound and surgical consultation in all patients, plus gynecology and urology referrals in selected cases (Chiarioni et al., 2010). This complex approach seems justified, since a diagnosis of an organic disease potentially responsible for the pain was eventually reached in the 15% of patients. In this study endoanal ultrasonography imaging was not considered. However, chronic anal pain secondary to an intersphincteric abscess diagnosed by ultrasonography has been reported in a small percentage of postsurgical patients (Andromanakos et al., 2011).

Differential diagnosis The organic diseases that are most commonly involved in chronic anorectal and pelvic pain are: cryptitis, chronic fissure, abscess, hemorrhoids, solitary rectal ulcer, inflammatory bowel disease, and rectal ischemia (Wald, 2001). One should also consider chronic prostatitis and pelvic endometriosis as potential contributors to pelvic pain of obscure etiology (Andromanakos et al., 2011). Local malignancies as anal cancer and perirectal sarcoma can also rarely present with chronic anorectal pain. When a firm diagnosis of functional anorectal pain is made, a simple rectal balloon evacuation test (BET) is worth considering to address disordered defecation features that might be relevant to treatment (Chiarioni et al., 2010, 2014). BET failure should prompt additional investigations (e.g. anorectal manometry, defecography) to refine the diagnosis (Table 2).

Conservative and surgical management No single treatment has been reported to be consistently effective in chronic proctalgia, and management can be a frustrating endeavor for both patients and physicians (Chiarioni et al., 2011; Ger et al., 1993). The first-line treatment is to reassure the patients that the pain is of benign origin and is not suggestive of malignancy. While it makes common sense to care about patients fears, no data are available on the impact of simple reassurance. However, education and counseling are often incorporated as a component of treatment in a number of therapeutic programs for chronic anorectal pain. As a rule of thumb, some physicians would also suggest sleeping on a heating pad and using a rubber ring to sit on when sitting for long period of time to decrease pelvic floor muscle tension (Wald, 2001). Again, no scientific evidence support this suggestion. Digital massage of the puborectalis sling, again intended to relax tense muscles, was one of the early treatments for chronic proctalgia (Chiarioni et al., 2011). Massage of the puborectalis muscle should be performed in a firm manner from anterior to posterior up to 50 times at 3–4 week interval. Some claim that if the massage is not uncomfortable to the patient while being performed, it may not be effective. It has also been reported that the most frequent reason for inadequate massage is failure to reach

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Anorectal Pain

Table 2

Structural and inflammatory diseases that may resembles functional anorectal pain: differential diagnosis.

Conditions

Cardinal symptom(s)

DRE

Testing

Cryptitis: anal gland localized infection Fissure-in-ano Abscess: anal gland suppurative process Thrombosed hemorrhoids

Pain worsened by defecation

Painful, occasionally tender puborectalis

Purulent discharge at anoscopy

Pain as defecating “broken glass” Pain worsened by prolonged sitting

Extremely painful, anal tone increased Painful bulge of the anorectum

Sentinel pile at anoscopy Tracks visualization by MR, US imaging

Painful defecation of bloody discharge Mild anal ache, occasional bleeding Dull ache worsened by defecation Rectal discomfort, tenesmus, urgency Deep, burning rectal pain

Protruding, bluish, tender vessels

Thrombosed vessels at anoscopy

Hard anal mass

Polyps, verrucous ulcerated growths

Rectal ulcerated, polypoid mass Blood and muco-purulent discharge

Rectal ulceration resembling cancer Rectal friable, ulcerated mucosa

Uneventful

Autonomic dysfunction

Tender prostate gland, occasionally tender puborectalis

Enlarged tender gland, urethral discharge on prostate massage

Anal cancer Solitary rectal ulcer Proctitis diverse etiology Paroxysmal extreme pain disorder Chronic prostatitis

Perineal pain associated with bladder symptoms

DRE, digital rectal exam; MR, magnetic resonance; US, ultrasonography.

high enough in the rectum to palpate the levator ani. However, massage has been rarely performed as sole therapy, with the most common adjunctive treatments being hot sitz baths and/or a short course of oral Diazepam, both of which are assumed to have myorelaxant properties on the pelvic floor muscles (Salvati, 1987). Modalities of hot sitz bath have not been standardized. However, 5 min sitz bath of 40
C were found to decrease significantly resting anal canal pressures up to 30 min in a cohort study of 57 subjects. Earlier open-label studies suggested that digital massage combined with hot sitz baths and/or Diazepam were effective for relieving pain in 68% of 316 chronic proctalgia patients (Salvati, 1987). However, benefits seemed to fade away at follow-up, and the addictive potential of Diazepam discourages long-term treatment (Salvati, 1987). Electrogalvanic stimulation (EGS), traditionally used by physiatrists to treat muscle spasticity, has also been advocated for the treatment of LAS when conservative therapy is ineffective (Salvati, 1987). A low frequency oscillating current applied to the pelvic floor muscles through a self-retaining anal probe induces fasciculation and prolonged muscular fatigue, which breaks the spastic cycle and might produce sustained pain relief. Low frequency current has no thermal effect. No side effects have ever been reported other than mild worsening of pain on the first days of treatment as it is also seen in similar electrotherapy modalities (Salvati, 1987). Sohn and coworkers were the first to test EGS in an open study of 80 LAS patients (Chiarioni et al., 2011). They recommended a pulse frequency of 80 cycles per second with the voltage being gradually increased from zero to the point of discomfort and then reduced to a voltage the patient is comfortable with. The voltage can be increased in different sessions to 250–300 Volts as the patient’s tolerance increases. Recommended treatment duration was 1 h per day for three sessions in a 10-day period. In the Sohn study, EGS was the primary treatment approach with 91% of patients reporting pain relief from EGS in the short-term (Salvati, 1987). This high percentage of success was not replicated by subsequent open label studies where EGS therapy was applied to patients resistant to conservative treatment. However, approximately two-thirds of patients did report short-term pain relief (Salvati, 1987). Treatment protocols varied widely in terms of number and duration of sessions. Authors claimed that nonresponders showed features of psychological disturbances, but no convincing evidence was provided. Encouraging short-term results were not confirmed in the long-term. Three additional studies reported persistent pain improvement in only 25%–38% chronic proctalgia patients after EGS treatment (Chiarioni et al., 2011). A modality of administering an additional course of EGS therapy on symptom recurrence has been suggested, but poorly substantiated in clinical practice. In an effort to modulate anal tone, intrasphincteric injection of Botulinum Toxin A (BoTox A) was also considered. BoTox A is a neurotoxin produced by the anaerobic bacterium, Clostridium botulinum, which inhibits the release of acetylcholine at the nerve terminals thus producing chemical transient denervation. The injected muscles loose strength for 2–20 days and may recover in over 2–4 months as new terminal axons sprout and restore neurotransmission. After encouraging preliminary results, intraanal injection of BoTox A has been tested in a randomized controlled trial run in a small sample of 12 LAS patients. However, no differences in rectal pain scores were observed between patients injected with active BoTox versus those injected with saline (Rao et al., 2015). The average amount of time required to defecate a rectal balloon was actually increased after BoTox injection suggesting worsening of potential outlet dysfunction (Rao et al., 2015). The inflammatory (tendinitis) hypothesis for chronic proctalgia has been tested by steroid caudal block and by pelvic tender point injection of a mixture of Triamcinolone acetonide and Lidocaine with negative results (Chiarioni et al., 2011). A recent cohort study compared the outcomes of steroid injection therapy and electrogalvanic stimulation in a small sample of 53 chronic proctalgia patients. In the short term injection treatment was more effective than nonspecific muscle relaxant electrotherapy on inducing total pain relief (26% vs. 9% of patients), but the benefits were lost at 1 year follow-up (Chiarioni et al., 2011).

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Biofeedback treatment of LAS was first described in 1991 by Grimaud and coworkers (Rao et al., 2015). They treated 12 patients with biofeedback techniques focused on voluntary relaxation of external anal sphincter tone. Pain disappeared in all patients after a mean of eight sessions. Additional biofeedback studies failed to replicate these positive results, with highly variable success rates, ranging from 35% to 87.5% of successful pain outcome (Rao et al., 2015). All studies were small sized, uncontrolled and limited by poor standardization of treatment modalities (Rao et al., 2015). To address these limitations, we recently reported a prospective, randomized controlled trial of 157 chronic proctalgia patients to investigate the comparative effectiveness of biofeedback to teach pelvic floor muscle relaxation, EGS, and digital massage of the levator muscles (Chiarioni et al., 2010). The biofeedback protocol was identical to the one commonly used in constipation due to dyssynergic defecation to improve defecation effort (Chiarioni et al., 2010). Anorectal physiology testing including BET was carriedout at baseline and at 1–3 month follow-up. In addition, self-reported stool frequency was assessed at baseline and at 6-months follow-up. The primary outcome was subjective reporting of adequate pain relief by the patient. Secondary outcomes included subjective pain improvement on an ordinal scale, number of days per month with rectal pain, and visual analog scale (VAS) ratings of pain. Primary and secondary outcomes were assessed at 1, 3, 6, and 12 months follow-up. Chronic proctalgia patients were sub grouped according to Rome II criteria into highly likely LAS (Rome III and Rome IV LAS) and possible LAS (Rome III and Rome IV unspecified functional anorectal pain) based on the presence or absence of levator tenderness at DRE (Labat et al., 2008), and randomization to treatment groups was stratified so that each treatment group contained a similar number of patients with a highly likely diagnosis of LAS. At 1-month follow-up, biofeedback was significantly more effective than EGS and massage by intention-to treat analysis, with adequate relief of pain reported by 59.6% vs. 32.7% vs. 28.3% for biofeedback, EGS, and massage, respectively. Benefits were maintained long term and no relevant side effects were reported in any treatment arm. Subgrouping the patients lead to the finding that no treatment was effective in “possible LAS” patients (unspecified functional anorectal pain). However, among patients with highly likely LAS (Rome III and Rome IV LAS) adequate relief was reported by 87% for biofeedback, 45% for EGS and 22% for massage at 1 month follow-up. Improvements were maintained for the whole follow-up. The superiority of biofeedback was supported by all the secondary outcome measures including number of days per month with pain, which decreased from 14.7 per month to 3.3 per month for biofeedback, 8.9 for EGS, and 13.3 for massage (Chiarioni et al., 2010). The mechanism for achieving adequate pain relief was consistent with improved pushing effort in responders both on gaining the ability to relax anal canal on straining and to effectively evacuate a rectal balloon (Chiarioni et al., 2014). This interpretation was confirmed by a posthoc analysis showing that 94.2% of those who improved outlet dysfunction on one or both of these measures reported adequate pain relief, while only 13.6% of those who failed to improve pelvic floor function reported a positive outcome regardless of the treatment provided. In addition, stool frequency increased from baseline to posttreatment in responders, even in the absence of a former complaint of constipation. We concluded that biofeedback is an effective treatment for LAS, and EGS is somewhat effective (Chiarioni et al., 2010). Reinforcing this conclusion, the recently convened American Neurogastroenterology and Motility Society and the European Society of Neurogastroenterology and Motility task force on biofeedback therapy for anorectal disorders stated that biofeedback therapy may be useful for the short-term treatment of LAS with dyssynergic defecation (Level II, Grade B) (Rao et al., 2015). Unfortunately, unspecified functional anorectal pain patients are still left without a satisfactory treatment option. Depression and anxiety are both frequently reported in nonresponsive proctalgia patients (Wald, 2001). Brain processing of pain may be altered in FGID, but data in functional anorectal pain patients are lacking (Wald, 2001). In addition, no trial has systematically evaluated the effect of either psychotherapy intervention or psychotropic drugs in these patients. Small case series report significant improvement of pain in approximately 40% of LAS patients by means of tricyclic antidepressant therapy (Wald, 2001). Drug schedule and correlation with psychological wellbeing were ill defined. When conservative management fails, surgical consultation is often obtained by chronic proctalgia patients in an additional effort to exclude minor anal diseases. However, when the meticulous search of an organic pathology potentially responsible for the symptom has proven negative, evidence that surgery can help these disabled patients is highly controversial at best. Atkin et al. reported prospectively on the clinical characteristics and treatment outcomes of 170 patients referred to the St. Mark Hospital for functional anorectal pain, most of them with a final diagnosis of LAS (Andromanakos et al., 2011). The vast majority of patients had previously undergone some surgical intervention in the unfortunate effort to solve the pain. This included treatment of hemorrhoids (55 subjects), anal sphincterotomy (29 subjects), anal stretch (27 subjects), rectocele plication (1 subject), and even defunctioning ileostomy (1 subject). Three patients with increased anal pressures and internal anal sphincter thickness on imaging underwent prospective lateral sphincterotomy with no symptom improvement (Andromanakos et al., 2011). In this article, the most effective treatment was biofeedback to teach relaxation of the pelvic floor muscles. Sacral nerve stimulation (SNS) has also been considered as a treatment option in LAS patients. SNS is a marginally invasive surgical procedure that has been reported to benefit patients with fecal incontinence by unknown mechanism(s). SNS is a two phase procedure consisting of (Andromanakos et al., 2011) a trial evaluation interval; and (Chiarioni et al., 2011) a second stage with permanent stimulator implantation, provided the trial results are clinically successful. The first stage, also termed percutaneous nerve evaluation (PNE), is of most relevance to determine the feasibility of electrode implantation into the sacral foramina, and to determine whether clinical benefits are worth pursuing with permanent implantation. SNS was reported to be beneficial in an open study involving 27 chronic proctalgia patients. However, when benefits were assessed by intent to treat analysis, pain relief was reported in 50% reduction in pain while sitting immediately after infiltration strongly support the role of the pudendal nerve entrapment. It is common practice to add corticosteroids at the time of the anesthetic nerve block with the therapeutic objective of treating a possible inflammatory component. However, a recent RCT failed to evidence any benefit of corticosteroid augmented infiltration compared to lidocaine alone (Chiarioni et al., 2011). Duration of action of anesthetic block is highly variable going from hours to weeks and occasionally up to recovery in referral centers. Some Authors believe that symptomatic relief depends on the accuracy of injection technique, but no supporting evidence has been published. The improvement in sensory, motor or autonomic symptoms is variable and long term outcome data of the procedure are lacking. In refractory patients surgical decompression of the pudendal nerve may be considered. However, the surgical approach is poorly standardized and a fair percentage of those operated report either persistence of the pudendal neuralgia or manifestation of a diverse gluteal pain after decompressive surgery (Labat et al., 2008).

Pearls of Practice Clinical presentation and objective findings at digital rectal examination are of paramount relevance to improve diagnosis and management of chronic perineal pain syndromes. The following are our recommendations based on clinical experience to ease the

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everyday care of these difficult patients. This compendium of differential diagnosis is meant to cover only the prevalent diseases potentially determining acute and/or chronic perineal pain. Anal fissure: a deep anal fissure with severe sphincter spasm can be mistaken for chronic proctalgia. Massage will obviously make the fissure worse. A local anesthetic will usually allow a proper diagnosis in doubtful cases. Intersphincteric abscess: a high intersphincteric abscess might resemble chronic proctalgia; however, the onset is typically acute and an abscess should be promptly referred for a surgical consultation. DRE is usually too painful to be performed without sedation. Thrombosed hemorrhoids: this very painful disease can be mistaken for proctalgia fugax, but a careful DRE will yield an appropriate diagnosis. Prostatitis: an inflamed prostate may mimic chronic proctalgia at first referral, but DRE will reveal a tender, enlarged gland and generally cause prostatic secretion. Mucosal prolapse: an uncomfortable ball in the rectum similar to chronic proctalgia may be reported by patients at a preliminary stage of rectal procidentia. DRE on straining will demonstrate the prolapse. When in doubt, proctoscopy will confirm the structural alteration. Solitary rectal ulcer syndrome: painful defecation and chronic rectal discomfort may be reported in this uncommon syndrome. However, intermittent mucus and blood discharge will be disclosed by a dedicated history. Coccygodynia: coccygodynia pain may mimic LAS and DRE might reveal a tender puborectalis muscle at palpation. However, DRE should never be able to evoke the typical symptom, and a previous back trauma is commonly reported. Pudendal neuralgia: pudendal neuralgia can be mistaken for both proctalgia fugax and LAS. Symptoms of disordered cutaneous sensitivity are commonly reported in association with the pain, and pain becomes worse in the sitting position. DRE might be inconclusive. Cauda equina and Conus medullaris syndromes: neurologic disorders of the distal spinal cord have all been reported to cause some degree of pelvic and or coccygeal pain. Pain is usually not worsened by the sitting position and saddle anesthesia or paresthesia are common associated complaints. DRE is uneventful. Neurologic disorders might show a slowly progressing clinical picture. Neurologic evaluation should be considered when appropriate management of chronic proctalgia fails to provide relief.

Competing Interests Dr. Chiarioni is a member of the consulting/speaker Board of Takeda Italia, Allergan Italia, Malesci, Omeopiacenza and Alfa-Sigma Italia and member of the Anorectal Committee of the Rome Foundation. Dr. Granato has no conflict of interest to declare.

References Andromanakos NP, Kouraklis G, and Alkiviadis K (2011) Chronic perineal pain: Current pathophysiological aspects, diagnostic approaches and treatment. European Journal of Gastroenterology & Hepatology 23: 2–7. Chiarioni G, Nardo A, Vantini I, Romito A, and Whitehead WE (2010) Biofeedback is superior to electrogalvanic stimulation and massage for treatment of levator ani syndrome. Gastroenterology 138: 1321–1329. Chiarioni G, Asteria C, and Whitehead WE (2011) Chronic proctalgia and chronic pelvic pain syndromes: Newetiologic insights and treatment options. World Journal of Gastroenterology 17: 4447–4450. Chiarioni G, Kim SM, Vantini I, and Whitehead WE (2014) Validation of the balloon evacuation test: Reproducibility and agreement with findings from anorectal manometry and electromyography. Clinical Gastroenterology and Hepatology 12: 2049–2054. Drossman DA, Li Z, Andruzzi E, Temple R, et al. (1993) U.S. householder survey of functional gastrointestinal disorders: Prevalence, sociodemography and health impact. Digestive Diseases and Sciences 38: 1569–1580. Dudding TC, Thomas GP, Hollingshead JR, George AT, Stern J, and Vaizey CJ (2013) Sacral nerve stimulation: An effective treatment for chronic functional anal pain? Colorectal Disease 15: 1140–1144. Ger GC, Wexner SD, Jorge JM, et al. (1993) Evaluation and treatment of chronic intractable rectal pain: A frustrating endeavor. Diseases of the Colon and Rectum 36: 139–145. Kamm MA, Hoyle CH, Burleigh DE, et al. (1991) Hereditary internal anal sphincter myopathy causing proctalgiafugax and constipation: A newly identified condition. Gastroenterology 100: 805–810. Karadimas EJ, Trypsiannis G, and Giannoudis PV (2011) Surgical treatment of coccygodynia: An analytic review of the literature. European Spine Journal 20: 698–705. Labat JJ, Riant T, Robert R, Amarenco G, Lefaucheur JP, and Rigaud J (2008) Diagnostic criteria for pudendal neuralgia by pudendal nerve entrapment (Nantes Criteria). Neurourology and Urodynamics 27: 306–310. Rao SS, Benninga MA, Bharucha AE, Chiarioni G, Di Lorenzo C, and Whitehead WE (2015) ANMS-ESNM position paper and consensus guidelines on biofeedback therapy for anorectal disorders. Neurogastroenterology and Motility 27: 594–609. Rao SSC, Bharucha AE, Chiarioni G, et al. (2016) Anorectal disorders. Gastroenterology 150: 1430–1442. Salvati EP (1987) The levator syndrome and its variant. Gastroenterology Clinics of North America 16: 71–78. Traycoff RB, Crayton H, and Dodson R (1989) Sacrococcygeal pain syndromes: Diagnosis and treatment. Orthopedics 12: 1373–1377. Wald A (2001) Functional anorectal and pelvic pain. Gastroenterology Clinics of North America 30: 243–251.

Further Reading Armananzas L, Arroyo A, Ruiz-Tovar J, et al. (2015) Chronic idiopathic anal pain. Results of a diagnostic-therapeutic protocol in a colorectal referral unit. Cirugí a Española 93: 34–38. Atkin GK, Suliman A, and Vaizey CJ (2011) Patient characteristics and treatment outcome in functional anorectal pain. Diseases of the Colon and Rectum 54: 870–875. Beer-Gabel M, Carter D, Venturero M, Zmora O, and Zbar AP (2010) Ultrasonographic assessment of patients with chronic anal pain referred to a tertiary referral center. Techniques in Coloproctology 14: 107–112.

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Chiarioni G and Whitehead WE (2009) Biofeedback therapy for constipation. In: Parkman HP, Rao SSC, and Mc Callum R (eds.) Gastrointestinal motility testing: Laboratory and office handbook. Thorofare, NJ: Slack Inc. Christiansen J, Bruun E, Skjoldbye B, and Hagen K (2001) Chronic idiopathic anal pain: Analysis of ultrasonography, pathology, and treatment. Diseases of the Colon and Rectum 44: 661–665. Daniels JP and Khan KS (2010) Chronic pelvic pain in women. BMJ 341: c4834. de Paredes V, Etiennev I, Bauer P, Taouk M, and Atienza P (2006) Proctalgia Fugax: Demographic and clinical characteristics, what every doctor should know from a prospective study of 54 patients. Diseases of the Colon and Rectum 50: 893–989. Finamore P, Goldstein H, and Whitmore K (2008) Pelvic floor muscle dysfunction: A review. Journal of Pelvic Medicine and Surgery 14: 417–422. Hompes R, Jones OM, Cunningham C, and Lindsey I (2011) What causes chronic idiopathic perineal pain? Colorectal Disease 13: 1035–1039. Jeyarajah S, Chow A, Ziprin P, Tilney H, and Purkayastha S (2010) Proctalgia Fugax, an evidence-based management pathway. International Journal of Colorectal Disease 25: 1037–1046. Kleimeyer JP, Wood KB, Lønne L, et al. (2017) Surgery for refractory coccygodynia: Operative versus nonoperative treatment. Spine 42: 1214–1219. Labat JJ, Riant T, Lassaux A, et al. (2017) Adding corticosteroids to the pudendal nerve block for pudendal neuralgia: A randomised, double-blind, controlled trial. BJOG 124: 251–260. Mayer EA, Aziz Q, Coen S, et al. (2009) Brain imaging approaches to the study of functional GI disorders: A Rome Working Team Report. Neurogastroenterology and Motility 21: 579–596. Mazza L, Formento E, and Fronda G (2004) Anorectal and perineal pain: New pathophysiological hypothesis. Techniques in Coloproctology 8: 77–83. Renzi C and Pescatori M (2000) Psychologic aspects in proctalgia. Diseases of the Colon and Rectum 43: 535–539.

Antithrombotics and Gastrointestinal Endoscopy Andrew Veitch, New Cross Hospital, Wolverhampton, United Kingdom © 2020 Elsevier Inc. All rights reserved.

Introduction Antithrombotic drugs (antiplatelet agents and anticoagulants) are very widely prescribed, and frequently encountered in patients scheduled for endoscopy. While these drugs have proven benefits for patients with ischemic heart disease, cerebrovascular disease or peripheral vascular disease, they also convey a risk of hemorrhage. This hemorrhage may be spontaneous, or as a consequence of endoscopic procedures. Management of such patients is therefore a balance of the risks of hemorrhage, if antithrombotics are continued, versus thrombosis if they are discontinued. Management in an individual patient can be guided by the relative risk of hemorrhage or thrombosis, and this will depend on the indication for antithrombotic therapy and the risk of hemorrhage associated with the endoscopic procedure. Comprehensive guidelines have been produced by the American Society of Gastrointestinal Endoscopy (ASGE) (Acosta et al., 2016), jointly by the British Society of Gastroenterology (BSG), and European Society of Gastrointestinal Endoscopy (ESGE) (Veitch et al., 2016), and jointly by the Asian Pacific Association of Gastroenterology (APAGE) and Asian Pacific Society for Digestive Endoscopy (APSDE) (Chan et al., 2018). The guidance in these documents differs slightly, and this reflects the limited data available upon which to determine management strategies. There are few prospective studies, and fewer still that are comparative. While the body of data on endoscopy on antithrombotics is growing, some recommendations are based on extrapolation from studies in nonendoscopic situations, and some are based on consensus expert opinion. Particular challenges have been raised with the development of newer antiplatelet drugs, and with introduction of direct oral anticoagulants (DOACs). The data underlying the recommendations in these guidelines will be discussed, together with the areas of uncertainty.

Management of Antithrombotics in Patients Undergoing Elective Endoscopic Procedures There are high and low risk indications for antithrombotic therapy based on the risk of thrombosis without therapy (Table 1), and high and low risk endoscopy procedures based on the risk of hemorrhage (Tables 1 and 2). The estimate of risk of hemorrhage due to endoscopic procedures is largely based on studies in patients not taking antithrombotics on the reasonable assumption that the risk will be much greater in patients on the more potent therapies such as dual antiplatelet therapy or anticoagulants. The relatively low risk of therapeutic endoscopic procedures on aspirin is well characterized, but there are few studies of therapeutic endoscopy on more potent antithrombotic regimens. The risks presented in Table 2 can sometimes underestimate the risk on anticoagulants; for example the baseline risk of hemorrhage for endoscopic ultrasound (EUS) with fine needle aspiration (FNA) was 0.13% in a metaanalysis, but in a study of EUS with FNA on LMWH, the risk of hemorrhage was 33.3% (Kien-Fong Vu et al., 2006).

Patient Factors Hemorrhage as a result of endoscopic therapy can often be managed with hemostatic techniques, and is rarely fatal. The statistical risk of thrombosis in a patient with a short, temporary, cessation of anticoagulation may be low, but if this resulted in a stroke, then this may be catastrophic for the patient. In a retrospective study of patients with atrial fibrillation (AF) whose anticoagulation with warfarin was adjusted for endoscopy the subsequent risk of stroke was low, but was significantly higher in patients with added cardiovascular risk factors (Blacker et al., 2003); range from 0.31% for patients with uncomplicated AF to 2.93% for complex patients with advanced age and severe illness. Alternatives to diagnostic endoscopy include radiological investigations, but if endoscopic therapy is indicated, then it may be possible to defer this for patients who are anticoagulated for a defined period such as those with venous thromboembolism. For patients on dual antiplatelet therapy (DAPT) for coronary stents it may be possible to defer the endoscopic therapy until the P2Y12 inhibitor can be discontinued, and aspirin continued alone. Given the limited data underlying management strategies for antithrombotics in endoscopy, those patients that require temporary cessation of long-term anticoagulation or antiplatelet therapy should be counseled regarding the risks of discontinuation of therapy versus the benefits of the procedure, as well as advised of alternatives investigations.

Drug Factors Aspirin Aspirin is very widely prescribed for the prevention of thrombosis in cardiovascular, cerebrovascular and peripheral disease. It inhibits platelet function via its action on cyclooxygenase (COX). Platelet activation depends on thromboxane synthesis by the platelets, and this is dependent on COX. Aspirin irreversibly inactivates COX by acetylation, and whilst the pharmacokinetic halflife of aspirin is only 20 min, the pharmacodynamic effect persists for the duration of the platelet lifespan of 7–10 days as the platelet is unable to synthesize new COX enzyme.

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Management of antithrombotics in patients undergoing elective endoscopic procedures Low risk procedure Diagnostic procedures
biopsy Biliary stenting without sphincterotomy

Aspirin

Primary or secondary prophylaxis

Continue therapy

P2Y12 inhibitors Clopidogrel Prasugrel Ticagrelor

Low risk indication (Usually monotherapy) Ischaemic heart disease without coronary stent Peripheral vascular disease Cerebrovascular disease High risk indication (Usually DAPT) Coronary stents: DES 12 months BMS > 1 month Continue aspirin Restart DAPT 24–48 h postprocedure Stop warfarin 5 days before procedure Ensure INR 48 h before procedure (Except Dabigatran with CrCl 30–50 mL/min take last dose 72 h before procedure) Seek Hematology advice for any DOAC in a patient with evolving renal failure Restart DOAC 24–48 h postprocedurea

DAPT, dual antiplatelet therapy; DES, drug-eluting stent; BMS, bare metal stent AF atrial fibrillation; VTE, venous thromboembolism; INR, international normalized ratio; DOAC, direct oral anticoagulant; CrCl, creatine clearance. a Consider delaying re-starting therapy up to 7 days if there is a high risk of postprocedure bleeding. b Most thrombophilia syndromes will not require heparin bridging if warfarin is temporarily discontinued, but a hematology opinion should be sought in each instance. Adapted from Veitch, A. M., Vanbiervliet, G., Gershlick, A. H., et al. (2016). Endoscopy in patients on antiplatelet or anticoagulant therapy, including direct oral anticoagulants: British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guidelines. Gut 65, 374–389.

Aspirin can be prescribed alone or in combination with other antiplatelet drugs, and for primary or secondary prophylaxis. The value of aspirin for primary prophylaxis of thrombosis is uncertain. Patients who discontinue aspirin therapy for secondary prophylaxis have three times the risk of cerebrovascular events, the majority occurring within 7–10 days after discontinuation (Maulaz et al., 2005). In a randomized controlled trial of interruption of aspirin for noncardiac surgery, major cardiac events were five times more common in the placebo group compared to the aspirin group (9% vs. 1.8%), but with no difference in hemorrhage between the groups (Oscarsson et al., 2010).

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Risk of hemorrhage associated with therapeutic endoscopic procedures

Procedure

Risk of hemorrhage (%)

Colonoscopic polypectomy Colonic EMR (>10 mm) Esophageal EMR Duodenal EMR Endoscopic submucosal dissection ERCP þ sphincterotomy ERCP þ sphincteroplasty Ampullectomy Esophageal dilatation Esophageal/duodenal/enteral stent Colonic stent Percutaneous endoscopic gastrostomy EUS with FNA EUS with brushing of pancreatic cysts

0.07–1.7 3.7–11.3 0.6–0.9 6.3–12.3 2–6.9 0.1–2 0.19 1–7 0–1.7 0.5–1 0–4.5 3, < 2% had mitral stenosis and < 3.4% had CHADS2 scores of 5 or 6. There was no significant difference in rates of thromboembolism between the LMWH and placebo groups, but there was a significant increase in major hemorrhagic events in the LMWH group versus placebo (3.2% vs. 1.3%). Caution should be exercised when interpreting the results in the high-risk thromboembolic groups as the study was not designed or statistically powered to examine these categories. BSG/ESGE guidelines (Veitch et al., 2016) do not recommend bridging for nonvalvular AF, ASGE guidelines (Acosta et al., 2016) recommend bridging with LMWH for CHA2DS2VASc > 2 and the APAGE/APSDE guidelines recommend bridging for CHA2DS2VASc > 5. Further research on the benefits of heparin bridging is required in high-risk nonvalvular AF patients on warfarin in order to determine the optimum approach. Bridging with LMWH has also been studied in patients on DOACs. In a German registry, heparin bridging led to a higher rate of major hemorrhage (2.7% vs. 0.5% P ¼ .01) with no reduction in thromboembolism (Beyer-Westendorf et al., 2014). In the RE-LY trial bridging of dabigatran with LMWH resulted in higher major hemorrhage rates compared to no bridging (6.5% vs. 1.8% P < .001) with no difference in thrombosis rates between the groups (Douketis et al., 2015a). Bridging with heparin is therefore not recommended for DOACs, and the short half-lives of these drugs may render it unnecessary in any case.

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Procedure Factors Therapeutic procedures have an intrinsic risk of hemorrhage and data regarding this is presented in Table 2. Interpretation of the literature is often confusing due to different definitions of hemorrhage, and a mixture of intra-procedural and postprocedural hemorrhage within studies. The latter can be a particular problem, as postprocedural hemorrhage can be delayed by several days, by which time antithrombotic therapy has been recommenced. Measures to help prevent this, such as routine clipping of polypectomy sites, may be considered in patients on antithrombotics. Large studies involving endoscopic biopsies in patients not on antithrombotics have found no significant risk of hemorrhage. Other studies, involving a limited number of biopsies, have demonstrated no increased risk of hemorrhage in patients on aspirin, clopidogrel or warfarin (Ono et al., 2012; Whitson et al., 2011). For patients on anticoagulants, the risks associated with multiple biopsies for Barretts surveillance, for example, or large volume “jumbo” biopsies, are uncertain. The risk of hemorrhage from biopsies in patients on DOACs has not been specifically studied. Unlike warfarin, the level of anticoagulation for DOACs is not readily measurable, plasma levels may peak postdosage, and the effects are not easily reversible. For these reasons a pragmatic approach was taken in the BSG/ESGE guidelines to recommend omitting the morning dose of DOAC for diagnostic procedures which might require biopsy (Veitch et al., 2016). The ASGE and APAGE/APSDE guidelines recommend continuation of DOAC in this situation (Acosta et al., 2016; Chan et al., 2018), and further studies are required to determine the safety and efficacy of either approach. Analysis of large studies (>20,000 patients in total) involving continuation of aspirin during therapeutic endoscopic procedures, for example, colonoscopic polypectomy and ERCP with sphincterotomy, have confirmed the safety of this strategy. Endoscopic submucosal dissection (ESD) (Cho et al., 2012) or large (>20 mm) colonic endoscopic mucosal resections (EMR) (Burgess et al., 2014) have been found to have an increased risk of hemorrhage on aspirin. The indications for aspirin therapy need to be considered, however, in relation to the risks of hemorrhage before discontinuing therapy. For patients on DAPT, therapeutic procedures are usually avoided, or DAPT is modified temporarily in appropriate patients according to published guidelines. Data relating to the risks of modifying or continuing antithrombotics for therapeutic endoscopic procedures are reviewed extensively in Veitch et al. (2016). Analysis of much of the literature reveals retrospective case series including a range of antiplatelet regimens and differing approaches to modification. Definitions of significant hemorrhage are often unclear for both intra-procedural and postprocedural hemorrhage. There is a need for more prospective comparative studies with clear definitions of hemorrhage and standardized approaches to management of antithrombotics. There have been some studies of continued antithrombotic therapy for therapeutic procedures. A meta-analysis of studies of colonoscopic polypectomy on continued clopidogrel (88% of polyps 40 years old.

Special Cases Chronic Appendicitis Evidence exists that recurrent appendicitis may cause episodes of chronic waxing-and-waning RLQ pain from intermittent obstruction and inflammation. However, descriptions in the literature of this phenomenon are scanty and the morphologic information is often brief or incomplete. If a chronic inflammatory infiltrate is seen in the appendix, possibilities include self-resolving AA or a specific infection. These patients are often difficult to diagnose and treat. There appears to be two distinct groups of patients: those with recurrent episodes of abdominal pain who ultimately have a chronically inflamed appendix, and those in whom a histologically normal appendix is removed. Characteristics of these patients with recurrent episodes of pain are the presence of chronic inflammatory changes at the time of appendicectomy, and the presence of appendicolith on CT scan with a thickened appendix greater than 9 mm in width. In those with a normal appendix neuroimmune changes with an increased expression of substance P and vasoactive intestinal peptide (VIP) containing nerves have been demonstrated suggesting, a possible neuroimmune explanation for symptoms. There is no current standardized strategy for the management of chronic appendicitis, although these patients usually feel better after the appendix is removed.

Appendiceal Abscess Preoperative intra-abdominal or pelvic abscess occurs in 3%–8% of patients presenting with AA, and should be suspected in those presenting with a palpable mass (Fig. 5). Patients with an appendix abscess have a tender mass with a swinging pyrexia, tachycardia, and leucocytosis. The abscess is most often located in the lateral aspect of the RLQ but may be pelvic. A rectal examination is useful to identify a pelvic collection. Although pre-hospital delay has traditionally been viewed as a risk factor for perforation and abscess formation, evidence demonstrates that some patients might be at risk of abscess formation despite prompt treatment. The presence of a mass may be confirmed on US or CT scan. In elderly patients, the possibility of an underlying malignancy must be excluded. The initial treatment in a patient who is otherwise well is conservative, with initiation of appropriate resuscitation and intravenous broad spectrum antibiotics. Careful clinical review is required to ensure resolution of the inflammatory process. Meta-analyses of mainly retrospective studies demonstrate that percutaneous drainage of a periappendicular abscess, if accessible, is an appropriate treatment in addition to antibiotics.

Fig. 5 CT image of complicated AA with large RLQ abscess (white arrow). Courtesy of Andrea Figus, M.D., Department of Radiology, San Francesco Hospital, Nuoro, Italy

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Fig. 6 Intraoperative laparoscopic image of perforated AA, with extraluminal faecalith (black arrow). Courtesy of Francesco Balestra, M.D., Department of Surgery, San Francesco Hospital, Nuoro, Italy.

However, the recent randomized clinical trial by Mentula et al. demonstrates that LA in experienced hands is safe and feasible first-line treatment for appendiceal abscess, and it is associated with fewer readmissions and fewer additional interventions than conservative treatment with percutaneous drainage and antibiotics (Fig. 6) (Mentula et al., 2015). Interval appendectomy is recommended for those patients with recurrent symptoms.

Appendicitis in Pregnancy AA in pregnancy poses a particularly difficult diagnostic problem, because the enlarging uterus displaces the appendix. AA can occur during any trimester, although perforation is more common in the third trimester. The pregnant woman may complain of abdominal pain at any location to which the appendix is shifted. However, RLQ pain is still the most common location of discomfort. Symptoms such as nausea, vomiting, and anorexia occur in both AA and pregnancy and thus do not contribute to differentiating the diagnosis. The condition is a true emergency requiring rapid diagnosis and surgical treatment. US, and eventually MRI, are particularly helpful in making the diagnosis, both because they do not pose a radiation risk and because they enables visualization of pelvic pathology. There is no strong current evidence as to the preferred modality of appendectomy, open or laparoscopic, during pregnancy from the prospect of foetal or maternal safety. However, low grade evidence shows that LA during pregnancy might be associated with higher rates of foetal loss. The literature does not clearly define the balance between advantages and disadvantages in this particular setting and the choice of the approach should be taken by the attending surgeon after a thorough discussion with the patient, balancing the advantages of laparoscopy versus the theoretical risk of fetal loss (Di Saverio et al., 2016).

Incidental Appendectomy Incidental appendectomy (removal of the appendix when an operation is being performed in the abdomen for another reason) is not warranted unless future diagnostic difficulties are anticipated. It can lead to increased infectious complications during certain procedures such as those involving vascular grafts. Even in operations not associated with increased complications from incidental appendectomy, it is associated with increased operative time and cost with questionable benefit. Most patients who develop appendicitis are young, whereas most people who undergo other intra-abdominal operations are elderly and have a much smaller chance of ever needing an appendectomy.

References Andersson M and Andersson RE (2008) The appendicitis inflammatory response score: A tool for the diagnosis of acute appendicitis that outperforms the Alvarado score. World Journal of Surgery 32: 1843–1849. Bhangu A, Søreide K, Di Saverio S, Assarsson JH, and Drake FT (2015) Acute appendicitis: Modern understanding of pathogenesis, diagnosis, and management. Lancet 386: 1278–1287. https://doi.org/10.1016/S0140-6736(15)00275-5. Carr NJ (2000) The pathology of acute appendicitis. Annals of Diagnostic Pathology 4: 46–58.

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Di Saverio S, Birindelli A, Kelly MD, et al. (2016) WSES Jerusalem guidelines for diagnosis and treatment of acute appendicitis. World Journal of Emergency Surgery 18(11): 34. Flum DR (2015) Clinical practice. Acute appendicitis—Appendectomy or the “antibiotics first” strategy. The New England Journal of Medicine 372: 1937–1943. Gorter RR, Eker HH, Gorter-Stam MA, Abis GS, Acharya A, Ankersmit M, Antoniou SA, Arolfo S, Babic B, Boni L, Bruntink M, van Dam DA, Defoort B, Deijen CL, DeLacy FB, Go PM, Harmsen AM, van den Helder RS, Iordache F, Ket JC, Muysoms FE, Ozmen MM, Papoulas M, Rhodes M, Straatman J, Tenhagen M, Turrado V, Vereczkei A, Vilallonga R, Deelder JD, and Bonjer J (2016) Diagnosis and management of acute appendicitis. EAES consensus development conference 2015. Surgical Endoscopy 30: 4668–4690. Humes D, Speake WJ, and Simpson J (2007) Appendicitis. BMJ Clinical Evidence 2007: 0408. Mentula P, Sammalkorpi H, and Leppäniemi A (2015) Laparoscopic surgery or conservative treatment for Appendiceal abscess in adults? A randomized controlled trial. Annals of Surgery 262: 237–242. Podda M, Cillara N, Di Saverio S, et al. (2017) Antibiotics-first strategy for uncomplicated acute appendicitis in adults is associated with increased rates of peritonitis at surgery. A systematic review with meta-analysis of randomized controlled trials comparing appendectomy and non-operative management with antibiotics. The Surgeon 15: 303–314. Swidsinski A, Dörffel Y, Loening-Baucke V, et al. (2011) Acute appendicitis is characterised by local invasion with Fusobacterium nucleatum/necrophorum. Gut 60: 34–40. https://doi. org/10.1136/gut.2009.191320.

Further Reading Andersson RE (2007) The natural history and traditional management of appendicitis revisited: Spontaneous resolution and predominance of prehospital perforations imply that a correct diagnosis is more important than an early diagnosis. World Journal of Surgery 31: 86–92. Debas AT (2003) Appendix. In: Debas AT (ed.) Gastrointestinal surgery. 1st edn, Pathophysiology and management1st edn, pp. 311–317. New York: Springer. Petroianu A (2012) Diagnosis of acute appendicitis. International Journal of Surgery 10: 115–119. Guidelines Di Saverio S, Birindelli A, Kelly MD, et al. (2016) WSES Jerusalem guidelines for diagnosis and treatment of acute appendicitis. World Journal of Emergency Surgery 18: 11–34. Gorter RR, Eker HH, Gorter-Stam MA, et al. (2016) Diagnosis and management of acute appendicitis. EAES consensus development conference 2015. Surgical Endoscopy 30: 4668–4690. Korndorffer JR Jr., Fellinger E, and Reed W (2010) SAGES guideline for laparoscopic appendectomy. Surgical Endoscopy 24: 757–761.

Appetite Margo A Denke, University of Texas Southwestern Medical Center, Dallas, TX, United States © 2004 Elsevier Inc. All rights reserved.

Glossary

anorexigenic Appetite suppressing. appetite Instinctive desire to eat. Appetite promotes eating behaviors to sustain life. leptin Adipocyte peptide hormone that serves to decrease appetite. orexigenic Appetite stimulating.

Regulation by the Hypothalamus Eating behaviors are chemically encoded in the hypothalamus. Orexigenic signals of neuropeptide Y, galanin, endogenous opioid peptides, melanin-concentrating hormone, glutamate, and g-aminobutyric acid promote food consumption behavior. Anorexigenic signals, including the entire family of corticotropin-releasing hormone(CRH)-related peptides, neurotensin, glucagon-like peptide1, melanocortin, and agoutiprotein, promote the cessation of food consumption. Each neuropeptide has its own specific cellular receptors, occurring in high concentration in the paraventricular nucleus of the hypothalamus but present in other areas of the brain. All appear interconnected with feedback loops whereby one signal peptide can alter the secretion of another signal peptide. No single peptide is the gatekeeper to turning on or off appetite; what is apparent is an entire network of signals, and their frequency and amplitude are responsible for triggering behaviors. The network of appetite signals accounts for the behavioral observations that appetite and food consumption patterns are dynamic. Biological, environmental, and psychological events readily influence behavior. Habitual intake, memories of foodrelated activities, and the sheer anticipation of consumption have been shown to influence single meal consumption of specific foods. External clues, such as the appearance of food, aroma, anticipated palatability, and the number of food choices, have been shown to modify the perception of appetite as well as the behaviors of eating. Psychosomatic consequences of eating, such as reduction in anxiety, can exert additional influences on behavior. Appetite appears analogous to memory; although memory and appetite are chemically encoded, every individual has their own unique signal circuitry underlying their eating behaviors. Just as memories change over time, the circuitry for appetite can also be modified.

Regulation by Fat Cells A major breakthrough in the physiology of appetite regulation came with the discovery of leptin and resistin, two hormones synthesized by adipocytes. Leptin secretion increases as adipocytes enlarge, and decreases during fasting. Identification of leptin receptors in the hypothalamus has provided an intriguing biochemical explanation for the ability of an animal to regulate body weight tightly within a fairly narrow set point range. The leptin signal may serve as an anorexin by its ability to alter secretion of orexins and anorexins. Obese persons have appropriately elevated leptin levels, but whether this is an epiphenomenon of obesity or a clue to its pathologic cause is uncertain. Resistin secretion increases during feeding and during adipose tissue exposure to insulin. In contrast to leptin, a hypothalamic receptor for resistin has not yet been identified. Instead, resistin appears to induce adipocyte resistance to insulin. Resistin also inhibits adipocyte differentiation. Rosiglitazone, a drug classified as an “insulin sensitizer,” reduces resistin levels, suggesting that resistin plays a key role in determining insulin resistance.

Genetic Disorders of Appetite Regulation The importance of the orexigenic and anorexigenic signals and their receptors has been highlighted by the identification of rare families with specific genetic defects associated with childhood obesity. Mutations in leptin, the leptin receptor, prohormone convertase 1 (PC1), pro-opiomelanocortin (POMC), melanocortin 4 receptor (MC4-R), and peroxisome proliferator-activated receptor (PPAR) g2 genes have been described in children with severe obesity.

This article is reproduced from the previous edition, volume 1, Pages 110–111, ©2004 Elsevier Inc.

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Prader–Willi syndrome is a rare disorder characterized by a preoccupation with food, lack of satiation, and incessant foodseeking behaviors due to loss of paternal gene expression from chromosome 15q11–q13. The dysregulation of appetite in Prader–Willi patients may be due to deletion of key genes that alter synthesis, release, metabolism, binding, intrinsic activity, or reuptake of appetite-regulating neurotransmitters.

Further Reading Chen D and Garg A (1999) Monogenic disorders of obesity and body fat distribution. J. Lipid Res. 40(10): 1735–1746. Dimitropoulos A, Feurer ID, Roof E, et al. (2000) Appetite behavior, compulsivity, and neurochemistry in Prader–Willi syndrome. Ment. Retard. Dev. Disabil. Res. Rev. 6: 125–130. Kalra SP, Dube MG, Pu S, et al. (1999) Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr. Rev. 20: 68–100. Rogers PJ (1999) Eating habits and appetite control: A psychological perspective. Proc. Nutr. Soc. 58: 59–67. Steppan CM, Bailey ST, Bhat S, et al. (2001) The hormone resistin links obesity to diabetes. Nature. 409: 307–312.

Ascites☆ John D Ryan and Emmanuel A Tsochatzis, UCL Institute for Liver and Digestive Health, London, United Kingdom © 2020 Elsevier Inc. All rights reserved.

Glossary

Azotemia Elevation of blood urea nitrogen due to impaired renal function. Budd–Chiari syndrome Obstruction of the hepatic venous outflow at the level of the large hepatic veins or the suprahepatic or intrahepatic segment of the inferior vena cava. Child–Pugh classification Grouping based on determination of hepatic functional reserve; a useful predictor of surgical morbidity and mortality. Cirrhosis Advanced liver disease characterized by distorted architecture secondary to hepatic fibrosis and regenerative nodules. Constrictive pericarditis Fibrous scarring and noncompliance of the pericardium that results from causes of chronic pericarditis, including tuberculosis, malignancy, or radiation. Hepatic hydrothorax Pleural effusion (more than 500 mL) in patients with cirrhosis, in the absence of cardiopulmonary or subdiaphragmatic pathology. Hepatojugular reflux Sustained increase in jugular venous pressure elicited by compression of the abdomen in patients with right heart failure. Hepatorenal syndrome Impaired renal function in the presence of advanced liver disease. Meig’s syndrome Triad of benign ovarian fibroma with ascites and right-sided pleural effusion. Myxedema Thyroid deficiency in adults associated with skin and soft tissue edema. Pseudomyxoma peritonii Metastatic peritoneal tumor that results in gelatinous implants on the peritoneum. Pulsus paradoxicus Exaggerated decrease (greater than 20 mmHg) in inspiratory systolic blood pressure. Renin–angiotensin–aldosterone system Vasoactive system that causes renal vasoconstriction and retention of sodium and water. Spontaneous bacterial peritonitis Primary infection of ascitic fluid in patients with advanced liver disease. Venoocclusive disease Hepatic venous outflow obstruction that occurs in patients undergoing bone marrow transplantation, radiation therapy, liver transplantation, or ingestion of alkaloid toxins; the result of occlusion of hepatic sinusoids and small venules.

Ascites is defined as the excessive accumulation of fluid in the peritoneal cavity. Cirrhosis is the most common cause of ascites, followed by malignancy and cardiac failure. In cirrhosis, ascites reflects the presence of significant portal hypertension. Patients with advanced liver disease develop infections of the ascitic fluid, a condition known as spontaneous bacterial peritonitis. Moreover, these patients can develop hepatorenal syndrome, a functional renal failure with poor prognosis. Alternatively, patients may present with hepatic hydrothorax, which involves symptomatic pleural effusions.

Etiology Cirrhosis is the cause of ascites in up to 80% of cases; malignancy and cardiac failure are the causes in 10% and 5%, respectively. Other causes account for fewer than 5% of cases of ascites. About 5% of patients have ascites due to more than one cause. Fifty percent of cirrhotic patients eventually develop ascites; up to 10% of these have ascites refractory to treatment. Ovarian cancer is the most common cause of malignant ascites and accounts for almost 50% of cases of the disease. Occult malignancies account for 20% of cases of malignant ascites and the remaining 30% of cases result from pancreatic cancer, gastric cancer, colon cancer, lung cancer, breast cancer, or lymphoma. The causes of ascites are summarized in Table 1.

Pathogenesis Ascites in cirrhotic patients results from a combination of portal hypertension and renal retention of sodium. As a result of factors such as nitric oxide (NO), which are present in excess in cirrhosis, there is splanchnic and peripheral vasodilatation (Tsochatzis et al., 2014). ☆

Change History: January 2018. John D Ryan and Emmanuel A Tsochatzis updated the text and further reading to this entire article.

This is an update of Shabana F. Pasha, Patrick S. Kamath, Ascites, In Encyclopedia of Gastroenterology, edited by Leonard R. Johnson, Elsevier, New York, 2004, Pages 114–119.

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Etiology of ascites

Hepatic Cirrhosis Budd–Chiari syndrome Liver metastases Alcoholic hepatitis Hepatic veno-occlusive disease Portal vein thrombosis Cardiac Congestive heart failure Constrictive pericarditis Right atrial myxoma Malignant Peritoneal carcinomatosis Pseudomyxoma peritonii Infectious Tuberculous peritonitis HIV infection Renal Nephrotic syndrome Continuous ambulatory peritoneal dialysis Other IVC obstruction Pancreatitis Myxedema Meig’s syndrome Lymphatic obstruction/disruption Collagen vascular diseases Protein-losing enteropathy

Venous collaterals also develop around the liver, with blood pooling in the splanchnic venous circulation. This results in a decrease in the effective arterial blood volume (EABV). In an attempt to correct the EABV, there is stimulation of the renin–angiotensin–aldosterone system (RAAS), the sympathetic nervous system (SNS), and vasopressin. These vasoactive systems work in concert to cause renal retention of sodium and water, as well as renal vasoconstriction. The result is an increase in plasma volume. The excessive fluid retained is compartmentalized to the peritoneal cavity as a result of portal hypertension, which is an increase in pressure within the hepatic sinusoids. A hepatic sinusoid pressure greater than 12 mmHg is usually required for ascites to develop. Hypoalbuminemia and increased permeability of peritoneal membrane capillaries are likely to also contribute to ascites formation. Malignant ascites results from exudation of fluid from peritoneal carcinomatosis and occlusion of diaphragmatic lymphatics, with impairment of peritoneal fluid absorption. Tumor infiltration in the liver, leading to hepatic venous obstruction, is a less common cause of malignant ascites. Ascites in patients with hepatocellular carcinoma may be secondary to portal hypertension or to portal vein thrombosis due to tumor. Tuberculous peritonitis leads to exudation of proteinaceous fluid into the peritoneal cavity, and resultant ascites. Pancreatic ascites can be seen in both acute and chronic pancreatitis and results from disruption of the pancreatic duct and leakage of pancreatic secretions into the peritoneum. Chylous ascites occurs from a lymphatic disruption as a result of trauma or malignant obstruction of the lymphatic ducts.

Physical Examination Normally there is less than 75–100 mL of fluid in the peritoneal cavity. Ascites can be detected by eliciting shifting dullness by percussion in the flanks when peritoneal fluid exceeds 500 mL. A fluid thrill is seen in the presence of tense ascites; patients with tense ascites may also have concomitant lower extremity edema. Peripheral stigmata of chronic liver disease, including spider angiomata, palmar erythema, distended superficial abdominal veins and rarely the “caput medusae,” gynecomastia, and testicular atrophy, may be seen when ascites results from cirrhosis and portal hypertension. Some patients may have generalized anasarca, abdominal herniae, and scrotal edema. The cirrhotic liver in patients with an advanced stage of disease is usually shrunken and may not be palpable. The spleen may be palpable following a therapeutic paracentesis. Umbilical hernias that can occasionally ulcerate or even rupture are sometimes prominent. Patients with congestive heart failure and ascites have elevated jugular venous pressure, peripheral edema, and presence of S3 or S4 (low-pitched sounds detected on auscultation) on cardiac examination. Constrictive pericarditis is characterized by presence of pulsus paradoxicus, rapid X and Y descents of the jugular venous pulse, pericardial knock, and ascites out of proportion to peripheral edema.

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Differential Diagnosis Other etiologies of a distended abdomen, including pregnancy, ovarian mass, gaseous distension from bowel obstruction, and obesity, must be excluded in a patient suspected to have ascites. On percussion of the abdomen, ascites presents with flank dullness, whereas an ovarian mass typically presents with central dullness and tympanitic flanks.

Diagnosis Bedside ultrasonography is useful to confirm the presence of ascites prior to safe paracentesis, and can detect as little as 100 mL of peritoneal fluid. An ultrasound is also important to determine the patency of hepatic vasculature, the presence of portal hypertension and abdominal or liver lesions. Abdominal paracentesis is the most rapid and cost-effective method of diagnosing the etiology of ascites. An early diagnostic paracentesis (approx. 30 mL) has been shown to reduce mortality in patients with decompensated cirrhosis, and should therefore be performed in all patients with new-onset ascites or at the time of every hospital admission. A low threshold must be maintained for repeating the paracentesis, because infection may present with only minimal symptoms. The only absolute contraindication to paracentesis is an uncooperative patient, while a diagnostic paracentesis can be performed safely in a coagulopathic patient with no need of prophylactic transfusion. Complications occur in fewer than 1% of cases and include abdominal wall hematomas. Serious complications such as hemoperitoneum and bowel perforation occur in less than 1 in 1000 paracenteses. Sampling of ascites should preferably be performed in the flanks, to minimize the risk of bleeding, particularly from the inferior epigastric artery which courses near the midline. In all patients, ascitic fluid analysis should include total protein and albumin concentration, total and differential cell count, gram stain and bacterial culture. The nucleated cell count is less than 500 cells/mm3, with fewer than 250 neutrophils/mm3 in uninfected ascites secondary to portal hypertension. The yield from microbial culture can be greatly enhanced by inoculation of the ascitic fluid into blood culture bottles immediately following aspiration. The serum–ascitic fluid albumin gradient, which is the difference between the serum albumin and ascitic fluid albumin, has a sensitivity and specificity of greater than 95% in differentiating ascites secondary to portal hypertension from other causes (Table 2). Other tests include ascitic fluid amylase, triglyceride, glucose, and lactate dehydrogenase (LDH) concentration. Ascitic fluid cytology has a low sensitivity in the diagnosis of malignancy but is highly specific. Ascitic fluid culture has a sensitivity of only 50% in the diagnosis of tuberculous peritonitis. Chylous ascites is diagnosed when ascitic fluid triglyceride concentrations are higher than simultaneously drawn plasma triglyceride concentrations. Grossly hemorrhagic ascites may occur in 22% of cases of malignant ascites and in 50% of cases of ascites secondary to metastatic hepatocellular carcinoma. Hemorrhagic ascites due to malignancy is differentiated from hemorrhage caused by a needle trauma during paracentesis by the absence of clotting of the sample in malignant ascites.

Management Diet The goal of the management of ascites is to maintain a negative sodium balance. This is achieved with dietary sodium restriction and the use of diuretics. Response to dietary sodium restriction alone, with increased renal sodium excretion manifesting as weight loss of between 250 and 500 g/day and a decrease in ascites, occurs in 10%–20% of patients. Most patients with ascites can be managed with dietary sodium restriction (80–120 mEq/day) along with use of a diuretic. In practical terms, recommending avoidance of foods with high salt content and a “no added salt” approach yields the best outcomes for compliance.

Table 2 Gradient

Serum and ascitic fluid albumin gradient Cause of ascites Ascitic fluid total protein 1.1

Cirrhosis Fulminant hepatic failure

2.5 g/dL Congestive heart failure Constrictive pericarditis Budd–Chiari syndrome Venoocclusive disease Peritoneal carcinomatosis Tuberculous peritonitis Pancreatic ascites Chylous ascites

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Diuretics Spironolactone is the diuretic of choice administered as a single dose. The initial dose is 100 mg/day and can be increased to a maximum dose of 400 mg/day as tolerated. Its effectiveness reflects the importance of hyperaldosteronism in the development of ascites in cirrhosis. Furosemide can be used in combination with spironolactone, particularly in individuals with recurrent ascites. The initial dose of furosemide is 40 mg/day and can be increased to a maximum dose of 160 mg/day. Patients on diuretics should be monitored for the development of electrolyte abnormalities, worsening of renal function, and excessive diuresis that can lead to the precipitation or worsening of hepatic encephalopathy. In some cases, diuretics may be reduced or withdrawn should liver function recover and dietary sodium is successfully restricted.

Response Monitoring Weight loss Weight loss should not exceed 0.5–0.75 kg/day in patients without pedal edema, because this can lead to intravascular volume depletion and azotemia. A higher weight loss target 0.8–1 kg/day may be achieved safely in edematous patients (Runyon and AASLD, 2013).

Urinary electrolytes The measurement of urinary electrolytes is an informative test when managing patients with ascites. A 24-h urinary sodium of 1 predicts a >78 mmol/day excretion in 90% patients (El-Bokl et al., 2009).

Refractory Ascites Refractory ascites includes diuretic-resistant ascites and diuretic-intolerant ascites. Diuretic-resistant ascites is defined as ascites that cannot be managed with dietary sodium restriction and intensive diuretic use of spironolactone (400 mg/day) and furosemide (160 mg/day) for at least 1 week, or ascites that re-accumulates early despite this treatment regime. Diuretic-intolerant ascites is defined as ascites that cannot be treated or that recurs as a result of inability to use an adequate diuretic regime due to diureticinduced complications such as hyponatremia or renal dysfunction. Diuretics should be withheld should the serum sodium fall to 125 mmoL/L and concentrated human albumin can be supplemented to restore sodium levels to safe levels. The mortality rates for patients with refractory ascites exceed 50% in 1 year and 80% in 2 years. Most patients with refractory ascites belong to Child class C. Medications that inhibit prostaglandin synthesis, such as nonsteroidal antiinflammatory drugs (NSAIDs), worsen renal function by provoking renal vasoconstriction in patients with ascites and should not be used. Other drugs to avoid in patients with ascites include angiotensin converting enzyme inhibitors and aminoglycosides.

Management of Refractory Ascites Medical therapy The optimization of nutrition is crucial in the management of patients with refractory ascites, given the high prevalence of sarcopenia in these patients. Concern regarding an increased mortality associated with the use of non-selective beta-blockers in refractory ascites was not supported by a recent meta-analysis (Chirapongsathorn et al., 2016); however caution is still advised in patients with hypotension and renal dysfunction, and an increased risk of paracentesis-induced circulatory dysfunction is hypothesized (de Franchis and R. Baveno VI, 2015). Non-selective beta-blockers should be stopped after an episode of spontaneous bacterial peritonitis in patients with refractory ascites; the decision to restart them once the episode resolves should be on a case-to-case basis depending on hemodynamics and laboratory parameters. If beta-blockers are not restarted, a banding ligation program should be implemented. Oral midodrine may increase urinary sodium and volume in patients with refractory ascites.

Therapeutic paracentesis Refractory ascites can be managed with repeated large-volume paracentesis. However, removal of excessive peritoneal fluid can result in decreased effective intravascular volume, with decreased pulmonary capillary wedge pressure and atrial natriuretic peptide levels, and increased renin–angiotensin–aldosterone activity, the so-called paracentesis-induced circulatory dysfunction. Therefore, 6–8 g of albumin should be infused intravenously for every liter of ascitic fluid that is removed to counteract this circulatory dysfunction if the total paracentesis volume is larger than 5 L. Patients undergoing large-volume paracenteses have been shown to have a higher response rate, shorter hospital stay, and fewer complications, with similar survival as compared to patients treated with diuretics.

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Peritoneovenous shunt The LeVeen shunt is a subcutaneous peritoneovenous shunt placed between the superior vena cava and peritoneum via the internal jugular vein. It has no benefit in the reduction of mortality or complication rate as compared to patients undergoing repeated paracenteses for the treatment of refractory ascites. Complications include catheter infection, thrombosis, occlusion, and low-grade disseminated intravascular coagulation. Peritoneovenous shunts are currently seldom used because the alternative of transjugular intrahepatic portosystemic shunts is available for patients who fail paracentesis therapy.

Transjugular intrahepatic portosystemic shunt The transjugular intrahepatic portosystemic shunt (TIPS), placed by interventional radiologists, has largely replaced surgical shunts in the management of refractory ascites. The TIPS is effective in reducing activity of the renin–angiotensin–aldosterone system and hence leads to diuresis and natriuresis. Relatively normal renal function is required for a TIPS procedure to be effective in reducing ascites. The TIPS has been associated with increased 1-year transplantation-free survival and cost-effectiveness when compared with repeated therapeutic paracentesis (Salerno et al., 2007; Bureau et al., 2017). Complications include hepatic encephalopathy, shunt stenosis, and worsening of liver synthetic function (Malinchoc et al., 2000). Contra-indications to a TIPS therefore include the presence of overt encephalopathy, a serum bilirubin >5 mg/dL, portal vein thrombosis and significant cardiac dysfunction. Predictors of a survival benefit with a TIPS procedure include a combination of a serum bilirubin level 75,000/mm3.

Surgical portosystemic shunts Creating a side-to-side anastomosis between the portal vein and inferior vena cava leads to a reduction in portal pressure, natriuresis, diuresis, and relief of ascites. However, the high rates of mortality and complications from the procedure, as well as the development of safer alternatives, have led to the abandonment of the procedure for refractory ascites.

Orthotopic liver transplantation Liver transplant is the only therapy for refractory ascites and hepatorenal syndrome, and is associated with an improvement in long-term survival.

Complications Hepatorenal Syndrome Hepatorenal syndrome (HRS) is the presence of impaired renal function as demonstrated by a glomerular filtration rate below 40 mL/min or a serum creatinine >1.5 mg/dL in the presence of advanced liver disease and portal hypertension. Shock, bacterial sepsis, nephrotoxic agents, fluid loss, or excessive diuretic use should be excluded before the diagnosis is made. Patients with HRS have proteinuria 2.5 mg/dL or the creatinine clearance decreasing to 250/mm3 (neutrocytic ascites) is required for the diagnosis of spontaneous bacterial peritonitis (SBP). The ascitic fluid protein concentration is usually less than 1 g/dL, and those with low albumin ascites are at greatest risk of developing SBP.

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The most common organisms seen in SBP include Escherichia coli, Streptococcus pneumoniae, and Klebsiella pneumonia however this depends on previous use of antibiotics and hospitalizations. Diagnostic yield of ascitic culture is increased if ascitic fluid is inoculated into blood culture bottles immediately on paracentesis. Secondary bacterial peritonitis is polymicrobial, as opposed to monomicrobial SBP. SBP is characterized by a very low bacterial count and thus gram stain carries a sensitivity of 10% or lower in the diagnosis of spontaneous bacterial peritonitis. Secondary bacterial peritonitis should be suspected if ascitic fluid protein is more than 1 g/dL, glucose is less than 50 mg/dL, and ascitic fluid LDH is greater than serum LDH. The antibiotic of choice for the treatment of a community episode of SBP is a third-generation cephalosporin, usually cefotaxime for a minimum of 5 days. In patients with nosocomial SBP, the choice of antibiotic should be based on the local microbiological resistance profile until culture results become available. Intravenous human albumin should be given to patients with SBP on days 1 and 3 of treatment (1.5 g/kg on day 1 and 1 g/kg on day 3); this has been shown to reduce the incidence of hepatorenal syndrome and death (Sort et al., 1999). A repeat ascitic tap should be performed on day 3 to assess response to therapy (Tsochatzis and Gerbes, 2017). Patients who have experienced even one episode of SBP should be treated indefinitely with quinolones such as norfloxacin to prevent subsequent episodes, due to risk of recurrence of 40%–70% after 1 year. Low ascitic fluid total protein levels (500 mL in patients with cirrhosis in the absence of cardiopulmonary or subdiaphragmatic pathology. The pathophysiology of hepatic hydrothorax is similar to the pathophysiology of ascites. In fact, it is ascitic fluid that moves from the peritoneal cavity into the pleural space through diaphragmatic defects. Because the intrathoracic pressure is negative, this favors movement of fluid into the thoracic space. Thus, patients may have hepatic hydrothorax even in the absence of ascites. The right pleural space is more commonly involved. Similar to patients with ascites, patients with hepatic hydrothorax can have spontaneous bacterial infection of the fluid that results in spontaneous bacterial empyema. Patients with hepatic hydrothorax have advanced liver disease and are usually candidates for liver transplantation. Therapy in such patients is directed at relieving symptoms and preventing pulmonary complications until such time that a liver transplant can be carried out. The initial management is with sodium restriction and diuretics, similar to the management of patients with ascites. Therapeutic thoracocentesis is carried out to relieve symptoms of dyspnea. Pleurodesis and chest tube placement should be avoided at all costs. If sodium restriction and diuretics fail, then transjugular intrahepatic portosystemic shunts can be placed. These shunts are usually effective in preventing the accumulation of fluid in the pleural space.

Management of Malignant Ascites Diuretics are not effective in the treatment of malignant ascites. Therapeutic paracenteses may be employed to alleviate pressure symptoms related to large-volume ascites. Peritoneovenous shunts have occasionally been placed in patients with malignant ascites and may have a role in treating patients with a life expectancy greater than a few months. There is no evidence to support the theory of widespread metastases due to dissemination of malignant cells via the shunt, leading to decreased survival rates.

See Also: Hepatorenal Syndrome. Portal Hypertension and Esophageal Varices

References Bureau C, Thabut D, Oberti F, et al. (2017) Transjugular intrahepatic portosystemic shunts with covered stents increase transplant-free survival of patients with cirrhosis and recurrent ascites. Gastroenterology 152(1): 157–163. Chirapongsathorn S, Valentin N, Alahdab F, et al. (2016) Nonselective beta-blockers and survival in patients with cirrhosis and ascites: A systematic review and meta-analysis. Clinical Gastroenterology and Hepatology 14(8): 1096–1104. e9. de Franchis R and Baveno VI (2015) Expanding consensus in portal hypertension: Report of the Baveno VI consensus workshop: Stratifying risk and individualizing care for portal hypertension. Journal of Hepatology 63(3): 743–752. Eisenmenger WJ (1952) Role of sodium in the formation and control of ascites in patients with cirrhosis. Annals of Internal Medicine 37(2): 261–272. El-Bokl MA, Senousy BE, El-Karmouty KZ, et al. (2009) Spot urinary sodium for assessing dietary sodium restriction in cirrhotic ascites. World Journal of Gastroenterology 15(29): 3631–3635. European Association for the Study of the Liver (2010) EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. Journal of Hepatology 53(3): 397–417. Malinchoc M, Kamath PS, Gordon FD, et al. (2000) A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology 31(4): 864–871.

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Runyon BA and AASLD (2013) Introduction to the revised American Association for the Study of Liver Diseases practice guideline management of adult patients with ascites due to cirrhosis. Hepatology 57(4): 1651–1653. Salerno F, Camma C, Enea M, et al. (2007) Transjugular intrahepatic portosystemic shunt for refractory ascites: A meta-analysis of individual patient data. Gastroenterology 133(3): 825–834. Sort P, Navasa M, Arroyo V, et al. (1999) Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. The New England Journal of Medicine 341(6): 403–409. Tsochatzis EA and Gerbes AL (2017) Diagnosis and treatment of ascites. Journal of Hepatology 67(1): 184–185. Tsochatzis EA, Bosch J, and Burroughs AK (2014) Liver cirrhosis. Lancet 383(9930): 1749–1761.

Further Reading Arroyo V, Gines P, Gerbes AL, et al. (1996) Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology 23: 164–176. de Franchis R and Baveno VI Faculty (2015) Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. Journal of Hepatology 63: 743–752. Garcia-Tsao G (2011) Ascites. In: Dooley JS, Lok ASF, Burroughs AK, and Heathcote EJ (eds.) Sherlock’s diseases of the liver and biliary system, 12th edn, pp. 210–233. UK, Wiley & Sons Ltd: West Sussex. Gines P, Uriz J, Calahorra G, et al. (2002) Transjugular intrahepatic portosystemic shunting versus paracentesis plus albumin for refractory ascites in cirrhosis. Gastroenterology 123: 1839–1847. Ginès P, Angeli P, Lenz K, et al. (2010) European Association for the Study of the Liver (EASL) clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. Journal of Hepatology 53: 397–417. Lazaridis KN, Frank JW, Krowka MJ, et al. (1999) Hepatic hydrothorax: Pathogenesis, diagnosis, and management. The American Journal of Medicine 107: 267–272. Malinchoc M, Kamath PS, Gordon FD, et al. (2000) A model to predict survival in patients undergoing transjugular intrahepatic porto-systemic shunts. Hepatology 31: 864–871. Moore KP and Aithal GP (2006) Guidelines on the management of ascites in cirrhosis. Gut 55(Suppl 6): vi1–12. Runyon BA (2013) Introduction to the revised American Association for the Study of Liver Diseases practice guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology 57: 1651–1653. Sort P, Navasa M, Arroyo V, et al. (1999) Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. The New England Journal of Medicine 341: 403–409. Tsochatzis EA, Bosch J, and Burroughs AK (2014) Liver cirrhosis. Lancet 383: 1749–1761.

Aspirin and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)☆ Aitor Lanas-Gimeno, Hospital Universitario de la Princesa, Madrid, Spain Angel Lanas, University of Saragossa, Saragossa, Spain © 2020 Elsevier Inc. All rights reserved.

Glossary

Cyclooxygenases Family of enzymes, of which at least two isoforms exist, cyclooxygenase-1 and cyclooxygenase-2. They act on arachidonic acid to produce a number of compounds, including prostaglandins and thromboxane. Prostaglandins One form of eicosanoids (biologically active lipids formed by the oxidation of 20-carbon fatty acids); produced by the cyclooxygenase pathway, they are responsible for a variety of physiologic and inflammatory reactions.

Abbreviations COX H2RA NSAIDs PPI RCT

Cyclooxygenase Histamine type 2 receptor antagonist Non-steroidal anti-inflammatory drugs Proton pump inhibitor Randomized controlled trial

Definition First acknowledgement of salicylic acid use throws us back to the ancient Egypt and Greece for its antipyretic and painkiller properties. Acetylsalicylic acid, also known as aspirin, was first introduced by Bayer Company in 1899 thanks to Felix Hoffman and his investigations. Since the introduction of aspirin several numbers of agents have been developed, with great changes in prescription habits, recommendations and restrictions due to improved understanding over the last 10–20 years, of its mechanisms of action and adverse effects. John Vane in 1971 established the mechanism of action of aspirin and NSAIDs, with the inhibition of three enzymes, cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), and cyclooxygenase-3 (COX-3) which is a recently described variant of COX-1. Nowadays NSAIDs are one of the most widely prescribed drugs to treat pain and inflammation, with a wide range of prescriber specialists such as general practitioners, rheumatologists, oncologists, orthopedists, etc. It is estimated that NSAIDs are used by over 30 million people every day. Gastroenterologists have special interest in this pharmacological group in view of the gastrointestinal adverse effects derived from their use and the recent data on colorectal cancer prevention.

Pharmacology Nomenclature and Pharmacodynamics Nonsteroidal anti-inflammatory drugs (NSAIDs) constitute a large and heterogeneous group of drugs which present a common mechanism of action consisting of the inhibition of the enzymes responsible for prostanoid synthesis, the cyclooxygenases. There are three principal prostanoids: prostaglandins, which are the base of both analgesic and anti-inflammatory effect, and prostacyclin and thromboxane which are known to be involved in vascular permeability and platelet aggregation. COX-1 enzyme has a constitutive level of expression, with a broad level of expression in most tissues including platelets and the gastrointestinal tract, where it is involved in the mucosal integrity by facilitating mucus formation, cell replacement and maintaining blood flow. On the other hand, COX-2 enzyme is inducible and specific to some type of cells and tissues, increasing its level of expression under inflammatory states and regulating pain, fever, vasodilation and leukocyte infiltration. The COX-2 isozyme is also likely involved in fluid balance and renal homeostasis (Lanas, 2016; Crofford, 1997; Bjarnason et al., 2018).

☆

Change History: December 2018. Aitor Lanas-Gimeno and Angel Lanas: This is a fully new edited chapter where the major changes have been introduced in the adverse events section.

This is an update of Salahuddin Kazi, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), In Encyclopedia of Gastroenterology, edited by Leonard R. Johnson, Elsevier, New York, 2004, Pages 737–739.

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Based on their specific COX isozyme inhibition and chemical structure, NSAIDs are classified into two major classes: nonselective NSAIDs and COX-2 selective inhibitors. Non-selective NSAIDs include aspirin and sulfasalazine, which are salicylate derivatives, indole acetic derivatives such as indomethacin and etodolac, heteroarylacetic acid derivatives such as diclofenac. Ibuprofen and naproxen are included in the arylpropionic acids group; piroxicam and meloxicam are enolic acids derivatives. Most are organic acids with relatively low pKa, with their acidic nature influencing their pharmacodynamics and pharmacokinetic profiles. Two exceptions for this particular characteristic are pyrazolic derivatives (metamizole, propyphenazone) and paraaminophenol derivatives (paracetamol or acetaminophen). These two groups are often excluded from the NSAIDs group due to their low anti-inflammatory activity. Selective COX-2 inhibitors were a breakthrough attempting better efficacy and lower toxicity; sadly its deleterious cardiovascular effect seems to have stopped their progression. COX-2-selective inhibitors include rofecoxib, celecoxib, valdecoxib, and etoricoxib, among others (Crofford, 1997).

Pharmacokinetics NSAIDs present high bioavailability (80%–100%) following oral ingestion. Their absorption is generally quick with a peak plasma concentration within 2–3 h except for some derivatives of the enolic acid (piroxicam) and certain coxibs (celecoxib and rofecoxib). Most NSAIDs are metabolized in the liver and excreted in the urine which has important implications for patients with hepatic or renal impairment. Nearly all NSAIDs undergo different degrees of biliary excretion and enterohepatic circulation. Some NSAIDs such as aspirin or diclofenac have a significant first-pass hepatic effect that reduces their bioavailability while some NSAIDs need this first-pass effect to transform into their active compound (sulindac, etoricoxib). Most NSAIDs are highly bound to plasma proteins, mostly to serum albumin at 95%. This binding may be saturable with interactions with some drugs that compete for the same binding site. Most compounds achieve sufficient concentrations over the majority of tissues including the central nervous system. Their distribution among inflamed tissues seems to be affected by particular chemical characteristics like acidity, which reduces their binding to plasma proteins and increase the free drugfraction. Therefore, drugs like diclofenac, ibuprofen or ketoprofen seem to easily accumulate and persist in the inflammatory loci (Bjarnason et al., 2018).

Clinical Uses As mentioned before, NSAIDs are one of the most commonly used class of drug in developed countries. They are widely prescribed on a daily basis for pain relief such as headaches, musculoskeletal pain after a traumatism, bone pain secondary to malignant diseases, dysmenorrhea, biliary and renal colic or early postoperative pain. They can be prescribed as monotherapy for short-term treatment due to the potential adverse effects. They can also be prescribed adjunct to opioids for the management of severe pain. Due to their anti-inflammatory effect they are also indicated for the treatment of rheumatic diseases such as osteoarthritis, rheumatoid arthritis, ankylosing spondylitis. In addition, they are effective against fever because of their antipyretic effect, which is comparable to acetaminophen. Other recognized uses for NSAIDs are acute gout and colorectal cancer chemoprevention in familial adenomatous polyposis. Due to aspirin’s capacity for permanent inhibition of platelet-derived thromboxane formation, low-dose aspirin is used in preventing arterial thromboembolism such as myocardial infarction and ischemic stroke (Lanas, 2016).

Adverse Events Gastrointestinal Toxicity Despite being commonly prescribed, NSAIDs usage carries out substantial risk of adverse events at different organ systems (kidney, heart, liver, central nervous system, etc.), but gastrointestinal toxicity is the most common. It is estimated that almost 30% of longterm NSAIDs users present peptic ulcers on upper gastrointestinal endoscopy, which may be asymptomatic, and every year almost 1%–2% patients develop complications (Lanas, 2016; Laine et al., 2003). NSAIDs toxicity also affects the lower gastrointestinal tract with almost half of chronic NSAIDs users presenting some degree of injury on the small bowel mucosa (Laine et al., 2003). Peptic ulcer disease patterns are clearly changing due to the declining incidence of Helicobacter pylori and increased prescription of aspirin and NSAIDs in a continuing aging population. Also, with wide prescription of proton pump inhibitors (PPI) in patients under NSAIDs usage, lower gastrointestinal tract complications are as frequent or even more frequent than upper GI complications. Shortterm (95% of cases) or pulmonary carcinoid (Chinn and Schuffler, 1988). In a case series of seven patients: all patients suffered constipation, six had gastroparesis, four had esophageal dysmotility suggestive of spasm or achalasia, and two had other evidence of autonomic neuropathy that affected bladder and blood pressure control (Chinn and Schuffler, 1988). The myenteric plexus is infiltrated with lymphocytes and plasma cells, suggesting an immune ganglionitis. Our group has detected a circulating IgG antibody directed against enteric neuronal nuclei (Lennon et al., 1991), which suggests that the enteric neurons are the major target of this paraneoplastic phenomenon. However, some patients also have evidence of extrinsic visceral neuropathies (Sodhi et al., 1989). The chest X-ray is often negative in these patients; hence, a chest computed tomography scan is indicated when the syndrome is suspected clinically.

Autoantibodies for Diagnosis of Autonomic Dysfunction Autoimmune gastrointestinal dysmotility is a limited autoimmune autonomic dysfunction which can be idiopathic or paraneoplastic. Several autoantibodies have been identified to aid in the diagnosis of autoimmune gastrointestinal dysmotility. Antineuronal nuclear antibodies type-1 (ANNA-1 or anti-Hu), an IgG autoantibody, is reactive with nuclear and cytoplasmic elements of both tumor cells and neurons, and found most frequently in serum of patients with SCLC and paraneoplastic neuropathies (Hillel and Miller, 1987). Autoantibodies specific for nicotinic acetylcholine receptors (ganglionic antibodies) have been demonstrated in autonomic ganglia of patients with idiopathic autonomic neuropathy, a severe, subacute disorder with a presumed autoimmune basis (Vernino et al., 2000). It is generally indistinguishable from the paraneoplastic autoimmune neuropathy; therefore the identification of these autoantibodies can help distinguish these entities. The serologic profile of 24 patients presenting with subacute gastrointestinal dysmotility was evaluated. Plasma membrane cation channel autoantibodies were detected in 23 patients: neuronal voltage-gated calcium channel (5 N-type and 1 P/Q-type), acetylcholine receptor (11 ganglionic-type and 4 muscle-type), and 4 neuronal voltage-gated potassium channel autoantibodies. Two patients had ANNA-1. Approximately half of the patients had neural autoantibodies (including skeletal muscle striational and glutamic acid decarboxylase, 65kd isoform) or other antibody markers of organ-specific autoimmunity (thyroid or gastric parietal cell specificities) (Dhamija et al., 2008).

Porphyria Gastrointestinal involvement is common in porphyria and usually presents with symptoms of abdominal pain, nausea, vomiting, and constipation (Berlin and Cotton, 1950; Stein and Tschudy, 1970). Patients with porphyria have a polyneuritis characterized by demyelination of peripheral and autonomic nerves; dilation and impaired motor function may be seen in any part of the intestinal tract and are likely the result of autonomic dysfunction. Effects of porphyria on the enteric nervous system have not yet been described.

Chronic Sensory and Autonomic Neuropathy of Unknown Cause This is a rare, nonfamilial form of slowly progressive neuropathy affecting various autonomic functions (Okajima et al., 1983). Patients may have only a chronic autonomic disturbance manifesting for many years as a gastrointestinal dysfunction before any involvement of the sensory nerves becomes apparent. In most patients, however, cardiovascular or sweating abnormalities precede

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involvement of the gut. This condition is important because it suggests that autonomic dysfunction may be the cause of functional gastrointestinal motor disorders, including the common problem of irritable bowel syndrome (Camilleri and Fealey, 1990). Other investigators have reported familial cases of intestinal pseudo-obstruction with degeneration of the myenteric plexus and evidence of sensory or motor neuropathies (or both) affecting peripheral or cranial nerves (Krishnamurthy and Schuffler, 1987).

Identification of Extrinsic Neurologic Disease in Functional Gastrointestinal Symptoms Lesions at virtually any level of the nervous system may result in gastrointestinal motor dysfunction symptoms. Therefore a strategy in the diagnostic evaluation of disordered gastrointestinal function is necessary to determine the etiology and location of the lesion. This requires interdisciplinary collaboration between the neurologist (particularly one with an interest in the autonomic nervous system) and the gastroenterologist. Recognition and identification of clinical features suggestive of autonomic or peripheral nerve dysfunction would prompt further testing in patients with gastrointestinal motor dysfunction. The first steps in the history and physical examination should identify evidence of a generalized neurologic disorder; the physician should thoroughly evaluate all systems and inquire about the past medical history and family history. It is essential to record the use of all medications which may influence gut motility. Gastrointestinal motility and transit measurements help the clinician to confirm the disturbance in the motor function of the gut and to distinguish between neuropathic and myopathic disorders. Autonomic testing may be useful in patients with a neuropathic pattern. These tests can help identify the level of pathology, whether preganglionic or central versus peripheral neuropathy associated with autonomic dysfunction. When a central lesion is suspected, a brain and spinal cord magnetic resonance imaging should be pursued. When a peripheral autonomic dysfunction is suspected, further screening for a paraneoplastic (e.g., small cell carcinoma of the lung), toxic (e.g., lead poisoning), or metabolic (e.g., porphyria) etiology should be done. Indirect tests of autonomic function are useful for identifying the presence of other types of visceral denervation and for localizing the anatomic level of the disturbance in extrinsic neural control (Camilleri, 1990). The close concordance between abdominal vagal dysfunction and cardiovagal neuropathy in patients with diabetes (Stein and Tschudy, 1970) suggests that these tests may provide a good evaluation of the overall function of the autonomic supply to the viscera, including the gastrointestinal tract. Table 4 lists the autonomic investigations, the normal values at the Mayo Clinic, and the interpretations of abnormal tests (Prather and Camilleri, 1997). Table 4

Interpretation of results of autonomic function tests.

Test of autonomic function Pupillary tests Response to light Latency Constriction Pharmacologic tests 0.125% Pilocarpine 0.1% Epinephrine 5% Cocaine Blood pressure reduction on tilt to 80 Systolic Diastolic Valsalva ratio Pulse rate change with deep breathing Thermoregulatory sweat test (% Surface area of anhidrosis) Quantitative sudomotor axon reflex test Sweat output (mL/cm3) Forearm Foot Latency (min) Forearm Foot Plasma norepinephrine Patient supine Patient standing Response to I.V. edrophonium

Normal value

Abnormal result implies Dysfunction of:

0.2–0.3 s 2–4 mm

P P

0–0.5 mm constriction No change >1.5 mm dilation

P pg, S S

65 years), BE is present in 19.8% and 14.9%, respectively, of the patients with and without reflux symptoms (Ward et al., 2006). The incidence of BE is 27.7 per 100.000 patient-years in The United Kingdom. The incidence increases with age from 15.6 per 100.000 patient-years for patients aged 40–44 years to 85.6 per 100.000 patient-years for patients aged 70–74 years (Masclee et al., 2014).

Pathobiology The Origin of the Columnar Cell The esophageal wall is originally covered by squamous epithelium. In case of BE, this normal lining is replaced by columnar cells, as a result of prolonged exposure of gastroesophageal reflux and inflammation of the mucosa. This reflux esophagitis led to BE, which potentially progresses to dysplasia and sequentially to cancer. The origin of the columnar (metaplastic) cell remains uncertain, different theories have been enounced, which are described in (Fig. 1) (Kapoor et al., 2015).

Three Columnar Cell Types In a metaplastic esophagus three types of columnar cells are coexisting: the junctional or cardiac type (containing mucous glands), the gastric-fundic type (containing parietal cells), and the specialized intestinal type (containing goblet cells) (Paull et al., 1976). Particularly the intestinal type predisposes malignant development. The American College of Gastroenterology (ACG) states that intestinal-type columnar epithelium with goblet cells is required for BE diagnosis (Shaheen et al., 2016), in contrast to European guidelines that advocate the neoplastic possibilities of nonintestinal metaplasia and the risk of underdiagnosis when it is not recognized (Gatenby et al., 2008; Takubo et al., 2009).

Acid Exposure BE is a result of long-standing reflux of gastric acid into the esophagus. Some gastroesophageal reflux is a physiological event in healthy individuals. It is called gastroesophageal reflux disease (GERD) if the reflux causes symptoms (e.g., heartburn or regurgitation), complications (tissue damage) or both (Vakil et al., 2006). The normal squamous esophageal wall is not permeable to acid. However, after long-standing acid exposure the epithelial integrity is disturbed, which results in dilated intercellular spaces (DIS) (Farre et al., 2008) between epithelial cells. DIS have been reported frequently in patients with BE and is a major pathological marker for the existence of acid exposure from the stomach or duodenal bile. Other causes are stress, aspirin-use and alcohol abuse (Farre et al., 2008; Appelman et al., 2013). Specifically reflux of bile acids into the esophagus leads to oxidative stress and can, combined with a low pH, induce pathways that are associated with carcinogenesis (Dvorak et al., 2007). Examples are: (1) Caudaltype homeobox 1 and 2 (CDX 1 and 2), which regulate the intestinal phenotype, an increased expression is found in reflux

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(A)

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i

Reflux-induced injury

Cardia

Stratified squamous epithelium

ii

Barrett’s metaplasia

Reflux-induced injury

Barrett’s metaplasia

Submucosal gland (B)

Reflux-induced injury

Barrett’s metaplasia (C)

i

Reflux-induced injury Residual embryonic cells

Barrett’s metaplasia

ii

Reflux-induced injury

Transitional basal cells (D)

Barrett’s metaplasia

Reflux-induced injury Barrett’s metaplasia

Bone marroe cells

Fig. 1 The different theories proposed to explain the origin of BE. (1) Transdifferentiation of native squamous cells into columnar cells; (2) Abnormal differentiation of resident squamous stem cells into columnar cells; (3) Colonization by circulating pluripotent progenitor cells from the bone marrow; (4) Emergence of stem cells from submucosal glands to repair damaged epithelium; (5) Eruption of blocked esophageal glands; (6) Regeneration of embryonic columnar cells, which are settled at the transitional zone; (7) Upward migration of cells from the gastric epithelium. From Kapoor, H., Agrawal, D. K., Mittal, S. K. (2015). Barrett’s esophagus: Recent insights into pathogenesis and cellular ontogeny. Translational Research 166, 28–40.

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esophagitis. (2) Acid and bile induce the expression of bone morphogenetic protein 4 (BMP-4), which stimulates columnar differentiation, CDX-2 and columnar like protein expression. (3) BMP-4 is also induced by the Hedgehog (HH)-signaling pathway, HH proteins are increased in patients with BE and EAC (Kapoor et al., 2015; Clemons et al., 2013).

Dysbiosis The culture in the esophagus, especially dysbiosis, is thought to increase esophageal inflammation. Esophageal microbiomes are divided into two types. Type I is associated with a normal esophagus and dominated by the streptococcus genus. Type II is associated with esophagitis (OR ¼ 15.4) and BE (OR ¼ 16.5) (Yang et al., 2009). This group consists mainly of gram-negative anaerobes and can increase inflammation by two pathways: (1) “Mechanic” by decreasing the tonus of the lower esophageal sphincter or delaying the gastric emptying. (2) By activating pathways that increase inflammation (NF-kB pathway, Toll-like receptor 4 (TLR-4)) (Yang et al., 2009; Elias and Castell, 2017; Freedberg et al., 2014). Helicobacter pylori (Hp) has a strong association with chronic gastritis, gastric ulcer disease, intestinal metaplasia (IM) of the stomach and gastric adenocarcinoma. There is increasing evidence that Hp plays a protective role against BE and EAC, showing an inverse relation between the Hp infection rate and the presence of BE (OR ¼ 0.50) (Wang et al., 2009). This may be the result of reduced acid production in atrophic gastritis. Additionally, cytotoxin associated gene positive (cagA þ)Hp strains may be protective against BE, but induce gastric inflammation (Vaezi et al., 2000). The decrease of Hp-infections in Western countries and increase of EAC prevalence supports this hypothesis, although there are likely other confounding factors, such as obesity (Runge et al., 2015).

Malignant Progression As described before, BE is acquired secondary to chronic inflammation in reflux esophagitis and is the most important risk factor for the development of EAC (30- to 40-fold increased risk). The malignant progression occurs by a multistep sequence from IM without dysplasia, to low grade dysplasia (LGD), high grade dysplasia (HGD) and, finally, EAC. Within the Barrett’s segment the different grades of dysplasia appear multifocal. The malignant progression (and dysplasia grade) is based on growth factors (e.g., proliferative cell nuclear antigen), cell cycle parameters (e.g., cyclin D1), suppressor genes (e.g., p53, p16), aneuploidy and several proteins (e.g., epidermal growth factor receptor, b-catenin) (Williams et al., 2006; van Dekken et al., 2008; Kalatskaya, 2016).

Clinical Manifestations The metaplastic transformation in Barrett’s does not cause symptoms. The clinical relevance is its predisposition to malignant progression. GERD is a major risk factor for the development of BE, although 46% of the BE patients do not have reflux symptoms (Zagari et al., 2008). Symptoms related to GERD are regurgitation, heartburn, and dysphagia.

Diagnosis BE diagnosis comprises the endoscopic appearance of any salmon-colored mucosa extending at least 1 cm above the gastroesophageal junction (GEJ) into the esophagus with histologic confirmation of columnar lined epithelium in biopsy specimens. There is disagreement in literature whether IM with goblet cells is essential for the diagnosis (Shaheen et al., 2016). Gatenby et al. (2008) performed baseline biopsies in patients with nondysplastic BE. He did not find a significant difference in dysplastic or malignant progression between patients with or without IM at baseline endoscopy. On the other hand, dropping the requirement for goblet cells would increase the number of diagnoses of BE by 147% (Westerhoff et al., 2012), which could label patients inaccurately as BE. Early pathological studies have proven that IM is the most biologically unstable (Skinner et al., 1983). The justification for excluding segments less than 1 cm is based on recent epidemiological data that such individuals have very low risk of progress to high grade dysplasia or cancer (Thota et al., 2017).

Differential Diagnosis BE itself does not have any symptoms and has no clinical differential diagnosis. If salmon-colored mucosa appears during EGD, the existence of IM should be confirmed, including ruling out both HGD and EAC, with biopsies.

Endoscopic Evaluation Endoscopic evaluation is the first step in the recognition of Barrett’s. The normal squamous lining of the esophagus has a pale color, while columnar epithelium is more bright and salmon colored. The Z-line or squamocolumnar junction is the border between these two epithelia. The anatomic border between the stomach and the esophagus is called the GEJ and is defined as the proximal end of

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the gastric folds. Normally, the Z-line and the GEJ are located on approximately the same location. In BE the Z-line is displaced to proximal (Sharma et al., 2006a). Previously, Barrett’s esophagus was endoscopically divided into short segment BE (SSBE) with a segment length of 3 cm. However, the 3-cm cut off lacked evidence and a considerable inter- and intraobserver variation was found. Documentation should be reproducible and assist the follow-up of disease (Kapoor et al., 2015; Dekel et al., 2003; Sharma et al., 1998). To address this problem Sharma et al. (2006a) developed the Prague C&M classification, which includes the assessment of the circumferential (C) and the maximum (M) length of visible BE in centimeters from the GEJ during real-time endoscopy (Fig. 2) (Anand et al., 2008). This method has high interobserver agreement and has become part of clinical practice (Alvarez Herrero et al., 2013). In addition to the Prague classification, the location of a hiatal hernia, GEJ and the Z-line should be documented.

Histologic Evaluation In patients with suspected Barrett’s, targeted tissue samples are obtained from visible (nodular) lesions, preferably with endoscopic mucosal resection (EMR) techniques. Additionally, four-quadrant random biopsies are performed at 2 cm intervals up to the proximal end of the visible Barrett’s. In patients with short segments (1–2 cm) at least four biopsies are obtained every cm of circumferential BE and one biopsy per salmon-colored tongue (Shaheen et al., 2016). This systematic method (Seattle protocol) has proven to detect more dysplasia and EAC than a nonsystematic method (Abela et al., 2008). A drawback of this protocol is the prolongation of procedure time, which led to reduced adherence by the endoscopist in patients with longer segment lengths (Abrams et al., 2009; Curvers et al., 2008). However, even if it is performed according to the protocol, only 4–6% of the BE segment is sampled (de Jonge et al., 2014) and the poor interobserver variability among pathologists for the diagnosis of dysplasia leads to under- and overestimations (Montgomery et al., 2001; Vennalaganti et al., 2017; Kerkhof et al., 2007). Methods to overcome these drawbacks is brush cytology (Padmavathy et al., 2011) and wide-area transepithelial sampling (WATS) (Vennalaganti et al., 2015). Another method is advanced imaging to precisely target tissue sampling at regions of dysplasia.

Endoscopic Imaging Modalities In the last decades, multiple imaging modalities are developed to either assist or replace the combination of white light endoscopy with the Seattle biopsy protocol.

Dye based chromoendoscopy During chromoendoscopy, stains are injected or sprayed on the mucosa to localize lesions, to enhance mucosal details and/or to delineate these lesions prior to endoscopic resection. An example is methylene blue (0.1–0.5%), which stains intestinal-type cells blue, but does not stain esophageal, gastric, nonspecialized, dysplastic, and malignant tissue (Fig. 3A). After application, targeted biopsies are needed from stained and unstained areas (Canto et al., 1996). Genotoxicity in ex vivo models of methylene blue combined with white light led to safety concerns (Hiraku et al., 2014). However, in vivo DNA damage has never been proven (Repici et al., 2012). Another frequently used dye is acetic acid (or vinegar 1.5%), which interacts with glycoproteins on the mucosal surface and enhances the microstructural surface patterns (Lambert et al., 2003) (Fig. 3B). Guelrud et al. (2001) reported that regularly ordered

Fig. 2 The C&M Prague Criteria with on (A) a frontal illustration of endoscopically visualized Barrett’s tissue, showing an area classified as C2M5 and (B) an endoscopic image with white light endoscopy of BE, representing a C1M5 lesion. From Anand, O., Wani, S., Sharma, P. (2008). When and how to grade Barrett’s columnar metaplasia: The Prague system. Best Practice & Research. Clinical Gastroenterology 22, 661–669.

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Fig. 3 Endoscopic view with dye-based chromoendoscopy. (A) Clear delineation of BE lesion with methylene blue. (B) Combination of acetic acid and magnification endoscopy with a clear villiform appearance. From (A) Ormeci, N., Savas, B., Coban, S. et al. (2008). The usefulness of chromoendoscopy with methylene blue in Barrett’s metaplasia and early esophageal carcinoma. Surgical Endoscopy 22, 693–700; (B) Shehab, H. (2010). Chromoendoscopy in gastroenterology. Arab Journal of Gastroenterology 11, 3–17.

round/oval pit en dot patterns are related to gastric columnar epithelium, while irregularly ordered pits with a villiform or cerebriform appearance are suggestive for specialized IM. Disorganization and hypervascularization of the mucosa is suspicious for HGD or EAC (Reaud et al., 2006).

Virtual chromoendoscopy A device, that uses virtual chromoendoscopy, is narrow band imaging (NBI). NBI is based on the application of high-intensity blue light for the detection of superficial vascular details and mucosal patterns. The penetration depth of light depends on its wavelength. The NBI-system consists of three filters: 415–30 nm, 445–30 nm, 500–30 nm. The filter range of 415–30 nm (blue light) is used to enhance capillaries in superficial mucosa and angiogenesis is a feature of neoplasia. The filter range of 500–30 nm is appropriate for the visualization of deeper vasculature. Sharma et al. (2006b) described a correlation between different mucosal and vascular patterns and either IM or HGD with high performance rates (Table 1, Fig. 4) (Sharma et al., 2006b). Qumseya et al. (2013) confirmed that NBI significantly increases the diagnostic yield for the detection of dysplasia or cancer within BE. However, Beg et al. (2017) did not find a significant difference in detection of dysplasia in patients with BE.

Confocal laser endomicroscopy Confocal laser endomicroscopy (CLE) is a technique that can provide real-time microscopic imaging by combining argon laser tissue illumination with fluorescence agents. It has an adjustable imaging depth of 0–250 mm and was developed to reduce unnecessary resections and decrease risks related to biopsies, by allowing real-time microscopic visualization of the Barrett’s segment (Fig. 5) (Sharma et al., 2011). The ASGE Technology committee performed a systematic review and meta-analysis and Table 1

Classification of mucosal and vascular patterns with narrow band imaging (NBI) (Sharma et al., 2006b). Most likely diagnosis

Pattern type

Pattern subtype

Features

Mucosal patterns

Ridge or villous

Longitudinal darker and lighter ridges (distributed uniformly)

IM

Circular Irregular or distorted

Circular, uniform pattern Distorted, nonuniform, irregular pattern

IM HGD

Normal vascularity

Presence of thin vessels, the branching pattern is uniform Increased vascularity with dilated, corkscrew vessels, the branching pattern is abnormal, and nonuniform

IM without HGD

Vascular pattern

Abnormal vascularity

Se, sensitivity; Sp, specificity; PV þ, positive predictive value.

HGD

Performance Se: 93.5% Sp: 86.7% PV þ: 94.7% (for diagnosis IM) – Se: 100% Sp: 98.7% PV þ: 95.3 (for diagnosis HGD) – Se: 100% Sp: 97.4% PV þ: 94.7% (for diagnosis HGD)

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Fig. 4 Endoscopic images of BE with NBI. (A) A ridge/villous pattern. The blue arrow indicates a darker longitudinal line (ridge), the yellow arrow indicates a lighter longitudinal line (villous). (B) A circular pattern. (C) An irregular/distorted pattern, area with HGD. From Sharma, P., Bansal, A., Mathur, S. et al. (2006b). The utility of a novel narrow band imaging endoscopy system in patients with Barrett’s esophagus. Gastrointestinal Endoscopy 64, 167–175.

Fig. 5 Two images of BE with Confocal laser endomicroscopy. (A) Nondysplastic BE. (B) BE with early EAC. From Sharma, P., Meining, A. R., Coron, E. et al. (2011). Real-time increased detection of neoplastic tissue in Barrett’s esophagus with probe-based confocal laser endomicroscopy: Final results of an international multicenter, prospective, randomized, controlled trial. Gastrointestinal Endoscopy 74, 465–472.

showed a pooled sensitivity, specificity and NPV of 90.4%, 89.9%, and 96.2%, respectively, for the recognition of dysplasia and EAC with CLE.

Volumetric laser endomicroscopy Volumetric laser endomicroscopy (VLE) uses optical coherence tomography (OCT) to create cross-sectional images of the esophageal wall with an imaging depth of 3 mm. This balloon-centered probe is passed through the endoscope and generates 1200 cross-sectional images during 90 s by analyzing backscattered infrared light. For the recognition of early neoplasia a VLE prediction score was developed a sensitivity and specificity of 83% and 71%, respectively (Swager et al., 2017a). This prediction score is based on three neoplasia features on VLE images: (1) lack of layering, (2) increased surface signal, and (3) increased number of irregular glands (Fig. 6) (Swager et al., 2017a). Recently, a feature has been added to the VLE device that places electrocoagulation marks on the esophageal mucosa, which allows precise targeted biopsies of dysplastic/malignant lesions and delineation of these lesions prior to endoscopic resection (Swager et al., 2017b).

Treatment Acid Suppression Proton pump inhibitors

Proton pump inhibitors (PPI’s) inhibit the Hþ/Kþ ATPase of the gastric parietal cells in the fundus and the corpus of the stomach, resulting in the reduction of acid exposure and an increase of pH. PPI-treatment is the key step in Barrett’s treatment; it protects the distal esophagus by decreasing the acid exposure and increases the numbers of “good bacteria” (e.g., lachnospiraceae, comamonadaceae) and decreases the numbers of “bad bacteria”(e.g., methylobacteriaceae) (Elias and Castell, 2017; Freedberg et al., 2014).

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Fig. 6 (A) Represents the histology of the EMR specimen with nondysplastic BE and (B) represents the VLE-image of the same specimen. (C) The arrows in square 1 shows some layered pattern. Square 2 shows a nonlayered pattern, the surface signal ¼ subsurface signal. Square 3 shows a dilated gland (black arrow). The ovals/circles show either a ink-mark or a electrocoagulation mark. (D) The VLE prediction score. From Swager, A. F., Tearney, G. J., Leggett, C. L. et al. (2017a). Identification of volumetric laser endomicroscopy features predictive for early neoplasia in Barrett’s esophagus using high-quality histological correlation. Gastrointestinal Endoscopy 85, 918–926.e7.

The use of PPI’s is related to an increase of differentiation markers, a decrease of markers that induce epithelial proliferation (Ouatu-Lascar et al., 1999), decrease of inflammation (Abu-Sneineh et al., 2010; Kedika et al., 2009) and a 71% risk reduction of progression to EAC/HGD (Singh et al., 2014).

Antireflux surgery PPI’s are shown to be effective against (milder forms of ) esophagitis. However, potential consequences of long-term PPI treatment and persisting reflux symptoms led to safety concerns. Fundoplication creates a mechanical barrier to stop gastric acid and bile reflux into the esophagus and in the long run, it reduces BE segment length, regression of dysplasia grade and prevents progression of BE into EAC (De Meester, 2015). A complete loss of IM is seen in 73% of the patients with ultra-short BE segment length (De Meester, 2015). Fundoplication is performed mostly laparoscopic and has relatively low morbidity and mortality rates. Concerns about the durability of antireflux surgery are rising. Recently, Maret-Ouda et al. (2017) published a retrospective study including 2655 patients who underwent antireflux surgery (median follow up 5.6 years). 17.7% of the patients had recurrent reflux symptoms requiring either anti-reflux medication or another antireflux procedure.

Ablative Therapy Ablation is based on replacement of columnar cells by squamous reepithelization. Ablative therapies are used to eradicate flat BE and residual BE after nodular EMR.

Radiofrequency Ablation Radiofrequency ablation (RFA) is used to eradicate the superficial layers of the esophageal wall with high-frequency energy through an external electrode array on a circumferential (balloon; the latest generation balloon inflates according to the size of the esophageal diameter) or a focal delivery device, providing 10, 12 or 15 J/cm2 energy. Brown and colleagues (Brown et al., 2015) found significantly more effect (73% vs. 39%) in patients with focal treatment. However, this device accounts for longer procedure times. Nowadays, it is the most used device for the treatment of flat BE and it is relatively safe. One large meta-analysis by Orman et al. (2013) with 3802 patients (18 studies) showed complete remission of IM and dysplasia in 78% and 91% of the patients, respectively. The risk of recurrence was 5.2% per year. The most common adverse event is the development of stricture (5.6%), followed by bleeding (1%), and perforation (0.6%). However, patients that underwent EMR were not excluded and this potentially overestimates the adverse event rates (Qumseya et al., 2016). In patients with low grade dysplasia, ablative therapy is recommended, because it reduces the progression to HGD or EAC by 25% (Phoa et al., 2014).

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Argon plasma coagulation Argon plasma coagulation (APC) is a noncontact device that uses ionized argon gas from the tip of the probe to deliver a high frequency electric current to ablate superficially. It is easy and relatively safe. It is mainly used to resolve bleeding in the gastrointestinal tract. The recurrence rate after APC ablation of residual BE is significantly lower in the APC group if compared to the surveillance alone (3% vs. 36.7%) (Manner et al., 2014). Bright et al. (2007) studied the long term effects of APC and found a >95% reduction of IM in 70% of the patients after 5 year. A newer method of APC, termed “hybrid APC” combines injection of saline fluid into the submucosal space to create a cushion, followed by APC to completely destroy the epithelial layer. Preliminary data suggest this method may be effective and may have lower stricture rates, but further data is required (Manner et al., 2016). Besides stricture formation, other potential side effects are: pain and dysphagia (Bright et al., 2007; Sharma et al., 2006c).

Photodynamic therapy Prior to the availability of RFA, photodynamic therapy (PDT) was used to treat early BE. It involves the administration of a photosensitizing agent (e.g., porfimer sodium, aminolevulinic acid), which reaches an optimum tissue concentration after 48 h. Exposure to red light results in a photochemical reaction that causes cell damage. Overholt et al. (2007) performed a large randomized controlled trial, which showed a significantly higher eradication rate in patients with HGD (77%) and IM (52%) that received PDT, when compared to the control group that only received omeprazole. After 5 years of follow up, this difference increased even more (77% vs. 39%). Drawbacks are the high costs and complications; skin photosensitivity (69%), stricture formation (36%), and odynophagia (20%) (Overholt et al., 2005). The efficacy of APC and PDT is similar in patients with IM. However, PDT might be more effective for BE with dysplasia (Ragunath et al., 2005).

Cryoablation Treatment with cryoablation is based on cell damage caused by cycles of rapid freezing, resulting in extra- and intracellular ice crystal formation, and slow thawing. The severity of injury depends on the duration of freezing, the number of “freezings” and the temperature of the target tissue. Commonly, cryotherapy is applied by a spray catheter, utilizing either liquid nitrogen or carbon dioxide. A balloon for focal ablation is also available (Overwater and Weusten, 2017). The therapy is well tolerated by patients and the costs are low. A study by Shaheen et al. (2010) shows complete remission in HGD, LGD, and IM in 97%, 87%, and 57% of the cases, respectively, after liquid nitrogen application. Three percent of the patients developed strictures.

Endoscopic Resection Endoscopic mucosal resection Endoscopic mucosal resection (EMR) is the first treatment of choice for nodular disease in a BE segment. It can be used prior to ablative therapy or individually to approach the BE segment more aggressive, resulting in a complete remission of IM in 96.9% of the cases (Chennat et al., 2009). However, the stricture rate is relatively high (37–88%) (Chennat et al., 2009; van Vilsteren et al., 2011). A large systematic review and meta-analysis by Tomizawa et al. (2018) has shown a complete eradication of IM and dysplasia 85% and 96.6%, respectively, in case of local nodular treatment. The recurrence of IM and dysplasia after >15 months in this study was 15.7% and 5.8%, respectively. Stricture, bleeding and perforation occurred in 37.4%, 7.9%, and 2.3% of the cases, respectively (Tomizawa et al., 2018). Two EMR methods are used most frequently; the cap-assisted and the ligation-and-snare technique. For cap-assisted mucosectomy, the tip of the endoscope is covered with a cap and a small sized snare is fitted through the biopsy channel. Prior to resection the submucosal space is injected with saline. The mucosa is sucked into the cap and resected with the snare, using electrocautery (Inoue et al., 1993). The ligation-and-snare technique (or multiband mucosectomy) does not use the saline injection, the mucosa is sucked into the cap straightaway. A band around the cap creates a pseudopolyp that is resected with a snare, which is placed below the band. If compared to the cap-assisted method, multiband mucosectomy is easier, the procedure time and the costs are significantly lower and the number of perforations is similar (Zhang et al., 2016). Postresection strictures develop as a process of scarring of the mucosal defect. Multiple treatments have been studied that may reduce the risk of postresection stricture formation. Examples are: prophylactive endoscopic balloon dilation, self expanding endoscopic metal stent placement, steroid therapy, botulinum toxin type A, orally administered agents (e.g., tranilast), tissue shielding methods (polyglycolic acid) and autologous cell sheet transplantation. Currently, a local injection with triamcinolone is used most frequently (Abe et al., 2017).

Endoscopic submucosal dissection Endoscopic submucosal dissection (ESD) is mostly used in patients with early EAC, that does not infiltrate the submucosal layer.

Esophagectomy In case of extensive (high grade) dysplasia, multifocal lesions or if extensive monitoring is not applicable to the patient, esophagectomy can be discussed. Williams et al. (2007) studied the outcomes of esophagectomies in 38 patients with HGD and

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found occult EAC in 29% of the cases, a overall survival of 97% after 32 months and acceptable morbidity. In case of final pathology diagnosis of HGD, the chance of lymph node involvement is very low and lymphadenectomy is not recommended (Dunbar and Spechler, 2012; Hagen et al., 2001). The trans-hiatal approach, open or laparoscopic, seems to be advisable in this case. Both the open and the laparoscopic approach should be performed in high-volume centers (Fitzgerald et al., 2013).

Prevention Primary Prevention During the past decade, a lot of research is done on the potential inverse relation between chemoprevention and the risk of progression from metaplasia, to dysplasia and eventually to carcinoma. According to the guidelines of the British Society of Gastroenterology, acid suppression is not recommended in asymptomatic patients, in contrast to symptomatic patients. Antireflux surgery is not superior to PPI’s, but should be considered in patients with limited PPI response (Fitzgerald et al., 2013). Mucin analysis confirmed that COX-2 inhibiters can inhibit inflammation and the development to EAC induced by reflux (Buttar et al., 2002). A meta-analysis by Veitonmäki et al. (2016) including 51 randomized controlled trials studied the effect of daily aspirin use on cancer incidence and found a significant reduction of cancer (of any kind) related death in the aspirin group. Liao et al. performed a pooled analysis studying the BE related EAC risk reduction related to Nonsteroidal antiinflammatory drugs (NSAID) and found that there is a reduced risk of EAC for individuals that use NSAID, especially when higher dosages were used. However, NSAID-use for the prevention of EAC is not recommended due to an increased risk of GI bleeding, hospitalization, perforation, gastric ulcers, and duodenal ulcers (Slattery et al., 1995; de Abajo and García Rodríguez, 2001).

Secondary Prevention Secondary prevention is the detection of a disease in a subclinical stage and early treatment. BE is the prestadium of esophageal cancer. Early treatment of BE is discussed in section “Treatment” of this article.

Risk Factors As described above, it is widely accepted that GERD promotes the development of BE. However, the existence additional risk factors is very likely, since not every patient with GERD develops EAC. Singh et al. (2013) performed a systematic review and meta-analysis (40 studies) and found a relation between central obesity and BE (OR 1.98; 95% CI 1.52–2.57), even after adjusting for BMI (OR 1.88; 95% CI 1.20–2.95). This is explained mechanically by Derakhshan et al. (2012) who showed a positive correlation between BMI and intragastric pressure (R 0.66–0.77, P < .001), and BMI and acid exposure (R 0.40, P < .001). But also nonmechanically by the correlation between BE and metabolically active peptides, associated with obesity (e.g., insulin-like growth factor, pro-inflammatory cytokines, leptin, ghrelin) (Greer et al., 2012; Garcia et al., 2014; Rubenstein et al., 2013). Patients who have ever smoked cigarettes are more likely to develop BE, compared to the general population (OR 1.67; 95% CI 1.04–2.67) and compared to patients with GERD (OR 1.61; 95% CI 1.33–1.96) (Cook et al., 2012). Additionally, men are at greater risk than women. This could potentially be explained by the predisposition of men to develop abdominal obesity or a protective feature of sex hormones. For example, Cronin-Fenton et al. (2010) found that women have a reduced risk of EAC after breastfeeding (OR 0.58; 95% CI ¼ 0.37–0.92). Other risk factors are the presence of a hiatal hernia (Zagari et al., 2008) or erosive esophagitis, family history of BE/EAC and excessive alcohol consumption (Crews et al., 2016). The more risk factors the higher the risk of BE (Crews et al., 2016).

Prognosis The incidence of EAC has increased more than sixfold over the past decades. The number of new esophageal cancer cases in the United States in 2016 was 16,910 with 15,690 deaths of esophageal cancer. The pooled annual risk of progression to carcinoma in BE patients ranges from 0.25% to 0.70% (Yousef et al., 2008; Cook et al., 2017; Thomas et al., 2007; Shaheen et al., 2000; Chang et al., 2007) and is 24 times higher than within the general population. This annual risk decreases with time. The incidence of esophageal adenocarcinoma might be higher in men than in women (P ¼ .18) and higher in long segment BE, compared to short segment (Yousef et al., 2008; Thomas et al., 2007). If esophageal cancer has developed, the 5-year survival rate is 20% and 50% of the patients die within a year of diagnosis. These rates get better when EAC is detected in an early stage (American Cancer Society, 2016). The mortality increases with 71% in patients with BE, however not specifically for EAC (Cook et al., 2017). Erichsen et al. found a mortality rate of cardiovascular disease, nonesophageal cancers, and esophageal cancer of 8.5, 14.7 and 5.4 per 1000 person-years, respectively, for patients with BE. The outcomes of RFA treatment vary extensively. The rate of complete eradication of IM ranges from 54% to 100%. Reported risk factors for recurrence after complete eradication of IM are: older age, non-Caucasian race, increased BE length, stricture

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formation and the duration that neoplasia exists. Other factors that are related to a poor response to RFA are: active reflux esophagitis during procedure (OR ¼ 37.4, 95%CI: 3.2–433.2) and treatment after scar regeneration with BE IM (OR ¼ 4.7, 95% CI: 1.1–20) (Fujii-Lau et al., 2017; van Vilsteren et al., 2013).

See Also: Esophageal Cancer. Esophageal Cancer Surgery. Esophageal Cancer Surveillance and Screening: Barrett’s Esophagus and GERD. Gastroesophageal Reflux Disease (GERD). Surgery for Gastroesophageal Reflux Disease

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Swager AF, Tearney GJ, Leggett CL, et al. (2017a) Identification of volumetric laser endomicroscopy features predictive for early neoplasia in Barrett’s esophagus using high-quality histological correlation. Gastrointestinal Endoscopy 85: 918–926.e7. Swager AF, de Groof AJ, Meijer SL, et al. (2017b) Feasibility of laser marking in Barrett’s esophagus with volumetric laser endomicroscopy: First-in-man pilot study. Gastrointestinal Endoscopy 86: 464–472. Takubo K, Vieth M, Aida J, et al. (2009) Differences in the definitions used for esophageal and gastric diseases in different countries: Endoscopic definition of the esophagogastric junction, the precursor of Barrett’s adenocarcinoma, the definition of Barrett’s esophagus, and histologic criteria for mucosal adenocarcinoma or high-grade dysplasia. Digestion 80: 248–257. Thomas T, Abrams KR, De Caestecker JS, et al. (2007) Meta analysis: Cancer risk in Barrett’s oesophagus. Alimentary Pharmacology & Therapeutics 26: 1465–1477. Thota PN, Vennalaganti P, Vennelaganti S, et al. (2017) Low risk of high-grade dysplasia or esophageal adenocarcinoma among patients with Barrett’s Esophagus less than 1 cm (irregular Z line) within 5 years of index endoscopy. Gastroenterology 152: 987–992. Tomizawa Y, Konda VJA, Coronel E, et al. (2018) Efficacy, durability, and safety of complete endoscopic mucosal resection of Barrett esophagus: A systematic review and metaanalysis. Journal of Clinical Gastroenterology 52(3): 210–216. Vaezi MF, Falk GW, Peek RM, et al. (2000) CagA-positive strains of Helicobacter pylori may protect against Barrett’s esophagus. The American Journal of Gastroenterology 95: 2206–2211. Vakil N, van Zanten SV, Kahrilas P, et al. (2006) The Montreal definition and classification of gastroesophageal reflux disease: A global evidence-based consensus. The American Journal of Gastroenterology 101: 1900–1920. quiz 1943. Veitonmäki T, Murtola TJ, Talala K, et al. (2016) Non-steroidal anti-inflammatory drugs and cancer death in the Finnish prostate cancer screening trial. PLoS One 11: e0153413. Vennalaganti PR, Naag Kanakadandi V, Gross SA, et al. (2015) Inter-observer agreement among pathologists using wide-area transepithelial sampling with computer-assisted analysis in patients with Barrett’s esophagus. The American Journal of Gastroenterology 110: 1257–1260. Vennalaganti P, Kanakadandi V, Goldblum JR, et al. (2017) Discordance among pathologists in the United States and Europe in diagnosis of low-grade dysplasia for patients with Barrett’s esophagus. Gastroenterology 152: 564–570.e4. van Vilsteren FGI, Pouw RE, Seewald S, et al. (2011) Stepwise radical endoscopic resection versus radiofrequency ablation for Barrett’s oesophagus with high-grade dysplasia or early cancer: A multicentre randomised trial. Gut. van Vilsteren FG, Alvarez Herrero L, Pouw RE, et al. (2013) Predictive factors for initial treatment response after circumferential radiofrequency ablation for Barrett’s esophagus with early neoplasia: A prospective multicenter study. Endoscopy 45: 516–525. Wang C, Yuan Y, and Hunt RH (2009) Helicobacter pylori infection and Barrett’s esophagus: A systematic review and meta-analysis. The American Journal of Gastroenterology 104: 492–500. quiz 491, 501. Ward EM, Wolfsen HC, Achem SR, et al. (2006) Barrett’s esophagus is common in older men and women undergoing screening colonoscopy regardless of reflux symptoms. The American Journal of Gastroenterology 101: 12–17. Westerhoff M, Hovan L, Lee C, et al. (2012) Effects of dropping the requirement for goblet cells from the diagnosis of Barrett’s esophagus. Clinical Gastroenterology and Hepatology 10: 1232–1236. Williams LJ, Guernsey DL, and Casson AG (2006) Biomarkers in the molecular pathogenesis of esophageal (Barrett) adenocarcinoma. Current Oncology 13: 33–43. Williams VA, Watson TJ, Herbella FA, et al. (2007) Esophagectomy for high grade dysplasia is safe, curative, and results in good alimentary outcome. Journal of Gastrointestinal Surgery 11: 1589–1597. Yang L, Lu X, Nossa CW, et al. (2009) Inflammation and intestinal metaplasia of the distal esophagus are associated with alterations in the microbiome. Gastroenterology 137: 588–597. Yousef F, Cardwell C, Cantwell MM, et al. (2008) The incidence of esophageal cancer and ehigh-grade dysplasia in Barrett’s sophagus: A systematic review and meta-analysis. American Journal of Epidemiology 168: 237–249. Zagari RM, Fuccio L, Wallander MA, et al. (2008) Gastro-oesophageal reflux symptoms, oesophagitis and Barrett’s oesophagus in the general population: The Loiano-Monghidoro study. Gut 57: 1354–1359. Zhang YM, Boerwinkel DF, Qin X, et al. (2016) A randomized trial comparing multiband mucosectomy and cap-assisted endoscopic resection for endoscopic piecemeal resection of early squamous neoplasia of the esophagus. Endoscopy 48: 330–338.

Further Reading Kapoor H, Agrawal DK, and Mittal SK (2015) Barrett’s esophagus: Recent insights into pathogenesis and cellular ontogeny. Translational Research 166(1): 28–40. Clemons NJ, Phillips WA, and Lord RV (2013) Signaling pathways in the molecular pathogenesis of adenocarcinomas of the esophagus and gastroesophageal junction. Cancer Biology & Therapy 14(9): 782–795. Kalatskaya I (2016) Overview of major molecular alterations during progression from Barrett’s esophagus to esophageal adenocarcinoma. Annals of the New York Academy of Sciences 1381(1): 74–91. Appelman HD, et al. (2013) The esophageal mucosa and submucosa: Immunohistology in GERD and Barrett’s esophagus. Annals of the New York Academy of Sciences 1300(1): 144–165. Elias PS and Castell DO (2017) The role of acid suppression in Barrett’s esophagus. The American Journal of Medicine 130(5): 525–529. Evans JA, et al. (2012) The role of endoscopy in Barrett’s esophagus and other premalignant conditions of the esophagus. Gastrointestinal Endoscopy 76(6): 1087–1094. Kandel P and Wallace MB (2017) The role of adjunct imaging in endoscopic detection of dysplasia in Barrett’s esophagus. Gastrointestinal Endoscopy Clinics 27(3): 423–446. Belghazi K, et al. (2016) Current controversies in radiofrequency ablation therapy for Barrett’s esophagus. Current Treatment Options in Gastroenterology 14(1): 1–18. Guidelines Shaheen NJ, Falk GW, Iyer PG, et al. (2016) ACG Clinical Guideline: Diagnosis and management of Barrett’s esophagus. The American Journal of Gastroenterology 111: 30–50. quiz 51. Fitzgerald RC, et al. (2013) British Society of Gastroenterology guidelines on the diagnosis and management of Barrett’s oesophagus. Gut 63(1): 7–42. di Pietro M, Fitzgerald RC, and BSG Barrett’s Guidelines Working Group (2017) Revised British Society of Gastroenterology recommendation on the diagnosis and management of Barrett’s oesophagus with low-grade dysplasia. Gut 67(2): 392–393. American Gastroenterological Association (2011) American Gastroenterological Association medical position statement on the management of Barrett’s esophagus. Gastroenterology 140(3): 1084–1091.

Relevant Website https://mediamotor.academy/born/index.php—The BORN project is an interactive training module that provides free online training for endoscopists, residents, or other interested individuals. It focuses on the delineation of BE related Neoplasia and is validated by the International Working Group for the Classification of Oesophagitis (IWGCO).

Behçet’s Disease Kavya M Reddy and Christine Hachem, Saint Louis University School of Medicine, St. Louis, MO, United States © 2020 Elsevier Inc. All rights reserved.

Introduction Behçet’s disease (BD) is a rare, systemic inflammatory disorder of unclear etiology and is characterized by a relapsing course of recurrent oral and genital ulcers as well as ocular lesions. Behçet’s disease, also known as Behçet’s syndrome, because of its variable presentation in terms of manifestations and severity (Barnes, 2006). The disease is a vasculitic process that involves vessels of all sizes and can also affect many organ systems causing vascular, neurological, musculoskeletal and gastrointestinal manifestations (Lopalco et al., 2017). The gastrointestinal tract is involved in 10%–50% of patients, and most commonly involves ulceration of the terminal ileum and cecum (Chung et al., 2001). Ulcers can be large and deep leading to complications such as gastrointestinal bleeding and occasionally perforation (Hatemi et al., 2018).

Epidemiology Behçet’s disease tends to occur mostly in areas extending from eastern Asia to the Mediterranean basin (Sakane et al., 1999). Prevalence rates vary by region, with Turkey having the highest prevalence with equal to or less than 421 cases per 100,000 (95% CI 340–510) in a population-based survey (Hatemi et al., 2018). The prevalence rate in the far East has been reported as 14 per 100,000 in China and 13.5 per 100,000 in Japan (Hatemi et al., 2018). The prevalence is lower in Western countries: 0.64 per 100,000 in the United Kingdom and 0.12–0.33 per 100,000 in the United States. Behçet’s disease is rare among Japanese immigrants in Hawaii and California (Sakane et al., 1999). Overall, the prevalence seems to be similar among men and women but follows a more severe course in men (Hatemi et al., 2018). The mean age of onset for gastrointestinal involvement is in the late thirties and most cases are sporadic. However, the frequency of BD within families is 2% to 5%, and is higher in Middle Eastern countries (10%–15%) (Sakane et al., 1999). The frequency of GI involvement among patients with BD varies in different countries with lower frequencies reported in Turkey (2.8%), India (3.4%) and Saudi Arabia (4%), moderate frequency in China (10%) and Taiwan (32%) and the highest frequency reported in the United Kingdom (38%–53%) and Japan (50%–60%) (Skef et al., 2015).

Pathology, Pathogenesis The mechanism of injury is likely multifactorial with both genetic and altered immune mediated mechanisms including humoral and cellular mediated responses, autoantibodies, and potential bacterial contributors. Behçet’s disease is characterized by vascular injury, hyperfunctioning neutrophils and an autoimmune response. The disease involves vessels of all sizes, however large vessels are most commonly involved (Lopalco et al., 2017). All lesions of Behçet’s disease, including oral and genital ulcers, erythema nodosum, posterior uveitis, epididymitis, enteritis, and central nervous system lesions will show evidence of vasculitis near the biopsy and will show infiltration of neutrophils. The neutrophils in patients with BD have been found to be overactive and lead to tissue injury. There is also activation of endothelial cells and activation of platelets which leads to hypercoagulability (Sakane et al., 1999). TNF-a has also been shown to have a role in the pathogenesis of BD with an upregulation of TNF-a and soluble TNF receptors (Lopalco et al., 2017). Susceptibility to Behçet’s disease is strongly associated with the presence of the HLA- B51 allele. The prevalence of the HLA-B51 allele is high among patients with Behçet’s disease endemic to regions along the Silk Road with up to 81% of Asian patients testing positive for this allele. The prevalence of this allele in those with BD in the United States, however, is much lower and approximately 13%. The HLA-B51 allele has also been shown to affect severity of disease and those with the allele develop more severe symptoms including posterior uveitis or progressive central nervous system disease. Furthermore, infectious agents have also been associated with the development of the disease. A variety of infections such as herpes simples virus, Hepatitis C, parvovirus B have been shown to be present in patients who develop BD. Streptococcus sanguis, is a bacterium that has been found in the oral microbiota and serum of patients with BD more frequently than in controls. However, none of these infectious agents have been proven to directly cause Behçet’s disease (Sakane et al., 1999) but may contribute to the immune response in BD through the concept of molecular mimicry. Molecular mimicry occurs when an autoimmune process is triggered by an environmental agent, and the disease may be perpetuated by an abnormal immune response to an autoantigen in the absence of ongoing infection (Sakane et al., 1999). Histopathological exam of mucocutaneous lesions (oral and genital ulcers) have a nonspecific pathology with mixed infiltration of lymphocytes, macrophages, and neutrophils at the base of the ulcer (Kokturk, 2012). Erythema nodosum, a manifestation commonly seen in BD, will have variable findings including leukocytoclastic vasculitis, neutrophilic vascular reaction, lymphocytic vasculitis, lymphohistiocytic septal/lobular panniculitis, granulomatous panniculitis, or acute necrotizing panniculitis. In cases of

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superficial thrombophlebitis, organized thrombus is observed in the vein lumen with fibrous thickening of the vein wall and infiltration of mononuclear cells. Pathology investigating central nervous system lesions, mainly demonstrate a perivascular lymphocytic infiltration with areas of necrosis in BD. The arterial involvement in BD resembles that of Takayasu’s arteritis, including aneurysm formation and arterial occlusion possibly due to neutrophilic vasculitis, which targets the vasa vasorum (Kokturk, 2012).

Clinical Manifestations (Natural History) Painful oral ulcerations are usually the initial presenting symptom of patients with BD and can precede other manifestations by many years. Aphthous ulcers appear in the gingiva, tongue, and buccal mucosal membranes. The lesion is typically round with a sharp, erythematous border and is covered by a yellowish pseudomembrane and usually last for 10 days without causing scarring (Sakane et al., 1999). Painful genital ulcers are also common and occur on the scrotum and penis in men and on the vulva in women. These ulcers are usually deeper, larger, and have an irregular border. They are usually recurrent and often scar (Sakane et al., 1999). BD can also involve the eye, with lesions in the uvea and retina. In 10% of patients, eye findings can be the initial manifestation. Patients may complain of blurred vision, eye pain, photophobia, lacrimation, and/or floaters. Ocular disease can progress to blindness if not treated. Classically, severe anterior uveitis is seen with findings of hypopyon, or a visible layer of pus in the anterior ocular chamber. Anterior uveitis usually resolves spontaneously, however due to repeated attacks, patients can develop deformities of the iris and can develop secondary glaucoma. Lastly, BD can lead to retinal disease with vaso-occlusive lesions and usually presents with painless, bilateral decrease in visual acuity. Evaluation may show hemorrhagic and exudative retinal lesions and cellular infiltration in the vitreous humor during the acute phase (Sakane et al., 1999). Cutaneous lesions are also common in BD in up to 75% of patients. Patients can present with variable skin findings. In female patients, erythema nodosum is common and occurs as painful lesions on the anterior shins that resolve spontaneously (Sakane et al., 1999). Erythema nodosum can lead to hyperpigmentation and can sometimes ulcerate. In men, pseudofolliculitis and acneiform nodules are more common and can appear on the back, face, and neck, especially along the hair-line. Patient’s with BD also may exhibit a positive pathergy test, which is useful in evaluating skin irritability. The test involves pricking a sterile needle into the patient’s forearm and is positive if a pustule that is greater than 2 mm in size develops after 24–48 h (Sakane et al., 1999). Behçet’s disease can involve blood vessels, both arterial and venous, of all sizes, with large-vessels being more commonly involved. There have been reports of inferior vena cava obstruction and Budd-Chiari syndrome, which is discussed further below. Furthermore, deep vein thrombosis and superficial thrombophlebitis also have been described. Superficial migratory thrombophlebitis of the arms and legs is also more common in male patients (Sakane et al., 1999). Occlusion of major veins and arteries may cause bleeding, infections, and organ failure. Aneurysms can also form and rupture, leading to death. CT, MRI, and angiography are useful for detecting these vascular lesions (Sakane et al., 1999). Central nervous system involvement is usually chronic and progressive and occurs in 10%–20% of patients with BD (Sakane et al., 1999). This is more common in men who are diagnosed at an early age. They can develop meningitis, meningoencephalitis, migraines, motor disturbances and psychiatric symptoms. Due to exacerbations and remissions, patients gradually develop irreversible damage and 30% can develop dementia in late stages (Sakane et al., 1999). Gastrointestinal involvement occurs in 10%–50% of patients and are particularly important as they are associated with significant morbidity and mortality (Chung et al., 2001; Skef et al., 2015). GI manifestations usually start 4–6 years after the onset of oral ulcers and can present with abdominal pain, nausea, vomiting, diarrhea, melena or hematochezia, or perforation (Skef et al., 2015; Cheon and Kim, 2015). The ileocecal region is the most commonly affected part of the gastrointestinal tract; however any segment can be involved (Sakane et al., 1999). It can be difficult to differentiate Behçet’s disease and inflammatory bowel diseases due to the overlap in symptoms and extraintestinal manifestations. Esophageal involvement in BD is uncommon with incident rates of 2%–11% (Skef et al., 2015). When esophageal involvement is present, it is more frequent in males. Patients may complain of substernal chest pain, dysphagia, odynophagia and rarely hematemesis (Chung et al., 2001). Usually, the middle portion of the esophagus is involved. Endoscopic findings can include esophageal erosions; aphthous, linear, or perforating ulcers; esophagitis; dissection of the mucosa; varices; and even severe stenosis (Chung et al., 2001). BD can also cause esophageal motility disorders with studies showing decreased lower esophageal sphincter pressure and impaired relaxation (Skef et al., 2015). The stomach is the least frequently involved segment in patients with BD but more commonly seen among those of Chinese descent. Dyspepsia and epigastric pain are the most common symptoms and endoscopic findings can reveal isolated gastric or duodenal ulcers or both. Rarely, patients with BD have been found to have Dieulafoy’s lesions, gastric non-Hodgkin’s lymphoma, pyloric stenosis, and gastroparesis. Studies have showed no increase in prevalence of Helicobacter pylori in patients with BD (Skef et al., 2015). Intestinal BD typically manifests as large (>1 cm), round/oval shaped, deep ulcers in the ileocecal region (Skef et al., 2015). The entire large intestine, including the rectum, can be involved, however, rectal involvement occurs in less than 1% of patients (Chung et al., 2001; Skef et al., 2015). BD can also involve the entire small bowel, and this has been demonstrated in studies using video capsule endoscopy. Rarely, complications such as strictures, abscess or fistula formation, and perforation can occur. There is a higher risk of perforation in those who are younger than 25 at time of diagnosis, have a history of laparotomy, and volcano-shaped ulcers on colonoscopy (Skef et al., 2015).

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Pancreatic involvement in BD is exceptionally rare, with few cases reported. However, some studies have shown that pancreatic involvement may be underreported or underdiagnosed as an autopsy series of 170 cases from Japan suggested 2.9% involvement of the pancreas. Vasculitis is thought to be the underlying cause of pancreatic inflammation (Skef et al., 2015). The most common manifestation of the liver in patients with BD is Budd Chiari Syndrome. It can be a serious complication and associated with a high mortality rate (Skef et al., 2015). It is thought to be due to venous thrombosis secondary to endothelial dysfunction from vasculitis. Studies have reported prevalence rates between 1.3%–3.2% and it is more common in men. Patients often present with right upper quadrant abdominal pain, hepatosplenomegaly and ascites. Thrombosis of the hepatic veins (HV), inferior vena cava (IVC) and portal vein (PV) may occur. The extent of IVC obstruction appears to be the major determinant of survival in BD patients with Budd Chiari syndrome. Some studies suggest that patients with BD should be screened for Budd Chiari syndrome with duplex ultrasonography (Skef et al., 2015). Due to vascular involvement of all size vessels, BD also has cardiac, pulmonary, and renal manifestations. Vascular lesions in the lung can cause thrombosis, aneurysms, and arteriobronchial fistulas which may present with recurrent episodes of dyspnea, cough, chest pain, or hemoptysis (Sakane et al., 1999). Furthermore, coronary artery disease and valvular disease may also occur. Renal disease is relatively uncommon. 50% of patient’s will also have musculoskeletal involvement with nondeforming monoarthritis or polyarthritis, usually affecting the knees, followed by the wrists, ankles, and elbows (Sakane et al., 1999).

Diagnosis The diagnosis is based on clinical criteria because histopathologic, laboratory and imaging findings are nonspecific. The International Study Group for Behçet’s Disease proposed new diagnostic criteria in 1990 (Table 1). These criteria require the presence of oral ulcers plus any two of the following: genital ulcers, typical eye lesions, typical skin lesions, or a positive result of a pathergy test (i.e., a sterile pustule developing after 24–48 h at the site of a needle prick to the skin) (Anon, 1990). However, many diseases produce symptoms similar to those of Behçet’s syndrome and should therefore be included in the differential diagnosis. Because of the variable and systemic presentation, it can be difficult to make a definitive diagnosis. Other diseases to consider in the differential include post-infectious arthritis, Stevens-Johnson syndrome, systemic lupus erythematosus or other rheumatologic diseases, tuberculosis, Crohn disease, ulcerative colitis, or other vasculitis. Other infectious etiologies such as herpes simplex virus or tuberculosis (TB) should be considered. For instance, in the event of esophageal involvement, herpes esophagitis should be suspected if there are more discrete esophageal ulcers (Chung et al., 2001). Endoscopic brushing, biopsy, and culture are therefore required to differentiate BD from viral esophagitis (Chung et al., 2001). Ruling out intestinal TB is extremely important especially in endemic areas, because immunosuppressive regimens such as corticosteroids and anti-TNF alpha monoclonal antibodies can exacerbate intestinal tuberculosis (Hisamatsu et al., 2014). In patients with BD, fecal calprotectin may be a useful marker to suggest intestinal involvement as fecal calprotectin levels have been found to be higher in cases with BD with intestinal involvement in a few studies (Ozseker et al., 2016; Kim et al., 2017). The anti-Saccharomyces cerevisiae antibodies (ASCA) have been shown to be higher in patients with BD with GI involvement than in controls (Kim and Cheon, 2016). Furthermore, those with positive ASCA were more likely to require surgical intervention (Kim and Cheon, 2016). A variety of imaging tests can also be helpful in diagnosing BD. Although not commonly used anymore, a barium study is useful in both determining the extent of lesions and in demonstrating characteristic deep, penetrating or punched-out ulcers (Chung et al., 2001). Computed tomography (CT) has advantages in demonstrating bowel wall thickening and lesions in the extraluminal space and is useful for early detection of complications. Gastrointestinal lesions are usually described as irregular, large (>1 cm), round or oval in shape. The ulcers have a punched-out appearance, are deep with discrete margins in a focal distribution (Lopalco et al., 2017). Endoscopically, ulcers are classified into volcano, geographic, and aphthous types with the volcano-type being associated with a poorer prognosis. At times, it is very difficult to differentiate gastrointestinal BD from inflammatory bowel disease, in particular Crohn’s disease. In contrast, in inflammatory

Table 1 Criterion

Criteria for diagnosis of Behçet’s disease Observation

Primary Recurrent oral Minor aphthous, major aphthous, or herpetiform ulceration observed by physician or patient, recurring at least three times in ulceration one 12-month period Plus two of the following symptoms Recurrent genital Aphthous ulceration or scarring observed by physician or patient ulceration Eye lesions Anterior uveitis, posterior uveitis, or cells in the vitreous (on slit-lamp examination) or retinal vasculitis observed by ophthalmologist Skin lesions Erythema nodosum observed by physician or patient, pseudofolliculitis, or papulopustular lesions; or acneiform nodules observed by physician in postadolescent patients not receiving corticosteroid treatment Positive pathergy test Read by physician at 24–48 h Modified from Anon (1990). Criteria for diagnosis of Behcet’s disease. International Study Group for Behcet’s Disease. Lancet 335(8697), p. 1078–1080.

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bowel disease, the ulcers have a cobblestone appearance with a segmental distribution. A clinical scoring system known as the Disease Activity Index for Intestinal BD (DAIBD) provides a score between 0 and 325 based on an 8-point index. It classifies disease activity as quiescent (19), mild (20–39), moderate (40–74), and severe ( 75), based on the patient’s intestinal and extraintestinal symptoms, stool frequency, and general condition (Lopalco et al., 2017).

Treatment The optimal medical treatment of Behçet’s syndrome has yet to be well established. Treatment plans are based on areas affected and patient related factors. Because of the systemic presentation and wide array of organs affected, all members of the treatment team should be play a role in optimizing treatment for patients with BD. Mucocutaneous disease can be treated with topical or intralesional steroids. Furthermore, oral and genital ulcers can be treated with colchicine, which inhibits neutrophil function or thalidomide. Systemic steroids are usually used in refractory cases for mucocutaneous lesions or if there is CNS involvement, gastrointestinal involvement or large vessel lesions (Sakane et al., 1999). During attacks of anterior uveitis, topical mydriatic agents and corticosteroid drops are given but colchicine can also be used to prevent both anterior and posterior uveitis. Furthermore, cytotoxic agents such as azathioprine, chlorambucil and cyclophosphamide have been shown to help prevent ocular attacks in 50%–70% of patients (Sakane et al., 1999). In refractory cases of ocular lesions, cyclosporine has been shown to be beneficial although it’s use is limited by its adverse effects. In CNS disease, high doses of steroids are used either alone or in combination with cytotoxic agents such as cyclophosphamide, chlorambucil, and methotrexate. Similarly, large vessel disease is treated with a combination of steroids and cytotoxic agents. Complications of large vessel disease, such as deep vein thrombosis, should be treated with antiplatelet agents and anticoagulants however care must be exercised when pulmonary vessels are involved given risk of life-threatening massive hemoptysis (Sakane et al., 1999). Corticosteroids are also the mainstay of medical therapy in gastrointestinal Behçet’s disease and many of the treatments used for inflammatory bowel disease are also effective, however the management is not standardized. Corticosteroids are usually first-line therapy in patients with severe systemic symptoms, recurrent gastrointestinal bleeding, or when treatment with 5- aminosalicylic acid (5-ASA)/sulfasalazine (SSZ) is inadequate (Lopalco et al., 2017). Corticosteroids are effective short term and dosing is based on severity of disease. 5-Aminosalicylic Acid (5-ASA)/Sulfasalazine (SSZ) is usually indicated in all cases of gastrointestinal BD because it is safe and can be used to induce remission in milder forms of BD and for maintenance once remission is achieved. However, there is conflicting data on the efficacy of these agents. Other immunomodulators such as 6- mercaptopurine (6-MP) and its prodrug azathioprine (AZA) have been shown to decrease reoperation rates in patients with gastrointestinal BD who have undergone surgical interventions. Although thiopurine therapy has been shown to be effective for maintenance of remission in gastrointestinal BD, there may be a poor response to this treatment in those younger age at diagnosis (2 years of painful complaints or health care seeking?] b. Why is the patient presenting now? It is often less important to obtain a detailed history of previous health care use and rather focus on the reason for the current visit, which can often drive diagnosis (e.g., fear of cancer diagnosis, change in stress, disability or litigation). c. Is there a history of trauma? The prevalence of trauma among chronic pain patients warrants early awareness of its presence, which may influence symptom perception, treatment response and the doctor–patient relationship. d. What does the patient understand about their condition? Developing a shared “story” about the condition can make a significant impact on adherence to treatment recommendations. e. How does pain affect their ability to function in life? It can also be helpful to ask patients what life would be like if they did not have pain—this can help with shared-decision making later on. f. Is there a psychiatric history? Sometimes, psychiatric screening questionnaires can be used to guide care.

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g. How does the patient’s family/support system handle his/her pain? This question can identify environmental triggers or reinforces as well as any cultural beliefs about pain. h. How is the patient coping with pain currently? What works? What does not?

Physical Evaluation While there is no physical finding that can establish a diagnosis of CAPS, it is critical to conduct a physical exam, particularly palpation, as part of understanding and validating the patient’s view of his/her pain location and any radiation patterns. Palpation can also allow the provider to observe any emotional reactivity around the pain site. One might notice scarring of the abdomen from prior surgeries, which can guide additional history taking. While rare, findings on physical exam may identify abdominal wall pain or indicate the need for additional workup. Carnett’s test can also help to differentiate visceral from somatic pain (Takada et al., 2011), albeit less reliably when determining abdominal wall pain versus CAPS. The below lists some ways to distinguish between chronic versus acute abdominal pain syndromes. a. Lack of autonomic arousal (e.g., sweating, increased blood pressure or heart rate) often differentiates acute from chronic pain. b. Chronic pain patients often wince with closed eyes, differentiating themselves from acute pain patients who keep eyes open in fearful anticipation of pain. c. When a stethoscope is used to palpate the abdomen, the acute patient exhibits pain behavior whereas the viscerally sensitive, chronic pain patient may have a decreased pain response with this technique.

Investigations Testing should be limited to addressing symptoms and signs that suggest organic disease only, and should be done to “exclude” other diagnoses. A minimal workup might include routine laboratory tests (e.g., inflammation, anemia, and fecal blood loss). If additional workup is indicated due to “alarm features” or “red flags,” the patient should be aware in advance that the results are likely to be negative and that CAPS is the most likely diagnosis (Fig. 1).

Differential Diagnosis It is important to distinguish CAPS from other functional gastrointestinal disorders, which have a visceral trigger such as IBS, in which pain is usually associated with bowel movements, and FD, in which pain is associated with eating. If pain is associated with menses or endometriosis, gynaecological conditions might be considered. Providers should be aware of abdominal wall pain, or Anterior Cutaneous Nerve Entrapment Syndrome (ACNES), although its importance in the diagnostic process of CAPS is controversial. Finally, CAPS can be distinguished from malingering or feigned pain, in which a patient intentionally produces or exaggerates pain with the goal of achieving secondary gain (e.g., avoiding work, seeking disability).

Fig. 1 The differential diagnosis for CAPS can be simplified using this algorithm (Keefer et al., 2016).

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Approaches to Treatment Treatment for CAPS is multipronged and always starts with an effective patient-provider relationship. The provider must demonstrate empathy and validation of symptoms as real, reassure the patient that she/he will not abandon them, educate and reassure the patient about his/her condition and obtain buy-in from the patient with respect to setting realistic goals, take personal responsibility for recovery, and maintain boundaries around time and frequency of contact. With respect to determining the role of pharmacological and nonpharmacological therapies, the provider might base his/her decision on the severity of symptoms and the degree to which the patient experiences disability. The provider must be familiar with referral to a mental health provider and/or a pain center so that these can be incorporated early on in care if needed.

Pharmacological Treatment Background and Rationale Antidepressants, such as tricyclic antidepressants (TCAs) and serotonin reuptake inhibitors (SNRIs), have already been proven to be helpful in managing chronic pain and some gastrointestinal disorders, like IBS (Sobin et al., 2017). Serotonin reuptake inhibitors (SSRIs), atypical antipsychotics, and antiepileptics have additional advantages for mood, anxiety, and pain management. There are limited studies available demonstrating efficacy in CAPS, but there are studies existing demonstrating efficacy of the aforementioned medications in pain management, IBS, and other FGIDs that can be extrapolated to CAPS.

Tricyclic Antidepressants (TCAs) TCAs are widely used in clinical practice for a range of pain disorders and are more effective than SSRIs in reducing pain (Sobin et al., 2017). TCAs have demonstrated strong clinical efficacy in functional disorders, such as fibromyalgia, and medical disorders, such as postherpetic neuralgia, and painful diabetic and nondiabetic polyneuropathy (Dharmshaktu et al., 2012). In a review of TCAs used for neuropathic pain in randomized clinical trials, the number needed to treat (NNT) to reduce neuropathic pain by 50%, as reported by the patient, ranged from 2 to 4 (Finnerup et al., 2005). In the gastrointestinal setting, TCAs have been commonly used to manage irritable bowel syndrome with a predominant diarrheal component (IBS-D), and TCAs can also be utilized to manage CAPS (Sobin et al., 2017). In a meta-analysis, the relative risk of persistent IBS symptoms when using TCAs compared to placebo was 0.68 (95% CI, 0.56–0.83) and the NNT was 4 (95% CI, 3–8) (Ford et al., 2014). The mechanism of action for TCA analgesia is incompletely understood, but may be attributed to serotonin and norepinephrine reuptake inhibition. Anticholinergic adverse effects from TCAs, such as blurred vision, constipation, confusion, dry mouth, and urinary retention may occur in more than 60% of patients. Nortriptyline or despiramine are usually better tolerated than amitriptyline and imipramine since they have a lower risk of anticholinergic effects. However, these anticholinergic effects may be advantageous for those patients suffering from diarrhea. TCA inhibition of alpha-1-adrenergic receptors can precipitate dizziness, orthostatic hypotension, and tachycardia. Importantly, TCAs may be cardiotoxic and may induce arrhythmias at high doses. It is recommended to avoid TCAs in patients with a relevant cardiac history, such a previous myocardial infarction, or a prolonged QTc interval. Lastly, TCAs exhibit antihistaminergic effects, such as sedation and somnolence, so they are often dosed near bedtime. For gastrointestinal disorders, TCAs are typically prescribed in low doses, ranging from 25 to 75 mg once daily, which is much lower than common doses for psychiatric indications (ranging from 200 to 300 mg once daily).

Selective Serotonin Reuptake Inhibitors (SSRIs) SSRIs are not primarily utilized for treating pain and, in the setting of gastrointestinal conditions, are more appropriate for augmenting treatment when there are dominant symptoms of anxiety (Drossman, 2009). Evidence for SSRIs for pain relief is conflicting. One older study, comparing the effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy, found that fluoxetine had no greater pain relief compared to placebo in patients with normal mood (Max et al., 1992). However, other studies have shown that paroxetine and citalopram may effectively reduce pain in diabetic neuropathy. Tack et al demonstrated that citalopram was able to significantly improve abdominal pain, bloating, impact of symptoms on daily life, and overall well-being compared to placebo in patients with IBS (Tack et al., 2006). However, citalopram failed to show improvement in IBS symptoms or pain in other studies. SSRIs increase the serotonin concentration in the synaptic space by selectively inhibiting their reuptake by their respective receptors. Common adverse effects include anxiety, diarrhea, insomnia, and sexual dysfunction. Selecting an appropriate SSRI requires consideration of the medication’s specific pharmacokinetics and pharmacodynamics. For example, sertraline, citalopram, and escitalopram are least likely to have drug interactions, whereas fluoxetine and paroxetine are most likely. Fluoxetine has the longest half-life and is least likely to induce withdrawal compared to paroxetine, which has a significantly shorter half-life. Dosing for SSRIs for CAPS is similar to psychiatric dosing.

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Selective Norepinephrine Reuptake Inhibitors (SNRIs) SNRIs, since they produce positive noradrenergic effects, are more potent analgesics than SSRIs. Duloxetine, in particular, is FDAapproved for treating diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain in addition to its indications for major depressive disorder (MDD) and generalized anxiety disorder (GAD). A Cochrane meta-analysis found that duloxetine 60 mg daily is effective in treating painful diabetic peripheral neuropathy with a risk ratio (RR) for  50% pain reduction of 1.73 (95% CI 1.44–2.08) (Lunn et al., 2014). In the same analysis, duloxetine was also effective for managing fibromyalgia (RR 1.57, 95% CI 1.20–2.06) and for painful symptoms in depression (RR 1.37, 95% CI 1.19–1.59). SNRIs have less data available assessing their safety and efficacy in IBS and CAPS. In an open-label pilot study (Lewis-Fernandez et al., 2016) of 17 patients with IBS and MDD, duloxetine significantly improved Gastrointestinal Symptoms Rating Scale (GSRS) and Montgomery-Åsberg Depression Rating Scale (MADRS) total scores. Notably, abdominal pain severity decreased by 56% (as measured by the GSRS questionnaire). Another open-label study of 15 patients with IBS and no comorbid depression showed duloxetine significantly improved abdominal pain (Brennan et al., 2009). SNRIs have a similar safety profile to SSRIs, including nausea, insomnia, headaches, and sexual dysfunction. SNRIs are typically less constipating than TCAs and also have the advantage of effective pain management. It is important to note that venlafaxine should be prescribed at a target dose greater than 150 mg. Doses lower than 150 mg do not effectively increase noradrenergic levels to manage pain.

Atypical Antipsychotics Antipsychotics were initially approved by the U.S. Food and Drug administration for management of schizophrenia, bipolar disorder, and for some, the management of refractory depression. Atypical antipsychotics, sometimes called “second generation,” differ from earlier antipsychotics like haloperidol because of the decreased risk of extrapyramidal adverse effects. Atypical antipsychotics have been used off-label for a number of indications, including anxiety, eating disorders, insomnia, obsessivecompulsive disorder, posttraumatic stress disorder, personality disorders, substance abuse, and Tourette’s syndrome. Quetiapine can be used to augment therapy in patients with CAPS who have increased anxiety, insomnia, or pain. In a retrospective review of 21 patients with FGID and symptoms refractory to centrally modulating agents, quetiapine was found to provide adequate relief from symptoms as measured by a questionnaire. Meanwhile 9 of 21 were categorized as responders as measured by the Treatment Efficacy Questionnaire (TEQ) (Grover et al., 2009). Some patients also reported improvement in abdominal pain, sleep and mood, and bowel movements. Low doses ranging from quetiapine 25 to 100 mg were used in the study, with a mean of 50 mg. However, doses as high as quetiapine 200 mg can be used for severe symptoms of anxiety, insomnia, or pain (Sobin et al., 2017). Quetiapine’s mechanism of action to improve symptoms is closely related to its adverse effects. Quetaipine, similar to other atypical antipsychotics, has a strong affinity for and antagonizes histamine H1, alpha 1 adrenergic, and serotonergic 5HT2A receptors. Meanwhile, quetiapine has a decreased affinity for dopamine receptors, which decreases the risk of extrapyramidal adverse effects. Quetiapine has a low rate of hyperprolactinemia, a low to moderate risk for QTc prolongation, and a moderate risk of metabolic effects, like weight gain. Other atypical antipsychotics have some evidence showing improvement of pain associated with fibromyalgia, but the evidence for gastrointestinal disorders is limited. In a small retrospective study, olanzapine improved pain and daily functioning in patients with treatment-resistant fibromyalgia, but adverse effects like weight gain and somnolence limited its use (Freedenfeld et al., 2006). Olanzapine can also alleviate chronic nausea and is utilized in oncology, anesthesiology, and gastroenterology for this indication.

Miscellaneous Psychotropic Medications Mirtazapine is an antidepressant that strongly antagonizes central alpha 2 adrenergic receptors, and both serotonergic receptors (5HT2 and 5-HT3). Mirtazapine is typically dosed from 15 to 45 mg per day. Mirtazapine is more sedating at lower doses, conversely, antidepressive effects are more potent at higher doses. Most common adverse effects include dry mouth, sedation, and increases in appetite and body weight. Mirtazapine has been found to help manage chronic nausea, dyspepsia, depression, and weight loss in patients with functional disorders. Buspirone is a 5HT1A-receptor antagonist, and has anxiolytic properties similar to that of benzodiazepines. However, it does not interact with GABAA receptors or have the sedative, muscle-relaxing, or anticonvulsant effects of benzodiazepines. Another advantage of buspirone is that it also does not have the same risks of dependence as benzodiazepines. Buspirone, via 5HT1A-antagonism, can relax the proximal stomach and help alleviate symptoms of dyspepsia, postprandial fullness, early satiation, and upper abdominal bloating.

Antiepileptics Antiepileptics have been used for pain management since the 1960s. There is evidence that carbamazepine, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, pregabalin, topiramate, and valproate may be effective in managing neuropathic pain (Wiffen et al., 2013). Gabapentin and pregabalin have the most evidence supporting their use in the management of painful diabetic neuropathy, postherpetic neuralgia, central neuropathic pain, and fibromyalgia (Wiffen et al., 2013). Gabapentin and pregabalin are derived from GABA, but do not act on the GABAnergic system. Instead they bind to the alpha-2/delta-1 subunit

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of voltage-gated calcium channels in the central nervous system. In animal models of visceral pain, pregabalin was shown to reduce allodynia and hyperalgesia. In a small, randomized study, pregabalin was shown to significantly increase rectal sensory thresholds to distension, and normalize thresholds for pain in hypersensitive IBS patients (Houghton et al., 2007). In patients with diarrhea predominant IBS, gabapentin helped to improve visceral hypersensitivity. Pregabalin and gabapentin have not yet been evaluated in the management of CAPS. However, evidence suggests that functional and visceral pain may be improved by central modulation. A small study using neuroimaging has shown that pregabalin is able to reduce the functional connectivity between two areas of the brain, which has been shown to have an increased connection in patients with chronic pain (Harris et al., 2013). Consequently, it is feasible that alpha-2-delta ligands may be able to be utilized in CAPS. The most common adverse effects for both medications include dizziness, somnolence, dry mouth, and edema.

Analgesics Analgesics, such as aspirin, acetaminophen, and nonsteroidal antiinflammatory drugs do not effectively manage pain associated with CAPS. This is most likely because their mechanisms of action are localized in the somatic nervous system. Opioids should be avoided because of the risk of opioid overdose and opioid use disorder. Opioids may also not be effective for patients suffering from CAPS long-term; opioids have not been found to be effective in managing pain lasting longer than 3 months. Furthermore, utilizing opioids may exacerbate gastrointestinal disorders. Adverse effects include constipation, nausea, bloating, ileus, and in some cases, pain. Opioids can induce hyperalgesia, which is when increasing doses of opioids provide no further pain relief. When abdominal pain, specifically, increases with increasing doses of opioids, it is termed “Narcotic Bowel Syndrome (NBS)” (Keefer et al., 2016). Developing NBS can further complicate the patient’s condition and delay proper management. Due to the fact that the risks of opioid use is much greater than benefits, it is not recommended in CAPS.

Augmentation Treatment In some patients, one medication may not be able to fully manage CAPS symptoms. In these cases, treatment may be augmented with another medication. Augmentation typically utilizes low doses of two or more medications with different mechanisms of action to target distinct receptors and improve pain management. For example, a low-dose SSRI in combination with a TCA can manage anxiety and pain, respectively. Buspirone can be added to a regimen for patients with anxiety who are not properly managed by an SSRI alone. Quetiapine can also be used synergistically with other antidepressants for patients with increased anxiety, insomnia, and/or pain. Lastly, pregabalin or gabapentin can be used to augment therapy when neuropathic pain is involved. The most concerning adverse effect that may manifest from augmentation is serotonin syndrome. Symptoms of serotonin syndrome include fever, muscle rigidity, tremor, hyperflexia, seizures, tachycardia, and pupillary dilation. If serotonin syndrome is suspected, the suspected medication should be discontinued immediately.

Psychological Treatment Background and Rationale Psychological treatment can be used as the primary modality of therapy or as an augmentation to antidepressant medication. While antidepressants are often particularly useful in the setting of vegetative symptoms of depression, psychological therapies can work on higher order cognitive processes including coping, re-appraisal of pain, and resolution of underlying psychopathology driving symptom reporting. Psychological consultation can also augment adherence to medical regimens, and improve motivation for care. Behavioral interventions for CAPS target some of the underlying cognitive-affective processes driving pain symptoms and behavior, including pain catastrophizing, fear of symptoms, hypervigilance and attention bias and somatization. Similarly, psychotherapy focused on the high comorbidity between CAPS and depression, anxiety and substance abuse can be effective. Four classes of psychotherapy hold the most promise in CAPS: cognitive-behavioral therapy (CBT), brief psychodynamic interpersonal psychotherapy, gut-directed hypnotherapy and mindfulness/acceptance based approaches (Keefer and Mandal, 2015).

Cognitive Behavioral Therapy (CBT) Cognitive behavioral therapy is based on the concept that coping skills deficits lead to maladaptive behaviors, negative emotions, and symptom-exacerbating thoughts in chronic pain. New skills can be acquired to replace the maladaptive ones, leading to improved symptoms and quality of life. CBT is well-supported in the treatment of refractory FGIDs, with the most robust data in IBS and several chronic pain conditions, including lower back pain, fibromyalgia and female sexual pain. Skills taught during a course of CBT might include relaxation techniques (e.g., diaphragmatic breathing, progressive muscle relaxation) to modify arousal, reduce muscle tension, and alter attentional focus during pain episodes. CAPS patients can learn to “pace themselves” to accommodate their new state, and to ensure they are still able to schedule restorative or pleasant activities to prevent depression and maintain health-related quality of life (HRQOL). Patients can be taught “distraction techniques” including counting, identifying a focal point, and using pleasant imagery for use during active pain episodes. These techniques can build self-efficacy, which is another critical component of pain management. Finally, CBT techniques focus on challenging negative or maladaptive thoughts, including pain catastrophizing and helplessness.

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Psychodynamic Interpersonal Psychotherapy (PIT) While not previously tested in CAPS, PIT has successfully improved outcomes and reduced costs in randomized controlled trials for severe IBS. PIT appears to be particularly helpful for patients who report a history of sexual abuse and treatment. PIT is associated with an increase in tolerance to pain and improvement in interpersonal issues and problems, which makes it particularly well suited to managing CAPS.

Hypnotherapy Hypnosis has long been used to treat acute and chronic pain, and therefore is a reasonable intervention for CAPS. Accumulating evidence suggests that gut-focused hypnotherapy is effective in relieving the symptoms of IBS. Patients with CAPS are often reluctant to engage in treatments that might imply that there is a psychiatric component to their condition, and this particular barrier is less apparent with hypnotherapy than with other psychotherapies.

Mindfulness and Acceptance-Based Behavioral Therapies Newer behavioral therapy approaches are mindfulness and acceptance-based, focusing less on cognitions and coping, and instead emphasize attentional bias and acceptance. Mindfulness-Based Stress Reduction (MBSR) is a common intervention associated with improved symptoms and HRQOL in a variety of medical conditions, including chronic pain. Research has also shown that greater acceptance of pain is associated with reports of lower pain intensity, less pain-related anxiety and avoidance, less depression, less physical and psychosocial disability, greater physical and social abilities, and greater work status; this can be achieved through a form of CBT called “Acceptance and Commitment Therapy” (McCracken and Vowles, 2014).

Prevention Prevention of chronic abdominal pain conditions such as CAPS relies heavily on early, effective diagnosis and management. As patients seek care that is ineffective, they undergo unnecessary surgeries and procedures, further amplifying pain and negative views of the medical system. Further, treatment of CAPS with opioids can increase the likelihood that the patient will develop narcotic bowel syndrome (Keefer et al., 2016).

Prognosis The prognosis of CAPS is unknown.

References Brennan BP, Fogarty KV, Roberts JL, Reynolds KA, Pope HG Jr., and Hudson JI (2009) Duloxetine in the treatment of irritable bowel syndrome: An open-label pilot study. Human Psychopharmacology 24(5): 423–428. Corazziari E (2004) Definition and epidemiology of functional gastrointestinal disorders. Best Practice & Research. Clinical Gastroenterology 18(4): 613–631. https://doi.org/10.1016/j. bpg.2004.04.012. Dharmshaktu P, Tayal V, and Kalra BS (2012) Efficacy of antidepressants as analgesics: A review. Journal of Clinical Pharmacology 52(1): 6–17. https://doi.org/ 10.1177/0091270010394852. Drossman DA (2009) Beyond tricyclics: New ideas for treating patients with painful and refractory functional gastrointestinal symptoms. The American Journal of Gastroenterology 104(12): 2897–2902. https://doi.org/10.1038/ajg.2009.341. Drossman DA, Li Z, Andruzzi E, Temple RD, Talley NJ, Thompson WG, et al. (1993) U.S. householder survey of functional gastrointestinal disorders. Prevalence, sociodemography, and health impact. Digestive Diseases and Sciences 38(9): 1569–1580. Finnerup NB, Otto M, McQuay HJ, Jensen TS, and Sindrup SH (2005) Algorithm for neuropathic pain treatment: An evidence based proposal. Pain 118(3): 289–305. https://doi.org/ 10.1016/j.pain.2005.08.013. Ford AC, Quigley EM, Lacy BE, Lembo AJ, Saito YA, Schiller LR, and Moayyedi P (2014) Effect of antidepressants and psychological therapies, including hypnotherapy, in irritable bowel syndrome: Systematic review and meta-analysis. The American Journal of Gastroenterology 109(9): 1350–1365. quiz 1366. https://doi.org/10.1038/ajg.2014.148. Freedenfeld RN, Murray M, Fuchs PN, and Kiser RS (2006) Decreased pain and improved quality of life in fibromyalgia patients treated with olanzapine, an atypical neuroleptic. Pain Practice 6(2): 112–118. https://doi.org/10.1111/j.1533-2500.2006.00072.x. Grover M, Dorn SD, Weinland SR, Dalton CB, Gaynes BN, and Drossman DA (2009) Atypical antipsychotic quetiapine in the management of severe refractory functional gastrointestinal disorders. Digestive Diseases and Sciences 54(6): 1284–1291. https://doi.org/10.1007/s10620-009-0723-6. Harris RE, Napadow V, Huggins JP, Pauer L, Kim J, Hampson J, and Clauw DJ (2013) Pregabalin rectifies aberrant brain chemistry, connectivity, and functional response in chronic pain patients. Anesthesiology 119(6): 1453–1464. https://doi.org/10.1097/ALN.0000000000000017. Houghton LA, Fell C, Whorwell PJ, Jones I, Sudworth DP, and Gale JD (2007) Effect of a second-generation a2d ligand (pregabalin) on visceral sensation in hypersensitive patients with irritable bowel syndrome. Gut 56(9): 1218–1225. Keefer L and Mandal S (2015) The potential role of behavioral therapies in the management of centrally mediated abdominal pain. Neurogastroenterology and Motility 27(3): 313–323. https://doi.org/10.1111/nmo.12474. Keefer L, Drossman DA, Guthrie E, Simren M, Tillisch K, Olden K, and Whorwell PJ (2016) Centrally mediated disorders of gastrointestinal pain. Gastroenterology https://doi.org/ 10.1053/j.gastro.2016.02.034.

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Lewis-Fernandez R, Lam P, Lucak S, Galfalvy H, Jackson E, Fried J, and Schneier F (2016) An open-label pilot study of duloxetine in patients with irritable bowel syndrome and comorbid major depressive disorder. Journal of Clinical Psychopharmacology 36(6): 710–715. https://doi.org/10.1097/JCP.0000000000000599. Lunn MP, Hughes RA, and Wiffen PJ (2014) Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database of Systematic Reviews 1: CD007115. https:// doi.org/10.1002/14651858.CD007115.pub3. Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, and Dubner R (1992) Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. The New England Journal of Medicine 326(19): 1250–1256. https://doi.org/10.1056/NEJM199205073261904. McCracken LM and Vowles KE (2014) Acceptance and commitment therapy and mindfulness for chronic pain: model, process, and progress. The American Psychologist 69(2): 178–187. https://doi.org/10.1037/a0035623. Seminowicz DA, Mayberg HS, McIntosh AR, Goldapple K, Kennedy S, Segal Z, and Rafi-Tari S (2004) Limbic-frontal circuitry in major depression: A path modeling metanalysis. NeuroImage 22(1): 409–418. https://doi.org/10.1016/j.neuroimage.2004.01.015. Shelby GD, Shirkey KC, Sherman AL, Beck JE, Haman K, Shears AR, and Walker LS (2013) Functional abdominal pain in childhood and long-term vulnerability to anxiety disorders. Pediatrics 132(3): 475–482. https://doi.org/10.1542/peds.2012-2191. Sobin WH, Heinrich TW, and Drossman DA (2017) Central neuromodulators for treating functional GI disorders: A primer. The American Journal of Gastroenterology 112(5): 693–702. https://doi.org/10.1038/ajg.2017.57. Tack J, Broekaert D, Fischler B, Van Oudenhove L, Gevers AM, and Janssens J (2006) A controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome. Gut 55(8): 1095–1103. https://doi.org/10.1136/gut.2005.077503. Takada T, Ikusaka M, Ohira Y, Noda K, and Tsukamoto T (2011) Diagnostic usefulness of Carnett’s test in psychogenic abdominal pain. Internal Medicine 50(3): 213–217. Thompson WG, Irvine EJ, Pare P, Ferrazzi S, and Rance L (2002) Functional gastrointestinal disorders in Canada: First population-based survey using Rome II criteria with suggestions for improving the questionnaire. Digestive Diseases and Sciences 47(1): 225–235. Walter SA, Jones MP, Talley NJ, Kjellstrom L, Nyhlin H, Andreasson AN, and Agreus L (2013) Abdominal pain is associated with anxiety and depression scores in a sample of the general adult population with no signs of organic gastrointestinal disease. Neurogastroenterology and Motility 25(9): 741–e576. https://doi.org/10.1111/nmo.12155. Wiffen PJ, Derry S, Moore RA, et al. (2013) Antiepileptic drugs for neuropathic pain and fibromyalgia—An overview of Cochrane reviews. Cochrane Database System Review 11: CD010567.

Further Reading Keefer L, Drossman DA, Guthrie E, Simren M, Tillisch K, Olden K, and Whorwell PJ (2016) Centrally mediated disorders of gastrointestinal pain. Gastroenterology https://doi.org/ 10.1053/j.gastro.2016.02.034. Keefer L and Mandal S (2015) The potential role of behavioral therapies in the management of centrally mediated abdominal pain. Neurogastroenterology and Motility 27(3): 313–323. https://doi.org/10.1111/nmo.12474. Sobin WH, Heinrich TW, and Drossman DA (2017) Central neuromodulators for treating functional GI disorders: A primer. The American Journal of Gastroenterology 112(5): 693–702. https://doi.org/10.1038/ajg.2017.57.

Relevant Websites https://theromefoundation.org/—The Rome Foundation. https://iffgd.org/—International Foundation for Gastrointestinal Disorders. http://www.abct.org/Home/—Association for Behavioral and Cognitive Therapies. https://www.umassmed.edu/cfm/mindfulness-based-programs/mbsr-courses/about-mbsr/history-of-mbsr/—Center for Mindfulness in Medicine, Health, Care, and Society.

Chagas’ Disease Jackie D Wood, The Ohio State University College of Medicine, Columbus, OH, United States © 2020 Elsevier Inc. All rights reserved.

Glossary

Megacolon Dilatation of the colon. Trypanosoma cruzi The blood borne protozoan parasite responsible for Chagas’ disease.

Introduction Intestinal pseudoobstruction and achalasia of smooth muscle sphincters are pathologic conditions that appear in Chagas’ disease. Achalasia (failure of relaxation) in the lower esophageal sphincter underlies swallowing disorders in Chagas’ disease. Damage to the enteric nervous system (ENS), known also as the brain-in-the-gut, underlies disordered gastrointestinal motility that includes intestinal pseudoobstruction, megacolon and megaesophagus (Wood, 1981). Chagas’ disease results from infection with the blood-borne, protozoan parasite Trypanosoma cruzi. T. cruzi multiplies intracellularly until the loaded cell breaks open to release the parasites, which are distributed in the blood to invade the cells of different kinds of tissues (Chagas, 1909). While free in the blood, the parasites are exposed to the immune system where stimulation of antibodies to the parasites occurs. The antibodies are autoimmune. They attack and destroy neurons in the enteric nervous system (brain-in-the-gut), as well as the parasite. Neuronal loss in the enteric nervous system results in gastrointestinal motility failure and failure of relaxation in gastrointestinal smooth muscle sphincters (Verne et al., 1997; Wood et al., 2012). The parasite is transmitted by large blood-sucking bugs of the family Reduviidae and affects an estimated 12–15 million people in Latin American countries, in a range that extends from Mexico to Northern Argentina. Neurons and cardiac muscle are favored targets for the parasites. Nearly all fatal cases show inflammatory damage to heart muscle that results in cardiac failure. Extensive neuronal degeneration in the ENS is characteristic in chronic stages of the infection. Debilitating degeneration of neurons occurs in sympathetic and parasympathetic divisions of the autonomic nervous system, as well as in the ENS. Neuropathy in the ENS in the advanced stages of Chagas’ disease is associated with megaesophagus, megacolon and lower esophageal sphincter achalasia (Verne et al., 1997; Köberle and Penha, 1959). The clinical picture in the large intestine is reminiscent of Hirschsprung’s disease (Wood et al., 1986). Megaesophagus and megacolon in Chagas’ disease reflect impaired transit through an obstructed region and accumulation of the luminal contents proximal to the obstruction. A marked reduction in the numbers of neurons in the ENS occurs in the affected regions of gut. Prolongation of gastrointestinal transit time is found in laboratory animals after infection with T. cruzi and the degree of transit prolongation is proportional to decrease in the numbers of neurons in the animal’s ENS. The obstruction is classified as pseudoobstruction because the lumen of the affected bowel is patent without any signs of a mechanical obstruction (Krishnamurthy et al., 1993). Pseudoobstruction may occur in the esophagus or the small and large intestine. Partial surgical resection of the affected segment of intestine provides relief in humans; nevertheless, later recurrences commonly occur.

Etiology As early assumption was that the parasite invaded cells in the walls of the viscera and destroyed the intramural neurons by the release of a toxin. Later evidence did not support direct cellular invasion by the parasite as the mechanism underlying the neuropathy. Current evidence suggests that autoimmune neuropathy is responsible for the destruction of the ENS in Chagas’ disease. The explanation given for the auto reactivity is that ENS neurons of the host and the parasite express common antigenic epitopes (Wood et al., 2012). As an immune attack is mounted against the parasite, cross-reactivity develops against the ENS. Blood from patients with T. cruzi infection can be shown to contain antibodies that recognize components of ENS neurons. A fluorescently-labeled antibody raised against mammalian sensory neurons (i.e., dorsal root ganglion neurons) is found to cross react with antigenic epitopes expressed by the parasite in studies of this nature. The same labeled antibody that reacts with the parasite also reacts with and fluorescently labels neurons in the myenteric and submucosal plexuses of the ENS. This suggests that the enteric neuropathy associated with Chagas’ disease results from development of antibodies against the parasite that later cross react with ENS neurons of the host. The autoimmune attack results in the ultimate destruction of the ENS.

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Change History: May 2019. JD Wood updated the text, references, and further reading to this entire article.

This is an update of Jackie D. Wood, Chagas’ Disease, In Encyclopedia of Gastroenterology, edited by Leonard R. Johnson, Elsevier, New York, 2004, Pages 293–294.

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Pathophysiology The degenerative inflammatory neuropathy associated with Chagas’ disease in the gut leads to pseudoobstruction (Krishnamurthy et al., 1993). Pseudoobstruction is a failure of propulsive motility that cannot be explained by mechanical blockage. Because propulsive motility is programmed and organized by the ENS, progressive autoimmune destruction of neurons in Chagas’ disease removes the gut’s minibrain and its control over digestive motor and secretory functions. Contractile activity of the intestinal musculature remains in the absence of the ENS, in autoimmune enteric neuropathies and the aganglionic segment in Hirschsprung’s disease, due to the myogenic nature of the smooth muscle (Wood, 1981; Wood et al., 1986). Nevertheless, in the absence of neural control, the contractile patterns are not coordinated and fail to achieve functional propulsion.

References Chagas C (1909) Über eine neue Trypanosomiasis des Menschen. Memórias do Instituto Oswaldo Cruz 1: 158–218. Köberle F and Penha P (1959) Chagas’ megaesophagus (Quantitative studies on the intramural nervous system of the esophagus). Zeitschrift für Tropenmedizin und Parasitologie 10: 291–295. Krishnamurthy S, Heng Y, and Schuffler MD (1993) Chronic intestinal pseudo-obstruction in infants and children caused by diverse abnormalities of the myenteric plexus. Gastroenterology 104: 1398–1408. Verne GN, Sallustio JE, and Eaker EY (1997) Anti-myenteric neuronal antibodies in patients with achalasia. A prospective study. Digestive Diseases and Sciences 42: 307–313. Wood JD (1981) Intrinsic neural control of intestinal motility. Annual Review of Physiology 43: 33–51. Wood JD, Brann LR, and Vermillion DL (1986) Electrical and contractile behavior of the large intestinal musculature of the piebald mouse model for Hirschsprung’s disease. Digestive Diseases and Sciences 31: 638–650. Wood JD, Liu S, Drossman DA, Ringel Y, and Whitehead WE (2012) Anti-enteric neuronal antibodies and the irritable bowel syndrome. Journal of Neurogastroenterology and Motility 18: 78–85.

Further Reading Wood JD (2011) Enteric nervous system neuropathy: Repair and restoration. Current Opinion in Gastroenterology 27: 106–111. Wood JD (2011) Enteric nervous system (the brain-in-the-gut). New Jersey, USA: Princeton, Morgan & Claypool Life Sciences Series. Wood JD (2018) Neuropathology of the irritable bowel syndrome. In: Ghishan FK, Kaunitz JD, Merchant JL, Said HM, and Wood JD (eds.) Physiology of the gastrointestinal tract, 6th ed San Diego: Elsevier.

Cholangiocarcinoma☆ Saumya Jayakumar and Mary Lee Krinsky, University of California San Diego, San Diego, CA, United States © 2020 Elsevier Inc. All rights reserved.

Introduction Cholangiocarcinoma (CCA) includes cancers of the bile duct, and arises from the bile duct epithelial cells. They are associated with a poor prognosis, and treatment options are limited.

Epidemiology CCA is uncommon, and rare in North America, approximately 8000 cases are diagnosed in the United States per year. However it accounts for 2% of the annual total worldwide cancer-related mortality (Bertuccio et al., 2013). In addition, it is the second most common primary liver tumor worldwide, and the incidence of intrahepatic CCA is rising, while the incidence of extrahepatic CCA is relatively stable. Unfortunately, CCA is often asymptomatic until the disease is more advanced, resulting in a later diagnosis with poor outcomes. However, with newer imaging techniques and advances in surgery, there is a trend to decreased mortality rates (Patel, 2001; Nathan et al., 2007; Khan et al., 2012). There is significant ethnic and geographical variability in the epidemiology of CCA, with the highest prevalence seen in Asia and the lowest in Australia (Bertuccio et al., 2013). In the US, there is a higher prevalence in the Hispanic population (1:100,000) while the lowest is seen in African Americans (averaging 0.17–0.50/100,000) (McLean and Patel, 2006). The average age at the time of diagnosis of CCA is older (70–80 years) unless there is a history of cystic bile duct (BD) disorders (age 30–40 years) (Soreide et al., 2004). Although CCA were initially thought to arise from cholangiocytes or peribiliary glands, recent data from animal studies suggests that they may also arise from normal hepatocytes that undergo malignant transformation (Cardinale et al., 2012; Fan et al., 2012), thereby potentially accounting for the variation in presentation, response to treatment, and outcomes.

Classification The term CCA refers to a group of malignancies that can arise from the epithelial cells of either the intra- or extra-hepatic ducts. They are classified based on their location—thus CCA can be intrahepatic, extrahepatic or perihilar. Intrahepatic CCA arise in the bile ducts proximal to the bifurcation of the right and left hepatic ducts. Perihilar cancers include the confluence itself, as well as any area of the CBD proximal to the insertion of the cystic duct into the CBD Extrahepatic CCA arise distal to this point, and involves the extrahepatic biliary tree distal to the perihilar region. Extrahepatic and perihilar tumors comprise the majority of CCA, with 50% of cases being perihilar, and 40% arising the distal CBD. Perihilar CCA, also known as Klatskin tumors, are often located at the confluence of the right and left intrahepatic biliary ducts. Intrahepatic disease is the minority of CCA, representing only 10% of cases (DeOliveira et al., 2007). The Bismuth-Corlette classification further subdivides perihilar tumors based on the involvement of the various hepatic ducts (Table 1). Intrahepatic CCA can also be classified by four different growth patterns, as different tumors behave and metastasize differently. Mass-forming tumors are the most commonly seen, and extrahepatic spread can be both hematogenous (through the venous system) and lymphatic. Other growth patterns can be periductal infiltrating type, intraductal growth, and mixed type. Extrahepatic CCA growth patterns can be mass-forming (nodular), periductal infiltrating (sclerosing), or intraductal growth (papillary) (Razumilava and Gores, 2013).

Risk Factors for CCA There are no known precipitating causes in approximately half of all cases of CCA. However, some well-identified risk factors exist that are associated with the development of CCA. The most commonly recognized is parasitic infections of the biliary system and liver, and primary sclerosing cholangitis (PSC). In both cases, chronic inflammation of the liver and biliary system are thought to be the underlying inciting mechanism. Opisthorchis viverrini (in Laos, Malaysia, and Thailand) and Clonorchis sinensis (in Japan, Korea, and Vietnam) infections are thought to account for the increased rate of CCA in Asia (Shin et al., 1996; Tyson and El-Serag, 2011),

☆

Change History: June 2019. S Jayakumar and ML Krinsky updated the text of this article and references and added new Fig. 1.

This is an update of Mary Lee Krinsky, Cholangiocarcinoma, In Encyclopedia of Gastroenterology, edited by Leonard R. Johnson, Elsevier, New York, 2004, Pages 301–304.

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Encyclopedia of Gastroenterology, 2nd Edition

https://doi.org/10.1016/B978-0-12-801238-3.65865-8

Cholangiocarcinoma Table 1

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Bismuth-Corlette classification of perihilar tumors.

Type

Area of the hilum affected

I II IIIa IIIb IV

Distal to the ductal bifurcation Tumors reaching the ductal bifurcation Occlusion of the common hepatic duct and right hepatic duct Occlusion of the common and left hepatic duct Multicentric OR Involving the bifurcation and both the right and left hepatic duct

accounting for a 25- to 50-fold increase in CCA risk. In Europe and North America, chronic viral hepatitis, cirrhosis, PSC, and recurrent choledocholithiasis are associated with the development of CCA (Tyson and El-Serag, 2011; Treekitkarnmongkol and Suthiphongchai, 2010; Shaib et al., 2005; Palmer and Patel, 2012). Other diseases that result in chronic cholestasis and inflammation, such as cystic bile duct disorders like Caroli’s disease, are strongly associated with CCA. This effect is thought to be due to the effect of the bile acids in causing inflammation and ductular inflammation, as well as impairing the FXT-dependent chemoprotection (Lozano et al., 2014). Exposure to potentially oncogenic chemicals, such as Thorotrast, dioxin, and vinyl chloride, have been found to cause CCA (Tyson and El-Serag, 2011). There are only two genetic conditions thus far known to be associated with CCA—Lynch syndrome and multiple biliary papillomatosis (Yeung et al., 2003). Both obesity and metabolic syndrome have been associated with an increased rate of PSC (Welzel et al., 2007; Grainge et al., 2009; Welzel et al., 2011), in keeping with the fact that both entities are associated with an increased risk of many other malignancies. PSC, a disease resulting in inflammation of the bile ducts leading to fibrosis and intraductal strictures, is closely associated with the development of CCA. Nearly one-third of all CCAs are diagnosed in patients with PSC, and the incidence of CCA in patients with PSC ranges between 0.5% and 1.5%/year (Bergquist et al., 2002; Burak et al., 2004). The lifetime risk, initially estimated to be around 10–15%, is likely closer to 30% based on autopsy studies (Claessen et al., 2009; Chapman et al., 2012), and patients with PSC develop CCA at a much younger age (between 30 and 50 years age) than those without this disease. The underlying pathophysiological mechanisms behind the development of CCA is still largely unknown. It is thought that the inflammation resulting from chronic cholestasis results in cell proliferation, with a resultant increase in the risk of somatic mutations (Jaiswal et al., 2000; Blechacz and Gores, 2008). Proinflammatory cytokines such as tumor necrosis factor a (TNFa) and interleukin 6 (IL-6) stimulate nitric oxide (NO) production in cholangiocytes by stimulating NO synthase. This NO combines with reactive oxygen species to inhibit DNA repair mechanisms, resulting in mutagenesis (Jaiswal et al., 2000; Pinlaor et al., 2005). NO can also interact with the cytokines to inhibit cholangiocyte apoptosis by stimulating cyclooxygenase 2 (COX-2) to produce prostaglandin E2 (PGE2), which in turn activates the cell cycle and inhibits apoptosis (Itatsu et al., 2009). Interestingly, members of the epidermal growth factor receptor EGFR) family, such as the tyrosine kinase ERBB2 (HER-2/neu) (Yoshikawa et al., 2008), have also been shown to activate COX-2, which is overexpressed in a proportion of extrahepatic CCA (Treekitkarnmongkol and Suthiphongchai, 2010; Endo et al., 2002). Serum IL-6 levels have been found to be elevated in patients with CCA (Goydos et al., 1998), and has been shown to upregulate the myeloid cell leukemia-1 (Mcl-1) protein, an anti-apoptotic protein (Isomoto et al., 2007), in addition to activating mitogen activated protein kinase p38, which promotes cell proliferation and stimulates telomerase activity, reducing senescence in malignant cholangiocytes (Park et al., 1999; Yamagiwa et al., 2006). Farnesoid X-receptor (FXR), which is a bile acid sensor, seems to have a protective effect against the development of liver tumor; murine FXR-knockout models have been demonstrated to spontaneously develop both hepatocellular carcinomas (HCC) and CCA (Yang et al., 2007; Kim et al., 2007; Trauner, 2004).

Presentation and Diagnosis of CCA The location of the tumor determines the presentation. Patients often become symptomatic only when there is biliary obstruction. Thereby, obstructive symptoms are more common in extrahepatic and hilar CCA. Obstructive signs and symptoms include painless jaundice, pruritus, anorexia, clay-colored stools, dark urine, nausea, vomiting, and weight loss. On exam, patients are often noted to be jaundiced or icteric, and, rarely, may have a palpable mass in the right upper quadrant of the abdomen. They often endorse claycolored stools and dark urine, a consequence of hyperbilirubinemia. Initial bloodwork may reveal elevated liver enzymes, especially alkaline phosphatase (ALP), elevated bilirubin (mostly conjugated), and an elevated prothrombin time (PT) and international normalized ratio (INR). It should be noted that the elevated INR can be due to fat soluble vitamin deficiency resulting from the biliary obstruction, and may be at least partially corrected with exogenous administration of vitamin K. Initially the transaminase levels may be normal (AST and ALT). Furthermore, an isolated alkaline phosphatase may be seen in patients with intrahepatic cholangiocarcinoma. The initial diagnosis of CCA is often made through the combination of a suggestive clinical history, radiographic evidence of a biliary obstruction, and histopathological diagnosis. In a patient with a concern for CCA, initial imaging with transabdominal ultrasonography should be performed to visualize the bile ducts, looking for biliary dilatation, and to assess for choledocholithiasis

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and a mass. Gadolinium accumulates in neoplastic tissue, making magnetic resonance cholangiopancreatography (MRCP) with contrast the imaging modality of choice for assessing both the location and extent of the CCA (Angulo et al., 2000; Peterson et al., 1998). CCA has a different pattern of contrast uptake and washout than HCC, thereby allowing for radiographic differentiation between these two liver tumors in patients with chronic liver disease, especially when tumors exceed 2 cm in diameter (Rimola et al., 2009). However, in patients with cirrhosis, imaging may not be able to differentiate between HCC and CCA, and a biopsy may be needed to definitively differentiate between the two. MRCP has an additional advantage of mapping out the involved segments of the biliary tree, thereby directing endoscopic interventions for biliary decompression. Computed tomography (CT) of the abdomen may be useful in determining extent of spread and lymphatic involvement, while positron emission tomography (PET) can be used to search for distant metastases. Recent advances in endoscopic imaging, such as endoscopic ultrasound and cholangioscopy, allow for closer imaging of the biliary ducts with direct visualization and sampling of the strictured area. In diseases such as PSC, where inflammatory strictures are present, both of these modalities are useful in both surveillance and biopsy of the strictures to differentiate between an inflammatory process and a malignant one. Endoscopic ultrasound (EUS) can be used to visualize the extent of the primary tumor (Fig. 1) and for the evaluation of regional lymph nodes with EUS-guided fine-needed aspiration (FNA). However, EUSguided FNA is a relative contraindication for the primary tumor with its risk of seeding. In comparison to ERCP, EUS-FNA has greater sensitivity for distal tumors, as well as the benefit of preventing contamination of the biliary tree. EUS has also been shown to be more sensitive in detecting both CCA and portal vein invasion than other imaging modalities, such as ultrasound, CT, or CT angio (Sugiyama et al., 1997). Cholangioscopy allows for the direct visualization of the bile ducts with sampling of strictures using either brush cytology or a targeted biopsy. The advantage to this method is that it allows for visualization of the tumor characteristics themselves (i.e. nodule vs infiltrative mass vs ulcerations) as well as of the vasculature within the mass (Seo et al., 2000; Ponchon et al., 1989; Shah et al., 2006; Awadallah et al., 2006; Fukuda et al., 2005; Iqbal and Stevens, 2009). Tumor markers, such as CA19-9 and CEA (carcinoembryonic antigen), are useful in both diagnosing CCA and monitoring for recurrence both during and after treatment. In patients with PSC, serum CA19-9 values >129 U/mL have a 79% sensitivity and 98% specificity for CCA, although the utility of this test is questionable in patients without PSC (Patel et al., 2000). Serum levels of matrix metalloproteinase 7, tumor M2-PK, and biliary levels of neutrophil gelatinase-associated lipocalin (NGAL) have all been shown, in small trials, to be able to differentiate CCA from benign biliary duct disease (Leelawat et al., 2009; Li and Zhang, 2009; Zabron et al., 2011). There are many different histologic types of CCA, but the most common is adenocarcinoma, which accounts for >95% of all bile duct malignancies. Histologic and immunologic stains against cytokeratin-7 (CK-7) and cytokeratin 19 (CK-19) are useful in confirming disease after resection.

Treatment of CCA CCA often spreads to adjacent structures, such as other organs, the peritoneum, and regional lymph nodes. >75% of patients will have regional LN involvement. Surgical resection with tumor free margins is the therapeutic option with the best long-term survival. However, given the high rate of LN involvement in many cases of CCA, and since the lymph node involvement is the most important prognostic factor in an R0 resection (DeOliveira et al., 2007; Marubashi et al., 2014), routine lymphadenectomy at the time of surgery is recommended except in patients with solitary, small, peripheral CCA. Larger tumor size, certain histological subtypes, and level of differentiation are indicators of poor prognosis.

Fig. 1 EUS investigation with radial echoendoscope tip placed in the duodenal bulb showing a small cholangiocarcinoma in the mid to distal common bile duct.

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Surgical resection may also be indicated in select patients with cirrhosis or with extrahepatic tumors, depending on, respectively, the degree of hepatic dysfunction and the extent of involvement of the biliary tree and hepatic vasculature. A recent study found that, in patients with compensated cirrhosis, the overall morbidity and mortality rates, progression to liver failure, and other complications were not significantly increased in comparison to patients without cirrhosis (Li et al., 2014). Even with a surgical resection with negative margins, the 5 year survival for extrahepatic CCAs is only 30%, with the majority of the patients experiencing recurrence, especially if the CCAs arose in the setting of PSC. Therefore, in patients with PSC or decompensated cirrhosis, transplant should be considered. The Mayo protocol, with neoadjuvant chemoradiation prior to transplantation, has been shown to result in a 5 year disease free survival rate of >80% (Rea et al., 2005; Salgia et al., 2014). The recurrence rate was lower in patients undergoing neoadjuvant chemotherapy, at 13% (vs 27%), and if it did occur, happened further out from transplant (mean time to recurrence 40 months vs 21 months). In patients who are not surgical candidates, either due to tumor characteristics or comorbidities, percutaneous radiofrequency or microwave ablation of the tumor is a therapeutic option. One study demonstrated complete tumor ablation in 85% of tumors (all less than 5 cm), with a median survival of 38.5 months and no evidence of local recurrence (Kim et al., 2011). In patients who are not candidates for surgical intervention, transplant, or ablation, palliation of jaundice and bile duct obstruction can be accomplished with biliary stenting. This stent placement can be done with endoscopic retrograde cholangiopancreatography (ERCP) (Fig.2). Percutaneous biliary drainage by interventional radiology can be pursued if the biliary obstruction is intrahepatic and/or not able to amenable to ERCP. Stenting is often done preoperatively, as cholestasis is associated with an increased risk of developing liver failure. Percutaneous approaches to drainage may be preferred in hilar tumors, with less associated morbidity (Kloek et al., 2010). Endoscopically facilitated ablative therapies have evolved for unresectable CCA, and include photodynamic therapy and radiofrequency ablation. The primary aim is biliary decompression. PDT may have a survival benefit in nonresectable CCA, in addition to improvements in bilirubinemia and quality of life (Ortner et al., 2003). Endoscopic radiofrequency ablation combined with biliary stenting compared to stent alone has been shown to improve mortality rates in patients with extrahepatic CCA, with the exception of Bismuth-Corlette class III and IV (Yang et al., 2018).

(A)

(B)

(C) (C)

Fig. 2 (A) ERCP with cannulation of the common bile duct and contrast injected in the biliary tree depicting a stricture in the mid common bile duct with upstream dilation (B) ERCP image of the same patient (A). After insertion of a fully covered metal stent into the common bile duct trough the ampulla of Vater across the stricture re-establishing biliary drainage into the duodenum. (C) Endoscopic view of metal stent that was deployed across the smid CBD stricture through the ampulla of Vater with abundant run-off of bile.

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Most oncology societies recommend adjuvant chemotherapy for all CCAs. Most CCAs have been found to respond to fluoropyrimidine or gemcitabine-based chemotherapies. Addition of radiation or capecitabine-based therapies, either concurrently or sequentially, have been studied and found to be effective (Ben-Josef et al., 2015; Regine et al., 2008; Neoptolemos et al., 2012). Liver transplant with combined neoadjuvant therapy may be an option for early stage, unresectable de novo hilar CCA or PSC related CCA. Intrahepatic CCA only cure is with surgical resections. However, early unresectable intrahepatic CCA may be suitable for liver transplant.

Conclusions CCAs are increasing in incidence and prevalence worldwide, with more patients developing the disease without any known risk factors. CCA is typically classified and distinct based on its location in the biliary tree. Furthermore, since patients do not present with symptoms until later in the course of the disease, timely diagnosis and treatment is difficult. In addition, the variety of pathogenetic mechanisms, progenitor cells, disease course, and prognoses seen in CCA have resulted in insufficient, standardized treatment options for this disease. The overall prognosis remains poor. Although surgery and transplant are currently the mainstays of treatment, future therapeutic directions may lie with targeted, molecular modalities for treatment.

See Also: Sclerosing Cholangitis. Small Intestine, Benign and Malignant Neoplasms of the

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Cholecystectomy☆ Wei Chieh Alfred Kow, National University Health System, Singapore, Singapore; Lin School of Medicine, National University of Singapore, Singapore, Singapore © 2020 Elsevier Inc. All rights reserved.

Background Cholecystectomy is probably one of the most common procedures performed in the world. It is estimated that around 10,000 cholecystectomies are performed per day worldwide. Barely 30 years ago, the standard approach to this surgical procedure was open surgery, commonly done through a Kocher’s incision (right subcostal incision), minimally invasive laparoscopic cholecystectomy is now the standard of care in most countries where laparoscopic facilities are available. The gallbladder is most commonly removed due to cholelithiasis and its related complications. The other indications include gallbladder polyps or malignancy. Oftentime, gallbladders are also removed during major liver resection or the gallbladder is removed together with the bile duct as part of biliary surgery (e.g., excision of the choledochal cyst). Most patients enjoy fairly normal quality of life after an uneventful cholecystectomy. Occasional, a small number of patients will experience frequent passing of soft loose stool after removal of the gallbladder but this is often a transient problem. After cholecystectomy, in the absence of the storage function of the bile in the gallbladder, the bile duct will take over this function to store more bile juice by expanding its diameter over time (provided the sphincter of Oddi is intact).

Pathophysiology of Cholelithiasis (Carey, 1993)

• • • • • • • • • • •

Gallstones form as a result of many disorders. Unphysiologic supersaturation, generally from hypersecretion of cholesterol, is essential for the formation of cholesterol gallstones (Fig. 1). The other common abnormalities of the hepatobiliary system in gallstone patients are accelerated nucleation, gallbladder hypomotility, and the accumulation of mucin gel. An attempt is made here to relate hypersecretion of cholesterol and biliary supersaturation to the molecular basis of the associated phenomena. Supersaturation of bile with calcium hydrogen bilirubinate, the acid calcium salt of unconjugated bilirubin, is essential for pigment gallstone formation, but its magnitude remains undefined in model systems. Nucleation and the precipitation of calcium hydrogen bilirubinate with the polymerization of the pigment in the gallbladder, together with the deposition of the inorganic salts, calcium carbonate and phosphate, result in black pigment gallstone formation (Fig. 2). On the basis of ex vivo muscle studies, gallbladder hypomotility is unlikely in patients with black pigment stones but is invariably present in patients with cholesterol stones. Pigment supersaturation in the gallbladder is the result of hepatic hypersecretion of bilirubin conjugates in hemolytic disorders and possibly enterohepatic cycling of unconjugated bilirubin in nonhemolytic states. Less common is bile salt hyposecretion from impaired synthesis in constitutional disorders and cirrhosis, and uncompensated interruption of the enterohepatic circulation in ileal dysfunction syndromes. Bile salt deficiency causes incomplete solubilization of unconjugated bilirubin and impaired binding of calcium ions. Stasis and anaerobic bacterial infection are responsible for brown pigment stones, which usually form in the bile ducts. In addition to the precipitation of calcium hydrogen bilirubinate that remains unpolymerized, there is also the deposition of the calcium salts of saturated fatty acids and free bile acids, both of which are the result of bacterial enzymatic hydrolysis of biliary lipids.

Indications for Cholecystectomy The most common indication for cholecystectomy is cholelithiasis and its related complications as shown in Fig. 3.

☆

Change History: June 2019. Alfred Wei Chieh Kow has updated the text and references, and the figures have also been updated.

This is an update of Patrick J. Javid, David C. Brooks, Cholecystectomy, In Encyclopedia of Gastroenterology, edited by Leonard R. Johnson, Elsevier, New York, 2004, Pages 317–321.

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https://doi.org/10.1016/B978-0-12-801238-3.66056-7

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Fig. 1 Cholesterol stones typically seen in patients that fit the 5Fs description (Fat, Female, Fertile, Forty, Fair).

Fig. 2 Pigmented stones are more often seen in areas with high incidence of hemolytic conditions.

Asymptomatic Gallstones About 10% of the population has the propensity to develop gallstones. A large number of them (up to 70% of them) will remain asymptomatic in their lifetime while the remaining one-third will experience symptoms due to pain or complications from the gallstones in the biliary or gastrointestinal system. The gallstones in an asymptomatic patient can be small or large, solitary or multiple and the underlying reason why the stone is formed has been illustrated previously. The gallstones in the asymptomatic gallstones are often detected incidentally when the patients undergo imaging studies for other unrelated conditions e.g., CT urography for microscopic hematuria or spine X-rays for lumbar back pain. When the abnormal finding of gallstones is detected, the relevant physicians will refer the patients to the surgeons for opinion and treatment. Patient in asymptomatic gallstones are usually not required to have the gallbladder removed unless they wish to do so as a preemptive measure to prevent stone related complications from happening. However, it is crucial to counsel this group of patients about the possible complications and early return advice must be given so that the patients can seek the necessary therapy when it occurs.

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Gallstones

Asymptomatic

Symptomatic

Biliary colic

In GB

Complication of gallstones

In bile duct

Acute cholecystitis

Obstructive jaundice

Empyema of GB

Acute cholangitis

In pancreas

Gallstone pancreatitis

Others

Bilioenteric fistula

Gallstone ilues

Perforation/ gangrene GB

Mucocoeleof GB

Gb CA Fig. 3 Common presentation of gallstones and its related complications.

Symptomatic Gallstones Patients with symptomatic gallstones are often misdiagnosed as having gastric issues. As the nature of the pain or discomfort is not specific, many patients often will mistake the symptoms as gastritis and will self-medicate with anti-acid therapies that are available easily over-the-counter. In fact, many doctors will also treat these group of patients as having gastric issue or “dyspepsia” with symptomatic therapy and only offer investigations to rule out gallstones when the symptoms worsen or when the situation recurs too frequently. Patients with symptomatic gallstones (or biliary colic) can present with a wide spectrum of symptoms. These include fatty food dyspepsia (ranging from discomfort to pain after oily meals), abdominal bloatedness, epigastric tightness or it can present atypically as chest pain associated with mild shortness of breath (having admitted to cardiology due to concerns about myocardial infarction). This group of patients may have been managed by primary care doctors who will investigate with ultrasound of the hepatobiliary system (US HBS) and detect the gallstones. They can also be managed by gastroenterologist who may have performed upper endoscopy and treated as gastritis but symptoms persisted despite the appropriate gastritis therapy. Upon confirming the presence of the gallstones, patients will be referred to a surgeon for opinion regarding cholecystectomy. Patient with symptomatic gallstones can consider to have the gallbladder after appropriate risk counseling regarding the surgery. Laparoscopic cholecystectomy is currently the gold-standard of care with extremely high success rate at 95–98% in most surgical centers. Majority of the patients can have this simple operation performed as day surgery due to the small incisions and minimal pain after surgery and relatively low morbidity operation. Even for patients with comorbidities, if they can tolerate a short duration of general anesthesia, this simple surgery can easily be performed successfully using minimally invasive method. Studying the imaging findings from the scan is important to determine if the laparoscopic cholecystectomy will likely to be easy or difficult. There is a subgroup of patients with symptomatic gallstones whom the gallbladders are chronically contracted due to the long-term chronic inflammation, which could potentially pose extreme difficulties in the cholecystectomy procedure. They will usually be informed of the slightly higher risk of conversion from laparoscopic to open procedure as well as higher risk of bile duct injury (which currently stands at 0.1–0.6% based on published literature) (Flum et al., 2003).

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Acute Calculous Cholecystitis The presence of an aging population, higher caloric diet and increasing obesity rates has resulted in an unprecedented rise in the prevalence of cholelithiasis in both Western and Asian populations (Gill, 2006; Wang and Beydoun, 2007) Currently, the condition affects up to 10% of the adult population, with AC being the most frequent complication, accounting for 15–26% of all complications (Halldestam et al., 2004; Kimura et al., 2013). Patients with acute cholecystitis often present with acute severe epigastric or right hypochondrial pain associated with fever. The pain usually starts gradually as abdominal discomfort, much like that of biliary colic or dyspepsia, and progressively the symptoms worsens despite on pain relief medications. Usually by this time, patients would have sought medical attention from a primary care doctor or visited the emergency department. Importantly, certain groups of patients may present with severe sepsis or septic shock in a collapsed state to the hospitals. They include elderly patients, patients who are immunocompromised such as patients receiving chemotherapy or transplant patients, as well as diabetic patients. Routine investigations of patients with acute cholecystitis often demonstrate elevated inflammatory markers such as raised total white cell count and C reactive protein. Occasionally, the liver function test may be abnormal, either due to the swollen gallbladder pressing on the bile duct or concomitantly stones from the gallbladder has dropped into the biliary tree. Radiological investigation is required to confirm the diagnosis of acute cholecystitis. US HBS is the standard investigation to perform. Features of acute cholecystitis as seen on US HSB include the presence of cholelithiasis associated with thickened gallbladder and pericholecystic fluid with oedema (Fig. 4). The presence of biliary dilatation with or without detection of hyperechoic stone(s) in the bile duct is important to guide the appropriate therapeutic decision. Patients with concomitant choledocholithiasis may require clearance of bile duct prior to cholecystectomy, especially if there is evidence of acute cholangitis. Treatment of acute calculous cholecystitis often starts with keeping the patient nil-by-mouth and administration of intravenous antibiotics (empirical choice is 3rd generation cephalosporin and metronidazole). Upon confirming the diagnosis, the managing team needs to decide on the timing of cholecystectomy, if the patient is fit for surgery. The conventional practice three decades ago was to offer the patients interval laparoscopic (LC) cholecystectomy about 4–6 weeks after the acute episode of inflammation had settled down with conservative treatment. However, the optimal timing of LC for AC has undergone a paradigm shift in recent years. While LC was once considered a relative contraindication in the presence of AC due to increased morbidity, longer operative duration and higher conversion rates (Gurusamy et al., 2013; Wu et al., 2015) the increasing experience and proficiency in laparoscopic techniques have seemingly mitigated the challenges faced while dissecting the Calot’s triangle in the setting of an acute inflammation (Menahem et al., 2015) In fact, various randomized controlled trials and meta-analyses have clearly shown the benefits of ELC, stating a shorter hospital length of stay and a resultant higher cost effectiveness, while maintaining similar intra- and post-operative morbidity (Lo et al., 1998; Macafee et al., 2009; Yadav et al., 2009; Kolla et al., 2004; Kaafarani et al., 2010; Lee et al., 2012; Papandria et al., 2013; Hutchinson et al., 1994). As a result, ELC has gradually become the standard of care in the management of patients with AC. This is reflected in our institution as 57.2% of AC patients had undergone ELC between the period of June 2010 and June 2015, while showing an upward trend towards ELC every year. Our results are also consistent with the existing literature as the current study found ELC to have a significantly shorter LOS with no differences in peri-operative complication and conversion rates. Despite the superiority of ELC, conversion (LOC) continues to be an important outcome measure in LC, in which a reported rate of up to 11.9% of cases required open surgery after difficulties encountered intra-operatively (Lengyel et al., 2012;

Fig. 4 US HBS showing thickened gallbladder wall with presence of hyperechoic stone and pericholecystic fluid.

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Graves Jr. et al., 1991; Chue et al., 2018; Parlak et al., 2012; Topal et al., 2007) Conversion to open surgery is associated with longer hospital stays and recovery time, increased post-operative pain and poorer cosmetic results. Therefore, it would be useful to identify patients at increased risk of conversion so as to provide better pre-operative counseling and patient selection and addressing patient expectation. While existing studies have identified several risk factors for LOC, they remain largely varied in nature with a noticeable lack of consensus. Apart from the aforementioned benefits, patients with ELC also experience an improvement in quality of life through faster return to work while avoiding gallstone-related morbidity while awaiting elective surgery. Wu et al. found that ELC was associated with lower hospital costs, fewer work days lost, higher patient satisfaction and quality of life (Kimura et al., 2013), while Gurusamy et al. reported that up to 18.3% of DLC patients had either nonresolution or recurrence of symptoms before their elective surgery and required surgical intervention (Gurusamy et al., 2013). In our study, 10 (5.0%) patients had recurrent manifestations of hepatobiliary sepsis requiring emergency LC. Despite the ostensible benefits, a potential drawback of ELC is the possibility of encountering a surgery that is of greater technical difficulty. The current study showed a higher intra-operative severity of AC in ELC, with only 54.1% of patients having Grade 1 inflammation as compared to the 90.0% seen in DLC. Similarly, our results also report a longer median operative time seen in ELC as compared to DLC. There was, however, no significant difference between the two treatment options in terms of conversion, with reported figures of 8.6% and 8.0% in ELC and DLC respectively. While we expect the operative times to become comparable eventually with increasing experience and proficiency in minimally invasive surgical techniques, a referral to specialist hepatopancreaticobiliary surgeons should remain a possible consideration in ELC cases. Bile duct injury as a consequence of LC is an important outcome measure due to its high morbidity, mortality and negative impact on quality of life. In addition, BDI has been established as one of the most litigious complications in the practice of general surgery (Carey, 1993). While existing studies demonstrate up to a 0.6% risk of BDI subsequent to LC, there was no significant difference in BDI rates between ELC and DLC (Gurusamy et al., 2013). This is unsurprising given the relative infrequency of BDI, and large patient databases would be required to validate BDI comparisons between both approaches. Nevertheless, established risk factors of BDI include obesity, peri-operative bleeding, severe inflammation, anatomical variation and surgical inexperience, highlighting the need for risk stratification and streamlined disposition processes so as to maintain safety in AC patients requiring LC.

Gallstone and Abnormal LFT From Passed Stone Occasionally, gallstones may drop into the bile duct and transiently cause mild abdominal discomfort or pain but the patients may not note any other obvious symptoms such as jaundice, tea-colored urine or pale stool. The mild abdominal discomfort is associated with abnormal liver function test (LFT) such as transaminitis (elevated AST and ALT) with mild rise in serum bilirubin level. However, the abnormal LFT soon returns to normal spontaneously without any intervention such as ERCP procedure. This phenomenon is likely due to transient passage of stones, which pass out through the ampulla of Vater into the duodenum spontaneously. The exact duration of the stone staying in the biliary system is difficult to determine. As the relaxation of the Sphincter of Oddi is influenced by the presence of mediators such as cholecystokinin (CCK), the sphincter will allow small stones or sludge to pass out intermittently. Oftentime, physicians managing patients with cholelithiasis associated with abnormal LFT which improves spontaneously will refer the patients to surgeons to discuss about the role of cholecystectomy. Sometimes, an endoscopic ultrasound or MRCP could be done in attempt to image the biliary system to see if there are stones within. If the LFT has improved spontaneously, there is also an option of doing a laparoscopic cholecystectomy with intra-operative cholangiogram (IOC) to see if there are any filling defects within the biliary tree. If the bile duct is grossly dilated on pre-operative imaging, it may be necessary to counsel the patients for possible concurrent laparoscopic common bile duct exploration during the surgery, if the IOC demonstrates the filling defects and the surgeon is skilled to perform this procedure. Alternatively, the patient can have ERCP to clear the bile duct after the laparoscopic cholecystectomy if the IOC is found to have filling defects intraoperatively.

Gallstone With Obstructive Jaundice Patients with cholelithiasis may have a reasonably large stone dropping into the bile duct causing significant obstruction to the bile flow and the first presentation of these patients may be jaundice. The nature of the jaundice is often accompanied by tea-colored urine and pale stool with pruritus. There may also be abdominal pain associated with the jaundice. One of the key signs to look out for during the physical examination of these patients is palpable gallbladder, as described in Courvoisier’s law. Courvoisier’s law states that patients with choledocholithiasis should not have palpable gallbladders as stones formation in the gallbladder is associated with chronic cholecystitis and therefore the gallbladder should be fibrotic and contracted. The main investigations in this situation should revolve around ruling out malignancy in the peri-ampullary region especially in the elderly patients or patients with significant constitutional symptoms such as weight loss. While initial LFT may show the picture of obstructive jaundice with conjugated hyperbilirubinemia and elevated alkaline phosphatase, an US HBS may show cholelithiasis with dilated biliary tree. If the suspicion for malignancy is high, it is crucial to

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perform a more thorough imaging such as contracted computer tomography (CT) scan of the abdomen to rule out any mass lesion in the lower end of the biliary tree such as a head of pancreas tumor, ampullary tumor or distal bile duct mass. If no malignancy is detected, the treatment is fairly straightforward. The obstruction in the biliary tree by stones needs to be cleared. It can be done through an ERCP or surgically via common bile duct exploration. However, the key difference between the two approaches is the dual-staged treatment in ERCP versus single-staged therapy. In centers with ERCP facilities, the dual-staged approach may be the services provided. Patients with choledocholithiasis can have the stones removed via ERCP and then proceed to have the gallbladder removed using laparoscopic cholecystectomy. However, ERCP may not be suitable in all cases. For example, patients with prior gastrectomy may be a poor candidate for ERCP to clear the bile duct due to the long afferent limb. In other situation, patients with multiple stones or stones too large to be removed via ERCP may be more suitable for common bile duct exploration. In the absence of acute cholangitis in choledocholithiasis, a percutaneous transhepatic cholangiographic (PTC) catheter may not be necessary as the patient is not septic. Single-staged therapy in the form of laparoscopic cholecystectomy and concurrent laparoscopic common bile duct exploration has become more commonly performed in recent years, either as an upfront approach to treat patients with choledocholithiasis or as salvage therapy to failed ERCP. In a study by our center, Chue et al. reported the predictors for a failed LCBDE were: prior antibiotic use, previous ERCP and an abnormal biliary anatomy. Using the nomogram, a patient with prior antibiotic use, previous ERCP and an abnormal biliary anatomy will have more than a 90% likelihood of a failed LCBDE. Parlak et al. have suggested previously that following an ERCP, there were more adhesions found intraoperatively during laparoscopic cholecystectomy, and this can make the surgery more complicated (Parlak et al., 2012). Topal et al. previously reported that a transcystic LCBDE was successful for stones averaging 5 mm, while a transcholedochal LCBDE was successful for stones averaging 11.5 mm (Topal et al., 2007).

Gallstone With Acute Cholangitis Slightly worse than patients with choledocholithiasis, patients with stones in the bile duct may present with Charcot’s triad (fever, jaundice and right hypochondrial pain) or Raynaud’s pentad (Charcot’s triad with altered mental state and hypotension). Upon achieving the diagnosis, it is important to institute appropriate intravenous fluid resuscitation and start empirical antibiotics. One of the key interventions after confirming the diagnosis is to decompress the biliary tree that is obstructed. The two main methods include an ERCP with biliary stenting (usually plastic biliary stents are inserted) and PTC catheter insertion. For patient who is hemodynamically stable, ERCP with stenting is usually preferred as there will not be a percutaneous tube inserted and it is much more comfortable for the patient. In event that the stone is impacted in the distal bile duct and ERCP is not able to cannulate the bile duct successfully, or patient is hemodynamically unstable, a safer approach will be insertion of a PTC catheter under radiological guidance. After the initial treatment has successfully controlled the source of sepsis, definitive treatment will be required. If the patient is fit for surgery, laparoscopic cholecystectomy should be offered. Whether the patient should go for further ERCP to clear the bile duct before the cholecystectomy will depend on the criteria as mentioned in the section prior to this (See “Gallstone With Obstructive Jaundice” section).

Gallstone Pancreatitis Gallstone pancreatitis is one of the most common causes of acute pancreatitis. While most of the patients presented with acute gallstone pancreatitis have mild pancreatitis which is self-limiting, about 2–3% of patients may present with severe life-threatening gallstone pancreatitis. After initial confirmation of diagnosis of acute pancreatitis in a patient with upper abdominal pain associated with raised serum amylase/lipase, gallstone pancreatitis can be confirmed when radiological investigations showed cholelithiasis or biliary sludge. This is often accompanied by deranged LFT. Most mild acute biliary pancreatitis are postulated to be due to transient passage of stones or sludge in the biliary tree. Spontaneous improvement often signifies resolution of the biliary obstruction. Previously, patients with acute pancreatitis are recommended to have laparoscopic cholecystectomy 4–6 weeks after the initial expectant treatment focusing on resting the alimentary system, there is a significant paradigm shift in this in the recent decades. Patients with mild acute biliary pancreatitis are encouraged to have laparoscopic cholecystectomy during the same admission, especially if the symptoms resolved quickly (Da Costa et al., 2015). The advantages of offering early same admission laparoscopic cholecystectomy are obvious. Patients enjoy definitive solution to the gallstone problem, which is the cause of the pancreatitis, during the same admission. In addition, there is no further risk of getting another episode of acute pancreatitis while waiting for the interval cholecystectomy. The risk of recurrent episode of biliary pancreatitis while waiting for definitive cholecystectomy is quoted to be up to 30%. They will enjoy early return to normal activities and this makes a lot of health economic sense too. However, in patients with severe acute biliary pancreatitis, there are usually major disturbances to the physiological functions of the body. Many of the organs are often affected in severe acute pancreatitis, and in its most severe form, there can be multiorgan failure. As such, early same admission cholecystectomy seems to be adding on further stress to the bodily function and is usually not recommended. Upon recovering from the episode of severe acute pancreatitis, the surgeon will need to assess the patient’s fitness

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and offer the appropriate timing for the cholecystectomy. Some patients with multiple comorbidities may not be fit for the procedure and it increases the risk of another episode of acute pancreatitis. In the rare occasion where patients with severe necrotizing pancreatitis from gallstone pancreatitis require necrosectomy in the operating theater, surgeons may consider removal of gallbladder in the same setting to avoid the need for further surgery later on.

Mirizzi’s Syndrome Similar to patients with gallstones dropping into the biliary tree causing obstructive jaundice, patients with Mirizzi’s syndrome can present in exactly the same manner. Mirizzi’s syndrome is defined as the presence of stone(s) impacted at the Hartmann’s pouch or cystic duct compressing on the common hepatic duct (CHD), leading to obstructive jaundice and cholangitis. There are varying degrees of the compression by the stones at the Hartmann’s pouch or cystic duct. Type 1 Mirizzi’s syndrome is associated with compression of the CHD by the stone without fistulation between the Hartmann’s pouch or cystic duct and the CHD. The more severe forms of Mirizzi’s syndrome in Type II to IV will have tissue damage with fistulation between Hartmann’s pouch or cystic duct with the CHD. Mirizzi’s syndrome is usually diagnosed radiologically. On initial US HBS, the gallbladder may have stones and a large stone may be noted in the Hartmann’s pouch or the neck of the gallbladder. The suspicion for Mirizzi’s syndrome should arise when the intrahepatic biliary ducts are noted to be dilated but the extra-hepatic biliary duct is not dilated. Detailed imaging studies such as CT scan of the abdomen or MRI scan like MRCP will lead to the diagnosis. In the presence of significant biliary obstruction causing obstructive jaundice or cholangitis, the initial management is usually ERCP with endobiliary stenting. Plastic stents that are placed will help to relieve the obstruction. A referral to the hepatobiliary surgeon is recommended as the operation to remove the gallbladder may be complicated. Patients need to be counseled regarding the potential damage to the bile duct by the longstanding pressure erosion onto the CHD by the impacted stones. As such, there is a likelihood that definitive hepaticojejunostomy is required to provide a complete solution to the problem. Occasionally, Type I Mirizzi’s syndrome can be successfully treated with laparoscopic cholecystectomy but the more severe forms of Mirizzi’s syndrome cannot escape biliary tract resection and reconstruction. If severe damage to the surrounding structures from the longstanding inflammation and scarring, the nearby portal vein and hepatic artery vasculature may also be affected. In extreme situation, partial hepatectomy may be required.

Gallbladder Polyps Gallbladder polyps are generally asymptomatic and they are often detected incidentally during screening scans done for other purposes. If the ultrasound of the gallbladder shows adenomyomatosis, it is usually benign and there is no further surgical intervention or treatment required. However, if there are concomitant gallstones, patients should be offered cholecystectomy as it is an associated risk factor for malignancy. Most small polypoid lesions of the gallbladder are benign and remain static for years. Three- to six-monthly ultrasonography examination is warranted in the initial follow-up period but it is probably unnecessary after 1 or 2 years. Age more than 50 years and size of polyp more than 1 cm are the two most important factors predicting malignancy in polypoid lesions of the gallbladder. Other risk factors include concurrent gallstones, solitary polyp, and symptomatic polyp. Laparoscopic cholecystectomy is the treatment of choice unless the suspicion of malignancy is high, in which case it is advisable to have open exploration, intraoperative frozen section, and preparation for extended resection. Lee et al. from The Chinese University of Hong Kong recommended the algorithm to follow up patients with polypoidal lesions in the gallbladder as shown in Fig. 5 (Lee et al., 2004). As a rule of thumb, if gallbladder polyp has not caused any symptoms, cholecystectomy should still be offered if the absolute size of the lesion is greater than 10 mm or if the rate of growth of the lesion is faster than 5 mm over a 6-month period. Oftentime, these are associated with high risk of malignant transformation of the polypoidal lesion in the gallbladder. When the polypoidal lesion in the gallbladder shows increase in internal vascularity on ultrasound doppler of the hepatobiliary system, the likelihood of malignancy increases accordingly. Further scans such as CT scan (Fig. 6) or MRI may be helpful to determine if the tissue plane between the gallbladder and the liver is involved. If it is, concomitant liver resection must be discussed as radical cholecystectomy with partial hepatectomy and radical lymph node clearance in the porta-hepatis may be necessary if potential curative outcome of the condition is desired. If the tissue plane is preserved and the likelihood of invasion of underlying liver bed is less likely, laparoscopic cholecystectomy may be sufficient. Extra care must be taken during the laparoscopic cholecystectomy not to breach the gallbladder wall, as spillage of bile content during cholecystectomy may lead to dissemination of malignant cells from the gallbladder polyp into the peritoneal cavity, converting a potential curative treatment with laparoscopic cholecystectomy to a stage IV disseminated gallbladder carcinoma. The carefully resected gallbladder specimen must be placed in a sterile bag and removed carefully without breakage of the specimen bag. For T1a lesion (Fig. 7), simple laparoscopic cholecystectomy is sufficient. The risk of lymph node involvement is only 0–4% and 5-year survival rate is almost 100%. As the lesion progresses to T1b, the risk of lymph node involvement is escalated to 12.5–20% and correspondingly, the overall survival will drop. Beyond T2 stage of gallbladder polyp, the lymph node positive rate quickly climbs to 60–80%. Radical cholecystectomy must be recommended with extended lymph node dissection of the porta-hepatis

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Fig. 5 Algorithm to follow up patients with polypoidal lesions in the gallbladder.

Fig. 6 CT scan showing a polypoidal lesion in the gallbladder fundus and the plane between the gallbladder and the liver bed remains intact.

Fig. 7 Resected specimen of carefully performed laparoscopic cholecystectomy for polypoidal lesions in the gallbladder. The histopathology reported this as T1a gallbladder carcinoma, in which simple cholecystectomy was sufficient treatment.

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following the index laparoscopic cholecystectomy to clear the remaining malignant cells that are potentially left behind during the first surgery. Upon receiving the final histopathological report of the laparoscopic cholecystectomy specimen, we recommend performing the radical clearance surgery within 2–4 weeks in order to reduce the chance of recurrence and dissemination of the tumor. However, the previous cholecystectomy site may now be difficult to evaluate due to the postoperative inflammation. Distinguishing between inflammatory changes versus malignant tissue changes will prove to be impossible.

Other Indications It is rather common that the gallbladder is removed concomitantly during major liver resection e.g., hepatic lobectomy and trisectionectomy. This is because the gallbladder sits on the Cantlie’s line at the junction between the left and right lobe of the liver. Concomitant cholecystectomy is required to achieve proper dissection of the hilar structures and also the liver parenchymal transection. In other situation such as in pancreaticoduodenectomy, as the pancreatic head and duodenum will be resected concomitantly with the whole biliary system, there is no role in preserving the gallbladder as a hepaticojejunostomy will be created to allow direct passage of bile from the liver into the small intestine.

Methods of Cholecystectomy The surgical approaches to cholecystectomy can be divided into the following:

• • •

Open—total, subtotal, with other procedure Laparoscopic—total, subtotal, with other procedure Single incision laparoscopic cholecystectomy (SILS)

Open cholecystectomy used to be the standard approach to this operation. A right subcostal incision (Kocher’s incision) is made to gain access to the right hypochondrium, where the gallbladder and the biliary structure are located. As the surgeon’s view of this area is antero-posterior, the structures that are visualized is seen from that same angle (Fig. 8). After exposing the peritoneal covering of the cystic-bile duct junction where the Calot’s Triangle is, cystic artery is carefully isolated, ligated and divided. Following that, cystic duct is dissected, isolated and ligated. After dividing the cystic duct, surgeon can choose to remove the gallbladder off the liver bed starting from the fundus.

Right hepatic artery giving off cystic artery

Common bile duct Duodenum Gallbladder Cystic duct

Gallbladder

Cystic duct

Fig. 8 The first surgeon’s view during open cholecystectomy is from the anterior part of the hilum.

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In laparoscopic cholecystectomy, the first surgeon’s view to the Calot’s area is from inferior to superior (Fig. 9A and B). Upon retraction of the Hartmann’s pouch antero-superiorly, the peritoneal lining covering this area will be cauterized and dissected free to isolate the cystic duct and artery. After clipping and dividing both the structures, gallbladder is removed off the liver bed using cautery. Care must be taken not to breech the capsule at the liver bed, as the terminal tributaries of the middle hepatic vein is usually located less than a few millimeters underneath the liver tissue there. In contracted gallbladder, it is even more crucial to be mindful of this. Port placement in conventional laparoscopic cholecystectomy is as shown in Fig. 10. A single Hassan’s port is placed in the umbilical region (can also be supra-umbilical or infra-umbilical) with gas tubing connected to this port to insufflate carbon dioxide pneumoperitoneum. Three 5 mm working ports are placed over the right subcostal area to facilitate the surgery. (B)

(A)

Right hepatic artery giving off cystic artery

Gallbladder Gallbladder

Cystic duct Cystic duct

Common bile duct Common bile duct

Duodenum

Gallbladder

Common bile duct Cystic duct

Fig. 9 (A) The first surgeon’s view during laparoscopic cholecystectomy is from the caudal (inferior) part of the hilum. (B) Laparoscopic view of gallbladder and its relationship to the liver, common bile duct and duodenum.

Fig. 10 Port placement in conventional laparoscopic cholecystectomy.

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While the 4-port approach is the standard technique in most surgical practice, the lateral most port on the right often can be avoided especially in fairly straightforward non-inflammed gallbladder (Fig. 11). The key to successfully performing the laparoscopic cholecystectomy with only two working ports is proper retraction of the grasper on the left hand on the Hartmann’s pouch while allowing the hook dissector to slowly cauterize the connective tissue at the Calot’s Triangle. Single incision laparoscopic (SILS) cholecystectomy is another alternative method to perform minimally invasive cholecystectomy. While many SILS ports have been made available commercially, they are rather costly and added more cost to a common and yet simple surgical procedure. In my center, we improvise the SILS technique using glove-port and small wound protector (Fig. 12A and B). Straight laparoscopic instruments will make the surgery slightly difficult and thus rotatable graspers and curved instruments are now available to facilitate this surgery. However, it is important to note that based on current evidence, SILS cholecystectomy only shows advantage in cosmetic outcome (Fig. 13) and the other benefits of this approach to perform cholecystectomy are comparable to conventional laparoscopic cholecystectomy.

Fig. 11 Port placement in laparoscopic cholecystectomy using two working ports.

Fig. 12 (A) Modified SILS port using sterile glove and existing laparoscopic ports. (B) As it is placed in the umbilical incision, the glove port is fitted onto the small wound protector.

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Challenges During a Difficult Laparoscopic Cholecystectomy: Avoiding Bile Duct Injury Bile duct injury (BDI) is a serious complication that can occur during cholecystectomy. In the days when open cholecystectomy was the standard of care for patients requiring removal of gallbladders, the risk of BDI was quoted to be 0.1% (Flum et al., 2003). Three decades ago when laparoscopy started to take shape in surgical practice, the risk of BDI during laparoscopic cholecystectomy was exceedingly high at 3% prompting many senior surgeons worldwide to condemn this approach to treat gallbladder pathology. However, as more surgeons who embraced laparoscopic surgical technique become more proficient with this new technique, the risk of BDI during laparoscopic cholecystectomy has improved tremendously, with the quoted risk now standing at 0.1% (1 in 1000 cases) of laparoscopic cholecystectomy. As mentioned before, the main guide to performing laparoscopic cholecystectomy safely is to identify the key structures in the Calot’s triangle bounded by cystic duct, lateral border of common hepatic duct and the liver bed. One should expect to see only a single small cystic artery crossing this triangle, where cystic artery branches off from the right hepatic artery (Fig. 14).

Fig. 13 Single incision at the umbilicus that eventually will be invisible, providing better cosmetic outcome for SILS cholecystectomy.

Liver bed

Cystic artery crossing

Cystic duct Common. Bile duct

Fig. 14 Normal anatomy that is expected at Calot’s Triangle (dotted yellow line).

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Two branches of cystic artery crossing the Calot’s Triangle

Cystic duct

Fig. 15 Sometimes, variation in the vascular anatomy may be seen at the Calot’s Triangle, in this case, the cystic artery gives rise to two branches early within the Calot’s triangle.

Occasionally, variation to the vascular anatomy can be seen crossing the Calot’s Triangle. For example, early branching of the cystic artery within the Calot’s Triangle (Fig. 15) may give rise to two vascular structures within, sometimes causing confusion to an inexperienced surgeon. That being said, laparoscopic cholecystectomy can still be challenging especially in fibrotic and contracted gallbladder due to long term chronic inflammation and fibrosis of the gallbladder and in late presentation of acute cholecystitis where the period of oedematous inflamed gallbladder has passed and the tissue planes become ambiguous. There are a few key learning tips to reduce the risk of BDI during cholecystectomy. It is important for surgeons who perform laparoscopic cholecystectomy to acknowledge that conversion should not be viewed as a failure of the surgery, but it is a calculated decision made to ensure patient safety during the intended surgery. 1. The key learning tips can be summarized as follows:

• • • • •

•

•

Patient selection is key to avoid BDI during laparoscopic cholecystectomy. Surgeons must scrutinize the patient’s imaging studies carefully prior to performing cholecystectomy. This is crucial in both elective and emergency (acute cholecystitis) settings. When planning for laparoscopic cholecystectomy in an elective setting, the ultrasound images or CT scan (or any other similar imaging studies) of the gallbladder MUST be studied. The key findings that will point to a difficult cholecystectomy include a small, contracted and fibrotic gallbladder (which often indicates that the Calot’s triangle may be obliterated by scar tissue, making dissection difficult). If there is concomitant involvement of the bile duct (e.g., Mirizzi’s syndrome), a more extensive counseling must be done preoperatively to plan for a possible bile duct repair or even hepaticojejunostomy (See “Mirizzi’s Syndrome” section). Patients must be informed that the risk of laparoscopic cholecystectomy converting to an open operation during the surgery will be higher than usual. Sometimes, a contracted gallbladder following a longstanding chronic cholecystitis may result in fistulation into surrounding structures such as the duodenum or the colon. Absence of well visualized tissue plane between the duodenum or colon must alert the surgical team about this possibility. Patient must be counseled about the possible need to repair the fistula opening intraoperatively. In extreme situation, segmental bowel resection may be required if the tissue surrounding the enteric part of the fistula turns out to be unhealthy for primary repair. In this case, the surgeon must also be prudent during the surgery to avoid any bile duct and vascular injury to the hepatic hilum. In an emergency setting, the scans that have been done pre-operatively must be studied to get a clear roadmap for surgical planning. While the gallbladder may not be contracted in the acute cholecystitis setting, there could be gangrenous or perforated gallbladder wall that will make the surgery complicated. In addition, there would also be concomitant Mirrizzi’s syndrome or compression of large stones in the Hartmann’s pouch or cystic duct that can make the surgery challenging. However, in an experienced surgeon’s hand, these issues can often be overcome by careful dissection of the structures based on the guidance of pre-operative imaging studies. Any aberrant or replaced vascular anatomy, especially the right hepatic artery, can also be identified in the pre-operative scan such as the CT scan. It is important to know the position of these aberrant vessels in order to avoid unnecessary injury that may

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(B)

Fig. 16 (A) A tubular structure was shown at the end of the Calot’s connected to the gallbladder (yellow dotted line). It was thought to be the cystic duct but a thicker structure (orange solid line) was noted in the Calots’ triangle leading to significant confusion. (B) The cystic artery turns out to be outside of the Calot’s Triangle (yellow dotted line). It has been clipped. The cystic duct was dissected free (orange solid line) after the proper Calots’ triangle (white triangular area with red margin) was located with careful dissection higher up.

•

lead to massive bleeding that is difficult to control and will force the surgeon to convert the surgery to open approach to contain the situation. Variable location of the cystic artery may also cause confusion to the surgeon. For example, the cystic artery may not be crossing the Calot’s Triangle but it is outside of the triangle. In this case, an inexperienced surgeon may be concerned and mistaken the cystic artery as the cystic duct while looking for the Calot’s Triangle window. As the normal anatomy is not visualized, he/she may find it difficult to progress further until the variation in anatomy is pointed out by a senior surgeon (Fig. 16A). Further careful dissection of the area as shown in Fig. 16B reveals that the cystic artery was lying outside of the triangle and the proper Calot’s Triangle is higher up as seen in the picture.

2. Always recreate familiar anatomy

• •

•

Misidentification of key structures is the most commonly quoted reason for BDI. However, some guiding principles may be useful to reduce this incidence (Strasberg and Helton, 2011). In patients with fibrotic Calot’s Triangle due to previous inflammation or from longstanding chronic cholecystitis, the gallbladder wall and cystic duct may be densely adherent to the surrounding structures. As a rule of thumb, structures that are too large are usually not the structures to be ligated and cut. Cystic artery and duct are usually not that large in diameter. Gallbladder is a rather small organ in the body and thus, it does not require a large blood vessel to provide blood supply. When one sees a reasonably large vessel crossing the Calot’s Triangle, one must think twice before clipping and dividing this structure. Carefully dissect the tissue around this structure will lead to discovery of a smaller cystic artery branching from this vessel (usually turns out to be right hepatic artery or the posterior sectoral artery). If there is another tubular structure traveling close to the gallbladder after the surgeon thinks that he/she has dissected free the Calot’s Triangle, one must be alerted to the possibility that this could be the common hepatic duct (Fig. 17A and B). The surgeon must avoid damaging or clipping this structure but dissect carefully higher up the gallbladder bed to free up this structure and look for the correct window to isolated the cystic duct instead (Fig. 17C). Sometimes, in gallbladder that has undergone longstanding chronic inflammation, the cystic artery may not be found anymore.

3. In the absence of puncture of the gallbladder wall, bile leakage is a sign of BDI. Intraoperative examination must be performed to try to identify the injury site. If this site cannot be identified accurately using laparoscopy, one must not hesitate to convert the operation to open method to completely examine the area in order to locate the site of injury and assess what appropriate next step is required. Patient safety must come first! 4. Call an experienced HPB surgeon to help when there is difficult cholecystectomy or when suspected to have BDI.

Quality of Life After Cholecystectomy Many patients with gallbladder pathology especially gallstones will ask if there are any long-term consequences following cholecystectomy. As the gallbladder functions to store and concentrate the bile juice that is produced by the liver, there is theoretically no significant impact to the physiological function of the gastrointestinal tract (GIT) after cholecystectomy. As the bile juice is required for emulsification of fat within the small intestine, which is crucial for absorption of fat and fat-soluble vitamins from our food, the efficiency of this function may take a slight hit in the immediate post cholecystectomy period.

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Fig. 17 (A and B) Initial dissection demonstrating that (A) was the Calot’s Triangle window and B was the cystic duct. However, further scrutiny of the structures in this area would reveal that there was an additional tubular structure (C) traveling close to the gallbladder bed. One must be alerted to the possibility of common hepatic duct (CHD) being adherent to the gallbladder. In fact, C was indeed the CHD after further carefully dissection of the area. (C) Further dissection to look for a new window (D) to free the common hepatic duct from the gallbladder bed had averted a bile duct injury.

However, adaptation of the GIT will take place following removal of gallbladder with ectasia of the bile duct to accommodate more bile storage. After a short while, the GIT function for absorption of fat will return to normal. Patients may experience a short duration of passing loose stool after meals (especially oily meals) or needing to go to the toilet shortly after meals to open the bowel, but this phenomenon tends to be transient. An initial quality of life study by Lien et al. showed that laparoscopic cholecystectomy that was performed for patient with cholelithiasis greatly reduce the gastrointestinal symptoms with significant improvement in the quality-of-life (Lien et al., 2010). There were significant improvements in total Gastrointestinal Quality-of-life score (GIQLI) as well as the other components such as physical well-being, mental well-being, gastrointestinal digestion, and defecation subscales scores. Patients with severe baseline

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conditions may benefit from greater quality-of-life improvement following LC. Interestingly, a QOL study performed by a Swedish group found that the original indication for cholecystectomy in combination with gender was found to predict the GIQLI score. Female gender in combination with biliary colic as indication for cholecystectomy was correlated with low GIQLI scores. Female gender also correlated with a higher risk for pain in the right upper abdominal quadrant after cholecystectomy. The author recommended careful evaluation of symptoms before planning elective cholecystectomy.

Post-Cholecystectomy Syndrome After the gallbladder is removed, most patients will have symptomatic relief and this is particularly for patients who had acute cholecystitis. However, at least 40% of patients undergoing cholecystectomy electively for suspected symptomatic choledocholithiasis and/or acalculous disease (biliary dyskinesia) continue to have distressing pain (Tarnasky, 2016; Bodvall, 1973; Cole and Grove, 1952; Ros and Zambon, 1987; Fenster et al., 1995). The more common reasons for unsatisfactory results after cholecystectomy including an incorrect diagnosis, coexisting functional symptoms, and/or psychological disorders were recognized many years ago (Cattell and Kiefer, 1929; Weir and Snell, 1935). Anatomical biliary issues such as partial cholecystectomy, long cystic duct remnant, operative bile duct injury and retained bile duct stone are other potential reasons for post-cholecystectomy pain. A small minority of patients with post-cholecystectomy pain may have sphincter of Oddi dysfunction (SOD). It has been suggested that 90 mEq/L, hypochloremia, hyponatremia and metabolic alkalosis. In contrast CSD, appears to be due to a series of autosomal monogenic disorders rather than defect in a single gene. Like CLD, the phenotype is associated with severe and persistent diarrhea, fecal [Naþ]: 90–140 mEq/L, high fecal HCO–3 and metabolic acidosis. Loss of function mutations in the NHE3 (SLC9A3) gene, or the serine peptidase inhibitor Kunitz type 2 (SPINT2) gene, or a gain of function mutation in GUCY2C were shown to be associated with the CSD phenotype. All three genes are involved in Na transport: NHE3 is the transporter, SPINT2 prevents peptidase from reducing NHE3 activity and GUCY2C inhibits NHE3 activity (Ameen et al., 2016; Rao, 2019). Finally an imbalance resulting in absorption >>> secretion results in constipation. The underlying causes can be opioidrelated(OIC), IBS-related (IBS-C), or are chronic idiopathic (CIC). An understanding of epithelial ion transport regulation has led to the development of three FDA approved drugs to treat constipation. First, a prostaglandin E analog, lubiprostone that increases

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cAMP and activates CFTR and Cl secretion, has been approved for treatment of OIC, IBS-C and CIC. The other two, linaclotide and plecanatide, approved for CIC and IBS-C are analogs of STa and guanylin respectively. Of great therapeutic value is that these are luminally acting drugs and yet, due to the production of cGMP, they also stimulate motility and reduce visceral pain (Fig. 5B) (Camilleri, 2015; Rao, 2019).

Summary Colonic homeostasis is essential for the conservation of water and electrolytes and regulating the net fecal fluid content. In a healthy colon, net absorption prevails and is achieved by a carefully orchestrated modulation of ion absorptive and secretory processes along the length of the colon. A complex array of regulatory systems, MALPINES (microbial, autocrine, luminal, paracrine, immunologic, neural and endocrine) underlie this modulation. Transport function varies along the crypt-surface axis, with net secretion predominantly occurring in the crypts and absorption in the surface cells. Absorption varies along the cephalocaudal axis, with electroneutral transport in the proximal colon and electrogenic transport in the distal colon. Genetic defects in transporters and/or dysfunctions in the multiplex regulatory systems can lead to imbalance of absorption: secretion and result in diarrhea or constipation. An understanding of colonic ion transport processes and their regulation has provided an understanding of disease pathophysiology and the tools for developing successful therapeutic strategies.

Acknowledgments The work reported here was supported by Institutional funds from the University of Illinois at Chicago.

See Also: Diarrhea; Anti-Diarrheal Drugs. Fat Digestion, Absorption, and Malabsorption. Laxatives and Other Drugs for Constipation. Pediatric Diarrheal Disorders. Small Intestine; Absorption and Secretion

References Ameen N, Kopic S, Ahsan MK, and Kravtsov DV (2016) Secretory diarrhea. In: Hamilton KL and Devor DC (eds.) Ion channels and transporters of epithelia in health and disease, physiology in health and disease, pp. 957–990. American Physiology Society. Binder HJ (2010) Role of colonic short-chain fatty acid transport in diarrhea. Annual Review of Physiology 72: 297–313. Binder HJ, Sangan P, and Rajendran VM (1987) Electrolyte absorption and secretion in the mammalian colon. In: Johnson LR (ed.) Physiology of the gastrointestinal tract, pp. 1389–1418. New York: Raven Press. Buckley A and Turner JR (2018) Cell biology of tight junction barrier regulation and mucosal disease. Cold Spring Harbor Perspectives in Biology 10(1): a029314. Published 2018 Jan 2 https://doi.org/10.1101/cshperspect.a029314. Camilleri M (2015) Guanylate cyclase C agonists: Emerging gastrointestinal therapies and actions. Gastroenterology 148: 483–487. Das S, Jayaratne R, and Barrett KE (2018) The role of ion transporters in the pathophysiology of infectious diarrhea. Cellular and Molecular Gastroenterology and Hepatology 6: 33–45. De Lisle RC and Borowitz D (2013) The cystic fibrosis intestine. Cold Spring Harbor Perspectives in Medicine 3: a009753. Donowitz M, Ming Tse C, and Fuster D (2013) SLC9/NHE gene family, a plasma membrane and organellar family of Na(þ)/H(þ) exchangers. Molecular Aspects of Medicine 34: 236–251. Field M (2003) Intestinal ion transport and the pathophysiology of diarrhea. The Journal of Clinical Investigation 111: 931–943. Furness JB (2012) The enteric nervous system and neurogastroenterology. Nature Reviews. Gastroenterology & Hepatology 9: 286–294. Gill R and Hecht GA (2018) Host-pathogen interactions in pathophysiology of diarrheal disorders. In: HM S (ed.) Physiology of the gastrointestinal tract, pp. 1547–1577. Academic Press (Elsevier). Halm DR (2016) Physiologic influences of transepithelial Kþ secretion. In: Hamilton KL and Devor DC (eds.) Ion channels and transporters of epithelia in health and disease: Physiology in health and disease, pp. 95–130. New York, NY: Springer. American Physiological Society. Ikarashi N, Kon R, and Sugiyama K (2016) Aquaporins in the Colon as a new therapeutic target in diarrhea and constipation. International Journal of Molecular Sciences 17. Messer JS and Chang EB (2018) Microbial physiology of the digestive tract and its role in inflammatory bowel diseases. In: Said HM (ed.) Physiology of the gastrointestinal tract, pp. 795–810. Elsevier-Academic Press. Priyamvada S, Saksena S, Alrefai WA, and Dudeja PK (2018) Intestinal anion absorption. In: Said HM (ed.) Physiology of the gastrointestinal tract, pp. 1317–1350. Elsevier-Academic Press. Rajendran VM and Sandle GI (2018) Colonic potassium absorption and secretion in health and disease. Comprehensive Physiology 8: 1513–1536. Rajendran VM, Schulzke J-D, and Seidler UE (2018) Ion channels of the gastrointestinal epithelial cells. In: Said HM (ed.) Physiology of the gastrointestinal tract, pp. 1363–1404. Elsevier-Academic Press. Rao MC (2019) Physiology of electrolyte transport in the gut: Implications for disease. Comprehensive Physiology 9: 947–1023. Rao MC, Sarathy J, and Sellin JH (2016) Intestinal electrolyte absorption and secretion. In: Feldman M, Friedman LS, and Brandt LJ (eds.) Sleisenger and Fordtran’s gastrointestinal and liver disease: Pathophysiology, diagnosis, management, pp. 1713–1735. Elsevier. Seidler UE (2013) Gastrointestinal HCO3- transport and epithelial protection in the gut: New techniques, transport pathways and regulatory pathways. Current Opinion in Pharmacology 13: 900–908. Worrell RT, Cuppoletti J, and Matthews JB (2004) Colonic absorption and secretion. In: Encyclopedia of Gastroneterology, 413–420. Zeuthen T (2010) Water-transporting proteins. The Journal of Membrane Biology 234: 57–73.

Colonic Ischemia Paul Feuerstadt, Yale University School of Medicine, Hamden, CT, United States Lawrence J Brandt, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, United States © 2020 Elsevier Inc. All rights reserved.

Glossary

Atherosclerosis Narrowing of an artery due to the build-up of plaque in the artery wall. This might limit the flow of blood to a specific site or organ. Colonocyte An epithelial cell lining the interior of the colon wall. Endovascular Surgical procedure that involves passage of a catheter into a blood vessel with usage of small instruments or medications through the catheter within the blood vessel to treat an underlying condition. Holter Monitor A small, wearable device that tracks heart rhythms. This device is used to assess patients for arrhythmias and other abnormalities of the heart rhythm. Hyalinization A process where normal tissue is replaced by a homogenous glassy appearing material that histologically stains pink with hematoxylin and eosin staining. Hyperkalemia Elevation of the potassium levels in the blood. Macrolides, cephalosporins, chloramphenicol, fluoroquinolones Classes of antibiotics which are associated with antibioticassociated hemorrhagic colitis. Neuroleptic Agents Medical therapies that reduce confusion, delusions, hallucinations and psychomotor agitation in patients who are psychotic. Also known as “antipsychotic agents.” Nonocclusive mesenteric ischemia Mesenteric ischemia is the term for physiologically relevant decreases in the blood supply to the small bowel (e.g., duodenum, jejunum or ileum). Nonocclusive mesenteric ischemia occurs when there is not an obstructive process. This usually is caused by systemic low blood pressure resulting from processes such as sepsis or congestive heart failure. Paralytic Ileus Intestinal obstruction of the small bowel resulting from the intestinal wall musculature being paralyzed and unable to propel digestive contents forward. Protein Losing Colopathy Alterations to the colon that result in loss of plasma proteins into the lumen of the digestive tract. This can be identified with low serum albumin levels in patients with frequent loose stools. Sympathetic input Portion of the nervous system that mediates response to stressors with the so called “fight or flight response.” Stimulating this element of the nervous system increases the heart and respiratory rate, dilates the pupils in the eye, increases blood flow to muscles and raises blood pressure. Sympathomimetic Input A term for a drug that mimics the sympathetic nervous system effects on an organ or other structure within the body. Vagal Cholinergic Activity Any stimulation of the digestive tract mediated by the release of acetylcholine, most commonly from the vagus nerve.

Abbreviations AAA AMI COPD CI COX-2 DVT HRT IMA IBD IBS IRCI NOMI NSAIDs SPS SMA

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Abdominal aortic aneurysm Acute Mesenteric Ischemia Chronic obstructive pulmonary disease Colon ischemia Cyclooxygenase-2 Deep Vein Thrombosis Hormone Replacement Therapy Inferior mesenteric artery Inflammatory bowel disease Irritable bowel syndrome Isolated-right colon ischemia Nonocclusive mesenteric ischemia Nonsteroidal Antiinflammatory Drugs Sodium polystyrene sulfonate Superior mesenteric artery

Encyclopedia of Gastroenterology, 2nd Edition

https://doi.org/10.1016/B978-0-12-801238-3.65627-1

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Definition CI is the condition that occurs when blood flow to the colon is reduced to a level insufficient to maintain cellular metabolic function, thereby resulting in colonocyte death. We now know that blood flow does not have to completely stop, but only diminish significantly to cause ischemic damage. The harm from the initial insufficient blood flow is not the only pathologic process causing damage to the bowel. Reperfusion has also been associated with ischemia-associated injury. The degree to which colonic blood flow must diminish to result in ischemia varies with the acuteness of the event, the degree of preexisting vascular collateralization, and the length of time the low flow state persists. CI may manifest with reversible (e.g., subepithelial hemorrhage or edema, and colitis) or irreversible (e.g., gangrene, fulminant colitis, stricture formation) damage. It remains important to remember that most instances of CI are benign and self-limited, however, identifying more severe presentations that require more aggressive management can optimize outcomes (Brandt et al., 2015).

Epidemiology The incidence of CI is underestimated, because many patients suffer only mild or transient symptoms and do not seek medical attention. Also, CI is commonly misdiagnosed and confused with other disorders, notably inflammatory bowel disease (IBD). Finally, most studies that assess the incidence of CI address the disease in its most severe presentations, focusing on patients who required hospitalization and using colonoscopy with biopsy to confirm the diagnosis. Given this, it is challenging to truly understand the whole disease burden. Nonetheless, the incidence of CI appears to be increasing. A retrospective study of patients from Rochester, Minnesota showed that incidence increased from 6.1 cases per 100,000 person years between 1976 and 1980 to 22.9 cases per 100,000 person years between 2005 and 2009. (Yadav et al., 2015). This increased incidence is likely multifactorial and includes better disease recognition, an aging population, more frequent surgical interventions associated with CI and increased polypharmacy with medications that predispose to this disease. CI has a female sex predilection. (Yadav et al., 2015; Yngvadottir et al., 2017) Medical comorbidities most commonly associated with CI include atherosclerosis, atrial fibrillation, heart failure, COPD, constipation, diabetes, diarrhea, hypertension, IBS, peripheral vascular disease and rheumatologic disease (Yadav et al., 2015; Yngvadottir et al., 2017; Walker et al., 2004a; Longstreth and Yao, 2010). Surgical procedures also may leave patients at risk for CI, most commonly abdominal, aortic and cardiovascular surgery, ileostomy formation, laparoscopy or prior colon cancer resection (Yadav et al., 2015; Chang et al., 2008; Walker et al., 2004b).

Pathobiology/Etiology The pathophysiologic mechanisms for CI are rooted in the vascular supply to the colon, therefore, a sound understanding of the vascular anatomy is important. The superior mesenteric artery (SMA) has its origin from the aorta near the neck of the pancreas. It gives rise to 5 major vessels: the anterior and posterior inferior pancreaticoduodenal vessels, middle colic, right colic, and ileocolic arteries, as well as to a series of jejunal and ileal branches, all of which supply their named portions of intestine. The colon receives blood from the ileocolic, right and middle-colic branches which supply blood to the cecum, ascending and proximal transverse colon. The inferior mesenteric artery (IMA) arises 3–4 cm above the aortic bifurcation close to the inferior border of the duodenum. It branches into the left colic artery, gives off multiple sigmoid branches, and terminates as the superior rectal artery. The IMA and its branches supply the colon from the mid-transverse colon to the proximal rectum. The distal rectum is supplied by branches of the internal iliac (hypogastric) artery from the systemic circulation. CI can result from alterations in the systemic circulation or from anatomic or functional changes in the mesenteric vasculature. Local hypoperfusion and reperfusion injury are believed to play an essential role in the pathogenesis. In most cases, no specific cause for ischemia is identified, and these episodes are considered localized nonocclusive ischemia, likely a result of small-vessel disease. Multiple causes for CI have been defined including autoimmune, cardiovascular, inflammatory, pharmacologic, toxin-mediated, iatrogenic and infectious. (Table 1). Etiologies for CI differ between the young and elderly. Vasculitis, coagulation and thrombophilic disorders, use of cocaine, and an assortment of iatrogenic causes, including a wide variety of medications such as estrogens, serotoninergic agonists and antagonists, sumatriptan, and methamphetamine are most common etiologies in the young. One study of patients with biopsy-proven CI compared an older cohort ( 65 years) with a younger cohort (18–64 years). Medications-associated with CI that were more frequent in the older group included diuretics, constipation-inducing medications and NSAIDS, whereas psychotropic treatments were more common in the younger cohort (Silverman et al., 2018). Moreover, when considering medical risk factors, atrial fibrillation and COPD were seen more frequently in older patients, while hypercoaguable states and CKD on hemodialysis was more common in younger patients (Silverman et al., 2018). Age-related abnormalities in the splanchnic vessels are common, including narrowing of small vessels, and tortuosity of the long colic arteries, although usually are just associated lesions and not causative of the ischemic injury. These differing age-specific underlying risk factors play a role in disease development. Elderly patients have more risk factors, greater medication exposures and a higher risk for anatomic abnormalities, leaving them more susceptible to CI. The colon is particularly susceptible to ischemia, owing to its relatively low blood flow, lack of robust collateral perfusion, its unique decrease in blood flow during periods of functional activity, and its sensitivity to autonomic stimulation. Given these

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Etiologies of Colonic Ischemia

Acute pancreatitis Allergy Amyloidosis Heart failure or cardiac arrhythmias Hematologic disorders and coagulopathies Activated protein C resistance Antithrombin deficiency Paroxysmal nocturnal hemoglobinuria Polycythemia vera Protein C and S deficiencies Prothrombin G20210A mutation Sickle cell disease Infection Bacteria (Escherichia coli O157:H7) Parasites (Angiostrongylus costaricensis) Viruses (hepatitis B and C, HCV, CMV) Inferior mesenteric artery thrombosis Long-distance running Medications and toxins Pheochromocytoma Ruptured ectopic pregnancy Shock Strangulated hernia Surgery/Procedures Aortic aneurysmectomy Aortoiliac reconstruction Barium enema Colectomy with inferior mesenteric artery ligation Colon bypass Colonoscopy Exchange transfusions Gynecologic operations Lumbar aortography Thromboembolism Cholesterol (atheroembolism) Myxoma (left atrial) Trauma (blunt or penetrating) Vasculitis and vasculopathy Buerger’s disease Fibromuscular dysplasia Kawasaki’s disease Polyarteritis nodosa Rheumatoid vasculitis SLE

factors, the colon is remarkably resilient to ischemic injury. This resiliency was reinforced in one study that showed reperfusion injury after an ischemic insult in the colon was much less severe than in the small bowel (Hundscheid et al., 2015). Another study showed that the epithelial chemical barrier of the colon is reinforced as goblet cells rapidly secreted mucus during an episode of ischemia, thus preventing luminal bacteria from accessing the epithelium and thereby potentially worsening an inflammatory reaction (Grootjans et al., 2016). Therefore, the colon has mechanisms of defense to prevent inflammation and bacterial translocation in the setting of ischemia that other areas of the gastrointestinal tract lack. Given the susceptibility of the colon to ischemic events, the likely high frequency of subclinical or minor ischemic events and the mostly benign nature of CI, it seems likely that with time we will uncover other protective physiologic mechanisms unique to the colon that prevent inflammation and bowel damage from episodes of CI.

CI in Patients With Carcinoma of the Colon and Other Potentially Obstructive Lesions In less than 5% of patients with CI there is an associated a distal and potentially obstructing lesion or disorder of the colon, including cancer, diverticulitis, fecal impaction, and stricture. The associated lesion is typically distal with a segment of normal bowel between the lesion and the proximal segment of CI. One hypothesized mechanism for this phenomenon involves increased intracolonic pressure proximal to the obstructing lesion with resultant decreased colonic blood flow. It is important to be aware of

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this association because if an anastomosis following colon resection is done for a distal neoplasm and is created in an unsuspected area of CI, it is likely that anastomotic leakage or suture disruption might occur.

CI in IBS CI occurs 4–5 times more frequently in the presence of IBS than without it. The cause for this association is unclear, however, chronic constipation and chronic diarrhea are both risk factors for CI independent of a diagnosis of IBS. Some believe this association is physiologic resulting from hypersensitivity of the colonic vasculature, autonomic hyper-responsiveness, or differences in the sensitivity of serotonin receptors. Others hypothesize that these patients are simply more likely to present to medical attention since those with IBS visit their doctor more frequently. (Brandt et al., 2009) This association was discovered when it originally was thought that the medications used to treat IBS were the main culprit (e.g., alosetron), however, further studies showed that the incidence of CI is higher in those with IBS, independent of treatment. The answer likely is multifactorial including all of these risk factors. More studies, better data, and a better understanding of the true pathophysiologic mechanisms of IBS, will help clarify this complex association.

CI Complicating Aortic Surgery CI is a very common complication of aortic surgery given that the aorta is the only source of blood for most of the large bowel. In the era of endovascular repair for abdominal aortic aneurysmal disease (AAA), it is estimated that CI complicates 2.2%–2.9% of allcases with an incidence of 2% for the endovascular approach, 5% for open procedures and an overall mortality estimated at 38.7% to 52.0% (Moghadamyeghaneh et al., 2016). Risk factors for CI in these patients include intra- or postoperative transfusion, rupture of the aneurysm before surgery, renal failure requiring hemodialysis, proximal extension of the aneurysm, and female sex. Mortality is strongly correlated with age and the need for surgical intervention for the CI. (Moghadamyeghaneh et al., 2016)

Medications as a Cause of Colon Ischemia (Vodusek et al., 2018) Medications should always be considered as a possible etiology for CI, although it is difficult, if not impossible, to distinguish association and causation. Many of the medications used to treat diseases that are known risk factors for CI also are implicated as being a cause, and it remains unclear whether the underlying medical disease, the medical therapy, or some combination of both is most important. The best example of this was when alosetron was first approved in 2000 for the treatment of irritable bowel syndrome (IBS) with diarrhea predominance in women, and a significant number of treated patients developed CI. When studied further, it was clear that patients with IBS-alone were approximately 3.4-fold more likely to have CI than the general population and the addition of alosetron further contributed to the likelihood of CI (Walker et al., 2004b). IBS is not the only disease for which associations of causality are seen. Patients with chronic obstructive pulmonary disease (COPD) frequently require corticosteroid therapy for disease exacerbation and both COPD as well as corticosteroids are risk factors for CI. Similar scenarios can be seen in patients with oncologic disease, heart failure and atherosclerotic cardiac and peripheral vascular disease (Bielefeldt, 2016). It remains important to remember that many people take medications and some people develop CI; the presence of a medication does not necessarily imply that it was responsible for the CI, although this possibility must be considered in all cases. (Vodusek et al., 2018) The currently available literature associating medications with CI is limited to case series and is unable to systematically assess causality based upon underlying medical comorbidity and pharmacologically mediated pathophysiologic mechanisms. In one review article that compiled the available literature regarding the associations of CI with various medications, strong associations were seen with constipation-inducing medications, digoxin, hormonal therapies, illicit drugs, immunomodulators, laxatives, and NSAIDs. Moderate associations were seen with antimicrobials, appetite suppressants, chemotherapy, decongestants, diuretics, ergot alkaloids, serotonin agents, statins and vasopressor agents. (Table 2) (Vodusek et al., 2018).

Antimicrobials Antibiotic-associated hemorrhagic colitis (AAHC) is believed to be a CI-mediated injury. The penicillins and their derivatives, including amoxicillin and ampicillin, most commonly have been associated, although macrolides, cephalosporins, chloramphenicol, fluoroquinolones, and tetracyclines also are known associations. The symptoms of AAHC typically manifest 2–7 days after antimicrobial initiation, beginning with lower abdominal pain and loose stools, followed several hours later by rectal bleeding. Case reports and basic science studies have shown overgrowth of the normally commensal Klebsiella oxytoca in patients presenting with AAHC and colonoscopic biopsies consistent with CI. It is believed that the toxin tilivalline, released by K. oxytoca, causes an ischemic insult to the colonic mucosa, however, the exact mechanism of injury remains unclear. If this etiology for CI is suspected, it is recommended that the antimicrobial be stopped and an alternative regimen started.

Chemotherapeutic Agents Patients with oncologic diagnoses are known to be hypercoagulable, and chemotherapeutic agents were reported in one study to be the most frequently associated pharmacologic risk factor for CI (Bielefeldt, 2016). Despite the frequency with which these

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Pharmacological Associations with CI

Strong Association Class Constipation-inducing medications

Digoxin Hormonal therapies

Illicit drugs Immunomodulators

Laxatives

Nonsteroidal antiinflammatory drugs

Moderate association Class Antibiotics Appetite suppressants Chemotherapy

Decongestants Diuretics Ergot alkaloids Interferon Serotonin agents

Statins Vasopressor agents Other

Examples Antipsychotics (e.g., quetiapine, clozapine) Opioid agonists (e.g., loperamide, oxycodone, hydrocodone, morphine, codeine) MUSCARINIC agonists (e.g., diphenhydramine, dicyclomine) Oral Contraceptive Pills (e.g., ethinyl estradiol and desogestrel, drospirenone and ethinyl estradiol, levonorgestrel-ethinyl-estradiol) Vaginal Rings (e.g., etonogestrel and ethinylestradiol) Amphetamines Cocaine Lenalinomide Corticosteroids TNF-a inhibitors Bisacodyl Glycerin enema Magnesium Citrate Polyethylene Glycol Low dose aspirin NSAIDs

Examples Fluoroquinolones Penicillin and derivatives Phentermine Platinum-based therapy Taxanes Vinorelbine Phenylephrine Pseudoephedrine Furosemide Dihydroergotamine mesylate Alosetron Clozapine Quetiapine Sumatriptan Rosuvastatin Simvastatin Glypressin Vasopressin Danazol Flutamide Gold salts Pit viper toxin

Adapted from Vodusek, Z., Feuerstadt, P., Brandt, L.J. Alimentary Pharmacology and Therapeutics. 2018.

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treatments are associated with CI, there is little insight into the pathophysiologic mechanisms to explain this complication; most are believed to result from direct toxicity to the colonic epithelium or antiangiogenic toxicities. When associated with chemotherapy, CI usually is seen with the alkaloid taxane and platinum classes of chemotherapeutic agents, such as vinorelibine tartrate (alkaloid), paclitaxel, docetaxel (taxanes) or cisplatin (platinum-based). Presentation usually has mild symptoms and outcome is favorable with conservative management. If patients develop CI while taking these medications, the clinician must reconsider the risks and benefits of their future usage.

Constipation-Inducing Agents Patients taking medications that have constipation as a known adverse effect potentially are at increased risk for CI (Walker et al., 2004a). There are many theoretical mechanisms for this association including: reduced baseline mucosal blood flow, possibly as a result of impaired efferent vagal cholinergic activity; impaired cholinergic innervation (a side effect of many constipation-inducing medications) and the resultant unopposed sympathetic input leaving the colon susceptible to ischemic injury; and increased intracolonic luminal pressure that diminishes colon blood flow. Most CI that results from constipation- inducing drugs is benign, however, given the diversity of therapies inducing constipation and how commonly these medications are used, it remains important to stop these treatments at the time of an initial episode of CI and consider alternative options for the future.

Decongestants Decongestants are products that reduce copious nasal discharge, by vasoconstrictive mechanisms, resulting from seasonal allergies or upper respiratory tract infections. Pseudoephedrine and phenylephrine, which has largely replaced pseudoephedrine, stimulate a1-adrenergic receptors, thereby constricting vessels and relieving the “runny” nose, but the drug can be absorbed and, by the same mechanism, cause mesenteric vasoconstriction with resultant CI. Patients with a history of CI, vasculitis, or a known thrombophilic state should be alerted to this potential complication of decongestants. If a patient presents with CI while on these medications, the drug should be stopped and avoided in the future.

Diuretics Diuretics, such as furosemide, have been implicated in NOMI and CI. The presumed mechanism for CI with these agents is a decrease in extracellular fluid volume and reduction in peripheral resistance, which prompts a “steal” of blood from the intestine to the arms and legs. Early correction of fluid balance is the preferred treatment.

Hormonal Therapies CI is most commonly seen in an older–age populations, but one cohort of susceptible younger patients are woman on oral contraceptive pills (OCP) or hormone replacement therapy (HRT). In young, otherwise healthy women, the OCP is usually their only risk factor for CI, although any woman who develops CI on OCPs should have their medication list assessed for other treatments associated with CI and consideration given to any medical comorbidity that may be a risk factor such as obesity, IBS, and thrombophilic disorders, especially Factor V Leiden deficiency. Vaginal rings with etonogestrel and ethinylestradiol also have shown an association with CI. It is believed that OCPs increase the risk of hypercoaguability and ischemia by disturbing the balance between factors that promote and inhibit clotting. In any patient with other risk factors for CI, the use of OCPs or HRT, if clinically appropriate, should be monitored closely. Patients who experience CI while taking these medications should stop taking them and consider other management options since continuing on these therapies leaves patients susceptible to both short- and long-term recurrence.

Controlled or Illicit Pharmacologic Agents Another category of pharmaceuticals that associates CI with a younger population is that of controlled and illicit drugs. Amphetamines are sympathomimetic vasoconstricting medications used for medicinal and recreational purposes. Significant increases in morbidity from a variety of ischemic insults attributed to their use have been reported, including myocardial ischemia and intestinal gangrene. Amphetamine-induced CI is rare and usually manifests with rectal bleeding and mild-to-moderate abdominal pain. These medications tend to affect the ascending colon, possibly as a result of selective vasoconstriction of the SMA. Cocaine is a recreational drug associated with CI. The main mechanisms of injury with this agent include mesenteric vasoconstriction, a hypercoaguable state, and direct toxicity to the vasculature. Symptoms of cocaine-induced CI most commonly develop within 48 h of drug intake and include acute onset abdominal pain, vomiting, melena and/or diarrhea; this entity sometimes presents with vomiting, reflecting small bowel involvement, which is uncommon with other pharmacologically mediated episodes of CI. Cocaine induced CI tends to occur in younger patients and has a significantly higher mortality than CI from other causes. Given how rarely young patients present with CI, it is essential to directly inquire about illicit drug use when someone younger than age 50 age presents with clinical symptoms and imaging consistent with this diagnosis. If this risk factor is missed, it could lead to continued use, repeated episodes and long-term complications. Therefore, being aware of this potential complication can lead to more rapid diagnosis, intervention and better outcomes.

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Laxatives Sodium Polystyrene Sulfonate (SPS, Kayexalate®, Sanofi-Aventis, Bridgewater, NJ) is frequently used to treat hyperkalemia and has been reported to cause immediate or delayed CI. The hypothesized pathophysiologic mechanism involves osmotic mucosal injury and vasoconstriction induced by fluid shifts, elevated serum renin values and angiotensin-mediated vasoconstriction. CI from SPS is usually self-limited, but other medications should be used to treat recurrent episodes of hyperkalemia in CI-affected patients. SPSinduced CI is easier to diagnose than most other medication-induced CI because the typical Kayexalate crystals can be identified on colon biopsy. Hyperosmotic laxatives, such as magnesium citrate and sodium phosphate have been shown to cause CI, which can manifest with abdominal pain and diarrhea as quickly as within 1 h of taking the medication. The mechanism leading to ischemia with these agents involves a rapid shift of fluids from the vascular space of the colonic circulation into the luminal space resulting in local hypoperfusion. Bisacodyl, a stimulant laxative, has also been associated with CI in young healthy patients. The mechanism of this disease is thought to be enhanced colonic motility resulting in decreased mucosal perfusion. Patients usually develop rectal bleeding and abdominal pain several hours after ingesting the drug. In patients with a history of CI, this medication is relatively contraindicated.

Nonsteroidal Antiinflammatory Drugs (NSAIDs) The association between NSAIDs and upper digestive tract ulceration has been established for a long time but their role in lower intestinal enteropathy and colopathy via ischemic mechanisms is now being better appreciated. The predominant mechanism for NSAID-induced ischemia involves the selective inhibition of cyclooxygenase-2 (COX-2) which is thought to cause localized inflammatory alterations resulting in both isolated ulcerations or continuous segmental mucosal involvement consistent with CI. NSAID-induced colitis manifests with abdominal pain, diarrhea, and rectal bleeding, and occasionally with fever and weight loss. The elderly seem to be at increased risk for NSAID-induced CI with one hypothesized mechanism being a decreased ratio of vasodilating to vasoconstricting prostaglandins, which is thought to be more pronounced in that population. Once NSAIDs have been identified as a likely culprit, it is important to consider stoppage of this therapy and pursuit of alternative treatments.

Serotonin Agonists and Antagonists Serotonin (5-hydroxytryptamine, 5-HT) plays a critical role in modulating enteric neurotransmission and CNS signaling. Alosetron, a 5-HT3 antagonist used to treat IBS-D in women, is probably the most studied medication associated with CI since it was removed from the market in the United States in 2000 as a result of its observed association. In 2002, Alosetron was reintroduced in a lowerdose for use in patients with IBS-D who had not responded to conventional therapies. The clear association of this medication with CI led to many epidemiologic studies of patients with IBS alone and IBS on this therapy and revealed that those with IBS are at a 3.4fold increased risk for CI, independent of this treatment (Walker et al., 2004b). Therefore, the combination of the medical comorbidity and the pharmaceutical, led to an alarming rate of CI. Alosetron-induced CI is usually reversible and rarely has caused stricture or gangrene. As a result of the association between serotoninergic medications and CI, these medications should not be used in any patient at an increased risk for CI or in women with a history of an ischemic event in any vascular bed. Relative contraindications to its use include a history of hyperactive vascular disorders (migraine headaches) and history of deep vein thrombosis (DVT). First and second generation neuroleptic agents are associated with mild hypomotility of the GI tract and CI. These therapies act on serotonergic and cholinergic pathways and, therefore, are hypothesized to affect the blood supply to the colon. Clozapine, cyamemazine, levomepromazine and haloperidol are agents frequently associated with CI and patients on more than one antipsychotic medication seem to be at increased risk for CI. Olanzapine, a second generation neuroleptic medication commonly used in the United States, also has been associated with mild episodes of CI. Quetiapine, a dopamine and 5HT-2 antagonist, when used in combination with other anticholinergic agents, has been associated with severe CI and death. The true frequency and relative severity of disease of these associations require further investigation, however, these medications should be stopped or changed if a patient develops CI while on active therapy.

Pathology Pathologic changes seen with CI are most commonly nonspecific including hemorrhage, edema, necrosis, inflammation, crypt abscesses, hyalinization of the lamina propria and capillary fibrin thrombi. These pathologic findings can support the diagnosis of CI in the appropriate clinical context, but are not specific. There are no clear pathologic diagnostic criteria for CI, and morphologic changes after CI vary with the duration and severity of the injury (Montoro et al., 2011). The mildest injury is mucosal and submucosal hemorrhage and edema, with or without partial necrosis and ulceration of the mucosa. With more severe injury, chronic ulcerations and changes that can mimic IBD can develop. Pseudomembranes also may be seen (Jessurun, 2017). One large retrospective multi-institutional study of consecutive patients with pathologically proven-CI showed that the most common pathologic findings were inflammation, ulceration, fibrosis and necrosis (Fenster et al., 2018). With severe ischemia, the muscular layer of the colon is replaced by fibrous tissue, forming a stricture. The most-severe form of ischemic damage causes transmural infarction.

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Clinical Manifestations Acute Clinical Manifestations CI usually manifests with sudden cramping, and mild, abdominal pain in the distribution of the segment of colon involved; an urgent desire to defecate; and passage within 24 h of bright red or maroon blood or bloody diarrhea (Brandt et al., 2015). Bleeding is not usually hemodynamically significant nor sufficient to require transfusion. The SMA perfuses the right- and proximal transverse colon, whereas, the IMA supplies the proximal transverse colon to the rectum. Given this difference in vascular supply, it was theorized that clinical presentations for those with right-sided CI differed from left-sided disease. One study compared isolated right-sided colonic ischemia (IRCI) with other segmental distributions. IRCI was associated with less rectal bleeding, less abdominal pain followed by bloody diarrhea, more frequent nonbloody diarrhea and more frequent abdominal pains without rectal bleeding (Montoro et al., 2011). Therefore, the left-sided presentation was consistent with the “classic” CI clinical manifestations, whereas right-sided disease presented with pain and nonbloody diarrhea; this observation has been reconfirmed in independent studies. A large retrospective study of patients with biopsy-proven CI showed that no region of the colon is spared from involvement. A segmental pattern is seen most commonly with the left-colon affected most often (32.6%), followed by the distal colon (24.6%), and right-colon (25.2%). Pan colonic and rectal involvement occur infrequently at 7.3% and 4.2% respectively (Brandt et al., 2010); the segmental nature of CI has been reconfirmed in multiple other studies. (Yadav et al., 2015; Montoro et al., 2011) Although no specific etiology is associated with any specific anatomic distribution, pancolitis and IRCI are seen frequently in patients with sepsis (Brandt et al., 2010). The length of affected bowel can depend on the cause of CI: atheromatous emboli involve short segments, and nonocclusive injuries involve longer portions of colon.

Isolated Ischemia of the Right Colon Ischemia that is isolated to the right side of the colon (IRCI) has been shown to occur in 25% of cases. (Yadav et al., 2015; Montoro et al., 2011; Brandt et al., 2010) This pattern is more likely than any other to be associated with coronary artery disease and CKD requiring hemodialysis (Brandt et al., 2010). As annotated above, these patients tend to present differently than others with CI, having less frequent rectal bleeding and abdominal pain followed by bloody diarrhea, but more frequent peritonitis, acute abdominal pain without rectal bleeding and nonbloody diarrhea (Montoro et al., 2011). IRCI seems clinically to mimic a less severe form of AMI, although, in fact, IRCI has a worse outcome with a greater risk of short-term colectomy or mortality than patients with CI affecting colon within the distribution of the IMA (Feuerstadt et al., 2015). Because the SMA supplies blood to the right side of the colon—as well as to the small intestine—and because patients with IRCI may have it as the heralding presentation of otherwise silent SMA obstructive disease, we recommend evaluating the splanchnic vasculature in all patients with IRCI. IRCI is an exception to our general practice of not evaluating the splanchnic vascular system in a patient with CI.

Chronic Clinical Manifestations A small portion of patients (10 to 16%) with CI are at risk for recurrent disease (as defined by 2 discrete episodes of CI) (Brandt et al., 2015). Symptoms that persist for greater than 2 weeks are associated with a higher incidence of acute complications and irreversible disease. These include gangrene and perforation, chronic segmental colitis, or stricture.

Gangrene Abdominal tenderness with fever and signs of peritonitis suggests infarction and the need for emergent laparotomy. Patients with gangrene are at very high risk of sepsis from bacterial translocation and resultant mortality. This is universally fatal without intervention.

Chronic Segmental Colitis Chronic segmental ischemic colitis may be present with recurrent fever and sepsis; continuing or recurrent bloody diarrhea; and persistent or chronic diarrhea with protein-losing colopathy. Patients with clinical symptoms concerning for persistent disease should undergo repeat colonoscopy within 1–2 months to determine whether the colitis is healing, becoming chronic, or forming a stricture. Those who are asymptomatic or do not have worrisome endoscopic findings during the initial colonoscopy do not require repeat endoscopic evaluation. Recurrent fever, leukocytosis, and septicemia suggest a segment of unhealed colitis. This will require surgical resection as a definitive measure. Patients with persistent diarrhea, bleeding, or protein-losing colopathy of more than 2 weeks’ duration are at high risk of perforation, and segmental resection is indicated. Patients who present with segmental colitis are frequently misdiagnosed as having IBD. Response to oral corticosteroid therapy usually is poor in patients with CI and may be associated with an increased incidence of perforation. It is essential for the practicing clinician to consider ischemia in patients with segmental colitis unresponsive to standard IBD therapies. Colonoscopy with biopsy should provide sufficient evidence to differentiate CI from IBD in these patients.

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Ischemic Stricture One severe ischemic episode or repeated ischemic insults to one segment of bowel can result in fibrotic change and stricture formation. Strictures that are asymptomatic can be observed; some resolve over 12–24 months with no therapy. CT is a good way of characterizing these strictures (see later). Strictures that cause obstructive symptoms, should be resected. There are very limited data regarding the usage of dilation and stent placement as a temporizing measure or as a bridge to a surgical procedure. These techniques seem promising but require further validation prior to widespread usage.

Universal Fulminant Colitis Sudden onset of a toxic colitis picture with signs of peritonitis and a rapidly progressive course are typical of universal fulminant colitis, a rare variant of CI. Total abdominal colectomy with ileostomy usually is required.

Diagnosis The diagnosis of CI is based largely on imaging and clinical presentation. If CI is suspected, CT is used to verify the diagnosis, stage the disease and evaluate for complications (Berritto et al., 2016). Patients presenting to the ED with signs and symptoms of CI will frequently have a CT as an early test. If the CT scan shows only nonspecific findings for example, a thick-walled segment of colon, colonoscopy is indicated to help confirm or exclude the diagnosis (Brandt et al., 2015). The current diagnostic utility of ultrasonography and MRI remains unclear. When IRCI is identified, further imaging of the mesenteric vasculature is typically recommended to rule out occlusive processes in the SMA or IMA. When the clinical presentation, imaging and blood tests leave the diagnosis of CI unclear, colonoscopy is the best test for further assessment and should be performed within 48 h of symptom onset on a cleansed colon. Colonoscopy is the preferred diagnostic modality because it is widely available and provides a means to obtain biopsy specimens to confirm the diagnosis. This technique rarely can establish causation. Findings on colonoscopy can vary widely including hemorrhagic nodules, segmental colitis and linear ulcerations along the longitudinal axis of the bowel. CI can also mimic findings of IBD and be confused with colon cancer. Hemorrhagic nodules seen at colonoscopy represent bleeding into the subepithelial space and are sometimes referred to as thumbprinting (Image 1). Segmental distribution of these findings, with or without ulceration, is highly suggestive of CI, but the diagnosis cannot be made conclusively on the basis of a single examination unless mucosal gangrene is seen (Image 2). A colonoscopic finding called the colon single-stripe sign has been described in patients with CI, and refers to a single line of erythema with erosion or ulceration oriented along the longitudinal axis of the colon (Image 3). Segmental disease, rectal sparing, and rapid spontaneous evolution usually resulting in resolution of disease are characteristics of CI. Initial colonoscopy should be considered and performed within 48 h of presentation, because thumbprinting disappears within days as the subepithelial hemorrhages are resorbed and the overlying mucosa sloughs. Colonoscopy or CT imaging performed 1 week after the initial study should reflect evolution of the injury—either normalization of the colon or replacement of the thumbprints with a segmental colitis-type pattern. Universal colonic involvement favors true UC, whereas fistula formation and involvement of the terminal ileum suggests Crohn’s disease. Occasionally, an abundant inflammatory response can produce heaping up of mucosa and submucosa that resembles a neoplasm. Most CI results from a transient decrease in blood flow to the colon via the SMA or IMA. This process is rarely caused by embolic or thrombotic disease, and once patients become symptomatic, blood flow to the colon typically has returned to normal, that is, reperfusion. Therefore, mesenteric angiography usually is not indicated. An exception to this rule is when the clinical presentation

Image 1 Thumbprinting.

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Image 2 Gangrene.

Image 3 Single Stripe Sign:

does not allow a clear distinction between CI and acute mesenteric ischemia (AMI) or perhaps when only the ascending colon is involved (i.e., IRCI). In these situations, there is a greater risk for poor outcome and for occlusive disease (i.e., thrombosis, embolism) as an etiology. These patients warrant further assessment of their mesenteric vasculature with either re-review of the original CT-imaging, CT-angiography, MR-angiography or selective mesenteric angiography.

Disease Severity In the 2015 American College of Gastroenterology guideline for the diagnosis and management of CI, it was recommended that patients be classified as having mild, moderate or severe disease based upon risk factors associated with 30-day colectomy and/or mortality. Triaging disease severity was recommended to guide subsequent management. Mild disease is defined by typical symptoms of CI with a segmental colitis not isolated to the right colon and with none of the commonly associated risk factors for worse-outcome that are seen in moderate disease. Moderate disease includes patients with up to 3 risk factors associated with poor-outcome including male sex, abdominal pain without hematochezia, hypotension, tachycardia, WBC >15  10 (Yngvadottir et al., 2017)/L, Hgb < 12.0 g/dL, BUN >20 mg/dL, serum sodium 350 U/L or colonic mucosal ulceration identified colonoscopically. Severe disease is defined as >3 of the risk factors associated with moderate disease or patients with peritoneal signs on physical examination, gas in the bowel wall or portal venous gas on CT scan, gangrene on colonoscopy, and pancolonic or isolated right colonic segmental distribution on imaging or colonoscopy (Brandt et al., 2015).

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Treatment In patients with mild disease, treatment should be supportive. Parenteral fluids are administered and the bowel rested. Antimicrobials are not recommended since ischemic bowel injury is believed to be least severe in these patients and there is a low risk for bacteremia. If the patient does not rapidly improve with conservative measures, then a colonoscopy should be considered to assess the differential diagnosis, determine severity of findings and guide future management. When patients meet criteria for moderate disease, they should receive standard conservative therapy with the addition of broadspectrum antimicrobials to “cover” the fecal flora because in experimental models, antibiotics reduce the extent and severity of bowel damage. Antimicrobials should cover Gram-negative bacteria (e.g., fluoroquinolone, aminoglycoside or third-generation cephalosporin) and anaerobic bacteria (e.g., metronidazole or clindamycin). No randomized, controlled, blinded trials have been performed, however, to validate this threshold for antimicrobial usage (Brandt et al., 2015). A cardiac assessment should be performed to assess cardiac output, cardiac function and to exclude or confirm a source of embolism. Other important tests to obtain include an electrocardiogram, Holter monitoring and transthoracic echocardiogram. Poor cardiac output and arrhythmias should be treated, and medications that may cause mesenteric vasoconstriction withdrawn. If the colon appears distended, it should be decompressed with a rectal tube. The patient’s hemoglobin, white blood cell count, and electrolyte levels should monitored daily until the condition stabilizes and improves. If no clinical improvement is seen over the subsequent 24 or 48 h after presentation, serial imaging studies or endoscopic evaluations of the colon should be considered. Patients with severe disease require the same treatment as those with moderate disease but should be transferred to the ICU for enhanced monitoring. These patients should receive cardiac optimization, appropriate hydration, antimicrobials and expedited assessment. Surgical consultation is recommended in the event these patients require subsequent operative intervention. Increasing abdominal tenderness and guarding, rising temperature, and paralytic ileus indicate colonic infarction and mandate immediate laparotomy and colon resection, if appropriate. At operation, the extent of resection should be guided by the distribution of disease as seen on preoperative studies rather than the appearance of the serosal surface of the colon at the time of operation. Mucosal injury may be extensive, despite normal-looking serosa. The most common surgical procedures include total/subtotal colectomy, right hemi-colectomy and segmental colectomy (Brandt et al., 2015). When operative interventions are required, the clinical features most frequently associated with mortality include low output heart failure (e.g., cardiac ejection fraction 2.5 mmol/L and pre- and intra-operative catecholamine administration (Brandt et al., 2015). Understanding these risk factors will help the surgical team determine the patient’s risk for mortality. It is essential to remember that CI, for the most part, is a benign and self-limited disease. Most cases are not believed to seek medical attention. The literature for CI is based upon a subset of patients that sought medical attention, and, by definition, already have more severe disease. Nonetheless, in more than half of patients with CI who do seek medical attention, the disease is reversible, symptoms usually resolve within 48–72 h, and the colon heals in 1 to 2 weeks. With severe injury, it may take 1–6 months for the colon to heal, however, during this time the patient is usually asymptomatic.

Guidelines As annotated throughout this document, the American College of Gastroenterology guidelines are the most updated guideline for the diagnosis and treatment of colonic ischemia (Brandt et al., 2015).

See Also: Bleeding, Lower Gastrointestinal and Severe Hematochezia. Colitis, Non IBD. Colon and Rectum; Anatomy and Development. Intestinal Ischemia and Infarction. Mesenteric Vascular Disease. Vasculitis, Gastrointestinal Manifestations of

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Grootjans J, Lenaerts K, Buurman WA, Dejong CH, and Derikx JP (2016) Life and death at the mucosal-luminal interface: New perspectives on human intestinal ischemia-reperfusion. World Journal of Gastroenterology 22(9): 2760–2770. Hundscheid IH, Grootjans J, Lenaerts K, et al. (2015) The human Colon is more resistant to ischemia-reperfusion-induced tissue damage than the small intestine: An observational study. Annals of Surgery 262(2): 304–311. Jessurun J (2017) The differential diagnosis of acute colitis: Clues to a specific diagnosis. Surgical Pathology Clinics 10(4): 863–885. Longstreth GF and Yao JF (2010) Diseases and drugs that increase risk of acute large bowel ischemia. Clinical Gastroenterology and Hepatology : The Official Clinical Practice Journal of the American Gastroenterological Association 8(1): 49–54. Moghadamyeghaneh Z, Sgroi MD, Chen SL, Kabutey NK, Stamos MJ, and Fujitani RM (2016) Risk factors and outcomes of postoperative ischemic colitis in contemporary open and endovascular abdominal aortic aneurysm repair. Journal of Vascular Surgery 63(4): 866–872. Montoro MA, Brandt LJ, Santolaria S, et al. (2011) Clinical patterns and outcomes of ischaemic colitis: Results of the working Group for the Study of Ischaemic colitis in Spain (CIE study). Scandinavian Journal of Gastroenterology 46(2): 236–246. Silverman MAO, Feuerstadt P, Fenster M, Huisman T, Mansoor S, and Brandt LJ (2018) Do associations with Colon ischemia vary by age group? American Journal of Gastroenterology. Abstract 133 Annual Meeting of the American College of Gastroenterology 2018. Vodusek Z, Feuerstadt P, and Brandt LJ (2018) Review article: The pharmacological causes of colon ischaemia. Alimentary Pharmacology & Therapeutics. Walker A, Bohn R, Cali C, et al. (2004a) Risk factors for colon ischemia. The American Journal of Gastroenterology 99: 1333–1337. Walker AM, Bohn RL, Cali C, Cook SF, Ajene AN, and Sands BE (2004b) Risk factors for colon ischemia. The American Journal of Gastroenterology 99(7): 1333–1337. Yadav S, Dave M, Edakkanambeth Varayil J, Harmsen WS, Tremaine WJ, Zinsmeister AR, Sweetser SR, Melton LJ 3rd, Sandborn WJ, and Loftus EV, Jr (2015) A population-based study of incidence, risk factors, clinical spectrum, and outcomes of ischemic colitis. Clinical Gastroenterology and Hepatology 13(4): 731–738. Yngvadottir Y, Karlsdottir BR, Hreinsson JP, et al. (2017) The incidence and outcome of ischemic colitis in a population-based setting. Scandinavian Journal of Gastroenterology 52(6–7): 704–710.

Further Reading Brandt LJ, Feuerstadt P, Longstreth GF, Boley SJ, and American G (2015) College of ACG clinical guideline: Epidemiology, risk factors, patterns of presentation, diagnosis, and management of colon ischemia (CI). The American Journal of Gastroenterology 110(1): 18–44. quiz 45. Brandt LJ, Feuerstadt P, and Blaszka MC (2010) Anatomic patterns, patient characteristics, and clinical outcomes in ischemic colitis: A study of 313 cases supported by histology. The American Journal of Gastroenterology 105(10): 2245–2252. quiz 2253. Feuerstadt P, Aroniadis O, and Brandt LJ (2015) Features and outcomes of patients with ischemia isolated to the right side of the colon when accompanied or followed by acute mesenteric ischemia. Clinical Gastroenterology and Hepatology 13(11): 1962–1968. Meyenfeldt GLB, Buurman WA, and Dejong CH (2015) The human Colon is more resistant to ischemia-reperfusion-induced tissue damage than the small intestine: An observational study. Annals of Surgery 262(2): 304–311. Montoro MA, Brandt LJ, Santolaria S, Gomollon F, Sanchez Puertolas B, Vera J, Bujanda L, Cosme A, Cabriada JL, Duran M, Mata L, Santamaria A, Cena G, Blas JM, Ponce J, Ponce M, Rodrigo L, Ortiz J, Munoz C, Arozena G, Ginard D, Lopez-Serrano A, Castro M, Sans M, Campo R, Casalots A, Orive V, Loizate A, Tito L, Portabella E, Otazua P, Calvo M, Botella MT, Thomson C, Mundi JL, Quintero E, Nicolas D, Borda F, Martinez B, Gisbert JP, Chaparro M, Jimenez Bernado A, Gomez-Camacho F, Cerezo A, and Casal Nunez E (2011) Clinical patterns and outcomes of ischaemic colitis: Results of the working Group for the Study of Ischaemic colitis in Spain (CIE study). Scandinavian Journal of Gastroenterology 46(2): 236–246. Vodusek Z, Feuerstadt P, and Brandt LJ (2018) Review article: The pharmacological causes of colon ischaemia. Alimentary Pharmacology & Therapeutics. Walker A, Bohn R, Cali C, et al. (2004) Risk factors for colon ischemia. The American Journal of Gastroenterology 99: 1333–1337.

Colonic Manometry Phil G Dinning, Flinders Medical Centre, Bedford Park, SA, Australia; Flinders University, Bedford Park, SA, Australia Greg O’Grady, University of Auckland, Auckland, New Zealand © 2020 Elsevier Inc. All rights reserved.

Abbreviation

HAPC High amplitude propagating sequence

Manometric Catheters In the late 1860s, Legros and Onimus pioneered recording rhythmic contractions from the stomach and small bowel from a rabbit, dog, and guinea pig using a rubber balloons attached to a Kymograph (details in Davenport, 2011). This technique was adapted over the years with researchers combining several rubber balloons to enable recording from several different locations simultaneously. In the 1960s, investigators began to use water perfused techniques. These studies initially involved the intubation of flexible catheters incorporating 2–3 small diameter tubes. Each of these tubes, ending at a different location within the colon, would connect to a perfusion port and pressure transducer outside the body. Water was perfused at a low rate (100 recording sites at 1 cm intervals, while remaining flexible and having an outer diameter of 3 mm. As with solid state catheters there is an inherent fragility, and the fiber-optic elements cannot withstand tight bends or lengthwise compression. The fiber-optic catheters also have no central core and therefore nothing can be infused through them into the colon, and they cannot be placed over a guidewire. At the time of writing, they are only in use in Australia and New Zealand.

High Resolution Versus Low Resolution Catheters Most published colonic manometry studies employed devices with sensors spaced at >7 cm intervals. Recently, the effects of sensor spacing on recording reliability were assessed, and results showed that larger sensor spacing had a dramatically increased chance of missing or mislabeling propagating sequences (Fig. 1) (Dinning, 2018). At a spacing of >7 cm, only higher amplitude propagating contractions that extend along long lengths of the colon, could be reliably recorded. With closer sensors, the improved spatial resolution enables investigators to gain increasingly clearer interpretations of motor patterns. These design advances are yet to translate into improved clinical capabilities.

Colonic Manometry Protocols Standardized protocols for colonic manometry are lacking. Studies have been commenced as soon as the subject wakes after placement (if sedated), after several hours of recovery, or even the following day. The recording time is largely determined by study goals and can be as short as 90 min or extend >2 days (Scott, 2003). Studies have assessed a diverse array of endpoints including meal responses, morning waking, sleep, stress, anger, anxiety or various chemicals/pharmaceuticals. Some studies have attempted to characterize motor patterns in health, while others have attempted to assess abnormalities in patients with constipation, fecal incontinence, irritable bowel syndrome or inflammatory bowel disease. Other studies have assessed the temporal association between motor patterns and defecation, abdominal pain or luminal transit. In sections below, studies conducted between 1895 and 1975 are fully referenced in (Davenport, 2011). The finding from 1976 onwards are referenced by published reviews or individual papers.

Colonic Motor Patterns and Their Association With Luminal Transit Motor patterns detected by manometry play a critical role in the mixing, movement and excretion of colonic content. Despite well over 100 years of studies, there remains a paucity of data quantifying the link between colonic motor patterns and transit. In most instances, these two measures are recorded independently and linked by indirect association to define the physiological significance of motor patterns. All initial description of human colonic motor activity and movement of content were from direct observations. From the 1890s, data has been published detailing movements of the colon in animals or humans. In early 1900, Arthur Hertz, using X-ray images of a bismuth meal, observed transit of content from the small bowel into the caecum. The cecum would distend and eventually content would move toward the transverse colon, where its progress was halted by antiperistaltic (retrograde) waves. Around the same time, after viewing around 1000 X-ray images of the human colon, Holzknecht observed two episodes of colonic propulsion in which proximal haustral indentations disappeared as content moved rapidly onwards to the descending colon. The haustral indentations then reappeared. In the 1920s, Welch and Plant used a single fluid-filled balloon, placed into the sigmoid colon to demonstrate that the distal colon was rarely inactive, showing regular pressure waves at 2–3/min. Templeton and Lawson followed up these studies using up to six fluid-filled balloons spaced at 5 cm intervals. They could show examples of simultaneous activity across several adjacent balloons, motor activity that appeared to pass continuously from the proximal to distal colon, and at times differing activity between the proximal and distal colon. In 1941, Adler, Atkinson, and Ivy conducted experiments in the human descending colon, collating over 150 h of contractile activity from one or two fluid filled balloons passed through a colostomy. They observed contractions that appeared to move along the colon toward the anus, and these were associated with flow of colonic content from the stoma. They also reported apparent episodes of retrograde peristalsis from the descending colon toward the splenic flexure. In 1949, Kern, Abbott, and Almy utilized a transverse colostomy in humans to place a balloon into the caecum, another at the splenic flexure and a third at the sigmoid colon. Using a subcutaneous injection of mecholyl to induce diarrhea, they demonstrated

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A. Low Resolution Manometry (sensors spaced at 10cm)

Recto/ Sigmoid

Rectum

Transverse colon

1 min B. High Resolution Manometry (sensors spaced at 1cm)

1 min C. High Resolution Manometry (spatiotemporal color maps) mmHg 200 0

1 min Fig. 1 Colonic manometry recorded from the colon of a healthy adult with a fiber-optic manometry catheter. (A) Pressure data has been show from every 10th sensor to represent a traditional low-resolution manometry recordings. (B) The full data is displayed. With a high-resolution recording, many short propagating sequences are visible and these are entirely missed with traditional low-resolution recording. (C) Data from high-resolution recordings can also be displayed as spatiotemporal color maps which facilitates visual recognition of patterns.

that an increase in proximal colon motor patterns was associated with inhibition of sigmoid colon motor patterns, and postulated that this coordinated activity between the proximal and distal colon assisted with stool expulsion. Utilizing established colostomies, Hardcastle and Mann in 1968 recorded both spontaneous and bisacodyl induced colonic peristalsis via four fluid filled balloons. Importantly they provided X-ray evidence that showed these motor patterns were propulsive. The first prolonged, 24-h recording of spontaneous colonic motor patterns across multiple sites were published by Narducci et al. (1987). Using a water perfused catheter, colonoscopically positioned with the tip in the transverse colon, colonic pressures were recorded from four recording sites spaced at 12 cm intervals. This paper identified spontaneous “high-amplitude” propagating contractions and coined the term HAPC. The HAPC was described as the manometric equivalent of the “mass movement” and was also likely equivalent with the peristaltic events/waves described above.

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Over the next 30 years the HAPC became a primary focus of many manometric studies, and have been described under various nomenclature including high amplitude colonic contractions, giant migrating contractions, high amplitude propagating sequences, and high amplitude propagating pressure waves. There is also no standardized definition of “high amplitude.” In general research groups tend to use one or more of: amplitude, duration, and minimum propagation distance to define them. However, defined amplitudes range amongst studies from >50 to >136 mmHg, duration of pressure waves ranges from 10 to 30 s and propagation distance from >4 to >30 cm (see Table 4 in Scott, 2003). Despite the variations, in general studies share similarities in that most of these patterns originate in the proximal colon and terminate at the sigmoid colon (rarely propagating into rectum) (Bharucha, 2012). When studies have combined manometry with measures of transit, HAPCs have been shown to be propulsive (Scott, 2003). Along with the HAPCs, Narducci et al. (1987) described rhythmic bursts of pressure waves occurring at 3–8/min in the sigmoid, descending and transverse colon. Originally labeled as “sporadic nonpropagating contractions,” this pattern is observed in all manometric studies. When recorded in the rectum it has been described as a rectal motor complex or periodic rectal motor activity. Activity at 2–8/min had been temporally linked to movement of content (Scott, 2003). While mostly labeled as nonpropagating, more recent studies utilizing high-resolution manometry have shown that much of this 2–8/min activity consists of individual propagating pressure waves traveling relatively short distances (3–10 cm; Fig. 1). As most traditional manometric catheters contained recording sites at >7 cm intervals, these events were missed or misinterpreted. In more recent studies, these motor patterns with pressure waves between 2 and 8/min are termed “cyclic motor patterns.” At times, rhythmic pressure waves at 3/min are seen in individual sensors spaced at 4 cm, possibly indicating the contractions of individual haustra. However, while radiological studies have shown that haustra width can vary from 3 to 50 mm, as yet there is no direct evidence linking haustral folds to the 3/min activity (Dinning, 2018). Other characterized motor patterns include low-amplitude antegrade and retrograde propagating contractions, propagating sequences or propagating pressure waves. The definitions of these motor patterns differ amongst studies, however in all instances they fail to meet the definitions of HAPC (usually because of their low amplitude pressure waves). These motor patterns have also been shown to be propulsive over short distances. Manometric studies have also reported synchronous pressure events across multiple channels over long lengths of the colon. These motor patterns labeled as “pan-colonic pressurizations” or “simultaneous pressure waves” have been temporally associated with the expulsion of gas (Dinning, 2018).

Manometric Recording of the Colonic Response to a Meal in Healthy Adults In early transit studies, it was noted that a key stimulus for “mass movements” was the consumption of a meal, which was coined the “Gastro-colonic reflex” (Hertz and Newton, 1913). Combined suction electrodes and manometric ports in the rectum and sigmoid, recorded a significant increase in both spike and contractile activity within minutes of starting a 1000 kCal meal. This response could be blocked by pretreatment with the anticholinergic drug clidinium bromide, suggesting neurally mediation (see studies by Snape et al. 1978, 1979 in Scott, 2003). Using water perfused manometry, a 1000 kCal meal rapidly increased contractile activity in the transverse and descending colon and increased the number of HAPC and low amplitude propagating contractions (Scott, 2003). With the introduction of high-resolution manometry, the colonic meal response could be described in more detail. As with earlier studies, a meal was shown to induce a rapid increase in colonic contractile activity, but with the closely spaced sensors this was observed to consist of a predominantly retrograde cyclic motor pattern. This was observed throughout the colon but primary site of origin was the rectosigmoid, with the motor patterns propagating through the sigmoid colon and into in the descending colon (see Lin et al., 2017 in Dinning, 2018). The physiological importance of this activity remains undetermined but it has been postulated that it acts as a break preventing premature rectal filling (Scott, 2003; Dinning, 2018). Studies utilizing low resolution manometry and combined scintigraphy have shown that the postprandial increase in contractile activity was also associated with retro-propulsion of content from the descending to the transverse colon. Radiologic studies have also shown postprandial retropropulsion of colonic content (Scott, 2003). In our view, it appears therefore that there are two main motor phenomenon that occur in the colon in response to a meal; the HAPC and pan-colonic pressurizations move content toward the rectum, while the cyclic activity prevents content from reaching the rectum.

Manometric Recording of the Colonic Response to Sleep and Morning Waking in Healthy Adults Radiological observations in the early 1900s suggested colonic transit was more sluggish at night and manometric recordings with fluid filled balloons, solid-state and water perfused catheters have all shown colonic motor patterns became inhibited when subjects sleep, with a strong correlation between depth of sleep and the suppression of activity (Davenport, 2011; Furukawa et al., 1994; Scott, 2003). One notable exception may be the distal colonic cyclic motor activity. In a studies by Rao and Welcher, the periodic rectal motor activity was more prolific at night than during the day (see reference in Scott, 2003). This cyclic activity has also been shown to be active in the distal colon during periods of anesthesia (Vather et al., 2018). Such studies suggest that this cyclic activity, under normal conditions when subjects are awake, may be under a greater degree of suppression. Upon morning waking the colonic

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motor activity increases, including a significant increase in the number of HAPCs, possibly explaining why flatulence and a call to stool is commonly experienced by many people soon after waking (Scott, 2003).

Manometric Recording of the Colonic Motility During Defecation Radiologic observation in the early 1900s, noted that during defecation all content below the splenic flexure could be evacuated from the body and at the same time the contents of the ascending colon moved into the transverse colon. This suggested that during defecation, content throughout the entire colon could move toward rectum (Davenport, 2011). In later years studies using radioopaque markers or scintigraphy confirmed that up to 100% of colonic contents could be emptied during defecation (Lubowski et al., 1995). If defecation was withheld, the contents in the rectosigmoid could undergo retropropulsion back toward the transverse colon (Halls, 1965). Manometrically, it was noted that HAPC could precede an urge to defecate or precede actual defecation (Narducci et al., 1987). In a study of combined scintigraphy and manometry, Herbst et al. (1997) reported that defecation was associated with HAPCs, and that stool expulsion was associated with median 13% movement of content out of the proximal colon, while average 32% of content from the left colon and rectum was excreted. Water-perfused manometry, detailed the colonic motor patterns in the lead up to spontaneous defecation. Stool expulsion was always preceded by HAPC events, if more than one of these occurred during the immediate lead up to defecation, then the site of origin progressive moved to a more orad location, such the first may originate in the descending colon, the second in the transverse colon and the final event would originate in the proximal colon (see Bampton et al. in Scott, 2003).

Colonic Motor Patterns Associated With Functional Colonic Disorders A substantial literature regarding colonic motor patterns in adults and children with suspected colonic motility disorders has accrued over many years. Patients with constipation, irritable bowel syndrome or inflammatory bowel disease are the most studied populations. In this section, the colonic motor patterns in colonic disorders in physiological conditions or in response to physiological stimuli will be discussed.

Adult Populations Using fluid filled balloons position in the sigmoid colon a series of studies were performed in the 1940 evaluating sigmoid motility patterns in patients with “irritable colons” with either constipation or diarrhea. In those with constipation, continuous wave-like activity was recorded for prolonged periods. When tandem balloons were used, these motor patterns did not seem to be propagating and were therefore more likely to hold content in the sigmoid colon. Conversely, in patients with diarrhea, hypomotility was recorded in the sigmoid colon, potentially allowing content to move freely into the rectum, leading to diarrhea. These differing symptoms of bowel complaints were also associated with emotions; those with constipation commonly reported agitation and anger and those with diarrhea commonly reported hopelessness and depression. To demonstrate the relationship between emotion and sigmoid motility the emotional state of volunteer was manipulated. Angering subjects induced strong sigmoid contractile activity, while verbal accusation inducing depression inhibited motility (see Almy et al. references in Davenport, 2011). Relating sigmoid colon contractile activity to stool expulsion continued into the 1950s with researchers showing that in patients with ulcerative colitis the number stools per day was inversely associated with the amount of sigmoid activity; hypermotility resulted in the lowest number of stools, while hypomotility the largest number (see Kern et al. 1951 in Davenport, 2011). Patients with diarrhea-predominant irritable bowel syndrome can often report postprandial urgency and manometric studies have shown that meals can induce HAPCs without the corresponding increase in distal colonic motility, thereby potentially allowing content to move freely into the rectum (Chey et al., 2001). The most common group of patients studied with colonic manometry are those with constipation. In comparison to healthy adults, patients with constipation have generally shown a reduced number of HAPC and a reduced colonic meal response. In some the normal nocturnal suppression of motor patterns is absent, while other may have an absent or diminished increase of colonic activity upon morning waking (Scott, 2003). Colonic manometry in patients with fecal incontinence, inflammatory bowel disease (IBD) or diverticular disease has been performed in a smaller number of studies. In fecal incontinence, there has been a suggestion of colonic abnormalities, but the details are currently vague. In patients with ulcerative colitis who are in remission, normal motor patterns are described. When the inflammation is active an increase the number of low and high amplitude propagating contractions is reported. In diverticular disease, a significant increase in colonic contractile activity has been suggested in regions with diverticula compared to healthy controls. However, a recent systematic review reported that in 10 studies from 1962 to 2005, there was overall only weak evidence for abnormal pressure profiles in diverticular disease (Jaung et al., 2017). Colonic manometry has also been applied in patients after colorectal surgery. An increase in tone in the postoperative period after left-sided colonic resections has been reported suggesting a contracted or “spastic” state might be present. While during and immediately after a right hemicolectomy a “hyperactive” cyclic motor pattern in the sigmoid colon has been reported (Vather et al., 2018).

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Pediatric Population Colonic manometry has also been used for many years in children with colonic motility disorders. Nearly all studies have been performed in children with symptoms of severe constipation. Studies can range from a few hours to several days. Like studies in constipated adults, these children also generally display colonic motor abnormalities with a diminished or absent meal responses, a reduced count of HAPCs or altered characteristics of HAPCs (Dinning, 2018; Scott, 2003; Koppen et al., 2016). The diagnostic implications are discussed in Clinical Utility of Colonic Manometry section .

Colonic Response to Chemical, Mechanical or Electrical Stimuli Chemical, mechanical or electrical stimulation are commonly used during colonic manometry studies and full details can be found in these reviews (Davenport, 2011; Scott, 2003; Camilleri, 2012; Bharucha, 2012; Dinning, 2018; Thaha et al., 2015; Koppen et al., 2016).

Chemical Stimulation Subcutaneous injection of mecholyl has been shown to induce proximal colonic motor patterns and inhibit wave like activity in the sigmoid colon. Drugs such as banthine, acetylcholine and methacholine inhibit wave like activity in the sigmoid colon. The Anticholinergic, clidinium bromide, reduced the postprandial increase in the 3-min sigmoid activity in patients with irritable bowel syndrome and blocked the normal sigmoid response in healthy controls. The bile acid deoxycholic acid was shown to increase sigmoid motility in patients with IBS, while chenodeoxycholic acid increased proximal colonic propagating motor patterns in healthy adults but not in patients with constipation. Cholinergic stimulation with edrophonium chloride significantly increased nonpropagating (or segmental) activity throughout the colon in healthy adults but its effect was attenuated in patients with slow transit constipation. The removal of the normal nitregic inhibition of colonic motility with a low-dose infusion of the nitric oxide inhibitor N(G)-monomethyl-L-arginine (L-NMMA) has been shown to increase the number of proximal colonic propagating pressure waves. The acetylcholinesterase inhibitor prostigmine significantly increased the number of pan-colonic pressurizations. Most studies using chemical stimulation have examined their effects upon HAPC. The frequency of HAPC were increased by the adrenergic a2 antagonist yohimbine, oxyphenisation, and neostigmine. However, the most commonly used drug to induce HAPC is biasocodyl. As described above, this laxative can induce HAPC when infused into the colon or rectum of healthy controls and adult/ pediatric patients with constipation. Prucalopride, a 5-hydroxytryptamine 4 receptor agonist, that has been shown to increase stool frequency and to accelerate colonic transit, is associated with an increase in colonic motility and HAPC frequency in constipated patients.

Mechanical Stimulation A potential stimulus of HAPC or other colonic propagating motor patterns is mechanical stimulation. As mentioned in section Colonic Motor Patterns and Their Association With Luminal Transit, cecal filling and distension appear to be a stimulus for propulsion of content out of the cecum and ascending colon. Testing whether distention of the colon can initiate HAPC has provided mixed results. In patients with established colostomies, that distal colonic distension with a balloon increased motor activity, but did not induce HAPC. In contrast, in healthy adults balloon distension in different colonic regions (transverse, descending, and sigmoid) was shown to induce low-amplitude propagating pressure waves or HAPC. In pediatric studies, colonic distension in the transverse or descending colon of constipated children with normal colonic motility induced HAPC in 30%. Rectal balloon distention inhibited proximal colonic motor propagating pressure waves in healthy adults, but had no apparent effect in patients with obstructed defecation.

Electrical Stimulation Few studies have attempted to examine the effects of electrical stimulation upon colonic motor patterns. In children with slow transit constipation transabdominal electrical stimulation was reported to increase the frequency of colonic propagating sequences. In adults with constipation, suprasensory but not subsensory sacral nerve stimulation increased the number of colonic propagating pressure waves. The same stimulation in patients with fecal incontinence increased the number of retrograde propagating sequences in the sigmoid colon, suggesting a potential contributing mechanism of action by enhancing the “rectosigmoid brake” effect.

Clinical Utility of Colonic Manometry Current perceptions of the clinical utility of colonic manometry differs between pediatric and adult populations.

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Pediatrics In pediatrics, colonic manometry is well established and widely used test in some United States and European Centers. The procedure is included as part of pediatric gastroenterology training and guidelines have been established by specialty societies. The typical procedure in children usually involves a basal period (up to 2 h) followed by a meal, a 1–2 h postprandial recording, then colonic infusion of bisacodyl. Traces are examined for spontaneous propagating motor patterns including HAPC, an increase in motility after a meal, and then evidence of HAPC induced by bisacodyl. Such tests may inform treatment decisions. For example, colonic manometry can help to distinguish if childhood constipation is behavioral or due to a neuromuscular disorder. Other potential indicators for colonic manometry include: (1) evaluating colonic function in symptomatic patients after surgery for Hirschsprung’s; (2) determining if colonic motor patterns are present in intestinal pseudo-obstruction; and if intestinal transplantation is considered whether the colon be kept; (3) determining colonic functionality prior to ileostomy closure; (4) determining whether antegrade enemas are of clinical benefit before a cecostomy or appendicostomy is fashioned. One study also correlated colonic motor abnormalities with histological evidence of a neuropathy (Koppen et al., 2016; Rodriguez et al., 2017).

Adults In adults, colonic manometry is not yet an established clinical utility (Camilleri et al., 2008). One study used low-resolution colonic manometry (six sensors spaced at 5–20 cm) in an attempted to subtype 80 patients with slow transit constipation. Using the number of HAPC, meal and waking responses as outcome measures, they classified patients has have a myopathy, neuropathy or normal motility. Just under half of the patients (41%) were identified with normal motility. Surgery was offered to those with a “neuropathy,” with others offered conservative therapy, with some reasonable results at a 1-year follow-up.

Current Limitations and Future Directions While colonic manometry has undoubtedly provided an ever-greater understanding of colonic physiology and pathophysiology, there a remain several significant limitations. The procedure is not standardized. Catheter types, number of sensors and their resolution, protocols, analysis techniques and terminology all differ amongst institutions, making data comparisons problematic (Scott, 2003; Dinning, 2018). This is particularly relevant when the potential differences in finding between low and modern highresolution approaches are considered. It is also apparent that most of the reported data has come from studies with very low sample sizes. Control data is sparse and does not exist in pediatrics due to ethical constraints, clouding interpretations of normal versus abnormal outcomes. While colonic manometry records contractile activity, a missing link is knowing what is happening to wall motion and flow of contents. It is highly likely that longitudinal muscle shortening, nonlumen-occluding circular muscle contractions, or alterations in regional wall tone may be (partially) missed by manometry. This may be particularly relevant when it comes to the relationships between pressure and flow. There remains no technique that is capable of recording flow and wall motion/intraluminal pressure throughout the colon, in real time over prolonged periods. A notable emerging trend is the increasing focus on high-resolution studies in both pediatric and adult population (Dinning, 2018). Due to widely spaced sensors it is now clear that many past interpretations of colonic motility may have been limited, and further applications of emerging high-resolution techniques in future may better clarify the clinical utility of colonic manometry in diverse disease states.

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Koppen IJ, Di Lorenzo C, Saps M, Dinning PG, Yacob D, Levitt MA, and Benninga MA (2016) Childhood constipation: Finally something is moving!. Expert Review of Gastroenterology & Hepatology 10: 141–155. Lubowski DZ, Meagher AP, Smart RC, and Butler SP (1995) Scintigraphic assessment of colonic function during defaecation. International Journal of Colorectal Disease 10: 91–93. Narducci F, Bassotti G, Gaburri M, and Morelli A (1987) Twenty four hour manometric recording of colonic motor activity in healthy man. Gut 28: 17–25. Rodriguez L, Sood M, Di Lorenzo C, and Saps M (2017) An ANMS-NASPGHAN consensus document on anorectal and colonic manometry in children. Neurogastroenterology and Motility 29: e12944. Scott SM (2003) Manometric techniques for the evaluation of colonic motor activity: Current status. Neurogastroenterology and Motility 15: 483–513. Thaha MA, Abukar AA, Thin NN, Ramsanahie A, and Knowles CH (2015) Sacral nerve stimulation for faecal incontinence and constipation in adults. Cochrane Database of Systematic Reviews (8): CD004464. Vather R, O’Grady G, Lin A, Du P, Wells CI, Rowbotham D, Arkwright JW, Cheng LK, Dinning PG, and Bissett IP (2018) Hyperactive cyclic motor activity in the distal colon after colonic surgery as defined by high-resolution colonic manometry. The British Journal of Surgery 105(7): 907–917.

Colonic Motility☆ David Gunn and Maura Corsetti, NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, United Kingdom; Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, United Kingdom © 2020 Elsevier Inc. All rights reserved.

Requirements of Colonic Motility Function The large intestine in humans functions to absorb water and electrolytes from the semifluid contents entering from the small intestine via the ileocaecal valve. Using bacteria to aid catabolism of larger carbohydrates by fermentation, uptake of nutrients too large for uptake in the small intestine are absorbed. It then stores the remaining waste prior to evacuation through the anal sphincter. Despite a wide variety of diets, the human colon adapts to regulate both the consistency and the frequency of bowel movements. It manages this by varying the rates of secretion and absorption, speed of propulsion of luminal contents through the bowel (colonic transit time) and the intensity of bowel wall contractions to expose luminal contents to the mucosal wall. This is controlled by complex interactions between the luminal wall mechano- and chemoreceptors, pacemaker cells in the enteric plexus and enteric neurons to cause slow progression of contents through the colon. This slow controlled propulsion through the colon is considerably slower than the small intestine despite a significantly shorter distance (1.5 m vs 7m). Alterations in colonic motor function have been implicated in several motility and organic bowel disorders, yet it is one of the least well understood organs in the body. Studying colonic motility to guide clinical management is still in its infancy, however it is the gold standard investigation for colonic motor dysfunction in treatment-refractory constipation in children and adults prior to referral for surgical intervention. There is broad consensus that despite the differences in colonic anatomy and diet consumed, the cellular mechanisms remain constant across the mammalian species, including humans. Paired with relative inaccessibility investigating the human colon in vivo, animal models have been widely used to further our understanding of colonic motility and the effect of drugs on bowel disorders.

Colonic Motor Patterns as Demonstrated in Animal Studies The human colon is more complex than that of other omnivores (such as mice, rats and dogs). The caecum is relatively small and has three taeniae extending from the proximal colon to the sigmoid, where it fuses to form a single longitudinal layer in the rectum. Rats and mice do not have separate taeniae. Surprisingly, herbivores guinea pigs and rabbits have a triple taeniated proximal colon like humans, thus their motor patterns are the most studied animal models as they are most likely to translate to human function. Since the end of the 19th century it has been hypothesized that rhythmic motor patterns of the bowel are driven by local neural activity. Subsequent research identified electrical signals in smooth muscle throughout the gastrointestinal tract controlled by pacemaker cells, identified as Interstitial Cells of Cajal (ICC). In the colon, the network of ICC located near the submucosal border (ICC-SMP) generates electrical oscillations in the circular smooth muscle called slow waves. The frequency is inversely related to species size, such that in humans it is 2–5 cycles per minute but 15–18 in the mouse colon. Slow waves propagate into the circular small muscle and generate rhythmic contractions when the action potential is reached. This motor pattern is referred to as “ripples,” defined in the guinea pig colon as orally and aborally propagating shallow circumferential contractions of the circular muscle which are not affected by tetrodotoxin administration. Ripples have subsequently been described in the rabbit colon. It is thought in the herbivore colon, ripples may be involved in the mixing of luminal contents and perhaps of halting progression of intraluminal fluid, and has no role in mass colonic movements. The network of ICC between the circular and longitudinal muscles have been variously described in the literature as ICC-MP (myenteric plexus), ICC-MY (myenteric) and ICC-AP (Auerbach plexus). This is probably responsible for a high frequency of electrical oscillations generating rhythmic contractions referred to as “high frequency ripples.” These fast propagating contractions have been described in rat and rabbit studies and remain despite the administration of tetrodotoxin. These synchronous longitudinal and circular smooth muscle contractions, occur over larger distances and at a higher frequency than the slow waves in the same species, and traverse ripples without annihilating them. This suggests a different pacing network to one driving the ripples.

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Change History: June 2019. D Gunn and M Corsetti updated ‘requirements of colonic motility function,’ ‘colonic motor patterns as demonstrated in animal studies,’ ‘colonic motor patterns in humans,’ ‘regulation of colonic contractions,’ and ‘colonic motility dysfunction in inflammation and irritable bowel syndrome.’ Figs. 1–2 have been updated.

This is an update of Sushil K. Sarna, Colonic Motility, In Encyclopedia of Gastroenterology, edited by Leonard R. Johnson, Elsevier, New York, 2004, Pages 425–433.

Encyclopedia of Gastroenterology, 2nd Edition

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The role of the high frequency ripples are unclear, as alone they are unlikely to be effective at either propulsion or mixing. However when slow wave ripples occur simultaneously with clusters of fast ripples, intraluminal pressure generated significantly increases. A slower myogenic motor pattern has been described in some species, called “slow phasic contractions.” Cyclic smooth muscle depolarisations and contractions have been measured in both the longitudinal and circular muscle of tissue without ICC-SMP, leading to conclusions the myogenic activity originates from within the ICC-MP. This has been described in the rat and rabbit colon, and similar myogenic contractions are described at the colonic flexure of guinea pigs. A distinct neurally-driven motor pattern has been described in the colon of several experimental animals. This consists of neurally-dependent spontaneous repetitive motor activity, with circular muscle contractions that slowly travel preferentially in an anal direction, called “colonic motor complexes.” These occur intermittently in the absence of content, and increase in frequency when distension is applied. In previous studies distension was typically applied to a short region of the isolated colon. A recent study has revealed new findings about cyclic motor complexes generated by maintained distension, applied to long segments of isolated colon to mimic multiple fecal pellets or pathological impaction. Using several methods to interrupt the distention-induced motor patterns, it has been demonstrated that this motor complex in the guinea pig colon requires the integrity of ascending and descending excitatory interneuronal enteric pathways. There is a critical length of colon (about 2–3 cm) required to express the colonic motor complex. The degree of mechanical distension influences the frequency of the complex and, once initiated, each colonic motor complex occurred nearly simultaneously along a considerable length of colon. Animal studies have repeatedly demonstrated in both in vivo and ex vivo models that local distension of the colon initiates a neurally mediated aboral propulsive movement. Peristaltic waves were first evoked in dog colons in response to a solid bolus while under deep anesthesia. This has since been shown in the mouse, guinea pig and the rabbit. Similar propagating contractions are seen on distension of the isolated proximal colon with liquid boluses, triggering propulsion of colonic contents aborally. It is felt the propulsive movements in response to a bolus are generated by enteric neural circuits and are thus regarded as neurogenic and are called neural peristalsis. It was observed in guinea pigs that peristaltic waves propagated at different speeds depending on the luminal contents viscosity, implying a complex sensory mechanism adapting to the intraluminal physiology rather than a simple reflex. This forms the neuromechanical loop hypothesis, a progression from the initial Bayliss and Starling proposal that “luminal propulsion is mediated by polarized reflexes of distension causing oral contraction and aboral relaxation.” The consistency of luminal contents affects how it is redistributed by contraction and relaxation of the circular smooth muscle, and in turn affects the pattern of distension, which will modify the subsequent motor complexes. This forms a dynamic functional loop of enteric neural pathways and mechanical stimulation to optimize colonic motility to a wide variety of contents. There are a few reports of “retrograde peristaltic movements” in animal models. Described as “antiperistalsis” by Bayliss and Starling in the large intestine of dogs and also shown in the rabbit colon to be neutrally mediated. This potentially important regulating motor pattern is relatively understudied and needs further assessment to be better understood.

Colonic Motor Patterns in Humans Studies in human colonic motility first used abdominal x-rays to visualize colonic wall contractions passing bismuth meals along the colon. Large propulsive waves were captured, giving rise to the conclusion that large movements occurred three to four times per day but that the colon remained dormant for the majority of the day. Manometry was introduced in the 1980s to give a greater understanding of these muscular movements, both in humans and animal models. Sited via colonoscopy the fluid perfused multilumen catheters were connected to external pressure transducers and dynograph recorders to record occlusion pressures up to 130 mmHg. Due to methodological constraints manometers would have 5–16 recording sites between 7 and 20 cm apart along the bowel. The sensors could try to either capture movements of the whole bowel with sensors 10 cm apart, or focus on a short segment by reducing the spacings. Both techniques were imperfect, as regional differences in colonic motor function have been described; therefore, focused recordings were unable to be extrapolated to the whole bowel. On the other hand, in whole bowel studies to measure a propagating sequence, traversing across three sensors, meant the motor pattern needed to travel at least 20 cm and any activity between recording sites was assumed, providing potentially erroneous information. Low-resolution manometry described very infrequent high amplitude propagating contractions which were seen on waking and after eating, propelling colonic contents large distances along the colon. The other main motor pattern was described as “nonpropagating motor patterns,” defined by increased intraluminal pressure > 5 mmHg above baseline with a duration >15 s, and bearing no temporal or morphological relationship to adjacent sensors. The high resolution manometer (HRM) was developed in 2009. Using fiber optic sensors instead of perfusion catheters the manometer is vastly more capable than previous manometers as it is able to sense 72–120 locations at intervals up to 1 cm apart. This provides a more comprehensive view of the colonic motor patterns and in turn has given greater understanding to the colon. HRM showed that as sensor spacing increased, the chances of both missing and mislabeling motor patterns greatly increased. Despite our ability to more closely record the motor patterns of the colon, we still lack definite manometric parameters for normal or abnormal colonic function, and so its diagnostic use is still in its infancy. Debate remains about the significance of the use of bowel cleansing prior to siting of the manometer. It is obviously safer to have a clean bowel during colonoscopy to avoid serious complications such as perforation, however the colon being investigated has been artificially cleaned and is no longer in

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a physiological state. Some studies show no difference between prepared and the unprepared bowel, with other studies noting an increased frequency of migrating colonic events in the prepped bowel. Others have tried to mitigate this by extending the study duration to 24 h.

High Amplitude Propagating Sequences (HAPS) HAPS are the largest and most powerful propagating motor pattern in the colon, and as such were the first motor pattern to be described by Holzknechtg in 1909. They are described as an infrequent occurrence, occurring 4–23 times per 24 h. These powerful propagating events are associated with mass movements of colonic content and with defecation. Various definitions occur throughout the literature as pressure waves with amplitudes between >50 and >136 mmHg, durations between 10 and 30 s and that extend at least 10–30 cm along the colon. Frequency varies through the day, being almost absent while asleep but increasing upon waking and after eating; and are associated with spontaneous defecation. They are considered the correlate of colonic motor complexes recorded in animal studies and discussed above (Fig. 1).

Simultaneous Pressure Waves These had previously been described in low resolution manometry studies but were thought to be artifacts due to abdominal wall contraction. Further analysis using HRM in the colon and anal sphincter have shown pressure increases occurring simultaneously at all colonic sensors with a concomitant relaxation of the anal sphincter, and no simultaneous abdominal wall EMG activity. Conversely movement, coughing or straining recorded increased pressure in the colonic sensors, increased pressure at the level of the anal sphincter, and increased abdominal wall EMG activity. In studies in healthy humans these colonic pressurisations were the most commonly recorded contractions and were associated with either the desire to expel gas or gas expulsion. These events have been interpreted as possibly being generated by maintained distension of the colon by the remaining insufflated air after colonoscopy, and therefore probably representing the correlate of the repetitive activity observed in the mouse and guinea pig colon during maintained distension and called colonic motor complexes (Fig. 2).

Cyclic Propagating Motor Pattern This is the most common propagating motor pattern recorded in the healthy colon with HRM. Each contraction comprises a sequence of repetitive propagating increased pressure events occurring at a frequency of 2–6 cycles per minute. They predominantly propagate in a retrograde direction and are most commonly (76%) identified in the rectosigmoid colon. Activity at similar frequencies in the rectosigmoid were described from low resolution manometry, using the terms segmental contractions and periodic rectal motor activity. They do not appear to be lumen occlusive, leading to theories that their main role is mixing luminal contents and exposing them to the gut wall to assist in absorption. The number and amplitude of cyclic motor patterns increases immediately after a meal. It was initially proposed by Rao and Welcher that the retrograde cyclic motor patterns act as a “rectosigmoid brake” to limit rectal filling, however the mechanism for this remains unclear. Repetitive events of motor activity of

Right colon

Transverse colon mm Hg 100

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Anal sphincter Fig. 1 High amplitude propagating sequences recorded by high resolution manometry. The sensors are sited at 2.5 cm intervals.

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Transverse colon mm Hg 100

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Fig. 2 Simultaneous pressure waves recorded by high resolution manometry. The sensors are sited at 2.5 cm intervals. Note that the simultaneous pressure increases are associated with relaxation of the anal sphincter and are occurring at a frequency of 1 per minute.

similar frequencies have been observed in animal studies generated by ripples from the ICC-MP. It is believed these correlate with cyclic propagating motor patterns in humans.

Low Amplitude Single Propagating Motor Patterns Described in low resolution manometric studies (with recording sites >7 cm apart) as elevations in intraluminal pressure less than 50 mmHg in amplitude, that propagate at least three recording sites. Approximately 61 occur per day per person, and more commonly progress distally. High resolution manometry studies have been able to describe three subtypes: Short single motor pattern—this propagating motor pattern occurs in isolation, with intervals greater than 1 min between motor patterns. It can move either orally or aborally, propagating approximately 7 cm at a velocity of 0.5 cm/s. They originate in the proximal (42%) or sigmoid (43%) colon and make up almost a quarter of all propagating motor patterns. Long single motor pattern—this propagating event travels over distances significantly longer than short single motor patterns (40.8  8.4 cm), often reaching the descending or sigmoid colon. They too are separated from other events by intervals of at least 1 min. Most originate in the proximal colon (76%) with the rest originating in the proximal descending colon. They have been shown to be increased by polyethylene glycol and linaclotide. These events are probably the correlate of long distance contractions or neural peristalsis observed in animal studies. Retrograde slowly propagating motor pattern—this motor pattern is very rare, making up 0.3% of all propagating motor patterns and was observed during fasting. The motor patterns traveled less than 0.5 cm/s over distances more than 40 cm. They started in the sigmoid colon and traveled in a retrograde direction to the transverse colon.

Haustral Activity The anatomical and functional nature of haustra are still a topic for debate. It has been argued that they represent fixed anatomical features, or that they represent transient contractions of the interteniae circular muscle, resulting in the typical triangular narrowing as observed in the transverse colon in colonoscopies. As they are seen to disappear during large mass movements it is likely the haustra are a result of functional contractions. An HRM study described rhythmic pressure patterns of isolated pressure events at sensors 3-4 cm apart, with very little activity recorded at intervening sensors for long durations. Without direct visualization, it can only be speculated that these areas of inactivity correspond to haustrations. The paper also described, when colonic pressurisations occurred, they recorded increased pressure every 3–4 cm. They suggested when a pressure wave moved across the sensors the lumen was narrower due to haustrations and thus recorded a higher pressure. Recent MRI tagging has shown decreased axial flow adjacent to the colon walls relative to the center of the lumen, likely due to the haustra. The authors postulate this is a mechanism to reduce mixing of oxygenated ileal contents with the anaerobic microbiota in the colon. Anaerobic bacteria thus escape poisoning by oxygen, and the mix of aerobic and anaerobic bacteria in the colon, essential for health, is preserved. Rhythmic intraluminal pressure changes recorded were surprisingly consistent with a frequency of 3 cycles per minute, which likely represent the myogenic contractions referred to as “ripples” in animal studies. This pressure activity was seen to occupy no more than 5 adjacent sensors, and thus may have been occurring within a single haustrum. The pattern of intrahaustral activity sometimes propagated in either an anterograde or retrograde direction at 2  1 cm/s, consistent with the slow wave based ripple propagation mechanism.

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What Have We Learnt About Colonic Motility and Its Possible Function Over Recent Years? The literature of the last 15 years have dramatically changed our knowledge on the colonic motility. Both in animal and human in vivo studies there have been impressive advances in the understanding of colonic motor patterns. We now know that the colon, at least in animals, is able to adapt its motor response to the physical characteristics of the intraluminal content. Therefore, it generates strong and slow contractions when the content is more solid, and less strong but faster contractions when the content is more liquid. Moreover we are starting to appreciate that the maintained distension of the colon, a condition that is likely to happen in vivo in humans in presence of feces and/or gas could trigger repetitive contractions. We still have to understand the meaning and function of these repetitive activities called colonic motor complexes in animals and whether this has correlation with humans. We now appreciate that the improved technology to study colonic motility in humans in vivo, via HRM, is revealing colonic motor patterns which were not so clearly identified in the past (cyclic retrograde activity) or considered artifacts (simultaneous activity). Unfortunately these studies are still difficult to compare as we are still missing a standardization of the protocol to study the colonic motility both in animals and humans. However the process is in progress and more exciting news is expected in the near future.

Regulation of Colonic Contractions The colonic contractions, described above, are coordinated both spatially and temporally at several levels. These are described below. 1. Mucosal mechano- and chemoreceptors sense distension and characteristics of the luminal contents. 2. Mucosal cells send signals either directly through intrinsic primary afferent neurons or via interneurons to the myenteric plexus. 3. The neurons release their respective neurotransmitters, bind to membrane receptors and start signaling pathways. Myenteric plexus neurons can initiate depolarization of smooth muscle irrespective of mucosal sensory neurons, such as when the lumen is empty, and extrinsic nervous input via the vagal nerve also modulates activity, such as in response to stress. 4. Circular and longitudinal colonic smooth muscles become depolarized and contract. 5. Oral and aboral reflexes relate conditions of lumen and modulate motility function.

Sensory Regulation The intrinsic primary afferent neurons (IPANs) have their nerve endings in the mucosa close to enterochromaffin (EC) cells containing serotonin. Mucosal stimulation releases 5-hydroxytryptamine (5-HT) from these cells, which acts on 5-HT type 4/5HT type 1p receptors on IPANs to send a signal to the enteric ganglia either directly or via interneurons. The neurotransmitter for IPANs is acetylcholine (ACh), acting on nicotinic receptors, and calcitonin gene-related peptide (CGRP), acting on CGRP receptors. In the small bowel, at least, CGRP administered close intra-arterially stimulates both cyclic motor patterns and HAPS. The 5-HT released from EC cells may also act on 5-HT type 3 receptors of first-order extrinsic sensory neurons to send signals to higher centers. It has been hypothesized that this route may transmit nociceptive signals, but a complete understanding of this afferent sensory limb is lacking.

Motor Neurons The enteric ganglia in the myenteric plexus project excitatory and inhibitory motor neurons to smooth muscle cells. ACh is the established physiological neurotransmitter of excitatory motor neurons to stimulate contractions and colonic tone. They contract in response to the release of ACh, subject to the concurrent occurrence of a slow-wave depolarization. The inhibitory neurotransmitters nitric oxide (NO) and purines (such as b-NAD and ADP-R) are released together as co-transmitters. However release of different neurotransmitters has been shown to be dependent on the frequency of nerve stimulation. High frequencies cause predominantly NO release, mediating prolonged smooth muscle relaxation such as for storage. Lower firing frequencies of inhibitory neurons stimulates principally purine releases, leading to transient relaxation such as during motor complexes. Tachykinins, particularly Substance P, are also putative neurotransmitters of excitatory motor neurons and are co-localized with ACh in the myenteric neurons.

Interneurons As noted above, the enteric motor neurons and smooth muscle cells are the primary regulators of gut contractions at any given location, in response to sensory input from the same location. However, the viscosity of luminal contents affects how it is redistributed by contraction and relaxation of the circular smooth muscle, and in turn affects the pattern of distension. This information from adjacent regions orally and aborally is relayed via interneurons, which will then modify subsequent motor complexes. In the context of overall gut function, regulatory mechanisms need integrated information from further proximal and distal locations to fine-tune the mixing and propulsion rates in the segment under their direct control. This information, transmitted via

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interneurons, may come from segments within the same organ, such as occurs in an “ileal brake,” or it may come from adjacent organs, such as duodeno-gastric and colo-ileal reflexes to regulate the rate of emptying of the proximal organ into the next gut organ. The information from the distal locations is used to sense the state of digestion and the readiness of the distal segments to receive more digesta. The information from the proximal segments is used to prepare the distal segments for the arrival of new digesta. A majority of interneurons in the human colon are immunoreactive for choline acetyltransferase (ChAT) and nitric oxide synthase (NOS). Specifically, approximately 90% of the oral-projecting neurons in the human colon contain ChAT, whereas no ascending neurons contain NOS. On the contrary, approximately 46% of the aboral-projecting neurons contain NOS immunoreactivity alone, 29% contain both ChAT and NOS immunoreactivities, and approximately 20% contain ChAT activity alone. In agreement with the oral or aboral projections of ChAT-containing neurons, both the oral and aboral reflexes are blocked by nicotinic receptor blockade with hexamethonium. The average length of orally and aborally projecting neurons is approximately 10 mm. This suggests that a chain of interneurons, where each neuron innervates the lateral excitatory or inhibitory motor neurons in the ganglia, as well as oral- or aboral-projecting interneurons in the same ganglia conveys the information along the entire length of the colon. The human colonic interneurons also display immunoreactivity for other neurotransmitters, including tachykinins, VIP, calretinin, and 5-HT. 5-HT from mucosal EC cells activates IPANs that trigger descending inhibition necessary for propagating sequence transmission. It is thought 5-HT interneurons also synapse with ascending interneurons and excitatory motor neurons.

Electrophysiological Regulation Periodic depolarization of smooth muscle cells, called slow waves, is important in the regulation of gut contractions. The slow waves regulate the maximum frequency of cyclic motor patterns, their timing of occurrence, and the direction and distance of their propagation. A phasic contraction can occur only once during cell depolarization. Therefore, the maximum frequency of contractions at a given location cannot exceed the frequency of slow waves. The slow waves are omnipresent but contractions occur only under the conditions of concurrent depolarization and excitatory neurotransmitter release from motor neurons. The frequency of slow waves in the intact human colon is highly irregular and varies from approximately 2–13 cycles/min. Since a local contraction occurs only once during a slow wave depolarization, it will propagate distally only if the slow waves are phase-locked in that direction. In the colon, the slow waves exhibit very poor coupling, which is the reason that the phasic contractions do not propagate or propagate only over very short distances. This is the underlying cause of slow distal propulsion of colonic contents, as noted above. It is important to note that not every slow wave depolarization causes a colonic smooth muscle contraction. This is in contrast to other organs in the body regulating spontaneous contractions, such as cardiac smooth muscle that contracts with each membrane depolarization. On the other hand, not every excitatory neuronal input will cause colonic smooth muscle contraction, unlike skeletal muscle which is under neuronal control alone. Also, the colonic smooth muscle cells are not like the vascular smooth muscle cells, which generate predominantly a tone to regulate blood flow. The colonic muscle generates both phasic contractions and tone, to regulate motility function. As discussed above, the gut of most species exhibits three types of pacemaker cells called interstitial cells of Cajal (ICC): the ICCMP, ICC-SP and ICC-IM. It is thought the ICC-MP generate high frequency contractions of low amplitude at 15–20 contractions per minute (cpm). The ICC-SP generate intermediate frequency contractions of about 2–4 cpm, likely due to electrical slow waves. Low frequency high amplitude contractions occurring less than every minute occur in isolated colonic smooth muscle strips devoid of ICC-SP, thought to be a response to stretch. These are considered to correlate with high frequency ripples, ripples and slow phasic contractions recorded in animal studies. Relative to rodents the presence and distribution of ICC in the human colon differ substantially. The highest density of ICC in the human colon has been reported to be in the myenteric plexus. The ICC (SM) at the inner layer of the circular muscle are sparse and may not form a continuous network as has been reported in rodents. The density of ICC (IM) is several-fold less than that of ICC (SM) or ICC (MP) in the entire human colon. The differences in the distributions of ICC between humans and rodents leave open the question whether there are differences in their roles in the two species. Several studies have reported a decrease in the density of ICC or damage to their processes in colonic motility disorders, such as constipation, but their exact role in the pathogenesis of these disorder is still unclear.

Colonic Motility Dysfunction in Inflammation and Irritable Bowel Syndrome Colonic Inflammation Colonic inflammation, both acute and chronic, has been associated with altered colonic motility. However the causes of this alteration are incompletely understood. In ulcerative colitis (UC), chronic inflammation of the colon causes symptoms of diarrhea, rectal bleeding, passage of mucus and abdominal pain. Abnormal motility is thought to contribute, at least in part, to the genesis of symptoms. Short duration manometric studies (up to 3 h) revealed decreased colonic contractility in UC, which correlated with diarrheal symptoms. Later use of combined scintigraphy and manometry confirmed reduced contractility is present in the more proximal UC colon, while anterograde propagating contractions were more frequent. 24 hour studies have demonstrated an increasing frequency of high and

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low amplitude propagating contractions in patients with moderately active UC compared to healthy volunteers, which coupled with decreased segmental contractions observed in other studies reducing impedance of colonic transit, are likely to explain the exacerbated symptoms in these patients.

Irritable Bowel Syndrome Irritable Bowel Syndrome (IBS) is characterized by recurrent abdominal pain with an associated change in stool frequency or form. Patients can be subtyped into constipation and diarrhea predominant, as well as fluctuating between the two. Mental stressors are a recognized trigger to worsening symptoms, suggesting central nervous system inputs contribute to the clinical presentation. About 25% of patients with constipation predominant IBS (IBS-C) have slow colonic transit, whereas diarrhea-predominant IBS (IBS-D) is associated with accelerated colonic transit in up to 45% of patients. 24-h low resolution manometry was unable to find significant differences between frequency of high and low amplitude contractions between healthy volunteers and patients. Unlike the inflammatory bowel, tone is normal in IBS; however visceral hypersensitivity has been demonstrated which may contribute to the symptoms of IBS-D patients.

Further Reading Bampton PA and Dinning PG (2013) High resolution colonic manometry–what have we learnt?—A review of the literature 2012. Current Gastroenterology Reports. https://doi.org/ 10.1007/s11894-013-0328-2. Bassotti G, Antonelli E, Villanacci V, Baldoni M, and Dore MP (2014) Colonic motility in ulcerative colitis. United European Gastroenterology Journal 2(6): 457–462. https://doi.org/ 10.1177/2050640614548096. Bayliss WM and Starling EH (1900) The movements and the innervation of the large intestine. The Journal of Physiology 26(1–2): 107–118. https://doi.org/10.1113/jphysiol.1900. sp000825. Chen J-H, Yu Y, Yang Z, et al. (2017) Intraluminal pressure patterns in the human colon assessed by high-resolution manometry. Scientific Reports 7: 41436. https://doi.org/10.1038/ srep41436. Corsetti M, Pagliaro G, Demedts I, et al. (2016) Pan-colonic pressurizations associated with relaxation of the anal sphincter in health and disease: A new colonic motor pattern identified using high-resolution manometry. The American Journal of Gastroenterology 0: 1–11. https://doi.org/10.1038/ajg.2016.341. Costa M, Wiklendt L, Keightley L, Brookes SJH, Dinning PG, and Spencer NJ (2017) New insights into neurogenic cyclic motor activity in the isolated Guinea-pig colon. Neurogastroenterology and Motility 29(10): 1–13. https://doi.org/10.1111/nmo.13092. Dinning PG, Wiklendt L, Omari T, Arkwright JW, Spencer NJ, Brookes SJH, and Costa M (2014) Neural mechanisms of peristalsis in the isolated rabbit distal colon: A neuromechanical loop hypothesis. Frontiers in Neuroscience. https://doi.org/10.3389/fnins.2014.00075 (8 APR). Mañé N, Gil V, Martínez-Cutillas M, Clavé P, Gallego D, and Jiménez M (2014) Differential functional role of purinergic and nitrergic inhibitory cotransmitters in human colonic relaxation. Acta Physiologica 212(4): 293–305. https://doi.org/10.1111/apha.12408. Mazzuoli-Weber G and Schemann M (2015) Mechanosensitivity in the enteric nervous system. Frontiers in Cellular Neuroscience 9(October): 408. https://doi.org/10.3389/ fncel.2015.00408. Ohama T, Hori M, and Ozaki H (2007) Mechanism of abnormal intestinal motility in inflammatory bowel disease: How smooth muscle contraction is reduced? Journal of Smooth Muscle Research 43(2): 43–54. https://doi.org/10.1540/jsmr.43.43. Smith TK and Koh SD (2017) A model of the enteric neural circuitry underlying the generation of rhythmic motor patterns in the colon: The role of serotonin. The American Journal of Physiology-Gastrointestinal and Liver Physiology 312(1): G1–G14. https://doi.org/10.1152/ajpgi.00337.2016. Smith TK, Spencer NJ, Hennig GW, and Dickson EJ (2007) Recent advances in enteric neurobiology: Mechanosensitive interneurons. Neurogastroenterology and Motility 19(11): 869–878. https://doi.org/10.1111/j.1365-2982.2007.01019.x. Spencer NJ, Dinning PG, Brookes SJ, and Costa M (2016) Insights into the mechanisms underlying colonic motor patterns. The Journal of Physiology 594(15): 4099–4116. https:// doi.org/10.1113/JP271919. Spiller R, Aziz Q, Creed F, et al. (2007) Guidelines on the irritable bowel syndrome: Mechanisms and practical management. Gut 56: 1770–1798. https://doi.org/10.1136/ gut.2007.119446.

Colonic Obstruction☆ Lisa Zhang and Sunil V Patel, Queen’s University, Kingston General Hospital, Kingston, ON, Canada © 2020 Elsevier Inc. All rights reserved.

Glossary Adynamic ileus Absence of intestinal motility, often occurring for several days following surgery. Diverticulosis Herniations of the mucosa and submucosa through the muscular wall of the colon. Intussusception Invagination or telescoping of proximal bowel into the adjacent distal bowel, often resulting in bowel obstruction. Volvulus Abnormal twisting of a segment of bowel around itself and its mesentery, often resulting in bowel obstruction.

Definition Colonic obstruction, or large bowel obstruction, refers to partial or complete blockage of fecal or other luminal contents from movement in the anal direction within the colon. There are many causes of colonic obstruction, most of which can be subdivided into mechanical or nonmechanical categories; nonmechanical obstruction may be congenital or acquired.

Introduction Mechanical colonic obstruction is an emergency condition that requires early identification and management. The etiology of mechanical colonic obstruction varies depending on age. In adults, mechanical obstruction is most commonly caused by colorectal cancer, followed by diverticular strictures and volvulus. In neonates, causes include imperforate anus and other congenital anomalies. Nonmechanical colonic obstruction results from failure of normal propulsive motility. Adynamic ileus and acute colonic pseudo-obstruction (Ogilvie syndrome) are the most commonly seen etiologies in adults. Patients with this syndrome may have an underlying congenital defect involving absence of the nerve supply to the intestinal wall or lack of circular smooth muscle, which causes severe dysmotility that can lead to megacolon. Congenital aganglionosis (Hirschsprung’s disease) is an example found in neonates and pediatric patients. The signs and symptoms of nonmechanical obstruction may be similar to those in mechanical obstruction.

Etiology The leading cause of mechanical colonic obstruction is cancer, which accounts for approximately 60% of all cases (Kahi and Rex, 2003). Most colorectal cancers occur in the distal third of the colon and up to 10% of these patients will require emergent surgery for obstruction. Up to 20% of colonic obstructions are caused by diverticular strictures, which are a complication of diverticular disease (Dite, et al., 2003). Diverticulosis is common in the United States and other developed countries, with a prevalence surpassing 60% in those over 60 years of age (Peery, et al., 2016). Diverticulitis, which is inflammation of a diverticulum, can lead to diverticular strictures due to repeated insult, fibrosis and narrowing of the lumen of the colon. This chronic process can lead to complete colonic obstruction and may be difficult to differentiate from colon cancer. The third most common cause of mechanical obstruction is colonic volvulus, which accounts for up to 5% of all cases (Flasar and Goldberg, 2006). Colonic volvulus is a twisting of a redundant segment of colon on its mesentery. The most frequent site of colonic volvulus is the sigmoid colon. Other sites, in order of decreasing frequency, are the cecum, transverse colon, and splenic flexure. Less common causes of mechanical colonic obstruction include incarcerated hernias, intussusception, stricture secondary to inflammatory bowel disease, fecal impaction, and extrinsic compression (i.e., from intraabdominal adhesions or masses). In neonates, mechanical colonic obstruction can be caused by a wide variety of anomalies. Meconium ileus, which causes blockage due to abnormally thick meconium, typically obstructs the ileum but can occur in the colon; this condition is typically associated with cystic fibrosis (Van der Doef et al., 2011). Anorectal malformation (or imperforate anus), colonic atresia, and

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Change History: June 2019. L Zhang and SV Patel updated the text, references, and further readings to this entire article.

This is an update of Ayaaz Ismail, Peter Lance, Colorectal Adenomas, In Encyclopedia of Gastroenterology, edited by Leonard R. Johnson, Elsevier, New York, 2004, Pages 466–470.

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colonic stenosis are among the more common etiology among newborns (Mitul, 2016). More rare causes include neonatal small left colon syndrome, bands, and adhesions. Nonmechanical colonic obstruction likewise has many causes and can be categorized as either congenital or acquired. Congenital absence of the enteric nervous system (aganglionosis), lack of circular smooth muscle, or loss of extrinsic nervous supply to the bowel can all lead to ineffective colonic motility and ultimately functional obstruction of the lumen. Hirschsprung’s disease is the classic example of congenital colonic aganglionosis (Amiel and Lyonnet, 2001). Due to lack of enteric inhibitory motor neurons, the involved segment of bowel fails to relax, resulting in narrowing of the lumen and obstruction to the passage of feces. This usually occurs in distal colonic segments or in the rectum and leads to megacolon in severe cases. Familial visceral myopathies, or progressive dystrophy of intestinal smooth muscle, can be the underlying cause of failure of propulsive motility resulting in functional obstruction (Mann et al., 1997). Finally, systemic neurologic disorders such as Parkinson’s disease and brain stem lesions can lead to colonic dysmotility and functional obstruction via compromise of nervous signaling from the brain and spinal cord to the bowel (Poirier et al., 2016). The most common acquired nonmechanical cause of acute colonic obstruction is Ogilvie syndrome, which involves massive dilation of the colon in the absence of an anatomic lesion. The etiology of this process is unknown; a postulated mechanism involves impairment of the autonomic nervous supply to the colon, usually following trauma, infections, surgery, or cardiac disease. Metabolic disturbances (i.e., hypokalemia, hypomagnesemia, or hypocalcemia) or use of narcotic drugs may occur in conjunction with Ogilvie syndrome and contribute to colonic dysmotility or may occur independently as a cause for transient colonic obstruction (Maloney and Vargas, 2005). Other drugs implicated as a cause for nonmechanical intestinal obstruction include calcium channel blockers, tricyclic antidepressants, antihistamines, phenothiazines, and clonidine (Ohri et al., 1991). Some rare cases of colonic pseudo-obstruction may be associated with a variety of degenerative changes to the musculature and nervous supply of the bowel that occur in other systemic diseases. Infiltrative diseases such as amyloidosis involve disruption of the contractile proteins in intestinal smooth muscle due to deposition of amyloid in the muscle (Ebert and Nagar, 2008). Systemic sclerosis causes similar disruption that is secondary to fibrosis and smooth muscle atrophy in the involved segments of bowel (McFarlane et al., 2018). Some visceral neuropathies reflect autoimmune attack on the enteric nervous system and can be the cause of intestinal pseudo-obstruction. Chagas disease is an example of a neuropathy of this nature, where circulating antineuronal antibodies directed to neural elements of the enteric nervous system can lead to functional dysmotility (Georgescu et al., 2008).

Symptoms Whether the cause is mechanical or nonmechanical, most patients with colonic obstruction develop similar symptoms. Crampy abdominal pain, distension, and bloating are the most common presenting symptoms. An acute onset of symptoms is suggestive of a more abrupt obstructive event (i.e., sigmoid volvulus). A chronic progression of constipation, straining, and use of cathartics may be more suggestive of cancer or diverticular stricture. The degree of abdominal pain varies considerably among affected patients and is usually more severe if total obstruction or peritonitis is present. If the pain is severe and persistent, then complications such as bowel perforation or strangulation must be considered. In complete obstruction, there is failure to pass any stool or flatus. In partial obstruction, the patient may continue to pass some gas and experience constipation or diarrhea. Change in stool caliber may reflect the location of the obstruction. Patients often report pencil-thin stools when a partially obstructing lesion is present in the distal colon or rectum. Vomiting can be a late symptom but is uncommon in colonic obstruction. Other symptoms, when present, may suggest the underlying cause of the obstruction. For example, weight loss, blood in the stools and poor appetite are common in patients with colorectal cancer.

Diagnosis Making the diagnosis of colonic obstruction starts with taking a history and performing a physical exam, including digital rectal exam. The most frequently reported symptoms are abdominal pain, distension, and bloating; however, it is important to consider that lack of pain does not exclude the diagnosis. This is especially true in elderly patients or postoperative patients being treated with narcotic medications. Duration of symptoms may also provide a clue to the cause of the obstruction. Acute onset of symptoms is common with volvulus or intussusception; whereas insidious onset tends to occur in patients who have colorectal cancer. Physical exam reveals a tympanic, distended abdomen with tenderness to palpation that is often more severe below the level of the umbilicus. Even with complete mechanical obstruction, bowel sounds may be present. Patients may appear unwell and in septic shock if perforation or strangulation of the colon is present. Examination of the inguinal and femoral regions is integral, as incarcerated hernias are a frequently missed cause of colonic obstruction (Sakorafas and Peros, 2008). Areas with previous surgical scars should also be examined for evidence of an incarcerated incisional hernia. A digital rectal exam must be completed to assess for a distal rectal cancer. However, there are no pathognomonic physical exam signs or symptoms for colonic obstruction. There are no reliable blood tests that confirm the diagnosis of colonic obstruction. Laboratory tests are helpful in assessing the degree of dehydration, electrolyte imbalance, and kidney function. A complete blood count can evaluate for evidence anemia, which is common in colorectal cancer, and leukocytosis. A serum lactate level is often obtained and, if elevated, suggests dehydration or compromise of blood supply to the affected bowel.

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Plain radiographs taken with the patient both in the supine and the upright positions are helpful in the initial evaluation of suspected colonic obstruction. The characteristic finding will be dilated loops of colon proximal to the site of obstruction with little or no gas in the distal colon or rectum. In patients with an incompetent ileocecal valve, small bowel can be distended, while those with a competent ileocecal valve may have no small bowel distension. The degree of distension of the cecum is important to note. The risk of ischemia and perforation increases significantly when the cecal diameter is >12 cm. Sigmoid or cecal volvulus may appear as a kidney-bean appearance on plain film, often with massive distension of the colon. Intramural air (or pneumatosis coli) is a sinister sign that suggests colonic ischemia. Finally, plain radiographs can demonstrate free air in those with perforation as a consequence of obstruction. Contrast studies with a water-soluble contrast enema can also aid in identifying the etiology of colonic obstruction. Computed tomography (CT) scan of the abdomen and pelvis is the imaging modality of choice if colonic obstruction is suspected. Oral, rectal and intravenous contrast is able to provide far more accurate and detailed images of the relevant pathology than plain film methods. CT can localize the level of obstruction and suggest the etiology. It is often difficult to differentiate between malignant and diverticular strictures on CT scan. Sigmoid and cecal volvulus can be readily identified on CT scan. “Swirling” or twisting of the mesentery, with two transition points are highly suggestive of volvulus. A gradual tapering of the diameter of the colon without an abrupt transition point can be suggestive of a non-mechanical cause of colonic obstruction (Ogilvie syndrome), but direct visualization of the colon may be required to rule out an obstructing lesion. Colonoscopy and proctosigmoidoscopy may be undertaken in stable patients. Direct visualization can differentiate between malignant and benign strictures and can be both diagnostic and therapeutic in the case of sigmoid volvulus. Colonoscopy or proctosigmoidoscopy is typically not possible in patients with complete colonic obstruction, or those who are unwell with suspected perforation and/or strangulation.

Treatment Surgical management is often required in patients with a mechanical cause of colonic obstruction, while supportive care is typically undertaken in those with non-mechanical cause of colonic obstruction. Patients with colonic obstruction are initially treated with supportive care. Intravenous fluids are given to restore blood volume and prevent dehydration and electrolyte imbalances are corrected. A nasogastric tube should be considered to decompress the stomach and proximal small bowel, especially if the patient has severe distension or is vomiting. Oral intake should be avoided. In well patients with partial bowel obstruction symptoms, further workup should be considered. In patients who are unwell, or have a complete colonic obstruction, surgical treatment should not be delayed. These patients are at high risk of developing ischemia and perforation of the proximal colon.

Colorectal Cancer In patients with a complete obstruction due to colorectal cancer, early surgical intervention is often required. Segmental resection is the surgical treatment for obstructing colon cancers. Surgeons can consider primary anastomosis in well patients. The use of diverting ostomies and end colostomy can be considered in unwell patients. Patients with obstructing rectal cancers can be treated with proximal diversion (loop ileostomy or loop sigmoid colostomy), to allow for resolution of obstructive symptoms. These patients often require neoadjuvant therapy prior to definitive resection. Colonic stents can be considered in patients with obstructing colorectal cancer (Atukorale et al., 2016). The purpose of stenting is to decompress the colon and relieve the obstruction. Colonic stents are ideally a temporary treatment until formal resection can be undertaken. A colonic stent will often allow the patient to undergo resection with primary anastomosis and avoid a diverting ostomy.

Diverticular Stricture Patients with suspected diverticular stricture should undergo segmental resection of the colon. Similar to patients with suspected colon cancer, primary anastomosis can be considered in well patients, while unwell patients may require an end colostomy or diverting ileostomy. Colonic stents can be used in diverticular strictures to temporarily relieve the obstruction.

Colonic Volvulus Sigmoid volvulus can be treated initially with detorsion and decompression using flexible sigmoidoscopy. Due to the high risk of recurrence, these patients should be considered for sigmoid resection. In patients with suspected colonic ischemia or perforation, or those who fail detorsion, emergency surgical resection is required. Endoscopic detorsion is generally not recommended for cecal volvulus. These patients require surgical resection (Vogel et al., 2016).

Acute Pseudo-Obstruction (Ogilvie Syndrome) Treatment of acute pseudo-obstruction begins with supportive care, treating predisposing conditions (such as electrolyte disturbances) and stopping precipitants such as narcotic or anticholinergic medications. In patients who have progressive symptoms,

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neostigmine can be considered. A distal obstruction must be excluded prior to use. Neostigmine has rapid onset of action, with decompression seen within 5 min. In those where neostigmine is contraindicated or ineffective, endoscopic decompression can be used. Although rare, if acute pseudo-obstruction progresses to ischemia or perforation, surgical treatment is required (Vogel et al., 2016).

See Also: Colorectal Cancer. Diverticulosis and Diverticular Disease of the Colon. Hirschsprung’s Disease. Ileus

References Amiel J and Lyonnet S (2001) Hirschsprung disease, associated syndromes, and genetics: A review. Journal of Medical Genetics 38: 729–739. Atukorale YN, Church JL, Hoggan BL, et al. (2016) Self-expanding metallic stents for the management of emergency malignant large bowel obstruction: A systematic review. Journal of Gastrointestinal Surgery 20(2): 455–462. Dite P, Lata J, and Novotny I (2003) Intestinal obstruction and perforation—The role of the gastroenterologist. Digestive Diseases 21(1): 63–67. Ebert EC and Nagar M (2008) Gastrointestinal manifestations of amyloidosis. American Journal of Gastroenterology 103(3): 776–787. Flasar MH and Goldberg E (2006) Acute abdominal pain. Medical Clinics of North America 90(3): 481–503. Georgescu EF, Vasile I, and Ionescu R (2008) Intestinal pseudo-obstruction: An uncommon condition with heterogeneous etiology and unpredictable outcome. World Journal of Gastroenterology 14(6): 954–959. Kahi CJ and Rex DK (2003) Bowel obstruction and pseudo-obstruction. Gastroenterology Clinics of North America 32(4): 1229–1247. Maloney N and Vargas HD (2005) Acute intestinal pseudo-obstruction (Ogilvie’s syndrome). Clinics in Colon and Rectal Surgery 18(2): 96–101. Mann SD, Debinski HS, and Kamm MA (1997) Clinical characteristics of chronic idiopathic intestinal pseudo-obstruction in adults. Gut 41(5): 675–681. McFarlane IM, Bhamra MS, Kreps A, et al. (2018) Gastrointestinal manifestations of systemic sclerosis. Rheumatology 8(1): 235. Mitul AR (2016) Congenital neonatal intestinal obstruction. Journal of Neonatal Surgery 5(4): 41. Ohri SK, Patel T, Desa L, et al. (1991) Drug-induced colonic pseudo-obstruction. Diseases of the Colon and Rectum 34(4): 347–351. Peery AF, Keku TO, Martin CF, et al. (2016) Distribution and characteristics of colonic diverticula in a United States screening population. Clinical Gastroenterology and Hepatology 14(7): 980–985. Poirier AA, Aubé B, Côté M, et al. (2016) Gastrointestinal dysfunctions in Parkinson’s disease: Symptoms and treatments. Parkinson’s Disease 2016: 6762528. Sakorafas GH and Peros G (2008) Obstructing sigmoid cancer in a patient with a large, tender, non-reducible inguinal hernia: The obvious diagnosis is not always the correct one. European Journal of Cancer Care 17(1): 72–73. Van der Doef HP, Kokke FT, van der Ent CK, et al. (2011) Intestinal obstruction syndromes in cystic fibrosis: Meconium ileus, distal intestinal obstruction syndrome, and constipation. Current Gastroenterology Reports 13(3): 265–270. Vogel JD, Fiengold DL, Steward DB, et al. (2016) Clinical practice guidelines for colon volvulus and acute colonic pseudo-obstruction. Diseases of the Colon and Rectum 59(7): 589–600.

Colonic Transit Victor Chedid and Michael Camilleri, Mayo Clinic, Rochester, MN, United States © 2020 Elsevier Inc. All rights reserved.

Glossary

Aborad In a direction away from the mouth. Biomarker An objectively measurable substance or diagnostic test in an organism whose presence is indicative of some phenomenon such as disease, infection, or environmental exposure. Chyme Acidic fluid that passes from the stomach to the small intestine, consisting of gastric juices and partly digested food. Colonic tone Pressure generated by the smooth muscle cells in the colon to maintain the baseline wall tension and diameter of the colon. Ingestion of a meal results in increased tone of the circular muscles of the colon, potentially narrowing its lumen, but not occluding it. Colonic transit The process involved in the transport of content through the colon. High amplitude propagated contractions (HAPCs) Rapidly propagating contractions that occur spontaneously in the colon and propagate over a long distance resulting in mass movement of luminal content in the anal direction. HAPCs often precede defecation. Intestinal transit time This can be given as the average time taken by an entire meal to pass from mouth to anus (also termed whole gut transit time), or the time for the head of a meal to appear in stools. Orad In a direction toward the mouth. Rhythmic phasic contractions (RPCs) Postprandial gut motility functions resulting in slow net distal propulsion and mixing of ingested meal. Such contractions occur in the stomach, small intestine and colon. Scintigraphy A diagnostic procedure consisting of the administration of a radionuclide with an affinity for the organ or tissue of interest, followed by recording the distribution of the radioactivity with a stationary or scanning external scintillation camera.

Introduction The colon plays a critical role in regulating the frequency of defecation and consistency of bowel movements. Stool frequency and consistency are determined by the rates of colonic propulsion, absorption, and secretion, and the degree of mixing of the luminal content. The colon’s absorptive role is limited to water and some electrolytes to maintain homeostasis. Colonic motility plays a key role in balancing the propulsion of luminal content in the aborad direction to allow expulsion of the intestinal content, while allowing for efficient absorption. Transit is intricately regulated through three types of contractions: rhythmic phasic contractions (RPCs) which may be antegrade or retrograde, giant migrating contractions (GMCs) also called high amplitude propagated contractions (HAPCs), and colonic tone. These are complex motor functions of the large intestine that produce the peristaltic response for the movement of chyme (Bayliss and Starling, 1899) and fluctuations in intestinal tone and capacitance that produce pressure gradients for the movement of gases (Tremolaterra et al., 2006). These phenomena are indirectly assessed by measurement of gastrointestinal transit, which is defined as the movement of intestinal contents or markers between two points in the gastrointestinal tract from orad to aborad direction. Colonic transit assessment is relevant in the study of physiology, pathophysiology, pharmacodynamics, and in clinical practice. The purpose of this article is to review the techniques available and the clinical applications of colonic transit measurement.

Measurement of Colonic Transit Colonic transit time, whether total or segmental, can be evaluated using different colonic transit modalities. Each method has different benefits and risks that guide the decision of which modality to use, based on the clinical scenario as well as patient preference.

Radiopaque Markers Radiopaque markers are available commercially, and the method is widely available to measure colonic transit time. There have been several methods described to measure colonic transit with radiopaque markers (Arhan et al., 1981; Hinton et al., 1969; Metcalf et al., 1987).

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Hinton et al. method The simplest method with the least radiation exposure is the method of Hinton et al. (Hinton et al., 1969). After ingesting on day 1 a gelatin capsule that contains 24 radiopaque 4.5 mm rings, a plain abdominal X-ray is performed 5 days later. With this simple method, the provider can identify normal transit (with 5 or less markers retained at day 5) or slow transit (6 or more markers retained at day 5); these values were established in 25 healthy subjects (Evans et al., 1992). Additionally, the retained markers can help provide suggestion of a possible evacuation disorder (markers localized around the rectosigmoid area) in contrast to slow transit constipation (markers distributed diffusely). Although these findings are helpful, they are only suggestive and not diagnostic of an evacuation disorder. It is important to note that, in individuals with pelvic floor dyssynergia, the slow rectosigmoid transit can result in inhibition of more proximal colonic transit and, hence, distribution of markers throughout the colon.

Metcalf et al. method In another method for studying colonic transit using radiopaque markers, Metcalf et al. used ingestion of 20 radiopaque markers daily at 24-h intervals for three consecutive days (Metcalf et al., 1987). In their validation study, Metcalf et al. obtained daily abdominal X-rays at 24-h intervals following the ingestion of the first set of markers until all the markers had passed. They ultimately concluded that a multi-marker, single-film technique (on day 4) is a valid and convenient estimate of total and segmental colonic transit in normal subjects. Ultimately, in those with mean colonic transit of >72 h, all markers were not captured with a single-film technique. They, thus, further recommended obtaining a plain abdominal X-ray on day 4 and then every third day until all the markers had passed (Metcalf et al., 1987). Typically, this required only one additional radiograph on day 7. Interpretation of colonic transit by Metcalf et al. method Interpretation of a colonic transit study using the Metcalf et al. radiopaque marker technique involves counting the number of markers in the entire colon or in a segment of interest on each X-ray obtained. The mean colonic transit (MCT) time is then calculated as the sum of all markers from all the X-rays obtained (typically only on day 4, and sometimes on day 7 also). Segmental transit times are measured by dividing the colon into three segments on the plain abdominal film based on the bony anatomic landmarks. The right colon segment is to the right of the vertebral spinous processes and above an imaginary line from the fifth lumbar vertebra to the pelvic outlet. The left colon segment is the area to the left of the vertebral spinous processes and the imaginary line above the fifth lumbar vertebra and the left anterior superior iliac crest. The rectosigmoid segment is the area below the imaginary line on the left side of the abdomen (Fig. 1). Normal values, based on this study of 73 healthy subjects (Metcalf et al., 1987), are as follows: whole colon 35 h (95th percentile: 68 h), right colon 11.3 h (95th percentile: 32 h), left colon 11.4 h (95th percentile: 39 h), and rectosigmoid 12.4 h (95th percentile: 36 h).

Fig. 1 Example of colonic transit test using radiopaque markers. In this example, the X-ray shows the segmental divisions of the colon based on the bony landmarks. It was taken at 120 h after ingestion of a single capsule containing 24 radiopaque markers in a subject with chronic constipation. It shows retention of several ring-shaped plastic markers indicating delayed colonic transit.

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Subsequently, the method was refined to include 24 (rather than 20) radiopaque markers ingested on days 1–3 to simplify the analysis of colonic transit by counting the number in each segment, rather than 1.2
the number in each region when participants ingested 20 markers each day.

Sadik et al. method A third method for measurement of colonic transit using radiopaque markers was described in Sweden by Sadik et al. (2008). Patients ingested 10 radiopaque rings daily for a total of 6 days. The patient was then instructed to fast overnight and, on the seventh day, the remaining radiopaque rings were counted under fluoroscopy. The aim of their method was to measure colonic transit with a “one-visit radiological method” (Sadik et al., 2008). During the radiological visit on day 7, the retained rings in every colonic segment (cecum and ascending colon, transverse colon, descending colon, and rectosigmoid) were counted and each number was divided by 10, which correlated with the daily dose, to calculate the colonic and segmental colonic transit in days. The left colon transit was assessed as the sum of transit in the descending and rectosigmoid segments (Sadik et al., 2004). In addition, use of a different marker and monitoring over 8 h on day 7 provided a measurement of gastric and small bowel transit. Normal values are based on gender. In 40 healthy men, normal values are: whole colon 31 h (95th percentile: 46 h). In 43 healthy women, normal values are whole colon 36 h (95th percentile: 89 h). Sadik et al. measured gastrointestinal transit in different unexplained gastrointestinal symptoms (diarrhea, constipation, vomiting, etc.. . .) in both men and women, using the above described method (Sadik et al., 2008).

Advantages of Radiopaque Marker Method Using radiopaque markers to measure colonic transit has several advantages. The test is readily available, does not require advanced technology/expertise, and is relatively inexpensive. The normal values are well established and the methods of measurement are standardized, making these tests reliable, and the results are fairly reproducible. The use of radiopaque markers is relatively safe for patients and is noninvasive. The method described by Sadik et al. is superior to the methods of Hinton et al. and Metcalf et al. to quantitate rapid colonic transit using radiopaque markers (Sadik et al., 2004).

Disadvantages of Radiopaque Marker Method Disadvantages of the radiopaque markers measurement include radiation exposure and multiple visits for the 1–3 abdominal X-rays that may be required. The true location of the radiopaque markers in the colon may be improperly characterized, since the bony landmarks are typically used to localize the markers rather than the actual colonic anatomy. Lastly, the radiopaque markers do not provide sufficient information on rapid transit unless daily radiographs are obtained, which would increase radiation exposure.

Colonic Scintigraphy Colonic scintigraphy is another noninvasive and safe method to measure colonic transit. Scintigraphy can measure overall and proximal (ascending or ascending plus transverse) colon transit (Proano et al., 1990). The most common technique to perform colonic scintigraphy involves having the subject consume a methacrylate-coated, pH sensitive capsule containing 111indium-labeled (111In) activated charcoal particles after an overnight fast (Burton et al., 1997; Camilleri and Zinsmeister, 1992). When the capsule reaches the terminal ileum, which has neutral or weakly alkaline pH, it dissolves and releases the radioisotope into the lumen. Another method uses a standard solid-liquid meal and assesses the transit of ingested water (liquid phase) radiolabeled with 111 In diethylene triamine pentaacetic acid (111In-DTPA) to evaluate small bowel and colonic transit (Bonapace et al., 2000). In either method, the subject undergoes repeated scanning of the anterior and posterior abdomen with a gamma camera. Each scan is of 2 min duration and is obtained at least at 24, 48, and 72 h (with the 111In-DTPA method) post-ingestion of the radiolabeled material to determine colonic transit (Deiteren et al., 2010a) (Fig. 2).

Interpretation of Colonic Scintigraphy Regions of interest (ROI) are drawn on the colonic images corresponding to each colonic segment: ascending colon (region 1), transverse colon (region 2), descending colon (region 3), rectosigmoid (region 4), and the expelled radioisotope in stool (region 5). Region 5 is measured by subtracting the radioisotope in the colonic images from the initially administered radioisotope and, hence, assumed to have been eliminated in the stool. In the alternative liquid-phase 111In-DTPA method, 6 colonic regions are included: the four main regions in addition to the hepatic and splenic flexure, and region 7 is stool. The evaluation of colonic transit by scintigraphy has two main endpoints: overall colonic transit and ascending colon emptying.

Overall Colonic Transit Overall colonic transit is expressed by the numeric value of the geometric center (GC). To calculate the geometric center of colonic transit, the following steps are undertaken. A geometric mean of the isotope counts is obtained by the square root of the anterior

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Fig. 2 Ileocolonic transit demonstrating the arrival of radiolabel in the right colon and movement of isotope from the ascending to the transverse colon in response to meal ingestion at 4 h. Reproduced from Deiteren A, Camilleri M, Burton D, et al. (2010). Effect of meal ingestion on ileocolonic and colonic transit in health and irritable bowel syndrome. Digestive Diseases and Sciences 55, 384–391.

counts multiplied by the posterior counts, which is used to correct for depth attenuation of counts. Additionally, radioisotope decay is accounted for and corrected in the counts. The summation of isotope counts from each ROI as a fraction of the total counts, weighted by the region number, calculates the geometric center [(% ascending colon  1) þ (% transverse colon  2) þ (% descending colon  3) þ (% rectosigmoid  4) þ (% stool  5)]/100] (Camilleri and Zinsmeister, 1992). This formula is used for the 111In-radiolabeled charcoal. For the 111In-DTPA labeled water method, the formula would be expanded to include the 7 regions described above (Bonapace et al., 2000). A geometric center can be calculated at every time when a scan is obtained. The times of greatest interest are 24, 48, and 72 h.

Ascending Colon Emptying Ascending colon emptying is measured as the time for emptying half of the ascending colon (T1/2) (Burton et al., 1997). The delayed release capsule reaches the ileum and dissolves in the alkali environment at the ileocecal junction. The ileum empties into the cecum in boluses and delivers the radiolabeled charcoal into the cecum with every bolus (Spiller et al., 1987). This allows for a clear accumulation of the 111In-radiolabeled charcoal in the ascending colon.

Regional Colonic Transit The group at Temple University showed that isolated retention of isotope in the rectosigmoid colon at 72 h after administering 111 In-DTPA labeled water was suggestive of functional rectal outlet obstruction in patients with constipation (Bonapace et al., 2000). This was also studied at Mayo Clinic comparing regional colonic transit in patients with slow transit constipation and those with defecatory disorder, and healthy controls (Nullens et al., 2012). Regional colonic transit is defined as ascending colon halfemptying time (AC T1/2) and residual content in descending, rectosigmoid colon and stool (DRS). Colonic transit at 48 h (GC48) can differentiate defecatory disorder and slow transit constipation from healthy controls, since both groups had lower GC24 and GC48 and slower AC T1/2 than controls. Colonic scintigraphy can further differentiate slow transit constipation from defecatory disorder. The AC T1/2 was found to be slower in patients with slow transit constipation compared to those with defecatory disorder. Additionally, the content of the descending colon and stool at 24 h and the cumulative content of the DRS at 24 and 48 h were significantly more than the content in patients with slow transit constipation. These findings suggest that regional scintigraphic

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Evacuation Disorder: M, 30y, ACt1/210.5h F, 63y, ACt1/2 19.9h

F, 39y, ACt1/2 22.9h

Slow transit Constipation: F, 53 y ACt1/2 29.5h

F, 54 y ACt1/2 40.3h

6h

24 h

48 h

Fig. 3 Examples of scintiscans at 6, 24, and 48 h in patients with evacuation disorder and slow transit constipation. Note that delayed transit is also demonstrated at 48 h in the patients with slow transit constipation and the retention of isotope in the left colon in patients with evacuation disorder. Reproduced from Nullens S, Nelsen T, Camilleri M, et al. (2012). Regional colon transit in patients with dys-synergic defaecation or slow transit in patients with constipation. Gut 61, 1132–1139.

transit profiles might help differentiate defecatory disorder from slow transit constipation. Additionally, in the presence of slow colonic transit, it is essential to exclude an evacuation disorder (Fig. 3).

Normal Values for Scintigraphic Colonic Transit Measurement (Kolar et al., 2014) Normal values for scintigraphic colonic transit measurement have been established in 145 females and 75 males for GC24, and 136 females and 63 males for GC48. GC24 60% of a standardized meal 2 h following ingestion and/or retention of >10% of the meal 4 h after food intake (Camilleri et al., 2013). The test meal proposed in the consensus statement comprises two large eggs, two slices of bread and strawberry jam (30 g) with water (120 mL), providing 255 kcal with little fat (72% carbohydrate, 24% protein, 2% fat, and 2% fiber) (Camilleri et al., 2013). Such standardization is useful but there are substantial variations between centers in the methodology used to measure gastric emptying at present. It should also be appreciated that this test meal, particularly because of its high carbohydrate content, may not appropriate in all circumstances. While scintigraphy enables precise measurement of both solid and liquid meal components (although the “consensus” test meal only labels the solid component), it entails radiation exposure and requires sophisticated equipment and technical expertise. Acceptable alternatives include 13C based

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breath tests and ultrasonography which do not involve radiation exposure, although the latter is operator-dependent (Phillips et al., 2015). Newer techniques such as the wireless motility capsule, MRI, and SPECT imaging have emerged, but at present these should be considered less accurate than scintigraphy.

Management of Gastroparesis General Measures The dietary management of gastroparesis has not been rigorously evaluated, but general advice in clinical practice revolves around smaller, frequent low-fat, low-fiber meals, with more calories as liquids than solids, and provision only of solids that fragment readily into smaller particles (Olausson et al., 2014). Such advice can be difficult to adhere to and the involvement of a dietitian is recommended (Tornblom, 2016). It is also prudent to review all concurrent medications and, if possible, cease those which may slow gastric emptying. The importance of optimizing glycemic control warrants emphasis, given the effects of acute hyperglycemia on gastric emptying as discussed above. In insulin-treated patients (T1D or T2D), it is important to match the prandial insulin dose to the anticipated delivery of carbohydrate to the small intestine; a mismatch is prone to occur in gastroparesis, with emptying of carbohydrate occurring later, thereby increasing the risk of hypoglycemia in the early phase after the meal, and hyperglycemia later in the postprandial period. It is possible that in the future, clinicians may routinely measure gastric emptying in people with diabetes.

Pharmacological Therapies Pro-kinetic medications have been the mainstay of pharmacological interventions; however, few formal comparisons exist between different drugs. Moreover, essentially all studies evaluating these agents have been of short duration with small numbers of patients. Because pro-kinetic drugs act on myenteric neurons, their utility is ultimately limited by the function of the residual innervation in the gut. Nonetheless, they remain widely used in clinical practice. Metoclopramide, a dopamine D2 receptor antagonist, improves gastric emptying compared with placebo (Tornblom, 2016), but is associated with central nervous system adverse events (including tardive dyskinesia) and, accordingly, is recommended for short duration use only by the Food and Drug Administration (FDA). An intranasal formulation of metoclopramide is being developed, and one recent study reported better symptom control than oral administration in diabetic gastroparesis (Parkman et al., 2014). In addition, metoclopramide can be injected subcutaneously to abort attacks of vomiting. A double-blind multicenter trial compared domperidone, another D2 receptor antagonist, with metoclopramide; the former does not cross the blood-brain barrier and was associated with fewer adverse events, yet yielded comparable improvement in gastric emptying and symptoms (Tornblom, 2016; Patterson et al., 1999). Domperidone may, however, prolong the QT interval and can affect metabolism of other medications through the CYP2D6 pathway (Tornblom, 2016). The antibiotic erythromycin acts on motilin receptors to initiate coordinated motor patterns in the stomach and upper small bowel that improve gastric emptying. While effective acutely, and inexpensive, erythromycin needs to be administered frequently and may also prolong the QT interval and affect metabolism of other medications, in this case through the CYP3A4 pathway (Tornblom, 2016). In addition, erythromycin is subject to tachyphylaxis that is, diminution in pharmacological effect over time. A number of promising novel agents are currently in Phase 2–3 trials (including, ghrelin receptor agonists, serotonin subtype 4 receptor agonists, acetylcholine esterase inhibitors, and a combined D2 receptor agonist/acetylcholine esterase inhibitor).

Treatment-Refractory Gastroparesis Gastroparesis refractory to dietary and pharmacological intervention is debilitating and management options are frequently unsatisfactory. In cases with antral hypomotility, jejunal or even parenteral feeding may be required. Gastric electrical stimulation (GES) using the “Enterra” device) is currently approved by the FDA for refractory gastroparesis. Two unblinded GES studies showed improved improvement of symptoms (Phillips et al., 2015; Tornblom, 2016); however, a subsequent blinded study failed to show a difference between periods where the stimulator was switched “on” or “off” (Phillips et al., 2015; Tornblom, 2016). Pyloric botulinum toxin injections have appeared promising in uncontrolled studies, but two sham-controlled trials, predominantly involving idiopathic gastroparesis patients, were negative (Phillips et al., 2015). Surgical and endoscopic interventions such as pyloroplasty and pyloromyotomy have been described, but lack controlled outcome data (Phillips et al., 2015; Tornblom, 2016).

Prognosis Previously gastroparesis was regarded as a feature of complicated, usually long-standing diabetes, it is now appreciated that delayed emptying may occur earlier. While it is clear that gastroparesis impacts quality of life negatively and results in considerable morbidity (Hyett et al., 2009), the impact on life expectancy is not clear with one community-based study (Jung et al., 2009) suggesting a reduction while the outcomes of studies from referral centers show no difference (Hyett et al., 2009; Chang et al., 2012). The longest longitudinal study (25 years) of gastric emptying in diabetes reported that rate of emptying is remarkably stable over time (Chang et al., 2012).

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Future Directions Although there has been an improvement of our understanding of gastric emptying over the past decade, key gaps in knowledge still exist. While it is clear that acute hyperglycemia slows while acute hypoglycemia accelerates gastric emptying; the impact of long-term improvement of glycemic control or strategies to avoid hypoglycemia on the rate of emptying needs to be established. Current antihyperglycemic medications are prescribed “empirically” rather than on a “physiological” basis. Some anti-hyperglycemic medications such as GLP-1 receptor agonists and pramlintide, slow gastric emptying. These medications are approved for use in combination with insulin. The effect of such anti-hyperglycemic agents on gastric emptying during either hyper-or hypoglycemia needs to be evaluated. Finally, treatment of symptomatic gastroparesis remains unsatisfactory. The results of a number of novel agents currently in development are, therefore, eagerly awaited.

References Bharucha AE, Batey-Schaefer B, Cleary PA, et al. (2015) Delayed gastric emptying is associated with early and long-term hyperglycemia in type 1 diabetes mellitus. Gastroenterology 149: 330–339. Boronikolos GC, Menge BA, Schenker N, et al. (2015) Upper gastrointestinal motility and symptoms in individuals with diabetes, prediabetes and normal glucose tolerance. Diabetologia 58: 1175–1182. Bytzer P, Talley NJ, Leemon M, Young LJ, Jones MP, and Horowitz M (2001) Prevalence of gastrointestinal symptoms associated with diabetes mellitus: A population-based survey of 15,000 adults. Archives of Internal Medicine 161: 1989–1996. Camilleri M, Parkman HP, Shafi MA, Abell TL, Gerson L, and American College of Gastroenterology (2013) Clinical guideline: Management of gastroparesis. American Journal of Gastroenterology 108: 18–37. quiz 38. Camilleri M, Chedid V, Ford AC, et al. (2018) Gastroparesis. Nature Reviews. Disease Primers 4: 41. Chang J, Russo A, Bound M, Rayner CK, Jones KL, and Horowitz M (2012) A 25-year longitudinal evaluation of gastric emptying in diabetes. Diabetes Care 35: 2594–2596. Fraser RJ, Horowitz M, Maddox AF, Harding PE, Chatterton BE, and Dent J (1990) Hyperglycaemia slows gastric emptying in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 33: 675–680. Horowitz M, Edelbroek MA, Wishart JM, and Straathof JW (1993) Relationship between oral glucose tolerance and gastric emptying in normal healthy subjects. Diabetologia 36: 857–862. Horowitz M, O’Donovan D, Jones KL, Feinle C, Rayner CK, and Samsom M (2002) Gastric emptying in diabetes: Clinical significance and treatment. Diabetic Medicine 19: 177–194. Hyett B, Martinez FJ, Gill BM, et al. (2009) Delayed radionucleotide gastric emptying studies predict morbidity in diabetics with symptoms of gastroparesis. Gastroenterology 137: 445–452. Jones KL, Horowitz M, Carney BI, Wishart JM, Guha S, and Green L (1996) Gastric emptying in early noninsulin-dependent diabetes mellitus. Journal of Nuclear Medicine 37: 1643–1648. Jung HK, Choung RS, Locke GR 3rd, et al. (2009) The incidence, prevalence, and outcomes of patients with gastroparesis in Olmsted County, Minnesota, from 1996 to 2006. Gastroenterology 136: 1225–1233. Kashyap P and Farrugia G (2010) Diabetic gastroparesis: What we have learned and had to unlearn in the past 5 years. Gut 59: 1716–1726. Kassander P (1958) Asymptomatic gastric retention in diabetics (gastroparesis diabeticorum). Annals of Internal Medicine 48: 797–812. Marathe CS, Horowitz M, Trahair LG, et al. (2015) Relationships of early and late glycemic responses with gastric emptying during an oral glucose tolerance test. Journal of Clinical Endocrinology and Metabolism 100: 3565–3571. Olausson EA, Storsrud S, Grundin H, Isaksson M, Attvall S, and Simren M (2014) A small particle size diet reduces upper gastrointestinal symptoms in patients with diabetic gastroparesis: A randomized controlled trial. American Journal of Gastroenterology 109: 375–385. Parkman HP, Carlson MR, and Gonyer D (2014) Metoclopramide nasal spray is effective in symptoms of gastroparesis in diabetics compared to conventional oral tablet. Neurogastroenterology and Motility 26: 521–528. Patterson D, Abell T, Rothstein R, Koch K, and Barnett J (1999) A double-blind multicenter comparison of domperidone and metoclopramide in the treatment of diabetic patients with symptoms of gastroparesis. American Journal of Gastroenterology 94: 1230–1234. Phillips LK, Deane AM, Jones KL, Rayner CK, and Horowitz M (2015) Gastric emptying and glycaemia in health and diabetes mellitus. Nature Reviews. Endocrinology 11: 112–128. Schvarcz E, Palmer M, Aman J, Horowitz M, Stridsberg M, and Berne C (1997) Physiological hyperglycemia slows gastric emptying in normal subjects and patients with insulindependent diabetes mellitus. Gastroenterology 113: 60–66. Tornblom H (2016) Treatment of gastrointestinal autonomic neuropathy. Diabetologia 59: 409–413. Vinik AI (2016) Clinical practice. diabetic sensory and motor neuropathy. New England Journal of Medicine 374: 1455–1464.

Diarrhea; Anti-Diarrheal Drugs☆ Matthew Woo, University of Calgary, Calgary, AB, Canada Seth Shaffer, University of Chicago, Chicago, IL, United States © 2020 Elsevier Inc. All rights reserved.

Glossary

Calmodulin An intracellular high-affinity calcium-binding polypeptide forming a calcium/calmodulin complex that regulates ion transport through the modification of cellular regulatory proteins. Enteric nervous system Largely autonomous nervous system, which regulates intestinal function. The cell bodies of enteric neurons lie in plexi within the intestine. Enterochromaffin cell Specialized intestinal epithelial cell that detects lumenal stimuli and activates signaling cascades through the release of mediators such as 5-hydroxytryptamine. Enterocytes Specialized epithelial ion-transporting cells, which collectively form a continuous monolayer lining the intestinal lumen. Tight junctions separate enterocytes, hence creating a selective barrier to electrolytes and nutrients. Enterohepatic circulation The process by which unconjugated bilirubin is reabsorbed in the small intestine and colon via the portal vein and returns to the liver to again undergo conjugation. Secretagogue Substance that induces intestinal secretion.

Introduction Diarrhea is one of the most troublesome symptoms encountered by patients, and approximately 5% of the population is affected by chronic diarrhea at any given time (Schiller, 2017). Patients vary with their definitions of diarrhea, as they will often describe loose stools, increased frequency, urgency, or even incontinence as the presenting symptom. Old definitions of diarrhea exist, such as >200 g/day; however, this can often be misleading, and is rarely used in clinical practice anymore. Antidiarrheal drugs are intended to treat these disabling symptoms. Acute diarrhea is distinguished from chronic diarrhea, as those episodes which last 4 weeks in immunocompetent patients are rarely infectious. The differential diagnosis for chronic diarrhea is quite long and includes: small bowel inflammation, small bowel malabsorption, pancreatic insufficiency causing malabsorption, motility disorders, colonic inflammation, or colonic neoplasia. The more common causes of chronic diarrhea include irritable bowel syndrome (IBS), celiac disease, bile acid diarrhea, diet-induced (e.g., excess caffeine or alcohol), inflammatory bowel disease (IBD), microscopic colitis, colonic neoplasia, or drugs (Arasaradnam et al., 2018). A detailed history and physical exam is paramount to try and understand the underlying primary cause. Initial investigations will often involve a combination of stool and serology tests. Therapies for these patients usually involves correcting the underlying cause; however, regardless of the diagnosis, controlling the patient’s diarrhea can often be the most important issue. The mainstay of antidiarrheal drug therapy, even after centuries of use, remains the opiate group of drugs. Surprisingly, despite the devastating effects of this condition in the underdeveloped world, there is still no effective, safe, antisecretory drug for the treatment of acute secretory diarrhea. This section will cover commonly used medical therapies for diarrhea; the role of the small bowel microbiome will not be discussed, nor will diarrhea relating to specific medical situations (e.g. short bowel syndrome).

Pathophysiology Normally, approximately 8–10 L of fluid enters the lumen of the small intestine daily both from ingestion and from endogenous salivary, gastrointestinal, and pancreatic secretions. Net absorption occurs in the small intestine, driven by osmotic gradients that result from the transport of electrolytes (mainly Naþ and Cl), sugars, and amino acids across the epithelial monolayer lining the length of the small intestinal lumen. Approximately 1–1.5 L of fluid enters the colon and from there approximately 100 mL will be excreted in the feces. Both the small intestine and large intestine have spare absorptive capacity and can absorb a maximum of 16 and 5 L, respectively. As stool consists mainly of water, especially in diarrhea, most cases of diarrhea can be ascribed to disorders of intestinal electrolyte and water transport. From a mechanistic viewpoint, diarrhea may have several causes. ☆

Change History: April 2019, S Shaffer and M Woo updated the section headings, figures, and the references.

This is an update of Matthew Banks, David Burleigh, Anti-Diarrheal Drugs, In Encyclopedia of Gastroenterology, edited by Leonard R. Johnson, Elsevier, New York, 2004, Pages 94–98.

Encyclopedia of Gastroenterology, 2nd Edition

https://doi.org/10.1016/B978-0-12-801238-3.65619-2

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Secretory Diarrhea Secretory diarrhea results from excessive secretion or diminished absorption, or both, of electrolytes (mainly Naþ and Cl) and water by epithelial cells of the intestinal mucosa. Maturing cells in the crypts of Lieberkuhn of the small intestine normally secrete electrolytes and water into the lumen. This process, stimulated by gastrointestinal hormones and neurotransmitters released after a meal, is essential for maintaining the liquidity of small intestinal contents, thereby allowing efficient digestion and absorption of nutrients. Mature epithelial cells on the intestinal villi are responsible for absorption of electrolytes, water, and nutrients. Secretory diarrhea can be produced by microbial infection, gastrointestinal hormone-producing tumors, bile salt malabsorption, and inflammatory mediators, such as prostaglandins and leukotrienes.

Osmotic Diarrhea Osmotic diarrhea occurs when an increased lumenal osmotic load results in retention of fluid in the intestinal lumen. Both electrolytes and nutrients, such as sugars and amino acids, can contribute to osmosis. If their absorption is reduced, then osmotic diarrhea can occur. Causes include celiac disease, laxative use, and lactase deficiency.

Increased Propulsive Motility Increased propulsive motility may result in diarrhea as the extent of absorption can be diminished by a decreased transit time of intestinal contents. This may occur in hyperthyroidism and also in irritable bowel syndrome.

Oral Rehydration Therapy In acute infectious diarrhea, rehydration is the first priority of treatment. This is particularly important in infants, the frail, and the elderly, where the risks of dehydration and electrolyte or pH imbalance are greatest. Promptly administered oral rehydration therapy (ORT) saves many lives and is the only therapy needed for the diarrhea of viral gastroenteritis in the young. Recourse to intravenous electrolyte and fluid replacement may be required in severe cases. ORT will not immediately reduce the volume of diarrhea, but absorption of the glucose electrolyte solution leads to the correction of fluid and electrolyte imbalances. ORT utilizes the ability of small intestinal epithelial cells to absorb sodium and glucose even in secretory states. This cotransport mechanism sets up an osmotic gradient across the intestinal mucosa, resulting in the transport of water from the intestinal lumen to the bloodstream. There are a number of approved formulations for ORT. Most have, as their basis, NaCl, KCl, sodium citrate, and glucose.

Antimotility, Antisecretory Agents Opioids and Enkephalinase Inhibitors Opioids are compounds that are chemically related to opium, which is obtained from the juice of the opium poppy. Opiate drugs include those derived from opium, such as morphine and codeine, as well as synthetic compounds, such as loperamide and diphenoxylate. The realization that these chemicals were reacting with receptors in the body led to the discovery of endogenous opioid peptides, Met- and Leu-enkephalin, which are the naturally occurring ligands for opioid receptors. Opioid receptors are divided into three main groups, designated mu (m), delta (d) and kappa (k). Opioid receptor agonists have multiple effects on intestinal smooth muscle. Excitatory neural pathways are blocked, which results in the inhibition of acetylcholine release and reduction of distension-induced peristaltic contractions. Furthermore, blockade of inhibitory pathways results in reduced nitric oxide release from inhibitory motor neurons, increased resting smooth muscle tone and sphincter contraction, and disinhibited GI muscle activity. The overall effect is increased nonpropulsive motility, which leads to a reduction in intestinal transit, thereby allowing increased time for the absorption of lumenal contents. Activation of the d receptor further contributes to decreased chloride secretion and reduction in intraluminal osmotic water movement (Galligan and Akbarali, 2014; Holzer, 2011). Morphine acts primarily on m receptors, whereas the enkephalins act on m and d receptors. Historically, morphine was the first drug widely used for the treatment of diarrhea and today opiates still remain the most useful class of antidiarrheal drugs. Extensive studies on the action of morphine reveal that it can act centrally where stimulation of m receptors in the central nervous system results in the slowing of transit throughout the intestine. Within the intestinal wall, opioid receptors have been found on enteric nerves, epithelial cells, and smooth muscle cells. Although most cases of diarrhea result from reduced absorption or increased secretion, or both, by the intestine, there is still much debate as to whether antisecretory actions or slowing of intestinal transit is the primary mechanism underlying the antidiarrheal actions of opiate drugs. The main opiates used for diarrhea today are loperamide and diphenoxylate. Unlike morphine, very little of these drugs cross the blood–brain barrier, and they are given exclusively for their actions on the gastrointestinal tract. In addition to its antimotility effects, loperamide is proposed to act as an antisecretory agent through the inhibition of calmodulin, and inhibition of voltagedependent calcium channels (Daly and Harper, 2000).

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Recently, there has been an increased interest in loperamide abuse. The pharmacokinetics of loperamide are determined by two main factors: (1) the multidrug efflux pump P-glycoprotein (P-gp), which limits passage of circulating loperamide into the brain, opposes the absorption of loperamide from the intestinal lumen, and facilitates the transport into bile for excretion; and 2) extensive first-pass metabolism via intestinal and hepatic cytochrome P450 (CYP) 3A4 and CYP2C8. Abuse occurs with the consumption of sufficiently high doses of loperamide, but also with the concurrent ingestion of substances which inhibit CYP3A4 (e.g., cimetidine or grapefruit juice), CYP2C8 (e.g., gemfibrozil) or P-gp (e.g., quinidine or black pepper). At high concentrations, loperamide interferes with cardiac conduction via interactions with cardiac potassium or sodium channels, and QT -prolongation and life-threatening arrhythmias have been reported (Wu and Juurlink, 2017). Eluxadoline, a peripherally acting mixed m-opioid receptor agonist, d-opioid receptor antagonist, k-opioid receptor agonist, has been approved for the treatment of diarrhea-predominant irritable bowel syndrome. Nonclinical trials have demonstrated a reduction in visceral hypersensitivity, likely through peripheral d-opioid receptor antagonism, which has been shown to reduce m-opioid receptor-mediated constipation and augment m-opioid receptor-mediated peripheral analgesia (Wade et al., 2012). Thus, this is likely a weaker antidiarrheal agent than pure m-opioid receptor agonist. Eluxadoline has been shown to increase the risk of pancreatitis in patients with heavy alcohol use as well as previous cholecystectomy. Although slowing intestinal transit relieves the symptoms of diarrhea, there is a risk that this may prolong the contact time of infectious agents with the intestinal mucosa. Such concerns turned out to be largely unfounded, but stimulated a search for compounds with a more favorable therapeutic profile. Enkephalins act on d receptors and may thus produce antisecretory effects. However, enkephalins had limited therapeutic benefit due to a short duration of action. However, inhibitors of enkephalinase, the enzyme that metabolizes enkephalins, are a novel class of drugs with marked antisecretory actions. Racecadotril (acetorphan) is a selective inhibitor of enkephalinase and reduces stool volume and disease duration in infectious diarrhea, without the side effect of altered gastrointestinal motility or constipation (Eberlin et al., 2012).

a-Adrenergic Receptor Agonists Noradrenergic neurons with projections to the gastrointestinal tract influence motility, mucosal transport, and blood flow. Reduction of gastrointestinal motility occurs as a result of presynaptic inhibition of acetylcholine release from cholinergic neurons. Some sphincters are also contracted by a direct action on the sphincteric smooth muscle. Noradrenergic neurons stimulate absorption and inhibit electrolyte and water secretion by an indirect inhibitory action on cell bodies of submucosal secretomotor neurons, as well as directly on enterocytes. All these actions are mediated through a2-adrenergic receptor stimulation. Clonidine, an a2 agonist, helps stimulate absorption and slow intestinal transit, and has proved effective when diarrhea is secondary to diabetic neuropathy, due to a loss of noradrenergic innervation. It may also be useful in diarrhea due to opiate withdrawal. One major disadvantage of clonidine is that since it crosses the blood–brain barrier, it can cause hypotension in patients.

Somatostatin Analogues Hormone-secreting tumors within the gastrointestinal tract are rare causes of diarrhea. Somatostatin, a peptide secreted by endocrine cells in the gut, serves a number of physiological functions in the gastrointestinal tract, including inhibition of exocrine, gastric, and pancreatic secretions, inhibition of the secretion of several gastrointestinal hormones, decrease in gastrointestinal motility, and inhibition of chloride secretion by epithelial cells. Somatostatin is limited by its short half-life and is therefore not very attractive as a therapeutic option. Octreotide, on the other hand, is a synthetic analogue of somatostatin, has a longer duration of action and increased potency, and therefore provides greater therapeutic potential. Octreotide has been used successfully in cases of diarrhea in patients due to carcinoid syndrome, VIPomas (among other peptide secreting tumors of the pancreas and gastrointestinal tract), chemotherapy-induced diarrhea, and HIV. Octreotide has also been used in dumping syndrome, where there is a rapid emptying of gastric contents, usually seen postoperatively after gastric bypass surgery, resulting in excessive release of enteric peptides into the general circulation. The beneficial effects of octreotide probably result more from its actions on decreasing gut motility and release of gastrointestinal peptides than from a direct pro-absorptive or antisecretory action. Somatostatin is often well tolerated, however side effects include cholelithiasis, elevated plasma glucose, and mild steatorrhea.

Bile Acid Sequestrants Bile acids are produced by the liver to aid in the digestion and absorption of dietary fat and fat-soluble vitamins. Roughly 95% of unbound bile acids are absorbed in the ileum and transported back to the liver for recycling via the enterohepatic circulation. Bile acid diarrhea is characterized by excess bile acids in the colon, causing an increase in colonic motility and stimulating water and electrolyte secretion. There are many potential underlying mechanisms for this, including disease of the ileum preventing reabsorption of bile acids (secondary to Crohn’s Disease, surgical resection, or radiation), malabsorption (secondary to chronic pancreatitis, celiac disease, or cholecystectomy), excessive bile acid synthesis, or idiopathic (Vijayvargia and Camilleri, 2019). The most common bile acid sequestrant is cholestyramine, a non-absorbable anion exchanger, which stays within the gastrointestinal lumen. This effectively binds and neutralizes excess bile salts, helping prevent diarrhea. While cholestyramine is available as a powder, colesevelam and colestipol are available in tablet form and work via similar mechanisms.

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Bismuth Subsalicylate Bismuth subsalicylate has antimicrobial properties, which probably account for the majority of its antidiarrheal actions. It binds to toxins produced by Escherichia coli and hence has been used successfully for the treatment of traveler’s diarrhea. It is safe to consume but does require large doses to be effective.

5-Hydroxytryptamine Receptor Antagonists Serotonin (5-hydroxytryptamine, 5-HT), primarily released from enterochromaffin cells and myenteric neurons, has a myriad of targets including enteric nerves, smooth muscle, and epithelial cells. The mechanism by which serotonin promotes bowel motility is incompletely understood. 5-HT regulates smooth muscle peristalsis both via excitatory cholinergic-mediated contraction and inhibitory nitric oxide-mediated relaxation. The peristaltic reflex occurs due to 5-HT release in response to increased intraluminal pressure. Furthermore, 5-HT induces intestinal secretion, likely through alterations in water transport (Sikander et al., 2009). 5-HT is implicated in the pathogenesis of cholera toxin-induced diarrhea and carcinoid diarrhea. Cholera toxin releases 5-HT from enterochromaffin cells; 5-HT then activates the sensory neurons of a neurosecretory reflex causing cholera toxin-induced diarrhea. 5-HT receptors on afferent neurons play a role in nociception, leading to the 5-HT3 antagonists alosetron and ramosetron being used to treat abdominal pain and diarrhea in irritable bowel syndrome. However, despite constipation being a known side effect of 5-HT3 receptor antagonists (including the antiemetic ondansetron), their use as general antidiarrheal agents is limited (especially given the incidence of colonic ischemia and severe constipation that has been reported in studies on alosetron).

Berberine Berberine is a plant-derived alkaloid that is the principal component of many different medicinal plants. It has been used in China and India as an antidiarrheal agent for centuries. It has shown antibacterial, antimotility, and antisecretory effects in animal models of secretory diarrhea. The precise mode of action in humans is still unknown. Small clinical trials, including a randomized control trial, have shown a modest benefit in those with infectious diarrhea and IBS-D (Chen et al., 2015).

Calmodulin Inhibitors Some secretagogues such as acetylcholine and 5-HT act by increasing intracellular calcium. Calcium combines with calmodulin, a calcium-binding protein, and the complex increases adenylate and guanylate cyclase activity, resulting in elevated concentrations of cyclic AMP and cyclic GMP. These nucleotides are fundamental intracellular messengers in electrolyte and water transport, causing enhanced chloride secretion and diminished sodium and chloride absorption. A positive correlation between calmodulin binding and antidiarrheal activity has been demonstrated for loperamide, chlorpromazine, and a number of other compounds. Zaldaride maleate, a selective and potent inhibitor of intestinal calmodulin, demonstrated a reduction of stool frequency and duration in traveler’s diarrhea.

Future Directions Bile Acid Diarrhea While uncommonly used in clinical practice, the 75SeHCAT test can be used to diagnose bile acid diarrhea. 75SeHCAT, a taurineconjugated bile acid analogue with gamma-emitting properties, is reabsorbed and recirculated in enterohepatic circulation similar to natural bile acids. A standard gamma camera is used to measure emission at baseline and percent retention at day 7; diminished percent retention is suggestive of bile acid diarrhea. The mainstay for bile acid diarrhea are bile acid sequestrants (e.g., cholestyramine, see above). However, obeticholic acid, a farnesoid X-receptor (FXR) agonist that stimulates FGF-19 production and decreases hepatic bile acid synthesis, has been demonstrated to improve diarrhea in patients with bile acid diarrhea (Oduyebo and Camilleri, 2017).

Chloride Channel Inhibition The opening of chloride channels in the apical membrane plays a central role in the promotion of intestinal secretion and is the final common pathway of agents that cause acute secretory diarrhea (Fig. 1). Chloride secretion is an electrogenic process, and the intestinal lumen becomes more negative, causing paracellular flow of sodium ions and a concomitant osmotic flow of water. These chloride channels include cystic fibrosis transmembrane conductance regulator (CFTR) and Ca2þ-activated Cl channels (CaCC), which activate in response to second messenger (e.g., cyclic AMP, cyclic GMP, and calcium) release into enterocyte cytoplasm. Stimuli for this includes neurotransmitters (e.g., 5-HT), inflammatory mediators (e.g., prostaglandins and interleukins), as well as bacterial enterotoxins. Given the role of CFTR and CaCC in secretory diarrhea, efforts have been made to block this step in the pathway. Crofelemer—an oligomer isolated from the sap of the croton tree—is a strong inhibitor of CaCC and partial inhibitor of CFTR that has demonstrated efficacy in HIV associated diarrhea. The small molecule CFTR inhibitors thiazolidinone and PPQ/BPO

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Fig. 1 Chloride ion secretion and its regulation. The effects of cyclic AMP (cAMP) and cyclic GMP (cGMP) are mediated through the actions of protein kinase A (PKA). This enzyme phosphorylates intestinal membrane proteins of ion channels, leading to increased apical conductance of chloride ions and basolateral conductance of potassium ions. The basolateral exit of potassium ions hyperpolarizes the cell, providing an electrical driving force for the exit of chloride ions via cystic fibrosis transmembrane conductance regulator (CFTR) and Ca2þ-activated Cl channels (CaCC). Not shown are receptors for secretagogues located on both the apical and basolateral membranes. Cholera toxin and Escherichia coli heat-stable toxin act apically to elevate cAMP and cGMP, respectively. Acetylcholine and vasoactive intestinal polypeptide act basolaterally to elevate calcium and cAMP, respectively.

compounds are promising inhibitors of CFTR, although not yet in clinical use (Thiagarajah et al., 2014). Agonists of the CaSR (extracellular calcium-sensing receptor) may reduce cyclic nucleotide accumulation, thus reversing activation of apical transporters (see below) (Cheng, 2016).

Calcium-Sensing Receptor Agonists The intestinal calcium-sensing receptor (CaSR) is an extracellular calcium-binding G protein-coupled cell surface receptor that is expressed on transporting enteric epithelial cells, fluid/motility-modulating enteric nerves, and cells that regulate gut inflammation. Thus, CaSR effectively acts as a sensor of extracellular calcium. Agonism of the CaSR has demonstrated a multitude of physiologic effects on fluid transport including: inhibition of apical anion secretion, inhibition of basolateral Cl- entry (via Naþ-Kþ-2Cl transporters, see Fig. 1), inhibition of HCO–3 secretion, as well as enhanced absorption via stimulation of apical sodium-hydrogen exchange, Cl-HCO3-exchange, and short chain fatty acid/HCO3-exchange. Furthermore, CaSR on the enteric nervous system may reduce neuronal mediated secretary response and motility. This is the putative explanation for constipation associated with hypercalcemia; furthermore, the antidiarrheal effects of calcium have been reported in case series (Cheng et al., 2015; Cheng, 2016).

Potassium Channel Inhibition It is possible to reduce chloride secretion by reducing the negative intracellular potential of the epithelial cell as this cellular hyperpolarization normally drives chloride ions through apical chloride channels into the intestinal lumen. Hyperpolarization is produced by the exit of potassium ions from the cell through basolaterally located (in the small intestine) potassium channels. It follows, therefore, that drugs blocking or inhibiting such channels have antisecretory potential. In the human colon, patch-clamp single-channel recording and the use of agents that block potassium channels have demonstrated more than one type of potassium channel. The established antisecretory agents berberine, clonidine, and loperamide possess potassium channel-blocking effects. The antifungal clotrimazole blocks cAMP and Ca2þ-sensitive Kþ channels in enterocytes (Rufo et al., 1997). Finally, secretory responses of human ileal mucosa to VIP and E. coli heat-stable enterotoxin can be inhibited by potassium channel blockade. With the multiplicity of potassium channels in existence, it is possible that those on basolateral membranes of intestinal epithelial cells may have individual characteristics that can be exploited for the development of selective antidiarrheal agents.

See Also: Bile Acid Diarrhea. Colonic Fluid and Electrolytes Absorption and Secretion. Diarrhea; Overview. Laxatives and Other Drugs for Constipation. Pediatric Diarrheal Disorders

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References Arasaradnam RP, et al. (2018) Guidelines for the investigation of chronic diarrhoea in adults: british society of gastroenterology, 3rd edition. Gut 67: 1380–1399. Chen C, et al. (2015) A randomized clinical trial of berberine hydrochloride in patients with diarrhea-predominant irritable bowel syndrome. Phytotherapy Research 29: 1822–1827. Cheng SX (2016) Calcium-sensing receptor: A new target for therapy of diarrhea. World Journal of Gastroenterology 22(9): 2711–2724. Cheng SX, et al. (2015) Calcium ameliorates diarrhea in immune compromised children. Journal of Pediatric Gastroenterology and Nutrition 56(6): 641–644. Daly JW and Harper J (2000) Loperamide: Novel effects on capacitative calcium influx. Cellular and Molecular Life Sciences 57(1): 149–157. Eberlin M, Mück T, and Michel MC (2012) A comprehensive review of the pharmacodynamics, pharmacokinetics, and clinical effects of the neutral endopeptidase inhibitor racecadotril. Frontiers in Pharmacology 3: 93. Galligan JJ and Akbarali HI (2014) Molecular physiology of enteric opioid receptors. The American Journal of Gastroenterology Supplements 2(1): 17–21. Holzer P (2011) Opioid receptors in the gastrointestinal tract. Regulatory Peptides 155: 11–17. Oduyebo I and Camilleri M (2017) Bile Acid Disease. Current Opinion in Gastroenterology 33(3): 189–195. Rufo PA, et al. (1997) The antifungal antibiotic, clotrimazole, inhibits chloride secretion by human intestinal T84 cells via blockade of distinct basolateral Kþ conductances demonstration of efficacy in intact rabbit colon and in an in vivo mouse model of cholera. Journal of Clinical Investigation 100(12): 3111–3120. Schiller LR (2017) Antidiarrheal drug therapy. Current Gastroenterology Reports 19(18). Sikander A, Rana SV, and Prasad KK (2009) Role of serotonin in gastrointestinal motility and irritable bowel syndrome. Clinica Chimica Acta 403(1–2): 47–55. https://doi.org/ 10.1016/j.cca.2009.01.028. Thiagarajah JR, et al. (2014) Discovery and development of antisecretory drugs for treating diarrheal diseases. Clinical Gastroenterology and Hepatology 12(2): 204–209. https://doi. org/10.1016/j.cgh.2013.12.001. Vijayvargia P and Camilleri M (2019) Current practice in the diagnosis of bile acid diarrhea. Gastroenterology and Hepatology 156: 1233–1238. Wade PR, et al. (2012) Modulation of gastrointestinal function by MuDelta, a Mixed m opioid receptor agonist/m opioid receptor antagonist. British Journal of Pharmacology 167(5): 1111–1125. Wu PE and Juurlink DN (2017) Clinical review: Loperamide toxicity. Annals of Emergency Medicine 70(2): 245–252. https://doi.org/10.1016/j.annemergmed.2017.04.008.

Diarrhea; Overview Lawrence R Schiller, Baylor University Medical Center, Dallas, TX, United States; Texas A&M College of Medicine, Dallas, TX, United States © 2020 Elsevier Inc. All rights reserved.

Glossary

Abetalipoproteinemia Abnormal fat absorption due to mutation of microsomal triglyceride transfer protein which limits synthesis and export of lipoproteins from enterocytes into the body. Amyloidosis Abnormal accumulation of certain proteins in tissue which interfere with normal function. Anions Negatively-charged ions, such as chloride and bicarbonate. Apical membrane The surface of the cell membrane of enterocytes that faces inward to the lumen. Autacoids Signaling chemicals released locally that affect function of nearby cells; examples include histamine, serotonin, nitric oxide, and kinins. Autonomic nerves The nerves that regulate the involuntary functions of the body. Bile acid malabsorption Bile acids are secreted by the liver into the intestine to facilitate fat absorption; almost all bile acid is recycled by absorption in the terminal ileum (enterohepatic circulation). When they are not reabsorbed, they enter the colon and may inhibit absorption in the colon and cause diarrhea. C4 (7a-hydroxy-4-cholesten-3-one) An intermediate in the biochemical synthesis of bile acids from cholesterol; serum concentration reflects rate of bile acid synthesis. Calprotectin A calcium-binding protein found in the cytosol of white blood cells that can be measured in stool as a surrogate marker for the presence of leukocytes. Cations Positively-charged ions, such as sodium and potassium. Celiac disease A condition in which gluten induces histologic changes in the small intestinal mucosa that may produce malabsorption and diarrhea. Chloride channels Pores through the apical membrane of enterocytes that allow chloride to enter the lumen when open. Chymotrypsin A digestive enzyme secreted by the pancreas that hydrolyzes protein; most survives passage through the intestine and its concentration in stool indirectly reflects pancreatic function. Colonoscopy The technique of passing an endoscope through the colon to inspect and biopsy the lining. Congenital chloridorrhea (congenital chloride diarrhea) An autosomal recessive genetic disorder characterized by defective function of the chloride—bicarbonate exchanger in the intestine which limits absorption of chloride ion. Congenital sodium diarrhea A heterogeneous group of genetic disorders, some of which involve a mucosal sodium—proton exchanger, that result in liquid stools with a high sodium content. Cotransporters Intrinsic membrane transport proteins that couple the transport of one molecule into or out of a cell down its concentration gradient with the transport of another molecule against its concentration gradient. Crohn’s disease A chronic inflammatory disease of the intestine that involves transmural inflammation in the small intestine and/or colon. Cyclic adenosine monophosphate A second messenger that mediates the intracellular effects of many peptide hormones; synthesized by adenylate cyclase from ATP. Cyclic guanosine monophosphate A second messenger that mediates the intracellular effects of many peptide hormones; synthesized by guanylate cyclase from GTP. Diarrhea Passage of loose stools, often associated with increased stool frequency. Digital rectal examination Insertion of a finger into the anus to assess the anal canal, anal sphincters, and lower rectum. Duodenum The first part of the small intestine extending from the pylorus to the ligament of Treitz. Elastase A proteolytic enzyme produced by the pancreas; its concentration in stool indirectly reflects pancreatic exocrine function. Enterocytes The absorptive cells of the intestinal mucosa. Enterography Imaging of the small intestine by fluoroscopy, computerized tomography or magnetic resonance imaging. Eosinophilic gastroenteritis A disease process characterized by disrupted gut function due to infiltration of the mucosa of the stomach or intestine with eosinophils. Epithelium The layer of cells lining the inside of hollow organs such as the gastrointestinal tract. Exchanger An intrinsic transport protein in the cell membrane that couples the passage of one molecule into the cell and another molecule out of the cell. Factitious diarrhea Deliberate, surreptitious production of diarrhea to simulate disease, usually by taking laxatives. Fecal antigen testing Use of enzyme-linked immunoassay to detect microbial antigens for diagnosis. Fibroblast growth factor 19 A protein produced by ileal enterocytes in response to absorption of bile acids that inhibits hepatic synthesis of bile acid; bile acid malabsorption is associated with low serum levels.

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Galactose Monosaccharide that combines with glucose to form lactose. Gastroenteritis Acute disease characterized by diarrhea, vomiting and abdominal pain, usually due to infection. Gastrointestinal motility The movements of the digestive tract and the transit of its contents. Glucose A monosaccharide that is the basic unit of starch and glycogen and part of both sucrose and lactose. Guanylate cyclase C receptor The receptor for uroguanylin and guanylin located on the apical membrane of enterocytes that triggers production of cyclic guanosine monophosphate intracellularly. Guanylin A signaling peptide released into the lumen of the intestine and modulates chloride secretion by enterocytes. Iatrogenic diarrhea Diarrhea that results from therapeutic use of drugs, surgery or radiation. Ileoscopy Endoscopic technique to visualize and biopsy the ileum through the rectum or orally. Ileum The distal 30%–40% of the small bowel, extending from the jejunum to the colon. Inflammatory bowel disease Chronic idiopathic inflammation of the small intestine and/or colon, usually categorized as Crohn’s disease or ulcerative colitis. Intestinal lymphoma Malignant proliferation of lymphocytes involving the intestine and mesentery. Intestinal transit The movement of material through the lumen of the intestine, usually from proximal to distal areas. Intestinal transport Process of absorption or secretion of fluid, nutrients, and electrolytes across the mucosa. Irritable bowel syndrome Chronic symptoms of abdominal pain temporally associated with altered bowel function in the absence of structural disorders. Jejunum The part of the small intestine that extends from the duodenum to the ileum. Lactoferrin A glycoprotein produced by activated neutrophils which can be used as a marker for fecal leukocytes when measured in stool. Leukocytes White blood cells. Lumen The hollow space inside a tubular structure like the intestine. Lymphangiectasia Pathologic dilatation of the lymph vessels of the gut, associated with diarrhea and loss of serum proteins into the lumen. Mastocytosis A condition in which symptoms are associated with excess mast cells in tissue. Mesenteric ischemia Reduced blood flow through the blood vessels supplying the intestine. Microscopic colitis A syndrome in which watery diarrhea is associated with increased intraepithelial lymphocytes, but little or no gross mucosal change; categorized as lymphocytic colitis and collagenous colitis. Mucosa The mucous membrane lining the interior of the gastrointestinal tract composed of epithelial cells, connective tissue (lamina propria), and a thin muscle layer (muscularis mucosae) that separates the mucosa from the submucosa. Mucosal transport The process of absorbing or secreting nutrients, fluid, and electrolytes across the lining of the intestine. Multiplex genetic panel Simultaneous automated analysis of multiple DNA markers to identify pathogens. Munchausen syndrome Feigned disease in which symptoms are created or simulated, resulting in evaluation and treatment of the factitious disorder, often by multiple providers. Neuroendocrine tumor Neoplastic proliferation of neuroendocrine cells of the gut, pancreas or other organs; these tumors may produce symptoms due to release of peptides and other autacoids; named varieties include carcinoid tumors, gastrinomas, VIPomas, somatostatinomas, insulinomas, glucagonomas, and medullary thyroid cancer. Opiate receptors Membrane proteins that mediate the effects of endogenous opioids and exogenous opiates; divided into mu, delta and kappa subtypes which produce different effects. Opiates Drugs that have effects similar to opium or morphine; endogenous opioids include enkephalins and endorphins. Osmotic gradients Variation in osmotic activity across a membrane; driving force for water transport in the intestine. Osmotic laxatives Poorly absorbed molecules that retain water within the lumen; examples include magnesium and polyethylene glycol. Osmotically active Capable of exerting an osmotic pressure. Peptide Short protein, typically containing fewer than 50 amino acid residues. Polyethylene glycol (PEG) Polymer of ethylene glycol; polymers with molecular weight >3000 are poorly absorbable; PEG 3350 is sold as a laxative. Pseudomelanosis coli Pigmentation of colon lining by lipofuscin as a result of chronic use of anthraquinone laxatives. Quantitative culture Bacterial culture technique that allows estimation of the number of bacteria (expressed as “colonyforming units”) per mL. Secretin test Traditional test of pancreatic exocrine function in which pancreatic juice is collected from the duodenum with a tube after stimulation with secretin
cholecystokinin injection. Small intestinal bacterial overgrowth >105 bacteria/mL in small intestinal contents which can be associated with diarrhea and steatorrhea; lesser degrees have been associated with irritable bowel syndrome. Steatorrhea Excess fat in the stool, typically >7 g/24 h. Stimulant laxatives Laxatives that work by affecting mucosal transport, muscle or nerve function to produce defecation. Stool fat test Fat excretion can be estimated quantitatively by chemical analysis on a timed stool specimen or qualitatively by examining a stool smear stained with a lipophilic stain (e.g., Sudan stain) and counting the number of fat droplets present.

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Succus entericus Fluid secreted by the wall of the small intestine. Tropical sprue Chronic malabsorptive diarrhea that develops after travel to tropical regions that seems to be related to altered bacterial flora in the small bowel. Ulcerative colitis A chronic inflammation of the colonic mucosa that typically extends proximally from the rectum and produces superficial ulceration, diarrhea, and bleeding. Uroguanylin A signaling peptide released into the lumen of the intestine and modulates chloride secretion by enterocytes. Whipple’s disease Chronic systematic infection with the bacterium, Tropheryma whipelii, which can produce malabsorptive diarrhea if it involves the intestinal mucosa.

Definition and Epidemiology Diarrhea—the passage of loose stools—is a common symptom. In most instances it is part of an acute illness lasting for a day or two, which rapidly subsides without medical attention. It is estimated that the average American has an attack of gastroenteritis like this every year or two. Chronic diarrhea (>4 weeks duration) also is a frequent problem, affecting up to 5% of the population in a given year. In developing countries diarrhea may be even more common and remains an important cause of morbidity and mortality, particularly among children. Because it is a common symptom, almost everyone has had some experience with diarrhea and has a personal definition of the problem. The cardinal symptom of diarrhea for most individuals is the passage of loose or fluid stools. Others concentrate on increased stool frequency (>2 bowel movements daily) and may include urgency of defecation or fecal incontinence as part of their definition. Physicians often concentrate on stool weight as an objective measure of diarrhea, with >200 g/day being the upper limit of normal. This is a flawed definition of diarrhea because some people have increased stool weight due to dietary fiber ingestion without having loose stools, and do not think of themselves as having diarrhea. Conversely, about 20% of patients presenting for evaluation of diarrhea have stool weights 70% is associated with increasing fluidity of stools. The ability of water-insoluble stool solids to bind water is a determinant of stool consistency, but varies over a relatively small range. Fecal fat is poor at binding water and so patients with steatorrhea tend to have looser stools for a given water content than those without steatorrhea. The excess stool water can be due to decreased absorption or increased secretion by the intestinal mucosa. These factors are modulated by the osmotic activity of luminal contents, the rate of net absorption or secretion by the mucosa, and the time available for absorption, which depends on transit time through the intestine. Thus, ingestion of osmotically active chemicals that hold water within the lumen, a decreased rate of absorption or an increased rate of secretion by the mucosa, or rapid transit through the intestine can result in increased stool water and the symptom of diarrhea. In health, the intestine handles a large volume of fluid each day (Fig. 1). Typically, 9–10 L of ingested food and drink, saliva, gastric juice, bile and pancreatic juice, and succus entericus enter the jejunum each day. Most of the nutrients are digested and absorbed in the jejunum and the total volume of fluid entering the ileum is about 4 L daily. The ileum absorbs the residual nutrients and an additional 2.5 L of fluid, leaving 1–1.5 L of fluid entering the colon each day. The colon absorbs almost all the remaining fluid, leaving only 0.1 L as stool water. Thus, in health, 99% of water entering the jejunum is reabsorbed. If the efficiency of water absorption decreases by as little as 1%, stool water will double, and loose stools may result. It does not take much going wrong with the process of water absorption for diarrhea to occur. Water is absorbed across the gut mucosa in response to absorption of nutrients and electrolytes. There is regional variation in the transporters and permeability properties of the mucosa that determine the capacity for water absorption in each region of the intestine. For example, the jejunum is the site of absorption of most nutrients due to the presence of sodium—nutrient cotransporters that mediate glucose, galactose and amino acid absorption, and has high permeability for water that allows large water fluxes in response to osmotic forces generated by solute absorption. The ileum and colon have different complements of transporters and are less permeable to water, producing different absorption properties. Diseases or resections that involve different regions of the gut produce different patterns of diarrhea. Mucosal absorptive and secretory function is regulated by neural, endocrine, inflammatory and luminal factors that ultimately affect transporter function for the most part via intraepithelial second messengers, such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Many diarrheal diseases result from co-opting this complex regulatory system. For example, the intestinal mucosa has chloride channels in the apical membrane that allow chloride secretion (and secondary sodium and fluid secretion) when these channels are opened. One of the regulators of this system is cGMP, produced by activation of the guanylate cyclase C receptor on the apical membrane of enterocytes. This receptor normally interacts with uroguanylin or guanylin, endogenous peptides secreted by the mucosa into the lumen to modulate mucosal chloride secretion. Pathogenic Escherichia coli

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Fig. 1 Fluid loads along the GI tract. Each day, close to 10 L of fluid composed of ingested food and drink and secretions from the salivary glands, stomach, pancreas, bile duct and duodenum pass the ligament of Treitz. The jejunum absorbs approximately 6 L and the ileum 2.5 L, leaving about 1.5 L to pass into the colon each day. The colon absorbs more than 90% of this load, leaving about 0.1 L in feces. Schiller, L. R. (2015). Chronic diarrhea. In: McNally, P. F. (ed.) GI/Liver Secrets Plus, 5th edn., Elsevier Saunders: Philadelphia, pp. 414–426.

bacteria produce a toxin, heat-stable enterotoxin, that activates the guanylate cyclase C receptor, producing increased intracellular cGMP, opening chloride channels, and resulting in mucosal secretion and watery diarrhea. Diarrhea can be the result of reduced water absorption due to the presence of abnormal transmucosal osmotic gradients due to ingestion of poorly absorbed solutes, altered mucosal transport, or abnormal gastrointestinal motility.

Osmotic Diarrhea One problem that can cause increased stool water content is ingestion of poorly absorbed, osmotically-active substances, such as magnesium salts, other osmotic laxatives, or poorly absorbed carbohydrates (e.g., lactose in a patient with lactase deficiency). These substances obligate water to remain in the lumen to maintain osmotic equilibration with plasma. Electrolyte absorption by the mucosa is normal, however. Thus, electrolyte concentrations in stool water are low, and most of the osmotic activity of stool water is due to the poorly absorbed substance that was ingested. This allows recognition of osmotic diarrhea by measurement of stool electrolyte concentrations and estimation of the fecal osmotic gap: 290  2X ([Naþ] þ [Kþ]), where 290 is the estimated plasma (and presumable luminal) osmolality, and 2X ([Naþ] þ [Kþ]) represents the total electrolyte contribution to osmolality (the sum of the predominant cations doubled to account for accompanying anions) (Fig. 2). Since electrolyte concentrations are low in osmotic diarrhea, the fecal osmotic gap would be high (>50 mosm/kg) in this condition. A search then can be made for the poorly-absorbable substance by looking at fecal magnesium concentration, pH (low pH is a marker of carbohydrate malabsorption due to fermentation to short-chain fatty acids), and fecal polyethylene glycol concentration.

Secretory Diarrhea If increased stool water is due to inadequate electrolyte and fluid absorption by the mucosa, secretory diarrhea is said to be present. This term is something of a misnomer, since most individuals with secretory diarrhea have reduced net absorption rather than net secretion by the mucosa. Stool volumes have to exceed the 9–10 L entering the jejunum each day before the intestine can be said to be in a net secretory state. This only occurs in a few conditions, such as cholera or extreme short bowel syndrome. When fecal electrolytes

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Fig. 2 Fecal electrolytes and the fecal osmotic gap. The osmolality of colonic fluid and body fluids is in equilibrium and is approximately 290 mosm/kg. The total concentration of electrolytes, therefore, cannot exceed 290 mmol/L. In secretory diarrhea almost all the osmotic activity of colonic contents is caused by electrolytes. In osmotic diarrhea electrolyte concentrations are low and most of the osmolality in colonic fluid is unmeasured and due to the poorly absorbed substance that has been ingested. The calculated osmotic gap is an estimate of the unmeasured osmoles. Schiller, L. R. (2015). Chronic diarrhea. In: McNally, P. F. (ed.) GI/Liver Secrets Plus, 5th edn., Elsevier Saunders: Philadelphia, pp. 414–426.

are measured in patients with secretory diarrhea, electrolyte concentrations are high and calculation of the fecal osmotic gap yields a small number (7 g/24 h usually is taken as the upper limit of normal, but up to 14 g/24 h can be seen with voluminous diarrhea induced by laxatives. The amount of steatorrhea and fecal fat concentration tend to be higher with conditions producing maldigestion due to luminal problems than with those producing malabsorption due to mucosal problems. The evaluation of fatty diarrhea centers on a structural assessment of the pancreas with CT or MRI cross-sectional imaging, small bowel biopsy to assess mucosal integrity, and a quantitative culture of a small bowel aspirate to assess for small intestinal bacterial overgrowth. Traditional secretin tests for exocrine pancreatic insufficiency are rarely done anymore and surrogate tests, such as measurement of stool elastase or chymotrypsin concentration, are insufficiently precise for definitive diagnosis. Empiric trials of pancreatic enzyme replacement therapy often are used to make or exclude a diagnosis of exocrine pancreatic insufficiency, but

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should be evaluated by measuring the effect of the trial on stool fat excretion. Quantitative culture of small bowel contents is still viewed as the “gold standard” for diagnosis of small intestinal bacterial overgrowth. Finding >105 colony forming units/mL on aerobic or anaerobic culture is considered abnormal. Noninvasive testing for bacterial overgrowth with breath hydrogen testing is less reliable, but can be suggestive. Inadequate postprandial duodenal bile acid concentration can be assessed by aspiration and chemical analysis, but is technically challenging. A trial of exogenous bile acid replacement with meals may be the best way of establishing that diagnosis.

Treatment of Diarrhea The most urgent treatment for diarrhea is to be sure that fluid and electrolytes are repleted. In most cases this can be achieved with oral rehydration. Fluids designed to capitalize on nutrient—sodium cotransport and containing additional electrolytes (e.g., WHO oral rehydration solution) can be used in most cases. Patients unable to ingest these solutions can be managed with intravenous fluids. Most patients with acute diarrhea do not need antimicrobial therapy; the immune system of the intestine will clear the causative agent relatively quickly. This process can be accelerated by judicious antibiotic use in select circumstances. For example, the duration of travelers’ diarrhea can be reduced by use of antibiotics tailored to the organisms prevalent in the visited country. Another instance might be patients with dysentery (fever and blood in stools) in which antibiotics might be started while microbiological tests are pending. Patients with acute diarrhea which has persisted for more than a week may have a higher likelihood of protozoal infection and empiric therapy with an antiprotozoal agent, such as metronidazole or nitazoxanide, might be reasonable while awaiting the results of diagnostic tests. Patients with chronic diarrhea benefit most from having a specific diagnosis made and being treated with a specific agent. There are three situations in which empirical therapy might be considered in patients with chronic diarrhea: (1) as temporizing therapy before diagnostic testing is completed, (2) as symptomatic therapy if diagnostic testing has failed to confirm any specific diagnosis, and (3) when a diagnosis has been made, but no specific therapy is available. Empiric therapy with a m-opioid receptor antagonist, such as loperamide or diphenoxylate, is the most widely used symptomatic therapy. When used for acute diarrhea, dosing after each evacuation up to four times a day usually checks diarrhea. When used for chronic diarrhea, opiates work best when given expectantly before meals and at bedtime. Occasionally opiates that are more potent than loperamide or diphenoxylate, such as codeine or morphine, may need to be used with careful monitoring.

See Also: Diarrhea; Anti-Diarrheal Drugs

Further Reading Afzalpurkar RG, Schiller LR, Little KH, Santangelo WC, and Fordtran JS (1992) The self-limited nature of chronic idiopathic diarrhea. New England Journal of Medicine 327: 1849–1852. Binder HJ, Brown I, Ramakrishna BS, and Young GP (2014) Oral rehydration therapy in the second decade of the twenty-first century. Current Gastroenterology Reports 16(3): 376. https://doi.org/10.1007/s11894-014-0376-2. Camilleri M, Sellin JH, and Barrett KE (2017) Pathophysiology, evaluation, and management of chronic watery diarrhea. Gastroenterology 152: 515–532. Chey WD, Kurlander J, and Eswaran S (2015) Irritable bowel syndrome. A clinical review. JAMA 313: 949–958. Cotter TG and Pardi DS (2017) Current approach to the evaluation and management of microscopic colitis. Current Gastroenterology Reports 19(2): 8. https://doi.org/10.1007/ s11894-017-0551-3. Dickinson B and Surawicz CM (2014) Infectious diarrhea: An overview. Current Gastroenterology Reports 16(8): 399. https://doi.org/10.1007/s11894-014-0399-8. Dosanjh G and Pardi DS (2016) Chronic unexplained diarrhea: A logical and cost-effective approach to assessment. Current Opinion in Gastroenterology 32: 55–60. DuPont HL (2016) Persistent diarrhea: A clinical review. JAMA 315: 2712–2723. Eswaran S, Tack J, and Chey WD (2011) Food: The forgotten factor in the irritable bowel syndrome. Gastroenterology Clinics of North America 40: 141–162. Ford AC, Lacy BE, and Talley NJ (2017) Irritable bowel syndrome. New England Journal of Medicine 376: 2566–2578. Genta RM and Sonnenberg A (2015) The yield of colonic biopsy in the evaluation of chronic unexplained diarrhea. European Journal of Gastroenterology and Hepatology 27: 963–967. Hecht GA, Gaspar J, and Malespin M (2016) Approach to the patient with diarrhea. In: Podolsky DK, Camilleri M, and Fitz JG, et al. (eds.) Yamada’s Textbook of Gastroenterology, 6th edn, pp. 735–756. Chichester: Wiley Blackwell. Holtmann GJ, Ford AC, and Talley NJ (2016) Pathophysiology of irritable bowel syndrome. Lancet Gastroenterology and Hepatology 1: 133–146. John ES and Chokhavatia S (2017) Targeting small bowel receptors to treat constipation and diarrhea. Current Gastroenterology Reports 19. 31. https://doi.org/10.1007/s11894017-0573-x. Lacy BE, Mearin F, Chang L, et al. (2016) Bowel disorders. Gastroenterology 150: 1393–1407. Oduyebo I and Camilleri M (2017) Bile acid disease: The emerging epidemic. Current Opinion in Gastroenterology 33: 189–195. Overeem AW, Posovszky C, Rings EHMM, Giepmans BNG, and van IJzendoorn SCD (2016) The role of enterocyte defects in the pathogenesis of congenital diarrheal disorders. Disease Models & Mechanisms 9: 1–12. https://doi.org/10.1242/dmm.022269. Pawlowski SW, Warren CA, and Guerrant R (2009) Diagnosis and treatment of acute or persistent diarrhea. Gastroenterology 136: 1874–1886. Quigley EM (2014) Small intestinal bacterial overgrowth: What it is and what it is not. Current Opinion in Gastroenterology 30: 141–146. Roerig JL, Steffen KJ, Mitchell JE, and Zunker C (2010) Laxative abuse: Epidemiology, diagnosis and management. Drugs 70: 1487–1503. Schiller LR (2015) Chronic diarrhea. In: McNally PF (ed.) GI/liver secrets plus, 5th edn, pp. 414–426. Philadelphia: Elsevier Saunders. Schiller LR (2017a) Antidiarrheal drug therapy. Current Gastroenterology Reports 19(5): 18. https://doi.org/10.1007/s11894-017-0557-x. Schiller LR (2017b) Malabsorption. In: Bope ET and Kellerman RD (eds.) Conn’s current therapy, pp. 229–235. Philadelphia: Elsevier.

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Schiller LR, Pardi DS, and Sellin JH (2017) Chronic diarrhea: Diagnosis and management. Clinical Gastroenterology and Hepatology 15: 182–193. Schiller LR, Pardi DS, Spiller R, et al. (2013) Gastro 2013 APDW/WCOG Shanghai working party report: Chronic diarrhea: Definition, classification, diagnosis. Journal of Gastroenterology and Hepatology 29: 6–25. Schiller LR and Sellin JH (2016) Diarrhea. In: Feldman M, Friedman LS, and Brandt LJ (eds.) Sleisenger and Fordtran’s gastrointestinal and liver disease, 10th edn, pp. 221–241. Philadelphia: Elsevier Saunders. Sood R, Gracie DJ, Law GR, and Ford AC (2015) Systematic review with meta-analysis: The accuracy of diagnosing irritable bowel syndrome with symptoms, biomarkers and/or psychological markers. Alimentary Pharmacology and Therapeutics 42: 491–503. Steffen R, Hill DR, and DuPont HL (2015) Traveler’s diarrhea: A clinical review. JAMA 313: 71–80. Steffer KJ, Santa Ana CA, Cole JA, and Fordtran JS (2012) The practical value of comprehensive stool analysis in detecting the cause of idiopathic chronic diarrhea. Gastroenterology Clinics of North America 41: 539–560. Vijayvargiya P, Camilleri M, Carlson P, et al. (2017) Performance characteristics of serum C4 and FGF19 measurements to exclude the diagnosis of bile acid diarrhoea in IBS-diarrhoea and functional diarrhoea. Alimentary Pharmacology and Therapeutics 46: 581–588. Wilcox C, Turner J, and Green J (2014) Systematic review: The management of chronic diarrhoea due to bile acid malabsorption. Alimentary Pharmacology and Therapeutics 39: 923–939.

Diet and Environment in Colorectal Cancer Development, Roles of☆ Alberto Martin and Bhupesh Kumar Thakur, University of Toronto, Toronto, ON, Canada © 2020 Elsevier Inc. All rights reserved.

Glossary

Adenoma Describes a wide range of localized neoplastic nodules with glandular appearance that arise in the epithelial tissue. Carcinogen Any substance that has the potential to cause cancer in biological tissues. Carcinoma Describes the stage of cancer growth when the cancer cells are still within their site of origin. Gene polymorphism The occurrence of multiple alleles at a locus, in which the least common allele has a frequency of about 1% or greater. Genotoxic The property of chemical agents (genotoxins) that damages the genetic information within cell causing mutations, which may lead to cancer. Metabolomics The systematic identification and quantification of the small molecule metabolic products (the metabolome) of a biological system at specific time. Microbiome The collective genomes of the microbes (composed of bacteria, bacteriophage, fungi, protozoa, and viruses) that live inside and on the human body. Probiotics Live microorganisms that when administered in adequate amounts, confer a health benefit on the host.

Nomenclature CAC CDT CRC GI GL IBD IGF NO PUFAs ROS SNPs

Colitis-associated cancer Cytolethal distending toxin Colorectal cancer Glycemic index Glycemic load Inflammatory bowel disease Insulin-like growth factor Nitric oxide Polyunsaturated fatty acids Reactive oxygen species Single nucleotide polymorphisms

Colorectal Cancer: Global Pattern and Mortality The average life expectancy in most parts of the world is considerably increased at present because of improved living standards and health care systems. Although medical advancements have led to reduced death rates from communicable diseases, there has been a
40% increase in cancer-related mortality over the past 40 years and a 60% further increase is expected in the next 15 years (Kuipers et al., 2013). Colorectal cancer (CRC) is one of the leading causes of morbidity and mortality worldwide, and ranks third as the most commonly diagnosed cancer. Moreover, it alone accounts for approximately 10% of total cancer-related mortality (Favoriti et al., 2016). According to GLOBOCAN 2012, it is the third-most common cancer in men with 10% of new cancer cases (746,000 men were diagnosed with CRC worldwide in 2012) and second most common cancer in women with 9.2% of new cancer cases (614,000 women were diagnosed with CRC worldwide in 2012) (Ferlay et al., 2013). Collectively, it accounts for about 1.4 million new cases and 700,000 deaths in 2012 and remains the fourth leading cause of cancer-related death worldwide after lung, liver, and stomach cancer (GBD 2013 Mortality and Causes of Death Collaborators, 2015). Current demographic projections and temporal profiles advocate an increasing trend in global burden of CRC, with more than 2.2 million new cases and 1.1 million deaths expected by 2030 (Arnold et al., 2017). About 50% of all reported CRC cases are from developed regions of the world, and thus is a predominant cancer in industrialized countries with moderate and high Human Development Index (HDI) (Kuipers et al., 2015). Its incidence varies globally with about six times higher incidence rates in countries with very high HDI compared to countries with low HDI. The highest incidence rates of CRC is observed in Australia and New Zealand (44.8 and 32.2 per 100,000 men and women, respectively), ☆

Change History: September 2018. Alberto Martin and BK Thakur have made minor changes in the text and references.

This is an update of M.E. Martinez, E.T. Jacobs, Diet and Environment, Role in Colon Cancer, In Encyclopedia of Gastroenterology, edited by Leonard R. Johnson, Elsevier, New York, 2004, Pages 593–597.

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whereas the lowest is in Western Africa (4.5 and 3.8 per 100,000 men and women, respectively). Highly-developed regions like New Zealand, Australia, North America, Europe, and Japan has a greater incidence (combined incidence, 29.2 per 100,000) than comparatively less-developed regions like Latin America, Africa, Asia (excluding Japan), Caribbean, Micronesia, Melanesia, and Polynesia (combined incidence, 11.7 per 100,000) (Ferlay et al., 2015, 2013). These variations in incidence are positively associated with differences in socioeconomic levels, as well as dietary and environmental factors (Rohani-Rasaf et al., 2013).

Colorectal Carcinogenesis and Predisposing Factors Both genetic and environmental factors have been reported to play an important role in the etiology of CRC (Table 1). Although CRC is heritable in some instances that is, in familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome (both of which account for
5% of CRC cases), the majority of cases are sporadic in nature. Individuals carrying mutation in APC gene develop FAP, however mutations in mismatch repair genes MSH2, MSH6, MLH1, and PMS2 cause HNPCC/Lynch syndrome. Moreover, individuals with inflammatory bowel disease (IBD) have a higher susceptibility to develop CRC, termed as colitis-associated cancer (CAC). Interestingly, all forms of CRC are strongly influenced by dietary and environmental factors (Danese et al., 2011; de la Chapelle, 2004; Kuipers et al., 2015). CRC progresses through the accumulation of mutations and epigenetic alteration of various oncogenic and/or tumor suppressor genes. The sequential accumulation of mutations support the transition of normal mucosa to premalignant lesions, followed by progression to adenoma and carcinoma. Mutations in the tumor suppressor gene adenomatous polyposis coli (APC) is usually the initial hit to start the adenoma–carcinoma sequence (Vogelstein et al., 2013; Pino and Chung, 2010). The APC gene encodes a multifunctional protein which plays an important role in Wnt signaling pathways, cell cycle regulation, cytoskeleton stabilization, intercellular adhesion and apoptosis. Mutations in the APC gene potentiate the growth of colon epithelial cells. Further mutations in these cells most often occur in the KRAS gene, which is a key component of G protein signaling pathways and regulates cellular proliferation/differentiation and clonal growth (Vogelstein et al., 2013; Pino and Chung, 2010). The mutations in these genes followed by clonal growth leads to adenomas, and any additional mutations in genes such as TP53, PIK3CA, BRAF, CTNNB1, and SMAD4 eventually promote carcinoma leading to malignancy (Louis et al., 2014). Chromosomal instability (genetic alteration through chromosomal losses/gains, translocations), microsatellite instability (genetic alteration through defective mismatch repair proteins), and aberrant DNA methylation at CpG rich promoter induced by genetic and/or environmental factors are the recognized causal mechanisms responsible for the initiation and progression of the adenoma–carcinoma sequence (Pino and Chung, 2010; Kuipers et al., 2015). Other than host genetics, CRC has been found to be largely influenced by age, chronic inflammation, metabolic syndromes including obesity, lifestyle (smoking, alcohol consumption, and physical activity), diet, and microbiota composition, and thus CRC is considered to be a multifactorial disease (Becker et al., 2009). Current advancement in our understanding of gut microbial composition and metabolism established their crucial role in human health and disease. The gut resident microbial community is largely modifiable and its plasticity is remarkably associated with diet and environmental factors. The greatest exposure of the human body to microbial community occurs in the colon, and thus association of diet, gut microbiota, and CRC is the prime focus of current research to identify prophylactic/therapeutic targets against CRC. Importantly, accumulating evidence suggests that dietary components impact the gut microbiota and their metabolism, which in turn influences various cellular processes like inflammation, proliferation, DNA damage and apoptosis, which can have significant impacts on CRC risk (Schwabe and Jobin, 2013). Finally, the penetrance of the genetic defect and aggressiveness of dietary and environmental insults have been identified as decisive factors regulating the rate of CRC development.

Table 1

Predisposing factors of colorectal cancer

Predisposing factors Genetic Inflammatory bowel diseases (IBDs) Microbiota

Diet Lifestyle

Familial adenomatous polyposis (FAP) Hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome Ulcerative colitis Crohn’s disease Escherichia coli NC101 Enterotoxigenic Bacteroides fragilis Helicobacter spp. Fusobacterium nucleatum Red and processed meat Diet high in fat and low in fiber Alcohol Smoking Sedentary lifestyle Obesity

• •

Mutation in APC gene Mutations in MSH2, MSH6, MLH1, and PMS2

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35

Gut Microbiota and Colorectal Cancer Within the healthy human gut resides trillions of symbiotic and metabolically active microbial communities representing all kingdoms of life, dominated primarily by two anaerobic phyla Firmicutes and Bacteroidetes, in addition to Proteobacteria, Actinobacteria, and Verrucomicrobia (Eckburg et al., 2005). The current understanding of the microbiota suggests that the composition of gut microbial community is crucial for the maintenance of host physiology, metabolism, and immune functions. However, its nature is highly plastic and influenced by various factors such as the host immune system, aging, oxygen availability, dietary metabolites, in situ microbial interactions, and environment (Maslowski and Mackay, 2011). Recent studies comparing microbial composition of CRC patients with that of healthy subjects revealed significant differences in microbial composition between the two groups (Sobhani et al., 2011; Flemer et al., 2017; Nakatsu et al., 2018), although interindividual heterogeneity was observed in the abundance of individual taxa. Community analysis of gut bacteria by comparing co-abundance groups/clusters identified in operational taxonomic unit (OTU) dataset from both groups reveals that Bacteroidetes cluster 1 and Firmicutes cluster 1 are significantly reduced in CRC patients, while Bacteroidetes cluster 2, Firmicutes cluster 2, pathogen cluster (members of Fusobacterium, Parvimonas, and Peptostreptococcus) and Prevotella cluster are highly enriched in CRC subjects (Flemer et al., 2017). Moreover, metagenomic analysis of viromes of fecal samples from both groups found alterations of the gut virome, with increased diversity of bacteriophage community, and most prominent enrichment of members of Orthobunyavirus in CRC patients compared with controls. Interestingly, this study also identified distinct gut virome associated with early- and late-stage CRC (Nakatsu et al., 2018). However, with these observed changes in specific microbes, it is difficult to specify whether microbes enriched on cancers are initiators or passengers of CRC (Tjalsma et al., 2012). Since CRC develops over a long period, it is also challenging to determine whether the associated changes are CRC-specific or a consequence of modifications in dietary and environmental factors. Adenomatous polyposis coli (APCmin) mice spontaneously develop benign adenomas in both small intestine and colon, and germfree APCmin mice develop reduced number of adenomas compared with APCmin mice harboring a conventional microbiota (Dove et al., 1997). Moreover, reduced tumorigenesis in colon has also been reported with disruption of innate immune receptor signaling (Fukata et al., 2007; Kobayashi et al., 2005). These studies clearly demonstrate the gut microbiota as causative/initiator of adenoma formation in mice. Exploring the role of specific microbes in CRC initiation and progression is highly challenging in humans due to factors such as bacterial genetic plasticity, host genetic variability, and the long period between initiation and diagnosis of CRC. However, there is strong evidence suggesting the involvement of specific microbes in promoting CRC, although these microbes require specific genetic alterations within the host for CRC initiation in animal models. Monocolonization with Escherichia coli NC101 in azoxymethane-treated IL-10/ mice promotes invasive colonic carcinoma, and deletion of the polyketide synthase (pks) genotoxic island within this bacteria significantly reduces its carcinogenic effect without altering inflammation (Arthur et al., 2012), suggesting that genotoxicity of a single bacteria is the primary cause of carcinogenesis in this animal model. Patients with familial adenomatous polyposis (FAP) develop colonic polyps early in life. Microbial biofilms in their colonic mucosa are found to be predominantly composed of E. coli NC101 and Bacteroides fragilis, and genes encoding the oncotoxins colibactin (clbB) and B. fragilis toxin (BFT) were also enriched (Dejea et al., 2018). Subsequent, animal studies found that these bacteria can induce CAC in genetically susceptible animals and could induce DNA damage through their secreted genotoxins (Dejea et al., 2018; Arthur et al., 2012). B. fragilis induces spermine oxidase through proinflammatory pathways in colonocytes, which further leads to generation of reactive oxygen species (ROS) and DNA damage (Goodwin et al., 2011). Moreover, B. fragilis can induce IL-17, NF-kB, and STAT3 in colonic mucosa, and also reduce mucus depth to enhance mucosal exposure to E. coli, to potentiate CAC in genetically susceptible mice (Dejea et al., 2018; Chung et al., 2018). Helicobacter hepaticus has also been reported to induced colitis and CAC in genetically susceptible animals through induction of inflammation and nitric oxide (NO)-mediated DNA damage. In Rag2/ mice, H. hepaticus activates inducible nitric oxide (iNOS) in macrophages leading to cecal epithelial hyperproliferation and DNA damage, dependent on IL-22 induction in crypt epithelial cells (Wang et al., 2017). H. hepaticus also secretes the genotoxic cytolethal distending toxin (CDT), which can induce DNA damage by activating ATM-CHK2 and ATR-CHK1 pathways, leading to intestinal carcinogenesis in genetically susceptible mice (Ge et al., 2017). Instead of DNA damage, the internalized nonpathogenic E. coli can also induce intestinal tumorigenicity through de-differentiation of lineage-specific intestinal epithelial cells into cancer stem cells. This result demonstrates that microbe-induced tumorigenesis is not always associated with toxigenic microbes but could be initiated by the chronic presence of nonpathogenic microbes through escalating stemness in host cells (Sahu et al., 2017). Overrepresentation of Fusobacterium spp. and Campylobacter spp. in CRC lesions was also recently observed, suggested their association with CRC. Subsequent studies have shown that F. nucleatum can induce intestinal tumorigenesis in APCmin mice by selectively recruiting the tumor-promoting myeloid immune cells and creating a CRC conducive proinflammatory microenvironment (Kostic et al., 2013; Warren et al., 2013). The increasing number of potential carcinogenic bacteria and their mechanisms of pathogenesis suggest that CRC is driven by pathways and/or mechanisms including induction of inflammatory pathways, increased stem ness in host cells, generation of ROS and/or NO, DNA damage, and interfering with DNA repair pathways, that are common to several bacterial groups rather than a single microbe (Fig. 1).

Diet and Colorectal Cancer Food and nutrition have long been considered to play crucial roles in human health and diseases, particularly in various cancers and cardiovascular disease. It is now clear from various studies that CRC incidence is strikingly higher in developed countries due to

36

Diet and Environment in Colorectal Cancer Development, Roles of

Fig. 1 Direct and indirect mechanisms of microbe-induced colorectal cancer (CRC) development. Enterotoxigenic Escherichia coli (ETEC) and Helicobacter hepaticus secrete colibactin and cytolethal distending toxin (CDT), respectively, which can directly induce double-stranded breaks (DSBs) in DNA, leading to genetic instability, and initiate colon carcinogenesis. However, microbes can indirectly induce CRC through increased proliferation and/or inflammation-induced reactive oxygen species (ROS)/reactive nitrogen species (RNS) mediated DNA damage. Enterotoxigenic Bacteroides fragilis (ETBF) interacts with pattern recognition receptors (PRRs) expressed on colonic epithelial cells and/or immune cells of lamina propria and triggers inflammatory responses by inducing the level of proinflammatory cytokines such as IL-6, TNF-a, and IL-1b. IL-6 induction leads to STAT3 activation, which can promote colon carcinogenesis by regulating proliferation, apoptosis, and angiogenesis processes. Moreover, IL-6 in association with TGF-b and IL-23 enhances the differentiation of naive T cells in to TH17 cells. IL-17 secreted by TH17 cells recruits polymorphonuclear cells, which leads to oxidative stress by inducing ROS and/or RNS. ROS and RNS are known to induced DNA damage and genetic instability, which could initiate colon carcinogenesis. Interestingly, ETBF can also degrade the mucus layer and promote ETEC access to epithelia. ETBF secretes B. fragilis Toxin (BFT), which cleaves E-cadherin to increase intestinal permeability and facilitate ETBF-immune cell interaction. BFT also can promote proliferation of cells by regulating Wnt/b-catenin pathway. BFT upregulates spermine oxidase (SMO) in colonic epithelial cells, which result in elevated ROS levels and DNA damage. Gut microbes metabolize dietary components and produce carcinogens such as H2S, secondary bile acids, and N-nitroso compounds, which also can induce carcinogenesis through ROS/RNS mediated DNA damage.

a westernized lifestyle and dietary habits (consumption of diets containing high animal proteins and less fibers). An excellent study performed by Doll and Peto in 1981 estimated that about 35% of cancer-related deaths and 90% of gastrointestinal cancer-related deaths could be associated with certain dietary factors (Doll and Peto, 1981). In the last several decades, multiple epidemiological studies and randomized trials have been conducted to categorize potential dietary components as CRC contributors or protectors (Vieira et al., 2017). These studies demonstrate that red and processed meat are causative agents in CRC, while milk and whole grains (rich in dietary fibers) protect from CRC (Vieira et al., 2017). The impact of diet and environment on CRC is best illustrated by the migration study on Japanese immigrants to Hawaii. The incidence of CRC was low for Japanese living in Japan. However, within one generation of their migration, incidence of CRC increased to the rate similar to local Hawaiian natives (Le Marchand and Kolonel, 1992). This study stimulated further investigation assessing the role of diet and environmental factors in CRC development that was unrelated to inherited genetic make-up. Importantly, a recent dietary interventional study on native Africans and African Americans demonstrated the effect of dietary changes on CRC incidence. Native Africans, who usually have a low incidence of CRC ( 90%) in MEN1 patients is located in the duodenum. In MEN1 patients, these tumors can manifest with the typical symptoms of the Zollinger-Ellison syndrome usually also before the age of 40 and are generally diagnosed when metastases have occurred. Gastrinomas represent one of the major causes of morbidity and mortality in MEN1 patients and are associated with a poor prognosis. Glucagonomas have also been reported in only a few MEN1 cases.

Lung and Thymus Neuroendocrine Neoplasms (NEN) Thymic carcinoids almost exclusively occur in male patients with MEN1. Their prevalence is between 3% and 4% and the 10-year survival of patients with these tumors is approximately 25%. Lung carcinoids occur in 20–25% of MEN1 patients. MEN1 patients with a lung carcinoid, as compared to those with a thymic carcinoid, have a much better survival.

Therapy The therapy of NEN & NEN syndromes in MEN1 patients is essentially not different from the therapies for their sporadic counterparts. However, there is discussion as to whether gastrinoma surgery should be generally attempted in MEN1 patients. Gastric NEN in MEN1 patients almost exclusively develop in the presence of the Zollinger Ellison syndrome. They are generally characterized as type 2 ECLomas, or gastric carcinoids/NEN. These, generally well-differentiated lesions usually show a benign clinical course. Surgery for nonfunctioning pancreatic NEN in MEN1 patients is associated with relatively high rates (up to 33%) of major short and long-term complications. It is generally recommended that MEN1 patients with non-functioning pancreatic NEN with a diameter 3cm, or those increasing in size, surgery is generally recommended.

Anterior Pituitary Tumors Most pituitary tumor patients with MEN1 have a prolactinoma (60%), followed in frequency by growth hormone (GH)-secreting tumors causing acromegaly in 25% of cases (Fig. 2). Patients with prolactinomas are usually treated with dopamine agonists and those with GH-secreting tumors can be treated with medical therapy (dopamine agonists, somatostatin analogs, or growth hormone receptor blocking drugs), or transsphenoidal pituitary surgery.

Fig. 2 62-year-old Male patient with the MEN1 syndrome and hyperprolactinemia. Coronal MRI image after the administration of Gadolinium DTPA showing a pituitary macroadenoma (macroprolactinoma—arrow-circle).

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Multiple Endocrine Neoplasia (MEN)

Screening Periodic screening for tumor manifestations and subsequent treatment of asymptomatic MEN1 mutation carriers can prevent complications and may lead to a more favorable course of the disease. Periodic biochemical and/or radiological screening for pancreatic, thymic and lung carcinoids is recommended every 1–2 years using thoracic and abdominal CT, or MRI. There might also be a role for 68Ga-DOTATOC, or DOTATATE PET-CT in the follow-up of MEN1. In experienced hands, endoscopic ultrasonography (EUS) appears to be the most sensitive localization technique for pancreatic NEN in MEN1.

MEN2 Syndrome Introduction The multiple endocrine neoplasia type 2 (MEN2) syndrome (Sipple syndrome) is an autosomal dominant inherited genetic disorder which is subdivided into three types: MEN2a, MEN2b and familial medullary thyroid carcinoma (FMTC) (MIM: 155240, 162300 & 171400). MEN2a is characterized by medullary thyroid carcinoma, bilateral pheochromocytomas and hyperplasia and/or multiple adenomas of the parathyroid glands. Medullary thyroid carcinoma is the most frequent manifestation, occurring in over 90% of cases. Pheochromocytoma with excess catecholamine production (mostly epinephrine) is present in about 50% of MEN2 patients. Patients with MEN2b also have a predisposition to medullary thyroid carcinoma and pheochromocytoma, but do not develop hyperparathyroidism. However, several other disorders are associated with the MEN 2B syndrome, including a marfanoid habitus, Hirschsprung’s disease, mucosal neuromas and epiphysiolysis.

Prevalence The prevalence of the MEN2 syndrome is approximately 0.001–0.01%, with the MEN2b syndrome being the most rare variant.

Genetics The MEN2 syndrome is the result of a constitutive activating mutation of the RET proto-oncogene located on chromosome 10q11-2. Different mutations lead to different levels of activation, resulting in genotype-phenotype correlations. MEN2 should be suspected in patients with characteristic endocrine pathology in 2 out of the 3 characteristic affected organs, or with a characteristic endocrine disorder in one of these organs plus a first-degree relative affected by the MEN2 syndrome. RET mutation carriers generally undergo preventive thyroidectomies usually at childhood at an age which is determined by the specific mutation-associated risk. Before a thyroidectomy is performed, pheochromocytoma should always be excluded using biochemical tests measuring catecholamines and/or their metabolites in blood or urine. MEN2 patients usually do not present with gastroenterological complaints, although patients with hypercalcitonemia in the presence of metastasized medullary thyroid carcinoma can present with flushing and secretory diarrhea.

MEN3 Syndrome The multiple endocrine neoplasia type 3 (MEN3) syndrome is synonym to MEN2b (see above).

MEN4 Syndrome The multiple endocrine neoplasia type 4 (MEN4) syndrome (MIM: 610755) is a recently characterized yet very rare MEN1-like syndrome. MEN4 is caused by heterozygous inactivating mutations in the CDKN1B gene (12p13.1-p12) encoding p27, a cyclindependent kinase inhibitor that acts as a negative regulator of cell cycle progression. The prevalence of MEN4 is unknown. Associated disorders with MEN4 are: hyperplasia and/or multiple adenomas of the parathyroid glands, adenomas of the anterior pituitary, gastrinomas, bronchial carcinoids, tumors of the reproductive organs, GEP NENs, NENs of cervix uteri and adrenal or renal tumors.

See Also: Pancreas; Endocrine Tumors

Multiple Endocrine Neoplasia (MEN)

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Further Reading Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri RG, Libroia A, Lips CJ, Lombardi G, Mannelli M, Pacini F, Ponder BA, Raue F, Skogseid B, Tamburrano G, Thakker RV, Thompson NW, Tomassetti P, Tonelli F, Wells SA Jr., and Marx SJ (2001) Guidelines for diagnosis and therapy of MEN type 1 and type 2. The Journal of Clinical Endocrinology and Metabolism 86: 5658–5671. Frederiksen A, Rossing M, Hermann P, Ejersted C, Thakker RV, and Nielsen MF (2019) Clinical features of multiple endocrine neoplasia type 4—Novel pathogenic variant and review of published cases. The Journal of Clinical Endocrinology and Metabolism 5450714-00082 Epub ahead of print. Hughes MS, Feliberti E, Perry RR, and Vinik A (2017) Multiple endocrine neoplasia type 2A (including familial medullary carcinoma) and type 2B. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, Dungan K, Grossman A, Hershman JM, Kaltsas G, Koch C, Kopp P, Korbonits M, McLachlan R, Morley JE, New M, Perreault L, Purnell J, Rebar R, Singer F, Trence DL, Vinik A, and Wilson DP (eds.) Endotext. South Dartmouth, MA: MDText.com, Inc. [Internet]. Marini F, Falchetti A, Del Monte F, Carbonell SS, Gozzini A, Luzi E, and Brandi ML (2006) Multiple endocrine neoplasia type 1. Orphanet Journal of Rare Diseases 1: 38. Thakker RV (2014) Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4). Molecular and Cellular Endocrinology 386: 2–15. Thakker RV, Newey PJ, Walls GV, Bilezikian J, Dralle H, Ebeling PR, Melmed S, Sakurai A, Tonelli F, and Brandi ML (2012) Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). The Journal of Clinical Endocrinology and Metabolism 97: 2990–3011. Vinik A, Perry RR, Hughes MS, and Feliberti E (2017) Multiple endocrine neoplasia type 1. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, Dungan K, Grossman A, Hershman JM, Kaltsas G, Koch C, Kopp P, Korbonits M, McLachlan R, Morley JE, New M, Perreault L, Purnell J, Rebar R, Singer F, Trence DL, Vinik A, and Wilson DP (eds.) Endotext. South Dartmouth, MA: MDText.com, Inc. [Internet].

Relevant Websites https://www.orpha.net/consor/cgi-bin/Disease_Search_Simple.php?lng¼EN – Orphanet. The portal for rare diseases and orphan drugs. https://en.wikipedia.org/wiki/Multiple_endocrine_neoplasia – Wikipedia. Multiple endocrine neoplasia. https://ghr.nlm.nih.gov/condition/multiple-endocrine-neoplasia – US National Library of Medicice. Genetics Home Reference – Multiple enndocrine neoplasia. https://www.uptodate.com/contents/multiple-endocrine-neoplasia-type-1-definition-and-genetics – UpToDate.

N Natural Orifice Transluminal Endoscopic Surgery Abraham Mathew, Jennifer Maranki, and Carl Manzo, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, United States © 2020 Elsevier Inc. All rights reserved.

Introduction The concept of natural orifice transluminal endoscopic surgery (NOTES) was first proposed by Kalloo and colleagues at the beginning of this millennium (Kalloo et al., 2004). The general vision of NOTES was to access a body cavity through a transmural incision of the gut wall to perform surgical procedures. The idea of intentionally violating the luminal boundaries was certainly disruptive. The lack of cutaneous incisions meant there were no scars nor complications attributed to skin incisions. A report from Reddy and Rao performing a transgastric appendectomy in a patient elevated “scarless” surgery into the lime light (Hochberger and Lamade, 2005). NOTES brought a new enthusiasm to surgical and interventional endoscopists all over the world, and has challenged fundamental concepts of both endoscopy and surgery. Similar to laparoscopy, which changed the landscape of traditional surgery, the idea of NOTES demanded a significant paradigm shift (McGee et al., 2006). The potential benefits of a natural orifice approach are appealing. Common post-surgical complications like wound infections, dehiscence, and incisional hernias that are simply a consequence of the cutaneous incision can be prevented by performing surgeries through transvisceral incisions. Additionally, there is cosmetic appeal with absence of a scar in the skin. A NOTES approach requires less tissue dissection and in theory could provide further benefits of less adhesions and post-operative pain. The discussion about NOTES took center stage and built tremendous momentum leading to a new and rather unusual collaboration between gastroenterology physicians and minimally invasive surgeons in the United States. ASGE, the American Society for Gastrointestinal Endoscopy and SAGES, the Society of American Gastrointestinal and Endoscopic Surgeons joined efforts, leading to the formation of NOSCAR or the Natural Orifice Surgery Consortium for Assessment and Research. Similar collaborative entities were subsequently born in Europe and Asia. These consortia were the result of a desire to responsibly advance NOTES from bench to bedside and a recognition that the advancement of NOTES was not possible without inter-specialty collaboration. These societies and their supporting industry paved a way for furthering NOTES and have changed the scope of endoscopic practice worldwide.

History of Endoscopy An endoscope is an amazingly enabling tool that has naturally evolved from a diagnostic to an interventional and surgical platform. Basil Hirschowitz invented the first fiber-optic, flexible endoscope in 1957 improving upon the primitive rigid scopes developed by Philipp Bozzini in 1805 (Cappell et al., 2000) and later by Adolf Kussmaul and Jan Mikulicz (Modlin et al., 2004; Fritscher-Ravens, 2008). As technology improved and endoscopes became more flexible and accommodated an instrument channel, more invasive endoscopic techniques became available. The capabilities of endoscopic ultrasound opened a new view of the periluminal structures enabling image-guided transluminal tissue sampling from internal organs (Fritscher-Ravens, 2008). Along with technological advancements, endoscopy practice, spearheaded by the Japanese, moved from a technique used strictly for biopsy to that which provided full-fledged treatment of mucosal pathology. At present, “resection” and “dissection”, terms that had once belonged strictly to the surgical realm, are routinely used by advanced endoscopists. Perforations during such mucosal therapy are not uncommon and are effectively treated by endoscopic techniques. In this background, NOTES appears to be the logical next step to the future evolution of endoscopy.

Initial NOTES Procedures in Animal Models Experimental NOTES procedures were primarily performed using the porcine model. A peritoneoscopy with liver biopsy was the first reported NOTES procedure and was received enthusiastically as the beginning of an endoscopic revolution (Kalloo et al., 2004). A plethora of research followed, confirming transluminal surgery was possible. These procedures ranged from a simple transluminal peritoneoscopy to more complex organ resections. Transesophageal, transgastric, transcolonic, transvaginal and transcystic procedures were described. A list of such original procedures with their references are shown in Table 1.

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https://doi.org/10.1016/B978-0-12-801238-3.65987-1

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Feasibility studies of NOTES procedures in porcine models.

Procedure

References

Number of swine

Key findings

Peritoneoscopy Cholecystectomy

Kalloo et al. (2004) Park et al. (2005)

17 (12 acute, 5 survivial) 16

Tubal Ligation Gastroenterostomy Pancreatectomy Splenectomy Uterine horn

Jagannath et al. (2005) Kantsevoy et al. (2005) Willingham et al. (2009) Kantsevoy et al. (2006) Sumiyama et al. (2006)

6 2 28 randomized 6 2

All of the survival animals recovered and gained weight. Transgastric gallbladder surgery. Full-thickness gastric incisions were safely closed. Transgastric ligation of the Fallopian tubes technically feasible and safe. Transgastric gastrojejunostomy is technically feasible. No difference between NOTES and laparoscopic approaches. Transgastric endoscopic splenectomy is feasible. Model for appendectomy.

Challenges of NOTES Gastroenterologist Versus Surgeon NOTES was conceived as transluminal expansion of the domain of flexible endoscopy. Thus, to effectively accomplish NOTES procedures in the peritoneum, advanced endoscopy skills and understanding of surgical anatomy are critical. Determining the appropriate NOTES provider was the first challenge and has been a subject of debate. Typically, advanced GI endoscopists have the best endoscopic skills while surgeons have a better understanding of surgical anatomy and techniques (Rattner and Kalloo, 2006). Thus collaboration of surgeons and gastroenterologists was essential to embark on a NOTES program. Surgeons are accustomed to rigid platforms and utilize spatial orientation to understand landmarks. Endoscopists, on the other hand, favor flexible platforms and are comfortable working in retroflexed positions with constant manipulation of the endoscope to balance position and view, in order to accomplish procedural tasks without much attention to spatial orientation. This difference in approach led to variations in opinion in regard to the optimum NOTES platform and technique (Mummadi and Pasricha, 2008). Surgeons began using NOTES in conjunction laparoscopic techniques as a “hybrid NOTES” procedures. Several of their NOTES techniques were transvaginal and with single-port laparoscopic assistance (Forgione et al., 2008). A few years after NOTES was proposed, single site surgery using an umbilical site incision gained momentum as a minimally invasive option and in some sense, stole the thunder away from NOTES. The theory was that a single site incision, albeit larger, would be beneficial and that fewer incisions would lead to fewer complications. However, future studies found that a single incision laparoscopic cholecystectomy did have worse outcomes in regard to incidence of bile duct injury and incisional hernia compared to those being performed with standard multi-incision technique or in combination with NOTES (Gaillard et al., 2015; Madureira et al., 2018).

Technique-Related Issues The biggest hurdle to clinical implementation of NOTES was the ability to provide a guaranteed leak-proof access (Mummadi and Pasricha, 2008). While surgical procedures were possible, there were questions as to whether rapid bleeding or an unintended injury to other organs could be controlled. Using flexible scopes in the peritoneal cavity had its challenges. The lack of support from a luminal wall causes less control of the scope shaft and hence hinders directional movement.

Market Forces NOTES could not flourish without investment from industry. However, with many uncertainties about who would perform NOTES procedures, what the ideal procedure, and predicted volumes are, the industry was reluctant to pursue investment with large capital.

The Technique for NOTES Access to the peritoneal cavity is feasible and safe by a variety of access points including the stomach, esophagus, rectosigmoid colon, vagina, and bladder. Mediastinal access has been accomplished via the esophagus and trachea (Moreira-Pinto et al., 2012; Liu et al., 2011). In one technique for transgastric access, a wire is passed through a needle after puncture of the luminal wall and then the tract is dilated via balloon for a larger access to pass the endoscope (Auyang et al., 2011). This technique, a modification of PEG tube placement, can be done under EUS guidance if needed. Alternatives to direct puncture of the lumen were studied in an attempt to facilitate secure closure of the access site. A submucosal flap created by rapid insufflation of CO2 under pressure allows relatively uncontrolled yet safe access and secure closure (Liu et al., 2011). A self-approximating transluminal access technique or STAT was described and shown to be advantageous in effecting leak-free closure (Mathew et al., 2011). In this technique, through a mucosal incision, a long submucosal tunnel is created in the stomach. From the tunnel, the seromuscular layer is incised to gain peritoneal access. This technique has been shown to be the most secure approach in comparison to different access and closure techniques (von Delius et al., 2008). The direction of the tunnel in STAT can

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be controlled in the gastric wall allowing a directional and targeted approach to a specific organ like the gall bladder or spleen (Pauli et al., 2010). STAT can easily be applied in the esophagus and was readily exploited for performance of a cardiomyotomy (Pauli et al., 2008a). A variety of pre-existing endoscopic accessories were used successfully for NOTES procedures. Examples include needle knives for dissection, endoscopic clips for closure, endoscopic loops for ligation, and snares for resection. Resected tissue was able to be easily retrieved through the transluminal access site. The tunnel created through the STAT technique proved to be durable enough to withstand extraction of large pieces of resected tissue through it (Moyer et al., 2011). From the gastric chamber, it was easy to access the pelvis whereas the upper abdomen was difficult as this requires a persistent retroflexion of the scope (Cassera et al., 2012).

Physiologic Studies Several physiologic parameters that are in play during NOTES procedures have been studied. Multiple studies have been published showing that pneumoperitoneum is well-tolerated during a NOTES procedure if the pressure is controlled (Bingener et al., 2008, 2011, 2015). The capnoperitoneum established by insufflation through the scope shows wider variations in the intra-abdominal pressures but this did not result in untoward hemodynamic effects (von Delius et al., 2007). Systemic inflammatory markers such as interleukin 6, TNF-alpha, and CRP have been directly compared among animals exposed to laparotomy, laparoscopy, and transluminal endoscopic surgery. The results suggest that the inflammatory response is comparable or less with transluminal approaches (Rezende et al., 2013; Guarner-Argente et al., 2012; Fan et al., 2009; Bingener et al., 2009; McGee et al., 2008). A transvaginal approach compares well with laparoscopy (Vieira et al., 2012) and has less inflammatory response compared to the transcolonic access (Fan et al., 2009). The significance of bacterial contamination that is bound to occur with a transluminal access has been extensively studied (Giday et al., 2010; Knuth et al., 2014; Memark et al., 2011; Fritscher-Ravens and Arlt, 2011). While peritoneal contamination was often appreciated, this did not translate into clinically significant infections. In a comparative study, the animals that underwent NOTES had higher rates of positive culture immediately after entry into the abdominal cavity and just before closure. However, none of the NOTES animals had positive cultures at necropsy while surgical groups did and in addition had wound infections (Azadani et al., 2012). In the submucosal tunnel access in pigs, microscopic abscesses were found that were asymptomatic (Mathew et al., 2011; Pauli et al., 2008b). Preoperative antibiotics and gastric lavage has been shown to be beneficial in minimizing peritoneal infection (Giday et al., 2010). Evidence from the POEM experience in humans confirms the findings from animal studies. In these procedures despite use of a nonsterilized endoscope through an unprepped mouth, the risk of mediastinitis is very low (Bechara et al., 2016; Crespin et al., 2017; Awaiz et al., 2017). Flexible endoscopic peritoneoscopy via the gastrotomy created during a laparoscopic gastric bypass and liver biopsy did not have any complications due to infection in humans (Steele et al., 2008).

Technology for NOTES Development of Closure Devices The full potential of a totally endoscopic, transluminal technique cannot be realized without a reliable, surgical-quality closure of transluminal defects. A variety devices and techniques are used for effective closure of transluminal defects. Endoscopic through-the-scope endoscopic clips, developed for hemostasis and widely available, were initially used for defect closure. These clips are effective at apposing mucosa, but are inadequate for full-thickness closure. Fulfilling this need, a variety of techniques and closure devices, including over-the-scope clips, cinching devices, and endoscopic suturing platforms were introduced, some of which are explained below. One technique for defect closure involves the use of hemoclips in conjunction with an endoloop (Martínek et al., 2013). The endoloop is placed on top of the defect, and clips are used to secure it in place along the defect wall. The endoloop in cinched, and the defect is centered underneath the closed loop, resulting in defect closure as the loop is tightened (Cai et al., 2016; Zhang et al., 2014). Modifications to this technique used a clip-fixed endoloop or a predetached endoloop system for defect closure have also been reported (Nomura et al., 2018; Wang et al., 2017). These approaches are attractive since they use a single-channel endoscope (Lin et al., 2018). Another technique for repair of large defects uses the omentum to act as a patch. The greater omentum is suctioned into the luminal cavity and the defect is closed by attaching endoclips to the omentum and edges of the defect, resulting in a patch-like cover over the defect (Hashiba et al., 2001; Stavropoulos et al., 2014). Over-the scope clips (OTSC, Ovesco, Tubingen, Germany; Padlock Clip, Aponos, Kingston, NH) are fitted as a distal attachment onto the tip of the endoscope similar to a banding device. The clips are released in a fashion similar to deployment of a band, rotating a threadable spool. The target defect is suctioned into the cap or the edges are grasped pulled in using specialized forceps with independently-articulating arms. Additionally, a tissue-anchoring device can allow the edges of the defect to be pulled into the cap. The clip is deployed over the tissue, resulting in improved tissue capture and greater durability when compared to hemoclips. Over-the-scope clips allow for robust, full-thickness closure of defects but are limited by the amount of tissue that can be captured within the cap (Martínek et al., 2013; Parodi et al., 2010; Haito-Chavez et al., 2014; von Renteln et al., 2009; Baron et al., 2012; Li et al., 2016a). More recently, a full-thickness resection device (FTRD, Ovesco, Tubingen, Germany) has been developed. It involves the use of a longer, wider transparent cap than the Ovesco clip, which allows for

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a larger diameter of tissue to be resected. This device provides closure at the time of resection, as target tissue is grasped and pulled into cap, the clip is released, resulting in a full-thickness, polypoid lesion that can then be snare resected. This device precludes the need for closure after resection, as the base of the site is securely closed in advance of the resection (Schmidt et al., 2014). Use of the Padlock clip (Aponos, Kingston, NH) for closure of anastomotic dehiscence and a number of other closure applications has also been described (Robertson et al., 2018). A variety of other devices for closure include those that are suction-based (EndoCinch, Bard, Murray Hill, NJ), as well as those that use a working overtube delivering a preloaded stitch (NDO Plicator, NDO Surgical, Mansfield MA), or T-bar deployment with cinching (TAS System, Ethicon Endo Surgery, Cincinnati, OH; T-bars Cook Endoscopy, Winston-Salem, ND, Olympus Optical LTD, Tokyo, Japan). A flexible stapler (PowerMedical, Medtronic, Minneapolis, MN) has also been developed. Aside from the EndoCinch, these devices are not currently available for clinical use. Endoscopic suturing devices have become available for the past 10 years, and include G-Prox (USGI Medical, San Clemente, CA) and the OverStitch device. The most widely available device, is the OverStitch endoscopic suturing system (Apollo Endosurgery, Austin TX). This single-use device is mounted on a double-channel therapeutic gastroscope. It includes a curved needle driver, tissue anchor, cinch, and T-fastener/needle. In an animal model, endoscopic suturing was shown to close a full thickness gastric defect after ESD using the OverStitch device (Rajan et al., 2012). The device has been used for full-thickness suturing of transluminal defects, repair of fistulas and leaks, over sewing of ulcerations, and stoma reduction after bariatric surgery (Banerjee et al., 2012; Pauli et al., 2013; Kantsevoy et al., 2016). After endoscopic resection of subepithelial tumors, the device has been used with success in achieving durable closure (Martínek et al., 2013). Barbed sutures, by virtue of the barbs, can be pulled only in one direction and holds tissue in place without a knot and may have a role in NOTES. Techniques that involve the use of a barbed suture have been shown in ex vivo models to accomplish gastrotomy closure without the tying a knot or placing a cinch. In the models, the repaired stomach could be insufflated to 20 mmHg without leakage (Sanchez-Hurtado et al., 2017). Such sutures has been successfully used in human surgery (Sanchez-Hurtado et al., 2017; Kassir et al., 2014; Lee et al., 2016; Wilhelm et al., 2014). This approach has the potential to make endoscopic suturing easier.

NOTES Platforms Application of the concept of NOTES in the clinical world has mostly been done by a “pushing the envelope” strategy by employing devices designed for intraluminal work. Multitasking platforms capable of accomplishing surgical tasks via a natural orifice must be developed for NOTES to reach its full capability and enter routine practice. While many of the platforms developed can accomplish surgical tasks, none has yet proved to be superior to alternative approaches. The ideal platform must be versatile, easy to master, and decrease the time, effort, and cost of surgical procedures. Several flexible and non-flexible platforms, employing either mechanical or robotic systems, were developed and used in the animal models. Some of the notable ones are discussed below. Flexible platforms that allow multitasking by mechanical systems include the dual channel endoscopes, R-scope (Olympus), EndoSamurai (Olympus), ANUBIScope (KArl-Storz), Incision Less Operating Platform (USGI) and Direct Drive Endoscopic System (DDES, Boston scientific) (Yeung and Gourlay, 2012; Kume, 2016). In the pipeline of flexible robotic surgical platforms are the Flex Robot, STRAS system (Karl Storz Germany), MASTER (Nayyang University, Singapore), ViaCath (Bingener et al., 2015) (Hansen Medical), Endomina (Endo Tools Therapeutics, Belgium) (Wallstabe et al., 2018) and Scorpion shaped endoscopic robot (Kyushu University, Japan). Baldwin et al provides a review of robotics developed for use in gastrointestinal endoscopy as a byproduct of the NOTES research (Yeung and Gourlay, 2012). The Incisionless Operating Platform (USGI, USA) incorporates four large-size working channels and in some sense is a glorified over tube whose shape can be locked into place at a target site. Through the channels a 6 mm flexible endoscope can be inserted. The other channels are then used for special articulated instruments. Manipulation of the platform requires the perfectly synchronized work of two skilled operators, one handling the scope and the other the surgical instruments. The Flex Robot System (Medrobotics), based on a snake robot, requires specific mention as it is the most widely used endoscopic robotic platform in humans, particularly by ENT physicians. The idea of a snake robot intended for human surgery was conceived and developed by Howie Choset, of Carnegie Mellon Univ.’s Robotics Institute (Watry, n.d.). It has primarily been used for surgery in the throat (Persky et al., 2018) and recently has been used in the rectum (Paull et al., 2018). The device is limited by its length, currently at about 20 cm and is currently approved for transoral and transrectal procedures in the United States. Alongside the scope are two channels to transfer robotically controlled accessories with multiple degrees of freedom. In comparison to the current endoscopes, the optical capability like narrow band imaging and magnification are lacking. Access to the natural orifice is by a port that is the conduit through which the robotically-controlled video scope is inserted. The rectal procedures are done through a 4 cm wide proctoscope similar to those used for trans-anal minimally invasive surgery. In its current form, only rectal and rectosigmoid areas can be reached with this device and is lacks a built in mechanism to provide suction. A slimmer, longer system is being developed for expanded application. The master and slave transluminal endoscopic robot (MASTER) (Fig. 1) under development by Endomaster Pte Ltd, a Singapore based firm (Sun et al., 2011) and is the only device demonstrated to be useful for deep luminal work in humans (Phee et al., 2012). The device has two robotics arms on a video endoscope that has multiple degrees of freedom allowing extensive tissue manipulation. One endoscopist operates the endoscope while the robotic arms are controlled by a second operator. The company has recently received additional government funding for further development of their platform (Brodie and Vasdev, 2018). Five patents have undergone MASTER assisted procedures successfully (Phee et al., 2012).

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Fig. 1 MASTER device. From Jang, J. Y. (2017). Future development of endoscopic accessories for endoscopic submucosal dissection. Clinical Endoscopy 50, 242–249.

The STRAS is based on the Isis-scope® therapeutic platform (Karl Storz Endoskope, Tuttlingen, Germany) and is a motorized version of the ANUBIScope primarily targeting endoluminal procedures like endoscopic submucosal dissection (ESD). This 18 mm wide flexible endoscope is 50 cm long. There are two 4.2 mm working channels for operative instruments and one 2.8 mm working channel for conventional flexible endoscopic instruments. The tip of the endoscope is equipped with two opening arms and provides endoluminal triangulation (Legner et al., 2017). A variety of operating tools with multiple degrees of freedom including graspers and knives have been developed (Fig. 2). The system is designed to be handled by a single operator unlike the MASTER that requires two operators. More than a robotic device, this is a motorized-master slave manipulator. Snake robots aimed at enhancing flexible endoscopy itself with potential wider applications have also been developed. Patel et al describe a robotic system consisting of a flexible snake robot with articulated distal section, delivery shaft and motor housing unit and seven degrees of freedom (Fig. 3). The distal articulated section was controlled by miniature motors (Patel et al., 2015). The ARES, or assembling reconfigurable endoluminal surgical system (Laboratory TIE, n.d.), offers a totally different concept of a surgical platform. This is a component-based miniature robotic platform that the patient ingests in multiple components which then assemble within the gastric lumen (Fig. 4).

Fig. 2 STRAS robotic platform. From Legner, A., Diana, M., Halvax, P., et al. (2017). Endoluminal surgical triangulation 2.0: A new flexible surgical robot. Preliminary pre-clinical results with colonic submucosal dissection. International Journal of Medical Robotics and Computer Assisted Surgery 13.

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Fig. 3 Flexible snake robot with articulated distal section. From Patel, N., Seneci, C. A., Shang, J., et al. (2015). Evaluation of a novel flexible snake robot for endoluminal surgery. Surgical Endoscopy 29, 3349–55.

Fig. 4 ARES robotic system. From Wilfong, C. D. and Schwaitzberg, S. D. (2017). The future and challenges of surgical technology implementation and patient safety. In: Sanchez, J. A., Barach, P., Johnson, J. K., et al. (eds.) Surgical patient care: Improving safety, quality and value, pp. 133–142. Cham: Springer International Publishing.

Platforms Enabling Endolumenal Surgery Over the scope platforms based on concept on an overtube are now available for endolumenal surgical procedures. These include Dilumen and ORISE. The Dilumen platform has a plastic sheath that moves over the scope and hosts two push rods on either side. The push rods are attached to a distal balloon attachment which can be push further from the tip of the scope. This element can be used to provide traction and aid dissection. A second balloon towards the anal side of the sheath when inflated stabilizes the scope (Kantsevoy et al., 2019). The ORISE Tissue Retractor System (Boston Scientific, Marlborough, Mass, USA) is a new endoscopic platform that can be mounted on an endoscope. It has an expandable intraluminal chamber that is armed with two specifically designed retractor graspers to aid dissection by providing traction (D’Amico et al., 2019). The design allows independent movement of the tissue graspers and the scope tip.

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Image Guidance for Navigation Reaching a specific target for performance of the NOTES surgery can be challenging. Researchers have developed real time imaging techniques allowing for more precise navigation (Córdova et al., 2013). Other investigators have made wireless and magnetic cameras that can be used to enhance intra cavitory views in addition to the endoscopy (Chang et al., 2013) (Fig. 5).

NOTES Simulation Efforts have been underway to create NOTES simulation systems (Gromski et al., 2016). NOViSE is the first force-feedback enabled virtual reality (VR) simulator for NOTES and has specifically been studied for hybrid transgastric cholecystectomy simulations effectively (Korzeniowski et al., 2016, 2017). ELITE is an ex vivo simulator for NOTES developed with the intention of providing a realistic model, replicating a female torso and potentially reducing the need for animal models (Fiolka et al., 2010).

NOTES in Clinical Practice Translation of NOTES from bench to bedside has happened on an incremental basis, given the lack of dedicated tools, relying on existing endoscopic or laparoscopic devices. Hybrid NOTES procedures utilizing assistance from percutaneous access points are also in clinical use.

Per Oral NOTES Trans gastric pancreatic necrosectomy Transluminal pancreatic necrosectomy truly qualifies as a NOTES procedure and is likely the most widely performed endosurgical procedure. This procedure was developed even before the coining of the term NOTES.

Per oral endoscopic myotomy or POEM The immediate and most successful procedure born out of the disruptive concepts of NOTES is the per-oral endoscopic myotomy (POEM) for treatment spastic motility disorders of the esophagus, primarily achalasia (Kandulski et al., 2016; Khashab et al., 2018; Kristensen et al., 2014). Soon after the development of submucosal access techniques (Pauli et al., 2008a; Moyer et al., 2007; Liu and Song, 2016), Inoue et al (Inoue et al., 2010; Inoue and Kudo, 2010) published the first human series on POEM. The lower esophageal sphincter is an optimal target for endoscopic therapy given the ease of access of the esophageal musculature from the gut lumen. The original POEM procedure specifically targeted the lower esophageal sphincter through a submucosal tunnel and may now be referred to as the E-POEM. The concept of submucosal tunneling and muscle incision has been successfully applied also to the upper esophageal sphincter (Z POEM), the pyloric sphincter (G-POEM) and the anorectal musculature (PREM) as detailed below.

Detailed steps of E-POEM E-POEM may be performed in the operating room or in an appropriately facilitated endoscopy unit. All patients are given a prophylactic antibiotic primarily to cover the oral flora, usually cefazolin, unless there is concern of an allergy to the medication. A standard endoscopy is first performed and the landmarks are noted. The esophageal mucosa is confirmed to be free of inflammation and significant candidiasis. In the authors practice, E-POEM is performed even if there is mild candidiasis after giving a dose of fluconazole intravenously. In preparation for POEM, the esophageal lumen is cleared of all debris and thoroughly lavaged. A patient who has a significantly dilated esophagus is ideally scoped a few days beforehand to clear the esophageal contents. Our protocol is to keep all patients on a clear liquid diet for three days prior to E-POEM.

Fig. 5 Use of wireless, magnetic cameras. From Chang, V. C., Tang, S. J., Swain, C. P., et al. (2013). A randomized comparison of laparoscopic, flexible endoscopic, and wired and wireless magnetic cameras on ex vivo and in vivo NOTES surgical performance. Surgical Innovation 20, 395–402.

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Typically for the POEM procedure, an adult upper scope fitted with a cap is used. Inoue’s initial technique used a slanted cap proposed to enable easy entrance into the submucosa and a favorable approach to the deeper muscle. Many endoscopists, including the authors, have moved to the commonly used transparent cap attachment (Olympus) and have found it easy to use. This cap is smaller in size and allows easy access into the submucosa through a smaller incision while allowing for a smaller tunnel lumen, overall translating into a shorter procedure. The access site for entrance into the submucosa has been chosen to be at different locations along the circumference of the esophagus, although the majority are done through an anterior or posterior approach (Stavropoulos et al., 2013). There appears to be no specific advantage for one over the other (de Pascale et al., 2017). The site for the incision is chosen to be 10–15 cm above the lower esophageal sphincter. In patients with type 3 achalasia or jackhammer esophagus, given that the lower esophagus itself is very spastic, a longer myotomy is performed and hence the access site is chosen at a more proximal location. At the selected site, a submucosal injection of a few milliliters of saline tainted with methylene blue or indigo carmine is performed to raise a cushion for safe mucosal incision. A traditional endoscopic injection needle is used unless a hybrid knife (ERBE) is used. The hybrid knife in addition to being a cautery knife is capable of injecting a high pressure jet which allows a needleless creation of the submucosal cushion. The jet at an effect of 50 penetrates the mucosa and expands the submucosa with saline without damaging the deeper muscle. An effect of 30 is used for additional submucosal injections. The mucosal incision is made in a vertical direction by most endoscopists to allow easier closure with clips at the end of the procedure. The incision has to be about 1.5–2 cm and deep into the submucosa. The beginner could mistake a prominent muscularis mucosa as the muscularis propria and be tricked into beginning a tunnel in the superficial mucosa. Creation of an adequate submucosal bulge with 2–3 cm3 of saline and a deep enough incision clearly exposing the blue fluid filled submucosa will land one in the correct plane. It is ideal to undermine the edges of the incision site to create space to introduce the cap fitted scope into the submucosa. For incision, a cutting current can be used. Our preference is to use the endo cut setting on the ERBE unit. Many operators use the triangle tip knife as initially demonstrated by Inoue. After the incision is completed, the scope fitted with the cap is introduced into the submucosa and a tunnel is dissected towards the cardia. The spray coagulation mode can be used to dissect without contact and thus can prevent formation of coagulum on the knife tip. The coagulation mode also minimizes bleeding. Adequate injection is needed and has to be done repeatedly to safely dissect the mucosa. The hybrid knife has the advantage of injection on demand without device exchange and thus save time. The swift coagulation (effect 2 and 50 Watts) mode works well with the hybrid knife for dissection. The authors prefers a “T” type hybrid knife while some others use an “I” type knife. As the tunnel moves distally from the location of the incision, it is ideal to take the dissection deep to expose the muscularis propria. For further dissection, the muscle layer is used as the guide. By keeping the direction perpendicular to the fibers of the muscularis propria, one can avoid getting lost in the submucosa and keep the tunnel propagating straight without spiraling down (Bechara et al., 2016). Further, staying on the muscle layer minimizes risk of mucosal injury. This approach is key in successfully completing E-POEM in those patients with submucosal fibrosis. Proper identification of the LES is necessary to perform a complete myotomy. The tunneling usually gets more difficult when the level of the LES is reached. Saline injection at this location provides limited expansion of submucosa due to the squeeze of the sphincter muscles. Occasionally, the LES is so tight that traversing the area is not possible without incising at least some of the circular fibers. The entrance to the gastric wall is evidenced by the disappearance of the tight circular fibers of the LES. The decrease in the thickness of the circular fibers and easier and longer lasting expansion of the submucosa with the saline injection will be noted. There are larger perforating vessels and a general increase in vascularity in this region. These findings should be correlated with the expected distance of the LES noted on the initial survey of land marks. Finally, the scope is withdrawn from the tunnel and the lumen is examined following the bluish hue noted on the mucosal side all the way into the stomach. Absence of any mucosal injury and penetration on to the gastric side is confirmed. A small injury or mucosal perforation can be treated with endoscopic clips. With a large perforation or rupture of the tunnel, one may have to discontinue the procedure as the self-approximating nature of the tunnel will be compromised with increased potential for a leak. Myotomy is initiated 2–3 cm below the level of the mucosal incision to separate the mucosal incision from the distal muscle incision. The circular fibers are carefully cut to expose the deeper longitudinal muscles. Saline injection between the muscle layers may help identify that plane better. The thickness of the circular fibers can vary from a few millimeters to more than a centimeter. The circular fibers are then hooked towards the lumen of the tunnel and cut. A cut current or coagulation setting can be used for this step. The incision is then taken down to at least 2 cm into the stomach. Identification of the longitudinal fibers and following them intently is key to staying in the proper plane. The longitudinal fibers form a very thin layer and often splay, exposing the adventitia and the adjacent pleuropericardial membranes. Loss of landmarks could lead dissection away from the esophagus. If the circular and longitudinal muscle are difficult to separate, the author’s practice is to perform a full thickness myotomy. Performance of a full thickness myotomy is reported by some authors and a routine strategy, but is not known to be of any added benefit and may cause increase incidence of acid reflux (Wang et al., 2016; Duan et al., 2017). After the myotomy is completed, the wider opening of the LES is readily appreciated form the esophageal lumen. Some endoscopists employ the EndoFlip device (Crospon/Medtronics USA). This device has a balloon catheter system that gives a 3D view of the configuration and movements of the esophagus to help diagnose achalasia and to evaluate completion of the myotomy after E-POEM (Kalapala et al., 2015; Familiari et al., 2014). The reported complications from E-POEM are minimal and have decreased with more experience. The major complications were from leakage of gas into the chest and pericardial cavity, mostly blamed on using air as the insufflation gas and rarely requires surgical intervention (Crespin et al., 2017). Use of CO2 has minimized though not eliminated this risk. Controlling the flow of CO2

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to minimum needed either automatically or manually by applying a clamp to the tubing that brings the CO2 into the water bottle is routinely done in our protocol. Fortunately, the much feared risk of infection appears to be minimal. Cases of fungal mediastinitis have been published (Crespin et al., 2017; Okada et al., 2018; Talukdar et al., 2015). Postoperative bleeding requiring reentry into the tunnel for hemostasis is very rare, but has been reported in the first 48 hours (Li et al., 2013). After E-POEM, severe pain is uncommon in our experience and less compared to Heller myotomy (Docimo et al., 2017). Postprocedural heartburn may responds to oral antacid medication. The majority of patients have minimal epigastric or retrosternal discomfort that improves over a few hours. Post-operative imaging studies often show trace gas in the vicinity and is of no clinical significance (Pannu et al., 2016; Lall et al., 2018). The frequency of postoperative leak is also very low. Original post-procedural protocols were to obtain STAT chest x-rays, observe patients overnight, and allow a clear liquid diet only after a swallow study was performed and negative for esophageal leak. At author’s institution, this protocol has been changed starting in January 2017. Now, we observe patients for 4–5 hours and then discharge the patients allowing ice chips that night. The following day, a clear liquid diet and then full liquids for next two is given. Diet is advanced after that. The immediate and short term outcome in patients with achalasia after POEM is very good. From a cost effectiveness stand point it compares with or is better than traditional Heller myotomy (Greenleaf et al., 2018). Expert opinion and society guidelines now acknowledge that POEM is comparable to the other treatment options available for achalasia and considers it superior to other alternatives specifically for type 3 achalasia (Zaninotto et al., 2018; Kahrilas et al., 2017).

Z-POEM Z-POEM refers to the criopharyngiomyotomy (upper esophageal sphincter myotomy) performed for the treatment of symptomatic Zenker’s diverticulum (Li et al., 2016a; Hernández Mondragón et al., 2018). Zenker’s diverticulum is a pulsion diverticulum formed at the Killian’s triangle consequent to the pressure excreted by swallowed food boluses fighting a tight and nonrelaxing upper esophageal sphincter. On endoscopic evaluation, a Zenker’s diverticulum is seen bordering the upper esophageal sphincter which is often difficult to traverse. The endoscopic treatment of this disease involves incision of the UES between the Zenker’s diverticulum and the esophageal lumen. A cap-fitted upper endoscope can easily identify this location as a bridge/septum between the diverticulum and the esophagus. In the classic endoscopic technique, a needle knife is used to incise the septum to two-thirds of its depth. In the Z-POEM technique (Hernández Mondragón et al., 2018), a mucosal incision is made on the bridge after saline injection and the deeper muscle is identified. The submucosal plane is developed as in the E-POEM and the muscle fibers are identified and cut extending into the upper esophagus. This technique guarantees complete ablation of the tight sphincter with violating the deeper adventitial tissue and minimizes the risk of a leak. The incision site is then closed with clips, particularly at the deepest end of the incision where the mucosa lining the bottom of the diverticulum tends to be away from the esophagus. Endoscopic treatment of Zenker’s diverticulum is very rewarding given that a very symptomatic patient overnight becomes asymptomatic in nearly all cases. The risks are minimal and include soft tissue infection at the root of the neck. Similar outcomes can be obtained via rigid scope through a variety of techniques that are performed by ENT surgeons (Ciuc et al., 2018). The flexible platform is relatively easier on the patient and is of advantage in patients with difficult neck and jaw extension. The cap-assisted flexible scope technique is especially helpful in treating small diverticula, where stapling across the septum with a rigid device is especially difficult.

G-POEM The G-POEM, also referred to as per oral pyloromyotomy or POP, is proposed as an option for patients with gastroparesis who fail other treatment strategies. Similar to esophageal POEM, a submucosal tunnel directed towards the pylorus is made after accessing the submucosa via a mucosal incision. Success of reaching the pylorus through tunnels made on the lesser curve and greater curve has been reported. As the pylorus is approached, the ring of the muscles constituting the pyloric sphincter can be identified and these are then incised (Khashab et al., 2013). A full thickness myotomy to the serosa is usually performed. On withdrawal of the scope, the mucosal incision site is closed. A liquid diet is allowed the next day if there is no clinical concern and maintained for a few days to allow for healing. While G-POEM provides a beneficial option for groups of patients with little to no alternative treatment options, its effectiveness is not as uniform as the Z or E POEMs. Up to 70% of patients may respond to the myotomy (Benias and Khashab, 2017; Khashab et al., 2017; Rodriguez et al., 2018). Long term data is not available at present to confirm long lasting benefits.

Endoscopic Resection of Submucosal and Mucosal Masses The success of ESD in accomplishing resection of large polyps and the confidence to tackle a serosal defect provides the foundation to address submucosal lesions endoscopically. Submucosal lesions like small gastrointestinal stromal tumors can be accessed through a short submucosal tunnel and the tumor can be resected and extracted via the tunnel (Liu and Song, 2016). Alternatively a full thickness resection can be performed followed by closure of the serosal defect (Cai et al., 2016; Mori et al., 2015). The endoscopic approach is of benefit for lesions close to the gastroesophageal junction and the pylorus. At these locations, a surgical wedge resection is difficult and therefore a more extensive surgery is required. An endoscopic approach therefore becomes much

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more attractive. Hybrid procedures with endoscopy and a transgastric laparoscopic port may be of advantage in select cases (Walsh and Heniford, 2001; Maker, 2013). In these procedures, the endoscope provides visualization and can apply traction on the lesion, allowing the stapler to be positioned underneath the lesion. Intra-gastric stapling is then performed. Small neuroendocrine tumors are another group of submucosal masses that can be treated endoscopically (Joo et al., 2016). Endoscopic resection should be limited to lesions 1000 IU/L Very high (often >20,000 ng/mL) Almost always normal

Normal Acute hepatic necrosis, inflammation, possible viral inclusion bodies

Normal Acute hepatic necrosis, evidence of hemophagocytosis

Abnormal Micro/macro-vesicular steatosis, hepatocyte swelling, possible portal fibrosis

Very high (often >20,000 ng/mL)

Variable elevation Variable elevation

GALD, gestational alloimmune liver disease; NH, neonatal hemochromatosis; HLH, hemophagocytic lymphohistiocytosis; IUGR, intrauterine growth restriction; CMV, cytomegalovirus; CNS, central nervous system; HSV, herpes simplex virus; ALT, alanine aminotransferase; AFP, alpha-fetoprotein; L:P, lactate: pyruvate. Table modified from: Taylor, S. A. and Whitington, P.F. (2016). Neonatal acute liver failure. Liver Transplantation 22, 677–685.

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the NH phenotype. Evaluation of NH should be pursued in a step-wise manner, and the second modality of testing should be performed only if the first is non-diagnostic. Diagnostic difficulties arise in cases of suspected GALD with a negative work-up for NH as well as in cases with low clinical suspicion of GALD but positive NH. In the first situation, a negative evaluation for NH may be secondary to limitations in the sensitivity of MRI and oral mucosal biopsy or due to the more rare presentation of acute GALD without NH. In this scenario, liver biopsy is important for supportive pathologic findings to aid in the diagnosis of GALD if it can be safely performed in the sick neonate. In the second scenario, if NH is confirmed but an infant has an atypical presentation for GALD, one should continue evaluation for non-GALD etiologies of NH based on the clinical presentation. While GALD is the most common cause of NH, the most common alternate etiology of NH in our experience is Trisomy 21 with myeloproliferative disorder (see full description of alternate causes of NH in pathobiology). Liver pathology is useful in the diagnostic evaluation of GALD as well as alternate etiologies of NALF. Feasibility of obtaining liver biopsy, however, is often limited due to the procedural risks in a critically ill neonate. In GALD, liver biopsy is often obtained after the neonate demonstrates some clinical improvement and has had an inconclusive work-up for NH. Many histology samples for evaluation of GALD are also obtained at autopsy. It is imperative to pursue pathologic examination in cases of fetal loss or neonatal death due to NALF without an identified cause as GALD can be prevented in future pregnancies with gestational IVIG therapy. Histologic examination of the liver in GALD-NH classically demonstrates severe parenchymal disease with sparing of the portal tracts. There is a pronounced paucity of hepatocytes and the remaining hepatocytes commonly demonstrate giant cell or pseudoacinar transformation. Ductular reaction is observed in the parenchyma and there is rare or absent extramedullary hematopoiesis. Pronounced fibrosis is usually present especially in the lobule with possible cirrhosis and regenerative nodules. Notably, the regenerative nodules commonly demonstrate normal hepatocytes as these nodules reflect the liver’s ongoing reparative efforts that have escaped antibody-mediated injury. While staining for the C5b-9 complex remains a research tool, additional evaluation of liver tissue for C5b-9 can help support a diagnosis of GALD in the right clinical-pathological context. In GALD, positive C5b-9 staining in the cytoplasm of residual injured hepatocytes is observed. Regenerative nodules represent areas that have escaped injury and are commonly negative for C5b-9 stain. The C5b-9 stain must be interpreted carefully as other causes of neonatal liver injury have demonstrated less prominent positive C5b-9 staining including cholestatic disorders, genetic and metabolic disorders, and cases of acute hepatic necrosis from various etiologies (Pan et al., 2010; Whitington et al., 2011). Additional histologic features not common in GALD-NH may point to an alternate etiology of NALF (Table 1). For example, inflammation, which is not characteristic of GALD, can be seen in infection or immune-mediated injury. Acute hepatic necrosis has been observed in cases of GALD with acute fetal onset and fetal demise, but is not characteristic for GALD-NH presenting with NALF. Instead, hepatic necrosis on liver histology is more commonly seen in NALF secondary to infection, HLH, or ischemia. Identification of viral inclusion bodies may be present in certain viral infections, hemophagocytosis is observed in HLH, and micro/macrovesicular steatosis and hepatocyte swelling/degeneration are common features on liver histology of mitochondrial disorders.

Treatment If the clinical scenario in NALF is suspicious for GALD-NH, infants should immediately receive one dose of high-dose IVIG (1 g/kg) as this treatment carries low risk and earlier initiation of treatment is more effective (Fig. 1). In GALD-NH, IVIG is thought to displace antibody already bound to the target antigen and bind to circulating complement to block further injury from the complement cascade. After confirmation of NH by MRI or oral mucosal biopsy, full treatment for GALD-NH with double-volume exchange transfusion (DVET) and a second dose of IVIG is recommended unless an alternate etiology of NH is identified. This additional treatment serves to remove and block remaining maternal antibody. Treatment with IVIG and DVET results in survival rates of 45%–75% in infants with GALD (Rand et al., 2009; Taylor et al., 2018) which is much improved from survival rates of 13% with either no disease-specific treatment or the historical cocktail of chelators and antioxidants (Taylor et al., 2018). Even after full treatment, recovery from GALD is prolonged, and it can take weeks to see a noticeable improvement in the INR and months for a full recovery. Affected infants should not be fed maternal breast milk to avoid further liver injury from passage of antibody in breast milk. Furthermore, supportive care rather than technically challenging liver transplantation is recommended. Outcomes of liver transplantation for infants 10% by age 30 years and >30% by age 60 years (Sastry et al., 2015).

Other obstructive/anatomic etiologies Inspissated bile syndrome is the result of accumulation of bile in canaliculi and in the small- and medium-sized bile ducts. This has been reported in the setting of hemolytic disease of the newborn (Rh, ABO), in infants receiving parenteral nutrition and in premature infants with prolonged time periods without enteral nutrition. The same mechanisms may cause intrinsic obstruction of the common bile duct. If inspissation of bile occurs within the extrahepatic biliary tree, differentiation from BA may be difficult. Although most cases improve, persistence or worsening cholestasis for >2 weeks requires further studies (ultrasonography, HIDA scanning, liver biopsy) with possible intraoperative cholangiography. Irrigation of the common bile duct is sometimes necessary to dislodge the obstructing inspissated biliary material. Spontaneous perforation of the common bile duct should be suspected in the setting of an ill-appearing infant with sudden onset of obstructive jaundice, acholic stools, and abdominal enlargement with ascites. In addition, a yellow-green discoloration can often be seen under the umbilicus or in the scrotum of males. In some cases, the etiology is due to stones or sludge that obstructs the common bile duct. Liver ultrasound shows fluid around the bile duct and a HIDA scan is diagnostic. A neonatal endoscopic retrograde cholangiopancreaticogram with biliary stenting is often effective at stopping the biliary leakage. A diversion anastomosis is constructed in cases associated with choledochal cyst or bile duct stenosis.

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Infection Infection as a cause of cholestasis should be considered in the ill-appearing infant with jaundice, hepatomegaly, vomiting, lethargy, fever, and/or petechiae. Infectious agents associated with neonatal intrahepatic cholestasis include bacterial sepsis, bacterial urinary tract infections, herpes simplex virus, varicella virus, enteroviruses (coxsackievirus and echovirus), cytomegalovirus (CMV), rubella virus, adenovirus, parvovirus, human herpesvirus type 6 (HHV-6), hepatitis B virus (HBV), human immunodeficiency virus (HIV), Treponema pallidum, and Toxoplasma gondii. The degree of liver cell injury caused by these agents is variable, ranging from massive hepatic necrosis (herpes simplex, enteroviruses) to focal necrosis and mild inflammation (CMV, HBV). CMV is the most common infectious cause of neonatal cholestasis. Most forms of neonatal viral hepatitis present in the first few days of life and are treated with supportive care. However, infections with herpes simplex virus, varicella, CMV, and toxoplasmosis have specific treatments. Multiple organ involvement can occur with neonatal infectious hepatitis and has a poor outcome. Hepatic or cardiac failure, intractable acidosis, or intracranial hemorrhage may be fatal in herpesvirus, adenovirus, or enterovirus infections. HBV rarely causes fulminant neonatal hepatitis. Although persistent liver disease with any virus can result in chronic hepatitis, the neonatal liver usually recovers after acute infections, without progression to fibrosis.

Genetic Paucity of interlobular bile ducts

Syndromic paucity of interlobular bile ducts—Alagille syndrome Alagille’s syndrome (AGS) was first described in 1969 in a group of children with idiopathic bile duct paucity and a constellation of anomalies. This disorder has been termed arteriohepatic dysplasia, intrahepatic biliary hypoplasia, and syndromic paucity of interlobular bile ducts. Associated findings include cardiovascular, musculoskeletal, ocular, facial, renal, pancreatic, and neurodevelopmental abnormalities. The prevalence has been estimated to be 1 in 30,000–70,000 live births, however this is likely a significant underestimate of the true frequency, as some affected individuals have subclinical expression (Kamath et al., 2018). Etiology of AGS AGS is an autosomal dominant disorder which develops secondary to mutations in two genes associated with the Notch signaling pathway, an evolutionarily conserved signaling pathway for cell fate. The majority of patients have a mutation of the JAG1 gene, which encodes the Jagged-1 ligand (approximately 90%–95% of AGS cases), with a smaller portion of patients having mutations in the NOTCH2 gene. The disrupted signaling in the Notch pathway leads to abnormal development of the intrahepatic bile ducts, as well as a constellation of other anomalies. There is significant variability in disease penetrance, with some patients having no apparent symptoms and others having progressive cirrhosis ultimately requiring liver transplant. Diagnosis of AGS Diagnostic criteria for AGS includes chronic cholestasis, cardiac defects, skeletal defects, abnormal facies, ophthalmologic abnormalities, renal abnormalities and vascular anomalies. The diagnosis is based on meeting three of the above seven criteria or two criteria plus identification of a mutation in the JAG1 or NOTCH2 gene. If there is initial concern for biliary atresia and biopsy is performed, liver histology will often demonstrate a paucity of interlobular bile ducts (500 mg dL1 and cholesterol may reach levels up to

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2000 mg dL1. Growth retardation is common and often beyond what would be expected for the degree of cholestasis, indicating a multifactorial cause of growth failure. Cholestasis progresses to end-stage liver disease and ultimately requires transplantation in 20%–50% of cases (Kamath et al., 2012). Alternatively, a significant portion of patients will have spontaneous improvement and/or stabilization of their liver disease over time. There are no clear correlations between genotype and phenotype, thus the type of disease-causing mutation is not predictive of disease severity or long-term outcomes. Early findings which have been shown to predict severe liver outcomes (i.e., death from end-stage liver disease, need for transplantation, medically refractory pruritus, pathologic bone fractures, and portal hypertension) include the degree of cholestasis early in life, fibrosis on liver biopsy done before 5 years of age, and presence of xanthomata on physical exam (Mouzaki et al., 2016). Patients with mild hepatic outcomes tend to have a rapid fall in total bilirubin levels between 12 and 24 months of age (a trend not readily observed in patients with severe hepatic outcomes). Indications for transplantation include liver synthetic failure, complications of portal hypertension, bone fractures, intractable pruritus, disfiguring xanthomata, and growth failure. Post-transplant outcomes are suboptimal in patients with AGS—in one multicenter study, the 1-year patient survival rate was 87% for AGS patients, as compared to 96% for an age and sex-matched group of patients with biliary atresia (Kamath et al., 2012). Of note, death among patients with AGS occurred early, mostly within the first 30 days following transplant. Vascular, biliary, renal, and CNS complications following transplant were associated with death in the AGS group, indicating that the multi-system nature of AGS may be responsible for worse outcomes.

Nonsyndromic paucity of interlobular bile ducts Nonsyndromic bile duct paucity is a term used to describe all instances of paucity which do not occur in the context of AGS. It is a non-specific finding and has been associated with a variety of conditions including infections, metabolic/genetic disorders, toxic insults, and chromosomal disorders. This term includes cases either with or without an associated “primary” disease. Nonsyndromic paucity of interlobular bile ducts has been described in trisomy 21, hypopituitarism, cystic fibrosis, a1-antitrypsin deficiency, congenital CMV, progressive familial intrahepatic cholestasis (PFIC), and inborn errors of metabolism. Nonsyndromic paucity without an identifiable primary disorder may be a result of a yet unknown metabolic defect. The overall prognosis of nonsyndromic paucity is quite unclear and is likely associated with the prognosis of the underlying disease.

Progressive familial intrahepatic cholestasis (PFIC) Progressive familial intrahepatic cholestasis is a group of rare disorders of canalicular hepatobiliary transport, resulting in accumulation of bile acids in the liver and subsequent hepatocellular injury and fibrosis. To date, there are 6 known genetic mutations representing distinct subtypes of PFIC (PFIC1-PFIC6) (Table 2). PFIC is an autosomal recessive mode of inheritance, with an overall incidence of approximately 1: 50,000 and often presents as cholestasis with significant pruritus in infancy. Accurate diagnosis is attained through genetic analysis and these gene mutations are frequently available as part of a targeted cholestasis gene panel. The modes of presentation and clinical course are heterogeneous between PFIC subtypes, however in most cases cirrhosis develops and liver transplantation is necessary for survival. All PFIC subtypes are associated with normal or low levels of GGTP, except PFIC3. PFIC1 (Byler disease) is associated with intestinal malabsorption and severe diarrhea due to lack of intestinal FIC1 protein function. Other manifestations include pancreatitis, deafness and pneumonia. PFIC1 and PFIC2 patients often present with significant fat soluble vitamin deficiencies, including Vitamin K deficiency with risk of coagulopathy and intracranial hemorrhage.

Table 2

Progressive familial intrahepatic cholestasis (PFIC) subtypes

Type

PFIC1

PFIC2

PFIC3

PFIC4

PFIC5

PFIC6

Gene Protein

ATP8B1 PS flippase (FIC1)

– Cholestasis with rapid progression to cirrhosis

– Recurrent cholestasis – MID

GGTP Therapy

Low – Anti-pruritics – Biliary diversion – Liver transplant

Low – Anti-pruritics – Biliary diversion – Liver transplant

High – Anti-pruritics – Liver transplant

TJP2 Tight junction protein 2 – Cholestasis – HCC – Pulmonary disease – Neurologic disease Low – Anti-pruritics – Liver transplant

MYO5B Myosin 5b

– Cirrhosis – Malabsorption/ diarrhea – Hearing defects – Pancreatitis

ABCB4 PC translocator (MDR3) – Cirrhosis – Gallstones – HCC/CCA

NR1H4 FXR: Nuclear bile acid receptor

Phenotype

ABCB11 Bile acid export (BSEP) – Cirrhosis – HCC

Low – Anti-pruritics – Liver transplant

Low – Anti-pruritics – Liver transplant

BSEP: bile salt export protein; CCA: cholangiocarcinoma; HCC: hepatocellular carcinoma; MDR3: multi-drug resistant 3; MID: microvillus inclusion disease; PS: phosphatidylserine; PC: phosphatidylcholine.

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The majority of PFIC2 (BSEP deficiency) cases progress to cirrhosis within 2 years of life and patients are at higher risk for the development of hepatocellular carcinoma (HCC) in this time frame. PFIC3 disease is associated with high GGTP levels, intrahepatic cholestasis of pregnancy and cholelithiasis. PFIC4 is due to dysfunctional tight junctions at the canaliculus, resulting in early onset cholestasis. PFIC5 is due to nuclear receptor FXR dysfunction, resulting in lack of activation of BSEP and loss of inhibition of bile acid uptake and synthesis. PFIC5 is more aggressive than the other subtypes, with rapid progression to cirrhosis. PFIC6 is due to defects of myosin 5b, a protein required for hepatocyte polarization. Severe MYO5B mutations can be associated with systemic microvillus inclusion disease (Reichert et al., 2018). All PFIC subtypes can be treated with anti-pruritics and some patients with PFIC1 and PFIC2 have improvement in pruritus after partial external biliary diversion. Liver transplantation is necessary for the majority of patients. Post-liver transplant complications in PFIC1 include steatosis of the allograft and persistence of intestinal disease. Post-liver transplant, a small proportion of PFIC2 patients develop antibodies to the allograft BSEP protein, leading to a clinical phenotype of recurrent disease.

Cystic fibrosis Cystic fibrosis (CF) is a relatively common genetic disease leading to dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR). Hepatobiliary manifestations in cystic fibrosis are common and can range from neonatal cholestasis, elevated transaminases, steatosis, gallbladder disease, and cirrhosis. Neonatal cholestasis is, however, one of the less common presentations of CF liver disease. CFTR is located on the apical surface of bile duct epithelium and functions to increase biliary chloride secretion, subsequently increasing bile acid independent bile flow. The leading theory for the development of CF-related liver disease is impaired alkalinization and dehydration of bile secondary to reduced biliary chloride transport, leading to inspissated bile, plugging, inflammation, and subsequently fibrosis. In evaluating a newborn with cholestasis, the diagnosis of CF may be supported by the presence of meconium ileus, although this association will not always be encountered. The diagnosis of CF is suspected with a positive newborn screen and abnormal sweat chloride testing and confirmed with genetic testing. CF-associated neonatal cholestasis usually resolves in infancy.

Bile acid synthesis disorders Bile acid synthesis disorders (BASD) are a group of genetic disorders related to enzymes involved in the synthesis of bile acids from cholesterol precursor molecules. BASDs are an extremely rare cause of neonatal cholestasis, however it is important to consider these disorders as many of them are treatable. Most cases present with normal or low GGTP and low total serum bile acids (which can be used as a screening tool). Clinical presentation includes a transient neonatal cholestasis, significant fat soluble vitamin deficiencies and growth failure. Further workup to confirm the diagnosis includes fast atom bombardment mass spectrometry of urine bile acids and genetic mutation analysis. Treatment with cholic acid or chenodeoxycholic acid are curative for several forms of BASDs (Setchell et al., 2013).

Metabolic Metabolic disorders present with a wide variety of clinical manifestations depending on the nature of the underlying defect. An exhaustive review of all metabolic disorders which can present with neonatal cholestasis is beyond the scope of this chapter, but some of the most relevant metabolic disorders are reviewed below.

a1-Antitrypsin deficiency

a1-Antitrypsin (A1AT) deficiency, an autosomal recessive disorder, is the most common inherited cause of neonatal cholestasis, with a prevalence of approximately 1 in 5000 people in the United States (De Serres and Blanco, 2014). The A1AT protein is a serine protease inhibitor synthesized mainly by the liver which acts to neutralize neutrophil elastase, among other enzymes. Genetic mutation results in a misfolded protein which cannot be secreted by hepatocytes, leading to low A1AT activity in the blood and accumulation of the abnormal protein in hepatocytes. Accumulation in the endoplasmic reticulum can lead to hepatocyte death, inflammation, fibrosis, and cirrhosis, the precise pathogenesis of which remains unclear. The normal gene is referred to as Pi (Protease inhibitor) M, and the two most common deleterious alleles are PiS and PiZ. The majority of severe A1AT deficiency occurs secondary to a PiZZ (homozygous ZZ) genotype, with a small portion occurring with combinations of PiZ, PiS, and some other rare alleles. Patients with PiSS do not develop liver disease. Only about 2.5% of PiZZ children identified will develop cirrhosis in childhood or adolescence, however the risk continues to increase with age (De Serres and Blanco, 2014). Although lung disease does not affect children, homozygous ZZ adults suffer from emphysema, most likely as a result of decreased circulating levels of the protease inhibitor and pulmonary damage by neutrophil elastase. Approximately 15% of affected infants with A1AT deficiency will present with neonatal cholestasis, however the jaundice is transient in the majority of cases. Serum aminotransferases, alkaline phosphatase, and GGT levels are typically elevated. This disorder must be distinguished from BA. Often patients exhibiting ZZ or SZ phenotypes have no radionuclide biliary excretion. Serum A1AT level will be markedly reduced; however, phenotype should be used to make the diagnosis, as the A1AT level can be transiently normal due to the acute-phase reactant nature of the protein. Liver biopsy will reveal characteristic periodic acid–Schiff (PAS)-positive diastase-resistant globules in the periportal hepatocytes. There is no specific treatment for this disorder. Liver transplantation is curative for end-stage liver disease and prevents the development or worsening of lung disease.

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Tyrosinemia type 1 Tyrosinemia type 1 is an autosomal recessive disorder resulting from deficiency of fumarylacetoacetate hydrolase, which is the last enzyme in the tyrosine degradation pathway. The result is an accumulation of succinylacetone, which can be measured in urine. Infants usually present in the first 2 months of life with cirrhosis or decreased hepatic synthetic function manifested as coagulopathy and ascites. The diagnosis is made by identification of succinylacetone in the urine. Previously, almost all patients died in infancy or early childhood unless they underwent urgent liver transplantation, until the discovery of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3cyclohexanedione (NTBC) as a therapeutic agent. NTBC, also known as nitisinone, is an herbicide that inhibits the second enzyme in the tyrosine degradation pathway, thereby preventing accumulation of toxic succinylacetone. In addition to NTBC, patients continue a phenylalanine- and tyrosine-restricted diet and are monitored for blood tyrosine and a-fetoprotein levels. Newborn screening is performed for tyrosinemia in most states. Concern remains regarding the development of hepatocellular carcinoma despite effective treatment.

Galactosemia Galactosemia is an autosomal recessive disorder of galactose metabolism resulting in accumulation of galactose-1-phosphate. Symptoms develop following exposure to lactose (either in breast milk or lactose-containing formula), which is metabolized in to galactose. Infants can present with jaundice, hepatomegaly, hypoglycemia, failure to thrive, vomiting, and lethargy. If untreated, there may be rapid progression to hepatic failure as well as sepsis due to gram-negative bacteremia. Cataracts may develop in early infancy and significant cognitive defects may become apparent after several months of life. Early diagnosis is imperative in order to initiate a galactose-free diet, which has prompted newborn screening in most states. Confirmatory testing is done via direct measurement of galactose 1-phosphate uridyltransferase activity, the enzyme affected in galactosemia. Treatment with a galactose-free diet leads to reversal of acute symptoms, normal growth, and recovery of liver function, however long-term neurologic outcomes are variable.

Mitochondrial disorders Mitochondria are important organelles which synthesize ATP to drive energy-dependent cellular processes. When mitochondrial defects exist, the highly energy-dependent tissues, namely liver, heart, skeletal muscle, and brain, are often affected. Mitochondrial disorders can be highly variable in presentation, manifesting as neonatal cholestasis, neonatal acute liver failure, or chronic hepatitis with a more insidious progression to cirrhosis and liver failure. Common mitochondrial DNA mutations include POLG, DGUOK, and MPV17, and organ system involvement beyond the liver is frequent but also highly variable. Newborns typically present with some combination of the following: cholestatic hepatitis, ketotic hypoglycemia, hyperammonemia, coagulopathy, lactic acidosis, lethargy, hypotonia, vomiting, and poor feeding with failure to thrive. Although lactate is typically markedly elevated, some mitochondropathies present with normal plasma lactate. Liver biopsy often demonstrates hepatocyte glycogen depletion and microvesicular steatosis. One can use the lactate to pyruvate ratio to screen for mitochondrial disease (concern if >20), and if a mitochondropathy is suspected, genetic testing can be done to evaluate for common mitochondrial DNA (mtDNA) mutations with aid from a Metabolic/Genetics specialist.

Toxins Parenteral nutrition (PN) PN can be lifesaving for critically ill neonates who cannot attain adequate enteral nutrition. However, parenteral nutritionassociated cholestasis (PNAC) is common and can be a significant challenge in the infant who is unable to gain enteral independence. Although the pathogenesis of PN-associated cholestasis is multifactorial, soybean oil lipid emulsions seem to play a prominent role in disease development. With the advent of fish oil based lipids, mixed lipid emulsions, and/or reduced lipid dosing (e.g., limiting soybean oil lipid to 1 g1 kg1 day), the risk of cholestasis and progression of liver disease can be reduced. SMOFLipid (soybean oil, mineral oil, olive oil, fish oil) has shown promising results in reducing cholestasis (Lam et al., 2017), although studies in pediatric patients are limited. The incidence of cholestasis increases with the length of PN exposure—one study showed an incidence of 14% in neonates who received PN for 14–28 days, 43% in those who received PN for 29–56 days, and 72% in those who received PN for 57–100 days (Christensen et al., 2007). In addition to PN duration and type of lipids, risk factors known to exacerbate PNAC include prematurity, sepsis, and bowel resection. Inflammatory cytokines released during sepsis act to down-regulates bile excretion. In infants who require jejunostomy, bile salt reabsorption is compromised which may lead to further reduction in excretion of bile. In the infant with intestinal failure and a prolonged fasting state, the normal stimuli for bile flow are absent, contributing to the development of cholestasis and intestinal-failure associated liver disease.

Drugs Medications which have been implicated in causing cholestatic hepatitis include penicillins, cephalosporins, and amoxicillin/clavulanate, among many others. A number of herbal products can lead to cholestasis and questions regarding herbals/supplements should always be included in the history. Maternal use of some medications has been linked to cholestasis in the newborn. For example, carbamazepine has been associated with neonatal cholestasis both with exposure in utero as well as with breast feeding. Prenatal exposure to some illicit substances, such as methamphetamines, have uncommonly been linked to neonatal cholestasis as well.

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Endocrine Hypothyroidism and panhypopituitarism Thyroid hormones stimulate both bile salt-independent bile flow as well as excretion of bilirubin. In the neonate with hypothyroidism, therefore, mild jaundice with a mixed conjugated and unconjugated hyperbilirubinemia is common. Although the mechanism is less clear, pituitary hormones are involved in the regulation of bile synthesis, excretion and flow. Congenital panhypopituitarism is frequently associated with neonatal cholestasis. Septo-optic dysplasia is characterized by pituitary hypoplasia with panhypopituitarism, optic nerve hypoplasia, and midline brain defects. Pituitary defects can be identified with brain MRI and these infants classically present with neonatal cholestasis, hypoglycemia, and roving eye movements. In both of these endocrine disorders, the cholestasis resolves with treatment of the underlying endocrinopathy.

Other Neonatal primary sclerosing cholangitis (neonatal PSC) The etiology of neonatal PSC is due to a genetic mutation in double cortin domain containing 2 (DCDC2). DCDC2 is a signaling and structural protein expressed within cholangiocyte cilia. Neonatal PSC can mimic BA, with significant elevation of GGTP, jaundice, acholic stools, hepatosplenomegaly and liver biopsy consistent with biliary obstruction. Intraoperative cholangiogram reveals a patent extrahepatic biliary tree, however the common bile duct often has irregular strictures and the intrahepatic biliary tree may have multiple strictures with pre-stenotic dilations. The majority of patients require liver transplantation for survival (Grammatikopoulos et al., 2016).

Idiopathic neonatal hepatitis (INH) Idiopathic neonatal (giant cell) hepatitis is a poorly characterized cause of cholestasis. It is more common in males and is usually self-resolving. It is defined based on histological findings of excessive giant cells, canalicular cholestasis, variable amounts of portal and lobular mixed inflammation and extramedullary hematopoiesis. However, the histologic findings are not unique and can be found in a variety of cholestatic diseases. Due to advancements in genetic analyses and identification of known causes of cholestasis, the incidence of INH has significantly decreased (Torbenson et al., 2010).

Tiered Investigation of the Jaundiced Newborn A fractionated bilirubin should be obtained to assess for cholestasis if jaundice persists beyond 2–3 weeks of age. A joint guideline published in 2017 by the North American and European Societies for Pediatric Gastroenterology, Hepatology, and Nutrition recommends that any formula-fed infant with jaundice at 2 weeks should have a fractionated bilirubin, but that breastfed infants who appear well can be followed clinically until 3 weeks of age, at which time a fractionated bilirubin should be obtained if jaundice persists (Fawaz et al., 2017). The conjugated (or direct) bilirubin level is considered abnormal if >1 mg dL1 (17.1 mmol L1) and warrants diagnostic evaluation (Fig. 3). The evaluation should start with a detailed history and physical exam, including prenatal history, birth history, family history, information on the first bowel movement, onset of jaundice, stool color, and urine color. Stool color should be observed first-hand if possible. Firm hepatomegaly with a prominent middle or left lobe may support the diagnosis of BA, however splenomegaly is rare in the first several weeks and may suggest a different etiology. Other important aspects of the physical exam include nutritional, cardiopulmonary, ocular, neurologic, and skin examinations, as well as assessing for dysmorphic features. Liver ultrasound and A1AT phenotype are important tests to obtain early. The goal is to promptly identify those etiologies which require specific therapies, especially BA. A1AT deficiency can mimic BA and should be ruled-out prior to biopsy. “Red flag” features which should spur prompt evaluation for BA include acholic stools, firm hepatomegaly, small or absent gallbladder on ultrasound (although a normal gallbladder may be seen), and a high GGT. If this combination of findings is present, the A1AT level/phenotype is normal, and there is not another surgical etiology found on ultrasound (such as cholelithiasis or choledochal cyst), expeditious liver biopsy to assess for BA is generally recommended. This approach may change in the infant who presents febrile and ill-appearing, in whom infectious etiologies will be pursued and treated prior to moving forward with liver biopsy. Similarly, if an infant is premature and very-low birth weight, receiving PN, and/or very unstable from a cardiovascular standpoint, the etiology of cholestasis is likely to be multifactorial and the risk of liver biopsy may be deemed too high. In this case, one can consider starting ursodeoxycholic acid while optimizing medical management (including enteral feeds and reducing PN, as possible), all the while closely monitoring cholestatic labs. In any infant, it is important to review results of the newborn screen, as screening in most states includes CF, hypothyroidism, galactosemia, and tyrosinemia. Second-tier testing to consider is listed below. However, these tests may be considered first-tier based on the clinical scenario. For example, Alagille syndrome testing may be pursued first if a murmur is present and there is a positive family history. If there is significant hypoglycemia and roving eye movements, endocrine tests should be pursued first. Second-tier testing to consider:

•

Total serum bile acid levels to assess for disorders of bile acid synthesis

Neonatal Cholestasis and Biliary Atresia

641

2-week old infant with jaundice

Direct bilirubin >1 mg dL−1 and 20% of the total bilirubin

• AST, ALT, GGT, total protein, alkaline phosphatase, albumin, PT/INR, CBC • Ultrasound (US) liver • Alpha-1 antitrypsin level • Review newborn screen • Urinalysis and urine culture

Newborn screen positive

US with stone, mass or CDC

PiZZ or PiZS phenotype

UA and culture consistent with UTI

Newborn screen, A1AT phenotype and US normal

Confirmatory testing for disease

Surgery consultation

A1AT deficiency

Treat UTI and continue to trend labs

Liver Biopsy

If persistent cholestasis

Biopsy NOT consistent with BA

Biopsy consistent with BA

2nd Tier Testing

IOC +/− KPE

Fig. 3 Flow diagram of workup for neonatal cholestasis. Shown is the recommended algorithm for the workup of neonatal cholestasis (Fawaz et al., 2017). BA: biliary atresia; CDC: choledochal cyst; IOC: intraoperative cholangiogram; KPE: Kasai portoenterostomy; UTI: urinary tract infection.

• • • • •

Endocrinology testing (beyond the newborn screen), to include TSH, T4, and cortisol Infectious studies, including urinalysis, urine culture, urine CMV Metabolic testing, including lactate, pyruvate, cholesterol, galactose-1-phosphate uridyltransferase, urine succinylacetone, urine organic acids, plasma amino acids Chest X-ray (assessing vertebrae), echocardiogram, and ophthalmologic exam if concern for Alagille syndrome Gene panel or exome testing for genetic causes of cholestasis

General Management of Cholestasis Nutrition Malnutrition is common in infants with cholestasis. Fat-malabsorption due to inadequate bile flow plays a large role, in addition to the abnormal glucose and protein metabolism associated with liver dysfunction, anorexia and/or vomiting seen with

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organomegaly and ascites, and the increased energy expenditure associated with cirrhosis. Energy needs may be high, often requiring up to 125%–140% of recommended caloric intake based on ideal body weight to attain adequate growth (Sundaram et al., 2017). Means of increasing caloric intake include nasogastric tube feeds, concentrating the caloric density of formulas or breast milk, and increasing the percentage of medium chain triglycerides in feeds (which do not depend on intestinal bile for absorption). At times, adequate growth cannot be achieved with enteral nutrition and parenteral nutrition is required (typically as a bridge to liver transplant). It is important to consider that weight gain alone is an unreliable marker of the overall nutritional status, as organomegaly and ascites, if present, can spuriously contribute to this measurement. Weight, height, head circumference, triceps skinfold thickness, and mid-upper arm circumference measurements should be tracked every 3 months to closely monitor nutritional status. Fat-soluble vitamin deficiency is common, secondary to abnormal bile flow, leading to impaired intestinal absorption. Multivitamin repletion or large doses of individual vitamins are frequently required (Table 3). Patients on high doses of fat-soluble vitamins should have monthly evaluation of serum vitamin levels to ensure adequate dosing and prevention of toxicity.

Pruritus Pruritus can be severe and may greatly affect quality of life. The pathogenesis of pruritus in cholestasis is associated with increased circulation and retention of bile acids in the bloodstream. Antihistamines are ineffective at treating pruritus, as the process is not histamine-mediated. Therapies which have demonstrated variable improvement in symptoms include ursodeoxycholic acid (a hydrophilic bile acid), rifampicin (an antibiotic), and naltrexone (an opioid antagonist).

End Stage Liver Disease Many neonatal cholestatic diseases may progress to end stage liver disease in the first 2 years of life. Therefore, it is necessary to monitor the patient for symptoms and signs of worsening liver disease and cirrhosis. This includes symptoms of variceal bleeding (hematemesis, melena), abdominal distension, worsening jaundice, lethargy and mental status changes (e.g., disturbed sleep wake cycle). Physical exam findings of a hard consistency of the liver, splenomegaly, and ascites are evidence of cirrhosis with portal hypertension. Laboratory findings may reveal evidence of hypersplenism (low platelets, low white blood cell count), anemia (from variceal bleeding), hypoalbuminemia and elevated PT/INR (liver synthetic dysfunction). Patients with progressive, end stage liver disease should be considered for liver transplantation.

Table 3

Management of cholestasis Diagnosis/assessment

Management

Macronutrient deficiencies

Height, weight, head circumference, triceps skinfold thickness, & mid-upper arm circumference every 3 months

Fat-soluble vitamin deficiencies

Vitamin A deficiency • Retinol: RBP molar ratio < 0.8 • Clinical: xerophtalmia, keratomalacia, Bitot spots Vitamin D deficiency • 25-OH-D1< 14 ng mL1 ¼ deficiency (95% of cases. Delayed passage of meconium in a term newborn is usually defined as meconium that is not expelled within the first 48 h of life. Older neonates that present with intestinal obstruction later than in the first days of life may experience absence of bowel movements after an initial timely passage of meconium. Neonates with distal or partial obstructions may expel a small amount of meconium or stool which may be wrongly reassuring. In fact, it is not uncommon to observe elimination of preexisting content of the colon in neonates with a distal obstruction or a pseudo-diarrhea, due to hypersecretion above the obstruction. Babies with meconium ileus will not pass meconium, but might expel pale, mucoid pellets. In cases of Hirschsprung’s disease, a rectal stimulation may cause explosive decompression of meconium. Finally, in preterm neonates, meconium passage may be delayed even in the absence of intestinal obstruction, likely due to the immaturity of the intestine.

Diagnosis The first assessment of a newborn with intestinal obstruction should include not just the patient’s clinical history, but also the maternal, family and prenatal history. A thorough evaluation of signs and symptoms could guide the physician towards the location and etiology of the obstruction. The baby’s perineum should be carefully examined to rule out anorectal malformations. Moreover, the physical examination should exclude associated congenital anomalies, as well as rule out causes of acquired intestinal obstruction, such as an incarcerated inguinal hernia.

Prenatal Diagnosis The prenatal diagnosis of intestinal obstruction is mainly achieved through the use of fetal ultrasonography, and usually occurs late in pregnancy (late second and third trimester). Typical ultrasound findings of intestinal obstruction are polyhydramnios and dilated bowel loops in the fetal abdomen proximal to the obstruction. Polyhydramnios is defined as an amniotic fluid index (AFI) > 25 cm and is generally associated with proximal obstruction. In physiological conditions, 25%–40% of the amniotic fluid is swallowed by the fetus and reabsorbed in the first 30 cm of jejunum. Therefore, proximal intestinal obstruction results in accumulation of amniotic fluid and polyhydramnios. As fetal bowel peristalsis occurs at 20 weeks, polyhydramnios may be diagnosed from 20 weeks onwards. Dilated bowel loops are defined prenatally as loops >15 mm in length and 7 mm in diameter and suggests an underlying intestinal obstruction distal from these dilated bowel loops (Shawis and Antao, 2006). Duodenal atresia can also be suspected with the antenatal ultrasound scan by the presence of a double-bubble sign that indicates a dilated stomach and proximal duodenum, separated by the pylorus. Maternal polyhydramnios is also present in 75% of the cases of DA, often diagnosed after 24 weeks (Kim et al., 2016). Jejunal and ileal atresias are detected prenatally in two-thirds of the cases if the lesion is on the jejunum, and in 26% if it is on the ileum (Virgone et al., 2015). Polyhydramnios is present in only 35% of the cases, while dilated bowels can be visualized in 62% of the cases (Virgone et al., 2015). Severe fetal intestinal dilatation can result in antenatal intestinal perforation and meconium peritonitis, that is, an aseptic, chemical peritonitis. In these cases, ultrasound findings can include peritoneal calcifications, ascites, and meconium pseudocysts. An antenatal magnetic resonance imaging (MRI) can be performed to distinguish meconium pseudocysts from other abdominal cysts. Moreover, although not routinely used for the diagnosis of intestinal obstruction, antenatal MRI can provide additional information regarding meconium distribution in the small bowel, as well as assessing the contents of the colon and rectum (Rubio et al., 2017). Finally, antenatal ultrasound can diagnose associated extra-intestinal anomalies, such as cardiac or urinary tract malformations.

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Abdominal X-Ray Although clinical signs can orient towards a high or low obstruction as discussed above, a plain abdominal X-ray should be performed as soon as possible. From the very first cry after birth, newborns swallow air, that reaches the proximal small intestine after 1 h, the caecum within 3 h and the rectum by 12 h (Prasad and Aziz, 2017). A plain X-ray can reveal dilated intestinal loops proximal to the obstruction and the absence of air in a segment of intestine distal to the obstruction. A duodenal obstruction often presents with a double-bubble sign similar to that described on the antenatal ultrasonography (Fig. 1). In the absence of air below the duodenum, duodenal atresia is suspected, whereas if some air is present below the double-bubble, a duodenal stenosis or web should be suspected. Jejunal and ileal atresias present with dilated bowel loops, whose number depends on the site of obstruction: few dilated loops suggest a proximal obstruction, whereas several dilated loops indicate a distal ileal or colonic obstruction (Fig. 2). In meconium ileus, signs of low intestine obstruction can be observed associated with images of “bubbles” or “breadcrumbs” in the right iliac fossa due to the mixture of air and meconium. A plain abdominal X-ray can also assess the presence of complications of the intestinal obstruction, such as prenatal perforation and meconium peritonitis (peritoneal calcifications), postnatal perforation (free peritoneal air, pneumoperitoneum), and intestinal pneumatosis (intramural air).

Upper Gastro-Intestinal (GI) Tract Study When a proximal intestinal obstruction is suspected, an upper GI tract study is still widely recognized as the gold-standard to diagnose malrotation. In the suspicion of intestinal malrotation without volvulus, the upper GI may reveal a distended duodenum, with a duodeno-jejunal junction localized on the right of the midline, and an anteriorized position of the fourth part of the duodenum. A volvulus can be suspected in the presence of corkscrewing of the distal duodenum and minimal passage of contrast into the jejunum. In jejuno-ileal atresias, an upper GI contrast study is usually not conclusive as the contrast will often dilute before reaching the obstructed bowel segment.

Fig. 1 Abdominal X-ray at 8 h of life, showing a double-bubble indicative of proximal intestinal obstruction in a female newborn with bilious vomiting and anorectal malformation. At surgery, this baby was found to have a duodenal atresia type I (web). She underwent a duodenoduodenostomy and colostomy formation during her first day of life, followed by a posterior sagittal anorectoplasty at 3 months of age.

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Fig. 2 (A) Abdominal X-ray at 6 h of life, showing a proximal intestine obstruction with distended jejunal loops. (B) Intra-operative image of the same newborn, who was found to have a jejunal atresia type IIIb (apple-peel atresia): a bulbous proximal segment of jejunum and a collapsed spiral shaped distal jejunum and ileum were found.

Contrast Enema For low intestinal obstructions, a contrast enema should be performed. The presence of a transition zone from a normal or slightly reduced intestine caliber to a proximal distended one may be suggestive of Hirschsprung’s disease. The presence of a microcolon suggests ileal atresia or meconium ileus. A reflux into the terminal ileum with filling defects is suggestive of meconium ileus. In cases of meconium plug, the colon is normal, with large filling defects of left colon. Colonic atresia and small left colon syndrome are revealed by a microcolon distally to the level of obstruction and a dilated intestine proximally.

Abdominal Ultrasound An abdominal ultrasound may be performed when suspecting a proximal obstruction, in order to assess the anatomic relationship between the superior mesenteric artery and vein and the presence of midgut volvulus. Ultrasonographic findings suggestive for malrotation include a superior mesenteric vein located to the left of the superior mesenteric artery, dilatation of the proximal duodenum indicating obstruction, and an abnormal position of the third part of the duodenum between the superior mesenteric artery and the aorta in the retroperitoneal space. Colored Doppler can reveal a “whirlpool sign” in cases of midgut volvulus, which appears when the superior mesenteric vein and mesentery wrap around the superior mesenteric artery. However, these vessels can sometimes be difficult to visualize in cases of abdominal distension. In neonates with cystic intra-abdominal masses, ultrasound can help delineate wall structure and cyst contents to aid in the diagnosis of intraabdominal cysts.

Rectal Biopsy A rectal biopsy should be performed in cases of low intestinal obstruction and suspicion of Hirschsprung’s disease. After checking the baby’s coagulation profile, a rectal suction biopsy, 3 cm above the dentate line, can be done safely as a bedside procedure and is highly accurate. An adequate technique and appropriate histological processing are required. Diagnosis of Hirschsprung’s disease will be confirmed by the absence of ganglionic cells, the presence of nerve trunk hypertrophy, and the lack of calretinin staining.

Screening for Associated Anomalies Depending on the condition leading to neonatal intestinal obstruction, a systematic screening for extra-intestinal associated malformations may be performed, including chest and abdominal X-ray, echocardiography, urinary tract ultrasound, and spinal ultrasound. In neonates with anorectal malformations, all these studies should be performed within the first 24 h of life, to help decide on the therapeutic strategy to adopt (Peña and Bischoff, 2015).

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Treatment Medical Treatment The early management of any neonatal intestinal obstruction includes gastric decompression with a nasogastric tube and resuscitation with appropriate fluids and electrolytes. Measures should be taken to prevent hypothermia and hypoglycemia. In the suspicion of sepsis, a full septic work-up is undertaken and intravenous antibiotics should be started. Babies with severe cardiac or urinary tract malformations may require specific treatment for these anomalies. In the absence of signs of complications, meconium ileus and meconium plug syndrome can be initially treated with enemas, that can be repeated until effective in relieving intestinal obstruction. Oral mucolytics have also been reported to help relieve the obstruction due to meconium ileus. In meconium plug syndrome, contrast enemas might result in the passage of a white plug formed of epithelial cells, followed by meconium and resolution of symptoms. In cases of Hirschsprung’s disease without enterocolitis or perforation, rectal irrigations should be started as soon as the diagnosis is suspected in order to establish a regular evacuation of stools and prevent bowel distension and enterocolitis. The initial management of necrotizing enterocolitis consists of stopping feeds, restoring hemodynamic stability, and starting broad-spectrum antibiotics. Classically, infants with stage I and II of Bell’s classification can be treated conservatively. Clinical improvement is expected to occur within 72 h of supportive care. Babies with advanced necrotizing enterocolitis (type III) or that fail to respond to optimal medical therapy require surgical treatment. The treatment of paralytic ileus is conservative, with gastric decompression until peristalsis starts again, and treatment of the cause of the ileus.

Surgical Treatment In general, urgent surgical intervention is indicated in all cases of neonatal intestinal obstruction that present with peritonitis or pneumoperitoneum. This applies especially to acutely ill neonates that are suspected to have midgut volvulus: urgent detorsion of the twisted bowel is necessary to prevent necrosis and intestinal failure. For the other causes of neonatal intestinal obstruction without any signs of complications, surgery should be performed as soon as possible, once the baby is stabilized and the full workup has been completed. The surgical treatment for duodenal atresia consists of re-establishing intestinal continuity, either by duodenoduodenostomy or duodenojejunostomy (Zani et al., 2017). Recently, laparoscopic duodenoduodenostomy has been reported as a safe and effective alternative to the open procedure. Small and large bowel atresias are treated surgically by limited intestinal resection and end-to-end anastomosis. However, cases of multiple intestinal atresia may be challenging and require the fashioning of a stoma. In all cases of intestinal atresia, the small and large intestine should be carefully inspected to rule out additional atresias. The surgical strategy for babies with anorectal malformations depends on the type of the malformation. Cases of perineal or vestibular fistula can be treated either with a primary anorectoplasty or with a protective colostomy followed by definitive surgery several weeks later. All the other cases are typically managed with a colostomy as a temporary strategy to totally divert stools and avoid contamination of the urinary tract. In these cases, reconstructive surgery in the form of a posterior sagittal anorectoplasty (PSARP) is performed later (Peña and Bischoff, 2015). Briefly, the surgery entails mobilization of the rectum through a sagittal and posterior incision between buttocks, to the center of the sphincter identified by an electrical stimulator. An open or laparoscopic abdominal approach can be necessary when the patient has a high anorectal malformation. In neonates that present with an incarcerated inguinal hernia, the initial attempt is to reduce the herniated bowel into the abdomen. If this is successful, surgery is carried out 24–48 h after reduction to allow resolution of the associated tissue edema. If the contents of the hernia cannot be reduced into the abdominal cavity, immediate surgery is necessary for reduction, inspection of the bowel, and possible resection in case a necrotic loop is present. In cases of midgut volvulus, the counterclockwise detorsion of the bowel is followed by the Ladd’s procedure. The latter is characterized by the division of abnormal peritoneal bands if present, broadening of the mesenteric root, and placement of the small intestine to the right of the midline and the colon to the left in a nonrotated position. As the appendix is located in the left upper quadrant at the end of surgery, some surgeons perform a prophylactic appendectomy or they invert the appendix, as to avoid future confusion in case of a possible episode of appendicitis. If diagnosis of midgut volvulus is delayed, extensive bowel necrosis might be found at laparotomy. In these cases, the bowel is untwisted and a “second look” surgery might be discussed at 24–48 h to assess bowel viability and proceed to limited bowel resection if possible. Congenital bands are resected surgically, without intestinal resection, unless in the presence of intestinal necrosis. Enteric duplication cysts are usually resected with the adjacent bowel, followed by an end-to-end anastomosis of the normal bowel. Mesenteric and omental cysts may be enucleated or resected with a limited segment of bowel if necessary. An alternative management consists of partial excision with marsupialization, if complete enucleation or resection is not possible, or sclerotherapy by interventional radiology. Babies with Hirschsprung’s disease that do not respond to rectal irrigations may require a colostomy. Once the obstruction is relieved either medically or surgically, elective surgery will be performed at a later stage. The surgery consists in the resection of the aganglionic intestine and pull-through of the proximal healthy intestine. This can be accomplished with different techniques, including open, laparoscopy, and endo-rectal approaches.

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Surgery is required for meconium ileus if signs of complications occur or if enemas fail to relieve the obstruction. The majority of neonates with meconium ileus will eventually require surgery for evacuation of the meconium by enterostomy or limited resection, associated to a distal intestinal irrigation (Jessula et al., 2018). In babies with advanced necrotizing enterocolitis, surgery is necessary for resection of necrotic bowel. The type of surgery depends on the extent and severity of the affected bowel. Intestinal resection may be followed by an anastomosis or stoma to divert the content of the bowel. In critically ill and very low birth weight neonates, peritoneal drainage under local anesthesia has been proposed as a temporary treatment and in order to delay surgery in these fragile babies. However, the benefit of this procedure is only temporary and definitive surgery should promptly ensue.

Prognosis In neonatal intestinal obstruction, prognosis is mainly dependent on associated anomalies or syndromes, underlying genetic conditions, gestational age and birth weight of the neonate, cause of obstruction, and length of remaining bowel. The overall survival of infants who have prenatally been diagnosed with intestinal obstruction has been reported as high as 88% (Lau et al., 2017). For babies with duodenal atresia, overall neonatal survival has been reported above 90%, and mortality is mainly due to associated anomalies, prematurity and low birth weight (Choudhry et al., 2009). Following small bowel atresia resection, prognosis is mainly related to the length of small intestine remaining. Mortality of babies with anorectal malformations is higher in than those with intestinal atresias and is mainly secondary to their associated cardiac and urinary malformations (Lau et al., 2017). Long-term bowel and urinary control depends on the specific type of anorectal malformation. Babies born with a cloaca or a “flat bottom” (absence of midline groove and anal dimple) present the poorest functional outcomes (Peña and Bischoff, 2015). The prognosis after midgut volvulus depends on the extent of intestinal necrosis and resection. Rarely, midgut volvulus can occur prenatally and has a very poor prognosis, due to the extent of intestinal necrosis. The long-term outcome of children with Hirschsprung’s disease can be affected by recurrent enterocolitis, soiling or constipation. Babies with long-segment Hirschsprung’s disease or total aganglionic colon have a poorer outcome than standard recto-sigmoid Hirschsprung’s. Neonatal prognosis is excellent in cases of simple meconium ileus, but mortality increases to 25% in cases of complicated meconium ileus. Overall, survival rate has been reported around 95%. However, meconium ileus seems to indicate a severe phenotype of cystic fibrosis, as shown by the poorer pulmonary function of children with a history of meconium ileus. Mortality due to necrotizing enterocolitis remains high, around 30%–50%. For those who survive, digestive morbidity is high, with 25% of the cases developing short-gut syndrome and 20% developing intestinal strictures. Necrotizing enterocolitis survivors are also at a high risk of neurodevelopmental impairment.

References Bahrami A, Joodi M, Moetamani-Ahmadi, et al. (2018) Genetic background of Hirschsprung disease: A bridge between basic science and clinical application. Journal of Cellular Biochemistry 119: 28–33. Best KE, Tennant PWG, et al. (2012) Epidemiology of small intestinal atresia in Europe: A register-based study. Archives of Disease in Childhood. Fetal and Neonatal Edition 97: F353–F358. Choudhry MS, Rahman N, Boyd P, and Lakhoo K (2009) Duodenal atresia: Associated anomalies, prenatal diagnosis and outcome. Pediatric Surgery International 25: 727–730. Gray S and Skandalakis J (1972) Embryology for surgeons: The embryology basis for the treatment of congenital defects. Philadelphia: Saunders. Haeusler MCH, Berghold A, Stoll C, et al. (2002) Prenatal ultrasonographic detection of gastrointestinal obstruction: Results from 18 European congenital anomaly registries. Prenatal Diagnosis 22: 616–623. Hall NJ, Drewett M, and Burge D (2018) Nutritional role of amniotic fluid: Clues from infants with congenital obstruction of the digestive tract. Archives of Disease in Childhood. Fetal and Neonatal Edition. Available at https://doi.org/10.1136/archdischild-2017-314531. Jessula S, Van Den Hof M, Mateos-Corral D, et al. (2018) Predictors for surgical intervention and surgical outcomes in neonates with cystic fibrosis. Journal of Pediatric Surgery 53: 2150–2154. Kim JY, You JY, Chang KH-J, et al. (2016) Association between prenatal sonographic findings of duodenal obstruction and adverse outcomes. Journal of Ultrasound in Medicine 35: 1931–1938. Lau PE, Cruz S, Cassady CI, et al. (2017) Prenatal diagnosis and outcome of fetal gastrointestinal obstruction. Journal of Pediatric Surgery 52: 722–725. Peña A and Bischoff A (2015) Surgical treatment of colorectal problems in children. Springer. Prasad GR and Aziz A (2017) Abdominal plain radiograph in neonatal intestinal obstruction. Journal of Neonatal Surgery 6: 6–11. Rubio EI, Blask AR, Badillo AT, and Bulas DI (2017) Prenatal magnetic resonance and ultrasonographic findings in small-bowel obstruction: Imaging clues and postnatal outcomes. Pediatric Radiology 47: 411–421. Shawis R and Antao B (2006) Prenatal bowel dilatation and the subsequent postnatal management. Early Human Development 82: 297–303. Sinha CK and Davenport M (2010) Handbook of pediatric surgery. London: Springer. Virgone C, D’antonio F, Khalil A, et al. (2015) Accuracy of prenatal ultrasound in detecting jejunal and ileal atresia: Systematic review and meta-analysis. Ultrasound in Obstetrics & Gynecology 45: 523–529. Yagi M, Kohno M, Asagiri K, et al. (2015) Twenty-year trends in neonatal surgery based on a nationwide Japanese surveillance program. Pediatric Surgery International 31: 955–962. Zani A, Yeh J-PB, King SK, Chiu PPL, and Wales PW (2017) Duodeno-duodenostomy or duodeno-jejunostomy for duodenal atresia: Is one repair better than the other? Pediatric Surgery International 33: 245–248.

Neurohumoral Control of Gut Motility and Secretions John R Grider, Charles D Anderson Jr., and Karnam S Murthy, Virginia Commonwealth University, Richmond, VA, United States © 2020 Elsevier Inc. All rights reserved.

Glossary

Postprandial or interdigestive period Relates to a period after a meal or in between meal. Biliary Referring to bile and the system through which bile flows. Chyme A thick semi-fluid mixture of partially digested food, digestive enzymes, and fluid which is found in the gastric and intestinal lumen. Paracrine Acting at a site close to the site from which an agent is released. Plexus Web-like network, usually of neurons. Motor neuron A neuron whose axon forms a synapse with effector organ such as muscle cell or secretory cell. Hyperpolarization A change in membrane potential toward more negative. Migrating motor complex Rhythmic mechanical activity of the gut during fasting or interdigestive period. Tastant A component of ingested food which acts as ligand for the taste receptors expressed on EEC. Enteroendocrine cell A special type of cell characterized by chromogranin-containing granules and found in the mucosal wall of the gut which releases neurohumoral agents in response to mechanical or chemical stimulation. Enterochromaffin cell A special subtype of enteroendocrine cell found in the mucosal wall of the gut which primarily releases serotonin (5-HT). Intrinsic Primary Afferent Neuron (IPAN) Sensory or afferent neuron within the ENS that participate in the intrinsic neural reflexes. Interstitial Cell of Cajal (ICC) A specialized cell in the wall of the gut which initiates or modulates the spread of electrical activity to smooth muscle. Peristalsis The main propulsive motility of the gut. Hirschsprung’s Disease A congenital disease in which the enteric nervous system is absent in a small portion of the distal colon. Orad On the oral side of a designated point. Caudad On the anal side of a designated point. Enterocyte Epithelial cell which makes up the mucosa and lines the luminal side of the gut. Segmental contraction Non-propulsive mixing contractions of intestine which occur postrandially. Chemosensation The detection of a chemical stimulus by a sensory neuron, enteroendocrine, or enterochromaffin cell. Brush Cell or Tuft Cell A subclass of cells in the mucosa which have extensive microvilli on their apical surface and may release bioactive agents in response to luminal stimulants but lack chromogranin-containing granules.

Introduction The regulation of gut motility and secretion is complex and exerted at many levels. It can be viewed from the top down (brain to gut) or from the effector organ up (gut to brain). It can be viewed from a temporal-functional point of view (between meal period (interdigestive) or after a meal period (postprandial)). It can be viewed in a spatial-regional fashion (esophageal, gastric, small intestinal, colonic, or biliary). Each approach emphasizes a different component or aspect of the regulation of the gut, and yet, functioning together, the neurohumoral control of gut motility and secretions results in adequate digestion and absorption of nutrients and elimination of wastes. It is our goal in this review to provide an overview of the system and highlight key components of the neural, hormonal, and paracrine systems that are responsible for control of gut motility and secretion. The neural component can be divided into the extrinsic control system which originates outside of the gut and the intrinsic component which originates from neurons within the gut. The extrinsic neural control system is part of the autonomic nervous system and is comprised of the parasympathetic and sympathetic nervous system. The intrinsic neural control system is the enteric nervous system (ENS) and is composed of the myenteric and submucosal plexuses in the gut wall. The hormonal and paracrine component of the regulatory systems is composed of a multitude of single cells, termed enteroendocrine cells (EEC), which are interspersed among the epithelial cells which line the gut. The distinction between the hormonal and paracrine roles largely depends on the site of action and mode of delivery of the active agent. Paracrine agents are usually released close to the site of action, diffuse short distances to target cells, and control local events, whereas, hormones are released into the circulation, are delivered to target cells at distant locations, and control widespread or multiple events. Often agents released from enteroendocrine cells act in both paracrine and hormonal fashion as well as include modulation of neural components to achieve a final response.

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A third component of the system could be viewed as the target cell or organ. Ultimately, the motility of the gut depends on the organized contractile and relaxant responses of smooth muscle cells which are organized into an outer longitudinal layer and an inner circular layer. While not the main focus of this review, the expression of specific receptor for neural and hormonal agents on smooth muscle cells and their coupling to intracellular signaling pathways determines the response of individual cells. It is noteworthy that a second cell type, the interstitial cell of Cajal (ICC) which regulates the electrical activity of smooth muscle, is intimately coupled to the regulation of motility as a result of its interposition between enteric neurons and smooth muscle cells and its expression of receptors for neurotransmitters and hormones. Thus, complex motility patterns depend on the regulation of both smooth muscle and ICC. The same general notion holds for the regulation of secretion; individual secretory cells, either solitary or grouped in glands, respond to neurotransmitters, paracrine agents and/or hormones via activation of specific receptors coupled to specific signaling pathways leading to modulation of specific secretions. The pattern of activation of enteric neurons and release of transmitter/paracrine agent, and the sequence of release of hormones in response to stimuli either locally within the gut lumen or following activation from sites outside the gut (e.g. central nervous system) generates the larger patterns of motility and secretion.

Neural Regulation of Gut Function Role of the Enteric Nervous System The enteric nervous system (ENS) is composed two ganglionated plexuses of nerve cell bodies and nerve fibers: the myenteric plexus located between the inner circular and outer longitudinal muscle layers and the submucosal plexus located in the submucosa between the circular muscle and muscularis mucosa. Together the total number of neurons in the ENS is comparable to the spinal cord, about 500 million neurons in humans. The ENS contains a full complement of functional neuronal types including motor neurons to smooth muscle, secretory cells, and solitary endocrine cells; sensory neurons which respond to a variety of inputs including chemical and mechanical; interneurons which connect between neurons to comprise reflex circuits; and intestinofugal neurons with project outside of the gut to structures such as gallbladder, prevertebral sympathetic ganglia and pancreas among others. The gut is unique among other organs in that these plexuses contain the reflex circuits necessary for generating motility patterns for most of the organ. By-in-large, the motility of the small intestine and colon is dependent on the ENS and circuits contained therein. The esophagus and stomach are more dependent on external neural input as discussed below. The primary propulsive motility of the small intestine and colon is peristalsis which proceeds virtually intact in isolated preparations which lack connection to the central nervous system or vascular system and therefore are mediated by neural components of the ENS. This notion is supported by many studies demonstrating that disruption of the ENS, either by chemical poisoning with toxins such as tetrodotoxin or in pathological setting such as Hirschsprung’s disease which is characterized by absence of the ENS in a small region of the distal colon, results in failure of the intestine to propel luminal contents. Peristaltic propulsion is accomplished by contraction of the circular muscle orad to a stimulus (often referred to as ascending contraction) coupled with relaxation of circular muscle caudad to a stimulus (often referred to as descending relaxation). In its simplest form, the reflex circuit which mediates the underlying peristaltic reflex is composed of an intrinsic primary afferent neuron (IPAN) or intrinsic sensory neuron, a series of interneurons, and motor neurons which innervate smooth muscle and/or ICC. Enteric secretory reflexes utilize a similar organization in the small intestine and colon: an intrinsic sensory neuron or IPAN, a series of interneurons, and secretory motor neurons which innervate enterocytes or secretory cells of glands. The sensory neurons often have a characteristic phenotype of multiple long processes which is termed type II morphology and demonstrate an after-hyperpolarization (AH) following an action potential and are thus often referred to as AH/type II neurons. Sensory neurons can have cell bodies in either the myenteric neural plexus or the submucosal plexus. Those in the myenteric plexus are more involved in motor reflexes while those in the submucosal plexus are more involved in secretory reflexes. The sensory neurons originating in the myenteric plexus may also play a role in coordination of intrinsic motor and secretory reflexes. Sensory neurons do not reach to lumen but rather have endings just beneath the mucosal surface or within deeper layers of the gut wall. Those just beneath the mucosal surface are activated by paracrine agents released from mucosal EECs, most notably serotonin (5HT) released in response to chemical and nutritional components in the luminal chyme, as well as mucosal mechanical stimuli. It is becoming increasingly evident that these EECs express G-protein coupled receptors for bile salts; taste receptors for sweet, umami, and bitter tastants; a variety of L-amino acids receptors; free fatty acid receptors; and receptors for compounds produced by the microbiota. Reflexes initiated by these endings are often referred to as mucosal reflexes. The response to 5-HT is mediated by 5-HT3 and/or 5-HT4 receptors depending on the species and region of the gut. Reflexes initiated by distension and mechanical stimuli applied to the gut wall can also be sensed by sensory neurons with mechanosensitive endings deeper to the mucosa in circular muscle and other structures. These reflexes do not likely require release of paracrine agents. Sensory neurons, once activated by appropriate stimuli, release neurotransmitters which have been identified to include acetylcholine, calcitonin gene-related peptide (CGRP), and tachykinins. Sensory neurons then activate any number of interneurons within the enteric plexuses which either have ascending projections or descending projections and which synapse with other interneurons or motor neurons innervating smooth muscle or secretory cells. The ascending interneurons are typically cholinergic and excitatory. In addition to acetylcholine, they often coexpress the tachykinin, substance P. The vast majority of interneurons, however, project in a descending direction. These can be subdivided

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based on their neurochemical composition. All descending interneurons express acetylcholine but separate sets express nitric oxide synthase, serotonin, or somatostatin. While these are the main ascending and descending interneurons, many neurotransmitters are expressed or coexpressed in these neurons including opioid peptides, gamma amino butyric acid (GABA), etc. The physiological role of many of these interneurons remains to be determined. Ultimately the interneurons end on motor neurons which innervate the target tissues and mediate the motor or secretory reflexes. With regard to the propulsive peristaltic reflex, these motor neurons are either excitatory or inhibitory. The ascending component of the reflex results in contraction of smooth muscle orad to the site of stimulation which provides the driving force of propulsive motility. This response is mediated by excitatory motor neurons which release acetylcholine and the tachykinin, substance P. These act on muscarinic receptors and neurokinin 1 and neurokinin 2 receptors on smooth muscle cells. These receptors are G-protein coupled receptors which activate signaling pathways ultimately leading to increase in intracellular calcium either by influx from extracellular sources in the case of longitudinal muscle or release from intracellular stores in the case of circular muscle. The increase in calcium is necessary for the activation of the calcium/calmodulin-dependent myosin light chain kinase which initiates the contractile machinery of the cell. The descending component of the peristaltic reflex results in relaxation of smooth muscle caudad to the site of stimulation which allows for ease of propulsion in the distal direction. Relaxation of circular smooth muscle is accomplished by activation of inhibitory or relaxant motor neurons which release vasoactive intestinal peptide (VIP), its homolog pituitary adenylate cyclase activating peptide (PACAP), nitric oxide (NO), and adenosine triphosphate (ATP). These neurohumoral agents act in concert to cause relaxation of smooth muscle through generation of the intracellular messengers cAMP and cGMP, and though hyperpolarization of the cell. The net effect is to inhibit intracellular calcium levels which as noted above are necessary to maintain the contractile machinery. The secretory motor neurons activated by interneurons in the secretory reflex are of two types: cholinergic and noncholinergic. As the name implies, the cholinergic secretory motor neurons release acetylcholine whereas the noncholinergic secretory motor neurons release VIP and its homolog PACAP. In addition, the noncholinergic secretory motor neurons release neuropeptide Y (NPY). Acetylcholine activates G-protein coupled muscarinic M1 and M3 receptors on epithelial cells in the intestine to cause chloride and the accompanying fluid secretion whereas VIP/PACAP activate G-protein coupled VPAC1 receptors. Unlike smooth muscle where calcium and cAMP signaling pathways lead to opposing actions (i.e. contraction and relaxation respectively) in the case of epithelial cells both an increase in calcium and cAMP lead to increased chloride secretion. NPY acts through Y2 and to a lesser extent Y1 and Y4 receptors on epithelial cells to inhibit chloride and fluid secretion. It is noteworthy that NPY is also released as a secondary neurotransmitter from VIPergic inhibitory motor neurons to smooth muscle and participates in the descending inhibitory component of peristalsis. The segmental type of contractions which serve to mix luminal contents with secretions are less well understood. These contractions make up a large part of the motility in the postprandial period and likely use the same excitatory and inhibitory neurotransmitters that are released during propulsive phases of motility to cause the alternating contractions and relaxations of segmentation. Recent evidence suggest that luminal fatty acids have a role in initiating the switch from propulsive to segmental contractions and that the neurohumoral agent neurotensin which is released from EECs also plays a role in initiating this process. The details of the enteric reflex circuits which mediate the response are unknown. The enteric nervous system is also a necessary component for the motility present during the interdigestive period. Again, the exact details of the reflex circuit and the extent of the role of the ENS in this interdigestive motility is not clear. During this interdigestive period, a wave of intense contractile activity termed the migrating motor complex (also sometimes referred to as the migrating myoelectric complex or interdigestive housekeeper) moves through the gut at a regular interval of about 70–90 min. As with segmentation, enteric motor neurons are likely the final mediators of contraction and secretion but the interneuronal pathways are not well known. A role of the neurohumoral agent motilin has been postulated to act through cholinergic neurons in the initiation of this motility pattern. The notion that the ENS is involved in this motility pattern is evident from the fact that neural toxins such as tetrodotoxin interfere with the progression of the migrating motor complex.

Role of the Extrinsic Nervous System The extrinsic nervous system interacts with the enteric nervous system and functions to relay inputs from the central nervous system through the sympathetic and parasympathetic branches of the autonomic nervous system. In addition, sensory components of the extrinsic nervous system act to relay information about gut status (e.g. volume, distension, presence of inflammatory mediators, pain) to the central nervous system. Thus, these extrinsic pathways coordinate between central and enteric nervous system and comprise what is often referred to as the brain-gut axis. In general the extrinsic nerves act through the neurohumoral agents released from enteric neurons and either inhibit (sympathetic) or enhance (parasympathetic) activity. The sympathetic innervation of the gut is through postganglionic neurons with cell bodies in the prevertebral ganglia that release norepinephrine and NPY. These transmitters act through receptors on enteric neurons to inhibit release of acetylcholine (ACh), largely at nicotinic synapses. Parasympathetic innervation is by way of preganglionic neurons that originate in the brain stem and travel in the vagus nerve, or originate in the sacral spinal cord and travel in the pelvic nerve. These synapse in neurons of the ENS which act as postganglionic neurons via a nicotinic cholinergic synapse. This latter view belies the fact that the interaction is more than the simple relay seen in parasympathetic regulation of other visceral organs. As an activator of enteric neurons and reflexes, stimulation of parasympathetic pathways can result in release of a wide range of both excitatory and inhibitory neurohumoral agents from enteric neurons.

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Control of function in the small intestine and colon is largely mediated by the local ENS reflexes described above with the autonomic inputs having a lesser role. In contrast, the autonomic neural input has a much greater role in controlling esophageal and gastric motility and secretion. While beyond the scope of this overview of neurohumoral control mechanisms, it should be noted that control of esophageal peristalsis and the regulation of gastric emptying is largely regulated by vago-vagal reflexes. These vagal inputs however result in the release of cholinergic and tachykinin neurotransmitters from enteric neurons to mediate contraction of gastric smooth muscle and release of VIP and nitric oxide from enteric neurons to mediate relaxation of gastric smooth muscle. These enteric neurohumors act on receptors and signaling pathways described above and are especially important in regulating gastric volume and tone as well as relaxation of lower esophageal sphincter and pylorus. Control of gastric secretion of hydrochloric acid and the digestive enzyme pepsinogen is a highly integrated function that involves coordination of enteric and extrinsic neurons, and several hormonal and paracrine agents. The overall control mechanism is mediated by an extrinsic vago-vagal reflex as evidenced by the loss of acid secretion when vagal neural inputs are severed. The regulation of gastric acid secretion provides an excellent example of the interaction of neurohumoral agents and various control systems and we will discuss this at the conclusion of this chapter as an illustration of the coordination of neurohumoral regulation of gut function (Fig. 1).

Hormonal Regulation of Gut Function Regulation of the Hormonal Release and Chemosensation Chemosensation is key to the regulation of the response to the environment and maintenance of homeostasis. In recent years, it has become evident that the receptors responsible for chemosensation, although perhaps initially identified because of association with a single function, tissue or location, are similar in a wide range of tissues. One of the main regions where chemosensation has a critical role is in the gut. As ingested material enters the gut and is processed, the nutrient molecules generated become extracellular signaling molecules that activate receptors on sensory cells which line the gut from stomach to colon. These sensory cells are the enteroendocrine cells (EECs) and brush or tuft cells which make up a very small proportion of gut mucosal cells. These are also the cells which contain and release gastrointestinal hormones and/or paracrine agents which affect motility and secretion at multiple levels. The population of EECs is heterogeneous with many expressing G-protein coupled receptors (GPCRs) on their apical or luminal surface. EECs as a class have been shown to express receptors for a variety of luminal molecules including the receptor for bile salts (TGR5), taste receptors for sweet and umami (T1R heterodimers), taste receptors for bitter or noxious substances (T2Rs), receptors for free fatty acids of differing chain lengths (FFARs), receptors for microbial products, receptors for phytochemicals, receptors responsive to acidic pH, etc. Heterogeneity also derives from the presence of numerous gut hormones, paracrine agents, and bioactive molecules released from these cells in response to activation of luminal receptors. These include peptide YY (PYY), neurotensin, cholecystokinin (CCK), glucose-dependent insulinotropic factor (GIP), glucagon-like peptide-1 and -2 (GLP-1, GLP-2), somatostatin, gastrin, and serotonin. Each of these is discussed briefly below. While the presence of a single bioactive agent has been used to classify EEC cell types in the past, it is becoming increasingly clear that these classical EEC cell types are themselves heterogeneous based on the colocalization of biological agents and presence in different regions of the gut. The cells themselves are diverse in morphology with some EEC extending from basal membrane to lumen (open-type EEC) and some EEC resting on basement membrane but not extending all the way to the lumen (closed-type). Brush cells or tuft cells extend to the lumen, have apical microvilli, express many of the chemosensitive receptors but differ from classical EEC by their lack of intracellular chromogranin-positive granules in which hormones are typically stored. Brush cells have not been extensively studied but it is likely that they play an important role in the response to mucosal pathology and inflammation as well as the normal regulation of motility and secretion. They have been reported to contain a wide range of neurohumors and biologically active agents such as opioid peptides, nitric oxide, prostaglandins, and interleukins. The lack of storage granules suggest that brush cells synthesize neurohumors on demand. Even the enterochromaffin cell, which is typically considered primarily a 5-HT containing cell, is now recognized to be heterogeneous with subpopulations identified based on their coexpression of additional hormones. It is unclear how best to group these given the current state of knowledge and diversity of receptor expression, content of neurohumoral agent, location along the gut, etc. There are over 30 identified EECs and many more potential agents which fit the role of endocrine or paracrine agents. We will focus on summarizing the key hormone or paracrine agents which relate to the regulation of gut motility and secretion as described below and listed in Table 1. This is meant as an overview of the effects of these neurohumoral agents and the reader is referred to specific chapters dealing with each agent for greater detail.

Cholecystokinin Cholecystokinin (CCK) is synthesized and released from classically described I cells in the proximal small intestine. CCK containing cells often coexpress serotonin as well as other neurohumoral agents such as ghrelin, GLP-1, GIP, PYY, and neurotensin. CCK was one of the first hormones identified in the gut and has been studied extensively. CCK is released in response to luminal nutrients especially lipids, fatty acids, and certain amino acids as well as other protein digestion products such as peptones. Its main functional role with regard to secretion is to stimulate the release of digestive enzymes from the pancreas. With regard to motility, CCK causes contraction of the gallbladder and subsequent release of bile into the gut lumen. These actions of CCK are of the classical hormonal type effects depending on distribution to the target organs via the blood supply as well as paracrine. In the latter case, locally released CCK acts on vagal afferent nerve endings which express the CCK type-1 receptors and increase vagal afferent nerve activity. The main result of activation of the vagal afferent neurons is inhibition of food intake as well as decrease in gastric

656 Table 1

Neurohumoral Control of Gut Motility and Secretions Summary of source and function of main neurohumoral agents in the gut.

Agent

Cell type

Mode of action

Main function

Acetylcholine Tachykinin Nitric oxide VIP/PACAP Norepinephrine ATP CGRP Opioids Gastrin Histamine Somatostatin

Motor neuron/Interneurons Motor neuron/Interneurons Motor neuron/Interneurons Motor neuron Sympathetic neuron Motor neuron IPAN/Sensory neuron Interneuron G cells ECL cells D cells

Stimulation of motility and secretion Stimulation of motility and secretion Inhibition of motility and stimulation of secretion Inhibition of motility and stimulation of secretion Inhibition of motility and stimulation of secretion Inhibition of motility and stimulation of secretion Activation of other neurons Modulation of motor neurons Stimulation of gastric acid secretion Stimulation of gastric acid secretion Inhibition of gastrin/gastric acid secretion

Serotonin

ECL cells

Cholecystokinin

I cells

GLP-1 and GLP-2 GIP Neurotensin Peptide YY Leptin Ghrelin Motilin

L cells K cells N cells L cells P cells A cells M cells

Neurocrine Neurocrine Neurocrine Neurocrine Neurocrine Neurocrine/paracrine Neurocrine/paracrine Neurocrine Endocrine Paracrine Paracrine/endocrine/ neurocrine Paracrine/neurocrine/ endocrine Endocrine/paracrine/ neurocrine Endocrine Endocrine Paracrine/endocrine Paracrine/endocrine Endocrine Endocrine Endocrine

Stimulation of peristaltic reflex and secretion, inhibition of gastric emptying Stimulation of pancreatic enzyme secretion and gallbladder contraction Stimulation of insulin release and inhibition of motility, (‘ileal brake’) Stimulation of insulin release Inhibition of motility Inhibition of motility (‘ileal brake’) Appetite regulation Appetite regulation Stimulation of migrating motor complexes

VIP: Vasoactive intestinal peptide; PACAP: pituitary adenylyl cyclase-activating peptide; IPAN: intrinsic primary afferent neuron; ATP: adenosine triphosphate; GLP: glucagon-like peptide; GIP: glucose-dependent insulinotropic peptide; CGRP: calcitonin gene-related peptide; ECL: enterochromaffin-like.

emptying. These effects decrease delivery of nutrients to the small intestine and result in the production of satiety. CCK has also been shown to accelerate small intestinal transit. It is noteworthy that CCK and its receptors are also expressed in neurons of the central nervous system and these may mediate some of the effects in the gut as well as have additional effects such as producing anxiety. Thus CCK represents a neurohumoral agent with a wide range of effects and which acts in multiple modes.

Gastrin Gastrin is synthesized and released from classically described G cells in the antrum of the stomach. It is not clear if these cells also produce or release additional neurohumoral agents. Gastrin is released by amino acids and peptones in the lumen generated by the degradation of proteins by pepsin in the stomach. Gastrin is also released by distension of the stomach and by vagal stimulation. The latter is mediated by release of ACh and the neurohumoral agent gastrin releasing peptide (GRP) from enteric neurons. A further paracrine regulation of gastrin release results from stimulation by histamine released from enterochromaffin-like cells (ECL) and inhibition by somatostatin released from D cells. The interaction of these cells and neurohumors is outlined at the end of this section. The primary effect of gastrin is the stimulation of acid secretion by parietal cells through activation of CCK type 2 receptors. These receptors are also present on the ECL cell and mediate the ability of gastrin to release the paracrine agent histamine which reinforces the stimulation of the parietal cells.

Ghrelin Ghrelin is released from EECs of the stomach and pancreas which have been designated by a variety of names but often referred to as A-like in pancreas or X-like in stomach and intestine. These cells often contain other neurohumors such as nesfatin-1 in stomach and CCK, motilin and glucagon in small intestine. The effects of ghrelin are species specific and variable. Ghrelin is released from the stomach during fasting or decrease in gastric distension and its release is decreased during feeding, thus it is considered an orexigenic hormone involved in appetite regulation. With regard to the regulation of gut motility, ghrelin has been shown to accelerate gastric emptying, an effect which may be due to activation of vagal preganglionic neurons through actions on central sites or peripherally by enhancing on-going motility. These motor effects appear to be pharmacological since the effects are not evident at physiological levels of ghrelin. Similarly, no physiological effects of ghrelin on gut secretion have been noted.

Glucagon-Like Peptide 1 and Related Peptides Glucagon-like peptide 1 (GLP-1) and related neurohumors glucagon-like peptide 2 (GLP-2) and oxyntomodulin are derived from the same precursor molecule proglucagon and are produced and stored in classically described L cells. These cells are located in the distal

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small intestine and proximal colon. Some of these cells co-express CCK, secretin, ghrelin, serotonin or neurotensin and are thus quite variable. GLP-1 is released by the presence of a variety of nutrients in the lumen especially glucose and fatty acids. GLP-1 release is also stimulated by neural mechanisms involving the vagus nerve and the ENS. GLP-1 has wide ranging effects and has recently been extensively studied as a result of its main incretin effect of enhancing glucose stimulated release of insulin and regulation of blood glucose levels. While GLP-1 has little effect on secretion, it has a major role in gut motility. It acts to slow gastric empting by inhibiting antral contractions and increasing phasic contractions of the pyloric sphincter. This effect in combination with the effects of another neurohumoral agent (PYY) released from the distal ileum is termed the ileal brake. GLP-1 and PYY released from the ileal region act as a brake to slow delivery of nutrient rich luminal content to the small intestine. This effect is also part of the role of GLP-1 in producing satiety and may be mediated by the activation of GLP-1 receptors on vagal afferent fibers in the stomach. Thus GLP-1 can act in an endocrine manner as well as a paracrine manner. The effects on small intestinal motility are less clear with both excitatory and inhibitory actions reported. No physiological effects on gastric acid or intestinal secretions have been reported. Although derived from the same precursor molecule, GLP-2 and oxyntomodulin do not appear to have physiological effects on gut motility or secretion.

Histamine Histamine is produced and released from the classically described enterochromaffin-like cells (ECL) located in the stomach. Histamine is released in response to the endocrine neurohumoral agent gastrin which is released by vagal stimulation and luminal peptide breakdown products as noted above. Histamine acts in a paracrine manner to stimulate H2 receptors on the parietal cell in the gastric fundus. In addition, histamine acts on H3 receptors on D cells in the gastric fundus to inhibit the release of somatostatin which normally restrains acid secretion. The net effects of these two paracrine actions of histamine is to enhance gastric acid secretion. Although there appears to be no physiological role of histamine in the regulation of motility, it is noteworthy that histamine H1 and H2 receptors are present on gut smooth muscle cells where they mediate contraction and relaxation respectively and that H1, H2, and H3 receptors are present on enteric neurons where histamine has been reported to both stimulate and inhibit release of other transmitters.

Motilin Motilin is released from EECs in the small intestine which are classically termed M cells and can be coexpressed with serotonin and ghrelin. Motilin is released primarily in response to bile acids. The action of motilin has been associated with the regulation of motility during the interdigestive period but it has differing effects depending on species. In human, peak motilin levels in plasma correlate with initiation of the intense contractile phase (Phase III) of the migrating motor complex in the stomach but not intestine. This effect appears to be mediated by the release of acetylcholine and thus represents an interaction between endocrine and neural regulation of motility. No physiological role for motilin has been postulated in postprandial motility or secretion, although motilin has been shown to stimulate histamine secretion and therefore may participate in the release of acid that accompanies the migrating motor complex in the interdigestive period.

Neurotensin Neurotensin is released from the classically defined N cells in the small intestine and colon and is often coexpressed with GLP-1 and PYY. Neurotensin is released in response to luminal nutrients, most notably the presence of fatty acids and bile acids. The release and actions of neurotensin are species specific however they are generally inhibitory to gut motility. Neurotensin can act in a paracrine, endocrine or neural fashion and has central nervous system actions including inhibition of food intake and regulation of appetite. Neurotensin receptors are present on brain stem nuclei of the vagus nerve and the inhibition of gastric empting produced by neurotensin may be mediated by this central nervous system effect.

Peptide YY Peptide YY (PYY) is produced and released from the classical L cell in distal small intestine and colon where it can be co-localized with CCK, GLP-1, neurotensin and several other neurohumoral peptides. Because of its localization in L cells and release by the same stimuli described for GLP-1, PYY shares many actions with GLP-1 and other neurohumoral peptides already described. For example, PYY is a key neurohumoral component of the ileal brake which inhibits gastric emptying and slows delivery of nutrients to the small intestine. This gastric effect is likely mediated by activation of receptors for PYY (Y2 receptors) on vagal afferent nerve fibers. These effects contribute to the role of PYY in the control of appetite as a satiety factor. PYY unlike GLP-1 inhibits gastric secretion, an effect that is mediated by inhibition of the enteric secretory motor neurons via activation of Y2 receptors as wells as direct inhibition of intestinal epithelial cells via activation of Y1 receptors. In addition, PYY inhibits colonic motility and transit via activation of Y2 receptors.

Secretin Secretin was the first hormone discovered. It is released from classical S cells in the proximal small intestine where it can be coexpressed with ghrelin, CCK, and serotonin. It is released in response to luminal acid and acts to stimulate bicarbonate secretion

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Neurohumoral Control of Gut Motility and Secretions

from pancreatic duct cells and enterocytes thereby returning luminal pH toward neutral levels. While secretin is capable of interacting with VIP/PACAP receptors, it is a poor activator of these receptors and therefore not thought to have a role in gut motility.

Serotonin Serotonin is produced and released from classic enterochromaffin (EC) cells which are found throughout the intestine and colon. Serotonin can be colocalized with a wide range of other neurohumors and the EC cells have been subdivided into several types based on this colocalization. Most serotonin is found in EC cells, in fact the EC cell represents the largest store of serotonin in the body. Serotonin can also be found in a group of enteric neurons which have descending projections to other enteric neurons suggesting a role as interneurons. There are multiple receptors for serotonin on enterocytes, enteric neurons, other EECs, and vagal afferent fibers to the gut. This widespread distribution of EC cells and serotonin receptors indicates that it has a wide range of actions in the gut. Serotonin acts mainly as a paracrine agent to initiate the peristaltic reflex and augment propulsive motility in the intestine and colon. In addition, serotonin stimulates intestinal secretion from epithelial cells. The presence of receptors for serotonin on vagal nerve fibers results in inhibition of gastric emptying and pancreatic secretion. Serotonin is also well known to have multiple actions in the central nervous system including induction of emesis, mood alteration, and effects on appetite to name a few. The reader is referred to the further readings for an extensive discussion of the effects of serotonin and its receptors.

Somatostatin Somatostatin in produced and released from the classical D cells located in the gastric fundus and antrum as well as small intestine and pancreas. Somatostatin is also present in descending interneurons of the ENS. In some cells, somatostatin is coexpressed with GIP. Somatostatin is released from the D cells of the gastric fundus and gastric antrum in response to vagal stimulation where it acts in a paracrine manner as the main inhibitor of acid secretion. As described in the model (Fig. 1), somatostatin directly inhibits the parietal cell as well as acting indirectly to inhibit the ECL cells thereby reducing histamine secretion in the gastric fundus. Somatostatin also acts as a paracrine agent to inhibit release of the neurohumoral agent gastrin in the antral region of the stomach thereby further reducing acid secretion. Somatostatin released from D cells in the pancreas acts in a paracrine manner to inhibit insulin and glucagon secretion and thereby playing a major role in glucose homeostasis. Somatostatin released from enteric neurons acts to inhibit release of other neurotransmitters such as opioid peptides and ACh. Somatostatin interneurons therefore act as descending interneurons in reflex circuits of the ENS. While this effect is variable, somatostatin has been reported in to enhance the descending inhibitory phase of the colonic peristaltic reflex.

Other Neurohumoral Agents As noted above there are over 30 different EEC which release many potential neurohumoral agents include glucose-dependent insulinotropic peptide (GIP), galanin, adenosine and adenosine triphosphate, leptin, nesfatin-1, atrial natriuretic peptide, amylin, adrenomedullin etc. These have potential actions in the gut as well as other tissues. It is beyond the scope of the present review to address all of these and the reviewer is referred to other chapters in this text as well as the many excellent reviews of regulation of gut function by specific neurohumoral agents.

Regulation of Gastric Acid Secretion as a Model of Neurohumoral Control of Gut Function As noted above, control of gastric acid secretion from the parietal cells in the gastric fundus provides an excellent example of the integration of neurohumoral agents from intrinsic and extrinsic neural, endocrine, and paracrine sources to regulate a gut function (Fig. 1). Vagal afferent fibers to the stomach, although extrinsic neurons in origin, contain the same neurohumoral agent as described for intrinsic primary afferent neurons (IPANs), namely calcitonin gene-related peptide or CGRP. These project to the brain stem and activate preganglionic vagal cholinergic efferent fibers to the fundus and antrum of the stomach which end on enteric neurons which release a variety of neurohumoral agents. In the fundus, enteric cholinergic (postganglionic) neurons release acetylcholine (ACh) which acts directly on muscarinic M3 receptors on the acid secreting parietal cell to stimulate acid secretion. In addition, ACh released from these neurons inhibits release of the neurohumoral paracrine agent, somatostatin from D cells. Somatostatin normally restrains acid secretion by inhibiting the parietal cell via activation of somatostatin type 2 receptors. Somatostatin in addition reciprocally inhibits the enterochromaffin like cells (ECL cell) in the fundus which secrete the neurohumoral paracrine agent histamine. Histamine acts to stimulate the parietal cells via an H2 receptor and inhibit the somatostatin D cell via an H3 receptor. Thus, the extrinsic cholinergic vagal effect of increased histamine (paracrine) and ACh (enteric neural) release coupled with decreased somatostatin (paracrine) release in the fundic region stimulates the parietal cell to secrete acid. In the gastric antral/pyloric region, preganglionic cholinergic vagal neural input to the ENS activates several pathways. Enteric cholinergic neurons and enteric neurons containing the neurohumoral agent gastrin releasing peptide (GRP) directly stimulate the endocrine G cell which releases the hormone gastrin into the blood. Gastrin (endocrine) in turn is transported to the fundus where it activates the parietal cell to secrete acid and the ECL cell to release histamine (paracrine). The enteric cholinergic neuron also innervates a somatostatin-secreting D cell in the antrum which

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659

Vagus

FUNDUS

D cells somatostatin

Acetylcholine

ACh (neurocrine)

(paracrine)

ACh (neurocrine)

GRP & ACh (neurocrine)

D cells somatostatin

(paracrine) ECL cells histamine

ANTRUM

(paracrine) Acid-secreting Parietal cells

(endocrine)

G cells gastrin

(endocrine)

Fig. 1 Model of the stimulation of gastric acid secretion by neurohumoral agents. In the antrum vagal preganglionic cholinergic fibers stimulate enteric neurons to release acetylcholine (ACh) and Gastrin Releasing Peptide (GRP) which stimulate gastrin release from the G cells. ACh also inhibits the release of the paracrine agent somatostatin which normally inhibits gastrin release. In the fundus, vagal preganglionic cholinergic fibers stimulate enteric neurons to release acetylcholine which directly stimulates the parietal cell to secrete acid. ACh also inhibits the release of somatostatin from the D cells which normally inhibits acid secretion. The hormone gastrin directly stimulates the parietal cell to secrete acid and the ECL cell to secrete the paracrine agent histamine. The latter increases acid secretion by directly stimulating the parietal cells and inhibiting the D cell. The dashed line denotes separation of fundic and antral regions.

normally restrains antral gastrin release. ACh inhibits this D cell resulting in a decreased somatostatin release and thus enhanced gastrin release. ACh also inhibits an enterochromaffin cell which releases another neurohumoral agent atrial natriuretic peptide (ANP). Normally ANP stimulates the D cell to secrete somatostatin so that this additional inhibitory effect of ACh removes the reinforcing effect of ANP on somatostatin. These effects are reversed to inhibit gastric acid secretion. Thus, the regulation of gastric acid secretion involves the coordinated control of the several neurohumoral agents from extrinsic neurons (CGRP and ACh), enteric neurons (ACh and GRP), paracrine agents (somatostatin, histamine, ANP), and a hormone (gastrin).

Regulation of the Colonic Peristaltic Reflex as a Model of Neurohumoral Control of Gut Function The peristaltic reflex is one of the main motor reflexes in the ENS and underlies many more complex motility patterns. In its simplest form, the mucosal reflex is illustrated in Fig. 2. The presence of nutrients in the lumen activate receptors on an enteroendocrine cell. A variety of receptors for carbohydrates (T1Rs), lipids (FFARs), L-amino acids (T1Rs, CaSR, etc.), bitter tastants (T2Rs), bile acids (TGR5) etc. are present on the apical surface. Activation of the receptors on the apical surface of the EEC causes the release of a paracrine neurohumoral agent from the basolateral surface, in this case serotonin (5-HT). Terminals of intrinsic primary afferent neurons (IPANs) are subadjacent to the EECs and express receptors including the 5-HT3/4 receptors. Binding to the receptors activates the IPAN which expresses several transmitters including calcitonin gene related peptide (CGRP). The IPAN in turn activates both ascending and descending interneurons within the ENS. The ascending interneuron can express several neurotransmitters, but ACh, NPY and a tachykinin such as substance P have been reported to be released during the ascending component of the peristaltic reflex. The ascending interneuron(s) ultimately activate excitatory motor neurons innervating the circular muscle layer which release ACh and the tachykinin (TK) substance P, and cause contraction. The descending interneurons also release a variety of neurotransmitters such as opioid peptides, ACh, and somatostatin. These descending interneurons ultimately activate inhibitory motor neurons innervating the circular muscle layer which release VIP, PACAP, ATP and NO, and cause relaxation. The combined effect of ascending contraction of circular muscle orad to the stimulus and the descending relaxation of circular muscle caudad to the stimulus results in moving luminal chyme in the caudad direction, where it elicits a similar reflex at a slightly more distal point.

Conclusion The neurohumoral control of gastrointestinal motility and secretion is complex and requires the coordinated action of many hormones, paracrine agents, and neurotransmitters. Some of these can act in a singular manner while others act in multiple ways

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Neurohumoral Control of Gut Motility and Secretions

Descending Relaxation

Ascending Contraction Interneuron

CGRP

Motor Neuron ACh/TK

Interneuron

myenteric plexus Motor Neuron

5-HT 3/4

circular muscle

VIP/PACAP/NO/ATP

IPAN

circular muscle

5-HT ORAD

mucosa

CAUDAD

Stimulus Fig. 2 Model of regulation of the colonic peristaltic reflex by neurohumoral agents. A luminal stimulus activates a receptor on the apical region of an enteroendocrine cell, in this cause an enterochromaffin cell, and causes the release of a paracrine agent such as serotonin (5-HT) from the basolateral surface. Serotonin acts on 5-HT3/4 receptor on the intrinsic primary afferent neuron (IPAN) to release the neurotransmitter calcitonin gene-related peptide (CGRP). CGRP activates ascending interneurons and descending interneurons. The ascending interneurons ultimately activate excitatory neurons to the circular muscle and cause contraction as a result of the release of acetylcholine (ACh) and a tachykinin (substance P) from enteric excitatory motor neurons. The descending interneurons ultimately activate inhibitory neurons to the circular muscle and cause relaxation as a result of the release of vasoactive intestinal peptide (VIP), pituitary adenylate cyclase activating peptide (PACAP), nitric oxide (NO) and adenosine triphosphate (ATP) from enteric inhibitory motor neurons. The combined result of the ascending contraction component and the descending relaxation component of the peristaltic reflex results in caudad propulsion of luminal contents.

and on multiple sites including the central nervous system. We have highlighted the major neurotransmitters involved in the regulation of both motility and secretion by focusing on the well know transmitters of sensory and motor neurons of the enteric nervous system in intrinsic reflex circuits and the influence of the extrinsic neural inputs to the enteric nervous system, with special emphasis on the role of the vagal afferent and efferent nerves. There remains a great deal to be identified with regard to the more complex networks involving the vast majority of interneuronal connections, how specific motility and secretory patterns are generated and intertwined into overall functions, and what determines the changing between patterns. We have reviewed the main gut hormones/paracrine agents and their main actions however many more await identification of their physiological and pathophysiological function. Where once it was thought that specific neurohumoral agents could be assigned to one or a few enteroendocrine cells, it is now clear that there are many subclasses of enteroendocrine cells with specific combinations of bioactive agent and presumable specific functions. We have touched on the nature of the response of enteroendocrine cells to luminal contents and their environment. The pattern of expression of apical receptors for nutrients, microbial products, and other agents adds a layer of complexity and specificity that has only recently been appreciated. Finally, further identification and clarification of the role of neurohumoral agents in the regulation of gut motility and secretion will lead to new and better therapeutic approaches to be developed from this knowledge.

Acknowledgments The authors are supported by grants DK34153 (J.R.G.) and DK28300 (K.S.M.) and DK15564 (K.S.M.) from the National Institutes of Health.

Further Reading Brooks SJH, Spencer NJ, Costa M, and Zagorodnyuk VP (2013) Extrinsic primary afferent signaling in the gut. Nature Review: Gastroenterology & Hepatology 10: 286–296. Browning KN and Travagli RA (2014) Central nervous system control of gastrointestinal motility and secretion and modulation of gastrointestinal functions. Comprehensive Physiology 4: 1339–1368. Christofi FL (2008) Purinergic receptors and gastrointestinal secretomotor function. Purinergic Signal 4: 213–236. Dockray GJ (2014) Gastrointestinal hormones and the dialogue between gut and brain. Journal of Physiology 592: 2927–2941. Fothergill LJ and Furness JB (2018) Diversity of enteroendocrine cells investigated at cellular and subcellular levels: The need for a new classification scheme. Histochemistry & Cell Biology 150: 693–702. Furness JB, Rivera LR, Cho H-J, Bravo DM, and Callaghan B (2013) The gut as a sensory organ. Nature Reviews: Gastroenterology & Hepatology 10: 729–740. Furness JB, Callaghan BP, Rivera LR, and Cho HJ (2014) The enteric nervous system and gastrointestinal innervation: Integrated local and central control. Advances in Experimental Medicine & Biology 817: 39–71.

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Gribble FM and Reimann F (2016) Enteroendocrine cells: Chemosensors in the intestinal epithelium. Annual Reviews in Physiology 78: 277–299. Kaji I and Kaunitz JD (2017) Luminal chemosensing in the gastroduodenal mucosa. Current Opinion in Gastroenterology 33: 439–445. Latorre R, Sternini C, DeGiorgio R, and Greenwood-VanMeerveld B (2016) Enteroendocrine cells: A review of their role in brain-gut communications. Neurogastroenterology & Motility 28: 620–630. Mawe GM and Hoffman JM (2013) Serotonin signaling in the gut-functions, dysfunctions and therapeutic targets. Nature Reviews: Gastroenterology & Hepatology 10: 473–486. Schubert ML and Peura DA (2008) Control of gastric acid secretion in health and disease. Gastroenterology 134: 1842–1860. Spencer NJ, Dinning PG, Brookes SJ, and Costa M (2016) Insights into the mechanisms underlying colonic motor patterns. Journal of Physiology 594: 4099–4106. Steensels S and Depoortere I (2017) Chemoreceptors in the gut. Annual Review of Physiology 80: 117–141.

Neurohumoral Control of Gut Mucosal Defense Antonio Di Sabatino, Marco Vincenzo Lenti, and Gino Roberto Corazza, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy © 2020 Elsevier Inc. All rights reserved.

Glossary

Cytokine Cytokines are a group of proteins that have a role in cell signaling. Cytokines act through receptors and are the key regulators of many biological processes, including cellular growth, cellular differenziation, reproduction, and immune responses. Gut–brain axis The gut–brain axis is a complex system characterized by the mutual, bidirectional interaction of the gut with the brain functions. This axis includes the central nervous system, the autonomic nervous system, the neuroendocrine system and the gut microbiota. Interleukin Interleukins are a group of cytokines, mainly—but not exclusively—secreted by immune cells, during any immune or inflammatory response.

Introduction The gastrointestinal (GI) tract plays a central role in a number of physiological processes, including digestion and absorption of nutrients, immunological tolerance to various antigens (e.g., food, allergens, commensal bacteria), and the mounting of an appropriate immune response (either adaptive or innate) to any potentially harmful agent. The immune system is organized in the so-called gut-associated lymphoid tissue (GALT) within the GI tract. It is known that an abnormal immune response mounted in the GALT may induce a number of immune-mediated GI disorders through a number of pathogenic mechanisms (Macdonald and Monteleone, 2005), that is, loss of self-tolerance with lack of autoreactive CD4þ T-cell deletion, impaired regulatory T-cell function with increased proinflammatory cytokine production and subsequent organ-specific lesions (Thewissen and Stinissen, 2008). The increasing body of knowledge regarding the mechanisms that interact with gut mucosal defense, has recently switched our attention from the well-known action of inflammatory cytokines, to the possible role of the nervous (autonomic and enteric) and the endocrine/paracrine systems. In particular, all these systems interact in a mutual, bidirectional fashion, involving multiple signaling pathways, forming the so-called gut–brain axis (Mayer, 2011) that may influence both the systemic and the GI mucosal immune response. Unfortunately, the neurohumoral control of gut immunity is a yet largely unexplored field of research in humans, and further studies are needed to clarify its function in steady-state conditions and its dysregulation in GI disorders.

Neural Regulation of Gut Immunity Autonomic (sympathetic and parasympathetic arms) and enteric nervous systems, that function involuntarily, are both involved in controlling gut mucosal defense mechanisms, and they mutally interact with the brain through the gut–brain axis. Their action is delivered by means of the released neurotransmitters, namely noradrenaline and acetylcholine (de Jonge, 2013). The nervous system and the GALT are anatomically contiguous, in particular noradrenergic fibers are highly represented in the intestinal lamina propria, and run close to the lymphoid cells, thus easily delivering neuropeptides and adrenergic neurotransmitters (Bellinger et al., 1992). The sympathetic nervous system (SNS) may influence both innate and adaptative immunity. Neurotransmitters can exert either antiinflammatory or proinflammatory effects, depending on their concentration, the expression and type of receptors, and receptor affinity (Straub et al., 2006). The adrenergic signaling generally inhibits the innate immune system through b-adrenoceptors. In particular, norepinephrine at high concentration inhibits phagocytosis, natural killer (NK) cell activation, and secretion of proinflammatory cytokines, for example, tumor necrosis factor (TNF)-a, interlukin (IL)-12, and interferon (IFN)-g (Straub et al., 2006; Elenkov et al., 2000). Instead, at low concentrations, noradrenaline binds the a-adrenoceptors, with a proinflammatory effect, increasing macrophage TNF-a secretion (de Jonge, 2013; Straub et al., 2006; Spengler et al., 1990). Regarding adaptive immunity, the SNS has opposite effects on T helper (Th)1 and Th2 lymphocytes, through b-adrenoceptors signaling. The parasympathetic nervous system (PNS) has an antiinflammatory effect on gut immunity, being acetylcholine the main effector of the PNS (de Jonge, 2013). It has been hypothesized that the PNS is able to “sense” inflammation and, through its activation, is able to induce an antiinflammatory response (the so-called vagal antiinflammatory reflex) (Hoover, 2017). Acetylcholine inhibits nuclear factor-kB (NF-kB), thus inhibiting cytokine production through the nicotinic receptor, also attenuating sepsis in experimental models (Wang et al., 2004). Both muscarinic and nicotin receptors are expressed on a number of immune

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cells, including macrophages, T-cells, dendritic cells, and mast cells. Nicotinic agonists inhibit the macrophage release of proinflammatory cytokines, such as IL-1b, TNF-a, and IL-6 (Hoover, 2017). Clinical trials testing cholinergic molecules in a number of human disorders, including inflammatory bowel diseases, rheumatoid arthritis, and systemic lupus erythematosus, are currently ongoing.

Hormone Regulation of Gut Immunity Endocrine cells are well represented within the gut mucosa, and they produce and secrete many different hormones which mainly act along the GI tract. Endocrine cells are contiguous to the immune cells of the GI tract, and it is likely that they play a major role in the activation and regulation of immune responses in physiological and pathological conditions. In this regard, serotonin (5hydroxytryptamine; 5-HT) and chromogranins (CGs) are among the most studied hormones released in the GI tract by enterochromaffin cells. 5-HT is a widely investigated neurotransmitter which plays a fundamental role in the regulation of numerous physiological processes and functions, such as memory, learning, mood, pain, appetite, GI motility and secretion, and metabolism (Kato, 2013). The larger amount of 5-HT is procuced in the GI tract and, besides all the aforementioned neurological effects, accumulating evidences suggest an important role in regulating inflammation in the gut, especially by means of the receptor 5-HT3. 5-HT3 is expressed in gut epithelial cells, the enteric nervous system, as well as in immune cells, such as monocytes, macrophages, T lymphocytes, and dendritic cells. It has been hypothesized that 5-HT has a proinflammatory effect, being increased in experimental colitis and inflammatory bowel disease (Ghia et al., 2009). In experimental colitis, 5-HT triggered the macrophage release of proinflammatory cytokines; moreover, a NF-kB inhibitor was able to prevent inflammation in this model (Ghia et al., 2009). 5-HT is overexpressed in the gut mucosa of patients affected by uncomplicated untreated and refractory celiac disease and, of note, 5-HT increases ex vivo IFN-g production in gut explants from celiac patients, thus strengthening the concept that monoamines sustain the local inflammatory response in Th1-mediated GI disorders (Di Sabatino et al., 2014). Finally, 5-HT3 receptor antagonists display an antiinflammatory effect, at least in experimental models, by inhibiting the production of IL-1, IL-6, TNF-a, and possibly other cytokines (Kato, 2013). CGA, which is the most widely characterized among different CGs, is a member of the granin family, which encompasses a group of protein precursors of many active hormones produced my neuroendocrine cells. CGA was shown to be increased in patients with inflammatory bowel disease (both Crohn’s disease and ulcerative colitis), also correlating with TNF-a levels) (Sciola et al., 2009). To support the hypothesis of a mutual influence of CGA and TNF-a, in one experimental mouse model, CGA was able to prevent vascular leakage induced by TNF (Ferrero et al., 2002). Moreover, CGA positive cells have been shown to be increased in the duodenal mucosa of patients with refractory celiac disease, as well as serum CGA levels (Di Sabatino et al., 2014). However, the molecular mechanisms underlying the neurohumoral regulation of the gut immune response both in steady-state and pathological conditions are yet unknown.

Conclusion Increasing evidences support the importance of the neurohormonal control of the gut immune response. The autonomic nervous system and the endocrine system deeply modulate the immune response with either pro- or anti-inflammatory effects, depending on the neurohormone types, concentrations, and receptors. Future studies are needed to better characterize the signaling pathways implicated in the neurohumoral control of gut immunity in order to elucidate the contribution of neurohumoral dysregulation in immune-mediated disorders of the GI tract.

References Bellinger DL, Lorton D, and Felten SY (1992) Innervation of lymphoid organs and implications in development, aging, and autoimmunity. International Journal of Immunopharmacology 14: 329–344. Di Sabatino A, Giuffrida P, Vanoli A, et al. (2014) Increase in neuroendocrine cells in the duodenal mucosa of patients with refractory celiac disease. American Journal of Gastroenterology 109: 258–269. Elenkov IJ, Wilder RL, Chrousos GP, and Vizi ES (2000) The sympathetic nerve—An integrative interface between two supersystems: The brain and the immune system. Pharmacological Reviews 52: 595–638. Ferrero E, Magni E, Curnis F, et al. (2002) Regulation of endothelial cell shape and barrier function by chromogranin A. Annals of the New York Academy of Sciences 971: 355–358. Ghia JE, Li N, Wang H, et al. (2009) Serotonin has a key role in pathogenesis of experimental colitis. Gastroenterology 137: 1649–1660. Hoover DB (2017) Cholinergic modulation of the immune system presents new approaches for treating inflammation. Pharmacology & Therapeutics 179: 1–16. de Jonge WJ (2013) The gut’s little brain in control of intestinal immunity. ISRN Gastroenterology 4: 630159. Kato S (2013) Role of serotonin 5-HT3 receptors in intestinal inflammation. Biological and Pharmaceutical Bulletin 36: 1406–1409. Macdonald TT and Monteleone G (2005) Immunity, inflammation, and allergy in the gut. Science 307: 1920–1925. Mayer EA (2011) Gut feelings: The emerging biology of gut–brain communication. Nature Reviews Neuroscience 12: 453–466. Sciola V, Massironi S, Conte D, et al. (2009) Plasma chromogranin a in patients with inflammatory bowel disease. Inflammatory Bowel Disease 15: 867–871.

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Spengler RN, Allen RM, Remick DG, Strieter RM, and Kunkel SL (1990) Stimulation of alpha-adrenergic receptor augments the production of macrophage-derived tumor necrosis factor. The Journal of Immunology 145: 1430–1434. Straub H, Wiest R, Strauch UG, Härle P, and Schölmerich J (2006) The role of the sympathetic nervous system in intestinal inflammation. Gut 55: 1640–1649. Thewissen M and Stinissen P (2008) New concepts on the pathogenesis of autoimmune diseases: A role for immune homeostasis, immunoregulation, and immunosenescence. Critical Reviews in Immunology 28: 363–376. Wang H, Liao H, Ochani M, et al. (2004) Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nature Medicine 10: 1216–1221.

Further Reading de Jonge WJ (2013) The gut’s little brain in control of intestinal immunity. ISRN Gastroenterology 4: 630,159. Di Sabatino A, Lenti MV, Giuffrida P, Vanoli A, and Corazza GR (2015) New insights into immune mechanisms underlying autoimmune diseases of the gastrointestinal tract. Autoimmunity Reviews 14: 1161–1169. Khan WI and Ghia JE (2010) Gut hormones: Emerging role in immune activation and inflammation. Clinical & Experimental Immunology 161: 19–27. Straub H, Wiest R, Strauch UG, Härle P, and Schölmerich J (2006) The role of the sympathetic nervous system in intestinal inflammation. Gut 55: 1640–1649.

Neuroimmune Signaling in the Gastrointestinal Tract Stephen Vanner, Alan Lomax, and Nestor N Jimenez-Vargas, Queen’s University, Kingston, ON, Canada © 2020 Elsevier Inc. All rights reserved.

Glossary

Afferent nerve Type of nerve that transmits sensory signals from a peripheral nerve terminal to the CNS. Histamine Is an amine derived by enzymatic decarboxylation of histidine, secreted mainly by immune cells and associated with inflammation; capable of modulating the excitability of neurons through activation of cognate receptor. Hyperalgesia Increased pain sensation in response to a given stimulus such as distention of the colon. Hypoalgesia Decreased pain sensation in response to a given stimulus. Immune mediators Molecules secreted by immune cells that may modulate a response in other cells including neurons. Microbiome Refers to the genomes of microorganisms present in the human body. Microbiota Refers to the microorganisms present in the human body. Microbiota-brain gut axis Bidirectional communication between nervous system and microbiota. Neural plasticity Ability of neurons to change their properties including those of ion channels, leading to changes in function such as neuronal excitability. Neurogenic inflammation Defense mechanism to a noxious stimuli regulated by nerve cells through releasing mediators such as CGRP, SP, VIP, NPY and neurokinins. Nociception Is the sensory nervous systems response to harmful or noxious stimuli and can lead to a change in the level of pain sensation or other sensations. Nociceptor Sensory neurons that process nociceptive stimuli and signal to the central nervous system, for example dorsal root ganglia (DRG) neurons projecting afferent nerves to colonic tissue. Proteases Enzymes secreted by immune cells or microorganisms capable of breaking down proteins and can signal to neurons and other cells by activation of their cognate receptors e.g. protease activated receptors (PARs). Supernatant Solution rich in endogenous mediators released from tissues after they were incubated in culture media.

Nomenclature IBS IBD POI CNS ENS ANS GI HPA-SA

Irritable bowel syndrome Inflammatory bowel disease Post-operative Ileus Central nervous system Enteric nervous system Autonomic nervous system Gastrointestinal Hypothalamic-pituitary-adrenal and sympathetic axis

Introduction In the past few decades, there has been a rapid growth in our understanding of neuroimmune signaling and how this can underlie symptoms in gastrointestinal disorders. Several core concepts have emerged, including: (1) there is ongoing bidirectional signaling between the nervous and immune systems in the gut, (2) superimposed on this signaling is an interaction with the microbiota, which can influence immune signaling, neural signaling and the mucosal barrier between these luminal—intestinal compartments, (3) there is a complex integration of this signaling at multiple levels e.g. within the intestine, the spinal cord, and the brain. This article reviews basic properties of the innervation and immune system of the gastrointestinal (GI) tract, setting the stage to explore neuroimmune signaling in three human GI disorders: irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and post-operative ileus (POI). The focus is on core concepts in the periphery (i.e., intestine) for which there is evidence in humans. There is a vast amount elegant work performed in preclinical models, much of which has yet to be validated in humans and hence will not explored in depth in this article. More detailed information based on the preclinical studies can be found in several excellent reviews (Mawe, 2015; Brierley and Linden, 2014; Simren and Tack, 2018; Sharkey et al., 2018).

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Overview of Innervation and Immunology of the Intestine Nervous System Neuroimmune signaling in the intestine can involve the afferent, autonomic (motor) and enteric nerve circuits, and many detailed reviews exist (Furness, 2006). Briefly, the enteric nervous system is a complex and semi-autonomous system within the intestinal wall that is organized into two plexuses, the submucosal (found within the submucosa) and myenteric plexus (found between the circular and longitudinal muscle). They are organized into collections of neurons (ganglia) connected by interganglionic connectives (axons). There is considerable complexity as these ganglia collectively contain more neurons than found in the spinal cord, release a wide range of neurotransmitters, and exhibit considerable plasticity (ability to change their properties). Classically, submucosal motoneurons were recognized to innervate the enterocytes and submucosal resistance arterioles, stimulating chloride and water secretion and dilation respectively, and myenteric motoneurons to innervate interstitial cells of Cajal (ICC) (specialized cells in close apposition to smooth muscle cells) or the smooth muscle cells leading to either contraction or relaxation of the muscle (Furness, 2006). More recently, it is evident they may also communicate with cells of the intestinal barrier, including enterocytes, neuroendocrine and mucosal immune cells. Enteric nerve circuits contain afferent, efferent and interneurons enabling localized independent reflexes within the ganglia between submucosal and myenteric ganglia, as well as prevertebral sympathetic ganglia (intestinofugal neurons). The communication with immune cells as well as glial cells found within the enteric ganglia modulates the excitability of many of these neurons. The extrinsic motor innervation of the gut is comprised of the sympathetic nerves (motoneuron cell bodies in the paravertebral and prevertebral ganglia), and parasympathetic nerves (motoneuron cell bodies originating in the brain stem (i.e., vagus nerve) or the distal spinal cord (i.e., sacral nerves)) (Fig. 1). Both innervate enteric ganglia but this innervation is not 1:1 (i.e., vagal inputs are very sparse in the distal small intestine and proximal colon). In general sympathetic nerves have an inhibitory action and parasympathetic nerves have an excitatory action on enteric neurons or other effector systems. Subsets of these extrinsic nerves

Fig. 1 Schematic representation of the enteric nervous system and extrinsic nervous system. Intrinsic primary afferent neuron and intestinofugal neurons in the enteric nervous system, and the spinal afferent (dorsal root ganglia, DRG) and vagal afferent neurons projecting to the gut integrate the sensory inputs from lumen content such as mediators derived from diet, microorganisms and chemical toxins. Luminal contents can activate receptors directly on nerves or indirectly through stimulation of enteroendocrine cells, lymphocytes and other immune cells such as mast cells and macrophages that in turn release neuroimmune mediators.

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can also communicate with immune cells. The afferent nerves travel with the vagus nerve (cell bodies in nodose ganglia) or spinal nerves (cell bodies in dorsal root ganglia nerves) (Fig. 1) (see Furness et al., 2013 for more details). A subset of these DRG neurons convey nociception (pain) to the central nervous system (CNS) but under certain conditions, some of these serve as “local effector” nerves. Substance P (SP) and calcitonin gene-related peptide (CGRP) are released from these nerve terminals within the wall of the intestine and signal to immune cells and other effector mechanisms that express their cognate receptors (e.g. enterocytes, arterioles) to cause neurogenic inflammation. There has been considerable attention given to the “nociceptive” DRG neurons given their fundamental role in the expression of pain by the CNS. Immune mediators can modulate their activity through multiple mechanisms leading to acute (minutes) and chronic (hours to days) signaling. While the majority of mediators exaggerate pain signaling (i.e. are pro-nociceptive) some decrease signaling (antinociceptive) and consequently nociceptive signaling is a balance of these factors. Pronociceptive signaling can underlie the development of the commonly recognized phenomenon of peripheral sensitization, leading to exaggerated pain signaling for a given stimulus such as distention of the intestine, i.e. visceral hyperalgesia. Alternatively however, some mediators can inhibit nociceptors causing hypoalgesia. Consequently, there is a complex integration of signaling at the level of the nerve terminals or cell bodies. Unlike the somatosensory system, visceral sensory neurons, including nociceptors, appear to lack any specialized structure to their nerve terminals.

Intestinal Immune System The immune system in the intestine is poised to communicate bi-directionally with the enteric nervous system (ENS), autonomic nervous system (ANS), and the brain, as well as the epithelium and microbiota. It plays an essential role in monitoring and responding to luminal challenges from pathogens and toxins while remaining “tolerant” to millions of commensal bacteria and antigens, including food and their metabolites. The key regulators include the mononuclear phagocytes, innate cells including lymphocytes and mast cells, and T cells (Fig. 2), which release a complex array of signaling molecules, including cytokines and chemokines, 5-HT, histamine, and proteases. Compared to other tissues, the intestine is considered to be in a state of “physiological inflammation” given the relative expansion of lymphocytes in the lamina propria and mucosa. Communication in the microbiota-brain-gut axis can activate and/or modulate fundamental response pathways of the intestinal immune system. The immune system can classically respond rapidly via innate immune cells in the lamina propria of intestine (i.e. non-specific defense that is rapidly activated) and/or via the slower adaptive immune response (antigen-specific T and B cells), to a specific antigenic challenge from the lumen. Trafficking of immune cells to the intestine is dependent on selective homing molecules, such as integrin a4b7, and these can be measured in the serum of patients as an indirect measure of immune activation. Immune responses by CD4þ T cell subsets can produced polarized cytokine responses categorized broadly as Th1, Th2, Th17 and Th22 (Fig. 2). Type 1 T helper cells secrete interferon Y (IFN-Y) and tumor necrosis factor (TNF-a) that have proinflammatory actions, Type 2 helper cells produce interleukins (IL-4, IL-5 and IL-13) and support activation, and maintenance of tissue mast cells and eosinophils (Fig. 2) (see Powell et al., 2017 for more details). This inflammatory pathway paradigm however appears to be an oversimplification as recent evidence suggests there is considerable overlap of these pathways in specific GI disorders. Nonetheless, an imbalance in these responses can lead to uncontrolled tissue damage and could underlie symptoms in both IBS and IBD. These inflammatory pathways could be activated by a number of factors, including diet, antibiotics, inflammation, and possible psychological stress through activation of the hypothalamic-pituitary-adrenal and sympathetic axis (HPA-SA). Immune-microbiota signaling could also by influenced by factors regulating the mucosal barrier, such as inflammation in IBD and the activation of the HPA-SA in IBS.

Irritable Bowel Syndrome (IBS) Altered Mucosal Immunity in IBS Irritable bowel syndrome is a disorder defined by abdominal pain and altered bowel habit, and historically one for which there is no known structural or biochemical cause. However, there is now a large body of evidence demonstrating altered mucosal immunity (so called “low-grade inflammation”) in at least a significant subset of IBS patients. This is a result of communication between nerves and immune cells and this bidirectional signaling appears to underlie symptom generation in many patients. This line of study has been stimulated by several fundamental discoveries in these patients compared to healthy volunteers: (1) increased proximity of nerve and immune cells, (2) altered numbers of immune cells expressing a relevant repertoire of receptors to enable communication and (3) elevated levels of immune mediators that have been shown to activate and sensitize nerves in the wall of the intestine. Whether these nerve immune interactions are important in all subtypes of IBS (i.e. diarrhea-predominant vs. constipation-predominant vs. post-infectious IBS), or differ within a given subtype, is unclear but many studies show abnormalities in all groups. Mast cells and their mediators, tryptase and histamine, have dominated the focus of studies to date, but there is growing evidence that other mediators and sources of these mediators are also important. There has also been considerable interest, but less clarity, in potential dysregulation of the adaptive immune system. Here there is evidence in the serum of IBS patients of increased expression of homing receptors of/and increased levels of activated T cell subsets, particularly CD4þ T cells, and elevation of their cytokines such as TNF-a (Bashashati et al., 2018; Simren and Tack, 2018; Zhang et al., 2016). The following discusses the key evidence supporting these concepts, the mechanisms that could underlie symptom generation in IBS patients, the growing repertoire of activators and modulators of this fundamental neuroimmune signaling, and the challenges in validating these concepts in IBS patients.

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Gut microbiota

Immunity to bacteria

Immunity to helminths

Histamine

Intestinal epithelium

TNF

Macrophage

Neutrophils Eosinophil granule proteins

IL-5 IL-5

IL-13 ILC1 TH2

TH1 T-bet

ILC2 GATA3 GATA3

T-bet

Epithelial resitution

Eosinophils

Mast cell IL-4

IFNγ

Immunity to bacteria and/or fungi

IL-17

IL-22 NCR+ ILC3

ILC3

TH17 RORγt RORγt

RORγt

IL-12 M2 macrophage M1 macrophage IFNγ

IL-4

Monocyte Fig. 2 Mucosal immune networks. The mucosal immune system has a crucial role in immunity to microorganisms and in epithelial restitution. Distinct arms of host immunity can be mobilized to defend against specific microbial threats. However, selective aspects of these immune response pathways can be inappropriately deployed in immune-mediated diseases. T-Bet-expressing type 1 T helper (Th1) effector memory T-cells and type 1 innate lymphoid cells (ILCs) respond to cytokine signals (including IL-12) to trigger their effector responses, which includes production of IFN-g, which in turn primes tissue mononuclear phagocytes, such as macrophages and monocytes, programming them for pro-inflammatory activation. This pathway is especially important in host resistance to intracellular bacteria, including mycobacterial infection. IL-12-producing M1 macrophages support the type 1 inflammatory response, and reciprocally IFN-g supports M1 differentiation. The type 2 response is characterized by activation of GATA3-expressing type 2 T helper (Th2) cells and ILC2, which produce cytokines (such as IL-4, IL-5 and IL-13) to support the activation, recruitment and survival of eosinophils and mast cells. The type 2 response is implicated in host resistance to helminths. RORgt-expressing type 17 T helper (Th17) and ILC3 (especially natural cytotoxicity receptor (NCR)–ILC3) cells produce IL-17 family cytokines, which support the activation and recruitment of neutrophils and have an important role in host immunity to extracellular bacteria and fungi. NCRþ ILC3 produce IL-22, which supports the epithelial stem cell niche by promoting proliferation of LGR5þ stem cells and also promote the production of antimicrobial peptides by epithelial cells. IL-22-producing ILC3 are implicated in host resistance to some mucosal pathogens. Reprinted by permission from Springer Customer Service Centre GmbH Powell, N., Walker, M. M. & Talley, N. J. (2017). The mucosal immune system: Master regulator of bidirectional gut-brain communications. Nature Reviews. Gastroenterology & Hepatology 14, 143–159.

Structural Evidence Supporting Neuroimmune Signaling in IBS Patients Nerve—Mast cell associations The cellular content in the lamina propria is increased in studies of IBS intestinal biopsies and up to 70% of these immune cells are in close contact with nerves. Mast cell signaling has been the major focus, these cells comprise approximately 2–3% of all cells in the lamina propria, and about 1% in the submucosa, but these numbers can be increased in response to a wide array of stimuli (Zhang et al., 2016). Increased mast cell numbers and/or activated mast cells have been shown using electron microscopy to be in close apposition, in some cases, making physical contact with axons. These cells contain numerous mediators that can signal to nerves, and express receptors for neurotransmitters, microbial products (e.g. toll-like receptors (TLRs)), and immune mediators. Many of these studies did not distinguish axons of enteric from DRG neurons, but studies showing close proximity to transient receptor potential vanilloid 1 (TRPV1) and SP immunoreactive fibers (potential markers of nociceptive nerves) suggesting at least some of these contacts are with axons of nociceptive DRG neurons. Studying their functional properties is challenging because they are highly plastic and hence their properties are dependent on signaling from their “local mileu” (for example SP mediated human mast cell activation requires other co-stimulatory mediators such as stem cell factor and IL-4) and human mast cell properties may differ from those in rodents. Changes in other inflammatory cells of innate immune system that could also modulate neuroimmune interactions have also been observed in IBS tissues including lymphocytes, eosinophils, and macrophages but this potential is less well studied.

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CD68 þ macrophages in IBS biopsies are decreased in number as well as the concentration of macrophage-attracting chemokines are decreased. These cells express Toll-like receptors (TLRs) and could suggest impaired ability to respond to antigenic stimuli (Bashashati et al., 2018). Other non-mast cell sources of tissue mediators in IBS patients are also likely important, including trypsin-3 originating from enterocytes, cysteine proteases from macrophages, and histamine and proteases from the microbiota (Rolland-Fourcade et al., 2017). In addition to these differences in the innate immune system, potentially important changes in the adaptive immune system in IBS patients have also been observed but the overall significance remains controversial. There is a greater proportion of T cells homing to the GI tract in IBS patients compared to healthy controls, possibly in response to an antigenic challenge. Circulating T cell numbers are unaltered in IBS but T helper (Th) and cytotoxic T cells and T cells residing in the colon of IBS patients are more likely to be in an activated state. Blood cytokine profiles are complex in IBS patients, where some show a Th1 profile (TNF-a, IL-6 etc.), some show a Th2 profile and others appear similar to healthy controls (Bashashati et al., 2018). These differences might provide important clues into mechanisms within subtypes of IBS (e.g. IBS-D, Th1 dominant in some studies) or even subsets within a given subtype of IBS, but this remains to be determined. There has also been interest in B cells in IBS patients, given their ability to secrete antibodies directed against luminal antigen or even autoantibodies to ion channels on nerves, but while some differences have been observed their significance is unclear. In addition to changes in immune cells numbers/activation, the neuroimmune communication may also be enhanced by increased density of nerve fibers. Intestinal biopsies from IBS patients have increased nerve fibers and axonal sprouting in the lamina propria. Some of these fibers are immunoreactive for SP and TRPV1, suggesting nociceptors could be involved. Nerve growth factor expression is increased in these tissues and is known to not only induce neuronal sprouting but could have other actions such as increasing expression of ion channels underlying visceral hypersensitivity (e.g. TRP channels and voltage gated Naþ channels (Nav)) and modulation of mast cells (Sharkey et al., 2018; Simren and Tack, 2018).

Functional Evidence of Neuroimmune Signaling in IBS Patients Much of our understanding of functional importance of neuroimmune interactions in IBS patients has been gained from the study of intestinal biopsies obtained from patients undergoing endoscopic procedures (see Nasser et al., 2014 for detailed review). Supernatants obtained by incubating these biopsies in culture media are thought to be representative of the “inflammatory mediators” signaling to enteric and nociceptive nerves and have been particularly important to the study of nociceptors, as these neurons are not accessible in humans. Enteric nerves, in contrast, have been studied in biopsy specimens (submucosal neurons) and resected human specimens (submucosal and myenteric neurons).

Nociceptors IBS supernatants have been shown to have two major actions on these nerves (DRG nerve terminals in the gut), acute activation (i.e. generate a burst of action potentials) and to sensitize nerves (i.e. lead to exaggerated signaling in response to a subsequent stimulus). These actions have been demonstrated using several complementary experimental recording techniques, including recording of ex vivo afferent nerve firing from the colon and the measurement of sensory thresholds (visceromotor reflexes) in the colon of conscious animals after exposure to the supernatants. Single cell patch clamp recordings of isolated DRG neurons from mice exposed to the supernatants has been particularly useful in elucidating the ionic mechanisms involved. A fundamental concept is that these inflammatory mediators, particularly histamine and proteases, signal via G protein coupled receptors to modulate the properties of TRP and voltage-gated ion channels (Fig. 3). This results in changes in ionic fluxes through these channels that ultimately lead to exaggerated action potential discharge in response to chemical and mechanical stimuli. Studies using supernatants from IBS patients have also revealed further complexities to this signaling where different agonists (e.g. proteases) can signal to the same receptor and have different effects (biased agonists) and certain mediators can signal intracellularly in endosomes leading to sustained signaling for hours (Jimenez-Vargas et al., 2018). Together, these mechanisms provide key insights into exaggerated pain signaling in IBS patients (visceral hypersensitivity) and potentially novel targets for treatment.

Enteric neurons Human enteric neurons can be isolated in human biopsies and fresh surgical specimens and thus it has been possible to directly show that the mediators in IBS supernatants can activate both submucosal and myenteric neurons. Using Ca2þ imaging, both histamine and proteases have been shown to activate enteric neurons. Such findings could explain altered motility and secretion in IBS patients but this remains to be demonstrated. Whether mediators can also sensitize these human neurons is less clear but there is evidence of increased signaling in submucosal neurons from IBS patients stimulated by supernatants compared to healthy controls and there is some electrophysiological data from animals suggesting mast cell mediators can lead to sustained excitation of at least some enteric neurons. Several potentially novel observations have also emerged from these human studies. For example, these studies have provided direct evidence for bidirectional communication between mast cells and nerves (Buhner et al., 2017) but somewhat unexpected, this mast cell-submucosal neuron signaling was readily evident from nerves innervating mast cells but uncommon from mast cells to nerves. Furthermore, differences may exist between species. For example, several studies suggest proteases-activated receptor (PAR) activation may vary between animal and human neurons. Further studies using human tissues are needed and this highlights the importance of confirming mechanistic insights in human

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Fig. 3 Mediators of neuroimmune interactions. Examples of some key mediators and receptors involved in the bidirectional signaling between immune cells and nervous system in the gut during IBD (black color) and IBS (red color). The proximity of immune cell to nerves, the expression of different neurotransmitter receptors on immune cells, as well as receptors for inflammatory mediators on neural structures are key elements in the bidirectional neuroimmune communication. Receptors: TLF, toll like-receptor; HR, histamine receptor; PAR, proteases activated-receptor; TNFR, tumor necrosis factor; NKR, neurokinin receptor; DOR, d opioid receptor; MOR, m opioid receptor; b2-AR, b2-adrenoreceptor; 5HTR, serotonin receptor; nAChR, nicotinic receptor; DAR, dopamine receptor; TRPV, transient receptor potential vanilloid; Nav/Kv, voltage gated Naþ/Kþ channels. Mediators: LPS, lipopolysaccharides; TNF-a, tumor necrosis factor; SP, substance P; ACh, acetylcholine; NE, norepinephrine; histamine, proteases, opioids. For a more complete review of the mediators and their receptors in this bidirectional communication see (Brierley and Linden, 2014; Mawe, 2015; Moynes et al., 2014; Nasser et al., 2014; Sharkey et al., 2018).

tissues given the differences in human mast cells and enteric neurons. Human nociceptor cell lines are being developed and will lead to key studies in this regard. Increases in mucosal permeability has also been widely implicated in the pathogenesis of IBS due to enhanced neuroimmune signaling resulting from increased luminal stimuli e.g. bacterial cell products, although these permeability changes have not been consistent between studies and their functional significance not fully understood. Tight junction protein expression (e.g. ZO-1) is reduced in IBS biopsies and associated with increased permeability. What causes this increased permeability is unclear, but immune mediators within the IBS mucosal biopsies, luminal stimuli, and extra-intestinal neurohumoral signaling (see below) have all been implicated.

Key Pathways That Modulate Neuroimmune Interactions in the Intestine Neurohumoral signaling activated by the CNS and luminal signaling from dietary components and the microbiome are key pathways that modulate intestinal neuroimmune signaling, acting alone or through a dynamic interplay. The intestinal microbiota in IBS patients appears to be important, at least in a subset of patients, but a precise role is unclear. There is no clear “signature” that correlates with IBS patients but several themes are emerging compared to healthy controls that implicates the microbiota: (1) there is less diversity in many IBS patients, (2) the proportion of specific bacteria are altered (3) the microbiota is less stable over time (4) the degree of variability of specific bacterial groups is different (5) gastrointestinal (GI) infections are strong risk factors for the development of functional dyspepsia and IBS (see Post-Infectious Functional Gastrointestinal Disorders); fecal micro- biota is substantially different in IBS and post-infectious (PI)-IBS compared with healthy controls, and shows reduced microbiota diversity (Sharkey et al., 2018; Simren and Tack, 2018). IBS patients report higher anxiety and depression scores as a group and psychological factors are predictive of the development of IBS in patients following a self-limiting enteric infection. Psychological stress activates the HPA-SA and releases corticotrophin releasing factor

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(CRF) resulting in neurohumoral signaling to effector cells in the GI tract including mast cells (Fig. 4). In studies with human mast cells, CRF can cause degranulation of mast cells whereas b2 adrenergic agonists, at least in isolated human mast cells, inhibit degranulation and mast cell migration and differentiation. There is also evidence, at least from preclinical data, that stress hormones can signal to select populations of the microbiome either indirectly (e.g. to enterocytes which leads to altering attaching and effacing of pronociceptive bacteria) or directly (e.g. bioamine transporters enable uptake of catecholamines and serotonin (5-HT)). Furthermore, there is some evidence that immune mediators (e.g. histamine and proteases) produced by the microbiota of IBS patients can also signal to nerves within the intestine, leading to activation and sensitization (Fig. 4). Dynamic bidirectional signaling with the microbiota is also evident as they also signal in turn to the brain, given the evidence that probiotics can modify depression in IBS patients. Studies have also shown that an anxiety phenotype can be transferred to germ free mice using the stool from IBS patients with anxiety. Diet-microbiome interactions are also emerging as an important modulator of neuroimmune signaling. Poorly absorbed complex sugars (fermentable oligo, di, mono saccharides and polyols; FODMAPs) are fermented by colonic bacteria, producing gaseous distention, short-chain fatty acids (SCFA’s) and changes in luminal pH, and other metabolites that may directly or indirectly activate the intestinal immune system (Fig. 4). Reducing these poorly absorbed complex sugars found in many foods reduces symptoms in IBS patients. Other dietary factors are also being studied, such as gluten in IBS patients who do not have celiac disease, bile acids and short-chain fatty acids (SCFA’s). Interestingly there is also preliminary data in preclinical models that psychological stress and/or a recent acute enteric infection could lead to loss of oral tolerance to common food antigens. Given the longstanding observation that histamine and proteases are elevated in random biopsies from IBS patients, increases in these mediators could be a final common pathway for several of these diet interactions.

Fig. 4 Microbiota-Immune Brain-gut axis. Intrinsic (e.g. microbiota) and external (e.g. psychological stress) factors contribute to this complex bidirectional communication. Dietary factors (e.g. prebiotics) can modulate the microbiota and their metabolites (i.e., short-chain fatty acids) and in turn lead to release immune mediators such as proteases and histamine that are capable of modulating neuronal excitability. Chronic stress activates the HPA-SA, releasing catecholamines such as norepinephrine (NE) that can modulate nerve and immune cells expressing adrenoreceptors. Microbiota might also be modulated by endocrine hormones, but this has not be proven in human. Ultimately, these luminal and tissue signaling pathways converge on neurons such as spinal primary (dorsal root ganglia) neurons and convey signals to the CNS (e.g. pain signaling) or enteric neurons innervating effector pathways within the intestine (e.g. motility). These mechanisms can underlie symptoms in GI disorders such as IBS and IBD.

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Inflammatory Bowel Diseases (IBD) The two major forms of IBD are Crohn’s disease (CD) and ulcerative colitis (UC), and these patients commonly present with chronic abdominal pain and diarrhea. Over the last few decades, understanding how neuroplasticity contributes to these symptoms has become an important focus in IBD research. IBD is thought to arise from inflammation of the GI tract triggered by hostmicrobial interactions in genetically susceptible individuals. Current treatments aim to mitigate the mucosal inflammation and alleviate symptoms. However, many IBD patients in remission continue to have symptoms despite evidence of mucosal healing. This highlights the potential role of inflammation-induced neuroplasticity persisting beyond the resolution on inflammation (Brierley and Linden, 2014). Part of the challenge in understanding the generation of symptoms lies in the complex relationship that exists between the immune system and the innervation of the gut. In this section, we will describe the key immune factors involved in the modulation of nerves in IBD.

Altered Immunity in IBD The alterations of the immune response underlying IBD involves both; (1) the innate system which leads to the loss of tolerance to microbial products signaling from the lumen and penetrating the intestinal mucosa, and (2) the adaptive immune system, that contributes to the pathogenesis of IBD through activation of T helper lymphocytes (Th1, Th2, Th17 and Th22) and the recruitment of B cells, leading to secretion of IgA and IgG in the mucosa (Fig. 2) (Powell et al., 2017). This creates a complex interaction between B cells and T lymphocytes mechanisms. Alterations in epithelial barrier integrity also contribute to chronic intestinal inflammation. In contrast to IBS where the focus has been largely on histamine and proteases, the study of inflammatory mediators in IBD patients has identified important actions by both pronociceptive and antinociceptive mediators. During an acute flare up of UC, pronociceptive signaling by T cell derived mediators such as TNF-a appear to have a dominant action whereas during the chronic phase of inflammation (e.g. > 6 months of active disease) there is the emergence of the endogenous opioid system. Here, endogenous opioids, such as b-endorphin and leu-enkephalin, are released from CD4 þ T cells. These endogenous opioids can exert an important antinociceptive effect through the activation of opioid receptors on nerve terminals of the nociceptive DRG neurons innervating the intestine (Fig. 3).

Structural Evidence Supporting Neuroimmune Signaling in IBD Patients Tissues from Crohn’s disease patients demonstrate an enhanced expression of antigen presenting cells (MHC class II) in enteric neurons and enteroglia, reflecting underlying activation of the immune system and likely dysfunction of the intestinal barrier. Together, this sets the stage for enhanced neuroimmune communication (Brierley and Linden, 2014; Furness et al., 2013).

Enteric nervous system changes during IBD The analysis of biopsies and resected specimens from patients with UC or CD have demonstrated ENS abnormalities including hypertrophy and/or hyperplasia of ganglia and nerve bundles in the mucosa, submucosa and myenteric plexus of the ileum and colon (Lomax et al., 2005; Mawe, 2015). In addition to these findings, neuronal and axonal degeneration have been also observed in both CD and UC. The presence of mast cells, lymphocytes and plasma cells in submucosal and myenteric ganglia have been well documented in both CD and UC, which implicates neuroimmune interactions in the loss of enteric innervation that accompanies IBD. Activation of P2X7 receptors by adenosine triphosphate (ATP) released via neuronal pannexin hemichannels has been reported as an important mechanism underlying neuronal death in IBD (Brierley and Linden, 2014; Mawe, 2015). A consistent finding of IBD patient tissues is plasticity of the immunoreactivity for a number of enteric neurochemicals. The main neurochemical changes have been described in substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), nitric oxidase synthase (NOS) and pituitary adenylate cyclase activating peptide (PACAP). However, it should be kept in mind that any changes in immunoreactivity may not necessarily reflect a loss of neuronal structures that contain the neurochemical; instead the loss of immunoreactivity may be due to a decrease in neurochemical abundance to below the level of detection by immunohistochemistry. Substance P immunoreactivity is contained in enteric neurons and in the axons of extrinsic primary afferent neurons with cell bodies in DRG. Enteric SP is involved in synaptic transmission between enteric neurons, neuromuscular transmission, nociception and has been implicated in neurogenic inflammation. Tissues from patients with UC exhibit increased SP immunoreactivity in cholinergic myenteric neurons in inflamed and non-inflamed regions of colon (Brierley and Linden, 2014). Interestingly, others reported that substance P immunoreactivity was the only neurochemical change reported in patients with UC; several markers of enteric neurons, including VIP and neuron specific enolase were not affected by UC (Moynes et al., 2014). Immunoreactivity for VIP in the ENS appears to be altered in IBD, although there have been contradictory findings, with some studies reporting an increase and others reporting a decrease. A recent study examined the effect of applying supernatants from IBD patient biopsies on VIP expression in rat enteric neurons. VIP mRNA and protein expression was reduced in neurons exposed to supernatants from CD but not UC patients, suggesting that these disease subtypes have differential effects on the expression of this neuropeptide. Interestingly, the authors provided evidence that interleukin 6 is an important mediator of this enteric neuroplasticity (Brierley and Linden, 2014). In contrast to this reduction in enteric VIP expression in response to IBD-associated cytokines, studies in animal models of IBD have reported an increased expression of VIP in the myenteric and submucosal neurons (Moynes et al., 2014).

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Functional Evidence of Neuroimmune Signaling in IBD Although there have been reports of altered enteric signaling to muscle in IBD tissues, functional studies in IBD patients have been limited to date. As seen in studies of IBS patients, much of our understanding of the functional relevance of neuroimmune interactions in IBD patients has come from the study of biopsies obtained from patients and the generation of supernatants. These contain the “inflammatory mediators” signaling to enteric and nociceptive nerves and are typically then studied in neurons in preclinical models. Recent studies have shown that these mediators sensitize a number of important ion channel families including the transient receptor potential (TRP) and the voltage-gated sodium (Nav) and potassium (Kv) channels which underlie action potential electrogenesis. There is increased release of a complex array of inflammatory mediators such as INF-g, TNF-a, endogenous opioids, as well as other cytokines and proteases from immune cells and their relative expression may vary during acute and chronic periods of inflammation (Fig. 3) (e.g. TNF-a in acute phases and endogenous opioids during chronic phases). The impact of this inflammatory milieu on neuronal excitability reflects of balance of pro- and anti-nociceptive mediators (Guerrero-Alba et al., 2017; Ibeakanma and Vanner, 2009).

Key Pathways That Modulate Neuroimmune Interactions in the Intestine A few clinical studies, supported by a number of preclinical IBD models, suggest that neuroimmune signaling in the intestine is modulated by signaling from the CNS and the lumen. This latter signaling likely involves dietary factors acting alone or in concert with the microbiota. Studies of the microbiota in IBD patients have shown that they exhibit distinct clusters by principal coordinates analysis compared to healthy controls (HC), and differences in diversity depending on the IBD subtype compared to HC. 16s RNA sequencing has identified specific families associated with health or disease, and a lower abundance of putative beneficial microorganism such as Faecalibacterium prauznitzii and Prevotella copri. Recently studies have shown that human microbial communities and their metabolites signal to the nerve terminals in the intestine of DRG neurons. For example, studies have shown that specific microbial species release proteases that signal across the mucosa to protease activated receptors on DRG nerve terminals causing inhibition. Preliminary studies suggest this signaling is altered in some patients with IBD. In studies examining signaling from the CNS, preclinical and/or translational human studies have shown that activation of the HPA-SA nervous system axis increases the acute inflammatory response, suppresses the release of endogenous opioids, and stress hormones signal directly to neurons causing sensitization. Other preclinical studies suggest this signaling may also increase intestinal permeability with the potential for bacteria to cross the epithelial barrier, signaling to receptors such as TLRs on immune cells or directly to these receptors on the neurons. It is also possible that stress hormones may impact the microbiota directly but this is yet to be demonstrated in humans (Fig. 4). The interaction of the diet and microbiota also has the potential to be a key modulator of neuroimmune communication. There is increasing interest in anti-inflammatory diets to treat IBD and given the known interaction of dietary factors and the microbiota, such as poorly absorbed complex carbohydrates, this may emerge as an important pathway.

Post-Operative Ileus Studies of post-operative ileus have identified another human disorder that exemplifies the importance of neuroimmune interactions. Seminal work by Tracey and colleagues highlighted the potential clinical utility of stimulating the vagus nerve to suppress inflammation (Chavan et al., 2017). Using animal models of sepsis and endotoxemia, they demonstrated that vagal nerve stimulation led to activation of a cholinergic signaling pathway that suppressed the secretion of pro-inflammatory cytokines, which enhanced survival in these models. Subsequent work confirmed that vagal pathways also could be involved in suppression of gut inflammation, including models of IBD and post-operative ileus. Using models of IBD, several laboratories have demonstrated that the vagus nerve acts tonically to suppress inflammation; vagotomy increases colitis severity (Chavan et al., 2017) and stimulating the vagus nerve suppresses inflammation (Bonaz et al., 2016). Recently, a pilot study of patients with CD highlighted a potential clinical application of vagal nerve stimulation. Five of seven patients implanted with a vagal nerve stimulator, and stimulated for 6 months (Bonaz et al., 2016), experienced an improvement in disease symptoms and a decrease in endoscopic damage scores. This approach to treating IBD is currently the subject of a multicenter clinical trial. Ileus, an impairment of intestinal motility that last several days following a surgical intervention, leads to nausea, vomiting, pain and a delayed recovery from surgery (Boeckxstaens and De Jonge, 2009). It is now generally accepted that handling of the intestines leads to two temporally distinct responses that inhibit coordinated motility patterns. The initial neurogenic component is mediated via activation of inhibitory sympathetic and enteric neural pathways, which predominantly result in the release of noradrenaline and nitric oxide, respectively. A longer lasting disruption of smooth muscle function is the result of an infiltration of myeloperoxidase immunoreactive leukocytes into the tunica muscularis. In addition to these infiltrating immune cells, tissue trauma and resident muscularis macrophages release several mediators that relax smooth muscle, including large quantities of nitric oxide generated by inducible nitric oxide. Using evidence from mouse models of POI, vagal nerve stimulation has been proposed as a potential therapy for POI. Vagal nerve stimulation led to activation of cholinergic enteric neurons that modulated the activity of muscularis macrophages via effects on a7 nicotinic receptors.

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A recent proof of concept study in patients undergoing colorectal surgery demonstrated that intraoperative abdominal vagal nerve stimulation suppresses the release of IL-8 and IL-6 from patient immune cells in response to lipopolysaccharide (Bonaz et al., 2016; Chavan et al., 2017).

Knowledge Gaps and Future Directions Despite the increasing number of studies in humans and translational and/reverse translational models, there remains considerable lack of studies confirming the importance of mechanisms in humans that have been identified in preclinical models. In IBS and IBD, correlating changes in neuroimmune signaling and symptoms has been challenging. These correlations have been best studied in IBS patients but the findings have been inconsistent. Some studies have shown positive correlations between mast cell-nerve interactions and symptoms. Others have demonstrated associations between immune activation in the serum or stool and symptoms, and successfully predicted therapeutic benefit targeting mast cells or their mediators. However, in each case other studies have been negative. Given the complexity and dynamic nature of neuroimmune interactions, longitudinal studies in highly phenotyped patients will be needed to firmly establish the relative role of each segment of the neuroimmune pathways. Such studies allow for fluctuating variables such as psychological stress and changes in the microbiota to be better understood. More in-depth phenotyping of patients is also needed to control for the complex variables such as diet that can directly or indirectly influence neuroimmune signaling. Another major barrier is a lack access to human enteric and dorsal root ganglia neurons. This may be overcome in the future through the use to human stem cells and greater access to fresh surgical specimens for study. Such advances, as well as other translational models such as human gut organoids, will enable greater ability to confirm mechanisms in human tissues and screen pharmacological agents, as well potential dietary and microbiota therapies. Finally, biomarkers of relevant mechanistic pathways in subsets of patients are greatly needed to identify enriched populations of patients for study and a better understanding of the “redundancy” in the inflammatory pathways is needed to clarify the most relevant targets for treatment.

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Further Reading Barbara G, Stanghellini V, De Giorgio R, Cremon C, Cottrell GS, Santini D, Pasquinelli G, Morselli-Labate AM, Grady EF, Bunnett NW, Collins SM, and Corinaldesi R (2004) Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 126: 693–702.

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Boeckxstaens GE and Wouters MM (2017) Neuroimmune factors in functional gastrointestinal disorders: A focus on irritable bowel syndrome. Neurogastroenterology and Motility 29(6): 1–10. https://doi.org/10.1111/nmo.13007. Boyer JD, Gima L, Karuppuchamy T, and Rivera-Nieves J (2018) Integrin beta 7 deficiency results in paucity of tertiary lymphoid tissues and decreased lamina propria Iga plus B cells leading to microbiome dysbiosis and worse inflammation in a model of Crohn’S-like ileitis. Gastroenterology 154: S33. Dothel G, Barbaro MR, Boudin H, Vasina V, Cremon C, Gargano L, Bellacosa L, De Giorgio R, Le Berre-Scoul C, Aubert P, Neunlist M, De Ponti F, Stanghellini V, and Barbara G (2015) Nerve fiber outgrowth is increased in the intestinal mucosa of patients with irritable bowel syndrome. Gastroenterology 148: 1002–1011. e4. Greenwood-Van Meerveld B and Johnson AC (2017) Stress-induced chronic visceral pain of gastrointestinal origin. Frontiers in Systems Neuroscience 11: 86. Gulbransen BD, Bashashati M, Hirota SA, Gui XY, Roberts JA, Macdonald JA, Muruve DA, McKay DM, Beck PL, Mawe GM, Thompson RJ, and Sharkey KA (2012) Activation of neuronal P2X7 receptor-pannexin-1 mediates death of enteric neurons during colitis. Nature Medicine 18: 600–604. Margolis KG, Gershon MD, and Bogunovic M (2016) Cellular organization of neuroimmune interactions in the gastrointestinal tract. Trends in Immunology 37: 487–501. Martin CR, Osadchiy V, Kalani A, and Mayer EA (2018) The brain-gut-microbiome axis. Cellular and Molecular Gastroenterology and Hepatology 6: 133–148. Munyaka P, Rabbi MF, Pavlov VA, Tracey KJ, Khafipour E, and Ghia JE (2014) Central muscarinic cholinergic activation alters interaction between splenic dendritic cell and CD4 (þ)CD25() T cells in experimental colitis. PLoS One 9: . Neunlist M, Aubert P, Toquet C, Oreshkova T, Barouk J, Lehur PA, Schemann M, and Galmiche JP (2003) Changes in chemical coding of myenteric neurones in ulcerative colitis. Gut 52: 84–90. Stakenborg N, Wolthuis AM, Gomez-Pinilla PJ, Farro G, Di Giovangiulio M, Bosmans G, Labeeuw E, Verhaegen M, Depoortere I, D’hoore A, Matteoli G, and Boeckxstaens GE (2017) Abdominal vagus nerve stimulation as a new therapeutic approach to prevent postoperative ileus. Neurogastroenterology and Motility 29: . Vasina V, Barbara G, Talamonti L, Stanghellini V, Corinaldesi R, Tonini M, De Ponti F, and De Giorgio R (2006) Enteric neuroplasticity evoked by inflammation. Autonomic NeuroscienceBasic & Clinical 126: 264–272.

Non-Nutritive Sweeteners and their Effects on Human Health and the Gut Microbiome Tauseef A Khan, Sabrina Ayoub-Charette, John L Sievenpiper, and Elena M Comelli, University of Toronto, Toronto, ON, Canada St. Michael’s Hospital, Toronto, ON, Canada © 2020 Elsevier Inc. All rights reserved.

Introduction Non-nutritive sweeteners (NNS), also known as artificial sweeteners, high intensity sweeteners or low-calorie sweeteners, are food additives with higher potency of sweetness per gram than sucrose. They are used in very small quantities and provide negligible to no calories. As such, NNS are mainly consumed as a strategy to reduce caloric contribution from sugars and/or to maintain weight. NNS intake has increased in recent years as they are widely used across various food categories including baked goods, desserts, gums, breakfast cereals, and diet beverages (Sylvetsky and Rother, 2016). NNS are largely studied in the context of cardio-metabolic health. Their role remains controversial with recent epidemiological evidence suggesting that NNS might in fact be associated with weight gain, type 2 diabetes, cardiovascular disease and mortality (Azad et al., 2017; Malik et al., 2019). In contrast, randomized controlled trials in humans demonstrate that NNS consumption may be beneficial for weight management (Rogers et al., 2016). Animal studies suggest that NNS may induce weight gain, alter gut microbiome and impair glucose control (Suez et al., 2014); however, translatability of these effects to humans is unclear. This article will first provide general concepts about commonly used NNS. It will then discuss the current state of the evidence from human intervention and epidemiological studies, as well as from animal studies, about their role in human health, including the gut microbiome. This article will also include some basic concepts on the investigation of causality in human and animal studies, in the hope that this helps the reader assessing the hierarchy of the evidence described for NNS and human health.

About Non-Nutritive Sweeteners Among more than a dozen of NNS compounds available, the most commonly used in food products are acesulfame-potassium, aspartame, saccharin, stevia and sucralose. These five NNS are approved by the Food and Drug Administration (FDA), the Joint FAO/WHO Expert Committee on Food Additives (JECFA), the European Food Safety Authority (EFSA), and Health Canada, and are among the most extensively tested food substances for human safety (Azad et al., 2017; Mortensen, 2016; Magnuson et al., 2016; Spencer et al., 2016; Health Canada, 2019; US Food and Drug Administration, 2019; World Health Organization, 2019). The intake of NNS has been increasing in the past decades and it is estimated that 25% of children and 41% of adults reported NNS consumption on a typical day between 2009 and 2012 in the United States (Sylvetsky and Rother, 2016). All NNS share a sweet taste, being approximately 200 to 20,000 times more potent than sucrose, but here their similarities end as they are chemically distinct compounds. Each NNS is absorbed, metabolized and excreted differently and thus their effects on the gastrointestinal tract and host physiology in general should not be expected to be the same (Table 1) (Magnuson et al., 2016). Each NNS interacts with the taste receptor at different binding sites resulting in slight differences in taste, intensity, duration and perception of sweetness, bitterness and lingering after-taste. In commercial food products, NNS are commonly used in combination, in order to at least partially mask their specific taste properties and better align with the perception generated by sucrose. As NNS are distinct compounds, their acceptable daily intake (ADI) levels also vary widely, with a maximum ADI range between 0.3 and 40 mg kg/body weight (Table 2). Specific properties for common NNS are described below.

Acesulfame-Potassium Acesulfame-potassium (AceK) is a white, odorless crystalline powder. It is an organic acid combined with potassium and is approximately 200 times sweeter than sucrose. After ingestion, AceK is rapidly absorbed in the gastrointestinal (GI) tract and is then excreted unchanged, predominantly in the urine (
85%), with smaller amounts excreted in the feces (
15%). AceK contains 20% potassium by weight, so, for example, a 355 mL diet soda would add only 12 mg of potassium to the dietary intake. AceK is heat stable and thus suitable for use in baked goods. AceK is predominantly used in combination with other NNS (Magnuson et al., 2016; Das and Chakraborty, 2016).

Aspartame Aspartame is a synthetic methyl ester of a dipeptide composed of the two amino acids aspartic acid and phenylalanine. Aspartame is calorically available (4 kcal/g) but as very small quantities are typically used, being approximately 200 times sweeter than sucrose, it contributes almost negligible calories. After oral intake, aspartame is rapidly and completely converted into its constituents viz.

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Characteristics of non-nutritive sweeteners commonly found in food. Sweetness intensity compared to sucrose (times more)

Name

Trade name

Metabolized

Excretion

Examples of use

Acesulfame-K

Sunnett™ Sweetone™ Ajisweet™

No

Urine

Yes

Aspartame

Nutrasweet™ Equal™

Yes

Cyclamate

Twin™

Yes

Constituent amino acids utilized by body Constituent amino acids utilized by body Urine

Backed goods, beverages, protein shakes, pharmaceutical products Tabletop sweetener, chewing gums, candies, beverages, desserts, cereals

Monk Fruit

Purefruit™

Yes

Feces

Neotame

Newtame™

Yes

Saccharin

No

Sucralose

Sweet N’Low™ Hermesetas™ Splenda™

Constituent amino acids utilized by body Urine, feces

No

Feces

Steviol glycosides

Truvia™ PureVia™

No

Feces

Advantame

200 20,000

Tabletop sweetener, chewing gums, candies, beverages, desserts, cereals

200

Beverages, ice-cream, desserts, canned food, biscuits, seasoning, pharmaceuticals, toothpastes, mouth fresheners, lipstick Beverages, powdered drinks, chewing gums, baked goods, dietary supplements, nutrition bars Beverages, cereals, tabletop sweeteners, chewing gums, confectionary, frozen desserts, ice-cream, yogurt Food products, beverages and non-food products

30–50

Tabletop sweetener, candies, beverage, confectionary, baked goods Soft drink, tabletop sweetener, confectionary, fruit productions, seafood

100–250 7000–13,000 300 600 300

For more details see (Mortensen, 2016; Magnuson et al., 2016).

Table 2

Acceptable daily intakes for non-nutritive sweeteners. Acceptable daily intake (mg intake per kg of body weight)

Non-nutritive sweetener

US Food and Drug Administration

Health Canada

European Food Safety Authority

JECFA

Acesulfame-K Advantame Aspartame Cyclamate Monk Fruit Neotame Saccharin Sucralose Steviol glycosides

15 32.8 50 – GRAS 0.3 15 5 4

15 Not specified 40 18 – Not specified 5 9 1

9 5 40 7 – 0–2 5 15 4

15 5 40 11 – 0.3 15 5 4

JECFA, Join Food and Agriculture Organization of the United Nations/WHO Expert Committee on Food Additives; GRAS, generally recognized as safe; –, information not-available. For additional details see (Mortensen, 2016; Magnuson et al., 2016).

methanol, aspartic acid and phenylalanine in the GI tract. All three components are absorbed into the circulation, and none of them are available to the lower GI microbiome. The two amino acids and methanol from aspartame are also found naturally in the diet e.g. meat, milk, fruits and vegetables, and are metabolized in the same way. The amount contributed by aspartame is negligible as it is far exceeded in a typical diet; for example, one glass of fruit juice contains larger quantities of methanol and phenylalanine than a 355 mL can of diet cola. Aspartame is not heat stable so it is not used in baked goods. As one of the constituents is phenylalanine, aspartame contains a warning label for those who have phenylketonuria (Magnuson et al., 2016; Das and Chakraborty, 2016).

Saccharin Saccharin is the first NNS to have been discovered in the year 1879 and it has been in use since then. It is a synthetically produced sulfur-containing compound, which presents as a white odorless powder. It is approximately 300 times sweeter than sucrose, is heat stable and does not contain any calories. Saccharin is not metabolized in the body, but is absorbed from the GI tract and excreted unchaZnged in the urine (Magnuson et al., 2016; Das and Chakraborty, 2016).

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Sucralose Sucralose is a synthetic chlorinated form of sucrose and is around 600 times sweeter than sucrose. It is a white crystalline solid and stable at a range of temperatures in both solid and liquid form. It is not metabolized in the body and is mainly excreted in the feces (85%) and the remainder in the urine (Magnuson et al., 2016; Das and Chakraborty, 2016).

Advantame and Neotame Advantame is the NNS most recently approved by FDA, JECFA and Health Canada. It is similar to aspartame, but about 20,000 times sweeter than sucrose. It is heat stable so it can be used in baked goods. Due to its very high sweetness, it is used in even smaller quantities compared to aspartame, and it can be consumed by people with phenylketonuria. Neotame is another heat-stable derivative of aspartame, and it is about 12,000 times sweeter than sucrose (Magnuson et al., 2016; Das and Chakraborty, 2016).

Stevia The herb Stevia rebaudiana Bertoni, a plant native to South America, has been used as a sweetener by the indigenous people for centuries. Recently, steviol glycosides, the highly purified compounds from the leaves of this herb, have been approved by FDA and JECFA as high-intensity sweeteners. The two major commercially available steviol glycoside compounds are stevioside (stevia) and rebaudioside A. After ingestion, these compounds are converted by the lower GI microbiome to steviol, which is absorbed into the circulation. Steviol is re-circulated through the enterohepatic circulation and is rapidly excreted in the feces without accumulating in the body. Steviol glycosides are approximately 300 times sweeter than sucrose. Stevia is considered a natural sweetener (Magnuson et al., 2016; Das and Chakraborty, 2016).

Monk Fruit Monk Fruit (Siraitia grosvenorii Swingle), also known as Luo Han Guo, fruit extract derives from a plant native to Southern China. Monk fruit is approximately 100–250 times sweeter than sugar. Monk Fruit has been labeled as GRAS and an ADI has not yet been established. Monk fruit is considered a natural sweetener. There are several other plant-derived natural high-intensity sweeteners (e.g. Monatin, Thamatin, Monellin, Brazzein etc.) with a historical tradition of use in several countries (Magnuson et al., 2016; Das and Chakraborty, 2016).

Hierarchy of Evidence for Substantiating Causal Effects and Its Application to Assess NNS in the Context of Cardio-Metabolic Health in Humans Evidence for the association of any dietary exposure with human health should be seen in the context of its potential to support certainty of causality (Mann and Truswell, 2017). The foremost issue that can reduce this certainty is bias. Bias is a systematic (as opposed to random) deviation of results from the truth and is affected by the research approach and process, such as the design of the study, data collection, analysis, interpretation and reporting (Porta et al., 2014). Research evidence can be hierarchically categorized based on the risk of bias associated with the study design it derives from. Randomized controlled trials (RCTs) are found at the higher end of this hierarchy and remain the gold standard for determining causation, since confounding variables are ideally equally distributed between the groups through the randomization process. Hence, RCTs are more protected from bias, compared to prospective cohort studies, which carry residual confounding. Crosssectional studies have the least protection from bias and they cannot establish a temporal relationship between exposure and outcome. Animal and cellular studies are represented towards the lowest level of the hierarchy due to their inherent generalizability and translatability limitations. As such, the certainty of evidence for causal effects can be displayed as a pyramid (Fig. 1). At each ascending level of the pyramid, the risk of bias decreases and the certainty of evidence improves. The shape of the pyramid indicates that as we ascend, the quantity of the available studies declines but the confidence in a causal relationship increases. Systematic reviews and meta-analyses are a lens (shown as glasses in Fig. 1) through which all evidence is viewed and appraised (Murad et al., 2016). As such, systematic reviews and meta-analyses can be performed at any level of evidence (or supportive study design), except for editorials/opinion pieces. Certainty (or quality) of the evidence can also be rated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework (Guyatt et al., 2008). GRADE assesses the methodological limitations of the study design, but also the limitations related to imprecision, inconsistency, indirectness and publication bias. A majority of health-related organizations have now adopted the GRADE framework for rating human health-related findings and to substantiate recommendations (See http://www.gradeworkinggroup.org/). The effects of NNS on cardio-metabolic health and the gut microbiome have been investigated through studies that span all levels of the pyramid. In the following sections, we will report findings from the most recently published systematic reviews and meta-analyses of human studies, since these incorporate the highest possible level of substantiated evidence. Evidence derived from other studies variously located along the pyramid will be discussed where RCTs are not available.

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Systematic reviews and meta-analysis of RCTs* Risk of bias Randomized controlled trials

Higher Lower

Cohort studies

Case-control studies

Cross-sectional studies, surveys Lower

Higher

Case reports, case studies

Mechanistic studies

Editorials, expert opinion

Certainty of evidence

Fig. 1 Hierarchy of evidence. The pyramidal shape is sorted according to study design and indicates the strength of evidence expected and the amount of evidence available. Ascending each level of the pyramid is generally associated with increased certainty (or quality) of the evidence and reduced risk of bias. Confidence in causality increases as one ascends the pyramid. Systematic reviews and meta-analyses are a lens through which evidence is viewed and appraised (Murad et al., 2016); eye-glasses indicate that a systematic review and meta-analysis can be used to summarize the data at that level.  RCTs: Randomized controlled trials.

Intervention Trials Two systematic reviews and meta-analyses were recently published assessing existing randomized controlled trials of up to 6 months duration and health outcomes (Toews et al., 2019; Azad et al., 2017). The systematic review and meta-analysis by Toews et al. (2019) included results from 21 RCTs assessing the effect of NNS consumption through a range of outcomes (Fig. 2). The authors showed a small beneficial effect of intake of NNS on body mass index (mean difference (MD) 0.6 (95% confidence interval (CI) 1.19 to 0.01); 2 studies), when compared to non-NNS. There was no association between NNS intake and body weight (MD – 1.29 (CI 2.8 to 0.21); 5 studies). However, a subgroup analysis showed that NNS intake was associated with weight loss in overweight and obese adults (MD 1.99 kg (CI 2.84 to 1.14); 3 studies), but not in those of normal weight (MD 0.03 (CI 0.03 to 0.09); 2 studies); this supports NNS benefits in the context of a weight loss strategy. In children, NNS intake was associated with reduced BMI z-score (MD 0.15 (CI 0.17 to 0.12)), but there was no effect on body weight. NNS intake reduced systolic blood pressure (MD 4.90 (CI 9.78 to 0.03) but not diastolic blood pressure, compared to control. Lipid markers including triglycerides, total–, low-density–, and HDL–cholesterol did not show an effect with NNS intake. In two RCTs, intake of NNS reduced blood glucose when compared to sugar (MD 0.16 mmol/L (CI 0.26 to 0.06)); however, there was no difference in plasma insulin, insulin resistance or b-cell function as measured by homoeostatic model assessment of insulin resistance (HOMA-IR). Pooled analysis showed that the mean daily energy intake was lower in those receiving NNS than in those receiving sugar (MD 1065 kJ (CI -1867 to 262); 4 studies). Furthermore, carbohydrate (MD 89 g (CI-104 to -75)) and daily sugar intake were lower (MD 90 g (CI 127 to 51); 3 studies) in those receiving NNS. Regarding the prevailing notion that NNS might increase the desire for sweet-taste (Swithers, 2013), the pooled analysis showed that this taste preference (on a scale of 10, with higher values indicating increased desire) was significantly lower in subjects with NNS intake compared to those not receiving NNS (MD 0.2 (CI 0.34 to 0.06); 1 study), and NNS intake did not increase the feeling of hunger (MD 0.20 (CI 1.03, 0.63); 1 study). Substantial heterogeneity (I2 > 50%) affected most outcomes but there were too few studies to undertake sensitivity analysis and explore the source of this heterogeneity. The GRADE assessment of the certainty of evidence ranged from “moderate” for reduction of BMI in children, to “low” for reduction of BMI in adults and to “very low” for the majority of the other outcomes. For some outcomes, the certainty of the evidence was not presented (Fig. 2). These results are aligned with those from a previous systematic review and meta-analysis by Azad et al. (2017) whereby no difference for adiposity and glycemic outcomes was observed using 7 RCTs.

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Fig. 2 Summary plot of pooled effect estimates from randomized controlled trials investigating the effects of the NNS intake on cardiometabolic outcomes. Pooled effect estimates are expressed as standardized mean differences, represented by red diamond and 95% CIs by the line through the diamond. Original mean difference (MD) and confidence interval (CI) were calculated using random effects models. Standardized mean differences (SMD) were calculated in order to display the results on the same graph. NA: Not available. Adapted from Toews, I., Lohner, S., Kullenberg De Gaudry, D., Sommer, H., and Meerpohl, J.J. (2019). Association between intake of non-sugar sweeteners and health outcomes: Systematic review and meta-analyses of randomised and non-randomised controlled trials and observational studies. BMJ, 364, k4718.

Systematic reviews and meta-analyses of RCTs are considered the highest level of evidence (Fig. 1); limitations can derive from the included studies themselves (through risk of bias) and from issues related to the pooling of studies (through inconsistency, imprecision and indirectness). For NNS, the comparator used could play an important role in assessing their benefit in displacing calories from high sugar sources: if the NNS displaces calories, e.g. from a caloric comparator such as a sugar-sweetened beverage (SSB), a benefit would be expected; however, if the NNS is compared to a calorically matched control, e.g. NNS versus water, a change would not be expected. For example, the majority of studies included in Azad et al. (2017) were calorically matched and would be expected to be neutral (Sievenpiper et al., 2017) for this benefit, which is aligned with the conclusion of this study. Overall, the evidence from pooled RCTs supports a benefit of NNS intake on weight in overweight/obese adults, BMI, fasting glucose, systolic blood pressure, calorie intake and appetite. Importantly, there was no evidence of harm for any cardio-metabolic outcomes. There is only one human study available on the consumption of NNS and its effects on the gut microbiome (Suez et al., 2014). This is a single-arm study where seven healthy non-NNS consumers took saccharin at a 5 mg kg1 day1 dose (equal to ADI) for 6 days. An oral glucose tolerance test was performed each day during of the study; in the last 3 days, four subjects showed a reduced glycemic response (identified as responders) while three did not (identified as nonresponders). Fecal matter from responders, but not from nonresponders, was able to affect glucose tolerance in mice upon transplantation, suggesting a role of saccharin which is mediated by the microbiome. While this was a pioneer study suggesting potential interactions between saccharin and the gut microbiome, randomized controlled trials with this and other sweeteners are necessary before any conclusions can be drawn.

Prospective Cohort Studies Fig. 3 shows the summary of a recent systematic review and meta-analysis of prospective cohort studies on NNS intake by Azad et al. (2017). We could not use the results of the more recent systematic review and meta-analysis from Toews et al. (2019) as it did not include enough prospective cohort studies reporting cardio-metabolic outcomes (Toews et al. only included studies that reported the type of NNS used, which excluded the majority of cohort studies using food frequency questionnaires.). The weight of the results showed an association of harm for almost all cardio-metabolic outcomes including weight gain, obesity, metabolic syndrome, type 2 diabetes, hypertension, stroke, and cardiovascular disease (CVD). Potential limitations of observational studies in this context include confounders (lifestyle, diet) and reverse causality (Malik, 2019; Johnson et al., 2018) where in fact people who consume NNS, use it to control weight or reduce an already high metabolic risk (Sylvetsky and Rother, 2016; Mossavar-Rahmani et al., 2019). In a meta-analysis, in which the intake of non-nutritive sweetened beverages (NSB) was associated with the risk of diabetes,

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Fig. 3 Pooled estimates for the association of consumption of NNS with cardiometabolic outcomes. CHD: Coronary heart disease; CVD: cardiovascular disease. Adapted from Azad, M.B., Abou-Setta, A.M., Chauhan, B.F., Rabbani, R., Lys, J., Copstein, L., Mann, A., Jeyaraman, M. M., Reid, A. E., Fiander, M., Mackay, D.S., Mcgavock, J., Wicklow, B., and Zarychanski, R. (2017). Nonnutritive sweeteners and cardiometabolic health: A systematic review and meta-analysis of randomized controlled trials and prospective cohort studies. CMAJ, 189, E929–E939.

adjustment for adiposity attenuated the association, implying that reverse causality may be responsible for the association (Imamura et al., 2015). Analytical strategies can help to overcome the methodological limitations of prospective cohorts studies (Smith et al., 2015). For example, studies that have measured dietary intake at multiple times can use repeated measures analysis to assess the change in intake with the change in outcome. Three of the four studies included in the Azad meta-analysis have reported change-in-time data. We conducted an analysis of this data and Fig. 4 shows the risk ratios and pooled estimates from both the prevalent analysis and the change analysis. Prevalent analysis shows strong association of increased body weight with intake of NNS (MD 0.31 lb. (CI 0.28 to 0.35)), as per Azad et al. (2017); the change analysis shows an inverse association of NNS intake with weight gain (MD 0.07 lb. (CI 0.13 to 0.02)). It is also important to investigate if people who switch to regular NNS use from regular sugar-sweetened beverages (SSB) use actually reduce their cardiovascular disease risk. Two strands of evidence indicate that this might be the case. First, separate studies have showed that SSB, but not NSB, intake is associated with coronary heart disease (CHD), suggesting that NSBs might provide benefit as substitutes for SSBs (Fung et al., 2009; Malik, 2017). Second, substitution analysis has shown a lower risk of diabetes (Pan et al., 2012), CVD mortality (Malik et al., 2019) and total mortality (Malik et al., 2019) when 1 serving/day of NSB is substituted for 1 serving/day of SSBs (in substitution analysis, the association of substituting SSB with an equivalent amount of NSB is assessed by including both as continuous variables simultaneously in a multivariable model, with the difference between b coefficients being used to estimate effect estimates for the substitution association).

Fig. 4 Forest plot for the association of NNS intake and body weight using prevalent and change analysis. Estimates have been pooled using inverse-variance with fixed effects model. Re-analysis of data from Azad et al. (2017) restricted to studies that report both prevalent and change data. lb.: Pounds. For details see text.

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Overall, pooled analyses of prospective cohort studies show that NNS intake is associated with increased risk of obesity, type 2 diabetes, stroke, and cardiovascular disease. Though, this could be affected by reverse causality. Future studies using analytical strategies including change and substitution analysis will contribute to model these associations.

Cross-Sectional Studies A cross-sectional study is one in which the relationship between exposure and outcome is examined in a population at one particular point in time. Unlike prospective cohort studies, time order of cause and effect cannot be determined in these studies. No pooled analysis of cross-sectional studies exists, but one study has assessed the intake of NNS and the gut microbiome. Frankenfeld et al. (2015) conducted a cross-sectional observational study on 31 participants. With the help of four-day food records, participants were compared on whether they consumed saccharin (none), AceK (7 participants), aspartame (7 participants), both AceK and Aspartame (3) or no NNS (14 participants). Participants consuming AceK or aspartame showed no differences in relative fecal bacterial nor inferred gene function abundances compared to nonconsumers. However, AceK or aspartame consumers did show differences in overall microbial b-diversity compared to non-consumers. Future research needs to assess the effects of diet and lifestyle factors on these outcomes, as well as their clinical implications.

Animal Studies Overall, animal studies indicate that NNS may contribute to increased risk of obesity and diabetes, possibly via reduced glucose tolerance by alteration of gut microbiome (Suez et al., 2014), changes to and habituation to sweet taste (Vera-Rivera et al., 2018; Appleton and Blundell, 2007), alterations in gut peptides (Meyer-Gerspach et al., 2016) and hunger signaling (Mattes and Popkin, 2009), besides other mechanisms (Sylvetsky and Rother, 2018). Many studies employ relatively high doses of NNS (mouse ADI is unknown) and the overall results are inconsistent across studies. There has been one published systematic review and meta-analysis of animal studies by Rogers et al. (2016). In this review, among 47 rodent studies of NNS compared to sugars or unsweetened alternatives, body weight was found to be significantly decreased in 22 studies, increased in 4 studies, and unchanged in 21 studies. Studies varied in terms of dose amount and dose repetition, duration of treatment, route of administration and comparator type. This meta-analysis reported results using vote counting rather than using a pooled effect estimate so the magnitude of effect and consistency across studies could not be assessed (Borenstein, 2009). There are no systematic reviews of animal studies assessing other outcomes, including the gut microbiome. Individual rodent studies have suggested that NNS including sucralose and saccharine may alter the gut microbiome and such alteration is associated with a concomitant change in glucose intolerance (Suez et al., 2014) and inflammation (Palmnas et al., 2014). Various mechanisms have been suggested (Suez et al., 2015; Daly et al., 2016), including NNS-induced propionate production, which may play a role in metabolic control of insulin sensitivity (Palmnas et al., 2014). Microbiome-mediated increased energy extraction from food may also disturb energy balance and affect gut-neural pathways (Sylvetsky and Rother, 2018). In summary, animal studies offer a window into the mechanisms underlying the potential relationship between NNS and cardio-metabolic health and the gut microbiome. Though, further research is necessary to support translatability to humans.

Conclusions and Perspectives NNS are diverse compounds that are used as high potency sweeteners. Animal studies have raised some concerns by showing adverse effect of specific NNS intake on the gut microbiome and glucose tolerance; however, such studies need replication in humans. Prospective cohort studies show a consistent association of harm between NNS intake and cardiometabolic outcomes, however, these associations may be affected by reverse causality. Multiple measures of dietary exposure to assess changes in diet reveal that NNS may be associated with reduced weight gain and reduced risk of cardio-metabolic outcomes, if they displace high sugar intake from sugar-sweetened beverages. RCTs largely show potential benefits of NNS use in controlling weight and reducing cardio-metabolic risk factors when replacing high caloric sugars. While water remains the preferred replacement of choice for sugarsweetened beverages intake, the best evidence so far supports the intended benefit of NNS intake. Given the large use of NNS across various populations and the lifespan, it is imperative that further research is conducted to establish the effect of individual NNS compounds on outcomes including the microbiome and cardio-metabolic health, ideally using large well conducted randomized controlled trials for substantiation of dietary guidelines.

Acknowledgments Funding statement: Aspects of this book chapter were funded by a Canadian Institutes of Health Research grant to JLS, EMC and TAK [Funding #384593]. Tauseef A Khan was funded by a Toronto 3D Postdoctoral Fellowship Award. Dr. John L Sievenpiper was funded by a Diabetes Canada Clinician Scientist Award. Dr. Elena M Comelli holds the Lawson Family Chair in Microbiome

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Nutrition Research at the University of Toronto. She has received funding from the Joannah and Brian Lawson Centre for Child Nutrition, Faculty of Medicine, University of Toronto.

Conflict of Interests Dr. Tauseef A Khan has received research support from the Canadian Institutes of Health Research (CIHR) and an unrestricted travel donation from Bee Maid Honey Ltd. He was an invited speaker at a Calorie Control Council annual general meeting for which he received an honorarium. Dr. John L Sievenpiper has received research support from the Canadian Foundation for Innovation, Ontario Research Fund, Province of Ontario Ministry of Research and Innovation and Science, Canadian Institutes of health Research (CIHR), Diabetes Canada, PSI Foundation, Banting and Best Diabetes Centre (BBDC), American Society for Nutrition (ASN), INC International Nut and Dried Fruit Council Foundation, National Dried Fruit Trade Association, The Tate and Lyle Nutritional Research Fund at the University of Toronto, The Glycemic Control and Cardiovascular Disease in Type 2 Diabetes Fund at the University of Toronto (a fund established by the Alberta Pulse Growers), and the Nutrition Trialists Fund at the University of Toronto (a fund established by an inaugural donation from the Calorie Control Council). He has received in-kind food donations to support a randomized controlled trial from the Almond Board of California, California Walnut Commission, American Peanut Council, Barilla, Unilever, Unico/Primo, Loblaw Companies, Quaker, Kellogg Canada, and WhiteWave Foods. He has received travel support, speaker fees and/or honoraria from Diabetes Canada, Mott’s LLP, Dairy Farmers of Canada, FoodMinds LLC, PepsiCo, International Sweeteners Association, Nestlé, Pulse Canada, Canadian Society for Endocrinology and Metabolism (CSEM), GI Foundation, Abbott, Biofortis, ASN, Health Sciences North, INC Nutrition Research & Education Foundation, and Physicians Committee for Responsible Medicine. He has or has had ad hoc consulting arrangements with Perkins Coie LLP, Tate & Lyle, and Wirtschaftliche Vereinigung Zucker e.V. He is a member of the European Fruit Juice Association Scientific Expert Panel. He is on the Clinical Practice Guidelines Expert Committees of Diabetes Canada, European Association for the study of Diabetes (EASD), Canadian Cardiovascular Society (CCS), and Obesity Canada. He serves as an unpaid scientific advisor for the Food, Nutrition, and Safety Program (FNSP) and the Technical Committee on Carbohydrates of the International Life Science Institute (ILSI) North America. He is a member of the International Carbohydrate Quality Consortium (ICQC), Executive Board Member of the Diabetes and Nutrition Study Group (DNSG) of the EASD, and Director of the Toronto 3D Knowledge Synthesis and Clinical Trials foundation. His wife is a former employee of Unilever Canada. Dr. Elena M Comelli has received research support from Lallemand Health Solutions and Ocean Spray; and has received consultant fees or speaker or travel support from Danone, Nestlé and Lallemand Health Solutions.

References Appleton KM and Blundell JE (2007) Habitual high and low consumers of artificially-sweetened beverages: Effects of sweet taste and energy on short-term appetite. Physiology & Behavior 92: 479–486. Azad MB, Abou-Setta AM, Chauhan BF, Rabbani R, Lys J, Copstein L, Mann A, Jeyaraman MM, Reid AE, Fiander M, Mackay DS, Mcgavock J, Wicklow B, and Zarychanski R (2017) Nonnutritive sweeteners and cardiometabolic health: A systematic review and meta-analysis of randomized controlled trials and prospective cohort studies. CMAJ 189: E929–E939. Borenstein M (2009) Introduction to meta-analysis. Oxford: Wiley. Daly K, Darby AC, and Shirazi-Beechey SP (2016) Low calorie sweeteners and gut microbiota. Physiology & Behavior 164: 494–500. Das A and Chakraborty R (2016) An introduction to sweeteners. In: Merillon J-M and Ramawat KG (eds.) Sweeteners. Cham: Springer International Publishing. Frankenfeld CL, Sikaroodi M, Lamb E, Shoemaker S, and Gillevet PM (2015) High-intensity sweetener consumption and gut microbiome content and predicted gene function in a cross-sectional study of adults in the United States. Annals of Epidemiology 25: 736–742. Fung TT, Malik V, Rexrode KM, Manson JE, Willett WC, and Hu FB (2009) Sweetened beverage consumption and risk of coronary heart disease in women. The American Journal of Clinical Nutrition 89: 1037–1042. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schunemann HJ, and GRADE Working Group (2008) Grade: An emerging consensus on rating quality of evidence and strength of recommendations. BMJ 336: 924–926. Health Canada. 2019. List of permitted sweeteners. Available: https://www.canada.ca/en/health-canada/services/food-nutrition/food-safety/food-additives/lists-permitted/9sweeteners.html [Accessed Wednesday, April 3, 2019] Imamura F, O’connor L, Ye Z, Mursu J, Hayashino Y, Bhupathiraju SN, and Forouhi NG (2015) Consumption of sugar sweetened beverages, artificially sweetened beverages, and fruit juice and incidence of type 2 diabetes: Systematic review, meta-analysis, and estimation of population attributable fraction. BMJ 351: h3576. Johnson RK, Lichtenstein AH, Anderson CAM, Carson JA, Despres JP, Hu FB, Kris-Etherton PM, Otten JJ, Towfighi A, Wylie-Rosett J, American Heart Association Nutrition Committee of the Council on Lifestyle and Cardiometabolic Health, Council on Cardiovascular and Stroke Nursing, Council on Clinical Cardiology, Council on Quality of Care and Outcomes Research, and Stroke Council (2018) Low-calorie sweetened beverages and Cardiometabolic health: A science advisory from the American Heart Association. Circulation 138: e126–e140. Magnuson BA, Carakostas MC, Moore NH, Poulos SP, and Renwick AG (2016) Biological fate of low-calorie sweeteners. Nutrition Reviews 74: 670–689. Malik VS (2017) Sugar sweetened beverages and cardiometabolic health. Current Opinion in Cardiology 32: 572–579. Malik VS (2019) Non-sugar sweeteners and health. BMJ 364: k5005. Malik VS, Li Y, Pan A, De Koning L, Schernhammer E, Willett WC, and Hu FB (2019) Long-term consumption of sugar-sweetened and artificially sweetened beverages and risk of mortality in US adults. Circulation 139: 2113–2125. Mann J and Truswell S (2017) Essentials of human nutrition. Oxford University Press. Mattes RD and Popkin BM (2009) Nonnutritive sweetener consumption in humans: Effects on appetite and food intake and their putative mechanisms. The American Journal of Clinical Nutrition 89: 1–14.

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Meyer-Gerspach AC, Wolnerhanssen B, and Beglinger C (2016) Functional roles of low calorie sweeteners on gut function. Physiology & Behavior 164: 479–481. Mortensen A (2016) Sweeteners permitted in the European Union: Safety aspects. Scandinavian Journal of Food and Nutrition 50: 104–116. Mossavar-Rahmani Y, Kamensky V, Manson JE, Silver B, Rapp SR, Haring B, Beresford SAA, Snetselaar L, and Wassertheil-Smoller S (2019) Artificially sweetened beverages and stroke, coronary heart disease, and all-cause mortality in the Women’s Health Initiative. Stroke 50: 555–562. Murad MH, Asi N, Alsawas M, and Alahdab F (2016) New evidence pyramid. Evidence-Based Medicine 21: 125–127. Palmnas MS, Cowan TE, Bomhof MR, Su J, Reimer RA, Vogel HJ, Hittel DS, and Shearer J (2014) Low-dose aspartame consumption differentially affects gut microbiota-host metabolic interactions in the diet-induced obese rat. PLoS One 9: e109841. Pan A, Malik VS, Schulze MB, Manson JE, Willett WC, and Hu FB (2012) Plain-water intake and risk of type 2 diabetes in young and middle-aged women. The American Journal of Clinical Nutrition 95: 1454–1460. Porta M, Greenland S, Hernán M, Dos Santos Silva I, and Last JM (2014) A dictionary of epidemiology. USA: Oxford University Press. Rogers PJ, Hogenkamp PS, De Graaf C, Higgs S, Lluch A, Ness AR, Penfold C, Perry R, Putz P, Yeomans MR, and Mela DJ (2016) Does low-energy sweetener consumption affect energy intake and body weight? A systematic review, including meta-analyses, of the evidence from human and animal studies. International Journal of Obesity 40: 381–394. Sievenpiper JL, Khan TA, Ha V, Viguiliouk E, and Auyeung R (2017) The importance of study design in the assessment of nonnutritive sweeteners and cardiometabolic health. CMAJ 189: E1424–E1425. Smith JD, Hou T, Hu FB, Rimm EB, Spiegelman D, Willett WC, and Mozaffarian D (2015) A comparison of different methods for evaluating diet, physical activity, and long-term weight gain in 3 prospective cohort studies. Journal of Nutrition 145: 2527–2534. Spencer M, Gupta A, Dam LV, Shannon C, Menees S, and Chey WD (2016) Artificial sweeteners: A systematic review and primer for gastroenterologists. Journal of Neurogastroenterology and Motility 22: 168–180. Suez J, Korem T, Zeevi D, Zilberman-Schapira G, Thaiss CA, Maza O, Israeli D, Zmora N, Gilad S, Weinberger A, Kuperman Y, Harmelin A, Kolodkin-Gal I, Shapiro H, Halpern Z, Segal E, and Elinav E (2014) Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature 514: 181–186. Suez J, Korem T, Zilberman-Schapira G, Segal E, and Elinav E (2015) Non-caloric artificial sweeteners and the microbiome: Findings and challenges. Gut Microbes 6: 149–155. Swithers SE (2013) Artificial sweeteners produce the counterintuitive effect of inducing metabolic derangements. Trends in Endocrinology and Metabolism 24: 431–441. Sylvetsky AC and Rother KI (2016) Trends in the consumption of low-calorie sweeteners. Physiology & Behavior 164: 446–450. Sylvetsky AC and Rother KI (2018) Nonnutritive sweeteners in weight management and chronic disease: A review. Obesity (Silver Spring) 26: 635–640. Toews I, Lohner S, Kullenberg De Gaudry D, Sommer H, and Meerpohl JJ (2019) Association between intake of non-sugar sweeteners and health outcomes: Systematic review and meta-analyses of randomised and non-randomised controlled trials and observational studies. BMJ 364: k4718. US Food and Drug Administration. 2019. High-intensity sweeteners. Available: www.fda.gov/food/ingredientspackaginglabeling/foodadditivesingredients/ucm397716.htm [Accessed Wednesday, April 3, 2019]. Vera-Rivera G, Miranda MI, Rangel-Hernandez JA, Badillo-Juarez D, Fregoso-Urrutia D, and Caynas-Rojas S (2018) Effects of caloric or non-caloric sweetener long-term consumption on taste preferences and new aversive learning. Nutritional Neuroscience 1–11. World Health Organization. 2019. Evaluations of the Joint FAO/WHO Expert Committee on Food Additives. Available: apps.who.int/food-additives-contaminants-jecfa-database/search. aspx?fcc ¼ 1 [Accessed 26 March 2018].

Nuclear Medicine Imaging☆ Fabrice Hubelé, Cyrille Blondet, and Alessio Imperiale, University Hospitals of Strasbourg, Strasbourg, France; University of Strasbourg, Strasbourg, France © 2020 Elsevier Inc. All rights reserved.

Glossary

Gamma camera A device allowing detection and localization of gamma rays, forming an image of the underlying radiopharmaceutical distribution within a patient. Gamma cameras are able to product both planar and tomographic images. Hybrid imaging The combination of anatomic and functional imaging modalities (i.e. Positron Emission Tomography and Computed Tomography (PET/CT)). Positron emission tomography A technique that utilizes a system especially designed to produce tomographic images of positron-emitting radionuclides (such as fluorine-18, carbon-11, gallium-68). Radionuclide An atom with an unstable nucleus, which achieves stability by emitting excess energy in the form of gamma rays and subatomic particles (i.e. positrons). The radionuclides most commonly utilized in nuclear medicine are technetium-99m and fluorine-18 for gamma camera- and PET-based imaging, respectively. Radiopharmaceutical or radiotracer A biologically active molecule labeled with a radionuclide. Scintigraphy The process of obtaining images with a gamma camera.

Introduction Nuclear medicine is a functional imaging modality that uses biologically active molecules or cells labeled with radioactive isotopes as molecular probes to obtain in vivo images of physiopathological processes. The principle of nuclear medicine imaging consists in the administration of a radiopharmaceutical to the patient and to detect the radioactivity by external diagnostic devices like gamma camera and positron emission tomography (PET). By following these radioactive tracers as they are taken up, metabolized, and excreted by various organs and tissues, one is able to obtain a qualitative (and sometimes quantitative) assessment of a wide array of functional disorders of the gastrointestinal tract. Nuclear medicine differs from most other medical imaging techniques focusing on molecular, metabolic, and therefore functional dimension of the disease. The detection of lesions depends mainly on the amount of radiotracer located in the lesion itself, and indirectly on the lesion size. Thus, the fundamental postulate of molecular imaging techniques is to obtain a high target/background ratio in terms of radiotracer accumulation. In daily clinical practice, this principle translates into a limitation of spatial resolution with a detection limit of about 10 mm for conventional gamma camera and about 5 mm for PET. The new generations of gamma camera and PET are hybrid devices, combining nuclear imaging technology and CT. Image acquisition is performed according to each modality with a single positioning of the patient, and afterwards combined permitting accurate anatomical identification of functional abnormalities. Therefore, this methodological solution allows the integration of physiopathological and anatomical data from the same patient, with a significant improvement of sensitivity and specificity compared to the only gamma camera or PET.

Gastrointestinal Tract Scintigraphy Gastrointestinal Bleeding Gastrointestinal bleeding scintigraphy is a noninvasive study mainly performed to confirm the presence of active gastrointestinal bleeding and to establish the site of bleeding origin (Ford et al., 1999). Its sensitivity and specificity have been reported to be 93% and 95% respectively (Bunker et al., 1984), and overall accuracy about 90% (Bunker et al., 1984; Dusold et al., 1994). This information can be quite useful in guiding subsequent angiographic, endoscopic, or surgical therapy. Historically, gastrointestinal scintigraphy could be performed according to in vitro and in vivo labeling methodology. According to the in vivo labeling method, patient firstly receives intravenous (i.v.) injection of pyrophosphate followed by the i.v. administration of 99mTc-pertechnetate. Nowadays, due to a suboptimal labeling and a higher unbound circulating 99mTc-pertechnetate, the in vivo method is not recommended. On the other hand, the in vitro labeling procedure is the most utilized in clinical practices. Accordingly, red blood cells from about 50 mL of patient venous blood sample are labeled with 99mTc-pertechnetate and then intravenously injected ☆

Change History: January 2019. F. Hubelé, C. Blondet, and A. Imperiale updated the text and further readings to this entire article, and replaced all the figures adding new ones. Reference list has been also updated.

This is an update of Mohan R. Ramaswamy, Randall A. Hawkins, Nuclear Medicine Imaging, In Encyclopedia of Gastroenterology, edited by Leonard R. Johnson, Elsevier, New York, 2004, Pages 748–754.

Encyclopedia of Gastroenterology, 2nd Edition

https://doi.org/10.1016/B978-0-12-801238-3.65988-3

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to the patient. Planar dynamic scintigraphic imaging of the abdomen and pelvis is obtained for a period of 60–90 min after radiotracer injection. Typically, images are acquired digitally in 1 min frames, which can then be displayed dynamically on a computer screen in a cinematic loop. In order to confirm the origin of the bleeding, tomographic imaging eventually coupled with low-dose CT acquisitions may be performed. To increase the sensitivity of gastrointestinal bleeding searched by scintigraphic methods, the exam should be processed during active bleeding. In that case, bleeding rates as low as 0.05–0.1 mL/min could be diagnosed. Normal images show uniform distribution on liver, spleen, and great vessels. The unbound 99mTc-pertechnetate is excreted by kidneys and accumulates in the bladder. Any other focus of activity developing during the course of the study in the expected location of bowel is usually indicative of an active gastrointestinal bleed.

Ectopic Gastric Mucosa Gastric mucosa both within the stomach and in ectopic sites is able to uptake unbound 99mTc-pertechnetate via sodium-iodine symporter system. Accordingly, scintigraphic investigations can be used to localize gastric mucosa responsible for a bleeding, Meckel’s diverticulum, an enteric duplication, and Barrett’s esophagus. Scintigraphic examination is typically done after fasting and proton pump inhibitors are generally administered about 24–48 h before the test in order to increase the diagnostic sensitivity. Pretreatment with pharmacologic agents such as pentagastrin is no longer indicated. Scintigraphic acquisitions include standard dynamic phase during the first 30 min postinjection and delayed tomographic images. It is reported that at least 2 cm2 of gastric mucosa must be present for reliable scintigraphic detection.

Gastric Emptying A solid (i.e., fried eggs) or a liquid meal (i.e., water or fruit juice) may be easily labeled by 99mTc-sulfur colloid or by 111In-DTPA in order to assess abnormal gastric emptying after a standardized meal. Gastric emptying scintigraphy is mainly indicated for the diagnosis of dumping syndrome (i.e. accelerated gastric emptying) and gastroparesis in diabetic patients (Donohoe et al., 2009). It is possible to study the solid emptying only (most frequently), or both solid and liquid emptying by using double-isotope technique and single-phase data acquisition, or single isotope and double-phase data acquisition for liquid and then solid. By drawing a region of interest around the stomach, it is possible to assess the amount of activity within the stomach and the time-activity curve relative to the gastric area (Fig. 1). Thus, a quantitative estimation of gastric emptying can be obtained and usually expressed as emptying half-time (in minutes) or as emptying rate (expressed as the percentage per minute). The rate of gastric emptying may vary significantly with the type of meal (i.e., its quantity, consistency, and nutritional content), the imaging technique, and the method of quantitative analysis. It is therefore imperative for each laboratory to rigorously standardize its imaging protocol and to establish appropriate normal values specific to that protocol. Commonly, normal half-time (t1/2) gastric emptying is closed to 90 min for solids and 45 min for liquids (
15 min).

Other Techniques Several scintigraphic techniques are also available for the investigation of gastroesophageal reflux (Fig. 2), oesophageal motility, or colonic transit. However, these studies are not widely available and are not well standardized. Scintigraphic protocol is adapted to the physiology of the studied organ including fast dynamic acquisition for oesophageal dysfunction assessment, or delayed images for colonic transit (i.e., two acquisitions per day during a week).

Fig. 1 Results of gastric emptying scintigraphy performed after the administration of solid meal labeled by 111In-DTPA in two adult patients with normal gastric emptying (t1/2 ¼ 87 min, solid line), and diabetic gastroparesis [t1/2 ¼ 290 min (extrapolated value), dashed line], respectively. Normal and pathological gastric time-activity curves are reported. Normal value of half-time gastric emptying is usually considered about 90
15 min.

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Fig. 2 Results of scintigraphic examination in an 8-years-old child with previous history of Nissen fundoplication and clinical suspicion of persistent gastroesophageal reflux. Each reflux episode is marked by “ ” during dynamic scintigraphic acquisition measured at 12, 33, 44, and 46 min after the ingestion of 99m Tc-sulfur colloid-labeled solid meal.

Hepatobiliary Scintigraphy The radiopharmaceuticals utilized in hepatobiliary scintigraphy are the 99mTc-labeled iminodiacetic acid (IDA) derivatives, disofenin and mebrofenin (Tulchinsky et al., 2010). After i.v. administration, the diagnostic agent is taken-up through the same membrane transport mechanism as bilirubin and is then promptly secreted into the bile without conjugation. This radiolabeled bile then fills the gallbladder through the cystic duct and empties into the duodenum through the common duct. Immediately following the i.v. administration of radiotracer, consecutive 1 min scintigraphic images are acquired over the abdomen for a period of 60–90 min. Typically, the images are displayed dynamically on a computer screen in a cinematic loop. In a normal study, there is prompt extraction of activity from the blood by the hepatocytes in the liver. Secreted activity is identified in the major bile ducts within 10 min, with filling of the gallbladder and transit into the small bowel within 60 min after injection. Thus, the normal time activity curve is a bi phasic curve with accumulation in the liver, followed by a spontaneous mono-exponential decrease. Half-time decrease and time to peak are quantitative parameters commonly used for the assessment of radiotracer elimination. Failure of the gallbladder to fill within 4 h is usually indicative of acute cholecystitis. Many studies have found hepatobiliary scintigraphy to have both sensitivity and specificity of greater than 90% for the detection of acute cholecystitis. An important cause of false-positive studies is fasting for less than 4 h prior to the study, as a recent meal induces gallbladder contraction and thereby prevents filling. Fibrotic changes associated with chronic inflammation of the gallbladder can lead to diminished contractile ability, eventually resulting in pain. In properly selected patients with recurrent right upper quadrant pain, a gallbladder ejection fraction below 35% provides evidence of chronic cholecystitis or biliary dyskinesia. In the jaundiced newborn, hepatobiliary scintigraphy plays an important role in the differentiation of biliary atresia from neonatal hepatitis. In case of biliary atresia, the dynamic study shows persistent abnormal radiotracer accumulation in the liver (Fig. 3). Specifically, normal transit of activity from the liver into the small bowel virtually excludes the diagnosis of biliary atresia. Hepatobiliary scintigraphy may also be performed in patients with suspicion of bile enterogastric reflux or with Oddi’s sphincter dysfunction before of after surgical intervention.

Liver and Spleen Scintigraphy Sulfur Colloid Imaging 99m

Tc-sulfur colloid is a particulate radiopharmaceutical, with particle diameters in the order of 100–1000 nm. Following intravenous administration, these particles are rapidly phagocytized by the Kupffer cells of the liver (85%), the macrophages of the spleen (10%), and bone marrow (5%). 99mTc-sulfur colloid imaging of the liver has largely been supplanted by radiologic crosssectional imaging. This technique can play a role in the differentiation of hepatic tumors, in those most regenerating nodules, twothirds of focal nodular hyperplasia, and a small number of adenomas maintain enough Kupffer cell activity to take up the tracer, whereas most other hepatic lesions usually do not.

Radiolabeled Erythrocyte Imaging 99m

Tc-pertechnetate-labeled erythrocytes may be used to differentiate cavernous hemangiomas from other liver masses. This test makes use of the classic blood flow pattern of such hemangiomas, which initially appear as cold defects on images obtained

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Fig. 3 Hepatobiliary scintigraphy performed after the i.v. injection of 99mTc-labeled mebrofenin in two children with (Ford et al., 1999) and without (Bunker et al., 1984) biliary atresia, respectively. Pathological (dashed line) and normal (solid line) liver time-activity curves are reported.

immediately after injection, progressively filling-in to intensity greater than that of the liver background on subsequent delayed images obtained at 1–2 h post injection. Lesions over 2–3 cm in size can be detected with an accuracy of >95%.

Damaged Erythrocyte Imaging Although 99mTc-sulfur colloid may be used for splenic imaging, heat-damaged or chemically damaged 99mTc-pertechnetate-labeled erythrocytes demonstrate a much stronger affinity for the spleen. This latter imaging method obviously takes advantage of the spleen’s role in removing damaged erythrocytes from the blood. Images are acquired 1–3 h after injection, with standard planar acquisitions completed by tomographic scan. Radionuclide imaging of the spleen is most often utilized in detecting recurrent splenic tissue in patients with continuing laboratory abnormalities after splenectomy for thrombocytopenia. It is also useful in differentiating a left upper quadrant mass from an accessory spleen, establishing the diagnosis of splenosis, and evaluating congenital asplenia/polysplenia syndromes.

Inflammation and Infection 99m

Tc-hexamethylpropyleneamine oxime (99mTc-HMPAO) labeled leucocytes and 18F-Fluorodeoxyglucose (18F-FDG) are the two common radiotracers used in digestive tract inflammation and/or infection assessment. Interestingly, leucocytes can also be labeled with 18F-FDG, combining a satisfying spatial resolution to in vivo leucocyte recruitment; however, this promising technics needs further clinical validation (Dumarey, 2009). 67Ga-citrate and 111In-oxinate labeled leucocytes represent alternative radiopharmaceuticals but offer poor spatial resolution and need for delayed acquisitions (until 48 h).

Labeled Leukocytes Using in vitro labeling methodology, patient’s white blood cells can be labeled with 111In-oxine or 99mTc-HMPAO and intravenously reinjected in the patient. Thus, autologous labeled leukocytes are drawn to areas of active infection and inflammation through the usual chemotactic mechanisms. Because of better imaging characteristics, 99mTc-labeled leukocytes provide greater image quality and allow for earlier imaging (4 h after radiotracer injection). Unfortunately, 99mTc-labeled leukocytes undergo normal biliary and bowel clearance, somewhat limiting their use in the abdomen. As a precaution, this examination is not recommended in patients rectum > stomach > colon > duodenum > ileum–jejunum

Terada et al. (2005)

Transporter (gene); ion dependency

Amino acid substrates

4F2hc/LAT2 (SLC3A2/SLC7A8) (a heteromeric transporter consisting of solute carrier family 3 membrane 2/solute carrier family 7 member 8); Naþindependent TAT1 (SLC16A10, solute carrier family 16 member 10) 4F2hc/yþ LAT1 (SLC3A2/SLC7A7) (a heteromeric transporter consisting of solute carrier family 3 member 2/solute carrier family 7 member 7) 4F2hc/yþ LAT2 (SLC3A2/SLC7A6) (a heteromeric transporter consisting of solute carrier family 3 member 2/solute carrier family 7 member 6); Naþdependent ATA2 or SNAT2 (SLC38A2, solute carrier family 38 member 2); Naþ-dependent

Cationic and neutral amino acids: lysine, arginine, glutamine, histidine, methionine, leucine (transport of neutral amino acids requires sodium but that of cationic amino acids does not) Lysine, arginine, glutamine, histidine, methionine, leucine, alanine, cysteine

Glycine, proline, alanine, serine, cysteine, glutamine, asparagine, histidine, methionine

1. Vuille-dit-Bille et al. (2015) 2. Terada et al. (2005)

amino acids. Though these transporters have their own preferred amino acids, they can share amino acid substrates. That is, an amino acid can be absorbed into enterocytes by more than one type of apical transporters and be secreted out of enterocytes by more than one type of basolateral transporters. A number of basolateral membrane transporters exist as a heteromeric transporter which consists of a transmembrane protein, 4F2, encoded by SLC3A2 gene (solute carrier family 3 member 2); 4F2 plays a key role in trafficking these transporters to the membrane by way of associating its own heavy chain (hc) with the light chain of each one of these transporter. Such heteromeric basolateral membrane transporters include 4F2hc/LAT2, 4F2hc/yþ LAT1, and 4F2hc/yþ LAT2. The apical cationic amino acid transporter, rBAT/b0,þ AT, is also a heteromeric protein in which b0,þ AT stabilizes rBAT and facilitates trafficking of the transporter to the membrane.

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Nutrient Transport, Regulation of

Vectorial transport of each individual amino acid across enterocytes into circulation is typically mediated by an apical membrane transporter and then by a distinct basolateral membrane transporter (Broer, 2008). For example, neutral amino acids can be absorbed into enterocytes by apical membrane transporters, BoAT1 or ASCT2, and then secreted out of enterocytes by basolateral membrane transporters, TAT1 or 4F2hc/LAT2. Malabsorption of specific amino acids caused by genetic mutations of their intestinal transporters can adversely impact health. For example, Hartnup disease (an autosomal recessive metabolic disorder) is caused by mutations of the SLC6A19 gene which encodes the neutral amino acid transporter, BoAT1. Cystinuria results from mutations of cationic amino acid transporter, rBAT/bo,þ AT.

Transport of Monosaccharides Digestion of carbohydrate foods produces their constituting basic units, simple sugars (monosaccharides); monosaccharides including glucose, fructose, and galactose are absorbed by transporters by enterocytes, as highlighted in Fig. 1. Take for example, glucose is absorbed into enterocytes via the apical transporter, sodium-glucose co-transporter 1 (SGLT1), and then secreted out of enterocytes into interstitial space/circulation via the basolateral facilitative glucose transporter, type 2 (GLUT2) (Wright et al., 2003; Kellett et al., 2008). Co-transport of sodium and glucose by SGLT1 is driven by basolateral sodium/potassium ATPase so that absorption of glucose against its higher intracellular concentration can occur. Secretion of glucose or galactose by GLUT2 is a passive diffusion process down their individual concentration gradients. SGLT1 is encoded by SLC5A1 gene (solute carrier family 5 member 1) and GLUT2 by SLC2A2 gene (solute carrier family 5 member 2). Fructose is absorbed via the apical facilitative transporter GLUT5 into enterocytes, and is secreted out of enterocytes into interstitial space/circulation via two different basolateral membrane transporters, GLUT2 and glucose transporter, type 5 (GLUT5). GLUT5 is encoded by SCL2A5 gene (solute carrier family 2 member 5). Expression of SGLT1 mRNA is detected in duodenum, jejunum, and ileum. Similar levels of GLUT2 mRNA are detected in the jejunum and ileum; so are those of GLUT5 mRNA. In the fetal small intestine, transcription of SGLT1 reaches adult levels by week 19 but GLUT2 mRNA expression is significantly lower than that in adults (Davidson et al., 1992). SGLT1 is functional at birth. Fructose absorption is significantly lower in infants and toddlers than in children ages 4–5 years; children’s ability to absorb fructose increases with age (Jones et al., 2011). Both children and adults have limited ability to absorb fructose and too much dietary intake of fructose can cause gastrointestinal discomfort including abdominal pain, gas, and diarrhea. Genetic mutations of SGLT1-encoding gene (SLC5A1) cause glucose–galactose malabsorption, a rare autosomal recessive disease that cause life-threatening diarrhea in neonates when fed with a high sugar diet. Infectious diarrhea may impact SGLT1 (Das et al., 2018).

Transport of Vitamins Transport of Water-Soluble Vitamins Vitamin C, niacin, and cobalamin are supplied by dietary intake. Vitamin C (L-ascorbic acid) is absorbed into enterocytes via the apical transporter, sodium-dependent vitamin C transporter-1 (SVCT1), and transported out of enterocytes into the interstitial space and circulation via the basolateral transporter, sodium-dependent vitamin C transporter-2 (SVCT2). SVCT1 is encoded by SLC23A1

Intestinal lumen

Submucosal interstitial space and tissue Basolateral membrane

Apical membrane Glucose Galactose

Fructose

Glucose Galactose

Fructose

Transporters SGLT1

enterocyte

GUT2 GLUT5

Fig. 1 The schematic presentation of monosaccharide absorption across enterocytes. Glucose and galactose are both absorbed into enterocytes by sodiumglucose co-transporter 1 (SGLT1) in the apical membrane, and are secreted out of enterocytes by glucose transporter, type 2 (GLUT2) in the basolateral membrane. Fructose is absorbed into enterocytes by glucose transporter, type 5 (GLUT5) in the apical membrane and is secreted out of enterocytes by glucose transporters, GLUT2 and GLUT5, in the basolateral membrane. Both GLUT2 and GLUT5 are facilitative transporters.

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gene (solute carrier family 23 member 1) while SVCT2 is encoded by SLC23A2 gene (solute carrier family 23 member 2). Vitamin C absorption activity increases from duodenum to distal ileum (Malo and Wilson, 2000). Niacin is absorbed in the human stomach and small intestine; instillation of niacin into the upper small intestine of healthy subjects results in higher absorption compared to instillation into empty stomach. Intestinal absorption of niacin occurs via sodium-coupled monocarboxylate transporter (SMCT; also known as SMCT1), which is encoded by SLC5A8 gene (solute carrier family 5 member 8). Cobalamin (vitamin B12) forms a complex with intrinsic factor in the intestinal lumen, which then binds to cubulin, an apical membrane protein in the ileum. The resulting complex is endocytosed into enterocytes; the mechanism by which cobalamin exits ileal enterocytes either in free form and/or in a complex with trans-cobalamin is not well characterized. Once absorbed, cobalamin appears in the circulation as a complex with trans-cobalamin (Said, 2011). Dietary intake and bacterial production both constitute the sources for vitamin B1 (thiamine), folate, biotin, pantothenic acid, and riboflavin (vitamin B2). Vitamin B1 is absorbed into enterocytes vial the apical membrane sodium-independent, pH-dependent thiamine transporter 1 (THTR-1), and thiamine transporter 2 (THTR-2) (Said, 2011). THTR-1 is encoded by SLC19A2 gene (solute carrier family 19 member 2) while THTR-2 is encoded by SLC19A3 gene (solute carrier family 19 member 3). At the enterocyte level, THTR-1 is present in both apical and basolateral membranes of enterocytes while THTR-2 is only detected in the basolateral membrane. THTR-1 and THTR-2 are both expressed in human small intestine and colon but at different levels. Thiamine deficiency induces intestinal uptake of thiamine Dietary folates exist as folate monoglutamate and polyglutamate; the latter is digested in the intestine to monoglutamate. Dietary folate monoglutamate is absorbed in the proximal intestine while bacteria-derived folates are absorbed in the colon. Folate is absorbed into enterocytes via two distinct transporters, proton-coupled folate transporter (PCFT) and facilitative protonindependent reduced folate carrier (RFC). PCFT is encoded by SC46A1 gene (solute carrier family 46 member 1) and is expressed only in the apical membrane of enterocytes. RFC is encoded by SC19A1 gene (solute carrier family 19 member 1) and is also expressed in apical membrane of enterocytes. Loss-of-function mutations of PCFT cause hereditary folate malabsorption, indicating that RFC does not play as important a role as PCFT in oral folate absorption (Zhao et al., 2011). PCFT is expressed in proximal small intestine and at very low levels in distal small and large intestine whereas RFC is expressed at different levels along the human intestine. PCFT-mediated folate uptake reaches the maximum at acidic pH and takes place mainly in proximal small intestine where microclimate pH is acidic. The activity of RFC reaches the maximum at pH 7.4 and is minimal at acidic pH; its involvement in folate uptake is mostly in the distal small intestine and colon. The mechanism of folate exiting enterocytes through the basolateral membrane is not well characterized. Folate absorption is upregulated by folate deficiency. Biotin and pantothenic acid are both absorbed in the small intestine and colon via the sodium-dependent multivitamin transporter (SMVT), encoded by SLC5A6 gene (solute carrier family 5 member 6). Biotin exits enterocytes via a sodium-independent transporter in the basolateral membrane. Biotin deficiency causes expression of SMVT and upregulation of its intestinal uptake. Intestinal absorption of riboflavin (vitamin B2) involves two transporters, riboflavin transporter 2 (RFT2), which is encoded by SLC52A3 gene (solute carrier family 52 member 3), and riboflavin transporter 1 (RFT1) which is encoded by SLC52A1 gene (solute carrier family 52 member 1). RFT2 is only expressed in the apical membrane of enterocytes, and its activity is Naþ and Cl independent but pH-sensitive. RFT1 is expressed in the basolateral membrane, and its activity is Naþ, Cl, and pH independent (Yonezawa and Inui, 2013). Though dietary riboflavin is mainly absorbed in the proximal intestine, the colon is capable of absorbing riboflavin.

Transport of Lipid Soluble Vitamins Vitamin E represents a group of four tocopherols and four tocotrienols; both tocopherols and tocotrienols are lipophilic antioxidants. Their absorption across the apical membrane of enterocytes involves scavenger receptor class B type I, NPC1 like cholesterol transporter 1, and CD36 (Reboul, 2017). Inside enterocytes, vitamin E is incorporated into chylomicrons and then transported into the lymph. Dietary sources of vitamin A (retinol) include retinyl esters from animal-derived foods and provitamin carotenoids from vegetables and fruits. Retinyl esters are metabolized in intestinal lumen to retinol. Dietary retinol is absorbed across the apical membrane by a specific, saturable process into enterocytes, which is yet to be characterized. Carotenoids can be transported into enterocytes via nonspecific transporters, Scavenger Receptor Class B Type 1 (SRB1) and Niemann-Pick C1-L1 (NPC1-L1). Inside enterocytes (Reboul, 2013), retinol is esterified; intracellular trafficking leads to incorporation of large amounts of carotenoids and retinol ester into chylomicrons which then enter the lymph. Vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol) are the two major forms of dietary vitamin D. Vitamin D2 and D3 are derived from plant and animal foods, respectively. Both are hydroxylated to 25(OH)vitamin D in the liver and then to the active form of 1,25-dihydroxyvitamin D in the kidney. Intestinal absorption of vitamin D involves scavenger receptor class B type I, NPC1 like cholesterol transporter 1, and CD36 (Reboul, 2015).

Transport of Fatty Acids and Cholesterol Intestinal digestion of dietary lipids produces fatty acids, glycerol, and cholesterol; these products are solubilized in micelles that consist of bile salts before being absorbed through the apical membrane of enterocytes. Sufficient dietary intake of essential fatty acids, linoleic and alpha-linolenic acid, is important because they critically maintain the normal physiology of the human body and

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the human body cannot produce them. Based on the length of the hydrocarbon chain, fatty acids are grouped into short-chain fatty acid (less than 6 carbons), median-chain fatty acids (6–12 carbons), and long-chain fatty acids (>12 carbons). Fatty acids are also categorized into saturated and unsaturated fatty acids with the latter containing a carbon–carbon double bond (C]C) in their chemical structures. Short-chain fatty acids such as acetate, propionate, and butyrate are absorbed by passive diffusion in the small intestine. Uptake of long-chain fatty acid into enterocytes in the small intestine involves three distinct apical transporters, fatty acid transporter protein subtype 4 (FATP4), fatty acid translocase (FAT/CD36), and plasma membrane fatty acid-binding protein (FABPpm) (Iqbal and Hussain, 2009). FATP4 is encoded by SLC27A 4 (solute carrier family 27 member 4) gene. FAT/CD36 is known as FAT or CD36 and is encoded by CD36 gene. FAT/CD36, FABPpm, and FATP4 proteins are expressed throughout the human intestinal tract including colon. Cytosolic fatty acid binding protein aids transport of free fatty acids inside the enterocyte before they are esterified to form triglycerides which are incorporated with cholesterol and apolipoproteins before secretion into chylomicrons. In the colon, absorption of short-chain fatty acids (SCFAs) involves proton-coupled monocarboxylate transporter (MCT) isoforms (MCT1, MCT3, MCT4, and MCT5) and sodium-coupled monocarboxylate transporter (SMCT) (Gill et al., 2005; Iwanaga et al., 2006). MCT1, MCT3, MCT4, and MCT5 are encoded by SLC16A1 (solute carrier family 16 member 1), SLC16A8 (solute carrier family 16 member 8), SLC16A3 (solute carrier family 16 member 3), SLC16A5 (solute carrier family 16 member 5) genes, respectively. SMCT is encoded by SLC5A8 gene. Cholesterol comes from dietary intake and hepatic synthesis. Endogenous cholesterol synthesized by the liver is secreted into the lumen of the small intestine via biliary secretion, and then is reabsorbed by enterocytes back to the liver. Intestinal uptake of cholesterol occurs via Niemann-Pick C1 like 1 (NPC1L1) in the apical membrane of enterocytes. NPC1L1 is encoded by NPC1L1 gene. In enterocytes, cholesterol can efflux into the intestinal lumen via two transporters in the apical membrane, ATP binding cassette G5 (ABCG5) and G8 (ABCG8), or be esterified in the endoplasmic reticulum by acyl-CoA-cholesterol acyltransferase-2 (ACAT2). Intracellular triglycerides as well as free and esterified cholesterol are assembled and secreted out of enterocytes either by (1) ATP-binding cassette A1 (ABCA1) to form ApoA1-rich HDL and then enter the blood circulation, or (2) incorporation into ApoB48-containing chylomicrons before entering the lymph (Masson et al., 2010; Iqbal and Hussain, 2009). ABCA1, ABCG5, ABCG8, and NPC1L1 are expressed throughout the human intestinal tract, from jejunum to distal colon.

References Bai JPF, Burckart GJ, and Mulberg AE (2016) Literature review of gastrointestinal physiology in the elderly, in pediatric patients, and in patients with gastrointestinal diseases. Journal of Pharmaceutical Sciences 105: 476–483. Broer S (2008) Amino acid transport across mammalian intestinal and renal epithelia. Physiological Reviews 88: 249–286. Das S, Jayaratne R, and Barrett KE (2018) The role of ion transporter in the pathophysiology of infectious diarrhea. Cellular and Molecular Gastroenterology and Hepatology 6: 33–45. Davidson NO, Hausman AM, Ifkovits CA, et al. (1992) Human intestinal glucose transporter expression and localization of glut 5. The American Journal of Physiology 262: C795–C800. Gill RK, Saksena S, Alrefai WA, et al. (2005) Expression and membrane localization of Mct isoforms along the length of the human intestine. American Journal of Physiology. Cell Physiology 289: C846–C852. Iqbal J and Hussain MM (2009) Intestinal lipid absorption. American Journal of Physiology. Endocrinology and Metabolism 296: E1183–E1194. Iwanaga T, Takebe K, Kato I, et al. (2006) Cellular expression of monocarboxylate transporters (Mct) in the digestive tract of the mouse, rat, and humans, with special reference to slc5a8. Biomedical Research 27: 243–254. Jones HF, Burt E, Dowling K, et al. (2011) Effect of age on fructose malabsorption in children presenting with gastrointestinal symptoms. Journal of Pediatric Gastroenterology and Nutrition 52: 581–584. Kellett GL, Brot-Laroche E, Mace OJ, et al. (2008) Sugar absorption in the intestine: The role of Glut2. Annual Review of Nutrition 28: 35–54. Malo C and Wilson JX (2000) Glucose modulates vitamin C transport in adult human small intestinal brush border membrane vesicles. The Journal of Nutrition 130: 63–69. Masson CJ, Plat J, Mensink RP, et al. (2010) Fatty acid- and cholesterol transporter protein expression along the human intestinal tract. Plos One 5: e10380. Mooij MG, De Koning BE, Lindenbergh-Kortleve DJ, et al. (2016) Human intestinal Pept1 transporter expression and localization in preterm and term infants. Drug Metabolism and Disposition 44: 1014–1019. Reboul E (2013) Absorption of vitamin A and carotenoids by the enterocyte: Focus on transport proteins. Nutrients 5: 3563–3581. Reboul E (2015) Intestinal absorption of vitamin D: From the meal to the enterocyte. Food & Function 6: 356–362. Reboul E (2017) Vitamin E bioavailability: Mechanisms of intestinal absorption in the spotlight. Antioxidants (Basel) 6: 95. Said HM (2011) Intestinal absorption of water-soluble vitamins in health and disease. Biochemical Journal 437: 357–372. Terada T, Shimada Y, Pan X, et al. (2005) Expression profiles of various transporters for oligopeptides, amino acids and organic ions along the human digestive tract. Biochemical Pharmacology 70: 1756–1763. Vuille-Dit-Bille RN, Camargo SM, Emmenegger L, et al. (2015) Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors. Amino Acids 47: 693–705. Wright EM, Martin MG, and Turk E (2003) Intestinal absorption in health and disease—sugars. Best Practice and Research: Clinical Gastroenterology 17: 943–956. Yonezawa A and Inui K (2013) Novel riboflavin transporter family RFVT/SLC52: Identification, nomenclature, functional characterization and genetic diseases of RFVT/SLC52. Molecular Aspects of Medicine 34: 693–701. Zhao R, Diop-Bove N, Visentin M, and Goldman ID (2011) Mechanisms of membrane transport of folates into cells and across epithelia. Annual Review of Nutrition 31: 177–201.

Nutrition in Aging☆ Guylaine Ferland, University of Montréal, Montréal, QC, Canada © 2020 Elsevier Inc. All rights reserved.

Glossary

Bioelectrical impedance analysis Estimation of total body water by passing low-amperage electrical alternating current through the body and measuring the electrical properties of resistance and reactance. Computed tomography A computer-linked X-ray imaging technique where images taken from different angles are used to create three-dimensional views of tissues and organs. Dual energy X-ray absorptiometry An X-ray imaging technique where the amount of energy loss depends on the type of tissue through which the beam passes. Life expectancy Predicted number of years that will pass until only half of any cohort of people will still be alive. Longevity Length of time an individual survives; for humans, 120 years is considered the maximal life span. Magnetic resonance imaging An imaging technique that uses strong magnetic fields and magnetic gradients to visualize organs and components of the body. MRI does not involve the use of X-rays. Sarcopenia Age-dependent loss of skeletal muscle fibers and their replacement by intramuscular fat in the elderly, leading to reduced strength of gait and predisposition to falls. Senescence Age-dependent decline in physiological capacities and anatomic integrity that proceeds throughout adulthood.

Demographic Considerations Population aging is a global phenomenon. Recent statistics indicate that for the first time in history, most people can expect to live into their sixties and beyond. Sixty years of age or more is the criterion for being classified as elderly by the World Health Organization (WHO), whereas 65 years is the threshold in North America and the United Kingdom. The proportion of the world’s population over 60 is expected to nearly double over the next 40 years, increasing from 12% in 2015 to 22% in 2050. Further, individuals aged 80 or older are the fastest growing segment, currently totaling 125 million worldwide and increasing to 434 million over the next 40 years. Importantly, population aging is no longer limited to high-income countries. According to the WHO, it is now low- and middle-income countries that are experiencing the greatest change such that by 2050, 80% of older people will be living in developing countries. Life expectancy at birth, that is, the expected median survival of a birth cohort, has been advancing steadily worldwide. In developed nations, it now ranges from 75 to 81 years, always with a greater life expectancy for women than men. According to the United States Census Bureau, in 2012, women and men aged 65 were expected to live an additional 20.7 and 18.1 years, respectively. The growing number of older people will have an important societal impact. Countries facing these demographic shifts will need to ensure that their health care and social systems can adequately address this new reality (World Health Organization, 2018).

Chronological and Biological Aging Chronological age refers to the number of years an individual has lived. Survival to 120 years is considered to be the maximum life span for Homo sapiens. Biological aging is a process that begins at conception and continues throughout life, first as developmental changes, then, in adulthood, as “senescence.” It involves the anatomical changes in tissues and a decline in the capacity for physiological functions of most organ systems. Over the years, a series of theories regarding the nature and mediation of the aging process have been advanced, all of which can be rationalized on the basis of an evolutionary advantage to maximize reproductive efficiency at the expense of the mechanisms for genetic and cellular repair. Current theories of aging revolve around two themes, namely genetic alterations (e.g., telomere attrition, gene regulation dysfunction), and processes associated with molecular entropy and imperfect repair (e.g., oxidative stress, and failure in the immune and neuroendocrine systems). Although all these theories have strong scientific and theoretical basis, none is currently considered sufficient to fully grasp the complexity of the aging process. Calorie restriction, defined as the reduction of energy intake without malnutrition, delays the onset of age-related diseases and prolongs longevity in animals. As a physiological

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Change History: January 2019. G. Ferland updated all chapter sections; changed tables; replaced all the References.

This is an update of Noel W. Solomons, Nutrition in Aging, In Encyclopedia of Gastroenterology, edited by Leonard R. Johnson, Elsevier, New York, 2004, Pages 767–771.

Encyclopedia of Gastroenterology, 2nd Edition

https://doi.org/10.1016/B978-0-12-801238-3.66041-5

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stress, calorie restriction is deemed to induce adaptive responses at the cellular and organ levels, preparing the organism to face stronger stress, and increasing its chances of survival against adversity (Khan et al., 2017).

Successful Aging The classical public health goal for gerontology has been expressed as “adding life to years, rather than years to life.” This involves the so-called compression of morbidity, in which physical and cognitive capacities are maintained and individuals succumb rapidly in old age after a minimum period of disability and dependency. Such a life evolution has been termed “successful aging,” in which chronological age advances more rapidly than biological aging and people maintain normal health and adequate physical and cognitive function. A majority of survivors to the “Third Age,” however, exhibit “usual” (normative) aging, in which chronic diseases and some disability intercede. The most burdensome format for individuals, their relatives, and the community is the evolution to “frailty,” a geriatric syndrome that develops as a consequence of age-related decline in several physiological systems and which collectively results in a vulnerability to withstand low-level stressors (e.g., minor infection). The prevalence of frailty increases with age, affecting up to 25% of individuals over 85 years, and is associated with increased risk of falls, disability, hospitalization, longterm care, and mortality (McGuigan et al., 2017).

Physiologic and Pathophysiologic Changes With Advancing Age Body Composition Basic senescent processes and diseases common to advanced age impact the elemental, molecular, and tissue and organ composition of the body. Conversely, body composition influences resistance and susceptibility to disease and disability. Primary among senescent changes is a progressive decrease in height, beginning around age 30 and continuing thereafter. It is proportionately greater in aging women as compared to men. Settling and desiccation of intervertebral disks combines with compression of vertebral bodies to diminish the length of the spinal column. Curvatures produced by uneven vertebral compression can further reduce stature. In contrast, body weight increases up through the seventh decade and then stabilizes or decreases in later life. The composition of this weight follows a stereotyped modification in the last third of the life span, with an increased percentage of body mass as fat, a decreased percentage of body water, and a lower total cell mass. Fat mass increases by almost 50% and is characterized by the deposition of fat in the viscera and skeletal muscles, subcutaneous fat decreasing with aging. In contrast, lean muscle mass suffers a considerable decline with age and comes to represent from 50% of total body weight in young adult to about 25% in people aged between 70 and 80 years. As a result of skeletal muscle loss, the basal metabolic rate decreases by about 30% between the ages of 20 and 70 years. The term sarcopenia (from the Greek words sarx for flesh and penia for loss) has been assigned to this age-related loss of muscle mass and integrity (e.g., marbling of the skeletal muscle), and muscle strength. It is estimated to affect from 8% to 40% of older adults aged 60 years and approximately 50% in those aged 75 years. Sarcopenia is associated with increased risks of falls, fractures, disability, adverse health outcomes, and mortality. Physical inactivity is considered the major risk factor for sarcopenia, the gradual decline in muscle fiber numbers being more pronounced in individuals with sedentary lifestyle. However, factors such as age-related hormonal changes (e.g., insulin, testosterone, thyroid hormone, growth hormone, insulin-like growth factor), mitochondrial dysfunction, oxidative stress, and a pro-inflammatory state (e.g., tumor necrosis factor alpha, interleukin-6) could also contribute to the development of sarcopenia. Sarcopenic obesity, a condition in which age-related loss of skeletal mass and strength coexist with excess body fat, has also been found to increase with advancing age with reported prevalence of 2%–22%. However, the presence of sarcopenic obesity in older individuals poses a diagnostic challenge as the age-related reduction of muscle mass and strength is often masked by excess body weight. Sarcopenic obesity puts older adults at special risk for adverse outcomes and functional impairment as both predict disability. It has been shown that sarcopenic obesity results in worse physical functional declines than sarcopenia or obesity alone and that they potentiate their effects on disability, morbidity, and mortality (Han et al., 2018). Peak bone density is typically achieved by age 30. Osteopenia (scarcity of bone) occurs in both sexes with age and is characterized by the progressive demineralization of bone and loss of skeletal mass. A rapid, involutional bone demineralization occurs with menopause (around age 50), making women more susceptible (but not exclusively so) to a critical reduction in bone mineral density and loss of architecture that leads to pathological fractures of the vertebral bodies, wrists, and hips (osteoporosis). The prevalence of osteoporotic fractures rises from
5% in women at age 50–59 years to
50% in women age >80 years. It has been estimated that a white American woman age 50, has a 40% risk of suffering an osteoporotic fracture in her remaining lifetime, two thirds of the fractures occurring after age 75. Risk factors for osteoporosis include advanced age, female gender, ethnicity (white or Asian), family history, amenorrhea (absence of menstruation), androgen (men) and estrogen (women) depletion, underweight, low body fatness, sarcopenia, cigarette smoking, sedentariness, inadequate vitamin D or calcium intake, excessive intake of alcohol and caffeine, and prolonged use of certain medications (e.g., corticosteroids, thyroid hormone, thiazide diuretics) (Pisani et al., 2016).

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Masticatory and Sensory Functions Oral health plays a pivotal role in maintaining nutritional status of older individuals. Impaired dentition, masticatory function, and xerostomia (dry mouth) can lead to difficulty in swallowing and poor food selections. Alterations in the sense of taste and smell can decrease the pleasure of eating with subsequent impact on appetite and food intake. Missing, loose, or decayed teeth, and ill-fitting dentures are common problems among older individuals, notably those who are frail and in poor general health. When masticatory function is compromised, grinding of the food bolus is less efficient and this can lead to a preference for easily chewed foods (e.g., pasta, soft bread) in place of nutritionally dense foods such as whole grains, fresh fruits and vegetables, nuts, and meat. Xerostomia is a frequent complaint among older individuals, affecting up to 30% of the population aged 65 and older. Although salivary flow has been reported to decrease in old age (not all studies agree), xerostomia is usually associated with medical problems (e.g., diabetes) or, more generally, is a side effect of medication. It is estimated that 80% of the most commonly prescribed medications can cause xerostomia, with
400 of them inducing salivary gland dysfunction (Lamster et al., 2016). Taste and olfaction are central to the enjoyment of foods. Decreased sensory functions are often observed in old people, although the changes are highly variable and affect individuals to different degrees. Of the two domains, olfaction is more commonly affected, olfactory dysfunction increasing with age and affecting up to 60% of individuals over 65 years. Despite their prevalence, the independent role of age has been difficult to demonstrate as factors such as health disorders, medications, oral hygiene, periodontal disease, denture use, and chronic smoking are known to alter sensory functions. With respect to taste, hundreds of drugs have been reported to induce unpleasant taste or distort taste (dysgeusia) when administered alone or in combination with other medications. Further, the detrimental effect of medications on taste is linked to the extent of the medication, the larger the number of drugs consumed, the greater the impact on taste. Xerostomia, induced or not by medication, can also affect taste as saliva plays an important role in dissolving taste substances from foods, before their interactions with receptors. As for taste, the loss of olfaction with age can result from the use of certain medications however, other factors can contribute. Chronic nasal disease, environment-induced damage to the olfactory epithelium, and the presence of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease have been associated with impairment of the olfactory function. Finally, even when present, the link between taste and smell dysfunction, dietary patterns, and health status has been difficult to establish. Recent studies controlling for potential confounders, have largely failed to find a significant relationship between sensory abilities and nutritional status in the elderly. Nonetheless, vulnerable populations such as geriatric patients who are characterized by multi-morbidity and polypharmacy, should be considered at greater risk for sensory dysfunction (Kershaw and Mattes, 2018).

Gastro-Intestinal Functions Gastrointestinal functions are largely maintained in old age, although some changes can occur. The prevalence of atrophic gastritis, a condition induced by Helicobacter pylori infection and associated with a decline in gastric acid secretion, increases with age. An insufficient production of acid (achlorhydria) may decrease the bioavailability of vitamin B12 and minerals such as calcium and iron, which depend on a more acidic luminal pH for their release from foods and subsequent absorption. Gastric mucosal function can also be altered in old age (e.g., reduced production of bicarbonate and prostaglandins), increasing the susceptibility to injury by agents such as ethanol or aspirin and other nonsteroidal antiinflammatory drugs. Loss of mucosal integrity also decreases the ability to resist damage such as ulcers and infections. The rate of gastric emptying is slower in older versus younger adults when large meals are consumed, a physiological modification that can contribute to early satiation. In contrast, the transit times of the small intestine and colon are unaffected by aging. With respect to gastrointestinal absorption, there is also no evidence for systematic malabsorption as a consequence of aging. Currently available data do not suggest malabsorption of any of the macronutrients (i.e., fat, protein and carbohydrates) when consumed as part of a regular diet. Calcium absorption occurs via a passive nonsaturable absorption route, the paracellular pathway, and a metabolically driven transport pathway called transcellular. The effect of primary aging on paracellular absorption is currently unknown. By contrast, the expression of the main proteins involved in the transcellular pathway declines during aging. Further, intestinal calcium absorption is facilitated by the active form of vitamin D (1,25(OH)2D3), however, its ability to do so decreases with age. Finally, an impoverished vitamin D status decreases calcium absorption and may jeopardize status, especially in the presence of atrophic gastritis which reduces calcium solubility (Rémond et al., 2015).

Anorexia of Aging Nutrition surveys consistently show a gradual decrease in energy intake with age. Compared to younger adults, older individuals are not as efficient in upregulating their food intake following a period of food deprivation, and they tend to satiate earlier when eating a meal. This decline in appetite and food intake has been termed “anorexia of aging.” It cannot be solely explained by age-associated illnesses but is deemed to result from changes in gastrointestinal motility, and concentrations and activity of gastrointestinal hormones. Specifically, it is suggested that a decrease in compliance of the upper part of the stomach (i.e., fundus) and subsequent stretch of its lower part (i.e., antrum), sends increased satiety signals to the brain through ascending fibers in the vagus nerve. Cholecystokinin, a hormone produced in the duodenum and ileum in response to the inflow of food into the small intestine, has strong satiation effects. When investigated in controlled conditions, levels of cholecystokinin are higher in older than in younger adults, and its satiating effect is more potent. Similarly, circulating levels of ghrelin, an orexigenic hormone (stimulates feeding)

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synthesized in the fundus of the stomach, are decreased in older compared to younger adults, and recovery of ghrelin levels following a meal is less pronounced. Limited evidence also suggests that health status such as frailty can modulate these gastrointestinal changes even further (Landi et al., 2017).

Conditions of Concern Dysphagia Dysphagia is a clinical symptom defined as the difficulty to effectively move the alimentary bolus from the oral cavity to the esophagus. This condition is deemed to affect between 15% and 35% of free-living older individuals and up to 50% of geriatric patients. Dysphagia increases with age, frailty, sarcopenia and functional impairment, and is particularly prevalent in patients suffering from neurodegenerative diseases (e.g., Parkinson’s disease, dementia). Dysphagia also affects up to 65% of stroke patients, and although many of them regain functional swallowing within the first month following the event, dysphagia may persist beyond 6 months in some patients. Complications associated with dysphagia include malnutrition, dehydration, respiratory complications, and aspiration pneumonia, an infection caused by food or fluids entering in the lungs. In addition, dysphagia increases the rates of readmissions and length of hospitalization, and often requires increased rehabilitation time and need for long-term care assistance. Finally, in some patients, dysphagia represents a psychological burden that can lead to anxiety and depression, with a consequent decrease in quality of life. Treatment of swallowing impairments involves compensatory measures that include thickened liquids and texture-modified foods, as well as posture adjustments, all of which are put in place to ensure individuals with dysphagia eat safely (Ortega et al., 2017).

Constipation Constipation is defined as infrequent stools, difficulty in passage of stools, hard stools, painful bowel movements and a sense of incomplete emptying. It is one the most common functional disturbances encountered in older individuals, affecting
30% of community-dwelling adults aged 65 and older, and over 50% of nursing home residents. Although physiologic changes affecting colonic motility can lead to constipation, primary contributory factors include insufficient total calorie and fluid intakes, diets low in dietary fibers, lack of physical activity and impaired mobility, increased dependence, age associated diseases (e.g., diabetes, cognitive disorders) and chronic medications. Commonly prescribed drugs known to promote constipation include anticholinergics, antidepressants, calcium supplements, opioid analgesics, and antacids. Treatment strategy is usually based on ensuring adequate fluid intake and increasing daily fiber intake through inclusion of foods with high-fiber content such as whole-grain bread, bran, beans, vegetables, and fresh fruits (Rémond et al., 2015).

Malnutrition Malnutrition (undernutrition) can be generally defined as a state of nutrition in which a deficiency of energy, protein and micronutrients causes measurable adverse effects on tissue, body composition and function, and clinical outcome. It typically occurs along a continuum of inadequate intake and/or increased requirements. Impaired absorption, altered transport, and altered nutrient utilization deprive cells and tissues of proper nourishment whereas inflammatory, hypermetabolic, and/or hypercatabolic conditions increase nutritional demands. Inflammation is increasingly recognized as an important underlying risk factor for malnutrition, and may impair response to nutrition intervention. Malnutrition has variously been reported to affect one-fourth of community-dwelling elders, one-half of hospitalized elderly, and up to two-thirds of the residents of long-term chronic-care facilities, estimates varying depending on criteria used to identify its occurrence. Malnutrition is a major contributor to loss of quality of life and increased morbidity and mortality. It is notably associated with decreased immune competency, a factor that increases the risk for infections, pneumonia, and pressure ulcers, and which delays wound healing and recovery from surgery. Malnourished individuals also tend to lose muscle mass and strength resulting in increased fatigability, impaired functionality, and increased risk of falls and fractures. As a consequence, malnutrition increases the frequency of hospitalization and length of hospital stay, and leads to higher healthcare costs. Malnutrition can have many etiologies. Among them are physical factors such as poor dental and oral health, loss of appetite, dysphagia, and decreased physical functioning, all of which can reduce food intake. Psychological factors, notably depression, anxiety, cognitive impairment and dementia (e.g., Alzheimer’s disease), are also associated with malnutrition. Medical conditions such as gastrointestinal disease, malabsorption syndromes, acute and chronic infection, hypermetabolic and hypercatabolic conditions, increased energy requirements, and micronutrient deficiencies will lead to malnutrition if left unattended for prolonged periods of time. Medications can cause gastrointestinal symptoms, malabsorption of nutrients, and affect appetite. Individuals who take multiple medications (polypharmacy) are at increased risk of drug-induced malnutrition. For community-living older individuals, socio-economic factors such as financial hardship, social isolation, difficulties with shopping, meal preparation and self-feeding, may add to the risk of malnutrition. Likewise, malnutrition can be compounded in the institutional context by factors such as the lack of ability to detect clinical signs of malnutrition, poor-quality foods, diets that are

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too restrictive or that do not meet patients’ nutritional needs, lack of assistance during meals, and poor feeding environment (Rémond et al., 2015). A summary of the etiologies and consequences of malnutrition in old adults appear in Table 1. Finally, in addition to traditional malnutrition observed in frail, ill older adults, a new nutrition paradox of increasing concern is the presence of malnutrition and nutrient deficiencies in overweight and obese older adults. Long-term consumption of excessive energy and poor-nutrient diets coupled with age-related decreases in physical activity can lead to excess weight. It is not uncommon to now encounter overfat individuals with reduced muscle mass, functional limitations, and multiple nutrient deficiencies. In light of their physical and nutritional profiles, these individuals are at additional risks of developing metabolic disorders and chronic conditions.

Nutritional Assessment The physical and metabolic changes that accompany the senescent processes confound the assessment of nutritional status of the elderly when standards derived from younger adults are employed. With aging, height decreases as result of vertebral compression. Measuring height accurately can be difficult in patients who cannot stand up straight, who are bedridden, or present spinal deformation as a result of severe osteoporosis. In such cases, two proxy measurements—arm span and knee height—can provide an estimate for height. The senescent shortening of stature also has implications for the calculation of Quetlet’s body mass index (BMI) (weight in kilograms divided by the square of height in meters) in individuals and in groups of elderly individuals. By international BMI standards, underweight begins with a BMI equal to or 30 kg m–2. However, emerging evidence suggest that the associations between BMI thresholds, health and mortality risk differ in the elderly. When investigated in community-dwelling older adults, BMI between 24.0 and 30.9 kg m2 have been associated with greater survival. There is also good evidence that BMI values below 21–22 kg m2 are associated with significant adverse events and increased mortality, BMIs below 18.5 kg m2 exacerbating the risks. Thus, with increasing age, the association between BMI and survival follows a U-shape curve, BMI in the overweight range being potentially protective.

Table 1

Etiologies and consequences of malnutrition in old adults

Etiologies Physical factors Poor dental and oral health # Appetite Dysphagia Sarcopenia and physical dysfunction # Food intake Psychological factors Depression Anxiety Cognitive impairment Dementia Medical factors Gastro intestinal disease Malabsorption syndromes Acute and chronic infection Hypermetabolic conditions Medication/polypharmacy Compounding factors Community-living Financial hardship Social isolation Difficulty shopping and preparing meals Difficulty self-feeding Clinical setting Inability to detect clinical signs of malnutrition Poor-quality foods Restrictive diets Diets that do not meet patient’s nutritional needs Lack of assistance during meals Poor feeding environment

Consequences # Immune competency " Risk for infections " Risk for pneumonia " Incidence of pressure ulcers Delayed wound healing Delayed recovery from surgery # Muscle mass and strength " Fatigability # Functional status " Risk of falls " Risk of fractures " Morbidity " Hospital admission and length of stay " Healthcare costs # Quality of life " Mortality

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Assessment of body compartments based on anthropometric measures also presents some challenges in the elderly. Caliper assessment of skinfolds are confounded both in their measurement and their interpretation in older individuals. Laxity of skin makes the dermis more compressible between the jaws of the calipers, producing a falsely low value. Moreover, because fat deposition shifts from the subcutaneous to the intramuscular compartment (i.e., intramuscular marbling), the relation of skinfolds to total body fat is distorted. A global estimation of total body water, from which fat mass and fat-free mass can be derived, can be assessed by bioelectric impedance analysis, a safe, rapid non-invasive technique. However, accurate results with this technique require the person to be well hydrated, a condition not always met in older adults. Objective measures of fat mass and fat free mass can also be obtained with techniques such as dual energy X-ray absorptiometry, computed tomography, and magnetic resonance imaging, although their sophistication and costs limit their use in the usual practice. For decades, acute phase proteins such as serum albumin and prealbumin have been considered to be nutritional indicators. However, it is now increasingly recognized that these proteins more accurately reflect the severity of the inflammatory response rather than poor nutrition status. Albumin does not consistently or predictably change with weight loss, and does not typically respond to feeding interventions in the context of active inflammation. For these reasons, use of these proteins in the nutritional assessment process is now viewed as limited, although they are useful as indicators of disease severity and outcome.

Nutritional Screening Nutrition screening is performed to identify individuals at nutritional risk. It is an important step as those identified as at risk need to undergo in depth nutritional assessment. The Mini Nutrition Assessment is one of the most frequently used tools to assess malnutrition in adults age 65 and older. It is available in two forms, a screening Short Form (MNA-SF), and a full assessment version (MNA-Long Form). The validated MNA-SF comprises six questions relating to dietary intake and health status, and includes a measure of BMI or a calf circumference, when a BMI is not possible. The MNA-SF has undergone extensive validation and is one of the most widely used screening method to identify malnutrition in non-institutionalized older adults and in short-term stay units. The full assessment version (MNA-Long Form), consists of 18 questions totaling 30 points from which a grading of the nutritional status can be obtained. This form, as well as interactive versions of the MNA-SF, are available in multiple languages at the official website (https://www.mna-elderly.com/).

Diagnosis of Malnutrition There is currently no single, universally accepted approach to the diagnosis of malnutrition in old adults. However, in recent years, leading international clinical nutrition societies have carried out initiatives to provide a consensus-based set of criteria for the diagnosis of malnutrition. Various etiologic and phenotypic criteria have been proposed, and continue to be assessed for their clinical and prognostic usefulness (White et al., 2012; Cederholm et al., 2015). However, nonvolitional weight loss, low body mass index, reduced muscle mass and subcutaneous fat, and diminished functional status have consistently been viewed as significant manifestations of malnutrition. With respect to weight loss, the Academy of Nutrition and Dietetics and the American Society for Parenteral and Enteral Nutrition proposed different interpretations in 2012, depending on whether malnutrition occurs in the context of acute illness or injury, chronic illness, or social or environmental circumstances, weight loss cut-offs being proposed for moderate and severe malnutrition (White et al., 2012). More recently, the European Society of Clinical Nutrition and Metabolism proposed the following criteria: >5% weight loss over the last 3 months, and >10% weight indefinite of time. Considering that malnutrition can occur at any BMI and in light of the high prevalence of increased BMI in the elderly in certain parts of the world, the use of low BMI as a phenotypic criterion for malnutrition diagnosis has not met consensual agreement. Nonetheless, BMI < 20 kg m2 if 70 years. By definition, DRIs are reference values that are quantitative estimates of nutrient intakes to be used for planning and assessing diets for healthy people. Furthermore, evidence has been growing suggesting that specific food patterns and global diet quality can benefit the health and quality of life of older adults.

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Table 2 Commonly used criteria for the diagnosis of malnutrition in old adults

• • • • •

Weight loss Low BMI Reduced muscle mass Reduced subcutaneous fat Reduced functional status

Nutrient Requirements and Recommendations in Later Life Considering that the DRIs are aimed at healthy individuals and given the limited evidence regarding specific requirements during aging, nutrient recommendations for older adults are the same as for adults ages 19–50 years, with the exception of vitamins D, B6, B12, calcium, and iron. Dietary recommended intakes are not different for protein in older adults (0.8 g protein/kg of body weight) although some suggest that intakes up to 1.2 g protein/kg could protect against age-related sarcopenia. At a minimum, current DRI should be met with high quality meat or vegetable protein with daily proteins distributed across meals, as evenly as possible. Requirements for vitamin D, a nutrient with key roles in the maintenance of calcium and phosphate balance and bone mineralization, increases to 800 IU per day (20 mg/d) in men and women age > 70 years. This is in part based on the fact that exposure to sunlight tends to decline with age, vitamin D synthesis at the level of the skin decreases, as does its conversion to the active hormone form in the kidneys. Recommended intakes for vitamin B6, a coenzyme involved in the metabolism of amino acids, glycogen, and sphingoid bases are slightly increased at age  51 years (men: 1.7 mg/d; women: 1.5 mg/d), as higher intakes are required to maintain normal plasma levels. Recommendations for vitamin B12, a nutrient essential for normal blood formation and neurological function are not different in older men and women (i.e., 2.4 mg/d). However, given that older individuals may malabsorb food-bound B12 due to a decline in gastric acid (i.e., atrophic gastritis), it is recommended that adults age  51 years consume foods fortified with the vitamin or rely on vitamin B12 supplements. As mentioned previously, calcium is less efficiently absorbed during aging, recommended intakes are hence increased to 1200 mg/d in women  51 years, and in men >70 years. Finally, considering that monthly menses stop at menopause, recommendations for iron decrease to 8 mg/d in women  51 years. Quantitative DRI values for total daily calories and macro- and micronutrients for men and women 50–70 years and >70 years, are available at the National Academies of Science, Engineering and Medicine website (http://nationalacademies.org/hmd/Activities/Nutrition/SummaryDRIs/DRI-Tables.aspx).

Food Selection Patterns for the Elderly As it is acknowledged that nutrients contained in foods interact with each other in complex ways and that dietary components are consumed in combination, there has been an increased interest in the role of dietary patterns and global diet as determinants of chronic diseases and ill health in old age. Epidemiological studies have provided evidence that older adults whose diets are rich in vegetables, fruit, whole grains, poultry, fish, and low-fat dairy products have superior nutritional status, more years of healthy life, and increased survival. Studies conducted with the Dietary Approaches to Stop Hypertension (DASH) and the Mediterranean diet, support these findings. The DASH diet which emphasizes high consumption of fruit, vegetables and whole grains, as well as foods low in saturated and trans-fats, sodium and sugar, while limiting red meat, has been shown to be protective against coronary and heart disease, type 2 diabetes, age-related cognitive decline, and all-cause mortality. Similarly, the Mediterranean diet which shares many of the characteristics of the DASH diet, has been found to protect against age-related decrease in muscle strength, osteoarthritis and hip fractures, frailty and dementia. The most recent Dietary Guideline for Americans, emphasizes the importance of integrating a healthy dietary pattern. Such pattern typically includes a variety of plant food sources, notably vegetables, fruits, whole grains, nuts, and legumes, and limit foods rich in saturated fats, trans fats, sodium, and added sugars. Food intake should aim to maintain calorie balance and sustain a healthy weight, and nutrient needs should be met primarily through consuming foods. Considering the reduced caloric needs of older adults, nutrient-dense foods and beverages should have priority. Finally, healthy dietary patterns should be accompanied by an active lifestyle (U.S. Department of Health and Human Services and U.S. Department of Agriculture, 2015).

References Cederholm T, Bosaeus I, Barazzoni R, Bauer J, Van Gossum A, et al. (2015) Diagnostic criteria for malnutrition—An ESPEN Consensus Statement. Clinical Nutrition 34: 335–340. Han A, Bokshan SL, Marcaccio SE, Mason DePasse J, and Daniels AH (2018) Diagnostic criteria and clinical outcomes in sarcopenia research: A literature review. Journal of Clinical Medicine 7: 70. Kershaw JC and Mattes RD (2018) Nutrition and taste and smell dysfunction. World Journal of Otorhinolaryngology-Head and Neck Surgery 4: 3–10. Khan SS, Singer BD, and Vaughan DE (2017) Molecular and physiological manifestations and measurement of aging in humans. Aging Cell 16: 624–633. Lamster IB, Asadourian L, Del Carmen T, and Friedman PK (2016) The aging mouth: Differentiating normal aging from disease. Periodontology 2000 72: 96–107. Landi F, Picca A, Calvani R, and Marzetti E (2017) Anorexia of aging assessment and management. Clinics in Geriatrics Medicine 33: 315–323.

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McGuigan FE, Bartosch P, and Åkesson KE (2017) Musculoskeletal health and frailty. Best Practice & Research Clinical Rhumatology 31: 145–159. Ortega O, Martín A, and Clavé P (2017) Diagnosis and management of oropharyngeal dysphagia among older persons, state of the art. Journal of the American Medical Directors Association 18: 576–582. Pisani P, Renna MD, Conversano F, Casciaro E, Di Paola M, et al. (2016) Major osteoporotic fragility fractures: Risk factor updates and societal impact. World Journal of Orthopedics 7: 171–181. Rémond D, Shahar DR, Gille D, Pinto P, Kachal J, et al. (2015) Understanding the gastrointestinal tract of the elderly to develop dietary solutions that prevent malnutrition. Oncotarget 6: 13858–13898. U.S. Department of Health and Human Services and U.S. Department of Agriculture (2015) 2015–2020 Dietary Guidelines for Americans. 8th ed. Available at https://health.gov/ dietaryguidelines/2015/guidelines/. Accessed December 13, 2018. White JV, Guenter P, Jensen G, Malone A, and Schofield M (2012) Consensus statement: Academy of Nutrition and Dietetics and American Society for Parenteral and Enteral Nutrition: Characteristics recommended for the identification and documentation of adult malnutrition (undernutrition). Journal of Parenteral and Enteral Nutrition 36: 275–283. World Health Organization (2018) Ageing and health. http://www.who.int/news-room/fact-sheets/detail/ageing-and-health. Accessed October 1, 2018.

Further Reading Mini Nutritional Assessment (2018) Nestle Nutrition Institute. Available at https://www.mna-elderly.com/. Accessed December 13, 2018. The National Academies of Sciences (2018) Engineering and Medicine. Dietary Reference Intakes Tables and Application. Available at http://nationalacademies.org/hmd/Activities/ Nutrition/SummaryDRIs/DRI-Tables.aspx Accessed December 14, 2018. Yannakoulia M, Mamalaki E, Anastasiou CA, Mourtzi N, Lambrinoudaki I, and Scarmeas N (2018) Eating habits and behaviors of older people: Where are we now and where should we go? Maturitas 114: 14–21.

Nutritional Assessment in Adults☆ Maria Rubino, Jennifer Jin, and Leah Gramlich, Division of Gastroenterology, Royal Alexandra Hospital, University of Alberta, Edmonton, AB, Canada © 2020 Elsevier Inc. All rights reserved.

Glossary

Bioelectrical impedance analysis (BIA) Measurement of body resistance and reactance by the use of a fixed high-frequency alternating current. Body mass index (BMI) The body weight in kilograms divided by the height expressed in meters squared (kg/m2). Nutrition Associated Complications (NAC) Disease complications that can be influenced by the nutritional status. Sarcopenia Loss of muscle mass and muscle strength. Subjective global assessment (SGA) A clinical tool that is used to evaluate a patient’s nutritional status.

Introduction Nutritional health is maintained by a state of equilibrium in which nutrient intake and requirements are balanced. Malnutrition occurs when this equilibrium is perturbed by nutrient intake (adjusted for pathologies affecting digestion and absorption) being less than nutrient requirements. The effect of the above processes are changes to the composition of the body and blood and these changes have traditionally been used to assess nutrition. Traditional nutritional science was first developed in the field of agriculture where the effect of nutrition was entirely judged by animal growth. It is therefore not surprising that nutritional assessment methods previously used were based on changes in body and blood composition. Questions pertaining to nutritional status are whether measurement of body composition and blood components can help predict outcomes and whether these measurements can be used to help devise treatments. To answer these questions, it is necessary to examine the effects of malnutrition and the ability of nutritional assessment techniques to predict outcomes related to malnutrition. Malnutrition leads to a succession of metabolic abnormalities, physiological changes, reduced organ and tissue function, and loss of body mass. Concurrent stress such as trauma, sepsis, inflammation, and burns accelerates the loss of tissue mass and function. Ultimately, critical loss of body mass and function occurs, resulting in nutrition-associated complications (NAC) and even death. The assessment of the nutritional status, to be of clinical importance, must be able to predict if the individual is at increased risk for morbidity and mortality in the absence of nutritional intervention. In short, can it predict the occurrence of NAC and thus predict outcome? Disease and nutrition interact in such a way that the disease itself may cause secondary malnutrition just as the presence of malnutrition may adversely influence the underlying disease. Patient outcomes are multifactorial and attempting to formulate the influence of malnutrition based on outcomes of single parameters or simple models fails to take this into consideration. Measurements of body composition and blood components are a snapshot in time and cannot predict the direction of change. Three major factors alter the direction of malnutrition: nutrient intake, nutrient absorption and utilization, and disease induced metabolic stress. The presence or absence of these factors ultimately determines whether critical malnutrition will occur.

Traditional Nutritional Assessment Indices Nutritional status has been traditionally defined by body composition, plasma protein concentrations and immune competence. Assessment of nutritional status based on body composition involves detecting the loss (or gain) of body components relative to previous measurements and comparing the values to population standards. The reproducibility and error in the measurements themselves affect the former, and the latter is dependent on the normal range of values. For instance a person who starts off at the upper end of the normal range may be still be classified as “normal” despite considerable decrease in the measured value. Therefore, it is possible for a person to be in a negative nutritional state for a long time before anthropometric measurements fall below normal.

☆

Change History: November 2018. M Rubino, J Jin, and L Gramlich updated the text and references to the entire article.

This is an update of K.N. Jeejeebhoy, Nutritional Assessment, In Encyclopedia of Gastroenterology, edited by Leonard R. Johnson, Elsevier, New York, 2004, Pages 759–766.

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Body Weight and Weight Loss Body weight is a simple measure of total body components and is compared to an “ideal” or desirable weight. This comparison can be made by using formulas or tables, or calculating a body mass index (BMI). Body mass index is calculated as follows: weight in kilograms divided by height in meters squared. Although BMI can be misleading as patients can be at risk at normal and increased BMI ranges, a BMI below 14–15 supports malnutrition and is associated with significant mortality. Involuntary weight loss is an important factor in nutrition assessment. In hospitalized patients obtaining a body weight can be challenging because of perturbed hydration status. For example, patients with liver disease, heart failure, renal failure, can all have changes in total body water. Changes in volume status can be mistaken as a change in nutrition status.

Anthropometry Triceps and subscapular skinfold thicknesses provide an index of body fat and midarm muscle circumference provides a measure of muscle mass. Although these measurements seem to be useful in population studies, their reliability in individual patients is less clear. The most commonly used standards for triceps skinfold thickness and midarm muscle circumference are not universally applicable in patients because they do not correct for age, ethnicity, hydration status, and physical activity. Several studies have demonstrated that 20%–30% of healthy control subjects would be considered malnourished based on these standards. They also do not reflect muscle and fat mass in sick patients, especially those in ICU, with liver disease, with renal disease, where edema makes assessing skin folds and arm circumference difficult.

Creatinine–Height Index The excretion of creatinine in the urine is related to muscle mass. Normalized for height, the 24 h creatinine excretion is an index of muscle mass. In theory, it is a good and simple way of assessing the lean body mass. A value of 60%–80% is seen in mild malnutrition and 40% is seen in severe malnutrition (Bharadwaj et al., 2016). However, it is dependent on complete 24 h urine collections, and urinary losses or oliguria may result in an inappropriate diagnosis of malnutrition. Patients on diuretics such as those with cardiac and liver failure and those with renal disease are especially likely to have low levels of excretion of creatinine.

Serum Albumin Serum albumin is one of the most extensively studied proteins. Several studies have demonstrated that a low serum albumin concentration correlates with an increased incidence of medical complications. Disease, rather than nutrition, in adults mainly influences serum albumin. The concentration of serum albumin represents the net sum of albumin synthesis, degradation, losses from the body, exchange between intra- and extravascular albumin compartments, and the volume in which albumin is distributed. Albumin is highly water soluble and resides in the extravascular space. The half-life is 14–20 days. The total body pool of albumin in a normal 70 kg man is  280 g (3.5–5.3 g/kg). Approximately one-third of the total pool constitutes the intravascular compartment and two-thirds constitutes the extravascular compartment. The concentration of albumin in blood is greater than that in lymph or other extracellular fluids and the ratio of intravascular to extravascular albumin concentration varies from tissue to tissue. Each day,  5% of the total albumin pool is degraded and replaced by newly synthesized albumin. Protein–calorie malnutrition causes a decrease in the rate of albumin synthesis because adequate nutrient intake is important for polysomal aggregation and maintenance of cellular RNA levels needed for protein synthesis. Within 24 h of fasting, the rate of albumin synthesis decreases markedly. However, a short-term reduction in albumin synthesis has little impact on albumin levels because of a compensatory decrease in albumin degradation and a transfer of extravascular albumin to the intravascular compartment. Prolonged protein–calorie restriction, induced experimentally in human volunteers or observed clinically in patients with anorexia nervosa, causes marked reductions in body weight but little change in plasma albumin concentration. A protein-deficient diet with adequate calories in elderly persons causes a decrease in lean body mass and muscle function without a change in plasma albumin concentration. Hospitalized patients may have low levels of plasma albumin for several reasons. Inflammatory disorders cause a decrease in albumin synthesis, an increase in albumin degradation, and an increase in albumin transcapillary losses. Gastrointestinal diseases and some cardiac diseases increase albumin losses through the gut and renal diseases may cause considerable albuminuria. Wounds, burns, and peritonitis cause major losses from the injured surface and in certain circumstances cause an increase in albumin losses through the gut, kidneys, or damaged tissues. Also, because the exchange between intra- and extravascular albumin is so large, even small changes in the percentage of exchange can cause significant changes in plasma albumin levels.

Prealbumin Prealbumin is a transport protein for thyroid hormones and exists in the circulation as a retinol- binding–prealbumin complex. The turnover rate of this protein is rapid, with a half-life of 2–3 days. It is synthesized by the liver and is catabolized partly in the kidneys. Protein-energy malnutrition reduces the levels of prealbumin and refeeding restores levels. Although prealbumin is responsive to nutritional changes, levels decrease in infection, inflammation, and hyperthyroidism; renal failure increases levels and liver failure may cause decreased levels. As such, it is unreliable as an index of nutritional status.

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Measurement of Body Composition The body consists of compartments or components. There are over 35 well-recognized components and these are organized into five levels of increasing complexity: atomic, molecular, cellular, tissue-system, and whole body. In healthy weight-stable subjects, there are relatively constant relationships among these components, which are correlated with one another. Interest in these methods pertains to being able to estimate fat-free mass and its correlation to NAC.

Isotope Dilution Total body water, measured by isotope dilution, is usually the largest molecular-level component. Water maintains a relatively stable relationship to fat-free body mass and thus measured water isotope dilution volumes allow prediction of fat-free body mass and fat (i.e., body weight minus fat-free body mass). The relationship between total body water and other body composition components may change with disease and this should be considered when interpreting data from hospitalized or chronically ill patients.

Bioelectrical Impedance Analysis Bioelectrical impedance analysis (BIA) is a method of estimating body fluid volumes by measuring the resistance to a highfrequency, low-amplitude alternating electric current (50 kHz at 500 to 800 mA). Using BIA, the resistance (R) (resistant component of water and electrolytes in the fluids and tissues) and the reactance (Xc) (tissue capacitance) are obtained (Lukaski et al., 2017). These variables are then applied to a mathematical equation which calculate phase angle (PA) (Lukaski et al., 2017). Phase angle has been used as a screening tool for malnutrition and to predict nutrition associated complications. It has been studied in many different populations including ICU, cancer, cirrhosis, COPD, and geriatrics. Overall, a low phase angle predicts poor functional status, muscle wasting and increased mortality (Lukaski et al., 2017). It has even been suggested that phase angle can be used to follow and assess the effects of nutritional intervention. BIA requires specialized equipment and training but is noninvasive and quick.

Dual-Energy X-Ray Absorptiometry Dual-energy X-ray absorptiometry (DXA) is a method developed originally for the measurement of bone density and mass. DXA can also be used to measure soft tissue composition. DXA can measure total and regional fat, bone mineral, and bone mineral-free lean components. The method is based on the attenuation characteristics of tissues exposed to X rays at two peak energies. Mathematical algorithms allow calculation of body components using various physical and biological models. The method provides an accurate measurement of bone mineral mass and also of soft tissue mass.

Computerized Axial Tomography and Magnetic Resonance Imaging Computed tomography and magnetic resonance measure components at the tissue-system level of body composition, including skeletal muscle, adipose tissue, visceral organs, and brain. Investigators have looked at specific areas to assess body composition. Using cross-sectional CT images at L3 and regression models, body composition (fat-free mass and skeletal muscle) can be estimated (Shen et al., 2004). Multiple investigators have looked at L3 skeletal muscle index (SMI) in various patient populations and it has been found that low SMI at L3 predicts poor outcomes in cirrhosis, post aortic valve replacement and ICU populations. Building upon this, Prado et al., established gender specific L3 SMI (SM area adjusted for height) cut-off values (males 52.4 cm2/ m2; females 38.5 cm2/m2) to identify sarcopenia in obese cancer patients (Prado et al., 2008). In this study they found that the sarcopenic obese patients had poorer functional status than those who were not sarcopenic (Prado et al., 2008). In addition, sarcopenia was associated with mortality in this population (Prado et al., 2008). A current area of interest is the use of SMI to predict chemotherapy dosing and toxicity. Given the ability of magnetic resonance to accurately evaluate body composition, there has been interest in using it to evaluate adipose tissue and skeletal muscle in a wide variety of populations (Prado and Heymsfield, 2014). Magnetic resonance protocols can either include whole body or regional body. In addition, MRI can evaluated the quantity of adipose tissue and of fibrous connective tissue within a muscle and using these parameters the quality of the muscle can be determined (Zoico et al., 2013). It has been suggested that muscle adiposity and fibrosis maybe be useful to diagnose sarcopenia (Zoico et al., 2013). Despite the utility of CT and MRI in assessing body composition and the relative ease of access to these imaging techniques, their use is often limited to clinical studies. Possible factors contributing to this include the need for specialized software and the need for additional time for the analysis. With CT there is also radiation involved; in research studies, the CT images are often taken from stored CT images already performed for other diagnostic purposes, which represents an opportunistic use of these images.

Ultrasound Measurements of Quadriceps Muscle Layer Thickness There has been growing interest in finding a noninvasive bedside tool that is relatively simple to operate to help assess nutritional status in patients, particularly in the critically ill (Paris et al., 2017). Ultrasound is mobile and is relatively easy to use. The

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quadriceps are the muscle of choice as they are easy to access and identify, and have been shown to related to functional outcomes (Parry et al., 2015). The VALIDUM study investigated the use of ultrasound measured quadriceps muscle layer thickness (QMLT) in identifying low muscle mass in the critically ill (Paris et al., 2017). They defined QMLT as the area between the femoral bone and rectus femoris and measured it at two predetermined points on each quadricep (Paris et al., 2017). Although they found a correlation between QMLT and low muscle mass it was not robust enough to be used alone (Paris et al., 2017).

Functional Tests of Malnutrition It was shown that muscle function and mitochondrial function are very sensitive to nutritional manipulations and are influenced before changes in body composition are seen. Hence, measurement of muscle function has been shown to predict malnutrition. Although, many such tests exist (hip flexion), hand-grip strength (HGS) is most widely used as it is a quick, simple and reliable test. HGS has been shown to accurately identify malnourished patients and correlate with SGA status (Flood et al., 2014). It has also been shown that it can identify change in nutritional status. In the elderly, a hand-grip strength of 39% of adults (1.9 billion globally) were overweight and 13% were obese. Over 340 million children and adolescents (age 5–19) were overweight and 41 million of children (age < 5 years old) were overweight or obese (World Health Organization, n.d.; World Obesity Federation, n.d.).

Definition of Overweight and Obesity According to WHO definition, the definition of each age group is different:

• • •

Adults: a. Overweight is a BMI
25 kg/m2 b. Obesity is a BMI
30 kg/m2 Children and Adolescence (age 5–19 years old): a. Overweight is weight-for-height >1 standard deviations (S.D.) above WHO Growth Reference median b. Obesity is weight-for-height >2 S.D. above the WHO Growth Reference median Children (age 2 standard deviations (S.D.) above WHO Growth Reference median b. Obesity is weight-for-height >3 S.D. above the WHO Growth Reference median

Mechanisms of Overweight and Obesity Brain-gut interaction and brain-obesogenic environment interaction caused obesity have recently be elucidated. It is common to know weight gain is caused by energy imbalance. Numerous polymorphic gene products may also be a cause of obesity. Li and colleagues reported that 12 obesity-susceptible loci have been identified. Variants had a cumulative effect on obesity measures, with each additional allele associated with an increase in weight of 444 g and increased risk of obesity of 10.8%. The genetics appear to determine who will become obese, and the environment appears to determine the extent of obesity. As for hormones, there are simply two different hormone categories regulate precisely in our body to make the set-point of our body fat storage, the anorexigenic hormone and the orexigenic hormone. Among them, the leptin and ghrelin are crucial for metabolic regulation and energy homeostasis. Diet-induced obesity (DIO) will attribute the leptin and ghrelin resistance which altered their original functions and then have impacts on promoting adiposity and further cause metabolic disorders (Zigman et al., 2016). (1) Leptin: Leptin is a 16 kDa cytokine that is produced predominantly by adipose tissue: it is released into the bloodstream and circulates in proportion to body fat mass. Obesity is related with leptin resistance. Leptin resistance is associated with elevated circulating levels of leptin, as well as with the inability of exogenous leptin to decrease food intake and body weight. Leptin circulates as either a free protein or in an inactive form that is bound to the circulating form of the receptor (LepRe). Interestingly, in contrast to lean individuals in whom up to 65% of circulating leptin is bound to LepRe, obese population predominantly have the active free form of circulating leptin (85% of total leptin). Consequently, individuals with obesity might have chronically elevated levels of active free leptin in the brain, which desensitize LepRb and increase leptin resistance (Cui et al., 2017).

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(2) Ghrelin: Ghrelin was identified in 1999 as the endogenous ligand of the growth hormone secretagogue receptor (GHSR) from extracts of rat stomach. Ghrelin has many associations with food intake, adiposity and metabolism regulation (Nakazato et al., 2001; Muller et al., 2015). Ghrelin has also been considered as a target to treat obesity and the metabolic disorders. Ghrelin ultimately increases the potential firing of AgRP-expressing and NPY-expressing neurons and implies its function in rise of orexigenic AgRP and NPY neuropeptides in the ARC (López et al., 2008) and enhances the orexigenic effect of the body. (3) Glucagon-like peptide-1 (GLP-1): GLP-1 has effects on glucose adjustment, cardiovascular, neurologic, and renal benefits, along with changes in taste perception. GLP-1 is also involved in gut-brain axis for control of weight. Secretion and function of GLP-1 is impeded in obese populations (Ryan and Acosta, 2015). (4) Peptide Tyrosine-Tyrosine (PYY): PYY regulates food intake in lean and obese persons and has function of increasing energy expenditure. The exact mechanism of its anorectic effects are unclear. Obese populations have been found to have lower PYY level. Low concentrations are observed in those with obesity (Simpson et al., 2012). (5) Cholecystokinin (CCK): CCK works peripherally only because of nonpenetration of blood brain barrier. CCK induces hunger suppression and decrease food intake by working on vagus nerve. The exact mechanism is still unclear and need further investigation. CCK also has synergic effects while working with leptin together (Simpson et al., 2012). (6) Multi-mediators: Obesity involves many mechanisms and a whole aspect consideration for approaching a obese patient is very important. According to Obesity Systems Map introduced by United Kingdom, multimediators should be considered for the possible pathophysiologic mechanisms of obesity (Ziauddeen et al., 2012).

Common Health Consequences of Overweight and Obesity Patients with obesity are at increased risk of morbidity from dyslipidemia, T2D, hypertension, coronary heart disease, stroke, gallbladder disease, respiratory problems, sleep apnea, osteoarthritis, and some cancers (Jensen et al., 2014). A pooled analysis of 20 studies reported that heart disease was the most common underlying cause of death in patients with class III obesity (BMI 40.0–59.9 kg/m2), followed by cancer and diabetes. There was a 2.57-fold increased risk of death in people with a BMI of 40.0–59.9 kg/m2 versus 18.5–24.9 kg/m2. In addition, people with a BMI of 40–59 kg/m2 live 6.5–13.7 years less than those with a BMI of 18.5–24.9 kg/m2. Childhood obesity is associated with a higher chance of obesity, premature death and disability in adulthood. But in addition to increased future risks, obese children experience breathing difficulties, increased risk of fractures, hypertension, early markers of cardiovascular disease, insulin resistance and psychological effects.

Bariatric Surgery Bariatric surgery is now accepted to be the well-established procedure for treating severe obesity and its associated comorbidities. In 1954, Kremen and Linner introduced jejunoileal bypass. Modifications in the original procedures and the development of new techniques have led to three basic concepts for bariatric surgery, as follows: (1) gastric restriction such as vertical-banded gastroplasty and adjustable gastric banding, (2) gastric restriction with mild malabsorption like Roux-en-Y gastric bypass and (3) a combination of mild gastric restriction and malabsorption as duodenal switch. Recent 20 years, the evolution of bariatric surgeries has progressed over time in an attempt to constantly improve outcomes while minimizing adverse effects at same time. Recent studies of the biochemical mechanism of bariatric procedures has lead us to understand how anatomical changes in the digestive tract result in hormonal modifications of decreasing ghrelin with an exaggerated incretin effect. This drives weight loss and improved glucose metabolism, that also make surgeons to start to implicate bariatric surgery for treating type 2 diabetes.

Indications and Contraindications for Bariatric Surgery Indications 2 2 > Body mass index (BMI) > ¼ 35 kg/m with comorbidities or BMI ¼ 40 kg/m Class III obese BMI > 40 kg/m2 with DM BMI > 37.5 kg/m2 with DM for Asians

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Indications Class II Obese

Class I Obese

BMI 35–39.9 kg/m2 with DM BMI 32.5–37.4 kg/m2 with DM for Asians Surgery is recommended if poor glycemic control Surgery may be considered if adequate glycemic control BMI 30–34.9 kg/m2 Type II D.M with poor glycemic control BMI 27.5–32.4 kg/m2 Type II D.M with poor glycemic control for Asians

Contraindications Psychiatric illness: active psychosis, purgative behaviors, untreated or undertreated psychopathology and medical nonadherence Drug abuse/alcohol abuse

Bariatric Procedures Laparoscopic Adjustable Gastric Banding (LAGB) Introduction Laparoscopic adjustable gastric banding (LAGB) has been proved to be an effective option for treatment of severely obese patients. As a purely restrictive modality, the band effectively restricts passage of food into the distal stomach, resulting in early satiety and slowed gastric emptying. When appropriately adjusted and with adequate restriction, the patient should feel diminished hunger, early satiety with small meals, and minimal dysphagia with certain foods, such as dry meats, fibrous vegetables, or bread.

Adjustable gastric banding.

Surgical technique The device consists of an adjustable inflatable band placed around the proximal part of the stomach. This creates a small gastric pouch (approximately 15 mL in volume) and a small stoma. Band restriction is adjustable by adding or removing saline from the inflatable band by a reservoir system of saline attached to the band and accessible through a port, which is attached by a catheter to the band. The port is placed subcutaneously in the anterior abdominal wall after the band is secured around the stomach. Adjustment of the band through the access port is an essential part of laparoscopic adjustable gastric banding therapy. Appropriate adjustments, performed up to six times annually, are critical for successful outcomes.

Outcomes Excess weight loss (EWL) of adjustable gastric banding is reported raging from 40% to 60%. Weight loss is more gradual compared to other operations; 0.5–1 kg per week is a reasonable goal for many patients. Compared to conventional medical therapy, there is

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also a clear benefit to surgery in diabetic patients, with remission seen in 40%–73% (Dixon et al., 2008; Zhang et al., 2009). Improvements are seen in insulin sensitivity and pancreatic beta cell function. Hypertension, dyslipidemia, and other components of metabolic syndrome would improve after even modest weight loss with LAGB. Obstructive sleep apnea and other disturbed sleep conditions similarly get better. Using a modified obesity staging system to evaluate in severity stages of physical, psychological, socioeconomic, and functional disease, Neff and colleagues showed improvement in all scores in patients who underwent LAGB (Neff et al., 2014).

Complication In O’Brien’s 15-year follow-up series of 3227 patients showed that revisional surgery after laparoscopic adjustable gastric banding is an important issue. Band slippage, esophageal dilatation, band erosion, port and tubing complications, and failure of weight loss/ weight regain are all reasons for surgical revision.

Roux-en-Y Gastric Bypass (RYGB) Introduction Laparoscopic Roux-en-Y gastric bypass created a small pouch size along with bypassing 90% of stomach, duodenum and proximal jejunum, which is referred to foregut exclusion and the rapid transit of food reaching the distal part of small intestine modified hind-gut hormones. It basically alters the endogenous gut hormones response to a meal. GLP-1, PYY and Ghrelin have all been studied to their effect of RYGB. The food reaching the gastric and proximal small bowel mucosa induces a mechanical stretch (Zhang et al., 2009). After RYGB, bile progresses down the biliopancreatic limb without actually mixing with the food. Due to this the undiluted reabsorbed bile acids in the intestine may enhance stimulation of TGR5 receptors on L cells of the small intestine which in may facilitate the effects of bile acids on energy homeostasis through FGF19, which can lead to an increase in metabolic rate and a decrease in adiposity (MacDonald Jr et al., 1997).

Roux-en-Y gastric bypass.

Results

LRYGB has shown >60% EWL. The longest prospective data base of Swedish Obese Subjects shows EWL went to 67%. Studies at 3 years after LRYGB have established a 68.7% remission rate of type 2 diabetes mellitus. This is in proportion to weight loss. Rates of 80% partial remission of type 2 diabetes mellitus have also been quoted in different studies (Zhang et al., 2009). There is a 48% resolution of hypertension observed with LRYGB, along with a 61% decline in the hyperlipidemia/dyslipidemia. These results are comparable with medical management and even better. Another interesting observation was the decrease of gastroesophageal acid reflux (GERD) to about 56% (Higa et al., 2001).

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Complications Apart from the surgical complications like bleeding, leak, DVT, Ulcers, fistulae, herniation, obstruction and structuring the patient may develop the following medical problems Vitamin Deficiencies: The most commonly diagnosed vitamin deficiencies include Vit B12 (37%–50%), Iron (47%–66%), folic acid (15%–38%), vitamin D (20%–51%) and calcium at 10%. There may be up to 20% preexisting iron deficiency prior to procedure. Though the effect of vitamin B12 maybe late to manifest, however it is prudent to supplement the diet with the requisite recommended dose along with vitamin supplements. The best way is to properly educate the patient and utilize the services of a nutritionist for the same. There may be the presence of dumping syndrome in almost 18%–20% of the patients after a Roux En Y gastric bypass. This is due to the fact that there is rapid emptying of the stomach contents into jejunum. As a result of it a hyperosmolar solution in the jejunum there is a feeling of diaphoresis dizziness and flushing followed by a feeling of hypoglycemia due to the large amount of insulin release. These are known as early and late dumping syndromes. Management revolves around division of food into small portions and frequent meals. Management should be done using a multidisciplinary team approach. Protein malnutrition is extremely rare and maybe caused after surgery when feeding is resumed. Refeeding syndrome can result in an event of cardiac failure 72 h after the procedure due to hypophosphatemia. Thiamine administration helps prevent this kind of complication (Podnos et al., 2003). Sometimes due to the overhanging roux limb tip patient may experience persistent nausea and post prandial epigastric pain which gets better after vomiting. This is referred to as the candy cane syndrome. It may require endoscopy to exclude other causes and eventually may require revisional surgery.

Sleeve Gastrectomy (SG) Introduction Sleeve gastrectomy started initially as a part of BPD/DS. The first open sleeve gastrectomy was done by Doug Hess, in Ohio in 1988. This was a part of the duodenal switch procedure. In 1999 the first laparoscopic approach was attempted by Ganger and colleagues for a duodenal switch (Hess and Hess, 1998). Ganger decided to break down the large operation into two steps. First doing a sleeve and later on completing the procedure by a duodenal switch. The initial weight loss by sleeve gastrectomy alone was enough to justify the sleeve gastrectomy procedure as a stand-alone procedure and thus bariatrics was ushered into the era of sleeve gastrectomy, so much so that sleeve gastrectomy has bypassed all other procedures as the most commonly performed procedure due to its excellent results and ease of performance. The first laparoscopic sleeve gastrectomy was thus performed in the year 2000 by McMahon in Leeds.

Sleeve gastrectomy.

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Mechanism In order to understand the mechanism of how sleeve gastrectomy results in a lowered intake, one needs to understand the neuro hormonal regulation balance. The constant interplay between different visceral organs and regulatory centers of brain has shown to activate complex neural networks along with reward center stimulation. These changes are associated with a reduction in subjective appetite, and this highlights the importance of deciphering how sleeve gastrectomy alters the communication pathways of the enter encephalic endocrine axis. This axis is believed to be at the core of the physiologic regulation of human appetite, the process of nutrient intake, energy homeostasis, and human metabolism. The group of hormones involved include Ghrelin, Neuropeptide and peptide YY. Post prandial and fasting Ghrelin levels are reduced resulting in decreased appetite. This influences the decrease in appetite and increases gastric emptying and intestinal motility. All this effect the circulating levels of gut hormones including Peptide YY and GLP 1 (Ionut and Bergman, 2011).

Results Short Term Weight loss: The excess body weight loss at 1–2 years after sleeve gastrectomy can vary from 47% to 76%. In a review analysis it was revealed (24 studies with 1749 patients) that excess weight loss of 60.7% with follow up period from 3 to 36 months. According to a report published by the American College of surgeons for LSG the average reduction in BMI is 11.87 kg/m2 at 1 year. Long term weight loss: The studies warranting 5 year or more follow up period constitute long term follow up. There is an EWL of 86% in several of the studies. In a recent review of several studies it was showed that LSG was associated with a 54% excess weight loss at 8 years. These results may have a conflict due to different procedures and bougie sizes used by different surgeons. However, this goes on to establish that LSG has acceptable long-term results. Diabetes Remission: Laparoscopic sleeve gastrectomy (LSG) has shown complete remission rates of 56%–80% in different studies ranging from few months to 3 years for patients with type 2 diabetes mellitus. Most studies have concluded that greater the weight loss greater is the diabetes remission rate. The rate of partial remission is 40–55% from 1 to 5 years. However, the results are dependent on the history in years of diabetes and total excess weight loss (Hoogerboord et al., 2014). Comorbidity Resolution: LSG has been effective at improving dyslipidemia, hypertension and sleep apnoea in most of the patients. Results have also shown positive effect on chronic kidney disease as well. The effect on dyslipidemia and hypertension is almost 90%–95% improvement as quoted in various studies. Studies observing sleep apnea have shown a remission of 70%–75%. Thus, laparoscopic sleeve gastrectomy has a better impact on quality of life along with comorbidity resolution. Complications Nutritional: Laparoscopic Sleeve Gastrectomy is associated with a few nutritional deficiencies. The need to be supplementing the diet with vitamin supplements is multifold. The major vitamin deficiencies expected with LSG include vitamin B12 at 3%, vitamin D (23%), folate (3%), iron (3%) and zinc (14%). Micronutrient deficiency is very less prevalent. There is need to supplement the food rich in vitamins as well as incorporate vitamin supplements in the diet plan as well. With proper diet guidance the deficiencies can be overcome and the patient be toned to have a normal lifestyle (Emile et al., 2017). Gastro esophageal Reflux Disease: The prevalence of GERD in patients after LSG has been attributed to be about 40%–47% across different studies. The treatment revolves around prescription of Proton pump inhibitors. In patients with a persistent GERD intractable to PPIs the need for an endoscopy arises. There are several causes of GERD and the presence of tube migration need to be ruled out as well by getting a CT scan done in patients refractory to medical management. After LSG there have been incidences of leak, bleeding, herniation and late stenosis. However, the management entails around keeping a close look at the patient in the post-operative phase. It has generally been accepted that tachycardia in a post-operative patient is a sign of leak and needs evaluation preferably by CT scan. It is always prudent to involve the surgeon in case of any unexplained outcome. There is a 70% of excess weight loss which can be maintained for >20 years. It also has profound effect on long term diabetic remission. Nearly all patients (97%) with diabetes was able to maintain a normal serum glucose level at 10 years after surgery. Similar rate of durable resolution of comorbidities was observed in hypertriglyceridemia, hypercholesterolemia and arterial hypertension in the same report. Being a strong malabsorptive procedure, BPD carries specific complications like anemia, bone demineralization, vitamin (A D E K & B12) deficiency and protein malnutrition. Protein malnutrition is the most severe complication of BPD. In standard BPD nowadays, incidence of PM is 3% with 1% being recurrent cases. Incidence of marginal ulcer varies from 3% to 15% in the literature. Most can be treated with medication. Because of these complications, eligible patients should have a life-long commitment to taking supplements (iron, calcium multivitamins) and follow up. Laparoscopic standard BPD was reported by Scopinaro and colleagues in 2002 with similar short term weight loss results compared with open manner.

Biliopancreatic Diversion with Duodenal Switch (BPD/DS) In late 1990s, Douglas Hess and Picard Marceau independently reported a hybrid procedure combining sleeve gastrectomy with BPD for the treatment of morbid obesity. Greater curve of stomach was resected and duodenum was divided a few centimeters distal to pylorus. Duodenoileal anastomosis is constructed to divert food into alimentary limb. By preserving the pylorus, there is less dumping syndrome and the incidence of marginal ulcer was reported to be 0.3%. Duodenal switch is effective in maintaining long term weight loss. Eighty-two percent of patients was reported to have >50% loss of initial excess weight in Marceau’s long-term (15 years) series. Hess reported an average excess weight loss of 75% at 10 years after operation. Both authors reported good control of metabolic comorbidities in their series. There was a decrease in the prevalence of hyperglycemia by 85%, hypertriglyceridemia by 65%, and high cardiac risk index by 86% in Maceau’s series (Shoar et al., 2018). For diabetic patients taking both insulin and oral hypoglycemic agents (OHA), 98% weaned off insulin and 61.3% had also stopped OHAs. In Hess’s series, all diabetic patients (105 in total), stopped using medications with normal blood glucose level after 6 months and maintained 6 years after operation. Complications after DS includes severe malnutrition (0.9%), severe anemia (95% excess weight loss maintained at 4 year after operation. For diabetic patients on oral medications only, complete remission rate was 92% at first year and 75% at 5th year (Sánchez-Pernaute et al., 2013). Similar to other malabsorptive procedures, nutrient deficiencies need to be monitored after SADI-S. Mineral deficiency (zinc, selenium and iron) was reported in 50% patients after SADI-S and vitamin A deficiency was seen in 53%. Protein deficiency was reported in up to 34% of patients (Sánchez-Pernaute et al., 2013).

Duodenojejunal bypass with sleeve gastrectomy (DJB-SG) In areas with high prevalence of gastric cancer like South East Asia, possibility for further endoscopic assessment is of practical concern.

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Kasama reported laparoscopic sleeve gastrectomy with duodenojejunal bypass in 2009 (Kasama et al., 2009). The duodenojejunostomy was constructed in Roux-en-y manner with 50–100 cm of biliopancreatic limb and 150–200 cm of alimentary limb. Mean percentage loss of total body weight was 30.7% at 5 years, remission rate of type 2 diabetes mellitus was 63.6%. Recurrence of diabetes was observed in 10.8% of patients who had remission at first year after surgery. This is an effective procedure for weight loss and diabetic control.

Loop duodenojejunal bypass with sleeve gstrectomy.

In 2013, Huang et al. reported loop duodenojejunal bypass with sleeve gastrectomy (LDJB-SG) as a novel operation in managing T2DM (Huang et al., 2013). The procedure entails a sleeve gastrectomy starting from 4 cm proximal to pylorus, over a 36 Fr orogastric tube. First part of the duodenum was divided with stapler and loop duodenojejunal anastomosis was made distal to the pylorus, bypassing 200–250 cm of proximal jejunum from ligament of Treitz. This procedure has several advantages. The sleeve component has the benefit of sleeve gastrectomy and preserving the pylorus reduces dumping as well as bile reflux, which plays a pathogenic role in intestinal metaplasia of gastric mucosa. Future endoscopic assessment for remnant stomach is possible. This is a practical concern in areas with high prevalence of gastric cancer. Duodenojejunostomy in LDJB-SG is constructed in a non-acidic environment as acid was neutralized by bile juice from afferent limb. Therefore, the chance of marginal ulcer was considered minimal. Bypassing the second part of duodenum and proximal jejunum has antidiabetogenic effect independent from food intake, malabsorption or nutrition delivery to hind gut (Huang et al., 2016a). One-year metabolic outcome LDJB-SG in low BMI (BMI  35 kg/m2) patients with T2DM was reported. Weight loss was  15.8 kg with complete diabetic remission rate 30%, and partial remission 16.7%. Increase in HOMA-%B level was observed as well. None of the patients had marginal ulcer or dumping syndrome. No mortality occurred in both groups. LDJB-SG is a promising novel procedure for T2DM balancing effectiveness, risk and quality of life. However, long term follow up is needed to confirm these potential benefits.

Proximal Jejunal Bypass With Sleeve Gastrectomy Introduction Patients with obesity come in a very wide range of BMIs and varying degree of comorbidities. Instead of a few routine surgeries applied to all patients, what would be ideal is a surgery tailored to the patients uniquely altered physiology that would give the best possible results while minimizing the adverse effects. Hence, a wider repertoire of surgical options needs to be created. Laparoscopic proximal jejunal bypass with sleeve gastrectomy (LPJB-SG) was developed in 2004 and had shown good results. Further publications by de Menezes Ettinger and Alamo showed it to be an effective surgery in weight loss and in control of the metabolic syndrome in a South American cohort.

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Proximal jejunal bypass with sleeve gastrectomy.

Surgical technique Sleeve Gastrectomy was carried out. The ligament of Treitz was identified and jejunum was divided at 20 cm. Distally, the jejunum was measured for a distance of 300 cm and was anastomosed to the proximal jejunal end.

Mechanism of action Sleeve gastrectomy part is often thought of as a purely restrictive technique. However, it a reduces the levels of fasting and postprandial ghrelin result in decreased the appetite increase gastric emptying and intestinal motility (Meier et al., 2006), influencing the rate of food reaching the small bowel and thus affecting circulating levels of other gut hormones including peptide YY (PYY) and glucagon-like peptide-1 (GLP-1). These changes may account for the increased satiety, decreased appetite and amelioration of the glycemic profile often seen after LSG. Proximal jejunal bypass part subscribes to the prevalent and accepted theory of incretins in the remission of diabetes. By early exposure of the food to ileum, there is an increase in GLP-1 and Peptide YY secreted by the L cells of the ileum that has been postulated to decrease apoptosis of beta cells, enhance insulin secretion, decrease glucagon response and also decreases the gastric emptying time.

Outcomes Huang et al. demonstrated 65 patients underwent LPJB-SG, the percentage of excess weight loss percentages (%EWL) were 26.44 (range, 4.7–167.4), 44.77 (19.7–169.3) and 65.87 (28.3–210.7) at 1, 3 and 6 months respectively. The mean HBA1C dropped from a mean of 6.9 preoperative to 6.04 at 6 months. For diabetic patients, at 1, 3 and 6 months, 11.53%, 60.86% and 66.66% patients respectively had achieved an HBA1C of 340 ms predicted unsafe swallow and aspirations. Pathogenesis of impaired efficacy of swallow is related to alterations in bolus transfer caused by low propulsion forces and/or impaired UESO. Both neurological and older patients present low bolus velocity (100 mOsm high; 50-100 mOsm intermediate; 0.5% indicates malabsorption or monosaccharides. Low pH ( 100mOsm

Carbohydrate Reducing substances > 0.25%, pH low

**Stool Na+-high Stool osmolar gap < 50mOsM

Clinical suspicion of carbohydrate malabsorption

Improves on fasting trial

Glucose/ galactose free formula

Improvement

Multiple nutrient induced

Diet-induced diarrhea*

Enteroendocrine cell loss¢

Protein-loss Normal villus/crypt architecture

Watery

Endoscopic biopsy

No/minimal improvement Stool electrolytes with fasting trial high Na+/Cl -/K+ Abnormal villus/crypt architecture

Yes

Stool elastase

Abnormal electrolyte-transport diarrhea**

CCD, CSD, hormone diarrhea, pBAD Tufting enteropathy, MVID, TTC7A, SKIV2L

Epithelial structural defect

AIE, post-infectious

Abnormal stool elastase

Normal stool elastase

Grossly normal blopsy Fat-laden enterocytes

Bloody

PCSK1, NEUROG3 DGAT1 deficiency, CD55, Lymphangectasia

Brush border/villus defects

Fatty

Suc/Iso, CLD

Hypoalbuminemia, edema, a-1-AT +ve

Inflammatory infiltrate and/or protein loss

Diarrhea type

GGM

Inflammatory infiltrate Crypt base apoptosis

Cystic fibrosis Lipase def, ShwachmanDiamond, BAM AbetalipoHypobetalipoChylomicron RD

VEO-IBD, AIE, PID

Targeted candidate sequencing Whole exome/whole genome sequencing

Functional confirmation

Specialized immunohistochemical analysis

Fig. 3 Diagnostic algorithm for evaluation of CODEs. Abetalipo, abetalipoproteinemia; CLD, congenital lactase deficiency; CMP, cow’s milk protein; DGAT1, diacylglycerol transferase 1; GGM, glucose galactose malabsorption; Hypobetalipo, hypobetalipoproteinemia; NEUROG3, Neurogenin3 deficiency; pBAD, primary bile acid diarrhea; BAM, bile acid malabsorption; PCSK1, proprotein convertase kinase deficiency; RD, retention disease; Suc/Iso, sucrose-isomaltase deficiency; TTC7A, tetratricopeptide repeat domain 7A; VEOIBD, very-early onset inflammatory bowel disease. Figure adapted with permission from Thiagarajah, J. R., Kamin, D. S., Acra, S., et al. (2018). Advances in evaluation of chronic diarrhea in infants. Gastroenterology 154, 2045–2059.

prescribed for FPIES, although those with a concomitant IgE mediated allergy should be prescribed an epinephrine autoinjector. The long term management of FPIES involves the elimination of the trigger food/s, alterations to diet, treatment of symptoms at presentation or upon reexposure, and a plan for oral food challenges to assess for resolution. Nutritional consultation should be advised, to ensure dietary avoidance and adequate nutrition within the constraints of a limited diet. Total lifelong avoidance of gluten ingestion is the mainstay of treatment for children with celiac disease. Wheat, rye and barley are the grains that contain the peptide triggers. These triggers should be eliminated from the diet, although daily intake of in excess of 10 mg are likely needed to cause mucosal reaction. GI symptoms in patients with symptomatic coeliac disease who adhere to a gluten free diet typically resolve within a few weeks, with normalization of nutritional measures, improved growth in height and weight and normalization of hematological and biochemical parameters. It has been well described that children with VEO-IBD who present early may have a more severe disease course. Shah et al. examined a cohort of infantile onset IBD, where 40% required parenteral nutrition, 31% extensive immunosuppression, 29% hematopoietic stem cell transplant and 19% surgery (Kammermeier et al., 2017). However, VEO-IBD represents a cohort, albeit the minority, which may be completely cured of their disease via hematopoietic stem cell transplantation (HSCT). Our growing understanding of the immunopathogenesis of this disease has opened new avenues for developing targeted therapies. Novel tools investigators are using include enteroids as a conduit to further understand the etiology of the disease, along with using them for high throughput drug screening to target enterocyte defects (Sato and Clevers, 2013). Recent advances have challenged investigators to address “actionable” genetic information. This is the identification of pathogenic genetic variants in IBD patients which offers individualized treatment pathways including the appropriate use of HSCT, pathway-specific biologic therapies and informed use of elective surgery. Importantly, it informs of treatment strategies which may not be appropriate and which may even cause harm. For example, there is evidence that patients with epithelial barrier defects should not be considered for HSCT, because this does not correct the defect that causes the disease (NEMO deficiency or TTC7A deficiency) (Chen et al., 2013) (Table 5). Furthermore,

Pediatric Diarrheal Disorders Table 5

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Potential “Actionable” Gene defects recognized in veo-ibd

Gene defect

Potential therapeutic approach

IL10 & IL 10 receptor FOXP3, IL2RA, CTLA4, MALT1. XIAP SH2D1A DCLRE1C ZAP70 WAS CGD CYBB, CYBA, NCF1, NCF2, NCF4

HSCT likely curative (Murugan et al., 2014) HSCT likely curative (Charbit-Henrion et al., 2017) HSCT likely curative (Worthey et al., 2011) HSCT likely curative (Booth et al., 2011) HSCT likely curative (Rohr et al., 2010) HSCT likely curative (Cuvelier et al., 2016) HSCT likely curative (Ngwube et al., 2018) HSCT likely curative (Chiriaco et al., 2016) Leukine antibiotics, IL1 receptor antagonist (Anakinra), possible use to bridge to HSCT or if HSCT not available (Kato et al., 2011)

EPCAM TTC7A Mevalonate kinase deficiency, NLRC4 gene defects, IL-10 R deficiency NLRC4 LRBA deficiency STAT1

IL-1 targets (Uhlig and Muise, 2017)

Contraindications to therapy

Anti-TNF contraindicated—increase risk of severe infections, may be fatal (Uzel et al., 2010) HSCT not helpful (Kammermeier et al., 2014) HSCT not helpful (Kammermeier et al., 2016)

IL-18, ILR inhibition (Canna et al., 2017) CTLA4 fusion protein—Abatacept, (possible use to bridge to HSCT) (Lo et al., 2015) HSCT or Janus kinase inhibitor Ruxolitinib (Weinacht et al., 2017)

engaging in genomic medicine should provoke referral for family counseling and screening for tumors and infections (Uhlig and Muise, 2017).

Congenital Diarrhea Accurate diagnosis of neonatal and infantile diarrheas may improve patient care, shorten length of hospitalization, provide better prognostication and provide clinical and pathological information for improved genotype and phenotype characterization and association. Many of the epithelial specific CODE disorders still require life-long PN or allogenic intestinal transplantation. Transplanted patients require lifelong high dose immunosuppression that is associated with significant risk for acute and chronic opportunistic infection, allograft rejection/loss and subsequent malignancy.

Prognosis The prognosis for all those with an acquired chronic diarrheal disorder of childhood is good when close attention is paid to monitoring adequate growth and optimizing nutrition, depending on dietary restrictions. With regards to CMPA, as per the ESPGHAN guidelines, the infant should be maintained on an elimination diet using a therapeutic formula for at least 6 months or until 9–12 months of age. Infants/children with severe immediate IgE-mediated reactions may remain on the elimination diet for 12–18 months before they are rechallenged after repeated testing for specific IgE. Infants should grow and thrive normally when treated with either an extensively hydrolysed formula or a free amino acid formula (Koletzko et al., 2012). These children should undergo a dietetic assessment to ensure adequate supply of nutrients especially protein, calcium, vitamin D and vitamin A is sufficient to support normal growth for age. There is insufficient evidence to recommend an optimal interval on the elimination diet before revaluation, yet it must be remembered that the prognosis for CMPA/CMPI in infancy is good. Approximately 50% of affected children develop tolerance by the age of 1 year, 75% by the age of 3 years and >90% are tolerant at 6 years (Koletzko et al., 2012). Similarly, if the diagnosis of coeliac disease is confirmed on biopsy, the family should receive professional dietary counseling for a gluten free diet (GFD). The patient should be followed up regularly for symptomatic improvement, growth surveillance and normalization of coeliac disease specific antibody tests. As per ESPGHAN guidance, the duration until the antibody titres fall below the cut-off for normal depends on the initial level, but generally is attained within 12 months following commencement of a GFD. A gluten challenge is not considered necessary except under unusual circumstances, including cases in which there was doubt about the initial diagnosis (Husby et al., 2012). The long term outcomes of children diagnosed with infantile IBD or VEO-IBD have not, to date been extensively reported. Several groups have evaluated the use of stem cell transplantation in specific cases of monogenic VEO-IBD and reported favorable outcomes. Researchers have looked at the possibility of using stem cell transplantation as a “curative” measure for IBD in a more general way. At this time, the use of stem cell transplantation for “typical” IBD should not be considered standard of care and should only be performed after definite confirmation of a monogenic variant in a tertiary pediatric hospital setting. Currently, unless the patient has one of the rare mutations outlined above, which may lead to more of a precision medicine approach, treatment for VEOIBD is the same as that given to adolescents and adults with IBD.

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As our understanding improves into the pathogenesis of CODEs, the potential to develop targeted therapies improves. Notably, the more severe forms at presentation produce life-threatening chronic diarrhea with massive loss of fluids and intestinal failure requiring long-term parenteral nutrition. In the case of CTE, an increased chance of weaning off parenteral nutrition with increasing age has been demonstrated—ranging from 10% chance at the age to 10 years to 40% at the age of 10–20 years. These findings suggest that intestinal transplantation should be avoided if possible. Given the complexity of these disorders, faster and more accurate diagnosis of neonatal and infantile diarrheas should improve patient care and provide better prognostication to children and their families. Many of the CODE disorders still require either lifelong PN or HSCT. Novel gene therapy or CRISPR/Cas9 technologies are being pursued. Longer term studies are still needed to provide greater insights on the prognosis of these conditions.

References Avitzur Y, Guo C, Mastropaolo LA, et al. (2014) Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease. Gastroenterology 146: 1028–1039. Baber KF, Anderson J, Puzanovova M, and Walker LS (2008) Rome II versus Rome III classification of functional gastrointestinal disorders in pediatric chronic abdominal pain. Journal of Pediatric Gastroenterology and Nutrition 47: 299–302. Benchimol EI, Fortinsky KJ, Gozdyra P, et al. (2011) Epidemiology of pediatric inflammatory bowel disease: A systematic review of international trends. Inflammatory Bowel Diseases 17: 423–439. Benchimol EI, Mack DR, Nguyen GC, et al. (2014) Incidence, outcomes, and health services burden of very early onset inflammatory bowel disease. Gastroenterology 147: 803–813. Benchimol EI, Bernstein CN, et al. 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Montgomery RK, Buller HA, Rings EH, and Grand RJ (1991) Lactose intolerance and the genetic regulation of intestinal lactase-phlorizin hydrolase. The FASEB Journal 5: 2824–2832. Moran CJ, Walters TD, Guo CH, et al. (2013) IL-10R polymorphisms are associated with very-early-onset ulcerative colitis. Inflammatory Bowel Diseases 19: 115–123. Murugan D, Albert MH, Langmeier J, et al. (2014) Very early onset inflammatory bowel disease associated with aberrant trafficking of IL-10R1 and cure by T cell replete haploidentical bone marrow transplantation. Journal Clinical Immunology 34: 331–339. Naik S, Smith F, Ho J, Croft NM, et al. (2008) Staphylococcal enterotoxins G and I, a cause of severe but reversible neonatal enteropathy. Clinical Gastroenterology and Hepatology 6: 251–254. Naim HY, Roth J, Sterchi EE, et al. (1988) Sucrase-isomaltase deficiency in humans. Different mutations disrupt intracellular transport, processing, and function of an intestinal brush border enzyme. 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(2006) Characteristics of inflammatory bowel disease with onset during the first year of life. Journal of Pediatric Gastroenterology and Nutrition 43: 603–609. Sato T and Clevers H (2013) Growing self-organizing mini-guts from a single intestinal stem cell: Mechanism and applications. Science 340: 1190–1194. Sicherer SH (2011) Epidemiology of food allergy. The Journal of Allergy and Clinical Immunology 127: 594–602. Sivagnanam M, Mueller JL, Lee H, et al. (2008) Identification of EpCAM as the gene for congenital tufting enteropathy. Gastroenterology 135: 429–437. Thiagarajah JR, Kamin DS, Acra S, et al. (2018) Advances in evaluation of chronic diarrhea in infants. Gastroenterology 154: 2045–2059. Uhlig HH (2013) Monogenic diseases associated with intestinal inflammation: Implications for the understanding of inflammatory bowel disease. Gut 62: 1795–1805. Uhlig HH and Muise AM (2017) Clinical genomics in inflammatory bowel disease. Trends in Genetics 33: 629–641. 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Further Reading Avitzur Y, Guo C, Mastropaolo LA, et al. (2014) Mutations in tetratricopeptide repeat domain 7A result in a severe form of very early onset inflammatory bowel disease. Gastroenterology 146: 1028–1039. Benchimol EI, Bernstein CN, Bitton A, et al. (2017) Trends in epidemiology of pediatric inflammatory bowel disease in Canada: Distributed network analysis of multiple population-based provincial health administrative databases. The American Journal of Gastroenterology 112: 1120–1134. Egan M and Furuta GT (2018) Eosinophilic gastrointestinal diseases (EGIDs) beyond eosinophilic esophagitis (EoE). Annals of Allergy, Asthma & Immunology. Hyams JS, Di Lorenzo C, Saps M, et al. (2016) Functional disorders: Children and adolescents. Gastroenterology. Leonard SA and Nowak-Wegrzyn A (2015) Food protein-induced enterocolitis syndrome. Pediatric Clinics of North America 62: 1463–1477. Montalto M, D’onofrio F, Santoro L, et al. (2009) Autoimmune enteropathy in children and adults. Scandinavian Journal of Gastroenterology 44: 1029–1036. Rigaud S, Fondaneche MC, Lambert N, et al. (2006) XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature 444: 110–114. Thiagarajah JR, Kamin DS, Acra S, et al. (2018) Advances in evaluation of chronic diarrhea in infants. Gastroenterology 154: 2045–2059. Uhlig HH (2013) Monogenic diseases associated with intestinal inflammation: Implications for the understanding of inflammatory bowel disease. Gut 62: 1795–1805. Uhlig HH and Muise AM (2017) Clinical genomics in inflammatory bowel disease. Trends in Genetics 33: 629–641. Uhlig HH, Schwerd T, Koletzko S, et al. (2014) The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology 147: 990–1007. Wales PW, De Silva N, Kim J, et al. (2004) Neonatal short bowel syndrome: Population-based estimates of incidence and mortality rates. Journal of Pediatric Surgery 39: 690–695.

Pediatric Lymphatic Development and Intestinal Lymphangiectasia Pierre-Yves von der Weid, University of Calgary, Calgary, AB, Canada Andrew S Day, University of Otago (Christchurch), Christchurch, New Zealand © 2020 Elsevier Inc. All rights reserved.

Glossary

Intestinal lymphangiectasia A syndrome featuring disruption of lymphatic function leading to loss of lymph contents into the gut. Can be primary (congenital) or secondary. Lymphatic system A system of vessels that connects the interstitial fluid with the blood circulatory system. Contributes to many essential physiologic activities including lipid transport, immune responses and fluid homeostasis. Protein-losing enteropathy An overall term that encompasses many conditions that involve the loss of protein from the gastrointestinal tract.

The Lymphatic System The lymphatic system is an indispensable element of integrated human and animal physiology. The existence of lymph itself has been recognized by Hippocrates since the historical beginnings of medicine (460–377 BCE) and the discovery of the lymphatic vessels as a vast vascular network functioning as an integrated system of the entire body in the mid 1600s (see review in Chikly, 1997). Despite the widespread recognition of the existence of lymph and components of the lymphatic system, efforts to conduct further investigations have only occurred in the last 50 years. As more sophisticated research techniques became available, allowing better access to lymphatic structures, knowledge of the lymphatic system and concepts of lymphatic physiology are slowly becoming more complete. This increase in knowledge is especially exemplified by a surge in the scientific interest of lymphatic biology that has occurred since the mid 1990s, which has led to scientific advances, particularly in embryogenesis of the lymphatic system, lymphangiogenesis in inflammation and cancer, and function of the lymphatic endothelium. Importantly, it has also become recognized that lymphatic functions are tightly regulated, which has become the subject of intense scientific investigation.

Lymphatic Structure and Anatomy The lymphatic system is composed of numerous vessels connecting interstitial tissue space to blood circulation and to lymphoid organs and structures such as lymph nodes, the spleen and Peyer’s patches in the small intestine. The lymphatic vessels, or lymphatics, are widely distributed throughout the body. They are particularly abundant in the gastrointestinal (GI) tract and the skin, where their extensive network parallels that of blood capillaries in the close proximity to which they lie. They pick up fluid and proteins that leave the cardiovascular system in order to maintain tissue fluid balance. Unlike the cardiovascular system, which is a closed circuit relying on a central pump to move blood, lymphatic vessels form a one-way system that collects lymph from the extremities, propels it via the pumping action of the succession of individual lymphatic chambers comprising the vessels and empties its contents into the venous circulation.

Initial lymphatics The interstitial fluid, along with various cellular components and proteins, enters the lymphatic system through initial lymphatics. These blind-ended structures, also known as lymphatic capillaries, terminal or peripheral lymphatics have walls composed of a single layer of flattened, non-fenestrated endothelial cells (Azzali and Arcari, 2000; Casley-Smith, 1972) and are usually significantly larger than blood capillaries (Leak, 1976; Ushiki, 1990; Lee, 1979). In humans and other mammals, initial lymphatics are devoid of muscle cells or pericytes and have an incomplete basement membrane. Neighboring endothelial cells are connected by buttonlike junctions, made of vascular endothelial (VE)-cadherin and tight junction proteins such as occludin, claudin-5, zonula occludens (ZO)-1, endothelial cell-selective adhesion molecule (ESAM), and junctional adhesion molecule-A (JAM-A) (Baluk et al., 2007). The nonconnected flaps of the endothelial cells form primitive valves that allow for entry of fluid from the interstitium into the lumen, elegantly preventing leakage of lymph in the opposite direction (Kitamura et al., 1989; SchulteMerker et al., 2011; Mendoza and Schmid-Schonbein, 2003). Performance of this primary valve system is supported by anchoring filaments, collagenous fibrils linking the surface of the endothelial flaps to elastin fibers in the surrounding interstitial matrix (Leak and Burke, 1968), preventing the thin walled vessels from collapsing under high interstitial pressure, and allowing it to expand instead, to favor entry of fluid, particulate matter, immune cells, proteins and chylomicrons (Barrowman et al., 1985; Casley-Smith, 1967).

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Collecting lymphatics Initial lymphatics empty their contents into collecting lymphatics, which have, as most important differences with the initials, an intimal monolayer of endothelial cells, tightly connected by zipper-like junctions that contain VE-cadherin, occludin, claudin5, ZO-1, ESAM, and JAM-A (Baluk et al., 2007) surrounded by a media comprised of one to three layers of smooth muscle cells (depending on tissue and species) intermixed with collagen and elastic fibers and an adventitia made of fibroblasts and connective tissue (Ryan, 1989). As vessels progress centrally, the amount of smooth muscle increases, with fibers laying in a more circular way (Horstmann, 1952). The smooth muscle cells are critically responsible for spontaneous contractions that provide the driving force for lymph propulsion. Collecting lymphatic vessels drain into lymph nodes along their path and coalesce to form larger and larger vessels (ducts and trunks) connecting via the thoracic and the right lymphatic ducts to the venous circulation at the root of the neck. Collecting lymphatics form functional units, termed lymphatic chambers or lymphangions (Florey, 1927), which are bordered by unidirectional valves, promoting centripetal flow of lymph, macromolecules, antigenic substances, and lipids into the adjacent chambers. These valves consist of a matrix core that is sandwiched between endothelial cells. Thanks to the intrinsic contractile activity of the lymphatic muscle, each chamber is transiently and independently compressed and thereby propels lymph into the next chamber. The ability of the lymphatic vessels to exhibit rhythmic phasic constrictions, or lymphatic pumping, is the mechanism by which the system performs its essential functions that is discussed in section “Lymph transport and lymphatic pumping.”

Lymph nodes and lymphoid structures Lymph nodes are the structures in which adaptive immune responses to antigens are initiated in most body parts. Many lymph nodes are spread along the lymphatic vessel network and are particularly abundant within the GI tract. Lymph nodes are subdivided into three compartments: the lymphatic system, the blood circulation and the parenchyma, which is further subdivided into B-cell follicles and the T-cell area that together form the cortex and the medulla. Cellular and molecular traffic between these compartments is an essential aspect of lymph node physiology. In areas in direct contact with the outside world, like the GI mucosa, additional lymphoid structures help to organize the host immune responses and often are the first to be stimulated. In the gut wall, secondary lymphoid structures are part of the gutassociated lymphoid tissue (GALT), which can be divided into Peyer’s patches and solitary lymphoid follicles. GALT is a local protection system responsible for inducing adaptive immune responses and lymphocyte proliferation and differentiation following stimulation by microbes and other enteric antigens. The immune response is initiated in these structures by specialized M cells, which sample luminal antigens and pass them to underlying dendritic cells (DCs), macrophages and T cells. It is commonly believed that T cells generate IgA and are carried to the bloodstream through the lymph. (Azzali, 2003; Jeurissen et al., 1984) In the human child, Peyer’s patches are abundant in the small intestine, where their dome-like shape protrudes between the villi in the gut lumen (Azzali, 2003). Solitary lymphoid follicles are predominant in the colon. Lymphoid follicles are wrapped by a network of submucosal lymphatic vessels, considered to have a high absorption capacity (Ottaviani and Azzali, 1969) and which are connected to the muscular network and the mesenteric prenodal collectors.

Functions of the Lymphatic System The lymphatic system serves three main functions: the maintenance of tissue fluid homeostasis to prevent tissue edema, defense against foreign body invasion and infection and in the GI tract, the transport and distribution of digested lipids throughout the body.

Tissue Fluid Balance The extracellular fluid volume is maintained remarkably constant thanks to a tight control of transport of salts and fluid across the blood capillary wall, and the return of fluid to the plasma. Although about 90% of the fluid that leaks out of the capillary beds is reabsorbed into the venous system, the remaining 10% enter initial lymphatics to form lymph. This amounts to about 5–6 L of fluid that is circulated through the human body every day via lymphatic vessels (Aukland and Reed, 1993). Lymphatics are also responsible for the daily clearance of about 60% of vascular proteins, most of this performed by lymphatics of the alimentary tract. Thus, in addition to removing fluid leaking from blood capillaries, intestinal lymphatics have the responsibility of transporting macromolecules synthesized in the digestive system, as well as fluid and nutrients absorbed through the mucosa, particularly lipids in the form of chylomicrons. (Barrowman et al., 1985) Greater than 50% of total lymph is formed in the abdominal viscera, particularly in the intestine, which is propelled through the mesenteric lymphatic vessels before reaching the thoracic duct and the venous circulation (Zawieja and Barber, 1987; Morris, 1956). The mesentery then not only provides protection and structural support for the digestive organs, and a route for nerves and blood vessels to reach the digestive viscera, but it also contains a dense network of collecting lymphatics, which are necessary for draining the abdominal viscera. The importance of the lymphatic system in fluid and macromolecule balance is obvious in the case of lymphatic failure. One of the most common clinical consequences of inadequate lymphatic functioning is lymphedema. This affliction is a swelling of the tissues caused by an accumulation of fluid and proteins (Harwood and Mortimer, 1995). Since lymphatic loading is directly proportional to interstitial fluid volume, the amount

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of lymph that is propelled in the vessels is also determined by the plasma volume filtrated into the interstitium; the greater this volume, the larger the amount of fluid that is transported via the lymphatics back into the blood stream. Protein transport out of capillaries must also be balanced with the same amount of proteins leaving the interstitium via the lymphatics. An inability to transport filtered proteins out of the interstitium results in edema. Proteins move across the capillary membrane by means of both diffusion and convection. There are several determinants of transvascular protein transfer, some which relate to the characteristics of the capillary membrane itself, and others related to the relative concentrations of protein across the membrane. The flux of proteins across the capillary wall is regulated by a complex set of physiological mechanisms. This is important because fluid flux depends largely on osmotic pressure, and protein concentration can have a large impact on fluid volumes. As in fluid loading in lymphatics, the amount of protein loaded into the initial lymphatics is determined by interstitial protein concentrations. Lymph formation must match the net transcapillary flux of fluid and solutes in order to prevent excessive tissue swelling and edema (Aukland and Reed, 1993).

Lymph Transport and Lymphatic Pumping As fluid, electrolytes, proteins and cellular elements, such as immune cells, freely enter the vessels, the composition of lymph is quite similar to that of the surrounding interstitial fluid. The main driving force behind vessel filling has been proposed to be interstitial fluid pressure (Aukland and Reed, 1993). When interstitial fluid accumulates, the tension on the anchoring filaments attached to lymphatic capillaries causes the walls of the initial lymphatics to be pulled apart, opening the primary valves and allowing fluid to enter the vessels. Fluid movement through the tissue toward the lymphatic vessel lumen is preserved because the downstream lymphatic vessels continue to drain fluid away. The centripetal drainage is maintained by the one-way valves that separate each chamber of the collecting vessels and via both active and passive compression of the vessels. Lymph propulsion is secondarily provided by extrinsic forces, such as skeletal muscle or inspiration movements, blood vessel vasomotion and suction effect due to blood flow in the subclavian veins (Ganong, 1991). Although these forces contribute to the movement of lymph, the primary mechanism of lymph propulsion is the rhythmic phasic constrictions of the lymphatic chambers, described as lymphatic pumping. Such activity is essential for the normal propulsion of intestinal lymph (Benoit et al., 1989), and has been reported in most mammalian species, including humans (Gashev and Zawieja, 2001). Contractions are independent of the innervation and the endothelium (McHale et al., 1980; Hanley et al., 1992) and intrinsic to the muscles in the vessel wall, as can be observed in the mesentery where no surrounding structures are present to exert any vessel compression. The spontaneous and rhythmic origin of lymphatic pumping requires the regular occurrence of pacemaker events able to transiently depolarize the muscle membrane potential to a level where action potentials can be evoked, leading to calcium entry and phasic contractions (Van Helden et al., 1996, 2000). Although the origin of the lymphatic pacemaker remains elusive, findings obtained from lymphatics of large mammals and rodents lead to two main theories. The first one proposes the activation of a pacemaker similar to cardiac pacemaking and involving a hyperpolarization-activated inward current with properties similar to the sinoatrial node “funny” current If (HCN channels), as well as other currents such as T-type Ca2þ current, Ca2þ-activated Cl current, and fast voltage-activated Naþ-current, all demonstrated to be functionally expressed in sheep, rat and human mesenteric and rat diaphragmatic lymphatic vessels (Hollywood et al., 1997; Toland et al., 2000; Telinius et al., 2015; Kirkpatrick and McHale, 1977; Ward et al., 1991; McCloskey et al., 1999; Negrini et al., 2016) (see review in Scallan et al., 2016). However, the incomplete abolition of lymphatic pumping in the presence of inhibitors of these channels support the idea that other ion conductance(s) or different mechanisms are involved. The second hypothesis emerged from the observation of small spontaneous transient depolarizations (STDs) occurring in the lymphatic muscle membrane that either individually or through summation, underlie action potentials and muscle contractions (Van Helden, 1993). More recent studies demonstrate that STDs reflect the opening of Ca2þ-activated inward current carried by Cl ions, or ClCa channels (now also known as anoctamin-1 (ANO1) or TMEM16a), upon the “packeted” release of Ca2þ from IP3-sensitive stores within the muscle cells (von der Weid et al., 2008; Toland et al., 2000). ANO1 has been shown to be expressed in human, mouse and rat lymphatics (Gui et al., 2016; von der Weid unpublished) and ANO1 current recorded from lymphatic muscle cells acutely dissociated from mouse inguinal-axillary collectors (SD Zawieja and MJ Davis, personal communication). The important role of ANO1 in lymphatic pumping was further demonstrated by the strong reduction of lymphatic contraction frequency and a lack of response to increase in transmural pressure after selective deletion of the Ano1 gene in mouse lymphatic muscle cells (SD Zawieja and MJ Davis, personal communication). Unfortunately, lack of reliable pharmacological inhibitors of ANO1 has so far precluded confirmation of the role of these channels in lymphatic pacemaker.

Digestive Functions Intestinal lymphatics are crucial to the absorption of dietary lipids, more specifically long chain fatty acids. Fat absorption involves emulsification of bile salts, hydrolysis of long-chain triglyceride (LCT) species by lipase, passive and or transporter-mediated diffusion into enterocytes, re-synthesis and repackaging into chylomicrons, large triacylglycerol-rich lipoproteins in these cells. Chylomicrons are exocytosed by the enterocytes and enter the lymphatic system through lacteals, the initial lymphatics in the villi of the small intestine. They then flow with the lymph into submucosal lymphatics and then into mesenteric collecting lymphatics (reviewed in Tso and Balint, 1986; Phan and Tso, 2001; Nordskog et al., 2001; Tso et al., 2004). The concentration of lipids in intestinal lymph is approximately 1%–2% (Tso et al., 1985; Tso and Balint, 1986) and is highly dependent on feeding patterns. Intestinal lymph flow is greatly enhanced following fat feeding (Borgstrom and Laurell, 1953;

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Simmonds, 1954). This action can be interpreted as a way to accommodate the increased lipid load and to help propel it through the lymphatic vessels for distribution throughout the body. However, the precise mechanisms by which this occurs and the impact of lipid metabolism on lymphatic function is poorly understood. Lipid absorption has also been linked to the special roles of intestinal lymphatics in terms of immune cell trafficking (Rothkotter et al., 1994; Miura et al., 1987; Husband and Dunkley, 1985).

Lymphatic System and Intestinal Immunity The lymphatic system is strongly implicated in the adaptive immune response. It is responsible for transporting and sequestering antigens in lymphoid tissues to bring about immune responses during disease and in response to infection. Immune cells, fluid and other macromolecules enter lymph nodes from tissues via afferent lymphatic vessels or from the cardiovascular network via high endothelial venules. Antigens present in fluid entering the lymph node can effectively elicit an immune response by activation of resident naïve T- and B-cells. Immune cells exit the lymphatic system and eventually return to the bloodstream, where lymphocytes are transported to tissues throughout the body and act as patrols on the lookout for foreign antigens. The lymphatic system provides an exclusive environment where immune cells can respond to foreign antigens, and also a network though which proliferating and circulating lymphocytes can return to the bloodstream. The lymphatic system also functions as a one-way communication system for molecular messages, such as chemokines, which can be transmitted to cellular constituents in lymph nodes. Afferent lymph transports antigen and antigen-presenting dendritic cells (DC) from peripheral tissues to draining lymph nodes. During cell trafficking, DC and their precursors enter lymph nodes through afferent lymphatics. Indeed, high numbers of immune cell subpopulations, such as monocytes, macrophages and DC, can be found in prenodal lymph, but not to any significant degree in postnodal lymph (Hay and Andrade, 1998). Due to their ability to capture and present antigens, DC are intimately involved in the initiation of both tolerogenic and immunogenic intestinal immune responses. The anatomical location and local environment in which DC acquire antigen is likely crucial in determining the nature of the subsequent response. DCs migrate toward initials along a gradient of the chemokine SLC/CCL21 robustly expressed by the lymphatic endothelium (Gunn et al., 1999; Kriehuber et al., 2001; Mancardi et al., 2003; Saeki et al., 1999; Tal et al., 2011) and which binds to its receptor CCR7 expressed by DCs. DCs then crawl through the endothelial cells to reach the lymph (Rouzaut et al., 2010; Takamatsu et al., 2010; Tal et al., 2011) and travel along with lymph flow until entering the lymph node (Algars et al., 2011; Braun et al., 2011). This trafficking underscores the importance of lymph flow in the microlymphatic to DC nodal homing and, thus, overall immune function. Inside the lymph node, chemokines expressed by the mature antigen presenting DC, MIP-3b and CCL18, recruit naïve T-lymphocytes while monocyte chemoattractant protein, MIP-1a, CCL17 and CCL22 attract activated and memory T lymphocytes, as well as B lymphocytes. This process allows the interaction of lymphocytes with the antigenpresenting DC. Naive and central memory lymphocytes continuously enter lymph nodes through high endothelial venules, reach the paracortex, migrate rapidly in random directions and contact numerous DC in search of a stimulating antigen. Activated T lymphocytes then undergo clonal expansion and acquire tissue-specific homing patterns. Lymphocytes then exit lymph nodes, presumably through the efferent lymphatics, and travel with lymph flow back to the bloodstream where they engage in their immune functions (see reviews by Randolph et al., 2005a, b). Several findings are also of particular interest to the involvement of lymphatics in intestinal and immune functions. Lipid absorption has been shown to increase lymphocyte transport in rat mesenteric lymphatics (Miura et al., 1987) and functions of intestinal DCs are differentially modulated by long- and medium-chain fatty acids. In particular, the chemotactic ability of mature DC toward SLC/CCL21 is abrogated by long-chain fatty acids (Tsuzuki et al., 2006). Presumably, this modulation occurs in the lymphatic vessel lumen, where lipids and DC co-exist in the lymph.

Lymphatic Embryology With the recent discovery of reliable molecular markers to specifically detect lymphatic vessels, such as Prox1, LYVE-1 and podoplanin, progress in understanding of the origin and development of lymphatic vessels has greatly advanced. Studies of mice deficient in the homeodomain protein Prox1 (Wigle and Oliver, 1999; Wigle et al., 2002) revealed that this transcription factor is critical for the development of the lymphatic vascular system and is required for a subset of venous endothelial cells in the embryonic cardinal veins to migrate out and to form the initial lymphatic vessels during early embryogenesis (Harvey and Oliver, 2004). Studies of avian development indicate that independent lymphangioblasts might contribute to the formation of the lymphatic vascular system in the early wing buds, limb buds, and the chorioallantoic membrane of birds (He et al., 2003; Papousti et al., 2001; Schneider et al., 1999; Wilting et al., 2001). Whether lymphangioblasts also contribute to lymphangiogenesis (the formation of new lymphatic vessels) in mammals remains to be demonstrated. While vascular endothelial growth factor A (VEGF-A) is known as the primary angiogenic growth factor (Rafii and Skobe, 2003), vascular endothelial growth factor C (VEGF-C) and D (VEGF-D) are essential for lymphangiogenesis and interact with vascular endothelial growth factor receptor 3 (VEGFR3). VEGF-C is required for sprouting of the first lymphatic vessels from embryonic veins (Karkkainen et al., 2004) and in VEGF-C null mice, endothelial cells commit to the lymphatic lineage but do not further develop to form lymph vessels. As a result, the entire lymphatic system does not develop and embryos are not viable. Vessel development, via sprouting, returns upon addition of VEGF-C, confirming its role as a paracrine factor essential

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for lymphangiogenesis. Yet, VEGF-C also promotes early angiogenesis, which indicates overlapping function (Shibuya and Claesson-Welsh, 2006). The expression of the homeobox gene Prox-1 in endothelium provides essential signals for lymphatic endothelial differentiation (Wigle and Oliver, 1999). In addition, angiopoietin-2 (Ang-2) and podoplanin are required for lymphatic development, whereas VEGF-A, VEGF-C, VEGF-D, fibroblast growth factor and Ang-1 are implicated in postnatal lymphangiogenesis (Saharinen et al., 2004; Tammela et al., 2005). Further, it has been demonstrated that the tyrosine kinase Syk and its adaptor protein SLP-76, both mainly expressed in hematopoietic cells, contribute to anatomical separation of lymphatic from blood vasculature during embryogenesis and post-natal development (Abtahian et al., 2003). Without either of these factors, mice have disorganized blood and lymphatic vessels, and as a result, develop arterio-venous-lymphatic shunts that lead to enlargement of the heart and mixing of blood and lymph. Endothelium-derived signals mediate the recruitment of lymphatic muscle cells to the nascent vessel to form collecting vessels and promote the maturation of the functional lymphatic system. Maturation of lymphatic vessels is governed by key proteins such as ephrinB2, Ang-2 and the forkhead transcription factor FOXC2 (Fang et al., 2000; Makinen et al., 2005; Karkkainen et al., 2004; Alitalo et al., 2005). Ephrin ligands and their receptors are critical in the formation and function of luminal valves as well as the remodeling of the lymphatic plexus into a proper lymphatic vascular phenotype (Makinen et al., 2005). Ang-2 can also signal through its receptor Tie2 to initiate proper formation of initial lymphatics and smooth muscle cell recruitment (Gale et al., 2002). During adulthood, FOXC2 is abundantly expressed in the valves in collecting lymphatics (Karkkainen et al., 2004) and has been shown to be critical for proper valve formation and smooth muscle recruitment. Furthermore, FOXC2 has been demonstrated to be a downstream target of VEGFR3 signaling, and an important mediator for defining lymphatic collector phenotype (Norrmen et al., 2009). The embryologic origin of lymphatic muscle cells and their recruitment and investiture into the developing lymphatic vessels is an area about which very little is currently known. If lymphatic muscle development follows the course of vascular smooth muscle, the cells generally will have a mesodermal origin with local variations (Hungerford and Little, 1999). For example, vascular smooth muscle of the great arteries and cardinal veins differentiate from cells of the cardiac neural crest (Bergwerff et al., 1998). One of the few studies documenting lymphatic muscle development provides evidence in the postnatal rat diaphragm that lymphatic muscle cells arise from mesenchymal progenitors in this fashion (Ohtani and Ohtani, 2001). Another possible route of lymphatic muscle development in cardiac lymphatics may follow that of the vascular smooth muscle cells of the coronary circulation, where muscle cells differentiate from proepicardial cells (Hungerford and Little, 1999; Mikawa and Gourdie, 1996). This route of development fits with similarities seen in the molecular characteristics of cardiac and lymphatic muscle, as well as the role of lymphatic muscle in the phasic contractile lymph pump. This potential route of lymphatic development may also be related to the primitive lymphatic hearts that are seen in lower vertebrate species that contain both smooth and striated muscle (Wilting et al., 1999).

Lymphangiogenesis Lymphangiogenesis occurs in normally developing tissues and also in pathological processes like inflammation, wound healing, lymphedema and cancer. Understanding the formation of the lymphatic system as a biological regulation system transporting tissue fluid, immune cells and fatty nutrients in the GI tract, as well as in diseases involving lymphangiogenesis is important. The use of the newly characterized lymphatic endothelium molecular markers (50 -nucleotidase, VEGFR3, podoplanin, Prox1, LYVE-1) has helped improving our understanding of the molecular mechanisms involved in lymphangiogenesis. The elucidation of these processes in normal and pathological situations could lead to the development of novel therapies for problematic diseases, such as malignant tumors, chronic inflammation, lymphedema, primary intestinal lymphangiectasia (PIL) and protein-losing enteropathy (PLE). Analysis of lymphatic organization and lymphangiogenesis during individual development and tissue repair in the gastrointestinal lymphatic system has also been facilitated by identification of the specific lymphatic endothelial markers described above. The dense lymphatic network in the intestinal muscle coat develops by vascular sprouting consisting of thin lymphatic endothelial projections and splitting of vessels. Lymphatic regeneration during tissue repair is attributable to sprouting from preexisting lymphatics, and it progresses with vascular maturation. During regrowth, lymphatic endothelial cells exhibit structural changes indicating a high migratory potential and a close association with regenerating stromal cells (Shimoda and Kato, 2006). Upregulation of the specific lymphangiogenic molecule VEGF-C in a subpopulation of stromal cells probably contributes to lymphatic regeneration by activating its receptor, VEGFR3, on regrowing lymphatic endothelial cells.

Modulation of Lymphatic Pumping One important mechanism for maintaining the fluid-balancing function of the lymphatic system is the ability of the lymph pump to autoregulate the force and frequency of contraction in response to fluid load. Under normal conditions, an increase in interstitial and intraluminal lymphatic pressures causes a corresponding rise in contraction frequency to a maximum value, beyond which flow will drop due to a decrease in stroke volume (McHale and Roddie, 1976; McHale, 1992; Ohhashi et al., 1980). All lymphatics have an optimal pumping condition at relatively low transmural pressures (Benoit et al., 1989), which tend to be higher in more peripheral lymphatic vessels (Eisenhoffer et al., 1994), suggesting they can develop much higher pressures to prevail over the greater outflow resistance.

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Lymph flow also affects the contraction frequency of lymphatic vessels and increase in perfusate flow correspond to an increase in contraction frequency, and a decrease in the amplitude of contractions (Koller et al., 1999; Benoit et al., 1989). However, these experiments did not clearly separate the effects of increased flow from the well-known effects of increased transmural pressure. Indeed, inhibition of both amplitude and frequency of contraction were observed when imposed flow was increased at constant transmural pressure (Gashev et al., 2002, 2004). Whether such imposed flow-dependent inhibition of the active lymph pump decreases total lymph flow in vivo is difficult to assess and high levels of lymph formation may cause passive lymph flow that could become a greater driving force to move lymph than the active lymph pump. Flowdependent inhibition of the active lymph pump in such situations could be a reasonable physiological mechanism to save metabolic energy by temporarily decreasing, or stopping, contractions during the time when the lymphatic does not need it. Inhibition of the lymph pump under these circumstances could also reduce lymph outflow resistance, as a result of a net increase in average lymphatic diameter when contractions are inhibited. This reduction in outflow resistance could ease the removal of fluid from the affected compartment that is producing high lymph flows and thereby facilitate the resolution of edema (Gashev et al., 2002; Gashev, 2008). The lymph pump is also controlled by chemical modulators present in the lymph or in fluid surrounding the vessel, after being released from nerves or cells present in the interstitium, the vessel itself or the blood. These factors include inflammatory mediators such as histamine, serotonin and prostaglandins, endothelium-derived factors such as nitric oxide, neurotransmitters such as norepinephrine, CGRP and VIP, as well as many of the circulating hormones. This aspect has been dealt with in detail in several reviews to which the reader is referred (Johnston, 1985; von der Weid, 2001; von der Weid and Zawieja, 2004).

Protein-Losing Enteropathy and Intestinal Lymphangiectasia Numerous conditions lead to increased enteric protein losses (protein-losing enteropathy: PLE) that may reflect either lymphatic dysfunction or mucosal loss. Primary intestinal lymphangiectasia (PIL) is the most widely known cause of lymphatic dysfunction leading to protein loss in children (Walker-Smith and Murch, 1999), although the prevalence of this condition is not known. Various conditions can also lead to secondary focal or generalized intestinal lymphangiectasia. Examples of secondary lymphangiectasia are intestinal volvulus, post-repair of congenital heart disease, connective tissue disorders, sarcoidosis, inflammatory bowel disease, cancer and certain chromosomal abnormalities (e.g. Turner Syndrome). Appropriate investigations are required to exclude these conditions, especially with later presentation in adolescence or adulthood. A recent study demonstrated that lymphatic deletion of calcitonin receptor–like receptor (Calcrl) induced intestinal lymphangiectasia, characterized by protein-losing enteropathy and dilated lacteals unable to absorb lipids. (Davis et al., 2017) These features were shown to exacerbate intestinal inflammation. The authors further identified Calcrl/adrenomedullin signaling as an essential upstream regulator of the Notch pathway, previously shown to be critical for intestinal lacteal maintenance and junctional integrity (Bernier-Latmani et al., 2015). Of note, lacteal integrity has been shown to be essential for the structural and functional maintenance of the intestinal villi (Jang et al., 2013). Lack or decrease in lacteal integrity may thus contribute to the loss of mucosal integrity and gastrointestinal protein leakage characteristic of PLE.

Clinical Manifestations of Primary Intestinal Lymphangiectasia PIL most commonly presents in early childhood but may present in adolescence. Isolated case reports have included presentation in adults. PIL can present with a variety of symptoms, such as asymmetrical peripheral edema, ascites, immunologic deficiencies, lymphocytopenia, hypoalbuminemia, impaired lymphocyte transformation, gastrointestinal symptoms and impaired growth. It is characterized by abnormal, distorted and obstructed lymphatic vessels, consequent to an increased hydrostatic pressure throughout the lymphatic system of the gastrointestinal tract, resulting in lymph stasis, back-flow into the intestinal lacteals, which rupture and leak the nutrient-laden lymph into the lumen of the bowel. The presence of these abnormally dilated lymphatics is a feature of the disease and correlates with lymphatic dysfunction, such as the inability of the lacteals to adequately transport long-chain fatty acids, leading to fat malabsorption. Indeed, replacement of dietary long chain triglycerides (LCT) with medium chain triglycerides (MCT), which are transported directly into portal circulation rather than the lymphatic system, reduces intestinal protein losses, suggesting that restoring lymphatic function by decreasing the lymphatic burden ameliorates the disease outcome (Desai et al., 2009).

Diagnosis of Primary Intestinal Lymphangiectasia In a child with symptoms suggestive of possible PIL, initial testing would typically reveal hypoalbuminemia, lymphopenia and hypogammaglobulinemia. Levels of the fat-soluble vitamins (vitamins A, D, E and K) should be measured. Stool samples can be sent to measure levels of a-1-antitrypsin: elevated levels reflect increased enteric protein loss from the small or large intestine. Exclusion of secondary causes of intestinal lymphangiectasia may also be required. Definitive diagnosis can then be obtained by analysis of duodenal mucosal biopsies obtained during upper gastrointestinal endoscopy. Capsule endoscopy and double-balloon enteroscopy have also been described as diagnostic tools. The typical endoscopic appearance of lymphangiectasia is of multiple white-tipped villi in the duodenum. Some physicians advocate the

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administration of a volume of full cream prior to fasting, in order to enhance the appearance of the villi. Histologically, the typical appearance seen on small bowel biopsies is of dilated lacteals. One group described two phenotypes of IL based on the enteroscopic appearance: white-tipped villi and non-white-tipped villi (Ohmiya et al., 2014). The six patients with non-white tipped villi type had lower serum albumin and higher a-1-antitrypsin levels, higher immunoglobulin A and M, but better response to corticosteroids than the eight individuals with white tipped villi.

Management of Primary Intestinal Lymphangiectasia Currently, there are no curative management options for PIL. In IL secondary to other causes, however, the lymphatic dysfunction may be resolved by appropriate management of the underlying cause. With mechanical causes, such as volvulus, surgical management may be curative. Similarly, optimal management of other conditions, such as sarcoidosis, should remedy the lymphatic dysfunction. The management options considered for PIL, especially nutritional interventions, also may be appropriate and helpful for secondary causes. The key management options for PIL fall into three broad areas: nutritional, medical or surgical. Nutritional treatments are based upon first principles and reflect the understanding of the pathogenesis of PIL. The other interventions are based predominantly upon anecdotal data, including case reports and series. There are no randomized controlled data to support the merits of one intervention over another. A further key aspect of the management of lymphangiectasia is ensuring a multi-disciplinary approach. In addition to a pediatric gastroenterologist with good understanding of the key principles, other key personnel include an experienced pediatric dietitian, a coordinating nurse and access to psychological support as required. Surgical support may also be required.

Nutritional Management The first line of management of lymphangiectasia involves the restriction of dietary LCT and the use of MCT as an ongoing intervention (Reviewed by Vignes and Bellanger, 2008). As earlier, the use of MCT predominant formulae or supplements and the avoidance of LCT reduces intestinal lymph flow. The absorption of MCT via the portal venous system (bypassing the intestinal lymphatics) ensures the provision of dietary fat and the required calories. As the complete exclusion of LCT also reduces essential fatty acids intake, these need to be supplemented with options such as walnut oil. A diet completely devoid of LCT is very difficult to achieve as many foods will contain small amounts of LCT. Furthermore, such a diet is very difficult to maintain, and requires high levels of acceptance and adherence. Children and parents must receive comprehensive education and training about the diet and receive ongoing support and review from a knowledgeable and experienced dietitian. MCT can be provided as MCT predominant enteral formulae. MCT liquid can also be used as a fat substitute in cooking as well as an oral nutritional supplement. Access to resources and appropriate recipes to ensure that MCT is used adequately is clearly vital. In the setting of fat malabsorption and enteric fat loss, the absorption of fat soluble vitamins will also be compromised. While uncommon, case reports illustrate presentation of lymphangiectasia with tetany or hypocalcaemia secondary to severe vitamin D deficiency. Correction of any fat-soluble vitamin deficiency and ongoing supplementation is required.

Monitoring of outcomes of nutritional interventions Monitoring after commencement of these dietary interventions includes symptom assessment, physical examination, anthropometric evaluations (to ensure normal growth), measurement of serum albumin, Immunoglobulin (Ig)G and fat-soluble vitamins. Fecal a-1-anti-trypsin can also be measured at intervals as a further assessment of enteric protein losses. Successful management should lead to normalization of serum albumin and IgG, with resolution of peripheral oedema and any other presenting manifestations and re-establishment of appropriate growth patterns. Enteric protein loss would be expected to be reduced (but likely still greater than the normal range). Many reports demonstrate short- and medium-term improvements with nutritional management alone. One early report showed the outcomes of this approach in six children with PIL for periods of up to 8 years duration (Tift and Lloyd, 1975). Overall, this dietary intervention consistently resulted in improvement or resolution of gut symptoms and ensured normal growth patterns. Relaxation of the dietary restrictions was followed by recurrent symptoms. Furthermore, repeated assessments demonstrated that there was no change to the degree of underlying enteric protein loss, indicating that although these interventions were modulating the lymphatic dysfunction, they were not curative. Wen and colleagues (Wen et al., 2010) reviewed four cases at their institution and then reviewed additional cases of PIL managed with diet that have been reported in the literature to that date. Dietary restrictions were reported to be beneficial in 24 (63%) of 38 reported cases. Dietary restrictions were reported to be more beneficial in the children than in the adult cases. A further nutritional option is parenteral nutrition with complete gut rest. This option bypasses the gut entirely, with consequent reduction in lymphatic losses. However, this requires placement of intravenous access, and has the implications of administering parenteral nutrition (training, prolonged hospitalization, risk of infection, etc). It also relies on the exclusion of oral intake, with the consequent social limitations and need for adherence.

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Intravenous correction of albumin and immunoglobulins Albumin can be administered in conjunction with frusemide to augment serum albumin, thereby increasing oncotic pressure, with the objective to reduce complications of hypoalbuminemia such as peripheral oedema and ascites. Albumin infusion would normally be considered according to the degree of fluid overload and consequences of this, rather than be based upon a certain serum level. In most settings a single albumin infusion will lead to an elevation in serum albumin; however, this would be expected to be transient as the increased amount of circulating albumin is then lost into the gut lumen via the lymphatics. Given the transient benefits, albumin infusions may need to be repeated at various intervals to maintain the serum albumin. While replacement of albumin clearly has a role in the management of lymphangiectasia, there is not a clear role for routine administration of intravenous immunoglobulin (IVIG) to correct hypogammaglobulinemia. Generally, the benefits are again very transient and infusions only partially normalize serum levels. There may be a role for IVIG infusions in the setting of recurrent infections secondary to severe enteric IgG loss, as has been described in isolated case reports. One report described the use of IVIG in one individual diagnosed with PIL complicated by severe hypoalbuminemia (Patuzzo et al., 2016). In this case, subcutaneous IVIG was more beneficial than intravenous IVIG.

Medical Therapies for the Management of PIL Octreotide A number of case reports and small series of patients with PIL have described the use of octreotide, a long-acting analogue of somatostatin. Although, authors have hypothesized that octreotide works by decreasing splanchnic flow and decreasing triglyceride absorption, the mechanisms have not clearly been determined. Interestingly, in describing a patient who did not respond to octreotide, one group used an animal model to elegantly demonstrate that octreotide did not have any effect on lymphatic function (Makhija et al., 2004).

Corticosteroids Corticosteroids have been considered to have a role for the management of PIL. The rationale primarily comes from PLE secondary to inflammatory conditions (secondary IL). Corticosteroids can be administered as prednisone or budesonide.

Antiplasmin Two single case reports have shown that anti-plasmin therapy resulted in improvements in PIL. The first report described an adolescent girl with PIL who had not responded to dietary restrictions or octreotide (MacLean et al., 2002). Tranexamic acid treatment lead to improvement in serum albumin and a reduction in episodes of GI bleeding. The longer-term benefits of this intervention in this girl were not reported. Balaban et al. (2015) described one case of PIL who had presented as a young adult. Initial dietary therapy and subsequent trial of octreotide was not sufficient to control his symptoms. Although selective embolization was partially successful, it was only with commencement of tranexamic acid that his symptoms and his severe anemia were able to be controlled adequately.

Heparin Several studies have shown reduction of heparin on basolateral aspects of epithelial cells in several settings of secondary lymphangiectasia. In vitro models clearly demonstrated the impact of these changes and also showed that the addition of heparin in these models abrogated the protein leak. Clinically, low dose heparin has been helpful in a handful of cases but appears to be more helpful in secondary IL than in PIL.

mTOR inhibition The drugs rapamycin and everolimus, which inhibit the kinase mammalian target of rapamycin (mTOR), and have immunomodulator and anti-angiogenic effects, have been shown to be helpful in PIL. One report illustrated the outcomes of everolimus in a 12 year child with PIL who had ongoing symptoms and excessive intestinal losses despite nutritional interventions (Ozeki et al., 2016). Upon commencing everolimus, the boy’s diarrhea resolved and his intestinal losses reduced, leading to less albumin replacement requirements. The benefits were maintained for 12 months after commencement of everolimus. In a second single case report, rapamycin was shown to improve PIL in a child with coincident tuberous sclerosis (Pollack et al., 2015). Commencement of rapamycin lead to rapid improvement in symptoms and evidence of reduced lymphatic losses. Interestingly, a recent study also showed that rapamycin reduced lymphangiectasia in a neonatal mouse model of widespread airway and lung lymphangiectasia by suppression of VEGF-C–driven mTOR phosphorylation and lymphatic endothelial cell sprouting and proliferation (Baluk et al., 2017). These findings indicate that further analysis of the role of mTOR inhibition in PIL is required.

Other medical interventions Two single case reports have described cases of PIL who received chemotherapy following the development of lymphoma. In both cases the PIL was reported to have resolved completely. The first case involved a 22-year-old woman with congenital IL who developed non-Hodgkin’s lymphoma (Shpilberg et al., 1993). Chemotherapy and local irradiation lead to successful cure of her lymphoma and also resulted in complete resolution of her gastrointestinal symptoms. The second report (Broder et al., 1981)

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described a girl who was diagnosed with PIL at 2 years of age who was managed symptomatically for the following 13 years. At age 15, she diagnosed with non-Hodgkin’s lymphoma and underwent chemotherapy with a regimen that included oral corticosteroids. Subsequent to the chemotherapy her gastrointestinal symptoms resolved completely. Her daily protein loss reduced from 40% of total protein pool before treatment to 2% afterwards.

Surgical interventions Surgery involving intestinal resection has been described for PIL, but appears to be most relevant when isolated or restricted involvement has been demonstrated (Kim et al., 2009). Otherwise, the role of surgery in the management of PIL is limited. Although this strategy has been shown to be efficacious in a handful of cases, the longer-term outcomes are not well-described. Intestinal technetium-dextran lymphoscintigraphy to specify the location of intestinal protein loss was developed and described many years ago (Bhatnagar et al., 1995). This investigation was used to guide surgical intervention in a teenage girl who had welldefined and intractable lymphangiectasia following previous Fontan procedure for her congenital tricuspid atresia (Connor et al., 2003). Lymphoscintigraphy demonstrated intestinal losses from one specific section in the proximal jejunum. Localized jejunal resection with re-anastomosis lead to significant improvement in her intestinal losses, based on resolution of ascites and symptoms. Subsequent to the resection, she had significant catch-up growth and entered puberty. Follow-up of this case was documented for over 2 years.

Intestinal Lymphatic Hypoplasia Another well-documented cause of neonatal PLE is intestinal lymphatic hypoplasia, which shares many clinical features with PIL but is typically associated with a normal lymphocyte count (Hardikar et al., 1997; Stormon et al., 2002). Lymphatic hypoplasia is characterized by the absence or marked lack of lymphatics. However, diagnosis is difficult because identification of lymphatic vessels in the mucosa requires antibodies specific to lymphatic antigens. The recent availability of antibodies against lymphatic markers has improved the diagnosis of lymphatic hypoplasia. In a study performed over a 15-year period, immunostaining with D2-40, a mouse monoclonal antibody demonstrated to react with a sialoglycoprotein found on human lymphatic endothelium (Kahn and Marks, 2002) was analyzed in mucosal and muscular biopsies from the alimentary tract of children in normal and disease conditions (including both lymphangiectasia and intestinal lymphatic hypoplasia) (Zeng et al., 2005). The study showed that lymphatic vessels are preserved, and sometimes increased, in many common alimentary tract diseases of children, confirming what has been reported in adults with inflammatory bowel disease (Kaiserling et al., 2003; Fogt et al., 2004). In young patients with lymphatic hypoplasia, D2-40 immunostaining confirmed the absence, or marked paucity, of lymphatic vessels in the small intestine. Lymphatic vessels were not detected in the duodenal mucosal biopsy of a patient whose sibling had confirmed lymphatic hypoplasia and in another patient with similar clinical and laboratory findings in whom lymphatic vessels could not be identified by electron microscopy. Among these patients, the degree and extent of lymphatic hypoplasia were variable, but suggested to be related to the severity of the disease (Zeng et al., 2005).

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Further Reading Alshikho MJ, Talas JM, Noureldine SI, Zazou S, Addas A, Kurabi H, and Nasser M (2016) Intestinal Lymphangiectasia: Insights on management and literature review. American Journal of Case Reports 17: 512–522. Bode L, Eklund EA, Murch S, and Freeze HH (2005) Heparan sulfate depletion amplifies TNF-alpha-induced protein leakage in an in vitro model of protein-losing enteropathy. American Journal of Physiology. Gastrointestinal and Liver Physiology 288: G1015–G1023. Bode L, Salvestrini C, Park PW, Li JP, Esko JD, Yamaguchi Y, Murch S, and Freeze HH (2008) Heparan sulfate and syndecan-1 are essential in maintaining murine and human intestinal epithelial barrier function. The Journal of Clinical Investigation 118: 229–238. Ingle SB and Hinge Ingle CR (2014) Primary intestinal lymphangiectasia: Miminreview. World Journal of Clinical Cases 2: 528–533. Levitt DG and Levitt MD (2017) Protein losing enteropathy: Comprehensive review of the mechanistic association with clinical and subclinical disease states. Clinical and Experimental Gastroenterology 10: 147–168. Sari S, Baris Z, and Dalgic B (2010) Primary intestinal lymphangiectasia in children: Is octreotide an effective and safe option in the treatment? Journal of Pediatric Gastroenterology and Nutrition 51: 454–457. Tang QY, Wen J, Wu J, Wang Y, and Cai W (2011) Clinical outcome of nutrition-oriented intervention for primary intestinal lymphangiectasia. World Journal of Pediatrics 7: 79–82. Thacker D, Patel A, Dodds K, Goldberg DJ, Semeao E, and Rychik J (2010) Use of oral budesonide in the management of protein-losing enteropathy after the Fontan operation. The Annals of Thoracic Surgery 89: 837–842. Zhu LH, Cai XJ, Mou YP, Zhu YP, Wang SB, and Wu JG (2010) Partial enterectomy: Treatment for primary intestinal lymphangiectasia in four cases. Chinese Medical Journal 123: 760–764.

Pediatric Primary and Secondary Hyperlipidemias☆ Emile Levy, Research Centre, CHU Ste-Justine and Departments of Nutrition & Pediatrics, University of Montreal, QC, Canada Valérie Marcil, Research Centre, CHU Ste-Justine and Department of Nutrition, University of Montreal, QC, Canada Edgard Delvin, Research Centre, CHU Ste-Justine and University of Montreal, QC, Canada © 2020 Elsevier Inc. All rights reserved.

Abbreviations ABCA1 ABL Apo BA CE CETP CHOL CM CRD CVD EFA ER FA FC FH HBL HDL HLP IDL LCAT LDL LDLR LPL MTP NAFLD PCSK9 PL RCT SR-B1 TG VLDL

ATP binding cassette A1 Abetalipoproteinemia Apolipoproteins Biliary acids Cholesteryl esters Cholesteryl ester transfer protein Cholesterol Chylomicron Chylomicron retention disease Cardiovascular disease Essential fatty acids Endoplasmic reticulum Fatty acids Free cholesterol Familial hypocholesterolemia Hypobetalipoproteinemia High-density lipoprotein Hyperlipoproteinemia Intermediate-density lipoprotein Lecithin-cholesterol acyltransferase Low-density lipoprotein LDL receptor Lipoprotein lipase Microsomal triglyceride transfer protein Nonalcoholic liver disease Proprotein convertase subtilisin kexin 9 Phospholipids Reverse cholesterol transport Scavenger receptor BI Triglycerides Very-low-density lipoprotein

Atherosclerosis in Childhood and Youth Available data show that pediatric patients with hyperlipidemia develop increased carotid intima-media thickening (Jarvisalo et al., 2001). Indeed, atherosclerosis can be detectable in children from 8 years old, and lipid deposits (fatty streaks, the precursors of atherosclerosis) have been discovered in children as young as 5 years old (Velican and Velican, 1979). There is even evidence that the atherosclerotic process starts from the fetal stage. The postmortem presence of fatty streaks and atherosclerotic lesions in the aorta and coronary vessels were amply documented in children consequently to lipid and lipoprotein disorders. Moreover, the atherosclerotic process beginning in childhood has the potential to lead to coronary heart disease in adults. There is definitely a consistently strong correlation between pediatric hyperlipidemia, intima-media thickening and cardiovascular disease (CVD) in adults (Schmitz and Orso, 2015). As the relationship between different lipoprotein classes and atherosclerosis becomes increasingly apparent, it is mandatory to clearly understand lipoprotein origin, composition and function. ☆

Change History: September 2018. E. Levy, V Marcil and E Delvin rewrote the entire text of the manuscript, built new Tables and Figures and modified Table 3.

This is an update of Manisha Chandalia, Nicola Abate, Hyperlipidemia, In Encyclopedia of Gastroenterology, edited by Leonard R. Johnson, Elsevier, New York, 2004, Pages 403–410.

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Lipid and Lipoprotein Species In view of their insolubility in water, lipids interact with specific proteins or apolipoproteins (Apos) to produce soluble lipidprotein complexes called lipoproteins. It is only in this form that the major exogenous (dietary) and endogenous lipids [e.g. triglycerides (TG), cholesterol (CHOL) and phospholipids (PL)], are transported in the blood stream. As noted in Fig. 1, the type and proportion of lipids in association with Apos dictate the properties (density, size and electrophoretic mobility) and define the lipoprotein species (Table 1). Generally, globular or spherical lipoproteins are characterized by a nonpolar core lipid [consisting mainly of cholesteryl esters (CE) and TG], which is surrounded by a layer containing PLs, Apos and small amounts of free cholesterol (FC) (Fig. 2). Chylomicrons (CM) and very-low density lipoproteins (VLDLs) are the largest particles with the highest TG content, whereas low-density lipoproteins (LDL) and high-density lipoproteins (HDL) are the smallest particles that essentially transport CE and PL along with Apos.

Lipoprotein Metabolism and Disorders Chylomicron Chylomicron formation Following intraluminal lipid emulsification by biliary acids (BA) and hydrolysis by pancreatic digestive enzymes, the lipolytic products are transported from the intestinal lumen to the enterocytes (Fig. 3). They are reesterified in the endoplasmic reticulum (ER) and shuttled to Apo B-48 by microsomal triglyceride transfer protein (MTP) to form pre-CM. Finally, this particle is transferred to the Golgi with the involvement of activated Sar1B GTPase and coat protein complex II before its release by exocytosis from the enterocytes into the lacteals and then into the bloodstream where it acquires Apo C-II and Apo E (Dash et al., 2015).

100 90

% of particle mass

80 70

50

PR PL FC CE

40

TG

60

30 20 10 0

CM

VLDL

IDL

LDL

HDL

Fig. 1 Lipoprotein composition. It should be noted that as TG decreases from chylomicron to HDL, protein and phospholipid levels increase. This change in profile results in an alteration of the density and size of the lipoproteins. CM, chylomicron; VLDL, very-low-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein. PR, protein; PL, phospholipid; FC, free cholesterol; CE, cholesteryl ester; TG, triglyceride.

Table 1

Plasma lipoprotein structure and composition

Lipoprotein (LP) class

Origin

Density (g/ml)

Diameter (nm)

Apolipoproteins

CM VLDL

Intestine Liver Intestine From VLDL From IDL Intestine Liver TG-rich LP metabolism

0.95 1.006

100–1200 40–50

B-48, A-I, A-IV, C-I, C-III, E B-100, A-I, A-II, A-V, C-I, C-II, C-III, E

1.006–1.019 1.019–1.063 1.063–1.210

25–30 20–25 6–10

B-100, C-I, C-II, C-III, E B-100 A-I, A-II, A-IV, A-V, C-II, C-III, E

IDL LDL HDL

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Apolipoprotein Phospholipid Triglyceride Free cholesterol Cholesteryl ester

Fig. 2 Chylomicron form and structure. The basic structure of chylomicron contains a core of neutral lipids consisting in triglycerides and cholesteryl esters, and a surface coat of more polar lipids, including phospholipids, unesterified cholesterol or free cholesterol and apolipoproteins, especially B-48, A-I and A-IV.

APO B

Alimentary lipids ER

FA PL

A-I

G

Lyso-PL

MTP

TP

as

e

(C

O

P

II)

Pase B-48

Sa

r1

b

FC CE

TG

PL

2FA

MGAT DGAT PL enzymatic system

ACAT-2

LIPASE

TG

β-MG ER FA Esterase

GOLGI

CE

FC

Enterocyte B-48 A-I

BA

FC A-IV

Chylomicron

Fig. 3 Schematic representation of lipid digestion and metabolism. Following the digestive phase, triglycerides (TG) are hydrolyzed by pancreatic lipase, cholesterol ester (CE) by cholesterol esterase, and phospholipids (PL) by phospholipase A2. Lipolytic products are emulsified and absorbed by the enterocyte. The transfer of TG, PL and CE to apolipoprotein (Apo) B-48 is provided by microsomal triglyceride transfer protein (MTP), which protects Apo B-48 from proteasome degradation. Other Apos are appended to the lipoprotein macromolecule, which is transferred to the Golgi apparatus by the complex COP II-containing Sar1b GTPase.

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Congenital malabsorptive disorders and treatment Importantly, defects in the crucial intracellular Apo B-48, MTP and Sar1b GTPase lead to hypobetalipoproteinemia (HBL), abetalipoproteinemia (ABL), and CM retention disease (CRD), respectively (Levy, 2015; Peretti et al., 2010). Young patients with these inherited disorders of CM elaboration are characterized by diarrhea, steatorrhea, acanthocytosis, low serum CHOL and Apo B deficiency, which are accompanied with failure to thrive and deficiency of both fat-soluble vitamins (E, A, D, and K) and essential fatty acids (EFA). Various multisystem manifestations are noted in Table 2. Fat intake should be reduced to 5–20 g/day, which will decrease steatorrhea while favoring marked clinical improvement and growth acceleration. Nevertheless, the diet has to be supplemented with EFAs (e.g., 5 g corn oil or safflower oil/day) to avoid EFA deficiency. Medium-chain TGs are often recommended to subjects with ABL as a caloric substitute for long-chain fatty acids (FA), but under high precautions given their secondary effects such as hepatic fibrosis. The classical treatment also includes supplements of fat-soluble vitamins. Noteworthy, oral a-tocopherol supplementation has to be initiated as early as possible to prevent neurological and retinal disability and halt/abrogate progression of the neuromuscular and myocardiopathy complications associated with this disease.

Chylomicron catabolism in the blood circulation In the circulation, postprandial CM interacts with lipoprotein lipase (LPL). After activation by Apo C-II, CM-TG are partially hydrolyzed by LPL resulting in the entry of FA into peripheral tissues and the formation of CM-remnants. Thanks to their Apo E content, CM-remnants interact with specific receptors on hepatocytes and are completely removed from the circulation (Fig. 4).

VLDL VLDL formation and assembly disorders VLDL is an important vehicle for the distribution of FAs to several peripheral organs. It is mainly produced by hepatocytes in two well defined steps: First, an Apo B-100-free lipid particle is synthesized in the smooth ER and it then fuses with the Apo B-100containing precursor particle synthesized in the rough ER to form a nascent VLDL, which will be further enriched with lipids in the Golgi apparatus before its secretion. Similar to CM, loss-of-function mutations within the MTP and APO B-100 gene are the cause of human ABL and HBL, respectively, characterized by the total absence of TG-rich lipoproteins and undetectable Apo B-100 and CHOL in the plasma of homozygous patients, along with liver steatosis.

Table 2

Molecular, biochemical and clinical phenotype in congenital malabsorption disorders

Inheritance mode Prevalence Defective gene Lipid/lipoprotein phenotype Fat-soluble vitamins Essential fatty acid Gastrointestinal manifestation Hepatic manifestation Hematologic manifestation Neurologic manifestation Ocular manifestation Anthropometric manifestation

Abetalipoproteinemia

Hypobetalipoproteinemia (homozygous)

Chylomicron retention disease

Autosomal recessive Very rare MTP ### TG, TC ### CM, VLDL, LDL # HDL ### Apo B # A, D, E, K ### "" fat malabsorption "" diarrhea, vomiting " steatosis, hepatomegaly with progressive fibrosis, cirrhosis Acanthocytosis, anemia, coagulopathy

Autosomal codominant Very rare Apo B ### TG, TC ### CM, VLDL, LDL # HDL ### Apo B # A, D, E, K ### """ fat malabsorption """ diarrhea, vomiting "" steatosis, hepatomegaly, hepatocarcinoma, cirrhosis Acanthocytosis, anemia, coagulopathy

Autosomal recessive Very rare SARA2 # TC ### CM after fat meal test # LDL, HDL # Apo B # A, D, E, K ## """ fat malabsorption """ diarrhea, vomiting "" steatosis, hepatomegaly

Peripheral neuropathy Delayed intellectual development Tremor, nystagmus # deep tendon reflexes Retinitis pigmentosa # night and color vision Blindness Failure to thrive

Peripheral neuropathy Delayed intellectual development Tremor, nystagmus # deep tendon reflexes Corneal disorders: corneal arcus and corneal opacification

Hyporeflexia Loss of proprioception Ataxia, myopathy

Failure to thrive

Failure to thrive

Anemia, coagulopathy

Electrophysiological abnormalities and retinopathy

MTP, microsomal triglyceride transfer protein; Apo B, apolipoprotein B; TG, triglyceride; TC, total cholesterol; CM, chylomicron; VLDL, very-low density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein; EFA, essential fatty acids.

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Liver

FA

Intestine FA

FA

LRP

A-I

LRP LDLR

LDLR

LDLR

TG CE

B-100

LDL

CL

B-48

E Chylomicron

E

LPL B-48

PL C-II

CM remnant

PL A-I

B-100

E

IDL

B-100

VLDL

FC E

C-II

LPL

LPL Vascular system

Vascular system

Fig. 4 Chylomicron and VLDL metabolism. Following secretion from the gut and passage through lymph and blood circulation, chylomicrons (CM) acquire Apo C-II and Apo E from HDL. As the mature CMs circulate in the bloodstream, their Apo C-II activates lipoprotein lipase (LPL) bound to capillary surfaces. Consequently, LPL hydrolyzes CM-TG, thereby allowing the distribution of FA to tissues, and the resulting CM-remnants lose their Apo C-II, interact with low- density lipoprotein receptor (LDLR) and low-density lipoprotein receptor-related protein (LRP), and are finally captured by hepatocytes.

VLDL catabolism in the blood circulation The lipolysis of VLDL by LPL generates smaller particles depleted of TG, which are called remnants or intermediate-density lipoproteins (IDL). A fraction of these particles undergoes further lipolysis and is converted to LDL particles that are taken up by the liver or peripheral tissues via the LDL receptor (LDLR) (Fig. 4).

HDL HDL formation and metabolism Nascent HDL are produced by the liver and intestine, as well as during the catabolism of CM and VLDL by LPL. These small and discoidal HDL particles contain Apo A-I that forms the initial structure of discoidal HDL and serves as the recognition molecule for most of the proteins that interact with HDL. In this way, nascent HDL can then acquire FC and PL that are effluxed from cells, a process mediated by ATP binding cassette A1 (ABCA1), resulting in the formation of mature HDL on which lecithin-cholesterol acyltransferase (LCAT) esterifies cholesterol (Fig. 5). CE accumulate in the center of HDL particles causing a change in the form from discoidal to spherical HDL3. These mature particles acquire additional CHOL from cells via ABCG1, scavenger receptor BI (SR-B1) or passive diffusion. Thereafter, the HDL transports its CHOL content to the liver either directly by interacting with hepatic SR-B1 or indirectly by transferring the CHOL to VLDL or LDL, a process facilitated by cholesteryl ester transfer protein (CETP).

HDL functions The principal HDL pathway, termed reverse cholesterol transport (RCT), ensures the dynamic movement of excess CHOL from peripheral tissues back to the liver where it is converted into BAs and excreted. By extracting CHOL from tissues, including atherosclerotic plaques, HDL reduces CVD risks. The beneficial effects of HDL may also be related to its additional functions. Indeed, HDL has anti-oxidant, anti-inflammatory, anti-thrombotic, pro-vasodilatory, antiapoptotic and atheroprotective properties. Accordingly, a wide array or proteins (50) is revealed in HDL class by proteomics, the technique allowing a large-scale analysis of proteins (Shao and Heinecke, 2018). For example, some studies reported increases in abundances of serum amyloid A and inflammatory proteins in HDL isolated from patients with CVD, which suggests a shift from an anti-inflammatory role to a proinflammatory state of HDL particles (Smith et al., 2016).

HDL disorders and treatments Deficiency of HDL-CHOL (hypoalphalipoproteinemia) results from genetic defects of ABCA1, LCAT and APOAI, which leads to Tangier disease, Fish-eye or Familial LCAT deficiency disease, and Apo A-I deficiency or Apo A-I variants, respectively (Table 4). Consequently, the patients may develop premature CVD (except for patients with LCAT deficiency), corneal opacity, neuropathy, kidney failure, hepatosplenomegaly and hemolytic anemia. Treatment should be directed at optimizing all non-HDL risk factors

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BA FC CE

TG FC PL

Liver

VLDL

ABCA1

Intestine ABCA1

CM

ABCA1

Apo A-I PL

PL FC

FC

B-100 FC

TG C-II

FC

Nascent HDL

VLDL LCAT

Peripheral cells

E

PL A-I

CETP

B-100

HDL3

PL

FC

LCAT

A-I B-100

HDL2

CE FC

Fig. 5 HDL Biogenesis. First, Apo A-I (synthesized by the gut and the liver) binds toABCA1 pore on the cell surface of peripheral cells (including enterocytes and hepatocytes). In a second step, lipid-poor Apo A-I is lipidated by ABCA1 using cellular free cholesterol (FC) and phospholipids (PL). Then, in the bloodstream, FC carried by nascent HDL particles is esterified by lecithin: cholesterol acyltransferase (LCAT) to produce spherical HDL3. Additional PL molecules are also transferred to nascent HDL by phospholipid transfer protein (PLTP). Following further extraction of FC from peripheral cells and esterification by LCAT, HDL3 is converted to mature HDL2. Importantly, cholesteryl ester (CE) may be transferred to Apo B-containing lipoproteins under the action of cholesteryl ester transfer protein (CETP) and to the hepatic scavenger receptor class B type I (SR-BI) receptor for selective uptake. The entire HDL2 may also be incorporated into the liver.

(Nair et al., 2014). There is a paucity of effective HDL-CHOL-increasing drugs in genetic hypoalphalipoproteinemia. Some reports indicate that fibrates and niacin have the capacity to raise HDL-CHOL and reduce major CVD.

LP(a) in Pediatric Population and Treatment Lp(a) is a complex of “normal” LDL with the specific glycoprotein apo(a) linked to Apo B-100 by a disulfide bridge. Lp(a) levels in youth are fully expressed by the first or second year of life, and are associated with an increased risk of arterial ischemic stroke in youth (McNeal, 2015). In fact, Lp(a) contributes to CVD because: it is avidly taken up by macrophages leading to foam cell formation, which promotes the formation of fatty streaks and atherosclerotic plaques; Apo(a) binds with high affinity to fibrinogen, which prevents binding of plasminogen to fibrin clots, interferes with fibrinolysis and inhibits activation of plasmin formation by tissue plasminogen activator; and Lp(a) has a high affinity for oxidized PLs, which allows it to interact with lymphocytes and macrophages, thereby aggravating inflammatory processes (Langlois and Nordestgaard, 2018). Antisense oligonucleotides targeting Apo(a) are a promising approach, but clinical trials are needed to obtain confirmation. Niacin and proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors have also been shown to reduce Lp(a) by 20%–30%. Importantly, good results were noted with agents used in the treatment of homozygous familial hypercholesterolaemia (FH) such as mipomersen and lomitapide.

Obesity, Obesity-Related Disorders and Hyperlipidemia Obesity and its serious comorbidities (e.g. metabolic syndrome, type 2 diabetes, nonalcoholic liver disease (NAFLD) and CVD) are global and perplexing pandemics. Obesity, defined as an excess of body-fat mass resulting from energy imbalance, leads to tissue stress and organ dysfunction. Metabolic abnormalities in adipose tissue favor accelerated lipolysis of stored TG, which translates into increased circulating free FA, provoking insulin-resistance, deregulation of hepatic glucose metabolism and, eventually, the occurrence of type 2 diabetes. The exaggerated free FA along with stimulated de novo lipogenesis and inhibited b-oxidation promote both hepatic lipid expansion and VLDL secretion. Noteworthy, the combination of adipose tissue dysfunction and ectopic fat deposition largely contributes to the genesis of atherosclerotic dyslipidemia, including significant hypertriglyceridemia, high

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LDL-CHOL, noticeable HDL lowering and postprandial CM overproduction (Higgins and Adeli, 2017). The lipid-lowering medications mentioned before can be used to counteract hyperlipidemia associated with obesity and insulin resistance.

NAFLD, Hyperlipidemia Ant Treatment With the increasing burden of obesity, there is and extent of NAFLD, which constitutes a growing public health problem. NAFLD is certainly a component of obesity and metabolic syndrome, and above all it affects about 75% of patients with type 2 diabetes. Importantly, NAFLD has emerged as the most common cause of pediatric chronic liver disorder. In infants, adolescents and adults, the occurrence of fatty liver characterizing NAFLD may progress to steatohepatitis, fibrosis and cirrhosis with elevated risk of hepatocellular carcinoma. In patients with NAFLD, LPL is not only blunted by insulin resistance, but the output of VLDL-TG is much higher than that encountered in healthy subjects. Furthermore, VLDL appear as greater particles, indicating an increased TG content. These mechanisms may explain the continuous oversecretion of VLDL that is generally associated with increased liver fat (Stahel et al., 2018). Additional information documents low plasma HDL-CHOL levels together with raised plasma concentrations of LDLCHOL, LDL, and small and dense LDL particles. Until now, there are no US Food and Drug Administration-approved medications to treat NAFLD. Similarly, guidelines for the management of NAFLD are less established. The initial management of patients typically starts with lifestyle modifications to induce weight loss in combination with omega-3 FA therapy (Spahis et al., 2018). Metformin monotherapy is added if type 2 diabetes is present. In case of failure, additional diabetes medications drugs may be suggested, which may substantially cause a decline in liver TG content and prevent progression to more severe conditions (Dibba et al., 2018).

Hypercholesterolemia in Primary Biliary Cirrhosis and Treatment Cholestatic states such as primary biliary cirrhosis and primary sclerosing cholangitis are closely associated with hypercholesterolemia and marked alterations of the enterohepatic circulation of BA. They are characterized by portal inflammation and slow progressive immune destruction of the bile canaliculi leading to cholestasis, fibrosis and cirrhosis (Brandt et al., 2015). Although raised CHOL levels represent a risk for cardiovascular morbidity and mortality, hypercholesterolaemia in patients with primary biliary cirrhosis was not considered at risk for CVD since accompanying lipoprotein X (Lp-X) in large amounts lower the atherogenicity of LDL-CHOL by preventing LDL oxidation, which suggests that Lp-X particles are able to protect the integrity of endothelial cells in the presence of hypercholesterolemia. Confirmation was obtained by measuring normal intima-media thickening of the common carotid artery and plaque scores for the extracranial carotid artery. In some studies, selective LDL apheresis, statins, fibrates and ursodeoxycholic acid improve cholestasis and clinical symptoms while lowering CHOL levels (Balmer and Dufour, 2008; Kurihara et al., 1993).

Hyperlipoproteinemia Family and Treatment Type I hyperlipoproteinemia (family chylomicronemia syndrome) In humans, LPL or Apo C-II (in 1–10/million individuals) deficiency leads to severe hypertriglyceridemia or Type I hyperlipoproteinemia (HLP), secondary to accumulation of TG-rich lipoproteins, especially CM. Biallelic mutations of lipase maturation factor 1, Apo A-5, and glycosyl-phosphatidylinositol–anchored high-density lipoprotein–binding protein 1 are among the genetic defects of Type I HLP (Hegele et al., 2018). The levels of primary chylomicronemia reaching TG > 1000 mg/dL (>11.3 mmol/L) result in eruptive xanthoma, lipemia retinalis, pancreatitis and hepatosplenomegaly (Table 3). The main therapeutic recommendation is the adherence to an extremely restrictive, low-fat diet (10–20 g daily). Patients must also avoid alcohol and medications known to increase TG concentrations, including antiretroviral agents, glucocorticoids, retinoids, atypical antipsychotic drugs, exogenous estrogen, beta-blockers, protease inhibitors and thiazides. Noteworthy, no approved treatments for primary chylomicronemia is available. Recently, Volanesorsen sodium, a new drug has been proposed to lower hypertriglyceridemia while improving physical, emotional and cognitive symptoms (Arca et al., 2018).

Type II hyperlipoproteinemia (familial hypercholesterolemia) A genetic defect either of LDLR or Apo B-100 results in abnormally low uptake of LDL by various organs and by the liver in particular (Brett et al., 2018). Consequently, there is a huge CHOL accumulation in the circulation of patients with this genetic FH disorder (Table 3), thereby explaining the associated high risk of LDL deposition in the vessel wall and the occurrence of atherosclerosis. Inheritance of only one mutant allele results in heterozygous state characterized by a 2- to 3-fold increase in circulating LDL-CHOL (5–10 mmoL/L; 200–400 mg/dL). On the other hand, a genotype with both mutant alleles, either with the same (true homozygosity) mutation (pathogenic variant) or with different pathogenic variants (compound heterozygosity), translates to total absence/ defect of the LDLR with markedly high CHOL levels (3- to 6-fold higher than normal; >15.5 mmol/L; >600 mg/dL) leading to worse prognosis. Homozygous patients develop atherosclerotic plaques and stenosis (e.g., coronary artery disease, calcifications in the aortic root and ascending aorta, aortic regurgitation, and even death) during the first two decades of life. Another causative gene in FH encodes PCSK9. Gain-of-function PCSK9 mutations were discovered to cause familial autosomal dominant hypercholesterolemia via degradation of LDLR. In addition, rare mutations in LDLR adapter protein 1, APOE p.Leu167del, or lysosomal acid lipase genes can mimic FH. Nevertheless, it is important to keep in mind that a causative mutation in candidate genes is not found in

Pediatric Primary and Secondary Hyperlipidemias Table 3

177

Classification of primary hyperlipidemia

Phenotype

Lipoprotein type

Molecular defect

Heritability

Prevalence

Lipid abnormality

Type of xanthomes

I

CM

IIb

LDL, VLDL

"" TG to 90th percentile "" TC to 90th percentile " TC & TG

Xanthoma eruptivum

LDL

III

" TC & TG

IV

CM and VLDL remnants VLDL

V

CM, VLDL

Autosomal recessive Autosomal dominant Autosomal dominant Autosomal recessive Autosomal dominant Autosomal dominant

Very rare

IIa

LPL. Apo C-II LPL inhibitor LDLR Apo B-100 LDLR Apo B-100 Apo E (E2/E3)

Xanthoma striatum palmare Xanthelasma palpebrarum Xanthoma eruptivum

Various factors and genes Various factors and genes

Common Most common Common Common

" TG

Less common

" TG to  90th percentile

Xanthoma tendineum Xanthoma tuberosum

Apo, apolipoprotein; TG, triglyceride; TC, total cholesterol; CM, chylomicron; VLDL, very-low density lipoprotein; LDL, low-density lipoprotein; LDLR, LDL receptor; LPL, lipoprotein lipase. Modified from Manisha Chanfalia and Nicola Abate. (2004). Hyperlipidemia. Encyclopedia of Gastroenterology, 404–409.

Table 4

Diseases leading to hypoalphalipoproteinemia

Gene defect

Disease

ABCA1

Inheritance mode

HDL-CHOL concentration (mg/dL)

LDL-CHOL concentration (mg/dL)

Apo-AI concentration (mg/dL)

Tangier

Autosomal recessive

5

#50%

10

LCAT

Fish-eye

Autosomal recessive

10

#50%

40

APO-AI

Apo A-I deficiency

Autosomal recessive

1

Normal

0

Clinical features Yellow-orange tonsils Neuropathy Hepatosplenomegaly Corneal opacity Early cardiovascular disease risk Corneal opacification " risk of renal failure Early cardiovascular disease risk? Corneal opacity Plane xanthoma þþþ early cardiovascular disease risk

approximately 20%–40% of clinically defined FH cases, suggesting that there are either other as yet unidentified genetic loci or these cases represent severe polygenic hypercholesterolemia. Statins and ezetimibe in type II HLP Young FH patients are first advised to adhere to a healthy lifestyle such as diet, physical activity and no smoking before pharmacological interventions. In a second step, statins- or 3-hydroxy 3-methylglutaryl coenzyme-A reductase inhibitors- are recommended since they represent the most effective drugs for lowering LDL-CHOL. However, treatment resistance, intolerance due to adverse effects, and lack of adherence are among the limitations of statins that contribute to poor outcomes. Therefore, many patients require adjunct therapies to properly control hypercholesterolemia (Cicero et al., 2018). Ezetimibe is often recommended since it selectively inhibits intestinal CHOL absorption by blocking the Niemann-Pick C1-like transporter and thus lowering CM-CHOL transfer to the liver, which upregulates LDLR expression in a compensatory way. In patients with primary hypercholesterolemia, ezetimibe monotherapy reduces LDL-CHOL by 17%–20%. The combination therapy of ezetimibe with statins resulted in 12%–23% incremental decrease of LDL-CHOL when compared to statin treatment alone. Bile acid sequestrants These drugs lower CHOL levels by binding BA in the gut and thereby interrupting the enterohepatic cycle. Therefore, to compensate for the diminished transfer of BA to the liver, more CHOL is converted to BA in the liver, thereby lowering intrahepatic CHOL content and enhancing LDLR expression, which reduces circulating LDL-CHOL (Duell and Jialal, 2016).

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Plant sterols and stanols Apparently, consumption of 2 g/day of plant sterols and stanols displace CHOL from mixed micelles, which reduces intestinal absorption and circulating LDL-CHOL by 10%. LDL apheresis The transient LDL-CHOL decrease mediated by this safe procedure is equivalent to 55%, but is expensive and must be repeated every 1–2 weeks. PCSK9 inhibition Alirocumab and evolocumab are two human monoclonal antibodies to PCSK9, which inhibit the interaction between PCSK9 and the LDLR, neutralize PCSK9, lead to an increase in the number of LDLR and, ultimately, decrease circulating LDL-CHOL (Ogura, 2018; Catapano et al., 2017). The Alirocumab is approved as an adjunct to patients with hypercholesterolemia who are already on maximally statin therapy and require further lowering of LDL. Noteworthy, these drugs can significantly reduce LDL by up to 60%–80% both as monotherapy and when combined with other lipid-lowering drugs in cases of heterozygous FH. For alirocumab, injection site reactions, myalgia, and neurocognitive and ophthalmologic events were more common when compared with placebo groups while for evolocumab, nonspecific adverse events such as arthralgia, headache, limb pain, fatigue and neurocognitive events were reported more frequently than in placebo groups. Apo B antisense Mipomersen, an antisense single-strand oligonucleotide that inhibits the production of Apo B by binding to the mRNA that encodes the synthesis of Apo B. The design is for biallelic knock-down (Gebhard et al., 2013). It is approved for use in the USA for treatment of homozygous FH and is administered by weekly subcutaneous injection. In clinical trials, weekly subcutaneous injections of mipomersen were able to reduce LDL-CHOL levels by 25%.

Type III Hyperliproteinemia (Lipoprotein Remnant Disorder) Aberrant metabolism of CM- and VLDL-remnants, due to absence or dysfunctional genetic variants of Apo E, leads to familial Type III HLP (Table 3). While Apo E3 represents the normal variant, Apo E2 (substitution of cysteine for arginine at residue 158 accounting for >90% of cases) interacts poorly with the LDLR, the low affinity high capacity heparan sulfate proteoglycans receptors and LDLR like protein, thereby producing hyperlipidemia essentially characterized by accumulation of remnants. A diagnosis of the autosomal recessive Type III HLP is made when plasma TG > 200 mg/dL and the ratios of total CHOL (mmol/L)/Apo B (g/L)  6.2 and TG (mmol/L)/Apo B (g/L) < 10. Heterozygotes do not develop Type III HLP. Approximately 10% of patients with Type III HLP have other variants of Apo E that will cause Type III HLP with only a single allele of the mutant Apo E gene, which will constitute a dominant trait with high penetrance (Blum and Type, 2016). Clinical manifestations include xanthomatosis and atherosclerotic CVD. Type III HLP responds exquisitely to lifestyle treatment and pharmacotherapy. Importantly, dietary therapy induces an approximately 60% reduction in total CHOL and non-HDL-CHOL, as well as an 80% reduction in TG. Statins, fibrates and nicotinic acid yield excellent lipid responses in patients with Type III HLP.

Type IV Hyperlipoproteinemia (Familial Hypertriglyceridemia) According to Fredrickson’s classification, Type IV HLP is characterized by fasting hypertriglyceridemia (1.5–4.9 mmol/L) and a family history of lipid abnormalities. Type IV HLP is due to a genetic autosomal dominant defect that increases the secretion of VLDL by the liver, thereby raising the risks of abnormal glucose tolerance, athero-eruptive xanthoma, pancreatitis and CVD (Table 3). Obesity, metabolic syndrome, type 2 diabetes, hypopituitarism, contraceptive steroids and glycogen storage disease I are secondary causes that trigger the development of Type IV HLP. Diet control (exclusion of saturated fat and alcohol, and restriction of processed sugar), exercise, weight loss, drugs (fenofibrate, niacin, gemfibrozil) and diabetes management are among the therapeutic conditions to significantly lower circulating VLDL.

Type V Hyperlipoproteinemia (Combined/Mixed Hyperlipidemia) Type V HLP is characterized by increased amounts of plasma CM and VLDL, as well as by decreased LDL and HDL after overnight fasting (Table 3). In these conditions, TG levels are considerably elevated (>1000 mg/dL) and enhance the risk of acute pancreatitis. Some patients exhibit high total CHOL concentrations that can be accounted for by primarily by increased VLDL-CHOL. Complete assessment of patients with Type V HLP also involves family sampling to discern the presence of familial Type V. In addition to primary Type V, secondary Type V has been noted and its development involves a multitude of metabolic derangements, including low TG clearance and/or their increased output aggravated by obesity, insulin resistance, type 2 diabetes, alcohol intake, or use of some hormones. Primary and secondary Type V often share eruptive xanthomata, lipemia retinalis, hepatosplenomegaly and pancreatitis. Nonpharmacologic management involves lifestyle modifications such as diet, exercise, weight reduction, smoking cessation and alcohol abstinence. Children and adults respond well to medications, such as fibric acid derivatives (gemfibrozil, fenofibrate), niacin and omega-3 polyunsaturated fatty acids (Liamis et al., 2002).

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Conclusions More and more overwhelming evidence is accumulating to highlight primary and secondary lipid disorders in the pediatric population, which obviously represents a major health challenge for clinicians. It has to be stressed that combined dyslipidemia is currently the predominant dyslipidemic pattern in youth, characterized by a moderate-to-severe raise in TG and non-HDL-CHOL, marginal elevation in LDL-CHOL, and decreased HDL-CHOL. Pharmacologic treatment in this disorder is rarely needed as even limited weight loss may be effective in ameliorating the lipid/lipoprotein profile. If the combination of lifestyle and recommended food choices is the cornerstone of prevention of cardiovascular disease, pharmacologic agents offer the possibility to lower lipid and lipoprotein levels while producing clinical benefits for young patients at high risk. Pediatricians are advised to consult clinical practice guidelines, which are largely based on expert opinion, and are devoted to significantly improve outcomes and reduce unnecessary practice variation.

Acknowledgments The authors thank Mrs. Schohraya Spahis for her technical assistance and graphical illustrations.

See Also: Cholesterol Absorption

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Pediatric Vascular Abnormalities☆ Henry Shiau and Ryan Himes, Baylor College of Medicine, Houston, TX, United States © 2020 Elsevier Inc. All rights reserved.

Glossary

Arteriovenous malformation High-flow lesions between abnormal arteries and veins via multiple anomalous communications, without a normal intervening capillary bed. Blue Rubber Bleb Nevus syndrome A disorder consisting of multifocal venous malformations of the skin, soft tissues/ muscles, gastrointestinal tract, or almost any organ. Capillary malformation Non-symptomatic, simple malformation consisting of dilated capillary or post-capillary venules. Hemangioma Common, benign endothelial tumor which follow a common pattern of proliferation followed by involution. Hereditary Hemorrhagic Telangiectasia Also known as Osler-Weber-Rendu disease; autosomal dominant inheritance of vascular malformations in multiple organ systems, including the lungs, brain and gastrointestinal tract. Kaposiform hemangioendothelioma Endothelial hyperplasia, which is less discrete and more aggressive than typical hemangioma. It can be associated with very low platelet counts (known as Kasabach-Merritt phenomenon). Kasabach-Merritt phenomenon Complication of platelet trapping within a vascular tumor, commonly associated with Kaposiform hemangioendotheliomas. Klippel-Trenaunay syndrome Rare congenital complex combined vascular malformation, consisting of capillary, venous and/or lymphatic malformations, with associated soft tissue and/or bone hypertrophy, generally of a single, lower extremity. Lymphatic malformation Low-flowing vascular malformations consisting of cystic, malformed lymphatic channels. Propranolol Non-selective beta-blocker commonly used for management of high blood pressure and irregular heart rates, which is also indicated in the treatment of symptomatic hemangiomas. Vascular malformation A result of abnormal development of vascular structures. They are sub-classified based on their predominant channel type (capillary, venous, lymphatic, arteriovenous). Vascular tumor Tumors that derive from vascular origin, which can be subcategorized into benign, aggressive/borderline, or malignant groups. Venous malformation Most common simple vascular malformation consisting of soft, compressible venous channels.

Classification Pediatric vascular anomalies were historically split into two categories: tumors and vascular malformations. Due to a better understanding of genetic etiologies and identification of more complex disease entities, recent guidelines by the International Society for the Study of Vascular Anomalies (ISSVA) further subdivide these groups to provide a more uniform classification (Table 1). Since tumors and vascular malformations are managed differently, it is important to differentiate between these diagnoses during initial work-up. Vascular tumors have been subcategorized into three groups (benign vascular tumors, locally aggressive or borderline vascular tumors, and malignant vascular tumors; see Table 2). As hemangiomas are common vascular tumors in pediatric hepatology and gastroenterology, they will be emphasized in this chapter. Antiquated terms such as “cavernous” or “angioma” are incorrect and should not be used in clinical practice. Often, lesions described as “cavernous hemangiomas” are in fact vascular malformations rather than true hemangiomas. Vascular malformations are the result of inborn errors of vascular morphogenesis and consist of non-neoplastic, quiescent endothelium. These lesions have been subcategorized into four groups (simple, combined, malformations of major named vessels, and malformations associated with other anomalies). Within the simple subcategory, malformations are further subdivided into their main vessel composition—capillaries, lymphatics, veins, and arteriovenous malformations, many of which can be found in the liver and/or GI tract. Specific syndromes with GI manifestations such as Klippel-Trenaunay syndrome will be discussed briefly. The suffix “-oma” often indicates a neoplastic process and its use should be avoided in describing vascular malformations (Wassef et al., 2015).

☆

Change History: November 2018. HH Shiau and RW Himes updated the text and further reading to the entire article, added Tables 1–4, and deleted original Fig. 5.

This is an update of Xenia B. Hom, Steven J. Fishman, Vascular Abnormalities, Pediatric, In Encyclopedia of Gastroenterology, edited by Leonard R. Johnson, Elsevier, New York, 2004, Pages 593–599.

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Pediatric Vascular Abnormalities Table 1

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2014 ISSVA classification of vascular anomalies

Vascular anomalies Vascular tumors

Vascular malformations

Benign

Simple

Combined

Associated with other anomalies

Malformations of major named vessel

Locally aggressive or borderline

CM

CM þ VM CM þ LM CM þ AVM LM þ VM CM þ LM þ VM CM þ LM þ AVM CM þ VM þ AVM CM þ LM þ VM þ AVM

See Table 4

Based on associated major vessel

LM VM

Malignant

AVM Arteriovenous fistula

CM—Capillary Malformations, LM—Lymphatic malformations, VM—Venous malformations, AVM—Arteriovenous Malformations. Wassef M, Blei F, Adams D, et al. (2015). Vascular anomalies classification: Recommendations from the International Society for the Study of Vascular Anomalies. Pediatrics 136(1), 203–214.

Table 2

Classification of vascular tumors

Classification of vascular tumors Benign vascular tumors

Locally aggressive or borderline vascular tumors

Malignant vascular tumors

• •

• • •

• •

• • • • •

Infantile hemangioma/hemangioma of infancy Congenital hemangioma ○ Rapidly involuting CH (RICH)a ○ Noninvoluting CH (NICH) ○ Partially involuting CH (PICH) Tufted angiomaa,b Spindle cell hemangioma Epitheliod hemangioma Pyogenic granuloma (or lobular capillary hemangioma) Others

• • •

a,b

Kaposiform hemangioendothelioma Retiform hemangioendothelioma Papillary intralymphatic angioendothelioma, Dabska tumor Composite hemangioendothelioma Kaposi sarcoma Others

•

Angiosarcoma Epithelioid hemangioendothelioma Other

CH—Capillary hemangioma. a Some lesions may be associated with thrombocytopenia and/or consumptive coagulopathy. b Many experts believe that these are part of a spectrum rather than distinct entities. Wassef M, Blei F, Adams D, et al. (2015). Vascular anomalies classification: Recommendations from the International Society for the Study of Vascular Anomalies. Pediatrics 136(1), 203–214.

Vascular Tumors Hemangiomas Epidemiology and pathogenesis Hemangioma is the most common tumor of infancy and childhood, affecting between 4% and 10% of pediatric patients and with predilection for infants of low birth weight, multiple births, Caucasian patients, and females (5:1 ratio F:M) (Gnarra et al., 2016; Wassef et al., 2015; Lee and Bercovitch, 2013). Animal models propose that hemangiomas derive from multipotent endothelial stem cells, leading to vasculogenesis and proliferation of size. Hepatic hemangiomas (except for the focal subtype) have pathognomonic immunostaining for glucose transporter-1 (GLUT-1) (Lee and Bercovitch, 2013; Khan et al., 2008). (1) Proliferation stage: Lasts from shortly after birth until around 1 year of age, characterized by rapid proliferation of new blood vessels and high expression of angiogenic factors such as vascular endothelial growth factor (VEGF). (2) Involuting stage: Begins after the proliferation stage and lasts up to several years, characterized by differentiation and apoptosis of endothelial cells. The rate of regression is unrelated to the appearance, site, size of tumor, or the gender of the patient. Involution is complete in 50% of children by 5 years and in 70% by 7 years of age, with gradual improvement until 10–12 years of age. (3) Involuted stage: Following the involuting stage, the hemangioma is replaced by fibrofatty tissue and may at this point become invisible. Lesions that have ulcerated during proliferation leave a scar (Fig. 1) (Table 2).

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Fig. 1 Typical cutaneous hemangioma.

Clinical manifestations Hemangiomatosis refers to multiple cutaneous and visceral hemangiomas. The liver serves as the most common extracutaneous location of hemangiomas, followed by the gastrointestinal tract (Gnarra et al., 2016; Wassef et al., 2015). Though generally benign, a small minority of hepatic hemangiomas may become symptomatic or even life-threatening. Typical initial presentation is right upper quadrant fullness. Other common findings include hepatomegaly, anemia, thrombocytopenia, and jaundice. More severe complications include abdominal compartment syndrome, high output cardiac failure, arteriovenous malformation shunting and severe hypothyroidism (secondary to high levels of 3-iodothyronine deiodinase activity in hemangioma tissue) (Huang et al., 2000). Large tumor size, facial involvement, and segmented morphology tend to be predictive of poor outcomes (Haggstrom et al., 2006; Canty et al., 2014; Gnarra et al., 2016). The pattern of liver involvement can be divided into three categories: Focal, multifocal, and diffuse. Focal hepatic hemangiomas are single, spherical lesions that can be detected on prenatal ultrasound. Most lesions will involute before or soon after birth. Unlike multifocal and diffuse hemangiomas, focal lesions stain negative for GLUT-1. Focal hemangiomas are associated with cutaneous lesions in 15% of cases and do not typically present with associated symptoms (Kulungowski et al., 2012). A majority of hepatic hemangiomas are of the multifocal subtype. These generally develop after birth and can be associated with cutaneous lesions. Multifocal hepatic hemangiomas stain positive for GLUT-1 and consist of multiple, individual spherical lesions separated by normal liver tissue. Multifocal lesions are commonly associated with high-flow shunting which can eventually lead to high-output cardiac failure (Lee and Bercovitch, 2013; Horii et al., 2011; Dickie et al., 2014). Diffuse hemangiomas develop in the post-natal period and also stain positive for GLUT-1. In contrast to the multifocal subtype, diffuse lesions replace most, if not all of the surrounding normal hepatic parenchyma. Diffuse hemangiomas may actually represent a continuum from a previously unrecognized and untreated multifocal hemangioma (Lee and Bercovitch, 2013; Horii et al., 2011; Dickie et al., 2014).

Radiologic features

If a patient has >6 cutaneous hemangiomas, miliary hemangiomas, or a large solitary cutaneous lesion in combination with one or more smaller hemangiomas, an initial screening ultrasound is recommended to evaluate for hepatic involvement. Other modalities, such as CT or MRI, can further define anatomic extent of lesions and may also help in differentiating from other hepatic lesions, such as hepatoblastoma, mesenchymal hamartoma, and angiosarcoma (Canty et al., 2014). On ultrasound, focal lesions appear as individual solitary spheres. On CT, focal lesions have a central hypodensity with centripetal enhancement. On MRI, focal lesions appear hypointense relative to the liver on T1-weighted sequences and hyperintense on T2-weighted sequences (Dickie et al., 2014). On CT, multifocal lesions are hypodense and homogenous with either uniform or centripetal enhancement. In addition, there may also be evidence for arteriovenous shunting. On MRI, multifocal lesions present as enhanced spheres that are hypointense relative to the liver on T1-weighted sequences and hyperintense on T2-weighted sequences (Dickie et al., 2014). On CT, diffuse lesions display as numerous, rapidly enhancing lesions. On MRI, diffuse lesions appear as variable proliferating lesions with hyper-enhancement (Gnarra et al., 2016). One should be aware that because both intrahepatic hemangioma and arteriovenous malformations (AVMs) are fast flow, they can often be mistaken for one another. Finally, radionuclide scanning with technetium Tc-99 m-tagged red blood cells can be used to document deep multiple hemangiomas in the GI tract.

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Treatment Most lesions require no treatment. However, if there is a threat to life, limb, vital function, or significant tissues, the lesions should be treated pharmacologically. Currently, the first-line agent is oral propranolol, 1–3 mg/kg/day, maintained for several months with subsequent wean. Though corticosteroids were previously the preferred treatment, propranolol is now favored due to fewer side effects and superior response time. Use of interferon-alpha has fallen out of favor, secondary to risk of motor developmental disturbances, including spastic diplegia, which have been reported in up to 5% of infants. Side effects of propranolol include hypotension, hypoglycemia, bradycardia, and exacerbation of bronchospasm (Leaute-Labreze et al., 2015; Gnarra et al., 2016). Because of the current success of medical therapy, the need for embolization or surgical intervention has become rare. However, in severe cases involving abdominal compartment syndrome, surgical decompression or even liver transplant may be considered (Dickie et al., 2014). In cases of such large lesions, it is crucial to screen for acquired hypothyroidism, as some hemangiomas have been demonstrated to express type 3 iodothyronine deiodinase, which inactivates circulating thyroid hormone. Prior screening for congenital hypothyroidism is generally normal in these individuals and a normal early thyroid-stimulating hormone does not ensure that hypothyroidism will not develop as a hemangioma enlarges. Thus, repeated testing should be performed if the lesion undergoes significant growth. Gastrointestinal hemangiomas are rare and typically found as either discrete or segmental lesions in the small bowel. In a study by Soukoulis et al., bleeding usually occurred within the first 4 months of life, corresponding with the typical early-onset involution pattern of hemangiomas. Persistent bleeding may necessitate repeat transfusions. Imaging modalities, such as highresolution Doppler ultrasound, CT with contrast, or MRI, are recommended for initial diagnosis. Given the predilection to the mid-gut (possibly secondary to a common SMA vascular blood supply), diagnosis by endoscopy is not recommended but may be used to rule-out other sources of proximal GI bleeding. Propranolol is used as first-line therapy, with other modalities, such as corticosteroids, reserved for recalcitrant cases (Drolet et al., 2012; Soukoulis et al., 2015). In the case of diffuse infiltrative hemangioma(s) with life-threatening hemorrhage, management consists of supportive care with repeated transfusions, parenteral nutrition, and antiangiogenic therapy (to accelerate involution), rather than surgical resection (as this is usually not possible). Congenital hemangioma is a rare variant in which a lesion is fully grown at birth and involutes rapidly, usually by 1 year of age. No congenital hemangioma has been reported in the gastrointestinal tract.

Kaposiform Hemangioendotheliomas Kaposiform hemangioendotheliomas (KHEs) are rare, early-onset pediatric vascular tumors that typically present within the first year of life (95%) or at birth (77%) (Liu et al., 2015). A recent retrospective analysis at a large pediatric vascular center estimated around 673 total documented cases of KHE in the United States (Croteau et al., 2013). Due to similar age of presentation and involvement of cutaneous lesions, KHEs may be confused with hemangiomas. Differentiation between the two is highly important, given the more aggressive nature of KHEs. An infiltrative tumor, KHE can cross tissue planes, sometimes between dermis, fascia, muscle and even bone. Visceral organ involvement (particularly retroperitoneal organs) has been reported, with scattered case reports of both gastrointestinal and liver disease (Nakaya et al., 2014; Haradome et al., 2015). On MRI, KHEs display as a hyperintense mass with reticular stranding in subcutaneous fat and with poorly defined tumor margins than may cross tissue planes (Croteau et al., 2013). KHEs consist of unique spindle-shaped tumor cells with small slit- or sieve-like blood vessels, which are intersected with sections of fibrous stroma. KHE’s are prone to the Kasabach-Merritt phenomena (KMP), a complication associated with platelet trapping within the tumor. KMP can present with thrombocytopenia and intravascular coagulation, which places the patient at risk for hemorrhage in various sites, including the gastrointestinal tract (Wang et al., 2015; Abdulrahman et al., 2017). Though corticosteroids currently serve as first-line therapy, prior studies with successful use of vincristine have been reported (Wang et al., 2015; Croteau et al., 2013). Platelet transfusion should be avoided unless there is active bleeding or a surgical procedure is indicated. Heparin should not be given, as it can stimulate tumor growth, platelet trapping, and worsen bleeding.

Vascular Malformations Simple malformations generally consist of a single type of vessel (capillary, venous, lymphatic). The exception is arteriovenous malformations which consist of several types of separate vessels in communication with one another, leading to subsequent shunting (Wassef et al., 2015) (Table 3).

Capillary Malformations Capillary malformations (CM) are typically present at birth and persist throughout life. Variants of nomenclature include “port wine stain,” “nevus simplex,” “salmon patch,” or “stork bite.” All CMs tend to fade before the age of 5 years. Histologically, CMs are composed of dilated capillary to venular sized vessels, with a paucity of normal nerve fibers around these vessels on

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Pediatric Vascular Abnormalities Table 3

•

•

•

• •

Simple Vascular Malformations

CMs ○ Cutaneous and/or mucosal CM (“Port wine” stain) – CM with bone and/or soft tissue overgrowth – CM with CNS and/or ocular anomalies (Sturge-Weber Syndrome) – CM of CM-AVM – CM of microcephaly-CM (MICCAP) – CM of megalencephaly-CM-polymicrogyria (MCAP) ○ Telangiectasia – Hereditary hemorrhagic telangiectasia (HHT; different types) – Others ○ Cutis marmorata telangiectatica congenital (CMTC) ○ Nevus simplex (“Salmon patch”, “Angel kiss”, “Stork bite”) ○ Others LMs ○ Common (cystic) LMs – Macrocystic LM – Microcystic LM – Mixed cystic LM ○ Generalized lymphatic anomaly (GLA) ○ LM in Gorham-Stout disease ○ Channel-type LM ○ Primary lymphedema ○ Others VMs ○ Common VM ○ Familial VM cutaneo-mucosal (VMCM) ○ Blue rubber bleb nevus (Bean) syndrome VM ○ Glomuvenous malformation (GVM) ○ Cerebral cavernous malformation (CCM; different types) ○ Others AVMs ○ Sporadic ○ In HHT ○ In CM-AVM AVFs ○ Sporadic ○ In HHT ○ In CM-AVM ○ Others

Wassef M, Blei F, Adams D, et al. (2015). Vascular anomalies classification: recommendations from the International Society for the Study of Vascular Anomalies. Pediatrics 136(1), 203–214.

immunohistochemical staining. It is extremely rare to have symptomatic capillary malformations of the viscera, and therefore they generally do not require treatment (Wassef et al., 2015).

Venous Malformations Venous malformations are the most common symptomatic vascular anomaly of the GI tract in childhood. Most patients have only a single lesion, though some have multiple malformations. Most of these malformations are sporadic, although studies do describe association with TIE2 mutations in some hereditary cutaneous venous malformations (Wouters et al., 2010). Histologically, VM channels are lined by endothelium and lack smooth muscle. Morphology and range of organ involvement is wide, with small, superficial lesions to larger lesions infiltrating multiple visceral organ planes. Grossly, VMs are blue-to-purple in color and can affect every organ system, including the skin, GI tract and/or liver. They are soft, refill shortly after compression and release, and can increase in volume with Valsalva maneuver. Secondary to this characteristic, VMs are sometimes termed cavernous hemangiomas. This term is incorrect as VMs are not tumors, do not involute, and do not response to pharmacologic treatment (Wassef et al., 2015; Cahill and Nijs, 2011). Though VMs are generally asymptomatic, some patients may present with swelling and pain due to stagnation of blood in venous channels (Cahill and Nijs, 2011). Formation of phleboliths—palpable, rounded thrombi—may be visible on imaging, if calcified (Wassef et al., 2015). These may serve as a distinguishing feature of venous malformations, as phleboliths do not form with

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Fig. 2 Typical cutaneous venous malformation.

hemangiomas. Thrombosis may also lead to local consumptive coagulopathy. In large lesions, systemic hypofibrinogenemia and prolonged prothrombin time may result from factor consumption. In the GI tract, they most commonly present with upper or lower, acute or chronic, gastrointestinal bleeding. Since GI bleeding is not common in childhood, it is often not suspected or identified until the patient is found to be profoundly anemic. This is highlighted by the fact that children independent in toileting may not report a change in bowel habits and if parents notice dark-colored stools, they may not appreciate their significance. Pain and obstruction are less common presenting symptoms of venous malformations in the gut. They are common in the liver and spleen (often improperly termed hemangiomas) and usually asymptomatic. Venous malformations are generally classified into two categories: focal and diffuse (Fig. 2). A single, focal venous malformation can occur anywhere in the gastrointestinal tract, vary in size (20 cm diameter), and can be mucosal, mural, or transmural (Fig. 3). Focal VMs drain through small channels into normal adjacent veins. Doppler ultrasound, CT and MRI can be used to evaluate the anatomical extent of VMs. Endoscopic ultrasound can be used to determine the depth of mural involvement, although the entire lesion must be viewed, as there can be varying depths of involvement in different parts of the same lesion. Therapeutic endoscopic procedures should be performed only on superficial lesions and surgical backup should be available for complications that may arise. Small, muscosal lesions can be eradicated with endoscopic band ligation. If the lesion is not transmural, endoscopic sclerotherapy may also be used. Sclerotherapy functions by destroying vascular endothelial cells within the lesion and may not be effective in treatment of larger lesions (Mulligan et al., 2014). Potential complications include perforation (if unsuspected transmural lesions are treated endoscopically) and intravascular migration of sclerosing material from large lesions (if there are anomalous or large vessels communicating with the lesion). In such cases, pretreatment angiography or intralesional injection of contrast under fluoroscopy may be helpful. Surgical procedures should focus on eliminating bleeding rather than complete removal of abnormal tissue (Dasgupta and Fishman, 2014). Diffuse venous malformations involve large contiguous sections of bowel and extraintestinal structures (such as mesentery, retroperitoneum, pelvis, muscles, subcutaneous tissues, and skin). Diffuse VMs, in contrast with focal VMs, may communicate with major conducting veins, posing increased risk for complications following sclerotherapy (Mulligan et al., 2014). Upper visceral diffuse venous malformations may involve the mesenteric, splenic, and portal veins. If the portal vein is anomalous, one should investigate for presinusoidal hypertension. These lesions may be untreatable, although portal decompression can be helpful by decreasing intralumenal pressure of the malformation. Lower visceral diffuse venous malformations can extend from the anorectum proximally. They usually are transmural and extend into the pelvis. They may involve the entire colon or just the left side. Imaging studies demonstrate a markedly thickened colon and anorectum with or without phleboliths. Colonoscopy reveals a massively engorged, purple mucosa with contiguous varix-like projections, which can cause chronic bleeding requiring life-long, repeated transfusions. However, endoscopic therapy is futile in all cases and may exacerbate the bleeding. Surgery can involve partial colectomy with end colostomy or colectomy with anorectal

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Fig. 3 Endoscopic appearance of colonic venous malformation.

Fig. 4 Skin lesions of the Blue Rubber Bleb Nevus syndrome.

mucosectomy and endorectal coloanal or ileoanal pull-through. Full-thickness rectal resection should be avoided because there can be uncontrollable hemorrhage from the extrarectal pelvic venous malformation. Blue Rubber Bleb Nevus syndrome (BRBNS) consists of multifocal venous malformations of the skin, soft tissues/muscles, gastrointestinal tract, or almost any organ. Skin lesions vary in size (usually 3–15 mm), are deep blue or purple in color, are flat or minimally raised, may be tender to palpation, and have a predilection for the trunk, palms, and soles (Fig. 4). A patient may have anywhere from a few to hundreds of skin lesions (Ballieux et al., 2015; Wassef et al., 2015) and clinical suspicion is typically elucidated by cutaneous physical exam findings. Gastrointestinal lesions have an endoscopically pathognomonic appearance: discrete, purple berry-like protuberances, several millimeters to centimeters in size, scattered from mouth to anus (Fig. 5). Most are broad-based, but some have a narrow pedicle. Typically, there is a broad rim of normal mucosa encircling the base and extending up

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Fig. 5 Intestinal lesions of the Blue Rubber Bleb Nevus syndrome.

to the reddish blue apex of the lesion, although normal mucosa may also cover the entire mass. Affected patients present from early infancy to young adulthood, invariably with chronic GI bleeding (usually consistent black stools rather than acute hemorrhage) and anemia. Some studies report association with chromosome 9p and potential for autosomal dominance in familial cases (Gallione et al., 1995). However, general consensus remains that BRBNS is a sporadic disease. Total body survey may be done by either contrast-enhanced CT or Tc-99 m-labeled red blood cell scan. CT or MRI may be used to exclude brain vascular involvement (Chen et al., 2017). Though cutaneous lesions generally remain asymptomatic, some patients may complain of pain. Symptoms are thought to be secondary to contraction of smooth muscle fibers or by activation of sweat glands in proximity to lesions. GI manifestations may present as anemia with melena; spontaneous hemorrhagic rupture is rarely reported. Intussusception or volvulus may also occur due to potential intestinal lead points (Chen et al., 2017). Currently, there is no consensus on therapy, though options include observation, chronic transfusions, and iron replacement therapy. Other potential pharmacological therapies include corticosteroids, propranolol, thalidomide, interferon-alpha, and sirolimus (Aksu et al., 2016). In patients with GI symptoms or anemia, endoscopic evaluation may be considered. Endoscopic interventions, including argon plasma coagulation, sclerotherapy, and band ligation have been reported with variable success. Surgical removal has remained controversial secondary to concern for lesion recurrence after removal and risk of short bowel syndrome (Chen et al., 2017). However, Fishman et al. reported success in eradication of GI bleeding by surgical excision, regardless of location or number. This study questioned the validity of “recurring” lesions and theorized that these were actually residual, incompletely removed lesions which subsequently expanded.

Arteriovenous Malformations AVMs are high-flow lesions between abnormal arteries and veins via many anomalous communications, without a normal intervening capillary bed. AVMs are classified within the “Simple Vascular Malformation” category. Forty percent of AVMs are present at birth and pathogenesis is thought to be sporadic. These lesions tend to be latent in early childhood with progression in adolescence to warm, pinkish-blue cutaneous lesions with pulsatile thrill (Wassef et al., 2015). Endoscopically, AVMs in the gut appear pulsatile and demonstrate high flow on endoscopic ultrasound. Embolization of GI AVMs generally results in necrosis and perforation. Thus, surgical resection is the only curative therapy for gut lesions and presurgical localization may be performed by tattooing during selective arteriography. Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu disease, is an autosomal dominant disorder characterized by AVMs in the GI tract, brain, and lungs. Patients may present with recurrent spontaneous epistaxis and may have characteristic telangiectasia found in the GI tract, oral cavity, lips, and nose (Canzonieri et al., 2014). GI bleeding may present with either occult anemia or findings of melena, hematemesis, or rectal bleeding. Liver involvement has been reported and may rarely present with portal hypertension (Zakko, 2013; Chao et al., 2012). EGD and colonoscopy can be used for evaluation of the stomach, proximal duodenum and colon. For small bowel disease that is out of range for normal endoscopy, video capsule endoscopy can be utilized (Canzonieri et al., 2014). Treatment modalities, such as endoscopic argon plasma coagulation, are reserved for symptomatic patients requiring multiple transfusions. Potential utility for therapies such as estrogen, progesterone, octreotide and thalidomide have been reported (O’Meara et al., 2015; Bauditz et al., 2004; Albinana et al., 2010; Szilagyi and Ghali, 2006; Canzonieri et al., 2014; Zakko, 2013).

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Lymphatic Malformations Lymphatic malformations (LMs) are low-flow vascular malformations that consist of cystic, malformed lymphatic channels. Lesions can be divided into macrocystic, microcystic, or mixed groups. Lymphatic malformations of the GI tract are generally rare and, if present, remain asymptomatic until adulthood. Children can present with non-specific symptoms such as abdominal pain, distention, diarrhea, constipation, or nausea. LMs can be evaluated through modalities such as ultrasonography or MR imaging (Dasgupta and Fishman, 2014). Treatment should be reserved for symptomatic cases. For macrocystic lesions, percutaneous image-guided intralesional aspiration with subsequent sclerotherapy (i.e. doxycycline, ethanol, STS, bleomycin) may be utilized. Microcystic lesions are generally asymptomatic but may require surgical resection if larger, confluent lesions sometimes lead to mass effect. Occasionally, LM can mimic symptoms similar to inguinal hernias, requiring sclerosis (macrocystic) or surgical dissection (microcystic) (Mulligan et al., 2014; Dasgupta and Fishman, 2014). Waldmann Disease (intestinal lymphangiectasia) is a rare disorder characterized by dilated intestinal lacteals within all layers of bowel. Common presenting symptoms are non-specific (e.g., abdominal pain, nausea/vomiting) though patients may also present with seizures secondary to hypocalcemia. Endoscopy can be utilized for direct visualization of intestinal lymphangiectasis. Treatment is generally supportive with close monitoring of fluid balance and electrolytes. Dietary management includes low-fat, high-protein diet with medium-chain triglycerides to prevent engorgement and subsequent rupture of intestinal lymphatic vessels. Surgical resection may be reserved for severe cases of localized disease (Dasgupta and Fishman, 2014).

Vascular Malformations Associated With Other Anomalies: Klippel-Trenaunay Syndrome Klippel-Trenaunay syndrome (KTS) is a complex combined vascular malformation consisting of capillary, venous and/or lymphatic malformations (Wassef et al., 2015). This rare congenital syndrome is characterized by associated soft tissue and/or bone hypertrophy, generally of a single, lower extremity. Purple capillary stains and/or vesicles may be visible and palpable on the skin. Slow bleeding from the rectum or distal colon may lead to a presentation of severe anemia, though GI bleeding is uncommon otherwise. On colonoscopy, the appearance of lesions is varied, sometimes with diffuse purple vascular discoloration and varied degrees of mural thickening. Lesions should not be biopsied due to the risk of severe bleeding. An endoscopic evaluation of the entire GI tract should be done for complete view of involvement/extension of lesions. Asymptomatic patients with mild anemia may be managed by iron supplementation and clinical observation. Patients with repeated need for transfusion secondary to chronic or severe anemia may require further intervention. Angiography can localize bleeding and subsequently may be used for intra-arterial embolization. Surgical resection is reserved for severe, life-threatening lesions. Due to large venous malformations seen in KTS, clinicians should also be aware of potential complications of hypercoagulable state and thrombosis (Samo et al., 2013) (Table 4). An appreciation of clinical patterns, accurate nomenclature, associated visible cutaneous lesions, endoscopic appearances, and radiologic findings is important in the proper diagnosis and treatment of vascular anomalies of the gastrointestinal tract (Fig. 6).

Table 4

Vascular malformations associated with other anomalies

Vascular malformations associated with other anomalies Klippel–Trenaunay syndrome Parkes–Weber syndrome Servelle–Martorell syndrome Sturge–Weber syndrome Limb CM þ congenital nonprogressive limb hypertrophy Maffucci syndrome Macrocephaly-CM (M-CM)/megalencephaly-CM-polymicrogyria (MCAP) Microcephaly-CM (MICCAP) CLOVES syndrome Proteus syndrome Bannayan–Riley–Ruvalcaba syndrome

CM þ VM þ/ LM þ limb overgrowth CM þ AVF þ limb overgrowth Limb VM þ bone undergrowth Facial þ leptomeningeal CM þ ocular anomalies þ/ bone and/or soft tissue overgrowth VM þ/ spindle cell hemangioma þ enchondroma

LM þ VM þ CM þ/ AVM þ lipomatous overgrowth CM, VM and/or LM þ asymmetric somatic overgrowth AVM þ AM þ macrocephaly, lipomatous overgrowth

Wassef M, Blei F, Adams D, et al. (2015). Vascular anomalies classification: Recommendations from the International Society for the Study of Vascular Anomalies. Pediatrics 136(1), 203–214.

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Fig. 6 Klippel–Trenaunay syndrome.

See Also: Pediatric Lymphatic Development and Intestinal Lymphangiectasia. Vascular Diseases of the Liver

References Abdulrahman A, Yan J, and Hou S (2017) Kaposiform hemangioendothelioma in an adult spleen: An unusual presentation. Human Pathology: Case Reports 10: 15–17. Aksu A, Sari S, Odul Egritas G, and Dalgic B (2016) Favorable response to sirolimus in a child with blue rubber bleb nevus syndrome in the gastrointestinal tract. Clinical and Laboratory Observations 39(2): 147–149. Albinana V, Bernabeu-Herrero ME, Zarrabeitia R, Bernabeu C, and Botella LM (2010) Estrogen therapy for hereditary haemorrhagic telangiectasia (HHT): Effects of Raloxifene on Endoglin and ALK1 expression in endothelial cells. Thrombosis and Haemostasis 103: 525–534. Ballieux F, Boon LM, and Vikkula M (2015) Blue bleb rubber nevus syndrome. In: Islam MP and Roach ES (eds.) 3rd series, Handbook of Clinical Neurology, vol. 132, pp. 223–230. Elsevier. Bauditz J, Schachschal G, Wedel S, and Lochs H (2004) Thalidomide for treatment of severe intestinal bleeding. Gut 53: 609–612. Cahill AM and Nijs EL (2011) Pediatric vascular malformations: Pathophysiology diagnosis, and the role of interventional radiology. Cardiovascular and Interventional Radiology 34: 691–704. Canty KM, Horii KA, Ahmad H, Lowe LH, and Nopper AJ (2014) Multiple cutaneous and hepatic hemangiomas in infants. Southern Medical Journal 107(3): 159–164. Canzonieri C, Centenara L, Ornati F, et al. (2014) Endoscopic evaluation of gastrointestinal tract in patients with hereditary hemorrhagic telangiectasia and correlation with their genotypes. Genetics in Medicine 16(1): 3–10. Chao C, Chuang S, Chen J, and Lee K (2012) Hereditary hemorrhagic telangiectasia presenting as portal hypertension. Kaohsiung Journal of Medical Sciences 28: 241–242. Chen W, Chen H, Shan G, et al. (2017) Blue rubber bleb nevus syndrome: Our experience and new endoscopic management. Medicine 96(33): 1–6. Croteau SE, Liang MG, Koazkewich HP, et al. (2013) Kaposiform hemangioendothelioma: Atypical features and risks of Kasabach-Merritt phenomenon in 107 referrals. The Journal of Pediatrics 162(1): 142–147. Dasgupta R and Fishman SJ (2014) Management of visceral vascular anomalies. Seminars in Pediatric Surgery 23: 216–220.

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Dickie BH, Fishman SJ, and Azizkhan RG (2014) Hepatic vascular tumors. Seminars in Pediatric Surgery 23(4): 168–172. Drolet BA, Pope E, Juem A, et al. (2012) Gastrointestinal bleeding in infantile hemangioma: A complication of segmental rather than multifocal, infantile hemangiomas. The Journal of Pediatrics 160: 1021–1026. Gallione C, Pasyk K, Boon L, et al. (1995) A gene for familial venous malformations maps to chromosome 9p in a second large kindred. Journal of Medical Genetics 32(3): 197–199. Gnarra M, Behr G, Kitajewski A, et al. (2016) History of the infantile hepatic hemangioma: From imaging to generating a differential diagnosis. World Journal of Clinical Pediatrics 5(3): 273–280. Haggstrom A, Drolet B, Baselga E, et al. (2006) Prospective study of infantile hemangiomas: Clinical characteristics predicting complications and treatment. Pediatrics 118(3): 882–887. Haradome H, Toda Y, Koshinaga T, Sugitani M, and Abe O (2015) A case of kaposifrom hemangioendothelioma at sigmoid colon. Japanese Journal of Radiology 33(8): 484–498. Horii KA, Drolet BA, Frieden IJ, et al. (2011) Prospective study of the frequency of hepatic hemangiomas in infants with multiple cutaneous infantile hemangiomas. Pediatr Dermatol 28: 245–253. Huang S, Tu H, Harney J, et al. (2000) Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas. New England Journal of Medicine 343(3): 185–189. Khan ZA, Boscolo E, Picard A, et al. (2008) Multipotential stem cells racpitulate human infantile hemangioma in immunodeficient mice. The Journal of Clinical Investigation 118(7): 2592–2599. Kulungowski A, Alomari A, Chawla A, Christison-Lagay E, and Fishman S (2012) Lessons from a liver hemangioma registry: Subtype classification. Journal of Pediatric Surgery 47(1): 165–170. Lee KC and Bercovitch L (2013) Update on infantile hemangiomas. Seminars in Perinatology 37: 49–58. Leaute-Labreze C, Hoeger P, Mazereeuq-Hautier J, et al. (2015) A randomized, controlled trial of oral propranolol in infantile hemangioma. New England Journal of Medicine 372(8): 735–746. Liu Q, Jiang L, Wu D, et al. (2015) Clinicopathological features of Kaposiform hemangioendothelioma. International Journal of Clinical and Experimental Pathology 8(10): 13711–13718. Mulligan PR, Prajapati HJS, Martin LG, and Patel TH (2014) Vascular anomalies: Classification, imaging characteristics, and implications for interventional radiology treatment approaches. The British Journal of Radiology 87(1035): 20130392. Nakaya T, Morita K, Kurata A, et al. (2014) Multifocal kapsoiform hemangioendothelioma in multiple visceral organs: An autopsy of 9-day-old female baby. Human Pathology 45(8): 1773–1777. O’Meara M, Cicalese M, Bordugo A, et al. (2015) Successful use of long-acting octreotide for intractable chronic gastrointestinal bleeding in children. Journal of Pediatric Gastroenterology and Nutrition 60: 48–53. Samo S, Sherid M, Husein H, et al. (2013) Klippel-Treanaunay syndrome causing life-threatening GI bleeding: A case report and review of the literature. Case Reports in Gastrointestinal Medicine 1–6. Soukoulis IW, Liang MG, Fox VL, et al. (2015) Gastrointestinal infantile hemangioma: Presentation and management. Journal of Pediatric Gastroenterology and Nutrition 61: 415–420. Szilagyi A and Ghali M (2006) Pharmalogical therapy of vascular malformations of the gastrointestinal tract. Canadian Journal of Gastroenterology 20(3): 171–178. Wang Z, Li K, Yao W, et al. (2015) Steroid-resistant Kaposiform Hemangioendothelioma: A retrospective study of 37 patients treated with vincristine and long-term follow-up. Pediatric Blood & Cancer 62(4): 577–580. Wassef M, Blei F, Adams D, et al. (2015) Vascular anomalies classification: Recommendations from the International Society for the Study of vascular anomalies. Pediatrics 136(1): 203–214. Wouters V, Limaye N, Uebelhoer M, et al. (2010) Hereditary cutaneomucosal venous malformations are cuased by TIE2 mutations with widely variable hyper-phosphorylating effects. European Journal of Human Genetics 18: 414–420. Zakko L (2013) Hereditary hemorrhagic telangiectasia: Gastrointestinal features. Atlas of Dermatological Manifestations of Gastrointestinal Disease 81–82.

Further Reading Fishman SJ, Smithers CJ, Folkman J, et al. (2005) Blue rubber bleb nevus syndrome: Surgical eradication of gastrointestinal bleeding. Annals of Surgery 241(3): 523–528. Han EC, Kim S, Kim H, Jung S, and Park K (2014) Gastrointestinal hemangioma in childhood: A rare cause of gastrointestinal bleeding. Korean Journal of Pediatrics 57(5): 245–249. Toro A, Mahfouz A, Ardiri A, et al. (2014) What is changing in indications and treatment of hepatic hemangiomas. A review. Annals of Hepatology 13(4): 327–339.

Peptic and Marginal Ulcer Disease☆ C Mel Wilcox, University of Alabama at Birmingham, Birmingham, AL, United States © 2020 Elsevier Inc. All rights reserved.

Definition Peptic ulcer is a mucosal defect extending to the muscularis mucosae traditionally located in the stomach or proximal duodenum. However, these lesions can be occur in the esophagus or distal duodenum and proximal jejunum. Marginal ulcers occur postoperatively.

Epidemiology In the late 19th century and early 20th century, peptic ulcer disease (PUD) was considered common (Graham, 2014). Such an assumption was based upon necropsy studies and subsequently, upper gastrointestinal (GI) series that demonstrated an ulcer. Gastric ulcer was considered much more common than duodenal ulcer, which was considered a phenomenon only witnessed over the last half century (see below). Also, during the mid and later 20th century, surgery was frequently utilized for both acute, complicated as well as chronic ulcer disease. Because of this prevalence, the study of ulcer disease and its management consumed gastrointestinal research during this time period. For some time, the prevalence rate of peptic ulcer in the United States was considered 5% (Chan and Lanas, 2017). However, based principally upon retrospective epidemiological studies of PUD using the surrogate markers of hospitalization and mortality, there is consensus today that this rate is much lower (Kivilaakso et al., 2002). This reduction in incidence is considered related to a fall in rates of Helicobacter pylori (HP) infection. While the incidence of PUD has fallen coincident with the overall reduction in HP incidence, complicated PUD remains important likely due to the wide spread use of aspirin and over the counter NSAIDs as well as the proliferation of newer anticoagulant agents, which may precipitate bleeding ulcer (McNeil et al., 2018; Arguedas et al., 2015).

Pathobiology Ulcer disease is considered a balance between protective and aggressive factors which impact the gastric and duodenal mucosa (Table 1). Imbalances in these factors may tilt a mucosal defect or injury to either healing vs. progression to ulceration. Protective factors include gastric mucosal blood flow and prostaglandin production. Aggressive factors include HP infection, gastric acid, pepsin, NSAIDs, tobacco, and a variety of other injurious agents (e.g. medications). It was not until the revolutionary discovery of HP and its association with chronic active gastritis and PUD in the 1980s and 1990s that the pathogenesis and natural history of ulcer disease changed course. Indeed, numerous studies have shown that HP leads to gastritis and duodenal ulcer as well as some gastric ulcers. Later, many multicentered randomized clinical trials demonstrated that eradication of the organism cures ulcer disease. Also, infection of HP in a volunteer resulted in dyspepsia and chronic active antral gastritis confirming cause and effect. In this case, the gastritis was ultimately cleared by antibiotic therapy confirming Koch’s postulate. While HP infection is more commonly associated with duodenal ulcer, and NSAIDs with gastric ulcer, there is wide overlap. At the turn of the century, it was hypothesized that HP infection was acquired at a very early age (