Textbook of Pediatric Gastroenterology, Hepatology and Nutrition: A Comprehensive Guide to Practice 3030800679, 9783030800673

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Stefano Guandalini Anil Dhawan Editors

Textbook of Pediatric Gastroenterology, Hepatology and Nutrition A Comprehensive Guide to Practice Second Edition

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Textbook of Pediatric Gastroenterology, Hepatology and Nutrition

Stefano Guandalini  •  Anil Dhawan Editors

Textbook of Pediatric Gastroenterology, Hepatology and Nutrition A Comprehensive Guide to Practice Second Edition

Editors Stefano Guandalini Section of Pediatric Gastroenterology Hepatology and Nutrition University of Chicago Chicago, IL USA

Anil Dhawan Pediatric Liver, GI and Nutrition Center Child Health, King’s College Hospital London UK

ISBN 978-3-030-80067-3    ISBN 978-3-030-80068-0 (eBook) https://doi.org/10.1007/978-3-030-80068-0 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Preface to the Second Edition

We are delighted to present the second edition of the Textbook of Pediatric Gastroenterology, Hepatology and Nutrition to you all. We were overwhelmed by the interest shown by the readers in the first edition, reflected in many thousand downloads of the chapters. In the meantime, during the past 5 years or so, a huge amount of research has been published in the field of gastroenterology, hepatology, and nutrition, resulting in a new understanding of the pathophysiological mechanisms of childhood gastrointestinal and liver disorders that has helped to develop newer diagnostics, therapies, and guidelines. It was time to compile the new relevant information in an updated second edition. Thus, our authors and the editors have worked hard to put together the most useful and upto-date practical information and present it in the revised chapters. Furthermore, new authors have been included who are the opinion leaders in their subjects, maintaining and enhancing the international inclusive approach that uniquely keeps characterizing our book. This edition, like the first one, maintains the practical and ready reference approach for all our readers: trainees, allied healthcare professionals, and established senior practitioners in the field of pediatric gastroenterology, hepatology, nutrition, and transplantation, maintaining the very vision that the late Dr. Branski originally had and that inspired us. We are humbly confident that we have succeeded in delivering that in this edition as well. Lastly, we would like to thank the publisher for the enthusiasm and trust in our leadership to help deliver the second edition despite the disruption caused by the Covid-19 pandemic. We, as editors, are grateful to all the authors for their work and their trust in our role. All of them have carefully and thoroughly reviewed and updated the information by including latest published evidence to enrich the learning experience of the readers and allow them to deliver the best care to all our patients, from babies to young adults. Chicago, IL, USA London, UK

Stefano Guandalini Anil Dhawan

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Acknowledgments

I take this opportunity to thank my colleagues who contributed to the second edition of this book for their attention to detail and punctuality. I would like to thank my wife Anita, who has been behind everything that I have done well in life, and our two boys, Atin and Ashish, for their love and support. – Anil Dhawan It’s hard to believe 5 years have already gone by since the first edition of this textbook appeared. Besides the original inspiration by the late David Branski, without whose input this book would have never seen the light, I want to acknowledge here not only again all those whom I thanked for the first edition, from my illustrious mentors to the colleagues in ESPGHAN and NASPGHAN and the broader world of my beloved creature FISPGHAN, but also my partners and friends – new and old – at the University of Chicago, who praised this enterprise. Last but not least, I am sincerely thankful to the unwavering love and support from my wife Greta both during the long years of work and now on my retirement, even more demanding! – Stefano Guandalini

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Contents

Part I GI-Nutrition 1 Microvillus Inclusion Disease and Tufting Enteropathy���������������������������������������    3 Agostino Nocerino and Stefano Guandalini 2 The Spectrum of Autoimmune Enteropathy ���������������������������������������������������������   19 Natalia Nedelkopoulou, Huey Miin Lee, Maesha Deheragoda, and Babu Vadamalayan 3 Congenital Problems of the Gastrointestinal Tract�����������������������������������������������   31 Nigel J. Hall 4 Pyloric Stenosis���������������������������������������������������������������������������������������������������������   45 Indre Zaparackaite, Shailee Sheth, and Ashish P. Desai 5 Gastrointestinal Problems of the Newborn������������������������������������������������������������   51 Christophe Dupont, Nicolas Kalach, and Véronique Rousseau 6 Enteral Nutrition in Preterm Neonates�������������������������������������������������������������������   65 Gianluca Terrin, Maria Di Chiara, Giulia Sabatini, Thibault Senterre, and Mario De Curtis 7 Parenteral Nutrition in Premature Infants�������������������������������������������������������������   87 Sissel J. Moltu, Alexandre Lapillonne, and Silvia Iacobelli 8 Infectious Esophagitis�����������������������������������������������������������������������������������������������  103 Salvatore Oliva, Sara Isoldi, and Salvatore Cucchiara 9 Eosinophilic Esophagitis�������������������������������������������������������������������������������������������  111 Mason Nistel and Glenn T. Furuta 10 Gastroesophageal Reflux�����������������������������������������������������������������������������������������  125 Yvan Vandenplas and Sébastien Kindt 11 Esophageal Achalasia�����������������������������������������������������������������������������������������������  157 Efstratios Saliakellis, Anna Rybak, and Osvaldo Borrelli 12 Helicobacter Pylori Gastritis and Peptic Ulcer Disease�����������������������������������������  169 Zrinjka Mišak and Iva Hojsak 13 Ménétrier Disease in Children���������������������������������������������������������������������������������  185 Jasmina Kikilion, Elvira Ingrid Levy, and Yvan Vandenplas 14 Viral Diarrhea�����������������������������������������������������������������������������������������������������������  189 Alfredo Guarino and Eugenia Bruzzese 15 Bacterial Infections of the Small and Large Intestine�������������������������������������������  203 Rachel Bernard and Maribeth Nicholson

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16 Intestinal Parasites���������������������������������������������������������������������������������������������������  219 Phoebe Hodges and Paul Kelly 17 Persistent Diarrhea in Children in Developing Countries �����������������������������������  231 Jai K. Das, Zahra Ali Padhani, and Zulfiqar A. Bhutta 18 HIV and the Intestine�����������������������������������������������������������������������������������������������  241 Andrea Lo Vecchio and Francesca Wanda Basile 19 The Spectrum of Functional GI Disorders�������������������������������������������������������������  255 Heidi E. Gamboa and Manu R. Sood 20 Disorders of Sucking and Swallowing���������������������������������������������������������������������  265 Francesca Paola Giugliano, Erasmo Miele, and Annamaria Staiano 21 Defecation Disorders in Children: Constipation and Fecal Incontinence�����������  279 Desiree F. Baaleman, Shaman Rajindrajith, Niranga Manjuri Devanarayana, Carlo Di Lorenzo, and Marc A. Benninga 22 Hirschsprung’s Disease and Intestinal Neuronal Dysplasias �������������������������������  305 Massimo Martinelli and Annamaria Staiano 23 Intestinal Pseudo-Obstruction���������������������������������������������������������������������������������  313 Efstratios Saliakellis, Anna Rybak, and Osvaldo Borrelli 24 Gastrointestinal and Nutritional Problems in Neurologically Impaired Children ���������������������������������������������������������������������������������������������������  327 Paolo Quitadamo and Annamaria Staiano 25 Cyclic Vomiting Syndrome���������������������������������������������������������������������������������������  333 Katja Kovacic and BU K Li 26 Food Allergy���������������������������������������������������������������������������������������������������������������  345 Ragha Suresh, So Lim Kim, Scott H. Sicherer, and Christina E. Ciaccio 27 Eosinophilic Gastrointestinal Disorders Beyond Eosinophilic Esophagitis���������  361 Eleni Koutri and Alexandra Papadopoulou 28 Crohn’s Disease���������������������������������������������������������������������������������������������������������  379 Marina Aloi and Salvatore Cucchiara 29 Inflammatory Bowel Disease Unclassified (IBD-U)/Indeterminate Colitis���������  393 Barbara S. Kirschner 30 Ulcerative Colitis�������������������������������������������������������������������������������������������������������  401 Anita Rao and Ranjana Gokhale 31 Microscopic Colitis���������������������������������������������������������������������������������������������������  423 Anita Rao and Ranjana Gokhale 32 Vasculitides Including IgA Vasculitis (Henoch–Schönlein Purpura)�������������������  431 Karunesh Kumar, Jutta Köglmeier, and Keith J. Lindley 33 Lymphonodular Hyperplasia�����������������������������������������������������������������������������������  443 Tuomo J. Karttunen and Sami Turunen 34 Acute Pancreatitis�����������������������������������������������������������������������������������������������������  451 Jonathan Wong, Praveen S. Goday, and Steven L. Werlin 35 Chronic and Hereditary Pancreatitis ���������������������������������������������������������������������  461 Elissa M. Downs and Sarah Jane Schwarzenberg

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36 Congenital Disorders of Intestinal Electrolyte Transport�������������������������������������  473 Lavinia Di Meglio and Roberto Berni Canani 37 Congenital Disorders of Lipid Transport���������������������������������������������������������������  485 Allie E. Steinberger, Emile Levy, and Nicholas O. Davidson 38 Immunodeficiency Disorders Resulting in Malabsorption�����������������������������������  495 Lavinia Di Meglio, Laura Carucci, and Roberto Berni Canani 39 Exocrine Pancreatic Insufficiency���������������������������������������������������������������������������  513 Amornluck Krasaelap, Steven L. Werlin, and Praveen S. Goday 40 Celiac Disease �����������������������������������������������������������������������������������������������������������  525 Stefano Guandalini and Valentina Discepolo 41 Cystic Fibrosis�����������������������������������������������������������������������������������������������������������  549 Zev Davidovics and Michael Wilschanski 42 Small Intestinal Bacterial Overgrowth�������������������������������������������������������������������  567 David Avelar Rodriguez, Paul MacDaragh Ryan, and Eamonn Martin Mary Quigley 43 Short Bowel Syndrome���������������������������������������������������������������������������������������������  585 Cecile Lambe and Olivier Goulet 44 Malnutrition �������������������������������������������������������������������������������������������������������������  609 Susan C. Campisi, Amira Khan, Clare Zasowski, and Zulfiqar A. Bhutta 45 Enteral Nutrition�������������������������������������������������������������������������������������������������������  625 Mora Puertolas and Timothy A. Sentongo 46 Parenteral Nutrition in Infants and Children �������������������������������������������������������  647 Susan Hill 47 Intussusception���������������������������������������������������������������������������������������������������������  663 Rachael Essig, Brian A. Jones, and Mark B. Slidell 48 Meckel’s Diverticulum���������������������������������������������������������������������������������������������  669 Meghna S. Vaghani and Ashish P. Desai 49 Appendicitis���������������������������������������������������������������������������������������������������������������  673 Megan E. Bouchard, Mark B. Slidell, and Brian A. Jones 50 Gastrointestinal Vascular Anomalies ���������������������������������������������������������������������  681 Melania Matcovici, Indre Zaparackaite, and Ashish P. Desai 51 Polyps and Other Tumors of the Gastrointestinal Tract���������������������������������������  689 Warren Hyer, Marta Tavares, and Mike Thomson 52 Fecal Microbiota Transplantation in Children������������������������������������������������������  709 Valentina Giorgio, Elisa Blasi, and Giovanni Cammarota 53 Prebiotics in Pediatrics���������������������������������������������������������������������������������������������  713 Francesco Savino 54 Probiotics in Pediatric Gastroenterology���������������������������������������������������������������  721 Hania Szajewska 55 Postbiotics �����������������������������������������������������������������������������������������������������������������  733 Seppo Salminen and Hania Szajewska

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Part II Hepatology 56 Normal Liver Anatomy and Introduction to Liver Histology�������������������������������  739 Maesha Deheragoda 57 Diagnostic Procedures in Paediatric Hepatology���������������������������������������������������  743 Andreas Panayiotou, Annamaria Deganello, and Maria E. Sellars 58 Infantile Cholestasis: Approach and Diagnostic Algorithm���������������������������������  765 Narmeen I. Khan and Ruba K. Azzam 59 Biliary Atresia and Choledochal Malformations���������������������������������������������������  773 Elke Zani-Ruttenstock and Mark Davenport 60 Congenital Hepatic Fibrosis, Caroli’s Disease, and Other Fibrocystic Liver Diseases �����������������������������������������������������������������������������������������������������������  791 N. M. Rock, I. Kanavaki, and V. A. McLin 61 Familial Intrahepatic Cholestasis ���������������������������������������������������������������������������  807 Tassos Grammatikopoulos 62 Alagille Syndrome�����������������������������������������������������������������������������������������������������  819 Shannon M. Vandriel and Binita M. Kamath 63 Chronic Viral Hepatitis B and C�����������������������������������������������������������������������������  833 Stefan Wirth 64 Bacterial, Fungal and Parasitic Infections of the Liver�����������������������������������������  843 Anita Verma 65 Liver Disease in Primary Immunodeficiencies�������������������������������������������������������  851 Nedim Hadzic 66 Autoimmune Liver Disease �������������������������������������������������������������������������������������  855 Giorgina Mieli-Vergani and Diego Vergani 67 Liver-Based Inherited Metabolic Disorders�����������������������������������������������������������  875 Roshni Vara 68 Wilson’s Disease �������������������������������������������������������������������������������������������������������  899 Piotr Socha and Stuart Tanner 69 Nonalcoholic Fatty Liver Disease ���������������������������������������������������������������������������  911 Emer Fitzpatrick 70 Vascular Disorders of the Liver�������������������������������������������������������������������������������  931 Ruth De Bruyne and Pauline De Bruyne 71 Portal Hypertension in Children�����������������������������������������������������������������������������  953 Angelo Di Giorgio and Lorenzo D’Antiga 72 Liver Tumors in Children�����������������������������������������������������������������������������������������  983 Mohamed Rela, Ashwin Rammohan, and Mettu Srinivas Reddy 73 Acute Liver Failure in Children �����������������������������������������������������������������������������  995 Naresh P. Shanmugam and Anil Dhawan 74 Complications of Cirrhosis in Children ����������������������������������������������������������������� 1007 Naresh P. Shanmugam and Anil Dhawan 75 Nutritional Management of Children with Liver Disease������������������������������������� 1025 Sara Mancell

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76 Paediatric Liver Transplantation ��������������������������������������������������������������������������� 1033 Annalisa Dolcet and Nigel Heaton 77 Growing Up with Liver Disease������������������������������������������������������������������������������� 1051 Marianne Samyn, Jemma Day, and Anna Hames 78 New Horizons in Paediatric Hepatology: A Glimpse of the Future��������������������� 1063 Emer Fitzpatrick and Anil Dhawan Index���������������������������������������������������������������������������������������������������������������������������������  1071

Contributors

Marina  Aloi Pediatric Gastroenterology and Liver Unit, Department of Women’s and Children’s Health, Sapienza University of Rome, Rome, Italy Ruba  K.  Azzam Department of Pediatrics, Section of Gastroenterology, Hepatology & Nutrition, University of Chicago, Chicago, IL, USA Desiree  F.  Baaleman Pediatric Gastroenterology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH, USA Francesca  Wanda  Basile Baylor College of Medicine Children’s Foundation, Kampala, Uganda Baylor International Pediatric AIDS Initiative, Pediatrics, Baylor College of Medicine, Houston, TX, USA Marc  A.  Benninga Pediatric Gastroenterology, Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands Rachel Bernard  Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, TN, USA Roberto Berni Canani  Department of Translational Medical Sciences, University Federico II, Naples, Italy CEINGE Advanced Biotechnologies Research Center, University Federico II, Naples, Italy European Laboratory for the Investigation of Food Induced Diseases, University Federico II, Naples, Italy Zulfiqar  A.  Bhutta  Division of Women and Child Health, Aga Khan University, Karachi, Pakistan Institute for Global Health & Development, Karachi, Pakistan Center for Global Child Health, Hospital for Sick Children, Toronto, ON, Canada Elisa Blasi  Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy Osvaldo  Borrelli  Department of Paediatric Gastroenterology, Division of Neurogastroenterology & Motility, Great Ormond Street Hospital for Children, London, UK Megan E. Bouchard, MD  Department of Surgery, MedStar Georgetown University Hospital, Washington, DC, USA Eugenia  Bruzzese Department of Translation Medical Science, Section of Pediatrics, University of Naples “Federico II”, Naples, Italy Giovanni Cammarota  Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Università cattolica del sacro cuore, Rome, Italy xv

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Contributors

Susan C. Campisi  Centre for Global Child Health, Hospital for Sick Children, Peter Gilgan Centre for Research and Learning (PGCRL), Toronto, ON, Canada Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada Laura Carucci  Department of Translational Medical Science, University of Naples Federico II, Naples, Italy CEINGE Advanced Biotechnologies Research Center, University of Napes Federico II, Naples, Italy Christina E. Ciaccio, MD MSc  Department of Medicine, University of Chicago, Chicago, IL, USA Department of Pediatrics, University of Chicago, Chicago, IL, USA Salvatore  Cucchiara  Pediatric Gastroenterology and Liver Unit, Department of Women’s and Children’s Health, Sapienza University of Rome, Rome, Italy Lorenzo  D’Antiga  Department of Pediatric Hepatology, Gastroenterology Transplantation, Hospital Papa Giovanni XXIII—Bergamo, Bergamo, Italy

and

Jai K. Das  Division of Women and Child Health, Aga Khan University, Karachi, Pakistan Mark Davenport  Department of Paediatric Surgery, King’s College Hospital, London, UK Zev  Davidovics Pediatric Gastroenterology Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel Nicholas O. Davidson  Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA Jemma Day  Institute of Liver Studies, King’s College Hospital, London, UK Pauline De Bruyne  Department of Pediatric Gastroenterology, Sophia Children’s Hospital, Erasmus Medical Center, Rotterdam, The Netherlands Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium Ruth De Bruyne  Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ghent University Hospital, Ghent, Belgium Mario De Curtis  Sapienza University of Rome, Policlinico Umberto I, Rome, Italy Annamaria Deganello  Department of Radiology, King’s College Hospital, London, UK Division of Imaging Sciences, King’s College London, London, UK Maesha  Deheragoda Liver Histopathology Laboratory, Institute of Liver Studies, King’s College Hospital, London, UK Ashish P. Desai  Department of Pediatric Surgery, Royal London Hospital, London, UK Niranga Manjuri Devanarayana  Department of Physiology, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka Anil Dhawan  Pediatric Liver, GI and Nutrition Center and MowatLabs, Child Health, King’s College Hospital, London, UK Maria Di Chiara  Sapienza University of Rome, Policlinico Umberto I, Rome, Italy Angelo Di Giorgio  Department of Pediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII—Bergamo, Bergamo, Italy Carlo Di Lorenzo  Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH, USA

Contributors

xvii

Lavinia  Di Meglio Department of Translational Medical Science, University of Naples Federico II, Naples, Italy Diagnostica Ecografica e Prenatale di A.Di Meglio, Naples, Italy Valentina  Discepolo  Department of Translational Medical Sciences, Section of Pediatrics, University of Naples Federico II, Naples, Italy Annalisa Dolcet  Institute of Liver Studies, Denmark Hill, London, UK Elissa  M.  Downs Pediatric Gastroenterology, Hepatology and Nutrition, University of Minnesota Masonic Children’s Hospital, Minneapolis, MN, USA Christophe  Dupont Department of Pediatric Gastroenterology and Nutrition, Necker  – Enfants Malades Hospital, Paris Descartes University, AP-HP, Paris, France Rachael  Essig, MD Department of Surgery, MedStar Georgetown University Hospital, Washington, DC, USA Section of Pediatric Surgery, Department of Surgery, Comer Children’s Hospital, University of Chicago Medicine, Chicago, IL, USA Emer Fitzpatrick  Paediatric Liver, GI and Nutrition Center and MowatLabs, King’s College Hospital, London, UK Glenn  T.  Furuta Department of Pediatrics, Mucosal Inflammation Program, Section of Gastroenterology, Hepatology and Nutrition and Gastrointestinal Eosinophilic Diseases Program, University of Colorado School of Medicine, Aurora, CO, USA Digestive Health Institute, Children’s Hospital Colorado, Aurora, CO, USA Heidi E. Gamboa, DO  Pediatric Gastroenterology, Nicklaus Children’s Hospital, Miami, FL, USA Valentina Giorgio  Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy Francesca  Paola  Giugliano Department of Translational Medical Sciences, Section of Pediatrics, University of Naples “Federico II”, Naples, Italy Praveen S. Goday  The Medical College of Wisconsin and Children’s Wisconsin, Department of Pediatric Gastroenterology, Hepatology and Nutrition, Milwaukee, WI, USA Ranjana  Gokhale  Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, IL, USA Olivier Goulet  Department of Pediatric Gastroenterology, Hepatology and Nutrition, Hopital Necker-Enfants Malades, Paris, France Université de Paris, Paris, France Tassos Grammatikopoulos  Paediatric Liver, GI, Nutrition Centre and Mowat Labs, King’s College Hospital NHS Foundation Trust, Denmark Hill, London, UK Institute of Liver Studies, King’s College Hospital NHS Foundation Trust, Denmark Hill, London, UK Stefano Guandalini  Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, IL, USA Alfredo  Guarino Department of Translation Medical Science, Section of Pediatrics, University of Naples “Federico II”, Naples, Italy Nedim  Hadzic Pediatric Centre for Hepatology, Gastroenterology and Nutrition, King’s College Hospital, London, UK

xviii

Nigel  J.  Hall Department of Paediatric Surgery and Urology, Southampton Children’s Hospital, Southampton, UK University Surgery Unit, Faculty of Medicine, University of Southampton, Southampton, UK Anna Hames  Institute of Liver Studies, King’s College Hospital, London, UK Nigel Heaton  King’s Healthcare Partners, Kings College Hospital FT NHS Trust, Institute of Liver Studies, Denmark Hill, London, UK Susan Hill  Department of Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK Phoebe  Hodges  Blizard Institute, Barts & The London School of Medicine, Queen Mary University of London, London, UK Iva Hojsak  Referral Center for Pediatric Gastroenterology and Nutrition, Children’s Hospital Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia Warren Hyer  The Polyposis Registry, St Mark’s Hospital, Middx, UK Silvia  Iacobelli Réanimation Néonatale et Pédiatrique, Néonatologie, CHU La Réunion, Saint Pierre, France Sara Isoldi  Pediatric Gastroenterology and Liver Unit, Department of Women’s and Children’s Health, Sapienza University of Rome, Rome, Italy Brian A. Jones, MD  Section of Pediatric Surgery, Department of Surgery, Comer Children’s Hospital, UChicago Medicine, Chicago, IL, USA Nicolas Kalach  Department of Pediatric Gastroenterology and Nutrition, Necker – Enfants Malades Hospital, Paris Descartes University, AP-HP, Paris, France Saint Antoine Pediatric Clinic, Saint Vincent de Paul Hospital, Groupement des Hôpitaux de l’Institut Catholique de Lille (GH-ICL), Catholic University, Lille, France Binita M. Kamath  Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON, Canada Department of Pediatrics, University of Toronto, Toronto, ON, Canada I. Kanavaki  3d Department of Pediatrics, Athens University, “Attikon” University Hospital, Chaidari, Greece Tuomo J. Karttunen  Department of Pathology, Cancer and Translational Medicine Research Unit and Medical Research Center Oulu, University of Oulu, Oulu, Finland Department of Pathology, Oulu University Hospital, Oulu, Finland Paul  Kelly  Tropical Gastroenterology & Nutrition Group, University of Zambia School of Medicine, Lusaka, Zambia Amira Khan  Centre for Global Child Health, Hospital for Sick Children, Peter Gilgan Centre for Research and Learning (PGCRL), Toronto, ON, Canada Narmeen I. Khan  Comer Children’s Hospital, University of Chicago Medicine, Chicago, IL, USA Jasmina Kikilion  Vrije Unversiteit Brussel (VUB), UZ Brussel, KidZ Health Castle, Brussels, Belgium So Lim Kim, MD  Department of Medicine, University of Chicago, Chicago, IL, USA Sébastien  Kindt Department of Gastroenterology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium

Contributors

Contributors

xix

Barbara S. Kirschner  Department of Pediatrics, Section of Gastroenterology, Hepatology & Nutrition, University of Chicago Medicine, Chicago, IL, USA Jutta  Köglmeier Division of Intestinal Rehabilitation and Nutrition, Department of Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK Eleni Koutri  Division of Gastroenterology and Hepatology, First Department of Pediatrics, University of Athens, Children’s Hospital “Agia Sofia’’, Athens, Greece Katja Kovacic  Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI, USA Amornluck  Krasaelap The Medical College of Wisconsin and Children’s Wisconsin, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Milwaukee, WI, USA Karunesh  Kumar Division of Neurogastroenterology and Motility, Department of Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK Division of Intestinal Rehabilitation and Nutrition, Department of Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK Cecile Lambe  Department of Pediatric Gastroenterology, Hepatology and Nutrition, Hopital Necker-Enfants Malades, Paris, France Université de Paris, Paris, France Alexandre  Lapillonne Paris University, APHP Necker-Enfants Malades Hospital, Paris, France CNRC, Baylor College of Medicine, Houston, TX, USA Huey Miin Lee  Paediatric Liver, GI and Nutrition Centre, King’s College Hospital, London, UK Elvira  Ingrid  Levy Vrije Unversiteit Brussel (VUB), UZ Brussel, KidZ Health Castle, Brussels, Belgium Emile Levy  Research Centre, CHU Ste-Justine and Department of Nutrition, Université de Montréal, Montreal, QC, Canada BU  K  Li Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI, USA Keith  J.  Lindley Division of Neurogastroenterology and Motility, Department of Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK Sara  Mancell  Paediatric Liver GI and Nutrition Center, King’s College Hospital, London, UK Massimo  Martinelli  Department of Translational Medical Sciences, Section of Pediatrics, University of Naples “Federico II”, Naples, Italy Melania Matcovici  Department of Pediatric Surgery, King’s College Hospital, Denmark Hill, London, UK V.  A.  McLin Swiss paediatric Liver Center, Department of Paediatrics, Gynaecology and Obstetrics, Geneva University Hospitals and University of Geneva, Geneva, Switzerland Erasmo  Miele Department of Translational Medical Sciences, Section of Pediatrics, University of Naples “Federico II”, Naples, Italy

xx

Giorgina  Mieli-Vergani King’s College London Faculty of Life Sciences & Medicine at King’s College Hospital, Paediatric Liver, GI and Nutrition Centre, and Institute of Liver Studies, King’s College Hospital, London, UK Zrinjka  Mišak Referral Center for Pediatric Gastroenterology and Nutrition, Children’s Hospital Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia Sissel J. Moltu  Department of Neonatal Medicine, Oslo University Hospital, Oslo, Norway Natalia Nedelkopoulou  Paediatric Liver, GI and Nutrition Centre, King’s College Hospital, London, UK Maribeth  Nicholson Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, TN, USA Mason  Nistel Department of Pediatrics, Mucosal Inflammation Program, Section of Gastroenterology, Hepatology and Nutrition and Gastrointestinal Eosinophilic Diseases Program, University of Colorado School of Medicine, Aurora, CO, USA Digestive Health Institute, Children’s Hospital Colorado, Aurora, CO, USA Agostino Nocerino  Department of Pediatrics, Azienda Sanitaria-Universitaria Friuli Centrale, Hospital “S. Maria della Misericordia”, University of Udine, Italy, Udine, Italy Salvatore  Oliva Pediatric Gastroenterology and Liver Unit, Department of Women’s and Children’s Health, Sapienza University of Rome, Rome, Italy Zahra  Ali  Padhani  Division of Women and Child Health, Aga Khan University, Karachi, Pakistan Andreas Panayiotou  Department of Radiology, King’s College Hospital, London, UK Alexandra Papadopoulou  Division of Gastroenterology and Hepatology, First Department of Pediatrics, University of Athens, Children’s Hospital “Agia Sofia”, Athens, Greece Mora  Puertolas Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, IL, USA Eamonn Martin Mary Quigley  Lynda K. and David M. Underwood Center for Digestive Disorders, Houston Methodist Hospital, Houston, TX, USA Paolo Quitadamo  Department of Pediatrics, A.O.R.N. Santobono-Pausilipon, Naples, Italy Shaman  Rajindrajith University Paediatric Unit, Lady Ridgeway Hospital for Children, Colombo, Sri Lanka Department of Paediatrics, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka Ashwin  Rammohan Institute of Liver Disease and Transplantation, Dr Rela Institute & Medical Centre, Bharath Institute of Higher Education & Research, Chennai, Tamil Nadu, India Anita Rao  Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, IL, USA Mettu Srinivas Reddy  Institute of Liver Disease and Transplantation, Dr Rela Institute & Medical Centre, Bharath Institute of Higher Education & Research, Chennai, Tamil Nadu, India Mohamed Rela  Institute of Liver Disease and Transplantation, Dr Rela Institute & Medical Centre, Bharath Institute of Higher Education & Research, Chennai, Tamil Nadu, India N.  M.  Rock Swiss paediatric Liver Center, Department of Paediatrics, Gynaecology and Obstetrics, Geneva University Hospitals and University of Geneva, Geneva, Switzerland

Contributors

Contributors

xxi

David Avelar Rodriguez  Pediatric Gastroenterology and Nutrition Unit, National Institute of Pediatrics, Mexico City, Mexico The Hospital for Sick Children, Toronto, ON, Canada Véronique Rousseau  Department of Pediatric Surgery, Necker – Enfants Malades Hospital, Paris Descartes University, AP-HP, Paris, France Paul MacDaragh Ryan  School of Medicine, University College Cork, Cork, Ireland Anna Rybak  Department of Paediatric Gastroenterology, Division of Neurogastroenterology & Motility, Great Ormond Street Hospital for Children, London, UK Giulia Sabatini  Sapienza University of Rome, Policlinico Umberto I, Rome, Italy Efstratios  Saliakellis  Department of Paediatric Gastroenterology, Division of Neurogastroenterology & Motility, Great Ormond Street Hospital for Children, London, UK Seppo Salminen  Functional Foods Forum, Faculty of Medicine, University of Turku, Turku, Finland Marianne Samyn  Pediatric Liver, GI and Nutrition Centre, King’s College Hospital, Denmark Hill, London, UK Francesco Savino  S.S.D. Early infancy special care Unit, Department of Pediatrics, Ospedale Infantile Regina Margherita. A.U.O. Città della Salute e della Scienza di Torino, Torino, Italy Sarah  Jane  Schwarzenberg Pediatric Gastroenterology, Hepatology and Nutrition, University of Minnesota Masonic Children's Hospital, Minneapolis, MN, USA Maria E. Sellars  Department of Radiology, King’s College Hospital, London, UK Thibault Senterre  University of Liege, CHU de Liege, CHR de la Citadelle, Liege, Belgium Timothy  A.  Sentongo  Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, IL, USA Naresh P. Shanmugam  Department of Pediatric Gastroenterology, Hepatology and Nutrition, Dr Rela Institute & Medical Centre, Chennai, India Shailee Sheth  Department of Paediatric Surgery, King’s College Hospital, London, UK Scott H. Sicherer, MD  Department of Pediatrics, Mt. Sinai School of Medicine, New York, NY, USA Mark  B.  Slidell, MD, MPH  Section of Pediatric Surgery, Department of Surgery, Comer Children’s Hospital, UChicago Medicine, Chicago, IL, USA Piotr  Socha The Children’s Memorial Health Institute, Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, Warsaw, Poland Manu R. Sood, MBBS, FRCPCH, MD, MSc  Pediatrics, University of Illinois College of Medicine, Peoria, IL, USA Annamaria  Staiano  Department of Translational Medical Sciences, Section of Pediatrics, University of Naples “Federico II”, Naples, Italy Allie E. Steinberger  Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA Ragha Suresh, MD  Department of Medicine, University of Chicago, Chicago, IL, USA Hania  Szajewska  The Medical University of Warsaw, Department of Paediatrics, Warsaw, Poland

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Stuart Tanner  University of Sheffield, Sheffield, UK Academic Unit of Child Health, Sheffield Children’s Hospital, Sheffield, UK Marta Tavares  Porto Children’s Hospital, Porto, Portugal Gianluca Terrin  Sapienza University of Rome, Policlinico Umberto I, Rome, Italy Department of Pediatrics, Neonatology Unit, Sapienza University of Rome, Rome, Italy Mike Thomson  Centre for Paediatric Gastroenterology, Sheffield Children’s Hospital NHS Foundation Trust, Weston Park, Sheffield, South Yorkshire, UK Sami Turunen  Department of Pediatrics, Oulu University Hospital, Medical Research Center Oulu and University of Oulu, Oulu, Finland Babu  Vadamalayan Paediatric Liver, GI and Nutrition Centre, King’s College Hospital, London, UK Meghna S. Vaghani  King’s College London, Strand, London, UK Yvan  Vandenplas Vrije Unversiteit Brussel (VUB), UZ Brussel, KidZ Health Castle, Brussels, Belgium Shannon M. Vandriel  Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON, Canada Roshni  Vara Department of Paediatric Inherited Metabolic Diseases, Evelina London Children’s Hospital, St Thomas’ Hospital, London, UK Andrea  Lo Vecchio  Department of Translational Medical Science, Section of Pediatrics  – University of Naples Federico II, Naples, Italy Diego Vergani  King’s College London Faculty of Life Sciences & Medicine at King’s College Hospital, Paediatric Liver, GI and Nutrition Centre, and Institute of Liver Studies, King’s College Hospital, London, UK Anita  Verma  Institute of Liver Studies, King’s College Hospital, NHS, Foundation Trust, London, UK Steven L. Werlin  The Medical College of Wisconsin and Children’s Wisconsin, Department of Pediatric Gastroenterology, Hepatology and Nutrition, Milwaukee, WI, USA Michael Wilschanski  Pediatric Gastroenterology Unit, Hadassah Hebrew University Medical Center, Jerusalem, Israel Stefan  Wirth HELIOS University Hospital Wuppertal, Department of Pediatrics, Witten/ Herdecke University, Wuppertal, Germany Jonathan Wong  The Medical College of Wisconsin and Children’s Wisconsin, Department of Pediatric Gastroenterology, Hepatology and Nutrition, Milwaukee, WI, USA Elke Zani-Ruttenstock  Department of General and Thoracic Surgery, The Hospital for Sick Children, Toronto, ON, Canada Indre  Zaparackaite Department of Paediatric Surgery, Great Ormond Street Hospital, London, UK Clare  Zasowski  School of Nutrition, Ryerson University, Faculty of Community Service, Cockwell Health Sciences Complex, Toronto, ON, Canada

Contributors

Part I GI-Nutrition

1

Microvillus Inclusion Disease and Tufting Enteropathy Agostino Nocerino and Stefano Guandalini

Introduction  he Larger Group of “Intractable Diarrheas T of Infancy” Before focusing on microvillus inclusion disease and tufting enteropathy, we will briefly review similar cases in the literature. In 1968, Avery, Villavicencio, and Lilly were the first to describe severe chronic diarrhea in 20 infants and named it “infantile intractable diarrhea”; according to their description, this was prolonged and intractable despite extensive hospital therapy [1]. This syndrome was defined on the basis of some clinical characteristics, namely: (1) Diarrhea of more than 2 weeks duration; (2) Age, less than 3  months; (3) Three or more stool cultures negative for bacterial pathogens; (4) Necessity of intravenous rehydration; and (5) Prolonged and intractable diarrhea despite hospital therapy. The death rate was very high: 9 out of the 20 babies (45%) in Avery et  al.’s report had died, and at 70% it was even higher in Hyman et al [2]. Heterogeneity and lack of specificity are evident in Avery’s original report: different pathologies were grouped in it, some of which with a diagnosis which was well defined even at that time. Only autopsy data were available for the first cases, and only after the introduction of total parenteral nutrition at the beginning of the 1970s [3] was it possible to study the matter in greater depth, thanks to proximal small intestinal biopsy [4] and later on to the development of endoA. Nocerino (*) Department of Pediatrics, Azienda Sanitaria-Universitaria Friuli Centrale, Hospital “S. Maria della Misericordia”, University of Udine, Italy, Udine, Italy e-mail: [email protected] S. Guandalini Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, Comer Children’s Hospital, University of Chicago, Chicago, IL, USA e-mail: [email protected]

scopic techniques which were safe and adequate for the infant as well. It became consequently possible to discriminate different causes for the so-called intractable diarrhea of infancy [5], but its definition superimposes on the definition of “protracted diarrhea of infancy”: the latter lasts for a similar length of time but a failure to gain weight is enough to define the clinical picture [6]. In 1995 the Pediatric Gastroenterologists of the Federico II School of Medicine of Naples (Italy) observed that in most cases of severe and protracted diarrhea (SPD) an etiological diagnosis was possible and that consequently the term “intractable childhood diarrhea” was now frequently inappropriate. They proposed to limit it to the group that needed total parenteral feeding, defining the clinical picture as “severe diarrhea requiring parenteral nutrition” [7]. In view of the changes in the spectrum of known causes of SPD over the past few decades, the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP) proposed in 1999 [8] to include in this definition autoimmune enteropathy (severe or partial villus atrophy with crypt hyperplasia and presence of anti-enterocyte antibodies and/ or associated autoimmune disorders), congenital microvillus atrophy, tufting enteropathy, epithelial dysplasia, and intestinal microvillus dystrophy (the latter later unified with microvillus inclusion disease). However, the definition of “protracted diarrhea of infancy” has remained prevalent in clinical practice and in the literature, even compared to the broader definition of “pediatric intestinal failure” [9], an entity resulting from various causes including trichohepatoenteric syndrome, tufting enteropathy, microvillus inclusion disease, and autoimmune enteropathy [10]. Many cases of “protracted diarrhea of infancy” are diet-­ associated, as a consequence of cow’s milk or lactose intolerance or malnutrition. Malnutrition causes intestinal atrophy and consequently a malabsorption syndrome with diarrhea, apparently improving with fasting. These features have almost disappeared in developed countries.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 S. Guandalini, A. Dhawan (eds.), Textbook of Pediatric Gastroenterology, Hepatology and Nutrition, https://doi.org/10.1007/978-3-030-80068-0_1

3

4 Table 1.1  Main causes of protracted diarrhea in infancy Small intestinal enteropathy of unknown origin Intractable ulcerating enterocolitis of infancy Congenital enterocyte heparan sulfate deficiency Congenital intestinal integrin deficiency Congenital secretory diarrheas  Congenital chloridorrhea  Congenital Na-losing diarrhea Autoimmune enteropathy Diseases of the intestinal epithelium Microvillus inclusion disease  Tufting enteropathy

The main causes of “intractable diarrhea of infancy,” including more severe and longer-lasting forms, can be summed up as follows (Table 1.1):

Autoimmune Enteropathy The term “autoimmune enteropathy” (AIE) was introduced to describe persistent diarrhea associated with autoimmune diseases with the production of antibodies directed against epithelial cells of the small and large intestine. This rare disorder (a recent review of the literature found a total of 98 reports published in the form of case reports and case series) [11] is frequently associated with primary immunodeficiencies and mostly occurs in young infants and children (6–18 months old). It is characterized by severe diarrhea and small intestinal mucosal atrophy resulting from immunemediated injury. A retrospective study on clinical and histological findings from 40 AIE patients showed a prevalent celiac disease pattern (50%), mainly in patients with primary immunodeficiencies, followed by the mixed pattern (35%), chronic active duodenitis (10%), and GVHD-­like pattern (5%) [12]. It remains a challenging diagnosis because of its clinical-pathological variability. This entity is dealt with in Chap. 2.

 mall Intestinal Enteropathy of Unknown S Origin This entity could be a variation of autoimmune enteropathy, as the increase in inflammatory cells in the lamina propria shows. It appears in infants less than 12 months, with a lower death rate compared to those with autoimmune enteropathy, but it can be very severe. Infants can become TPN-dependent [5].

A. Nocerino and S. Guandalini

Intractable Ulcerating Enterocolitis of Infancy A rare disease initially described in 1991 in five children presenting in the first year of life with intractable diarrhea, ulcerating stomatitis, and large ulcers with overhanging edges throughout the colon within the first year of life [13]. The affected infants can show a colitis whose severity may require a subtotal colectomy, even if the long-term prognosis is good. It has been suggested that affected children have a genetically determined primary immune dysregulation [14].

 ongenital Enterocyte Heparan Sulfate C Deficiency Described in 1995 in three infants who within the first weeks of life presented with secretory diarrhea and massive enteric protein loss [15]. The small intestinal mucosa is normal on light microscopy, but histochemical exams show a complete absence of enterocyte heparan sulfate. The sulfated glycosaminoglycans of the basocellular membrane are mostly deficient, particularly heparan sulfate, while the distribution of vascular and lamina propria glycosaminoglycans is normal [15]. Diarrhea is so severe as to make total parenteral nutrition (TPN) necessary, together with repeated albumin infusions because of severe protein-­losing enteropathy. Studies in men and mice show that heparan sulfate is essential in maintaining intestinal epithelial barrier function [16], and that the specific loss of heparan sulfate proteoglycans from the basolateral surface of intestinal epithelial cells is common to many forms of protein-losing enteropathy [17].

Congenital Intestinal Integrin Deficiency In 1999, Lachaux et al. described a case of intractable diarrhea starting 9 days after birth, associated with pyloric atresia and total epithelial detachment of gastric and intestinal mucosa. Immunofluorescence analysis showed α6β4 integrin deficiency at the intestinal epithelium–lamina propria junction [18]. Mutations in α6 or β4 integrins cause junctional epidermolysis bullosa with pyloric atresia. In 2008, two Kuwaiti brothers with pyloric atresia were described, respectively affected by intractable diarrhea and episodes of protein-losing enteropathy, with a novel mutation in β4 integrin that induced a desquamative enteropathy in infancy without significant skin disease [19].

1  Microvillus Inclusion Disease and Tufting Enteropathy

5

Congenital Secretory Diarrheas

Microvillus Inclusion Disease

Includes congenital chloridorrhea and congenital sodium diarrhea, dealt with in Chap. 36.

In 1978, Davidson et  al. described five infants presenting with intractable diarrhea of infancy characterized by secretive diarrhea and malabsorption, starting in the first hours after birth with hypoplastic villus atrophy in the small intestinal biopsy. Four of these infants had a deceased brother who had shown similar symptoms. In one of these infants, electron microscopy identified the presence of a peculiar abnormality of the microvilli of the enterocytes [26] (Fig. 1.1). Three new cases with the same clinical and histological characteristics as this infant were described in France in 1982, and the four of them were grouped into a new disease called congenital microvillus atrophy [27, 28]. Two new cases were described in Great Britain in 1985 [29], and one in Italy in 1986; a brother of the Italian child, who was born subsequently, was similarly affected [30]. A survey completed in 1987 among centers known for their involvement in pediatric gastroenterology identified more than 30 cases worldwide. Additional cases were later published. In 1989, Cutz et al. proposed the use of the term “microvillus inclusion disease” to highlight the characteristic ultrastructural lesions of the disease [31].

Diseases of the Intestinal Epithelium Microvillus inclusion disease and tufting enteropathy are the best-known diseases of the intestinal epithelium causing intractable diarrhea of infancy. In 1994, Girault et  al. described eight infants with early-­onset severe watery diarrhea associated to facial deformities and unusual tufts of woolly hair with trichorrhexis nodosa. Duodenal biopsies showed moderate to severe villus atrophy, with normal or hypoplastic crypts; colon biopsies were basically normal. As a consequence, severe malabsorption was present. All patients had no antibody response to immunization antigens; the immunological response to vaccinations was poor. Five children died despite TPN [20]. Two children from the series of Girault et  al. had hepatic cirrhosis; six additional patients had signs and symptoms compatible with this new “syndromic diarrhea,” associated to hepatic involvement (Trichohepatoenteric syndrome, THES) characterized by fibrotic livers with marked hemosiderosis [21–23]. Nine different mutations in TTC37 gene (5q14.3–5q21.2) were found in 12 children from 11 families with classical features of THES. TTC37 codes for a protein that has been named “thespin” (THES ProteIN) [24]. Enlarged platelets with abnormal α-granule secretion can be observed in some patients. The estimated incidence of the syndrome is 1  in 400,000 to 1  in 500,000 live births. A review of the literature conducted in May 2017 included 80 patients, 40 with mutations of TTC37 and 14 with mutations of SKIV2. This showed that parenteral nutrition was used in the management of 83% of the patients and that it was possible to wean 44% off parenteral nutrition. The mean duration was 14.97 months. Data on the efficacy of immunoglobulins were reported for only six patients, with a diminution of infection or reduced diarrhea. Antibiotics, steroids, and immunosuppressant drugs were used with little efficacy. Hematopoietic stem cell transplantation (HSCT) was performed in four patients, two of whom died [25].

Fig. 1.1  Microvillus inclusion disease. PAS staining highlights abundant PAS-positive material (arrows) in the apical part of the enterocyte cytoplasm. PAS × 260 [20] (Reprinted from Springer and Virchows Archive: Official Journal of the European Society of Pathology, Morroni et al. [99], Fig. 1, with kind permission from Springer Science and Business Media)

6

Clinical Presentation First child of parents with no blood relation, A.G. was born after 37 weeks of gestation, the pregnancy having been complicated by a risk of miscarriage in the fifth month. His weight at birth was 3500 grams. The infant was hospitalized when he was 40  days old because of abundant diarrhea (15–20 evacuations a day of liquid stools), which started on the sixth day of life and was resistant to numerous dietary and pharmacological therapies. On admission to hospital, the patient weighed 2800 grams, and was suffering from dystrophia and dehydration; total parenteral nutrition (TPN) was therefore immediately started. The acid-basic balance showed hyponatremic acidosis (pH 7,2; EB –8,3; Na 128 mEq/1). The secretive nature of diarrhea was confirmed by its entity (about 100 ml/kg/die) with a total absence of oral nutrition and with the persistence of TPN in progress. Moreover, the typical absence of ionic gap in the stools was present: osmolality 226  mOsm/l, Na 86  mEq/1, K 23.5 mEq/1 (gap 7 mOsm/l). Loperamide and chlorpromazine increased intestinal absorption but did not change the clinical picture. Microbiological tests including electron microscopic analysis of the feces for the identification of viruses and the search for enterotoxigenic bacteria and parasites with specific methods were repeatedly negative. The abdominal ultrasound showed adrenal hyperplasia associated with hyperaldosteronism (1160  ng/ml, v. n. 15 eosinophils/HPF with exclusion of other causes of esophageal eosinophilia. Aside from EoE and GERD, other clinical causes of esophageal eosinophilia are rare and can often be distinguished by specific presentation or histology (Table 9.1). Providers should have heightened suspicion for EoE in patients with co-­ occurring atopic conditions such as asthma, eczema, food allergies, and family history of food impactions, esophageal dilation, EoE, or dysphagia. Except for diminished growth, no physical exam findings are pathognomonic of EoE [9].

Factors Complicating EoE Diagnosis Multiple factors can complicate making a definitive diagnosis of EoE including treatment with systemic steroids or topical steroids for another indication (asthma, allergies) at the Table 9.1  Differential diagnosis for esophageal eosinophilia Gastroesophageal reflux disease Eosinophilic esophagitis Eosinophilic gastrointestinal disorders Infection (parasitic or fungal) Crohn’s disease Celiac disease Hypereosinophilic syndromes Drug hypersensitivity reactions Pill esophagitis Vasculitis Achalasia Graft-versus-host disease Oral immunotherapy Pemphigus Liacouras et al. [1]

M. Nistel and G. T. Furuta

time of a diagnostic endoscopy, seasonality, inadequate mucosal sampling with too few biopsies, or biopsies obtained from a patient with longstanding mucosal inflammation. Given the frequent coexistence of asthma and other atopic conditions with EoE, clinical experiences identified that some patients with comorbid allergic diseases may be treated with systemic or topical corticosteroids that could partially reduce esophageal eosinophilia found at the time of a diagnostic biopsy [1]. Patients may present with features highly suspicious of EoE, such as recurrent food impactions, endoscopic findings or esophageal rings, or family history of unexplained esophageal strictures, but demonstrate mucosal eosinophilia less than the 15 eosinophil/HPF threshold. In this case, consideration, in association with the patient and family, should ensue regarding a limited medication trial to assess for symptomatic response and eventual repeat endoscopic assessment. The seasonal timing of a mucosal biopsy may also influence mucosal eosinophilia. For instance, clinical studies have demonstrated that biopsies obtained in the fall and spring have increased esophageal eosinophilia compared to winter and summer, likely due to differences in pollen exposure. A retrospective analysis of 127 adults with EoE demonstrated seasonal variation in the frequency of EoE diagnosis that correlated with pollen levels [14]. Seasonality was also identified in a pediatric population through a retrospective review of 1,180 patients, 32 of whom were found to have definitive seasonal variation of their esophageal eosinophilia [15]. Thus, extent of eosinophilia in some patients may depend on the season, and the diagnosis could be missed if biopsies were obtained outside of an allergy season. The diagnosis may also be missed because of the patchy nature of EoE and the resultant inadequate sampling of an affected area. Both adult and pediatric studies support obtaining mucosal biopsies in at least two different locations with a total of six samples in order to approach a sensitivity greater than 90% [16–18]. The natural history of EoE continues to evolve, but multiple studies indicate that a number of different phenotypes exist. An acute inflammatory pattern is well described in pediatrics to be exhibited by white exudates and linear furrows. In adult patients, the chronicity of the disease is demonstrated by the strictures and fibrosis [19, 20]. A prospective study of 70 adults included functional luminal-imaging probe (FLIP) evaluation during endoscopy to assess esophageal distensibility compared to level of epithelial eosinophilia and risk of food impaction. Patients with previous food impactions had significantly lower distensibility; however, no correlation to mean eosinophil density was found [21]. In this subset of patients with longstanding inflammation, biopsies may not meet the >15 eosinophil/ HPF histologic threshold despite advanced symptomatic disease.

9  Eosinophilic Esophagitis

Clinical Presentation Presenting Symptoms Presenting symptoms of EoE vary based on age. Differences in reported symptoms may be due to the difficulty of younger patients to articulate their experiences. In the toddler age group, the most frequent symptoms are associated with GERD such as vomiting, regurgitation, as well as those related to feeding dysfunction or meal time problems [22]. Meal time behaviors may be nonspecific and include tantrums, spitting food out, poor appetite, and slow eating, all of which can be upsetting to families [22]. In addition to these symptoms, school age patients may also present with abdominal pain, reflux, and dysphagia [10, 23, 24]. Compensatory behaviors frequently develop and may be viewed as behavioral issues rather than as problems reflective of an underlying disease [22]. These behaviors are described with the acronym IMPACT: imbibe with meals, modify food (cutting into small pieces), prolong meal times, avoid hard textures, chew excessively, and turn away tablets/pills [25]. With these modifications, patients rarely progress to the point of frank failure to thrive or nutritional deficiency [22]. Adolescent and adult patients most commonly present with symptoms of dysphagia and food impaction and can also present with chest pain and heartburn [1]. Dysphagia may be described as the feeling that food is getting stuck or traveling slowly as well as gagging on food. Adult patients with EoE also can develop worsening of gastrointestinal symptoms with alcohol intake [26]. A novel syndrome found in some patients with EoE is referred to as food-induced immediate response of the esophagus (FIRE). This was recently described as an unpleasant or painful retrosternal sensation that occurs immediately and reproducibly after ingestion of a specific food or beverage [27]. Symptom latency is generally less than 5 minutes following the ingestion of the food and lasts less than 30  minutes with high symptom intensity. Patients clearly differentiate this phenomenon from EoE-related dysphagia or food impaction, and the most frequently implicated triggers include milk, wheat, nuts, fruits, wine, and beer. Rare presentation of EoE includes esophageal rupture or Boerhaave’s syndrome [28]. Patients diagnosed with EoE have a high likelihood of concomitant atopic history [29]. A large retrospective analysis compared the risk of 7,722 EoE patients having atopic conditions to controls without EoE. Results were notable for risk ratios of 2.24, 2.19, 1.53, and 17.05 for allergic rhinitis, asthma, atopic dermatitis, and food allergies, respectively, in patients with EoE [30]. Similarly, a prospective study of 70 pediatric patients, 33 with EoE and 37 healthy controls, evaluated responses to methacholine challenge [31]. In the EoE

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cohort, 33% of patients had significant increase in airway hyperresponsiveness compared to 11% of controls. EoE occurs in patients with IgE-mediated food allergies at a rate of 4.7% compared to the lower rate in the general population of 0.4% [2].

Natural History The natural history of EoE has yet to be defined, but several possibilities are proposed. A prospective study of 185 patients (88 children) identified 3 distinct EoE endotypes based on peak eosinophil count, a distinct set of genes identified in the EoE diagnostic panel (EDP), the EoE histologic scoring system (EoE-HSS), and the EoE endoscopic reference score (EREFS) [32]. Endotype 1 is the mildest and most steroid-sensitive. Endotype 2 has substantial inflammatory changes, demonstrates a Th-2 immune response, and is often steroid refractory. Endotype 3 is most common in adult-­ onset EoE, shows the lowest expression of epithelial differentiation genes, and the most severe esophageal narrowing, endoscopic, and histologic changes. Another consideration is that untreated EoE patients may progress from an acute inflammatory to a fibrotic pattern. During the acute stage, patients exhibit exudates and edema with reflux-like symptoms, whereas the fibrotic pattern is represented by strictures, dysphagia, and food impactions. A retrospective study of 379 children and adults with EoE determined that for each decade of life, the likelihood of developing a fibrostenotic phenotype more than doubled (OR 2.14) [33]. Similarly, in a retrospective review of 200 adult patients with EoE, a diagnostic delay of 0–2 years corresponded to a stricture prevalence of 17.8% compared to a diagnostic delay of >20 years which identified a stricture prevalence of >70.8% [20].

Endoscopic Findings Esophageal endoscopic findings associated with EoE include loss of vascular pattern (LOVP), rings, white exudates, linear furrowing, strictures, and mucosal fragility or crepe paper esophagus, a finding defined by the creation of longitudinal rents following passage of the endoscope (Fig.  9.1 and Table  9.2). Each of these represent different inflammatory states [34]. For instance, LOVP and furrows reflect edema and exudates represent eosinophilic pus. In contrast, rings, strictures, and longitudinal rents likely reflect evidence of chronic inflammation. A 2012 meta-analysis of 4,678 adults and children showed that the most common endoscopic finding was linear furrowing (48%) followed by esophageal rings (44%) and LOVP (41%) [35]. When evaluated by age, rings and strictures were more prevalent in adults while chil-

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a

b

Fig. 9.1  Endoscopic findings associated with eosinophilic esophagitis include (a). loss of vascular pattern, white exudates, and furrowing (EREFS score-E1E1F1 score 3) in a 13-year-old with history of a food

impaction; (b). longitudinal rent and furrows in a 14-year-old observed following passage of the endoscope

Table 9.2 Endoscopic esophagitis

score [37]. EREFS is effective in providing valuable diagnostic information and monitoring in both adults and children. Validation of the score revealed good interobserver agreement of 71–81% for rings, furrows, exudates, and edema in addition to 79% and 92% for stricture and crepe paper esophagus, respectively [37]. A prospective pediatric study of 371 patients evaluated EREFS in 192 diagnostic endoscopies and 229 post-treatment endoscopies [38]. Outcomes of the study showed a strong correlation between composite EREFS score and the degree of eosinophilia and no significant correlations with individual endoscopic findings. The score was also able to differentiate newly diagnosed EoE patients from controls, and active EoE from inactive EoE.

findings

associated

with

eosinophilic

Whitish exudates Loss of vascular pattern Furrowing Rings Long segment narrowing Strictures Crepe paper esophagus—rent formation Esophageal pull (tug) sign Kim et al. [35] and Dellon et al. [36]

dren present with significantly increased prevalence of white plaques (36%) and LOVP (58%). Importantly, 17% of cases appeared normal, emphasizing the necessity of obtaining mucosal biopsies when EoE is suspected regardless of mucosal appearance. Sensitivity, specificity, and positive predictive values of endoscopic signs are not presently sufficient for diagnosis; however, prevalence is high of at least one endoscopic finding in patients with EoE [35]. An endoscopic phenomenon referred to as the esophageal pull (tug) sign provides a strong independent predictor for diagnosis [36]. This sign is characterized by inability to completely close endoscopic biopsy forceps, prolonged tenting of the esophageal mucosa when the forceps is retrieved, and more force than usual needed to retrieve the forceps or the need of a “tug.” A validated EoE endoscopic scoring system called the EoE Reference Score (EREFS) uses the findings of exudates, rings, edema, furrows, and strictures to develop a numerical

Radiology Several radiologic findings raise concern for the diagnosis of EoE including proximal esophageal narrowing, long segment narrowing, or prolonged retention of barium pill; however, there are no pathognomonic signs for EoE.  Patients with a diagnosis of EoE may benefit from the use of contrast esophagram with barium pill to identify esophageal narrowing since occult strictures may be missed. In a retrospective study of 22 patients ranging in age from 2 to 20 years, 55% were found to have radiographic evidence of esophageal narrowing that had not been observed endoscopically [39]. Similarly, use of a barium-coated pill was shown to be of value in identifying occult narrowing in a retrospective study of three patients [40].

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Histology The histopathologic hallmark of EoE is dense esophageal eosinophilia with a diagnostic threshold of >15 eosinophils/ HPF.  The esophageal epithelium possesses characteristic features including thickening due to basal zone hyperplasia (normal is less than 3 cell layers), dilated intracellular spaces, and infiltration with other inflammatory cells including mast cells, T-cells, and B-cells (Table 9.3). Sampling of the lamina propria of the esophageal mucosa varies widely, but when obtained, it can appear fibrotic as defined by increased density of the collagen fibrils [41]. The EoE Histologic Scoring System (EoE-HSS) was developed to integrate elements of both eosinophilic and epithelial inflammation with grading (degree) and staging (extent) of each pattern [42]. Grade and stage scores are combined to create a composite score used to monitor therapeutic response.

Epidemiology EoE incidence ranges from 2.1 to 12.8 cases per 100,000 people/year with pooled meta-analysis data reflecting a rate of 3.7/100,000 people/year (95% CI, 1.7–6.5) [43, 44]. Studies estimate EoE prevalence ranging from 2.3 to 90.7/100,000 people with pooled meta-analysis data reflecting prevalence of 22.7/100,000 (95% CI, 12.4–36) [43]. Prevalence is similar in Europe, North America, and Australia, but few studies have examined this in other countries. For instance, epidemiological data from other regions including Central/South America, Asia, and North Africa suggest that EoE is scarce [43]. A large retrospective study evaluated over 6,500 patients and found the male prevalence of EoE was twice that in females, and prevalence peaked in the 35–39-year age group with decreasing numbers after age 45 years [45]. Similar findings were reported with prevalence peaks during childhood and in the 30–40-year age group [9, 30]. Increased prevalence of EoE cannot be completely explained by increased recognition. Contributions from Table 9.3 Histologic esophagitis

findings

associated

with

eosinophilic

Peak eosinophil count >15/HPF Epithelial basal zone hyperplasia: >15% of total epithelial thickness Eosinophil abscesses: aggregate leading to epithelial architecture disruption Eosinophil surface layering: rows of eosinophils in the upper one-third of epithelial layer Dilated intracellular spaces with intercellular bridges Lamina propria fibrosis/thickening Surface epithelial alteration Dyskeratotic epithelial cells Collins et al. [128]

both genetic and environmental factors also play a role. For instance, several genetic variants include a single nucleotide polymorphism (SNP) in CCL26 which encodes eotaxin-3, downregulated epidermal barrier protein filaggrin, calpain 14 (CAPN14), and thymic stromal lymphopoietin (TSLP) [46]. Twin studies identified relative risk ratios for EoE within families ranging from 10 to 64 with higher values in male family members than female members [47]. EoE is passed on to 1.8–2.4% of relatives with 58% concordance among monozygotic twins and 36% concordance in dizygotic twins [47]. This higher-than-­ expected concordance among dizygotic twins further supports the role of environmental impact on EoE risk. Environmental factors that increase the risk of developing EoE include seasonality, lower population density, and early life events (prematurity, infection, antibiotic exposure) [47, 48]. In one study, breast feeding was associated with a decreased likelihood of developing EoE [47].

 linical Associations with Esophageal C Eosinophilia At least four other clinical situations have been associated with the development of EoE or esophageal eosinophilia including herpes simplex virus (HSV) infection, oral or sublingual immunotherapy (OIT/SLIT), Helicobacter pylori infection, and celiac disease. Several case series document HSV infections preceding the development of EoE.  For instance, in one study, 5 of 11 immunocompetent children with HSV esophagitis developed eosinophilic infiltration on follow-up esophageal biopsy [49]. Findings from this study and other case reports raise the question of whether HSV may be associated with EoE. An inverse relationship exists between Helicobacter pylori gastritis and the finding of esophageal eosinophilia [50]. This is curious given that H. pylori was definitively characterized in the 1980s, and the prevalence of infection has significantly decreased over a similar time course to the increased prevalence of EoE. Clinical observations have associated the use of SLIT or OIT with the frequent development of abdominal pain with subsequent endoscopic biopsies frequently demonstrating esophageal eosinophilia. To address this observation, 21 adults with IgE-mediated peanut allergy were evaluated with a baseline EGD prior to start of OIT [51]. The subjects had no GI symptoms but 5 were found to have >5 ­eosinophils/ HPF and 3 had >15 eosinophils/HPF.  Similarly, a meta-­ analysis in 2014 evaluating 711 patients demonstrated a rate of 3% that developed eosinophilia during immunotherapy course [52]. After discontinuation of OIT, symptoms and histology resolved in most cases. Whether this finding is a transient clinicopathologic finding or a chronic condition is yet to be determined.

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Inherited connective tissue disorders have a predilection to develop various allergic phenotypes including EoE.  Disorders such as Loeys-Dietz syndrome (LDS), Marfan syndrome, and Ehlers Danlos syndrome are caused by or associated with mutations in TGF-β. Implicated mutations result in increased protein levels of TGF-β which has been linked to the pathogenesis of EoE [53]. A retrospective study evaluated 58 patients with LDS (either heterozygous mutation TGF BR1 or TGF BR2) and found that 66% of patients reported GI complaints including poor growth, vomiting, abdominal pain, and dysphagia [54]. Ten of these patients had undergone upper endoscopy with 60% revealing histologic findings of EoE. Esophageal eosinophilia can also be found in patients with celiac disease (CD). In a retrospective study, comparison of 421 patients with EoE and 763 patients with CD revealed that 3 children had both EoE and CD [55]. This corresponded with a 50- to 75-fold increased risk of each condition when diagnosed with the other. Treatment with gluten removal results in improvement in both conditions in 30–60% of patients [56].

Pathogenesis EoE is a chronic inflammatory disease triggered by esophageal allergen exposure that leads to a cascade of events with increased Th2 cytokines, development of epithelial barrier dysfunction, and influx of inflammatory cells. Most often, this is triggered by food allergens, but recent evidence demonstrates the contribution by aeroallergens or other unknown stimuli [2, 14, 15]. In addition to basic studies identifying Th2 pathways, one of the strongest pieces of evidence supporting a food allergic cause is the remission induced by dietary elimination of proposed allergens [2].

M. Nistel and G. T. Furuta

function SNP found uniquely in EoE patient samples supporting this as a potential cause for increased disease risk compared to allergic controls [59]. This SNP was significantly increased in males with EoE compared to controls, but not in females suggesting one reason for increased EoE prevalence in males. Genome-wide association studies identified a dysregulated EoE transcriptome that is conserved in patients with EoE, but not found in patients with GERD [2, 6, 60]. The most highly expressed gene in the transcriptome is CCL26 which encodes eotaxin-3 with up to 53-fold increase compared to controls [6]. CCL26 is induced by IL-13 and is a critical mediator of eosinophilic inflammation. The importance of this gene in EoE pathophysiology is supported by an SNP in the CCL26 gene that portends increased disease susceptibility and in vivo murine models with eotaxin receptor (CCR3) deletions that provide protection from developing EoE [60]. Transcriptome analysis also revealed five mast cell genes that are highly induced in EoE supporting the role of this cell in disease pathogenesis [60]. Mast cells express the eotaxin receptor, CCR3, and thus their increased activity may be a result of elevated eotaxin-3 levels. Despite the discovery of multiple genetic susceptibility genes, the EoE disease concordance in dizygotic twins of 36% compared to nontwin siblings at 2.5% supports a complex interplay between genetic predisposition, environmental exposure, and epigenetics [47].

Inflammatory Cascade

Once esophageal epithelial cells are exposed to triggering antigens, TSLP transcription is upregulated via the Toll-like receptor 3 pathway (TLR3) leading to Th-2 adaptive immune response differentiation. Evidence for a Th-2 response in  local dendritic cells is the increase in secretion of IL-4, IL-5, and IL-13 and upregulation of STAT6 downstream of the shared IL-4 and IL-13 receptor, IL-4Rα [2, 61]. IL-5 is a Genetic Predisposition potent chemoattractant and activator of eosinophils; upregulation leads to eosinophil transmigration into the epithelium A number of candidate genes increase susceptibility and and increased eosinophil-derived granule protein deposition subsequent development and progression of EoE.  These [2, 62]. Eosinophil granule products each have specific include thymic stromal lymphopoietin (TSLP) on chromo- effects that may propagate EoE pathogenesis. Although not some 5q22 and calpain 14 (CAPN14) on chromosome 2p23, proven in EoE, eosinophil granule proteins are associated as well as chromosome 1q21, the location of the epidermal with a number of biological effects including the ability of differentiation complex which contains genes involved with major basic protein to disrupt epithelial barrier, eosinophil-­ squamous epithelial cell differentiation [2, 57]. One of the derived cationic protein to increase cell membrane genes within this complex is filaggrin whose gene product is ­permeability, eosinophil-derived neurotoxin to potentiate the downregulated in EoE, thus leading to barrier dysfunction. Th-2 response, and eosinophil peroxidase to induce local tisOther contributing genes include STAT6 (Th2 adaptive sue injury [2, 46]. immune response development and an intermediate for IL-4 IL-13 also increases eosinophil chemotaxis and inflamand IL-13 signaling), EMSY (transcriptional regulation), mation by two mechanisms. First, IL-13 can increase and LRRC32 (a TGF-β binding protein) [2, 58, 59]. A study expression of eotaxin-3 via STAT6 leading to increased proof 172 patient samples demonstrated a TSLP gain-of-­ duction of periostin, an independent facilitator of eosinophil

9  Eosinophilic Esophagitis

adhesion and recruitment [2, 46, 63]. Second, IL-13 can increase upregulation of CAPN14 that impairs esophageal epithelial barrier function by decreasing levels of the desmosome, desmoglein 1 (DSG1). CAPN14 also increases eosinophil chemotaxis and has direct effects on esophageal remodeling [58].

 arrier Dysregulation and Esophageal B Remodeling Esophageal inflammation and the EoE cytokine cascade can lead to development of impaired barrier function, likely due in part to downregulation of epidermal differentiation complex genes at 1q21 [64]. Impairment of the epithelial barrier occurs via IL-13 induction of CAPN14 which in turn decreases expression of desmosomal proteins DSG1 and filaggrin. DSG1 is one of the most downregulated genes in the mucosa of EoE patients, and diminished expression can result in increased intercellular spaces in the esophageal epithelium [57, 65]. Importantly, topical steroid treatment normalizes DSG1 protein levels [65]. Another implicated mediator of impaired barrier function is TGF-β. In vitro and ex vivo experiments have demonstrated that increased TGF-β decreases the epithelial tight junction molecule, claudin-7. Decreased claudin-7 allows for increased cell separation in the basal and suprabasal epithelial layers and resultant impaired barrier function [66]. Finally, eosinophil granule proteins can directly affect barrier function and raise the possibility of either initiating or perpetuating a response by allowing the passage of allergenic molecules [2, 65]. Esophageal remodeling is reflected by histologic changes including basal cell hyperplasia, dilated intracellular spaces, rete peg elongation, increased collagen deposition, fibrosis, and angiogenesis [2]. The etiology of underlying fibrosis in EoE is not certain, but a number of recent studies shed light on the potential role of TNF superfamily member 14 (LIGHT), elevated TGF-β through a functional SNP in the TGF-β gene, activation of TGF-β1 by Plasminogen activator inhibitor 1, and TGF-β-induced phospholamban expression [67–70]. These changes can lead to esophageal stiffening and/or dysmotility that increase the risk of dysphagia and food impactions [33, 71]. Two cell types, eosinophils and mast cells, are implicated in causing remodeling via increased levels of TGF-β. TGF-β potentiates esophageal remodeling via the SMAD signaling pathway (pSMAD2 and pSMAD3) [2, 63, 72]. This pathway upregulates fibrotic gene expression and leads to transformation of the resident fibroblast population to the contractile myofibroblast. Myofibroblasts can increase esophageal smooth muscle contraction with production of contractile proteins phospholamban and periostin. The EoE cascade may be cyclically potentiated by periostin that increases production of

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TSLP furthering the Th-2 pathway [65]. Successful treatment of EoE can decrease mast cells and TGF-β levels, thereby strengthening the hypothesis that mast cells are a large component in the pro-­fibrotic changes and esophageal dysmotility observed in EoE [72].

Treatment Current treatments for EoE include drugs, diet, and dilation [73]. A standardized definition for treatment response in EoE is lacking, but clinical trials currently use co-primary endpoints involving peak eosinophil counts and other histopathologic findings (see EoE-HSS) along with patient-reported symptoms. The overall goal of treatment includes improvement in symptoms, endoscopic and histologic findings, and normal growth and development [25].

Proton Pump Inhibitors The AGREE consensus meeting of 2018 removed a PPI trial from diagnostic criteria for EoE and suggested that PPI-­ responsive esophageal eosinophilia (PPI-REE) is a likely subtype of EoE [10]. PPIs may have anti-inflammatory properties independent of acid blockade via blockade of the STAT6 transcription factor at the eotaxin-3 promotor [74– 76]. This leads to the subsequent decrease of Th2 pathway eotaxin-3 secretion. Pre- and post-PPI treatment histopathology from 10 pediatric patients showed decreased expression of eotaxin-3 in the proximal esophagus and supported the hypothesis of acid-independent anti-inflammatory properties [74]. PPI therapy is effective for treating EoE demonstrated by a large meta-analysis of 618 patients (188 children) that showed clinical improvements in 61% of patients with histologic remission in 54% of children and in 50% of adults [77]. The reliability of PPI use to maintain remission continues to be studied. In a prospective study, 109 pediatric EoE patients were treated with high dose PPI therapy (1 mg/kg BID) for 8 weeks, and then responders were decreased to a maintenance regimen (1 mg/kg daily) for 12 months [78]. After the initial 8-week course, 66% of study participants were in histologic remission, and at follow-up endoscopy, a median of 14.5 months later, 70% of these patients remained in remission. Twelve of the subjects then had a dose decrease to 0.5 mg/kg daily for an additional 1 year with histologic remission maintained in 11 of 12. One reason for variability in PPI responses may relate to PPI metabolism that can be divided into rapid, intermediate, and poor metabolizers. Phenotypes are dependent on CYP2C19 genotype, and the resultant plasma PPI levels and gastric pH levels are inversely proportional [79]. A retro-

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spective cohort of 75 adult patients with initial PPI response were evaluated for long-term remission on PPI maintenance dosing in association with CYP2C19 genotyping [12]. Of the initial PPI responders, dosage was decreased to a lowest daily dose that maintained clinical remission with 45 patients receiving double dose (omeprazole 40 mg or equivalent) and 30 patients on single dose (omeprazole 20 mg or equivalent). Results of the follow-up endoscopies showed 55 patients with continued histologic remission and 20 that despite recurrence of esophageal eosinophilia remained asymptomatic. The only independent risk factors for patients with recurrence of esophageal eosinophilia were co-occurring rhinoconjunctivitis and patients with CYP2C19 rapid metabolizing genotype (leads to lower plasma PPI levels) showing an odds ratio (OR) of 12.5 and 8.6, respectively. Adverse drug reactions associated with PPI use are rare, but the most common effects include nausea, abdominal pain, flatulence, headache, and diarrhea [80]. Additional adverse effects associated with longer term use have been described, both related and unrelated to acid inhibition [81].

Steroids Systemic and topical corticosteroids induce clinical and pathological remission in EoE patients [82]. In 2008, a randomized clinical trial (RCT) compared systemic steroid and topical steroid therapies in 80 patients with EoE, and both had clinical and histologic improvement within 4 weeks, with minimal differences in efficacy [83]. Placebo-controlled trials using topical steroids including fluticasone propionate (FP) and oral viscous budesonide (OVB) have shown a 66% histopathologic improvement [84]. FP is dosed via a metered dose inhaler (MDI) inhaler, but instead of inhaling, the medication is puffed into the mouth and swallowed [85, 86]. OVB uses liquid budesonide mixed with Splenda or another thickening agent to increase viscosity for amplified contact time in coating the esophagus [87]. In a randomized study of 24 children, OVB induced a significant clinicopathological response compared to those treated with placebo [88]. A study comparing the efficacy of OVB and FP showed no significant difference in histologic remission at 71% and 64%, respectively [86]. Another topical steroid formulation used for EoE, ciclesonide, is delivered as a pro-drug that is converted to the active form des-CIC by esterases on the esophageal epithelial surface [89]. In one pilot study, ciclesonide led to clinicopathological remission, and in another, findings were less clear; further study is required to see if ciclesonide will offer continued benefit [90, 91]. All steroid medications raise concerns for systemic absorption and complications such as adrenal insufficiency, altered bone metabolism, and slowed linear growth, but these are uncommon with topical formulations. Comparison of

M. Nistel and G. T. Furuta

systemic steroids with topical formulations showed 40% of the patients receiving systemic steroids developed weight gain, cushingoid features, and hyperphagia compared to none in the topical group [83]. The most common adverse drug reaction seen with topical steroid formulations is esophageal Candida infection with between 12% and 16% of patients effected [83, 86]. The rate of adrenal insufficiency in patients treated with topical corticosteroids varies between studies from 5% to 66% with the largest studies showing that adrenal insufficiency is unusual, and when it occurs, patients are generally also taking other topical steroid formulations for concomitant atopic conditions [92–96].

Elimination Diets In the first therapeutic study using dietary elimination, an elemental diet induced a clinical and histological response and allergenic food addition led to disease reactivation [5]. This study, as well as others, showed the benefits of food elimination, but because of impact on quality of life and other factors, this may not be suitable for all [97, 98]. No testing platform is available to identify EoE-related food allergens reliably and thus an empiric approach remains the standard of care [98, 99]. Implementation of an empiric six-food elimination diet (SFED; excludes milk, soy, egg, wheat, peanuts/tree nuts, fish/shellfish) leads to a clinicopathological response rate of 72% [84]. This diet was first evaluated in a retrospective study from 2006 of 60 children receiving either SFED or elemental formula diet [98, 99]. Results of this study showed 74% histologic remission in SFED compared to 88% in the elemental formula diet. Wheat and milk have been found to be leading EoE causative antigens at 58% and 68%, respectively, but with significant heterogeneity between studies [98]. After empiric elimination, foods were added back every 6 weeks with repeat endoscopy in order to determine specific food triggers [99, 100]. Four food elimination diet (FFED; excludes milk, soy, egg, and wheat) is another dietary intervention with 64% achieving histologic remission, symptom remission in 34%, and symptom improvement in 91% [100]. Since milk is thought to be the most frequently implicated trigger in rechallenged patients, milk-only elimination has been compared to the FFED in a recent RCT [101]. Results showed equivalent histologic improvement, slightly lower ­symptomatic improvement in the milk-only group, but a significant improvement in the quality-of-life scores of milkonly elimination. Recently, a step-up approach was proposed starting with the two most likely trigger foods, milk (all dairy) and gluten (stricter than just wheat to avoid cross-reactivity) [102]. This two-food elimination diet (TFED) led to histologic response

9  Eosinophilic Esophagitis

in 43% of participants. Those that did not respond were stepped up to the FFED. The step-up process helped limit the number of endoscopies required to find a food trigger by 20% during reintroduction. Limitations of elimination diets include potential reduction in quality of life and need for repeat endoscopic evaluation with the attendant costs and potential complications.

Allergy Medications Medications used in other allergic conditions such as cromolyn, montelukast, and omalizumab are not effective in treating EoE.  Lack of effect is likely because EoE is not an IgE-mediated allergic condition. In a retrospective study of 381 pediatric EoE patients, 14 were treated with cromolyn, a mast cell stabilizer, with no change in peak eosinophil count or symptom improvement [103]. Similarly, in an RCT of 41 adults that investigated maintenance of topical steroid induced remission, no symptomatic or histological differences were observed between montelukast, a leukotriene antagonist, and placebo [104]. The anti-IgE monoclonal antibody, omalizumab, has also been used in a small RCT of 30 adults and no difference in symptoms or eosinophil counts was reported [105].

Biologic Treatments A number of clinical trials are studying novel biologic therapies that target various points in the EoE cytokine cascade. Medications targeting IL-5 include IL-5 monoclonal antibodies mepolizumab and reslizumab and the IL-5Rα blocker benralizumab. Anti-IL-5 trials in both adults and pediatrics have shown reductions in mean eosinophil counts [106, 107]. However, in the adult study, no histologic remission (15 eosinophils per HPF. More 5.2% and regurgitation up to the pharynx in 8.2%, while recently, failure of PPI treatment as a condition to diagnose antiacids are taken by 2.3% and histamine receptor antagoEoE brought reflux esophagitis back in the picture of EoE nists (H2RA) by 1.3%, suggesting that symptoms of GER are [67]. EoE necessitates proper treatment (hypoallergenic not rare during adolescence and are underreported by parents feeding, corticoids, montelukast, etc.). Patients with allergic or overestimated by adolescents [50]. In infants, the issue is esophagitis are often younger and have atopic features such more complicated. Since per definition “heartburn” suggests as allergic symptoms or positive allergic tests, but have often that the individual with heartburn feels a burning retrosternal no specific symptoms. Atopic features are reported in more pain, parents and healthcare providers almost automatically than 90% and peripheral eosinophilia in up to 50% of hypothesize that a “crying baby” or a “distressed baby” is patients, but of course depending on selection of patients. At likely to suffer from heartburn or “occult GER.” As a conseendoscopy, a pale, granular, furrowed, and occasional ringed quence, acid-reducing medication is increasingly prescribed esophageal mucosa may appear [2]. While symptoms in in infants [74, 75]. Several randomized controlled trials were older children are more oriented to dysphagia for solids, performed for this indication, and for once all results come to symptoms in infants are more reflux-like [68, 69]. Repeated the same conclusion: proton-pump inhibitors are useless to endoscopy with esophageal histology in combination with decrease crying and distressed behavior in newborns and response to treatment may in some cases be the only way out infants [75]. Heine and coworkers identified no relation to separate reflux esophagitis from EoE in young children. between crying duration and the result of pH monitoring The cornerstone of treatment is an elimination diet (targeted [10]. In other words: many infants that regurgitate are disor empiric elimination diet, amino acid-based formula) and/ tressed and cry, but only very few infants presenting with or swallowed, topical corticosteroids [67]. Systemic cortico- distressed behavior or crying without regurgitation suffer steroids are reserved for severe symptoms requiring rapid GER(D). Occult GER in infants is almost nonexisting. relief or where other treatments have failed [66]. Significant The same amount of distress and crying may be evaluated differences in general practice between pediatric and adult by some parents as easily acceptable while it will be unbeargastroenterologist were demonstrated with notable diver- able for other parents. In fact, the coping capacity of the pargence from consensus guidelines [70]. Although elimination ents decides if medical help is looked for. Many factors, such diets remain an appropriate option, the vast majority of as tobacco smoke, may cause infant irritability. CMPA is adults suffering from EoE will be started on topical cortico- another well-identified cause of infant irritability. There is steroids for long-term management, mainly as a result of the substantial individual variability, and some healthy infants poor long-term compliance to elimination diets [71]. may cry up to 6 h a day [1, 2]. International practice variations are also apparent. An in-­ The concept that infant irritability and sleep disturdepth discussion on EoE is beyond the scope of this bances are manifestations of GER is largely derived from chapter. adult data [1, 2]. In adults, sleep disturbance attributable to GERD symptoms has been demonstrated, with a beneficial effect of PPI [76, 77]. The developing nervous system of infants exposed to acid seems susceptible to pain GER(D) and Heartburn, Infant Crying, and Distressed Behavior hypersensitivity despite the absence of tissue damage. In adults, NERD is an accepted entity as it is the most freWhile the verbal child can communicate pain, descriptions quent presentation of GERD. In adults, impaired quality of the intensity, location, and severity may be unreliable until of life, notably regarding pain, mental health, and social the age of at least 8–12 years [5]. In adults, adolescents, and functioning, has been demonstrated in patients with older children, heartburn and regurgitation are the character- GERD, regardless of the presence of esophagitis [78]. In

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an unselected population, 28% of the adults report heartburn, almost half of them weekly, with a significant impact on the quality of life in 76%, especially if the symptoms are frequent and long lasting. Despite that, only half of the heartburn complainers seek medical help, although 60% takes medication [79]. Thus, some adults “learn to live with their symptoms” and acquire tolerance to long-­ lasting symptoms. In infancy and young children, verbal expression of symptoms is often vague or impossible, and persistent crying, irritability, back-arching, feeding, and sleeping difficulties have been proposed as possible equivalents of adult heartburn. Infants with GERD learn to associate eating with discomfort and thus subsequently tend to avoid eating and develop an aversive behavior around feeds, although behavioral feeding difficulties are also common in control toddlers [80]. Esophageal pain and behaviors perceived by the caregiver to represent pain potentially affect the response of the infant to visceral stimuli and the ability to cope with these sensations, both painful and nonpainful. A placebo-controlled randomized trial with proton-pump inhibitors in distressed infants showed an equal decrease in distressed behavior in the treatment and the placebo group [81]. Up to date, there is no evidence that acid-suppressive therapy is effective in infants who present solely with inconsolable crying or distressed behavior. Moreover, inappropriate administration of acid-blocking medication in infants should be avoided as this medication often causes adverse effects. In infants and toddlers, there is no symptom or group of symptoms that can reliably diagnose GERD or predict treatment response. Infants presenting with isolated distressed behavior or crying should get appropriate care, but acid GERD not resulting in regurgitation or vomiting but causing excessive crying and distress is exceptional.

 ER(D) and Dysphagia, Odynophagia, G and Food Refusal Dysphagia is the difficulty of swallowing; odynophagia is pain caused by swallowing. Although GERD is frequently mentioned as a cause of dysphagia or odynophagia, there are no pediatric data showing this relation. Dysphagia is a prominent symptom in patients with EoE. Feeding difficulty and/ or refusal are often used to describe uncoordinated sucking and swallowing, gagging, vomiting, and irritability during feeding. Thickeners are effective in improving swallowing mechanics [82]. A relation between GER, GERD, and feeding refusal has not been established. In case of acute feeding difficulties, a trapped foreign body should be among the list of possible differential diagnoses. In case of chronic feeding difficulties, achalasia should be considered.

Y. Vandenplas and S. Kindt

GER(D) and Extra-Esophageal Manifestations Although there is sufficient evidence to support an association between extra-esophageal symptoms and GERD, there is no evidence for a causal relationship. Laryngopharyngeal symptoms of GERD such as globus sensation, hoarseness, and chronic cough are becoming increasingly recognized. In the pediatric literature, little attention has been given to globus pharyngeus sensation, probably related to the fact that young children will experience difficulties to express this sensation. There is no evidence that medical treatment reduces extra-esophageal manifestations. Pulmonary microaspiration as demonstrated by pepsin detection in a bronchoalveolar lavage fluid is common in children with chronic lung diseases, suggesting that GER may contribute significantly to the disease pathogenesis [83]. The bronchoalveolar lavage pepsin concentration correlates positively with the number of proximal reflux events [83]. Protein oxidation in the bronchoalveolar lavage is higher in children with extensive proximal acidic reflux, suggesting that pulmonary microaspirations contribute to lung damage [83]. Children >1 year with GERD-related respiratory symptoms showed a significantly higher number of weakly alkaline refluxes than children with GERD-related GI symptoms [84]. This supports the hypothesis that respiratory symptoms are less related to acidity than GI symptoms [84].

 ER(D) and Reactive Airway Disease G An etiologic role for GER in reactive airway disease has not been demonstrated, but the association between GERD and asthma is bidirectional: the asthma group has a 1.36 higher risk for GERD, and the GERD group has a 1.48 higher risk for asthma [85]. Prior severe asthma exacerbations (incidence rate ratio 3:45) and younger age increased the severe asthma exacerbation risk in all countries, whereas obesity, atopy, and GERD were a risk factor in some but not all countries. Rehospitalization rates were up to 79% within 1 year [86]. Different pathophysiologic mechanisms are proposed: direct aspiration, vagal mediated bronchial and laryngeal spasm, neural mediated inflammation. Esophageal acidification in infants with wheezing can produce airway hyperresponsiveness and airflow obstruction [87]. Few studies tempted to evaluate the opposite: the impact of asthma on the severity of GERD.  Chronic hyperinflation as occurs in asthma favors many GER mechanisms. An association between asthma and reflux measured by pH or impedance probe has been reported in many studies [2]. Wheezing appears more related to GERD if it is nocturnal. A recent study reports a high prevalence of GER in children and adolescents with persistent asthma, equally distributed in the supine nocturnal and upright positions [88]. But there was no

10  Gastroesophageal Reflux

correlation between the result of the pH metry and pulmonary function tests [88]. Very few prospective, randomized, and blinded treatment studies have been performed in children. In a series of 46 children with persistent moderate asthma despite bronchodilators, inhaled corticosteroids, and leukotriene antagonists, 59% (27/46) had an abnormal pH metry [89]. Reflux treatment did result in a significant reduction in asthma medication. Patients with a normal pH metry were randomized to placebo or reflux treatment: 25% (2 of only 8 children) of the treated patients could reduce their asthma medication, while this was not possible in any patient on placebo [89]. Another study found omeprazole ineffective in improving asthma symptoms and parameters in children with asthma [90]. Overall, although there seems to be an association between GER and asthma, the causal role of GER has not been demonstrated. There is no association between asthma control status and laryngopharyngeal reflux and GER [91]. Current evidence does not support the routine use of anti-GERD medication in the treatment of poorly controlled asthma of childhood [92]. Selection of patients is once more of importance. Children with asthma and heartburn should be treated with acid-reducing medication because of the heartburn, not because of the asthma. Many studies in children with extra-­ esophageal symptoms included children that also presented with typical reflux symptoms.

 ER(D) and Recurrent Pneumonia G The reported mechanisms are similar to those for reactive airway disease. Direct aspiration during swallowing may be more relevant in this group. No test can determine whether reflux is causing recurrent pneumonia. Upper esophageal and pharyngeal pH and impedance recordings provided contradictory information. A new technique to record pharyngeal reflux had been developed (Restech→) [93]. However, results could not confirm the utility of this technique [94]. As a consequence, pharyngeal pH recording is no longer used. Lipid-laden macrophages have been used as an indicator of aspiration, but their sensitivity and specificity for GER is poor. One study evaluating nuclear scintigraphy with late imaging reported that 50% of patients with a variety of respiratory symptoms had pulmonary aspiration after 24 h [95]. However, later studies failed to reproduce these findings [96]. Aspiration also occurs in healthy subjects, especially during sleep [1]. Weakly acid reflux events can be associated with a significant airway inflammation and injury that, because of the biochemical mechanisms involved, are likely not completely preventable and/or counteracted by antiacid treatments [97]. The role of reflux in patients with bronchopulmonary dysplasia and other chronic respiratory disorders is not clear. Today, the clinician has frequently no other option than to

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make management decisions based on inconclusive diagnostic studies with no certainty regarding outcome [1, 2]. As in reactive airway disease, it is very likely that nonacid reflux can cause airway manifestations.

 ER(D) and Cystic Fibrosis G The incidence of GER in children with cystic fibrosis is very high. Excessive acid reflux exists in the majority of cystic fibrosis patients, even before respiratory symptoms develop [2, 98, 99]. CF patients also suffer from duodenogastroesophageal reflux of bile acids [100, 101]. In the majority of patients, typical GER symptoms are absent [99]. Therefore, diagnostic procedures should be considered, regardless of lacking symptoms. Patients with cystic fibrosis have a relatively high number of proximal reflux episodes [99]. Such episodes also indicate an increased risk for aspiration. It is possible that as well the acid and bile reflux are aggravating the respiratory symptoms, and that the respiratory symptoms aggravate the reflux. Aggressive medical and surgical reflux treatment in this patient group seems reasonable. In children with cystic fibrosis, a better weight gain was reported during PPI treatment; whether this is due to a reduction of acid reflux or better buffering of acid gastric content in the intestine is not clear. Almost half of the children with cystic fibrosis and symptoms suggestive for GERD have increased acid GOR and almost a quarter has delayed gastric emptying [100]. However, there is no relation between GOR and gastric emptying [100]. Lung transplantation exacerbates gastroesophageal reflux disease [102]. Reflux burden and fundoplication status do not impact lung transplant outcomes, but gastric dysmotility may be linked to allograft dysfunction in children [103]. An association between GERD and allograft injury was reported, encouraging a strategy of early diagnosis and aggressive reflux management in lung transplant recipients to improve transplant outcomes [83, 104].  ER(D) and Cough and ENT Manifestations G Both acid and weakly acid GER may precede cough in children with unexplained cough, but cough does not induce GER [105]. Objective cough recording improves symptom association analysis. Treatment for GERD should not be used when there are no clinical features of GERD, and pediatric GERD guidelines should be used to guide treatment and investigations [106]. Several studies revealed the presence of pepsin in the middle ear fluid, but with a huge variation in incidence varying from 14% to 73% [2, 107]. Pepsin in saliva appears to be associated with laryngomalacia, suggesting a role for salivary pepsin as a noninvasive marker of laryngopharyngeal reflux in patients with laryngomalacia [108]. Recent data showed that salivary pepsin to detect GERD is not ready for clinical application [109]. Also, bile acids have

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been detected in middle ear liquid, even in higher concentrations than in serum [110]. The presence of pepsin and bile in middle ear fluid might as well be the consequence of reflux and vomiting at the moment of the acute middle ear infection than an argument to hypothesize that chronic GER may be at the origin of the chronic middle ear problem. Several epidemiologic studies suggest a low incidence of reflux symptoms in patients with recurrent middle ear infections. Data suggesting a causal relation between reflux and upper airway disease in children are limited. Data from several placebo-controlled studies and meta-analyses uniformly have shown no effect of antireflux therapy on upper airway symptoms or signs [2]. Well-designed, prospective, placebo-­ controlled, blinded studies are needed. Another bias might be selection of patients: these studies are frequently set up in tertiary care centers in highly selected patient populations. The question is how representative these patients are for the bulk of children with upper respiratory and/or ENT manifestations.

Neurologically impaired children accumulate many risk factors for severe GERD: spasticity or hypotonicity, supine position, constipation, etc. Diagnosis of reflux disease in these children is often difficult because of their underlying conditions. Empiric treatment will often be initiated. Whether this group of patients has more severe reflux disease, or has less effective defense mechanisms, or presents with more severe symptoms because of the inability to express and/or recognize symptoms remains open for debate. Response to treatment, both medical and surgical, was reported to be poor in the neurologically impaired child compared to the neurologically normal child. However, surgical experience for multiple centers reports different experience with no differences in outcome related to neurological impairment [116– 118]. Gastrostomy feeding may reduce aspiration but could exacerbate gastroesophageal reflux disease [115]. The impact of antireflux procedures in addition to gastrostomy is relatively unknown [115].

 ER(D) and Dental Erosions G Young children and children with neurologic impairment appear to be at greatest risk to have dental erosions caused by GER. Juice drinking, bulimia, and racial and genetic factors that affect dental enamel and saliva might be confounding variables that have been insufficiently considered [1, 2]. A positive correlation between mainly acid GERD and dental erosion has been as well confirmed as refuted, although the evidence for a relation between both seems to win the debate [110–113]. There are no long-term (intervention) follow-up studies in high-risk populations.

 ER(D) and Apnea, Brief Resolved Unexplained G Events, and Sudden Infant Death Syndrome

In adults, a relation between obstructive sleep apnea and GERD has been demonstrated [119, 120]. It is commonly assumed that nightly GER events causes sleep disturbance by arousal. However, a study combining polysomonography and pH/impedance monitoring challenged this hypothesis [121]. Literature can best be summarized as follows: series fail most of the time to show a temporal association between GER and pathologic apnea, apparent life-threatening events, and bradycardia [1, 122]. The term “brief resolved unexGER(D) and Sandifer Syndrome plained event” (BRUE) was created to replace “apparent life-­ Sandifer syndrome is an uncommon but specific manifesta- threatening event,” narrowing the definition and providing tion of GERD. The presenting symptoms of Sandifer’s may evidence-based guidelines for management. There are well-­ include any combination of abnormal movements and/or selected cases or small series that demonstrate that pathopositioning of head, neck, trunk, and upper limbs, seizure-­ logic apnea can occur as a consequence of GER. A relation like episodes, ocular symptoms, irritability, developmental between GER and short, physiologic apnea has been shown and growth delay, and iron-deficiency anemia [114]. [123]. GER is a frequent cause of interrupting sleep in Successful treatment of the underlying GERD led to a com- infants, and nonacid GER is equally important as acid GER plete or near-complete resolution of the neurological symp- for causing arousal and awakening in infants [124, 125]. toms in all of the reviewed cases [114]. GER events preceded cardiorespiratory events in 83% of these associations [82, 99]. These GER events had a higher proximal extent [124]. Discomfort is significantly associated GER(D) in Neurologically Impaired Children with reflux events and does not differ between weakly acidic and acid refluxes [126]. In general, GER is not related to Neurologically impaired children have more frequent, more pathologic apnea, significant bradycardia, and BRUE, but severe, and more difficult to treat GERD than neurologically exceptions do exist [122]. Gastroesophageal reflux can cause normal children. An ESPGHAN Working Group published a sudden death in a vulnerable infant during a critical period of consensus statement on the diagnosis and management of development through failure of “autoresuscitation” mechaGERD in neurologically impaired children [115]. nisms [127].

10  Gastroesophageal Reflux

GER(D) and Other Risk Groups There are no data in literature that preterm babies have more (severe) reflux than term born babies, although many preterms are treated for reflux. Symptomatic GER is extremely frequent in patients operated because of esophageal atresia and/or tracheoesophageal fistula because of serious structural and functional deficiencies [128]. The reflux in these children might be refractory to medical treatment. The high rates of wrap failure necessitate close follow-up [128]. Children with congenital abnormalities or after major thoracic or abdominal surgery are at risk for developing severe GERD.

GERD and Complications Children with neurological impairment, chronic lung disease (especially cystic fibrosis), esophageal atresia, and chemotherapy have the most severe pathologic reflux and are at high risk for the development of complications of GERD [1, 2]. Barrett’s esophagus, esophageal strictures, and adenocarcinoma are complications of chronic severe GERD. Barrett’s esophagus is a premalignant condition in which metaplastic specialized columnar epithelium with goblet cells replaces the squamous epithelium of the esophagus. Although Barrett’s esophagus is considered a premalignant condition, the incidence of carcinoma in pediatric population remains low [129]. Differences in esophageal mucosal resistance and genetic factors may partially explain the diversity of lesions and symptoms. Patients with esophageal atresia are at high risk of persisting GERD and Barrett’s esophagus [130]. The development of Barrett’s esophagus is related to GERD history. As Barrett’s esophagus represents a premalignant condition, long-term systematic follow-up of the esophageal mucosa including multistaged biopsies is warranted, even in asymptomatic patients [130]. More than 60 years ago, in the absence of acid-blocking medication, esophageal strictures were reported in about 5% of children with reflux symptoms [131]. Currently, esophageal stenosis and ulceration in children have become rare. In a series including 402 children with GERD without neurological or congenital anomalies, no case of Barrett’s esophagus was detected [57]. In another series including 103 children with long-lasting GERD, and not previously treated with a H2 receptor antagonist (H2RA) or a proton-pump inhibitor (PPI), Barrett’s esophagus was detected in 13%. An esophageal stricture was present in 5 of the 13 patients with Barrett [132]. Reflux symptoms during childhood were not

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different in adults without or with Barrett [133]. Barrett has a male predominance, and increases with age. Patients with short segments of columnar-lined esophagus and intestinal metaplasia have similar esophageal acid exposure but significantly higher frequency of abnormal bilirubin exposure and longer median duration of reflux symptoms than patients without intestinal metaplasia [134]. There is a genetic predisposition in families in patients with Barrett’s esophagus and esophageal carcinoma [1]. Peptic ulcer, esophageal, and gastric neoplastic changes in children are seldom observed. In adults, over the last 30 years, a decreased prevalence of gastric cancer and peptic ulcer with an opposite increase of esophageal adenocarcinoma and GERD has been noted. This has been attributed to independent factors among which changes in dietary habits such as a higher fat intake, an increased incidence of obesity, and a decreased incidence of H. pylori infection. The incidence of noninvasive in situ cancer has actually declined after 2003 [135]. Frequency, severity, and duration of reflux symptoms are related to the risk to develop esophageal cancer. Among adults with long-standing and severe reflux, the odds ratios are 43.5 for esophageal adenocarcinoma and 4.4 for adenocarcinoma at the cardia [136]. It is unknown whether mild esophagitis or GER symptoms persisting from childhood is related to an increased risk for severe complications in adults.

Diagnosis It is beyond the scope of the subject to provide a detailed discussion on all diagnostic procedures for GERD. Detailed information regarding indications and pitfalls of radiologic contrast studies, nuclear reflux scintigraphy, ultrasound, endoscopy, manometry, gastric emptying tests, and electrogastrography can be found in review papers and guidelines [1, 2]. The applicability of the recent Lyon consensus for diagnosing GERD in adults needs to be discussed for its applicability in pediatrics [137]. According to the Lyon consensus, conclusive evidence for reflux on esophageal testing include advanced grade erosive esophagitis (LA grades C and D), long-segment Barrett’s mucosa or peptic strictures on endoscopy, or distal esophageal acid exposure time (previously called “reflux index”) >6% on ambulatory pH or pH-­ impedance monitoring “off” PPI [137]. A normal endoscopy does not exclude GERD, but provides supportive evidence refuting GERD in conjunction with distal acid exposure time 35 kg 40 mg High dose 15–24 kg 25–34 kg >35 kg

Evening dose

AMO Morning dose

Evening dose

MET Morning dose

Evening dose

CLA Morning dose

Evening dose

20 mg 30 mg 40 mg

500 mg 750 mg 1000 mg

500 mg 750 mg 1000 mg

250 mg 500 mg 500 mg

250 mg 250 mg 500 mg

250 mg 500 mg 500 mg

250 mg 250 mg 500 mg

750 mg 1000 mg 1500 mg

750 mg 1000 mg 1500 mg

PPI proton pump inhibitor, AMO amoxicillin, CLA clarithromycin, MET metronidazole

92]. In a meta-analysis of 23 studies (with specified pediatric age groups) published in 2018, the prevalence of resistance to clarithromycin in children was from 10% in Eastern Mediterranean region and 19% in Americas region to 85% in Western Pacific region; to metronidazole from 20% in Europe to 40% in Americas region and 81% in Eastern Mediterranean region, and to levofloxacin from 4% in Europe region to 29% in Eastern Mediterranean region [93]. Based on the negative effect of antibiotic resistance on treatment outcomes, the rates of resistance in the area where the child lives should be taken into account when deciding on the initial therapeutic regimen for eradication [5]. In areas with high or unknown primary antibiotic resistance rate, culture and susceptibility testing should be performed in order to select proper treatment regimen [5]. Decreasing eradication rates with these standard triple regimens have led to the development of alternative treatment options, like sequential therapy, bismuth-based therapy, and concomitant therapy. Sequential therapy is a two-step, 10-day therapy typically consisting of a PPI combined with amoxicillin given for the first 5  days, followed by a triple therapy including a PPI, clarithromycin, and metronidazole/tinidazole for another 5 days [94]. Meta-analysis comparing sequential to standard triple therapy found that sequential therapy is superior to 7-day standard triple therapy, however, not significantly better than 10-day or 14-day triple therapy [94]. However, more recent studies performed in Europe showed that eradication rates with sequential therapy were only 56% when clarithromycin resistance was present, while in case of strains susceptible to both clarithromycin and metronidazole primary eradication rates with a high-dose sequential 10-day regimen in children were 85.8% in the intention to treat analysis [5]. Therefore, current guidelines suggest that sequential therapy should not be given if the strain is resistant to metronidazole or clarithromycin, or if susceptibility testing is not available [5]. Bismuth-based quadruple therapy is also recommended as an alternative first-line therapy. Well-designed, randomized, multicenter studies of H. pylori eradication in children

comparing bismuth-based regimens to the alternative recommended first-line therapies are lacking, but studies performed in adults indicate that bismuth-based therapies are effective. The results from the pediatric European register for treatment of H. pylori showed that when given as first treatment, bismuth-containing triple therapies were more efficacious than those containing PPI (77% versus 64%) [95, 96]. More recent studies evaluated bismuth-based quadruple therapies and showed higher eradication rates than standard triple therapy. According to current guidelines, it is recommended that bismuth quadruple therapy can be used in children if H. pylori antimicrobial susceptibility is unknown or in the setting of dual resistance to clarithromycin and metronidazole [5]. Concerning concomitant therapy, it was shown for adult patients that concomitant quadruple therapy (PPI and amoxicillin, metronidazole, and clarithromycin given for 10 to 14  days) was one of the most effective treatments, with a high eradication rate and acceptable frequency of adverse events. Currently, no studies assessing concomitant therapy in the pediatric setting are available. However, in children with primary double resistance to clarithromycin and metronidazole, concomitant therapy may be an option [5]. The duration of eradication therapy is still controversial. There are limited well-designed studies specifically addressing the optimal treatment duration in children. However, in adults, a recent systematic review showed that 14-day duration of treatment improves eradication rates compared to 10-day, and both are superior to 7-day treatment. Therefore, it is recommended that the duration of triple therapy should be 14 days [5]. It has been reported that, especially taking into account compliance rate, there is no benefit from longer duration of therapy [96, 97]. Rescue Therapy in Children Who Failed First-Line Treatment (Table 12.5). Emerging evidence suggests the development of secondary antibiotic resistance in children who failed initial eradication therapy [98]. Therefore, when H. pylori treatment fails, rescue therapy should be individualized considering antibiotic susceptibility, the age of the child, and available

12  Helicobacter Pylori Gastritis and Peptic Ulcer Disease

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Table 12.5  Rescue therapies (after the failure of first-line therapy) for treating H. pylori infection in pediatric patients (based on ESPGHAN/ NASPGHAN recommendations [5]) Initial antibiotic susceptibility Susceptible to CLA + susceptible to MET

Past treatment regimen Triple therapy using AMO + CLA Triple therapy using AMO + MET Sequential therapy

Resistant to CLA Resistant to MET

Triple therapy using AMO + MET Triple therapy using AMO + CLA

Unknown primary antimicrobial susceptibility

Triple therapy or sequential therapy

Rescue treatment Triple therapy using AMO + MET Triple therapy using AMO + CLA Tailored treatment for 14 days after second endoscopy or treat like double resistance (Table 12.3)a Treat like double resistance (Table 12.3)a Tailored treatment for 14 days after second endoscopy or treat like double resistancea (Table 12.3)a Tailored treatment for 14 days after second endoscopy or treat like double resistance (Table 12.3)a

PPI proton pump inhibitor, AMO amoxicillin, CLA clarithromycin, MET metronidazole a In adolescents, levofloxacin or tetracycline may be considered

antimicrobial options. If possible, primary culture with antibiotic sensitivity testing should be performed to guide second-­line therapy. If culture (and standard susceptibility testing) is not possible, molecular tests (including FISH) can be used to detect H. pylori and clarithromycin and/or fluoroquinolone resistance in gastric biopsies [78]. If primary culture and sensitivity testing are not available, when deciding on second-line therapy the initial therapy should be taken into account with avoidance of previously given regimens [5, 99]. As studies suggest that increasing acid suppression and antibiotic dose (metronidazole and amoxicillin) may improve efficacy of eradication therapy, using such regimens may be considered in children. Also, based on efficacy proved in adults, regimens using levofloxacin or tetracycline may be applied in adolescents. Another option as a salvage therapy may be a quadruple therapy which consists of PPI, metronidazole, amoxicillin, and bismuth [5]. However, this regimen is complicated to administer, and bismuth salts are not widely available. Although the studies on the ideal duration of therapy for second-line treatment are not conclusive, a longer duration of therapy of up to 14 days is recommended [5].

Assessment of Eradication All children who received treatment for H. pylori, even if they have no symptoms, should undergo the evaluation of the treatment success. The absence of symptoms is not reliable and does not necessarily mean the H. pylori is eradicated. The recommended tests for H. pylori eradication assessment are noninvasive tests: 13C-UBT and a two-step monoclonal ELISA test for the detection of H. pylori antigen in stool [5]. As previously presented these tests have a high sensitivity and high specificity and are not invasive. A follow-up endoscopy is not routinely indicated unless other causes of ulceration are suspected or if biopsies are needed for culture and antibiotic susceptibility testing [5].

Eradication therapy reduces the amount of H. pylori in the stomach, even when eradication failed because that antibiotic or PPI therapy can cause false-negative test results [100]. Therefore, assessment of eradication should be performed with noninvasive test at least 4 weeks following completion of therapy [5].

References 1. Zarrilli R, Ricci V, Romano M.  Molecular response of gastric epithelial cells to Helicobacter pylori-induced cell damage. Cell Microbiol. 1999;1(2):93–9. 2. Ricci V, Romano M, Boquet P.  Molecular cross-talk between Helicobacter pylori and human gastric mucosa. World J Gastroenterol. 2011;17(11):1383–99. 3. Delahay RM, Rugge M.  Pathogenesis of Helicobacter pylori infection. Helicobacter. 2012;17(Suppl 1):9–15. 4. Koletzko S, Jones NL, Goodman KJ, Gold B, Rowland M, Cadranel S, et  al. Evidence-based guidelines from ESPGHAN and NASPGHAN for Helicobacter pylori infection in children. J Pediatr Gastroenterol Nutr. 2011;53(2):230–43. 5. Jones NL, Koletzko S, Goodman K, Bontems P, Cadranel S, Casswall T, et  al. Joint ESPGHAN/NASPGHAN guidelines for the management of Helicobacter pylori in children and adolescents (update 2016). J Pediatr Gastroenterol Nutr. 2017;64(6):991–1003. 6. de Brito BB, da Silva FAF, Soares AS, Pereira VA, Santos MLC, Sampaio MM, et  al. Pathogenesis and clinical management of Helicobacter pylori gastric infection. World J Gastroenterol. 2019;25(37):5578–89. 7. Kao CY, Sheu BS, Wu JJ. Helicobacter pylori infection: an overview of bacterial virulence factors and pathogenesis. Biom J. 2016;39(1):14–23. 8. Testerman TL, Morris J. Beyond the stomach: an updated view of Helicobacter pylori pathogenesis, diagnosis, and treatment. World J Gastroenterol. 2014;20(36):12781–808. 9. Ansari S, Yamaoka Y.  Survival of Helicobacter pylori in gastric acidic territory. Helicobacter. 2017;22(4). 10. Chmiela M, Kupcinskas J. Review: pathogenesis of Helicobacter pylori infection. Helicobacter. 2019;24 Suppl 1:e12638. 11. Sterbenc A, Poljak M, Zidar N, Luzar B, Homan M. Prevalence of the Helicobacter pylori homA and homB genes and their correlation with histological parameters in children. Microb Pathog. 2018;125:26–32.

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Ménétrier Disease in Children

13

Jasmina Kikilion, Elvira Ingrid Levy, and Yvan Vandenplas

Abbreviations

Table 13.1  Menetrier disease in summary in children [1–9] Triggers

Herpes simplex virus, Giardia lamblia, Mycoplasma pneumonia, CMVa, and HPb Symptoms Edema, emesis, epigastric pain, anorexia, diarrhea, vomiting, and abdominal pain Diagnostics Endoscopy in combination of biopsy and cultures Treatment Self-limiting Supportive therapies: Albumin, diuretics, fluid restriction, high-protein diet, acid inhibitors, ganciclovir

HP Helicobacter pylori MD Ménétrier disease TGF-α Transforming growth factor alpha

Introduction

CMV Cytomegalovirus HP Helicobacter pylori

a

b

Ménétrier disease (MD) was described by the French pathologist Pierre Ménétrier in 1888 [1, 2]. MD is an uncommon acquired self-limiting disorder in children [3, 4]. Pathogenesis and etiology are not yet fully understood [4]. Up to now, there are only approximately 60 cases of children with MD reported in literature [3, 4]. Most of these are case series. In this chapter, we discuss etiology and propose guidance to diagnosis and management.

Clinical Manifestations Since there are no pathognomonic features described to diagnose MD, it continues to be a clinicopathological diagnosis. Symptoms described in adults (males more often affected than females) include vomiting, nausea, abdominal pain, diarrhea, weight loss, malnutrition, and peripheral edema secondary to hypo-albuminemia [1, 5]. In children, there is often a prodromal faze caused by a transient viral infection, followed by edema and gastrointestinal symptoms including emesis, epigastric pain, anorexia, diarrhea, vomiting, and abdominal pain (Table  13.1) [3, 4]. Edema is caused by hypo-albuminemia as a result of protein-losing edema of the J. Kikilion · E. I. Levy · Y. Vandenplas (*) Vrije Unversiteit Brussel (VUB), UZ Brussel, KidZ Health Castle, Brussels, Belgium e-mail: [email protected]; [email protected]; [email protected]

gastric mucosa [4]. The average age of affected children is 2–5 years [6], but a case series from Gökçe et al. describes two cases of neonatal MD, both presenting with edema as major symptom [4]. As in children a spontaneous remission is common, it is possible that the disease is associated with Helicobacter pylori (HP) infection or transient infections such as cytomegalovirus (CMV) [4, 5]. These associations will be discussed later in this review. There is a wide variation in clinical manifestations depending on the age of the patient. It is important to list MD in the differential diagnoses of edema occurring in combination with gastrointestinal symptoms.

Pathophysiology and Etiology The pathogenesis of MD is not yet fully understood [3, 4]. Observational studies in transgenic mice showed a relation between the possible overexpression of transforming growth factor alpha (TGF-α) and the development of gastric changes that are characteristic of MD [5]. TGF-α inhibits gastric acid production and stimulates growth of gastric epithelial cells [1]. TGF-α is a ligand that mediates signal transduction by binding epidermal growth factor receptor (EGFR), which leads to increased cellular proliferation [5]. More specifically in MD disease, overexpression of TGF-α redirects the gastric progenitor cells to surface mucous cell differentiation

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 S. Guandalini, A. Dhawan (eds.), Textbook of Pediatric Gastroenterology, Hepatology and Nutrition, https://doi.org/10.1007/978-3-030-80068-0_13

185

186

at the disadvantage of parietal and chief cell differentiation [5]. Remarkable is the observation that the gastrin levels in serum are normal, despite lower gastric acidity, which is a stimulus for increased production of gastrin [1]. In children, MD disease is transient and in general it is believed to be associated with infections such as herpes simplex virus, Giardia lamblia, Mycoplasma pneumonia, CMV, and HP [3–6]. Possible pathogenic mechanism is damage of the gastric mucosa caused by infection, which may lead to the production of abnormal local TGF-α [3]. CMV infection in the stomach causes elevation of intracellular messengers and activation of proto-oncogenes that causes an increase in the production of TGF-α in mucosal cells [6]. Some case reports show an association with some medications and allergies [4]. Several cases show MD with CMV and HP co-­ infection, although they propose that HP has the most causative role in the disease [4, 7]. However, given the high incidence of HP infection, these associations may just be by coincidence. A case series of two siblings with CMV-­ associated MD proposes the hypothesis that genetic factors could stimulate an increased production of TNF-〈 in response to CMV infection [6]. A unique, fourth-generation pedigree with autosomal dominant gastropathy exhibiting the typical clinical, endoscopic, and pathological MD-like findings, though in the absence of protein loss and with no increase in the levels of gastric TGF-α, proposes a genetic predisposition to develop MD [8]. In conclusion, the pathogenesis has still to be explored further; however, there is evidence of overexpression of TGF-α with transformation of the gastric mucosa which is possibly mediated by genetics and provoked by an infectious trigger.

Diagnosis and Histological Findings Diagnosis of MD starts with a thorough history of the patient, in which contact with family members with possible HP infection must be investigated. To confirm the diagnosis of MD, gastroscopy, biopsies, and cultures must be performed. Endoscopic findings are thickened gastric mucosal folds, and these are predominantly present in the body and the fundus of the stomach, relative sparing the antrum (Table 13.1) [5]. The most striking feature of MD, a histological sine qua non, is foveolar hyperplasia (expansion of the surface mucous cells) that leads to thickening of the gastric mucosa. There is a loss of parietal cells due to atrophic oxyntic glands, which secondarily leads to an increase of the gastric pH (normal pH of gastric fluid is 1–3, but in MD pH is rather 4–7) [1, 5].

J. Kikilion et al.

Additionally, deep glands are often dilated, forming cysts. Histologically, there is a chronic inflammatory cell infiltration at the lamina propria with the presence of eosinophils and plasma cells, hyperplasia of smooth muscle, and edema [1, 5]. Other diseases with similar endoscopic findings are hypertrophic lymphocytic gastritis, eosinophilic gastritis, Zollinger–Ellison syndrome, polyposis syndrome, gastric malignancies, and lymphoma [5, 6]. To investigate a possible association of juvenile polyposis syndrome with MD, a new mechanism that involves TGF-α-SMAD 4 pathway inactivation and TGF-α overexpression related to HP infection has been proposed [8]. Concluding, the golden standard for the diagnosis of MD is to perform gastroscopy with biopsy and the typical histological findings.

Treatment Management of MD in children is often supportive as most of the cases that are reported are associated with transient infections. As infection resolves spontaneously, MD usually resolves within several weeks to months [4, 5]. If there is evidence of HP infection, eradication can be considered, although there is a case described where MD resolved without the use of antibiotics [3, 6]. As HP is the only causative organism described that is not a transient infection, we think of the possibility that the association of MD and HP is a coincidence. Supportive treatment includes albumin infusion to correct the hypo-albuminemia and diuretics, fluid restriction, and high-protein diet [2, 3]. Acid inhibitors such as proton pump inhibitors and H2 receptor blockers and anticholinergic agents are used to protect the stomach. Preference for acid inhibitors was not reported. Ganciclovir treatment can be considered if there is evidence for active CMV infection and if the patient is immunocompromised, very young or if spontaneous improvement does not occur [4, 6]. In adults and adolescents with chronic and severe diseases, chirurgical therapy like partial or total gastrectomy can be considered [2, 5]. Further clinical trials with cetuximab, an immunoglobulin that binds to epidermal growth factor receptor and prevents binding of TGF-α, showed promising results with rapid improvement of symptoms after the first administration in adults [1]. In conclusion, the treatment of MD in children is mainly supportive with in some cases correction of hypo-­ albuminemia with albumin infusions, and administration of diuretics is needed (Table 13.1).

13  Ménétrier Disease in Children

Conclusion MD is a rare condition in children of which the pathophysiology and etiology are not yet fully understood. New possible mechanisms and the involvement of genetics in the pathophysiology of MD have been suggested and are further investigated. Some viral, bacterial, and parasite infections are associated with the condition. The disease can only be diagnosed by gastroscopy and histology of gastric biopsies. The disease is self-limiting, and supportive therapy is advised.

References 1. Coffey RJ Jr, Tanksley J. Pierre Menetrier and his disease. Trans Am Clin Climatol Assoc. 2012;123:126–33; discussion 33–4. 2. Azer M, Sultan A, Zalata K, Abd El-Haleem I, Hassan A, El-Ebeidy G.  A case of Menetrier’s disease without Helicobacter pylori or hypoalbuminemia. Int J Surg Case Rep. 2015;17:58–60.

187 3. Yoo Y, Lee Y, Lee YM, Choe YH.  Co-infection with cytomegalovirus and Helicobacter pylori in a child with Menetrier’s disease. Pediatr Gastroenterol Hepatol Nutr. 2013;16:123–6. 4. Gokce S, Kurugol Z. Cytomegalovirus-associated Menetrier disease in childhood. Clin Pediatr (Phila). 2017;56:382–4. 5. Huh WJ, Coffey RJ, Washington MK. Menetrier’s disease: its mimickers and pathogenesis. J Pathol Transl Med. 2016;50:10–6. 6. Tard C, Madhi F, Verlhac S, Hagege H, Epaud R, Jung C. Protein-­ losing gastropathy associated with cytomegalovirus in two sisters  – case reports and review of the literature. Arch Pediatr. 2019;26:232–5. 7. Iwama I, Kagimoto S, Takano T, Sekijima T, Kishimoto H, Oba A.  Case of pediatric Menetrier disease with cytomegalovirus and Helicobacter pylori co-infection. Pediatr Int. 2010;52:e200–3. 8. Piepoli A, Mazzoccoli G, Panza A, Tirino V, Biscaglia G, Gentile A, et al. A unifying working hypothesis for juvenile polyposis syndrome and Menetrier’s disease: specific localization or concomitant occurrence of a separate entity? Dig Liver Dis. 2012;44:952–6. 9. Strisciuglio C, Corleto VD, Brunetti-Pierri N, Piccolo P, Sangermano R, Rindi G, et  al. Autosomal dominant Menetrier-like disease. J Pediatr Gastroenterol Nutr. 2012;55:717–20.

14

Viral Diarrhea Alfredo Guarino and Eugenia Bruzzese

Epidemiology and Etiology Although childhood diarrhea deaths have declined more than 80% from 1980 to 2015, diarrhea is still the second leading cause of death due to infections among children below 5 years of age worldwide after lower respiratory tract infections [1, 2], and it is estimated that almost 2 million children aged less than 5 years die each year in the world accounting for almost 20% of total child deaths. African and South-East Asia Regions account for 78% of all diarrhea deaths occurring among children in the developing world, and 73% of these deaths are concentrated in 15 developing countries [2, 3]. A too slow progressive reduction is observed and the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimated that in 2016, diarrhea was the fifth leading cause of death among children younger than 5 years with a rate of 70.6 deaths per 100.000. Diarrhea was responsible for 8.92% of all deaths in children younger than 5 years in 2016, with an estimated incidence of 1.75 episodes per child younger than 5 years. The number of diarrhea deaths among children younger than 5 years decreased by more than 50%, and also diarrhea incidence decreased between 2000 and 2016 [4]. Childhood wasting, unsafe water, and unsafe sanitation were the leading risk factors for diarrhea [4]. Table 14.1 shows mortality rates and incidence of diarrhea due to the main etiological agents. Nevertheless, acute diarrhea is still a major problem in both developing and industrialized countries, but with two distinct consequences. In developing countries, enteric infections are highly common, and acute gastroenteritis is also responsible for a high mortality rate, whereas in industrialized countries, the incidence of diarrhea and the mortality is much lower than in poor countries, although not negligible. Gastroenteritis hospitalizations continue to require signifiA. Guarino (*) · E. Bruzzese Department of Translation Medical Science, Section of Pediatrics, University of Naples “Federico II”, Naples, Italy e-mail: [email protected]

Table 14.1  Mortality rates and incidence of acute diarrhea in children under 5 years of age due to specific viral agents in 2016 Deaths per 100.000 (95% UI) Adenovirus 1·3 (0·8–1·8) Norovirus 1.7 (0.8–3.1) Rotavirus 20.3 (16.6–24.5)

Episodes per 1000 (95% UI) 22·4 (16·0–30·1) 76.8 (30.1–159.6) 408.6 (311.6–533.1)

Modified from GBD 2016 Diarrhoeal Disease Collaborators [4]

cant inpatient resources also in the United States; from 2010 to 2011 about 4/1000 children were hospitalized for acute gastroenteritis with an estimated direct cost of $200 million annually [5]. Rotavirus is the leading cause of acute gastroenteritis [4], and it is the most frequent agent of severe diarrhea in children 90%). Additional congenital anomalies are found in 18% of cases, including gastrointestinal malformation, cleft palate, polydactyly, cardiac septal defects, and craniofacial anomalies. The higher rate of associated anomalies in familial cases than in isolated cases (39% vs. 21%) strongly suggests syndromes with Mendelian inheritance [2]. Isolated HD appears to be a multifactorial malformation with low, sex-dependent penetrance, variable expression according to the length of the aganglionic segment, and suggesting the involvement of one or more gene(s) with low penetrance [2]. These parameters must be considered for accurate evaluation of the recurrence risk in relatives. Segregation analyses suggested an oligogenic mode of inheritance in isolated HD.  With a relative risk as high as 200, HD is an excellent model for the approach to common multifactorial diseases [11]. A large number of chromosomal anomalies have been described in HD patients. Free trisomy 21 (Down syndrome) is by far the most frequent, involving 2–10% of ascertained HD cases [12]. Syndromes associated with HD can be classified as: [1] pleiotropic neurocristopathies; syndromes with HD as a mandatory feature; and occasional association with recognizable syndromes. The neural crest is a transient and multipotent embryonic structure that gives rise to neuronal, endocrine and paraendocrine, craniofacial, conotruncal heart, and pigmentary tissues. Neurocristopathies encompass tumors, malformations, and single or multifocal abnormalities of tissues mentioned above in various combinations. Multiple endocrine neoplasia type 2 (MEN 2) and Waardenburg syndrome are the most frequent neurocristopathies associated with HD [13, 14]. Waarderburg syndrome (WS), an autosomal dominant condition, is by far the most frequent condition combining pigmentary anomalies and sensorineural deafness, resulting from the absence of melanocytes of the skin and the stria vascularis of the cochlea. The combination of HD with WS defines the WS4 type (Shah-Waardenburg syndrome). Indeed, homozygous mutations of the endothelin pathway and heterozygous SOX10 mutations have been identified in WS4 patients with CNS involvement including seizures, ataxia, and demyelinating peripheral and central neuropathies [15].

M. Martinelli and A. Staiano

A wide spectrum of additional isolated anomalies has been described among HD cases with an incidence of sporadic types varying from 5% to 30% [2, 16]. No constant pattern is observed. These anomalies include distal limb, sensorineural, skin, gastrointestinal, central nervous system, genital, kidney, cardiac malformations, and facial dysmorphic features. These data highlight the importance of a careful assessment by a clinician trained in dysmorphology for all newborns diagnosed with HD.  Skeletal x-ray and cardiac and urogenital ecographic survey should be systematically performed. The observation of one additional anomaly to HD should prompt chromosomal studies.

Molecular Genetics Several genes have been implicated in isolated HD, the two major ones being the proto-oncogene RET (RET) and the endothelin B receptor (EDNRB) [2].

The RET Signaling Pathway The first observation was about an interstitial deletion of chromosome 10q11.2 in patients with TCA and mental retardation [17]. The proto-oncogene RET, identified as disease causing in MEN 2 and mapping in 10q11.2, was regarded as a good candidate gene owing to the concurrence of MEN 2A and HD in some families and the expression in neural crest-­ derived cells. Consequently, RET gene mutations were identified in HD patients [18]. Expression and penetrance of a RET mutation is variable and sex dependent within HD families (72% males and 51% females). Over 100 mutations have been identified including large deletions encompassing the RET gene, microdeletions and insertions, nonsense, missense, and splicing mutations [19–21]. Haploinsufficiency is the most likely mechanism for HD mutations. Biochemical studies showed variable consequences of some HD mutations (misfolding, failure to transport the protein to the cell surface, abolished biological activity). Despite extensive mutation screening, a RET mutation is identified in only 50% of familial and 15-20% of sporadic HD case [22]. However, most families with few exceptions are compatible with linkage at the RET locus [23]. Mutations in RET ligand, like GDNF, GFRA1-4, NTN, persephin (PSPN), and artemin (ARTN), may occur, but are not sufficient to lead to HD.

The Endothelin Signaling Pathway A susceptibility locus for HD in 13q22 was suggested for three main reasons: a significant lod score at 13q22 in a large

22  Hirschsprung’s Disease and Intestinal Neuronal Dysplasias

inbred Old Order Mennonite community with multiple cases of HD; de novo interstitial deletion of 13q22  in several patients with HD; and synteny between the murine locus for piebald-lethal (sl), a model of aganglionosis, and 13q22 in humans. Subsequently, an EDNRB missense mutation was identified in the Mennonite kindred (W276C) [24, 25]. Both EDNRB and EDN3 were screened in large series of isolated HD patients, and EDNRB mutations were identified in approximately 5% of the patients. It is worth mentioning that the penetrance of EDN3 and EDNRB heterozygous mutations is incomplete in those HD patients, de novo mutations have not hitherto been observed, and that S-HD is largely predominant [26].

SOX10 The last de novo mouse model for WS4 in human is dominant megalon (Dom). The Dom gene is Sox10, a member of the SRY (sex determining factor)-like, high-mobility group (HMG) DNA-binding proteins. Subsequently, heterozygous SOX10 mutations have been identified in familial and isolated patients with WS4 (including de novo mutation) with high penetrance [27].

Clinical Signs/Symptoms The clinical symptoms of HD usually start at birth with the delayed passage of meconium. More than 90% of term neonates, and 90% of affected patients, the symptoms start during the neonatal period, and in the majority, the diagnosis is made during the first 3 months of life, whereas 8 neurons/ganglion (so-called giant ganglia) in >20% of a minimum of 25 submucosal ganglia in patients older than 1  year [64]. However, concern has been expressed whether intestinal neuronal dysplasia can be safely diagnosed by mucosal and submucosal alteration alone, without myenteric plexus abnormalities. Submucosal hyperganglionosis may reflect a normal age-related phenomenon due to immaturity, with clinical and histochemical normalization after the first year of life. Furthermore, it has been reported that most of the patients with submucosal IND have a spontaneous clinical improvement which is sometimes associated with histological normalization [65, 66]. To date, submucosal intestinal neuronal dysplasia has been reported in several disorders such as intestinal malformations, meconium plug syndrome, cystic fibrosis, gastroschisis, pyloric stenosis, and inflammatory processes involving the gut. The high frequency of histological abnormalities in young infants may represent a normal variant of postnatal development rather than a pathological process. Investigations using more refined and morphometric methods in rectal specimens from infants and children without bowel disease are needed to define the normal range for different ages [66]. Therefore, most of the evidence suggests that the histological appearance of so-called IND is a normal variant related to age. Owing to the lack of sufficient normative data, IND remains a histological

22  Hirschsprung’s Disease and Intestinal Neuronal Dysplasias

description with poorly established clinical significance [40, 43]. Patients with IND have been subjected to multiple types of treatment; however, most patients with IND can be treated conservatively. If bowel symptoms persist after at least 6 month of conservative treatment, internal sphincter myectomy should be considered. The rapid AchE technique has been found to be of great value in determining the extent of IND intraoperatively [67].

Genetic Aspects Studies have been performed to investigate the potential role of HD associated RET, GDNF, EDNRB, and EDN3 genes in the development of IND. They demonstrated that only three RET mutation were detected in patients with HD, no mutation in this gene was observed in IND and mixed HD/IND patients, HD and HD/IND patients showed overrepresentation of a specific RET polymorphism in exon 2, while IND patients exhibited a significantly lower frequency of the same polymorphism comparable with that of controls. These findings may suggest that IND is genetically different from HD. A homozygous mutation of the EDNRB gene in spotting lethal (sl/sl) rats leads to HD phenotype with long segmented aganglionosis. The heterozygous (+/sl) EDNRB-deficient rats revealed more subtle abnormalities of the enteric nervous system (ENS): the submucous plexus was characterized by a significantly increased ganglionic size and density and the presence of hypertrophied nerve fiber strands, resembling the histopathological criteria for IND.  Other animal model, likes Ncx/Hox11L.1-deficient mice, suggests that many other genes could be involved in the pathogenesis of IND [68].

References 1. Heuckeroth RO. Hirschsprung disease – integrating basic science and clinical medicine to improve outcomes. Nat Rev Gastroenterol Hepatol. 2018;15:152–67. 2. Luzón-Toro B, Villalba-Benito L, Torroglosa A, Fernández RM, Antiñolo G, Borrego S. What is new about the genetic background of Hirschsprung disease? Clin Genet. 2020;97:114–24. 3. Gershon MD, Chalazonitis A, Rothman TP.  From neural crest to bowel: development of the enteric nervous system. J Neurobiol. 1993;24:199–214. 4. Badner JA, Sieber WK, Garver KL, et  al. A genetic study of Hirschsprung’s disease. Am J Hum Genet. 1990;46:568–80. 5. Staiano A, Corazziari E, Andreotti MR, Clouse RE.  Esophageal motility in children with Hirschsprung’s disease. Am J Dis Child. 1991;145:310–3. 6. Larsson LT, Shen Z, Ekbland E, Sundler F, Alm P, Ke A. Lack of neuronal nitric oxide synthase in nerve fibers of aganglionic intestine: a clue to Hirschsprung’s disease. JPGN. 1995;20:49–53. 7. Lake BD, Puri P, Nixon HH, Claireaux AE. Hirschsprung’s disease. An appraisal of histochemically demonstrated acetylcholinesterase

311 activity in suction rectal biopsy specimens as an aid to diagnosis. Arch Path Lab Med. 1978;26:288–91. 8. Romanska HM, Bishop AE, Brereton RJ, Spitz L, Polak JM.  Increased expression of muscolar neural cell adhesion molecule in congenital aganglionosis. Gastroenterology. 1993;105(4):1104–9. 9. Vanderwinden JM, De Laet MH, Schiffmann SN, et  al. Nitric oxide synthase distribution in the enteric nervous system of Hirschsprung’s disease. Gastroenterology. 1993;105:969–73. 10. Vanderwinden JM, Rumessen JJ, Liu H, Descamps D, De Laet MH, Vanderhaeghen JJ. Interstitial cells of cajal in humen colon and in Hirschsprung’s disease. Gastroenterology. 1996;111:901–10. 11. Brooks A, Oostra B, Hofstra R.  Studying the genetics of Hirschsprung’s disease: unraveling an oligogenic disorder. Clin Genet. 2005;67:6–14. 12. Moore SW.  Advances in understanding the association between down syndrome and Hirschsprung disease (DS-HSCR). Pediatr Surg Int. 2018;34:1127–37. 13. Decker RA, Peacock ML, Watson P. Hirschsprung disease in MEN 2A: increased spectrum of RET exon 10 genotypes and strong genotype-­phenotype correlation. Hum Mol Genet. 1998;7:129–34. 14. Cohen MS, Phay JE, Albinson C, et  al. Gastrointestinal manifestations of multiple endocrine neoplasia type 2. Ann Surg. 2002;235:648–54, discussion 54–5. 15. Edery P, Attie T, Amiel J, Pelet A, et  al. Mutation of the endothelin-­ 3 gene in the Waardenburg-Hirschsprung disease (Shah-­ Waardenburg syndrome). Nat Genet. 1996;12:442–4. 16. Auricchio A, Griseri P, Carpentieri ML, et al. Double heterozygosity for a RET substitution interfering with splicing and an EDNRB missense mutation in Hirschsprung disease. Am J Hum Genet. 1999;64:1216–21. 17. Edery P, Lyonnet S, Mulligan LM, et al. Mutations of the RET proto-­ oncogene in Hirschsprung’s disease. Nature. 1994;367:378–80. 18. Angrist M, Bolk S, Thiel B, et  al. Mutation analysis of the RET receptor tyrosine kinase in Hirschsprung disease. Hum Mol Genet. 1995;4:821–30. 19. Seri M, Yin L, Barone V, Bolino A, et al. Frequency of RET mutations in long- and short-segment Hirschsprung disease. Hum Mutat. 1997;9:243–9. 20. Attie T, Pelet A, Edery P, et al. Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung disease. Hum Mol Genet. 1995;4:1381–6. 21. Hofstra RM, Wu Y, Stulp RP, et al. RET and GDNF gene scanning in Hirschsprung patients using two dual denaturing gel systems. Hum Mutat. 2000;15:418–29. 22. Bolk S, Pelet A, Hofstra RM, et  al. A human model for multigenic inheritance: phenotypic expression in Hirschsprung disease requires both the RET gene and a new 9q31 locus. Proc Natl Acad Sci U S A. 2000;97:268–73. 23. Borrego S, Eng C, Sanchez B, Saez ME, Navarro E, Antinolo G. Molecular analysis of the ret and GDNF genes in a family with multiple endocrine neoplasia type 2A and Hirschsprung disease. J Clin Endocrinol Metab. 1998;83:3361–4. 24. Kiss P, Orsztovics M.  Association of 13q deletion and Hirschsprung’s disease. J Med Genet. 1989;26:793–4. 25. Puffenberger EG, Hosoda K, Washington SS, et al. A missense mutation of endothelin-B receptor gene in multigenic Hirschsprung’s disease. Nat Genet. 1996;14:345–7. 26. Auricchio A, Casari G, Staiano A, Ballabio A. Endothelin-B receptor mutations in patients with isolated Hirschsprung disease from a non-inbred population. Hum Mol Genet. 1996;5:351–4. 27. Southard-Smith EM, Angrist M, Eleison JS, et  al. The Sox10 (Dom) mouse: modeling the genetic variation of Waardenburg-­ Shah (WS4) syndrome. Genome Res. 1999;9:215–25. 28. Clark DA.  Times of first void and first stool in 500 newborns. Pediatrics. 1977;60:457–9.

312 29. Bekkali N, Hamers SL, Schipperus MR, et al. Duration of meconium passage in preterm and term infants. Arch Dis Child Fetal Neonatal Ed 2008; 93:F376–of Hirschsprung’s disease. Gastroenteology. 1993;105:969–73. 30. Barnes PR, Lennard-Jones JE, Hawley PR, et  al. Hirschsprung’s disease and idiopathic megacolon in adults and adolescents. Gut. 1986;27:534–41. 31. Coran AG, Teitelbaum DH.  Recent advances in management of Hirschsprung’s disease. Am J Surg. 2000;180:382–7. 32. Bill JAH, Chapman ND.  The enterocolitis of Hirschsprung’s disease: its natural history and treatment. Am J Surg. 1962;103:70–4. 33. Elhalaby EA, Coran AG, Blane CE, et al. Enterocolitis associated with Hirschsprung’s disease: a clinical- radiological characterization based on 168 patients. J Pediatr Surg. 1995;30:1023–7. 34. Swenson O, Fisher JH. Hirschsprung’s disease during infancy. Surg Clin North Am. 1956;36:115–22. 35. Murphy F, Puri P.  New insights into the pathogenesis of Hirschsprung’s associated enterocolitis. Pediatr Surg Int. 2005;21:773–9. 36. Marty TL, Matlak ME, Hendrickson M, et  al. Unexpected death from enterocolitis after surgery for Hirschsprung’s disease. Pediatrics. 1995;96:118–21. 37. Loening-Baucke V. Modulation of abnormal defecation dynamics by biofeedback treatment in chronically constipated children with encopresis. J Pediatr. 1990;116:214–22. 38. de Lorijn F, Kremer LC, Reitsma JB, et  al. Diagnostic tests in Hirschsprung disease: a systematic review. J Pediatr Gastroenterol Nutr. 2006;42:496–505. 39. Jarvi K, Koivusalo A, Rintala RJ, et al. Anorectal manometry with reference to operative rectal biopsy for the diagnosis/exclusion of Hirschprung’s disease in children under 1 year of age. Int J Color Dis. 2009;24:451–4. 40. Schappi MG, Staiano A, Milla PJ, et al. A practical guide for the diagnosis of primary enteric nervous system disorders. J Pediatr Gastroenterol Nutr. 2013;57:677–86. 41. Taxman TI, Yulish BS, Rothstein FC. How useful is barium enema in diagnosis of infantile Hirschsprung’s disease? Am J Dis Child. 1986;140:881–4. 42. Scudiere JR, Maitra A, Montgomery EA.  Selected topics in the evaluation of pediatric gastrointestinal mucosal biopsies. Adv Anat Pathol. 2009;16:154–60. 43. Knowles CH, De Giorgio R, Kapur RP, et  al. Gastrointestinal neuromuscular pathology: guidelines for histological techniques and reporting on behalf of the Gastro 2009 International Working Group. Acta Neuropathol. 2009;118:271–301. 44. Kapur R, Reed R, Finn L, et al. Calretinin immunohistochemistry versus acetylcholinesterase histochemistry in the evaluation of suction rectal biopsies for Hirschsprung disease. Pediatr Dev Pathol. 2009;12:6–15. 45. Guinard-Samuel V, Bonnard A, De Lagausie P, et  al. Calretinin immunohistochemistry: a simple and efficient tool to diagnose Hirschsprung disease. Mod Pathol. 2009;22:1379–84. 46. Holland SK, Ramalingam P, Podolsky RH, et al. Calretinin immunostaining as an adjunct in the diagnosis of Hirschsprung disease. Ann Diagn Pathol. 2011;15:323–8. 47. Langer JC, Fitzgerald PG, Winthrop AL, et  al. One vs two stage Soave pull-through for Hirschsprung’s disease in the first year of life. J Pediatr Surg. 1996;31:33–7. 48. Weidner BC, Waldhausen JH.  Swenson revisited: a one-stage, transanal pull-through procedure for Hirschsprung’s disease. J Pediatr Surg. 2003;38:1208–11. 49. Elhalaby EA, Hashish A, Elbarbary MM, et al. Transanal one-stage endorectal pull-through for Hirschsprung’s disease: a multicenter study. J Pediatr Surg. 2004;39:345–51. discussion 345–51

M. Martinelli and A. Staiano 50. Aslanabadi S, Ghalehgolab-Behbahan A, Zarrintan S, Jamshidi M, Seyyedhejazi M.  Transanal one-stage endorectal pull-through for Hirschsprung’s disease: comparison with the staged procedures. Pediatr Surg Int. 2008;24:925–9. 51. Cheung ST, Tam YH, Chong HM, et  al. An 18-year experi ence in total colonic aganglionosis: from staged operations to primary laparoscopic endorectal pull-through. J Pediatr Surg. 2009;44:2352–4. 52. Ammar SA, Ibrahim IA.  One-stage transanal endorectal pull-­ through for treatment of hirschsprung’s disease in adolescents and adults. J Gastrointest Surg. 2011;15:2246–50. 53. van de Ven TJ, Sloots CE, Wijnen MH, et al. Transanal endorectal pull-through for classic segment Hirschsprung’s disease: with or without laparoscopic mobilization of the rectosigmoid? J Pediatr Surg. 2013;48:1914–8. 54. Brooks LA, Fowler KL, Veras LV, Fu M, Gosain A.  Resection margin histology may predict intermediate-term outcomes in children with rectosigmoid Hirschsprung disease. Pediatr Surg Int. 2020;36:875–82. 55. Rolle U, Piotrowska A, Nemeth L, et  al. Altered distribution of interstitial cells of Cajal in Hirschsprung’s disease. Arch Pathol Lab Med. 2002;126:928–33. 56. Miele E, Tozzi A, Staiano A, Toraldo C, Esposito C, Clouse RE. Persistence of abnormal gastrointestinal motility operation for Hirschsprung’s disease. Am J Gastroenterol. 2000;95:1226–30. 57. Di Lorenzo C, Flores AF, Reddy SN, et al. Small bowel neuropathy in symptomatic children after surgery for Hirschsprung’s disease. Gastroenterology. 1997;112:783A. 58. Meier-Ruge W.  Casuistic of colon disorder with symptoms of Hirschsprung’s disease (author’s transl). Verh Dtsch Ges Pathol. 1971;55:506–10. 59. Fadda B, Meier WA, Meier-Ruge W, et  al. Neuronale intestinale Dysplasie: Eine Kritische 10-Jahres- Analyse Klinischer und Bioptischer Diagnostik. Z Kinderchir. 1983;38:305–11. 60. Smith VV. Isolated intestinal neuronal dysplasia: a descriptive pattern or a distinct clinicopathological entity? In: Hadziselimomic F, Herzog B, editors. Inflammatory bowel disease and Morbus Hirschsprung. Dordrect: Kluwer Academic; 1992. p. 203–14. 61. Kobayashi H, Hirakawa H, Surana R, et  al. Intestinal neuronal dysplasia is a possible cause of persistant bowel symptoms after pull-trough operation for Hirschsprung’s disease. J Pediatr Surg. 1995;30:253–9. 62. Fadda B, Pistor G, Meier-Ruge W, et al. Symptoms, diagnosis and therapy of neuronal intestinal dysplasia masked by Hirschsprung’s disease. J Pediatr Surg. 1987;2:76–80. 63. Borchard F, Meier-ruge W.  Wiebecke et  al: Innervations strunger des Dickdarms- Klassifikation und Diagnostik. For Pathol. 1991;12:171–4. 64. Knowles CH, De Giorgio R, Kapur RP, et  al. The London Classification of gastrointestinal neuromuscular pathology: report on behalf of the Gastro 2009 International Working Group. Gut. 2010;59:882–7. 65. Cord-Udy CL, Smith VV, Ahmed S, Ridson RA, Milla PJ.  An evaluation of the role of suction rectal biopsy in the diagnosis of Intestinal Neuronal Dysplasia. JPGN. 1997;24:1–6. 66. Koletzko S, Jesch I, Faus-Kebetaler T, et al. Rectal biopsy for diagnosis of intestinal neuronal dysplasia in children: a prospective multicentre study on interobserver variation and clinical outcome. Gut. 1999;44:853–61. 67. Kobayashi H, O’Briain S, Hirakawa H, et al. A rapid tecnique for acetylcolinesterase stainig. Arch Pathol Lab Med. 1994;118:1127–9. 68. Yamataka A, Datano M, Kobayashi H, et  al. Intestinal neuronal displasia-like pathology in Ncx/Hox11L.1 deficient mice. J Pediatr Surg. 2001;36:1293–6.

Intestinal Pseudo-Obstruction

23

Efstratios Saliakellis, Anna Rybak, and Osvaldo Borrelli

Introduction The term “pseudo-obstruction” literally denotes the absence of a true mechanical occlusion. Intestinal pseudo-obstruction can be either acute or chronic in nature, reflecting the duration of obstructive symptoms [1, 2]. Chronic intestinal pseudo-obstruction (CIPO) was first described in 1958 by Dudley and colleagues to report a series of 13 patients with symptoms suggestive of intestinal occlusion. These patients underwent exploratory laparotomies, which failed to identify a mechanical cause for their symptomatology [3]. In subsequent years, the existence of this pathological entity in both adults and children was substantiated by a number of other clinicians [4–7]. In 2018, an ESPGHAN-led group of experts introduced the term “pediatric intestinal pseudo-obstruction” (PIPO) in order to distinguish pediatric from adult-onset CIPO. The aforementioned group of experts defined PIPO as a clinical entity “characterized by the chronic inability of the gastrointestinal tract to propel its contents mimicking mechanical obstruction, in the absence of any lesion occluding the gut.” The group defined “chronic” as persistence of symptomatology for 2 months from birth or at least 6 months thereafter [8]. The pathophysiologic mechanism of PIPO is represented by abnormal antegrade propulsive activity of the gastrointestinal (GI) tract as a result of processes that affect its neurons, muscles, or interstitial cells of Cajal (ICC) [9]. This functional failure results in a number of clinical symptoms such as abdominal distention with or without abdominal pain, nausea, vomiting, and a reduced inability to tolerate enteral nutrition [10]. These symptoms are, however, nonspecific, and the condition can remain undiagnosed for a long period of time during which patients may undergo multiple diagE. Saliakellis · A. Rybak · O. Borrelli (*) Department of Paediatric Gastroenterology, Division of Neurogastroenterology & Motility, Great Ormond Street Hospital for Children, London, UK e-mail: [email protected]

nostic investigations and often repeated surgical explorations in an effort to identify the cause [10]. Although by definition the small intestine is always involved, any part of the GI tract can be affected in PIPO [1, 2, 8]. Esophageal involvement may lead to dysphagia from impaired peristalsis, in some cases akin to that seen in achalasia [11, 12]. Involvement of the stomach results in poor feed tolerance from gastroparesis suggested by the presence of delayed gastric emptying, while the large bowel by delayed colonic transit and constipation and the anorectum by sphincter dysfunction and defecation disorders [1]. This chapter focuses on various aspects of PIPO and attempts to address areas of controversy by exploring the most recent advances in the overall approach and management of this clinical entity.

Epidemiology PIPO is a rare disease with scanty epidemiological data and poorly defined incidence and prevalence in both adult and pediatric populations. One of the few initiatives to elucidate its epidemiology suggested that approximately 100 infants are born in the USA every year with PIPO, suggesting an incidence of approximately 1 per 40,000 live births [13, 14]. Adult studies reveal that the disease is more frequent in females [15–17]. In a national survey conducted in Japan, 138 cases of chronic intestinal pseudo-obstruction were identified, with an estimated prevalence of 1.0 and 0.8 cases and incidence of 0.21 and 0.24 cases per 100,000 males and females, respectively [18]. Moreover, a recently published nationwide survey for PIPO in Japan revealed that the prevalence of PIPO, among children younger than 15 years, was 3.7 per one million children. In the aforementioned population, 56.5% of children had developed PIPO during the neonatal period [19].

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 S. Guandalini, A. Dhawan (eds.), Textbook of Pediatric Gastroenterology, Hepatology and Nutrition, https://doi.org/10.1007/978-3-030-80068-0_23

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Undoubtedly, the development of national registries is of paramount importance to delineate more precise epidemiologic characteristics of this orphan clinical entity.

Classification Classification of PIPO is challenging. Conditions can be classified by whether they primarily affect intestinal nerves (neuropathy), smooth muscle (myopathy), or ICC (mesenchymopathy) and can be further subdivided into primary or secondary, congenital or acquired, mode of inheritance or what part of the GI tract is involved. Where classification is not possible, they are defined as idiopathic. In truth, there is a considerable overlap [1, 2, 8]. In primary PIPO, the disease is usually localized to GI tract, whereas in secondary cases, there is a systemic disorder that affects GI tract motility. It must be noted though that in some cases of primary PIPO extra-GI involvement may also be present, such as the urinary tract (hollow visceral myopathy and megacystis microcolon intestinal hypoperistalsis syndrome), the nervous system (central, peripheral, autonomous), and/or mitochondria (mitochondrial neurogastrointestinal encephalomyopathy, MNGIE) [2, 20–22]. Table 23.1 depicts the classification of PIPO. In children the disease may manifest with symptoms either during the nenonatal period (neonatal-onset form) or later (infantile or late-­ onset form); the majority of PIPO cases are congenital and primary, whereas in adults secondary forms of CIPO (mostly due to systemic disease) are more frequent [8, 23]. Based on histological findings, both primary and secondary PIPO can be further categorized into neuropathies, myopathies, and mesenchymopathies [24–29].

Etiology and Pathophysiology The integrity of GI sensorimotor function relies on precise coordination between the autonomic nervous system, enteric nervous system (ENS), ICC, and smooth muscle cells. Any noxious stimulus, irrespective of its origin and etiology, that affects the neuromuscular elements and control of GI tract can lead to impaired peristalsis and the stasis of luminal contents [1]. A variety of disorders and pathophysiological mechanisms can potentially affect the structure or function of the neuromuscular elements of the GI tract and lead to PIPO (Table  23.1) [8]. Neurological (e.g., multiple endocrine neoplasia (MEN) type IIb, familial dysautonomia) and metabolic (e.g., diabetes mellitus) conditions may affect the extrinsic GI nerve supply [23]. Neurotropic viruses may evoke an inflammatory process targeting both the ENS and extrinsic neural pathways [97]. Paraneoplastic syndromes may also exert a destructive effect on the ENS by initiating

E. Saliakellis et al. Table 23.1  Classification of Pediatric Intestinal Pseudo-obstruction [8] Primary PIPO Sporadic or familial forms of myopathy and/or neuropathy and/or mesenchymopathy that relate to disturbed development, degeneration, or inflammation [7, 20, 28–51] Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and other mitochondrial diseases [52–54] Hirschsprung’s disease (e.g., total intestinal aganglionosis)a [55–57] Neuropathy associated with multiple endocrine neoplasia type IIB [58–60] Secondary PIPO Conditions affecting GI smooth muscle  Rheumatological conditions (dermatomyositis/polymyositis, scleroderma, systemic lupus erythematosus, Ehlers–Danlos syndrome) [61–72]  Other (Duchenne muscular dystrophy, myotonic dystrophy, amyloidosis, ceroidosis, or alternatively reported as brown bowel syndrome) [73–83] Pathologies affecting the enteric nervous system (familial dysautonomia, primary dysfunction of the autonomic nervous system, neurofibromatosis, diabetic neuropathy, fetal alcohol syndrome, post-viral-related chronic intestinal pseudo-obstruction, e.g., CMV, EBV, VZV, JC virus) [84–99] Endocrinological disorders (hypothyroidism, diabetes, hypoparathyroidism, pheochromocytoma) [100–104] Malrotation or gastroschisis [105–107] Neuropathy post neonatal necrotizing enterocolitis [108] Idiopathic (i.e., where forms of PIPO classified as above do not, as yet, have a defined etiopathogenesis) CMV cytomegalovirus, EBV Epstein–Barr virus, VZV varicella-zoster virus, JC John Cunningham, GI gastrointestinal a Needs to be excluded in all cases of PIPO

an inflammatory process that targets the neurons of ganglia located in the submucosal and myenteric plexuses. This is mediated by both a cellular infiltrate and production of circulating antineuronal antibodies [23, 109]. Some pathologies (e.g., muscular dystrophy) may target enteric smooth muscle fibers, whereas others such as dermatomyositis, scleroderma, Ehlers–Danlos syndrome, and radiation enteritis may distort both ENS and gut smooth muscle leading to a mixed neuromyopathic disorder [14, 110, 111]. Finally, although entities such as celiac disease, hypothyroidism, hypoparathyroidism, and pheochromocytoma presumably cause PIPO by affecting the GI neuromuscular integrity, the exact mechanism is not fully understood.

Genetics Although there has been considerable progress, the elucidation of the genetic basis of PIPO has been rather limited. The majority of PIPO cases are sporadic [8]. Some familial cases of PIPO have been recognized, but there appear to be several patterns of inheritance, perhaps reflective of the great heterogeneity of PIPO conditions. Both autosomal dominant and

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recessive modes of inheritance have been described for neuropathic and myopathic types of PIPO [5, 15, 16, 110, 112]. More specifically, rare autosomal dominant mutations in the SOX10 gene, which encodes a transcription factor important in ENS development, result in a PIPO clinical phenotype along with features such as sensorineural deafness and pigmentary anomalies [113, 114]. Homozygosity on the region 8q23–q24 has been implicated in the pathogenesis of an autosomal recessive form of PIPO characterized by severe GI dysmotility, Barrett’s esophagus, and cardiac anomalies [115, 116]. X-linked inheritance (locus Xq28) with recessive transmission has been described in PIPO [17, 117, 118]. Mutations of filamin A (FLNA) and L1 cell adhesion molecule (L1CAM) genes, which are both located on chromosome Xq28, result in predominantly myopathic and neuropathic forms of PIPO, respectively. Additional involvement of the central nervous system, heart (patent ductus arteriosus), and blood (thrombocytopenia) in both conditions has also been described [118–120]. Mutations in mitochondria are increasingly implicated in PIPO. Mutations in the thymidine phosphorylase gene (TYMP, also termed as endothelial cell growth factor-1, ECGF1), or in the polymerase-γ gene (POLG) result in recessive myopathic forms of PIPO.  The former is the cause of MNGIE, whereas the latter leads to a form without encephalopathy. Apart from the GI dysmotility, MNGIE is characterized by severe malnutrition, opthalmoplegia, and leucoencepalopathy on brain MRI [121– 123]. Furthermore, mutations in the following genes, actin G2 [44], RAD21 [124], and SGOL1 [125], have been identified in recessive forms of PIPO with an associated syndromic phenotype. Of note, with the advancement in genetic testing, novel mutations (MYLK, LMOD1, MYL9, MYH11, PDCL3, and ACTG2 variants) were identified and were subsequently related to the etiopathogenesis of megacystis microcolon intestinal hypoperistalsis syndrome [126–132].

Histopathology In adults, GI histology is reported to be normal in approximately 10% of CIPO cases, while in the experience of the authors, this figure is likely to be higher in children. However, its role in PIPO remains crucial in order to inform prognosis and also guide further investigations for systemic diseases that require specific treatment; therefore, an adequate full-­thickness biopsy is recommended whenever surgery is being considered [29]. Recent initiatives are addressing a more standardized and hopefully effective histological approach to diagnosis in GI motility disorders such as PIPO [29, 133, 134].

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On the basis of histology, PIPO is classified into neuropathy, myopathy, or mesenchymopathy [29, 135]. However, mixed forms (e.g., neuromyopathy) are also recognized [29]. Neuropathies and myopathies can be further subdivided into inflammatory and degenerative. Inflammatory neuropathies are characterized by an infiltration of T lymphocytes and plasma cells in the myenteric plexuses (myenteric ganglionitis) and neuronal axons (axonopathy) [136–138]. It has been proposed that five or more lymphocytes per ganglion are required for the diagnosis of myenteric ganglionitis [137, 139]. Of note, patients with lymphocytic infiltration of the myenteric plexuses may also develop increased titers of antinuclear antibodies (ANNA-1/anti-Hu, anti-voltage-gated potassium channel or VGKC) [49, 140–142]. These immunologic responses may result in neuronal degeneration and loss by activating apoptotic and autophagic mechanisms [143]. Infiltration of the myenteric ganglia with other cells such as eosinophils and mast cells has been described, but their exact clinicopathological significance is yet to be clarified given limited data [144–146]. All these data support the role of the immune system in the pathogenesis of inflammatory PIPO [135, 147]. Degenerative neuropathies are poorly understood given the limited amount of available data [133, 147–149]. Main histopathologic characteristics of this group include a decrease in the number of intramural neurons along with changes in nerve cell bodies and axons [46, 150]. It has been postulated that apoptotic mechanisms are involved in the degenerative process potentially caused by aberrant calcium signaling, mitochondrial disorders, production of free radicals, and abnormalities in the function of glial cells [151, 152]. Similarly to neuropathies, myopathies are also divided into inflammatory and degenerative. Inflammatory myopathies, also reported by the term “leiomyositis,” are characterized by infiltration of T lymphocytes into both the circular and longitudinal enteric muscle layers. This process if not treated appropriately with immunosuppressive agents may lead to a severe clinical picture of PIPO [121, 123]. The histopathologic findings in degenerative myopathies include smooth muscle fiber vacuolization and fibrosis [153]. Diverticula may also be present especially if the longitudinal muscle coat is more affected compared to the circular muscle layer [147, 154]. Novel immunohistochemical techniques, such as smooth muscle markers, namely, smoothelin, smooth muscle myosin heavy chain, and histone deacetylase 8, may reveal histiopathologic subtleties otherwise not detectable with conventional immunostaining and histochemistry methods [29]. Mesenchymopathies are defined by ICC abnormalities (decreased density of ICC network, intracellular abnormalities) and have been demonstrated in patients with chronic intestinal pseudo-obstruction [8, 9, 155]. Although sufficient

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data exist regarding their role in the pathogenesis of diabetic gastroparesis, further research is required regarding ICC involvement in the etiopathogenesis of other GI motility disorders [26].

Clinical Picture In a few cases, the diagnosis of PIPO is suggested in utero by ultrasonographic findings of polyhydramnios, abdominal distention, and megacystis; however, the majority of cases present in the neonatal period or early infancy [9, 10, 156]. The symptomatology varies according to the age at diagnosis and the part of the GI tract, which is primarily affected. Approximately, one-third of children with congenital PIPO (myopathic and neuropathic) have intestinal malrotation [156]. Cardinal signs and symptoms of PIPO include those of obstruction, namely abdominal distention (88%), vomiting (72%, which can be bilious), and constipation (61%). Abdominal pain (44%), failure to thrive (31%), and diarrhea (28%) may also be part of the clinical picture [20, 122]. Dehydration (which can be severe) and malnutrition are often underdiagnosed especially given that weight can be an unreliable measure due to pooling of significant volumes of fluid (third spacing) within distended gut loops. Intraluminal gut content stasis can also lead to small bowel bacterial overgrowth which can further exacerbate symptoms of diarrhea and abdominal distention [62]. PIPO may also manifest with extraintestinal signs and symptoms, such as recurrent urinary tract infections or neurologic abnormalities [155]. Furthermore, patients may complain of symptoms indicative of an underlying disorder that accounts for secondary PIPO (e.g., proximal muscle weakness in dermatomyositis) [10, 156]. The clinical course of PIPO is characterized by exacerbations and remissions, where the former can be precipitated by a number of factors such as surgery, general anesthesia, infections, and emotional stress [8]. In the most severe cases, the natural course of the disease leads to worsening intestinal function and ultimately to intestinal failure [8]. This is especially true in cases where the diagnosis and/or institution of appropriate treatment has been delayed.

Diagnosis PIPO should be suspected in children with early onset, chronic, recurrent, or continuous signs of intestinal obstruction especially where a surgical cause cannot be established (e.g., repeated “normal” exploratory laparotomies). The diagnosis of PIPO should follow a structured algorithm as proposed by the ESPGHAN-led expert group [2, 156, 157]. Although a detailed history, clinical examination, and labo-

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ratory tests may suggest the presence of PIPO, or help elucidate its cause, the ESPGHAN-led expert group proposed that the definitive diagnosis requires at least two out of the four following criteria [158]: (i) Objective measure of small intestinal neuromuscular involvement (manometry, histopathology, transit studies) (ii) Recurrent and/or persistently dilated loops of small intestine with air fluid levels (iii) Genetic and/or metabolic abnormalities definitively associated with PIPO (iv) Inability to maintain adequate nutrition and/or growth on oral feeding (needing specialized enteral nutrition and/or parenteral nutrition support) Careful clinical history and physical examination may help in defining the onset, the severity and progression of the disease, and the part of the GI tract primarily affected, and they also provide useful information regarding associations (e.g., family history), potential secondary causes (e.g., medications), and complications (e.g., dehydration). Laboratory tests [e.g., serum electrolytes, thyroid-stimulating hormone (TSH), lactic acid, specific autoantibodies] are useful in cases of secondary PIPO and in order to assess the clinical state of the patients admitted acutely or undergoing a diagnostic protocol.

Imaging Plain abdominal radiographs may demonstrate a dilated GI tract, with air-fluid levels, whereas contrast GI series can reveal anatomical abnormalities (e.g., malrotation, microcolon) and exclude the presence of gut occlusive lesions (Fig. 23.1a) [159]. It needs to be kept in mind that a water-­ soluble substance should be used instead of barium in order to prevent flocculation and inspissation of the contrast material. Novel imaging modalities such as cine MRI have been recently performed with promising results in adult series, but there are no data regarding their applicability and usefulness in pediatrics [160, 161].

Endoscopy Endoscopy may identify fore- or hindgut mechanical occlusion previously missed on radiology, and it allows duodenal biopsies to exclude mucosal inflammation [9, 162, 163]. Novel techniques (e.g., natural orifice transluminal endoscopic surgery—NOTES) may revolutionize the role of endoscopy in the diagnosis of gut motility disorders by

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a

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b

c

Fig. 23.1  Investigation findings of a 3-year-old boy with a history of recurrent episodes of abdominal distension and vomiting since the neonatal period, and now showing a marked reduction in enteral feed tolerance. (a) Contrast follow-through study (administered via gastrostomy) showing filling of grossly dilated small intestinal loops, without any apparent hold up or change in caliber. (b) Plain abdominal radiograph taken following placement of antroduodenal manometry catheter into the same patient performed under fluoroscopic guidance. The tip of the

catheter has been advanced beyond the duodenojejunal junction to facilitate optimal manometric recording of both the stomach and small intestine. (c) Antroduodenal manometry tracing from patient showing the presence of some gastric antral contractions and a migrating motor complex (phase III activity) passing down the small intestine. The amplitude of small intestinal contractile activity is very low (not exceeding 20  mmHg) suggesting a diagnosis of myopathic chronic intestinal pseudo-obstruction

p­ roviding the ability of full-thickness biopsy sampling in a safe and minimally invasive way [164].

to adhesions formation, which can further complicate future diagnostic or therapeutic procedures. Where possible, investigations and then diagnostic/therapeutic surgery should be performed in timeline sequence and in referral center. Histopathology along with genetics can also be very useful in establishing or confirming the diagnosis of PIPO, highlighting the underlying pathophysiologic process, thus aiding the overall management.

Motility Investigations These studies are performed to assess the GI motility and to define the underlying pathophysiologic process, and these studies form the hallmark of diagnosis in pediatrics. Investigations include GI manometries (esophageal, antroduodenal, colonic, anorectal), GI scintigraphy (e.g., gastric emptying, colonic transit), electrogastrography, and radiopaque markers. The usefulness of novel technologies, such as SmartPill, remains to be determined [165–167]. Although in children with PIPO the involvement of GI may be generalized, the small intestine is always affected; thus, antroduodenal manometry remains the most discerning test, and its optimal placement is pivotal (Fig. 23.1b) [168– 170]. Neuropathic cases manifest with uncoordinated contractions, which are of normal amplitude, whereas in myopathic PIPO, motor patterns have normal coordination; however, the amplitude of intestinal contractions is low (Fig. 23.1c) [171, 172]. Additionally, manometry may facilitate the dynamic assessment of potential pharmacotherapeutic options and feeding strategies (e.g., feasibility of oral or enteral feeds) as well as indicate disease prognosis [156, 173, 174]. In the most challenging cases, exploratory surgery (laparotomy or laparoscopic-assisted procedures) may be required to definitively exclude mechanical obstruction from PIPO.  One however should bear in mind that surgery may precipitate a pseudo-obstructive episode and may also lead

Differential Diagnosis PIPO has to be differentiated from mechanical obstruction; the latter is usually characterized by marked abdominal pain (in keeping with the abdominal distention), specific radiologic signs, and manometric patterns [111, 175]. Acute functional obstruction (e.g., postoperative ileus), functional GI disorders (e.g., rumination syndrome), and pediatric condition falsification should be considered and appropriately investigated and managed [9].

Treatment The therapeutic approach in PIPO is threefold as it aims to (i) preserve growth and development by maintaining adequate caloric intake, (ii) promote GI motility with combined medical and surgical interventions, and (iii) treat disease-related complications or underlying pathologies that cause secondary PIPO. Despite the limited effects of the currently applied therapeutic modalities, refinements and evolution in nutritional, medical, and surgical strategies have considerably

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improved the overall management of PIPO [155]. Acute management of episodes of pseudo-obstruction is generally treated conservatively by nil by mouth, intravenous fluid, and drainage of stasis through nasogastric (NG) tube or preformed ostomies. Careful attention to fluid and electrolytes is imperative.

Nutrition The role of nutrition in PIPO is of paramount significance as it is well known that gut motility improves with optimal nutritional support and declines in the face of under- or malnutrition [176–180]. In the long term, approximately one-­ third of PIPO patients require either partial or total parenteral nutrition, another third require a degree of intragastric or intra-enteral feeding, whereas the remaining children are able to tolerate sufficient oral nutrition. However, within all of groups, patients able to tolerate feeds may require some dietary modification in order to maintain enteral nutrition and avoid bezoar formation (e.g., bite and dissolvable feeds, restriction diets, hydrolyzed formula). Although parenteral nutrition is lifesaving, it is associated with significant risk of complications, such as central line infections and liver disease, and therefore maintaining patients on maximally tolerated enteral nutrition is always strongly encouraged [169, 178]. In the more severe PIPO cases, continuous rather than bolus feeds administered via a gastrostomy or jejunostomy may be better tolerated particularly in children with impaired gastric motor function [8, 181–184].

Medications The therapeutic role of drugs in PIPO patients is mainly limited to the control of intestinal inflammation, suppression of bacterial overgrowth, and promotion of GI motility [185]. Prokinetics (e.g., metoclopramide, domperidone, erythromycin, azithromycin, octreotide, neostigmine, pyridostigmine) usually combined with antiemetics (e.g., promethazine, ondansetron) have been used in an attempt to improve the GI motor function and reduce the severity of nausea and vomiting [186–191]. The use of some of these agents is limited by variable efficacy and unacceptable extraintestinal side effects (e.g., metoclopramide, neostigmine). The best-studied and tested prokinetics, that is, cisapride and tegaserod have been withdrawn from the market due to safety concerns [169, 192]. The need for new prokinetics with increased safety and efficacy has resulted in new products (e.g., prucalopride, aprepitant, ghrelin), but there are limited data of their use in pediatric PIPO, further impacted on by restricted availability and licensing [178, 193, 194].

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Undoubtedly, current medical regimens for PIPO are based on limited literature and/or expert opinion (e.g., combined use of octreotide and erythromycin) and are yet to be tested in future in the context of controlled trials [178, 193].

Surgery Surgery remains a valuable intervention on patients with PIPO as it has a multidimensional role in both the diagnostic (e.g., full thickness biopsies) and therapeutic processes (e.g., insertion of feeding tubes, formation of decompressing ostomies such as gastrostomy, ileostomy) [195, 196]. Indeed, adequate bowel decompression is crucial not only in providing symptomatic relief by reducing the frequency and the severity of pseudo-obstructive episodes but also in limiting further deterioration of the intestinal motor activity secondary to chronic distention, and in enhancing the tolerance of enteral feeding [197]. Long decompression enteral tubes and extensive bowel resections are approaches mainly reported in adult CIPO cohorts but remain untested in terms of practicality, efficacy, and safety in pediatrics [198–201]. Rate of significant surgical complications, such as stoma prolapse, infection, and leakage can be significant. Novel surgical methods involve implantation of devices providing electrical pacing of the GI neuromusculature, but data in children are scanty and limited [8, 15–17, 144]. Small bowel transplantation remains the only definitive cure. Recent advances in both surgical techniques (e.g., multivisceral transplantation) and immunosuppression strategies have resulted in improved outcomes and survival as reported by centers with the relevant expertise showing a survival rate of 50% at 3 years [13, 25, 31, 202–206].

Natural History and Prognosis Both pediatric and adult chronic intestinal pseudo-­ obstructions have a severe clinical course, characterized by repetitive relapses and remissions. Unfortunately, the low index of suspicion among physicians along with lack of well-defined diagnostic criteria and readily available facilities in performing specialized diagnostic tests (e.g., manometry) often accounts for delays in the diagnosis and repetitive unnecessary investigations and surgery [206]. The majority of the patients complain of symptoms, which progressively worsen and impact upon the tolerance of enteral nutrition and increasing reliance on total parenteral nutrition [179, 180]. The latter in conjunction with disease-­ related adverse events (e.g., central line infections, impairment of the liver function, immunosuppression after small bowel transplantation, surgical procedures) accounts for

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Clin Gastroenterol Hepatol. 2005;3:449–58. genesis, which is reflected on the limitations encountered in http://www.ncbi.nlm.nih.gov/pubmed/15880314 both the diagnostic process and therapeutic management. 16. Amiot A, Joly F, Alves A, et  al. Long-term outcome of chronic Clearly, multinational initiatives are required to raise awareintestinal pseudo-obstruction adult patients requiring home parness and evolve current diagnostic modalities and therapeuenteral nutrition. Am J Gastroenterol. 2009;104:1262–70. https:// doi.org/10.1038/ajg.2009.58. tic options. 17. Lindberg G, Iwarzon M, Tornblom H. Clinical features and long-­ term survival in chronic intestinal pseudo-obstruction and enteric dysmotility. Scand J Gastroenterol. 2009;44:692–9. https://doi. References org/10.1080/00365520902839642. 18. Iida H, Ohkubo H, Inamori M, et al. Epidemiology and clinical experience of chronic intestinal pseudo-obstruction in Japan: a 1. 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high morbidity, poor quality of life, and mortality rates up to 30% [13, 25, 31, 202–206]. Despite recent diagnostic and therapeutic advances, PIPO in children remains a serious, life-threatening disease with significant impact on the well-being not only of patients themselves but also of their families [206].

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Gastrointestinal and Nutritional Problems in Neurologically Impaired Children

24

Paolo Quitadamo and Annamaria Staiano

Introduction The increasing survival of children with severe central nervous system damage accounts for a major challenge for medical care. Although the primary problems for individuals with developmental disabilities are physical and mental incapacities, several clinical reports have indicated that brain damage often results in significant gastrointestinal dysfunction [1–4]. The enteric nervous system contains more neurons than the spinal cord, and thus, it is not surprising that insults to the central nervous system may affect the complex integrated capacities underlying feeding and nutrition [5]. The increased awareness of such conditions, together with a better understanding of their etiology and interplay, is essential to achieve an optimal global management of this group of children.

Feeding and Nutritional Aspects Historically, severe malnutrition has been accepted as an unavoidable and irremediable consequence of neurological impairment. Poor nutritional status was often marked by linear growth failure, decreased lean body mass, and diminished fat stores [6, 7]. Over the past two to three decades, multidisciplinary feeding programs providing comprehensive evaluation and treatment of feeding disorders in children with developmental disabilities have been instrumental in improving the nutritional status and quality of life and reducing the hospitalization rates [8]. Nutritional assessment and nutritional interventions in neurologically impaired children P. Quitadamo Department of Pediatrics, A.O.R.N. Santobono-Pausilipon, Naples, Italy A. Staiano (*) Department of Translational Medical Sciences, Section of Pediatrics, University of Naples “Federico II”, Naples, Italy e-mail: [email protected]

are a challenge for physicians but should be part of the child’s comprehensive care and rehabilitation. Assessment of nutritional status is the first step in the clinical nutritional evaluation of children with neurological impairment. In these children, measurement can be difficult and the references commonly used in pediatric patients tend to misinterpret undernutrition. Whenever possible, weight measurement should be obtained on a digital scale or, if the child is unable to stand, on a wheelchair scale [9]. Standing height or supine length can be used in children who can stand or lay down straight. However, accurate evaluation of stature may not be possible because of spasticity, joint contractures, or scoliosis. In children who are unable to stand upright due to skeletal deformity, alternative measurements for the height assessment should be segmental lengths, such as knee-heel length, tibia length, and ulnar length, assessed by sliding calipers [9, 10]. Special equations or charts can then be used to calculate the standing height [11]. Assessment of nutritional status in neurologically impaired children should not be based on weight and height measurements alone, but should include the evaluation of body composition [9, 10]. The three most commonly used measurements to calculate growth charts in typically developing children, such as weight-to-height ratio, height for-age, and weight-for-age, are poor predictors of body composition in this group of patients [9]. Weight measurements do not distinguish between muscle and fat mass percentages. Neurologically impaired children have higher fat percentages and lower lean masses than typically developing children. Body mass index is not recommended especially when derivative measures of body length are used [9]. Therefore, parameters to assess malnutrition and overnutrition in the handicapped child have to be adjusted. Children should be studied as for anthropometric parameters, body composition, bone status, and laboratory nutritional values [9, 12]. An algorithm for the suggested approach to the nutritional assessment of the neurologically impaired child (from ref. 9) is reported in Fig. 24.1.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 S. Guandalini, A. Dhawan (eds.), Textbook of Pediatric Gastroenterology, Hepatology and Nutrition, https://doi.org/10.1007/978-3-030-80068-0_24

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P. Quitadamo and A. Staiano Multidisciplinary nutritional assessment of the neurologically impaired child: weight, length, triceps skinfold dietary history (e.g., meal duration) evaluation of oral motor function

Adequate nutrition

Safe

Inadequate nutrition

Unsafe

Safe

Unsafe*

Optimize intake Systematic reevaluation (yearly or on indication)

Ensure consistency, positioning Inadequate nutrition Unsafe Tube feeding (supplementary vs. exclusive)

GORD

No • Unsafe swallow is defined as occurring in a child who has both a history of aspiration pneumonia (antibiotics or hospital admission for chest infection) and objective evidence of aspiration or penetration on contrast videofluoroscopy GORD: gastro-oesophageal reflux PPI: proton inhibitor

Gastrostomy

Yes

Controlled (PPI, diet)

Not controlled (PPI, diet)

- Gastrostomy with fundoplication - Jejunostomy

Fig. 24.1  Algorithm for the nutritional evaluation of the neurologically impaired child. (Reproduced from ref. 9 with permission)

The true prevalence of undernutrition in neurologically impaired children is unknown. It has been estimated that approximately one-third of them are undernourished and many exhibit the consequences of malnutrition [13]. Yet, the incidence and severity of malnutrition increases with the duration and the severity of neurological impairment [14– 16]. Moreover, it should be considered that no single, universally accepted definition of undernutrition in children exists, neither in typically developing nor in neurologically impaired children [17, 18]. For clinical practice, ESPGHAN recommends the use of 1 or more red flag warning signs, including physical signs of undernutrition, such as pressure sores and poor peripheral circulation, weight for age z score   serum chemistries, liver and pancreatic assessment, abdominal ultrasound (vs CT or MRI), esophagogastroduodenoscopy. Fasting, high-protein meal, intercurrent illness precipitating episodes of vomiting >  serum and urine metabolic evaluation (lactate, ammonia, carnitine profile, amino acids, and organic acids) prior to intravenous fluid treatment during episode as well as metabolic consult. Abnormal neurological findings (altered mental status, papilledema) > brain MRI, neurology consult. Table 25.5  Rescue and abortive pharmacotherapy Antimigraine Sumatriptan 20 mg intranasal at episode onset and may repeat once vs. 25 mg po once vs. 3–6 mg s.c. once SE: Chest and neck burning, coronary vasospasm, headache Alternatives: Rizatriptan, zolmitriptan, frovatriptan (longer half-life) Antiemetic Ondansetron 0.2–0.3 mg/kg per dose (≤12 mg) q 4–6 h iv/po/rectal/ topical. SE: Headache, drowsiness, dry mouth Alternatives: Granisetron Aprepitant 3 day regimen: 125, 80, 80 mg one q.d. prior to anticipated episode Fosprepitant 3–4 mg/kg (max 150 mg) IV day one (aprepitant days 2–3) Sedative Lorazepam 0.05–0.1 mg/kg per dose q 6 h iv/po: Useful adjunct to ondansetron. SE: Sedation, respiratory depression Chlorpromazine 0.5–1 mg/kg per dose q 6 h iv/po. SE: Drowsiness, hypotension, seizures, dystonic reaction Diphenhydramine 1.25 mg/kg per dose q 6 h iv/po: Useful adjunct to chlorpromazine. SE: Hypotension, sedation, dizziness Dexmedetomidine bolus 0.5mcg/kg over 15 min > 0.5mcg/kg/h (up to 1.5 mcg/kg/h) continuous infusion Analgesic Ketorolac 0.5–1 mg/kg per dose q 6 h iv/po. SE: Gastrointestinal bleeding, dyspepsia Sunku and Li [11], with kind permission from Springer Science + Business Media SE side effects

zure should have a neurological evaluation and brain MRI.  Presentation of CVS under the age of 2 should also prompt further metabolic or neurological testing [2].

Treatment Current treatment for CVS can be divided into supportive or rescue therapy (during episodes), lifestyle modifications and prophylactic (daily treatment to prevent episodes), and abortive therapy (prodromal intervention to abort episodes). The goals of treatment are to reduce the frequency and severity of

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episodes, enhance functionality, and improve quality of life. Treatment of nausea, vomiting, abdominal pain, and dehydration during acute episodes requires a protocol for use at home, in emergency departments, and on hospital wards. Other strategies for management of CVS include avoidance of identified triggers (e.g., dietary cheese), psychological interventions (e.g., stress management), and treatment of comorbid symptoms. The NASPGHAN Consensus Statement recommendations on treatment are based upon therapeutic responses from case series and expert opinion of the task force [2]. The main recommendations include first line prophylactic use of cyproheptadine and amitriptyline in children under and over age 5 years, respectively, with propranolol serving as the second line. Sumatriptan was recommended as an abortive agent for those >12  years. For rescue therapy during acute episodes, IV rehydration with higher dose antiemetic ondansetron (0.3–0.4  mg/kg/dose) and sedation from diphenhydramine or lorazepam was recommended.

Supportive or Rescue Therapy Supportive or rescue care is used when the vomiting becomes well established in an episode and at that point usually fails to respond to any abortive strategies. The goal is to correct energy, fluid, and electrolyte deficits and render the child more comfortable through antiemetic therapy, analgesics, and sedation for relief from intractable nausea, vomiting, and abdominal pain. The recommendation is for an IV bolus of saline for rapid correction of fluid deficits and concurrent 10% dextrose 0.45 normal saline at 1.5 X maintenance rates to provide sufficient cellular energy to terminate ketosis. One may have to reduce IV rates and increase Na+ content when hyponatremia and diminished urine output ensues from elevated antidiuretic hormone release present in Sato-variant CVS.  Ondansetron has been the most widely used 5HT3 antagonist given safely at higher than standard doses (up to 0.3  mg/kg/dose) but can prolong the QTc interval [16]. It generally reduces both nausea and vomiting but usually does not stop the episode or the misery from nausea (Table 25.5). A recent systematic review found greatest evidence for ondansetron as rescue therapy in the emergency department for pediatric CVS with promising support for sumatriptan and aprepitant [51]. Diphenhydramine, lorazepam, diazepam, or chlorpromazine combined with diphenhydramine is used to induce sedation because sedation is often the only means of providing relief from the unrelenting nausea and abdominal pain. The analgesic ketorolac is recommended as first line as narcotics should be avoided and are felt to have a sensitizing effect in migraine analgesia. A nonstimulating environment including quiet, dark single room may be helpful. When all else fails

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and episodes are prolonged and debilitating (>1 week), we have occasionally used a dexmedetomidine infusion to achieve deep sedation in a PICU setting for 18  hours as described by Khasinwah [52].

Lifestyle Modifications Lifestyle modifications are used during the interictal phase of CVS when the child is not in an episode in order to keep the child properly conditioned and to avoid exposure to known and potential precipitants of episodes. The lack of sleep resulting from disturbed sleep patterns, sleepovers, or travel sports tournaments are often cited as triggers of episodes. Good sleep hygiene (e.g., turning off all phones, computers, music, TV) with a regimented sleep time can reduce the frequency of episodes. Providing at least maintenance volumes of fluids is widely used to prevent migraines and postural orthostatic tachycardia syndrome. Providing low glycemic energy sources before strenuous activity, sources may prevent an exercise-induced energy deficit. Routine exercise can help reverse the deconditioned state and improve mitochondrial function. Finally, avoiding identified triggers specific to the individual (e.g., sleepovers) or including those generally found in migraines (monosodium glutamate and fluctuations in caffeine intake) may help reduce the frequency of episodes. Fleisher reported that consultation and lifestyle modifications alone reduced the frequency of episodes in 70% of patients even before beginning standard prophylactic therapy [42].

Prophylactic Therapy For those with more frequent or severe episodes (e.g., more than once a month), prophylactic therapy daily (or twice weekly with aprepitant) is recommended during the interictal phase with the goal of preventing the next episode or to at least reduce the frequency, duration, or intensity (# emeses) of episodes. These prophylactic medications are traditionally used to treat other disorders including migraines. The NASPGHAN consensus recommendations for the initial treatment were for cyproheptadine for the younger (95%. It is also important to recneurologic. A combination of these symptoms may occur. ognize that although anaphylaxis represents the most severe Cutaneous manifestations of an acute food allergy reac- form of allergic reaction, there is a spectrum of severity in tion include erythema, hives, pruritus, flaring of eczematous anaphylaxis itself. Anaphylaxis can range from mild or tranlesions, and angioedema. Food allergy may account for up to sient symptoms to hemodynamic compromise/shock. Less 20% of new-onset urticaria [23, 24]. Food allergies rarely than 1% of anaphylaxis cases (including those not due to cause chronic urticaria (e.g., episodes occurring regularly for food ingestion) result in death, indicating fatal anaphylaxis is 6 weeks or longer). Eczema (atopic dermatitis) can be chronically exacerbated by specific IgE-mediated food allergy, Table 26.3  Diagnostic criteria for anaphylaxis with improvement upon removal of the suspect food [25– Anaphylaxis is highly likely when any ONE of the following three 27]. Overall, skin symptoms are the most common manifes- criteria is fulfilled: 1. Acute onset of an illness (minutes to several hours) with tation of IgE-mediated food allergies. Food can also induce involvement of the skin, mucosal tissue, or both (e.g., generalized skin symptoms by direct skin contact (contact urticaria) hives, pruritus or flushing, swollen lips-tongue-uvula) AND AT LEAST ONE OF THE FOLLOWING: [28–32]. Ocular symptoms include pruritus, tearing, conjunctival A. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, hypoxemia) erythema, and periorbital edema. B. Reduced BP* or associated symptoms of end-organ dysfunction Gastrointestinal symptoms include nausea, vomiting, (e.g., hypotonia, collapse, syncope, incontinence) diarrhea, and abdominal pain. Isolated acute gastrointestinal 2. TWO OR MORE OF THE FOLLOWING that occur rapidly after exposure to a LIKELY allergen for that patient (minutes to several reactions are uncommon. In the case of a food-allergic reachours): tion, upper gastrointestinal symptoms usually begin within A. Involvement of the skin mucosal tissue (e.g., generalized hives, minutes of ingestion, but may take as long as 2 h to develop. itch-flush, swollen lips-tongue-uvula) Diarrhea may have a more delayed onset, beginning 2–6 h B. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, hypoxemia) after ingestion of the allergen. Respiratory tract symptoms may be acutely induced by C. Reduced BP* or associated symptoms (e.g., hypotonia, collapse, syncope, incontinence) IgE-mediated reactions. Symptoms may include pruritus and D. Persistent gastrointestinal symptoms (e.g., crampy abdominal edema of the larynx, dyspnea, nasal congestion, rhinorrhea, pain, vomiting) 3. Reduced BP* after exposure to a KNOWN allergen for that hoarseness, stridor, tachypnea, wheezing, and cough. patient (minutes to several hours): Cardiovascular symptoms associated with acute food-­ A. Infants and children—Low systolic BP (age-specific)* or greater allergic reactions include increased vascular permeability, than 30% decrease in systolic BP widened pulse pressure, increased heart rate and cardiac out- B. Adults—Systolic BP of less than 90 mmHg or greater than 30% put, and flushing. These effects can lead to the decreased decrease from that person’s baseline BP: blood pressure. organ perfusion that is characteristic of anaphylactic shock. * Low systolic blood pressure for children is defined as: Neurologic manifestations include a sense of impending  Less than 70 mmHg from 1 month to 1 year doom, dizziness, confusion, incontinence, and loss of con-  Less than (70 mmHg + [2 × age]) from 1 to 10 years sciousness. Neurologic compromise is thought to result from  Less than 90 mmHg from 11 to 17 years Reproduced from: Sampson et al. [34] hypotension and hypoxia [33].

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rare [33–35]. Several grading systems have been used to ing the inconsistency in severity of reactions. Having asthma define reaction severity (Tables 26.4 and 26.5). is an additional risk factor for fatal anaphylaxis. In retrospective analyses, several factors appear to be Anaphylaxis is usually characterized by rapid onset and associated with the severity of the allergic response. A larger evolution of symptoms, but the time course can be unpredictquantity of food allergen ingested, concomitant alcohol con- able. Biphasic anaphylactic reactions occur in up to 20% of sumption, fever, and concomitant nonsteroidal anti-­ cases [41]. In this scenario, a second wave of symptoms inflammatory drugs (NSAID) use all appear to increase the occurs 1–4 hours following resolution of the initial anaphyrapidity and severity of the reaction [35–39]. Concomitant lactic reaction. Delayed anaphylaxis is rare and refers to anaingestion of fatty foods appears to slow the rate of absorption phylaxis characterized by a delayed onset of symptoms, and thus delay onset of symptoms. from minutes or even hours. Protracted anaphylaxis is an Risk-taking behaviors among adolescents and young allergic reaction that can last hours or even days [42]. adults, including increased incidents of exposure to the avoided allergen and a lack of a prompt treatment response to symptoms, contribute to the disproportionately higher Food-Dependent, Exercise Induced number of fatal food-induced anaphylaxis in this age group Anaphylaxis [40]. In one case series of fatal food-induced anaphylactic reactions, accidental ingestion of a known food allergen was Food-dependent, exercise-induced anaphylaxis is an IgE-­ present in 87% of cases [35]. In several cases, previous reac- mediated food-induced anaphylactic reaction that occurs tions to the known allergen were relatively mild, highlight- when vigorous exercise is performed within a few hours of food allergen ingestion. Neither exercise alone nor ingestion of the food allergen alone is sufficient to cause symptoms. Table 26.4  Criteria for severity grading (Muraro et al., 2007) staging While generally associated with specific causative foods system of severity of anaphylaxis (such as wheat, other grains, celery, seafood, or nuts), in some cases any food can cause the reaction when consumed Stage Defined By in close temporal relation to exercise [44]. Flushing, urticaria, periorbital or facial 1. Mild (skin and subcutaneous tissues, GI, and/or mild respiratory) 2. Moderate (mild symptoms + features suggesting moderate respiratory, cardiovascular or GI symptoms) 3. Severe (hypoxia, hypotension, or neurological compromise)

angioedema; mild dyspnea, wheeze or upper respiratory symptoms; mild abdominal pain and/or emesis Marked dysphagia, hoarseness and/or stridor; shortness of breath, wheezing and retractions; crampy abdominal pain, recurrent vomiting and/or diarrhea; and/or mild dizziness Cyanosis or SpO2 3 Episodes of emesis and mild lethargy

>3 Episodes of emesis, with severe lethargy, hypotonia, ashen or cyanotic appearance

1. Place a peripheral intravenous line and administer normal saline bolus, 20 mL/kg rapidly; repeat as needed to correct hypotension 2. If age 6 mo and older: administer intravenous ondansetron, 0.15 mg/kg/dose; maximum, 16 mg/ dose 3. If placement of intravenous line is delayed because of difficult access and age is 6 mo or older, administer ondansetron intramuscular, 0.15 mg/kg/dose; maximum, 16 mg/dose 4. Consider administering intravenous methylprednisolone, 1 mg/kg; maximum, 60–80 mg/dose 5. Monitor and correct acid base and electrolyte abnormalities 6. Correct methemoglobinemia, if present 7. Monitor vital signs 8. Discharge after 4–6 h from the onset of a reaction when the patient is back to baseline and is tolerating oral fluids 9. Transfer the patient to the emergency department or intensive care unit for further management in case of persistent or severe hypotension, shock, extreme lethargy, respiratory distress Strong consideration should be lent to performing food challenges in children with a history of severe FPIES in the hospital or other monitored setting with immediate availability of intravenous resuscitation. Oral challenges in the physician’s office can be considered in patients with no history of a severe FPIES reaction, although caution should be urged because there are no data that can predict the future severity of FPIES reactions. 1. If age greater than 6 mo: administer ondansetron intramuscular 0.15 mg/kg/dose; maximum, 16 mg/dose 2. Consider placing a peripheral intravenous line for normal saline bolus 20 mL/kg, repeat as needed 3. Transfer the patient to the emergency department or intensive care unit in case of persistent or severe hypotension, shock, extreme lethargy, or respiratory distress 4. Monitor vital signs 5. Monitor for resolution at least 4–6 h from the onset of a reaction 6. Discharge home if patient is able to tolerate clear liquids

Reproduced from Nowak-Węgrzyn et al. [54]

Mixed IgE- and Cell-Mediated Disorders Atopic dermatitis (also referred to as eczema), eosinophilic esophagitis, and eosinophilic gastroenteritis are disorders that have both IgE- and cell-mediated components. In up to 40% of patients with atopic dermatitis, food allergy may lead to increased erythema and pruritus of eczematous lesions [23, 25, 26]. IgE-mediated flares occur within minutes to a few hours, while cell-mediated reactions may take up to several days to manifest themselves [67, 68]. Elimination of the suspected food allergen leads to improvement. Eosinophilic gastrointestinal disorders are described in detail in other chapters. Briefly, eosinophilic infiltration of the gastrointestinal tract may result in dysphagia, vomiting, abdominal pain, poor growth, and food impaction and are the hallmarks of the eosinophilic gastrointestinal disorders (eosinophilic esophagitis and eosinophilic gastroenteropathy). A significant portion of patients with these disorders have other allergic diseases, and food is a primary trigger. In

the case of eosinophilic esophagitis, elimination of foods to which the child has demonstrated sensitivity can result in both clinical and histological improvement. Similarly, elimination diets may show benefit in eosinophilic gastroenteropathy. The role of allergy testing remains controversial, but skin tests (including atopy patch tests) and serum tests may be helpful in guiding elimination diets and the means to reintroduce foods that were excluded from the diet [69, 70].

Diagnostic Evaluation of Food Allergy Diagnostic evaluation of food allergy includes the history and physical examination, skin prick testing, serum-specific IgE testing, food elimination diets, and oral food challenges. The clinical history is paramount in diagnosing food allergy, as the pretest probability of food allergy determines what further testing is necessary. The history also discloses whether the illness is likely IgE antibody-mediated or not.

26  Food Allergy

History and Physical Examination The medical history plays a central role in determining which further steps in evaluation need to be performed. The symptoms and their temporal relation to the ingestion of food are particularly important. Acute IgE-mediated food-allergic reactions generally occur within seconds to minutes of ingestion of the food allergen. It is quite uncommon for these reactions to begin more than 2 h after the ingestion of the food. Chronic or delayed reactions may be cell-mediated and simple tests may not help to identify triggers—elimination diets and oral food challenges may be required. With regard to IgE-mediated reactions, the time to resolution of symptoms should be noted. Particularly in the case of new-onset urticaria, in which 80% of cases are due to causes other than food allergy, [71] hives lingering longer than 24–48 h are unlikely to result from food allergy, unless the suspected allergen has been repeatedly ingested concurrent with the urticaria. Hives lasting more than a day or two should raise suspicion for a viral or other process rather than food allergy. A food that has never been eaten before or is ingested rarely is much more likely to cause a reaction than foods that have been previously tolerated on a regular basis. Parents or other caregivers may have reached early closure regarding which substance was the causative food. The clinician must attempt to reconstruct an accurate history of all the food and drink ingested within 2 h prior to the reaction as best as possible. Dressings, beverages, side dishes, snacks, and sauces should be included in this evaluation. In addition, a careful review should take into consideration the possible cross-­ contact with a potential allergen. Cross-contact can be a cause of reactions at restaurants and buffet-style meals. A new allergy to a previously tolerated food is less likely than having a reaction to an ingredient that is not routinely ingested, or having had accidental exposure to a previously diagnosed allergen that was accidentally included in the meal that triggered a reaction. If the patient has experienced allergic symptoms in the past, it is important to ask whether they had been consistently associated with the same food. Acute IgE-mediated allergic reactions generally occur every time the same quantity and preparation of an allergen is ingested. While trace amounts of protein can result in severe allergic reactions in particularly susceptible individuals, others have a threshold amount of protein that must be ingested before symptoms develop [72–75]. This threshold level can be as high as 10 g of the allergenic protein. In addition, cooking of foods induces conformational changes in certain proteins. For example, patients may react to less-heated forms of a food, such as the egg white in scrambled egg or French toast, but may not react to extensively heated forms of the same food (e.g., eggs baked in breads).

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Depending on the patient’s age, certain foods are more likely to be causative agents of an acute food-allergic reaction. In young children and infants, the following foods constitute 90% of IgE-mediated allergies: cow’s milk, egg, soy, peanut, tree nuts, wheat, fish, shellfish, and sesame [1, 2]. In adolescents and adults, peanuts, tree nuts, fish, and shellfish are more common causes of serious acute reactions [15, 76, 77]. Besides the symptoms listed above that characterize acute reactions, the clinician should also note signs of chronic allergic processes, such as sinus venous congestion (and associated “allergic shiners”), horizontal nasal creases, boggy and pale nasal mucosa, or eczematous skin patches. While these signs of other allergic processes are not indicative of a food allergy in themselves, patients with other forms of atopy are more likely to experience food allergy, and therefore the presence of such signs increases the pretest probability of food allergy.

Tests for Food-Specific IgE When the history and physical examination raise concern for possible IgE-mediated food allergy, skin prick testing and serum food-specific IgE testing can be helpful in investigating the potential allergens in question. Of paramount importance prior to selecting and interpreting these tests is the accurate medical history to determine pretest probability for IgE-mediated food allergy. A positive test (sensitization) to tolerated food(s) is common; therefore, a positive test cannot be solely used to diagnose food allergy. In addition, occasionally a test is negative despite true allergy. Therefore, negative tests with a compelling history should not be considered sufficient evidence of no allergy [1, 78, 79].

Skin Prick Testing Skin prick testing is typically performed by allergist–immunologists. The allergen is introduced by scratching the surface of the skin and observing for a wheal and flare response, which is measured. Intradermal tests are not indicated as they are too sensitive and may induce systemic allergic reactions. Larger wheal size correlates with a greater concentration of food-specific IgE and greater likelihood of clinical allergy [80–82]. The size of the wheal does not correlate with severity of reaction. The sensitivity of skin prick testing is about 90%, the specificity is approximately 50% [83]. The skin of infants tends to be less sensitive than that of older children [84]. Given the high sensitivity of skin prick testing, it is a useful test for ruling out individual allergens in patients with a low pretest probability for food allergy to those specific allergens. However, performing skin prick testing to broad arrays of foods without attention to the medical history is not recommended, as the false-positive rate is high.

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In Vitro Testing In vitro testing methods, in contrast to skin tests, are not affected by antihistamine use, are not limited by skin conditions (such as urticaria, dermatographism, or eczema), and do not pose a risk of anaphylaxis. The first in vitro assays, termed “radioallergosorbent tests” (RAST), used radioactive isotopes to characterize relative IgE levels in a patient’s serum. These have been replaced by fluorescent enzyme immunoassay (FEIA) tests, which determine serum-specific IgE levels to a variety of foods. Multiple in vitro assays have been developed, but results are not comparable across the various assays [85]. Most studies establishing normative serum-specific IgE cutoff values in children have used the Phadia ImmunoCAP FEIA (CAP-FEIA) system. Using this system, a prospective trial determined 96–100% positive predictive values for reaction during a food challenge for egg (≥7 kUA/L), milk (≥15 kUA/L), peanut (≥14 kUA/L), and fish (≥20 kUA/L) among 5-year-olds, with reactive thresholds being lower for children less than 2 years of age [86]. A study by Sindher et al. further analyzed biomarker thresholds for other allergens including almond (≥12.2 kUA/L), hazelnut (≥14.6 kUA/L), sesame (≥7.5 kUA/L), walnut (≥ 13.5 kUA/L), and wheat (≥43.1 kUA/L) [87]. It is important to note that while skin prick testing and in vitro testing can determine the likelihood of a systemic reaction to ingestion of a particular food; they are unable to accurately predict the severity of that reaction should it occur. Newer generation tests evaluate specific IgE to specific proteins within a food. Foods are comprised of multiple proteins, of which those that resist degradation from heat or digestion are more likely to cause significant allergic reactions. Taking peanuts as an example, the peanut protein Ara h 8 is a labile protein homologous to a protein in birch tree pollen. When compared with the stable peanut storage protein Ara h 2, Ara h 8 is less likely to cause a significant allergic reaction. Elevated serum IgE levels to whole peanut can represent an allergy to Ara h 8, Ara h 2, or other peanut proteins. In individuals with allergy to whole peanut, performing component testing to determine which specific peanut proteins play a role in their food allergy is important in determining which patients may be appropriate for food challenge testing [78, 88].

Diagnostic Food Elimination Diets

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In a focused elimination diet, based on clinical history, one or several suspect foods are removed from the child’s diet. The child is then monitored for the improvement of symptoms. If the symptoms fail to improve over 2  weeks (in the case of chronic IgE-mediated processes) or over several weeks (in the case of cell-mediated and mixed IgE- and cell-­mediated food allergies), the food(s) removed from the diet are unlikely to be the underlying cause of the child’s symptoms. In the case of a child in whom no potential causative foods can be identified, an oligoantigenic diet may be pursued. In this diet, several of the most common causative foods are removed from the child’s diet while maintaining a nutritionally complete diet with other foods. One example is a diet consisting of rice, lamb, asparagus, spinach, lettuce, sweet potato, cooked apple, olive oil, sugar, and salt [89]. In rare circumstances, children with multiple suspected food allergy triggers and continued significant disease burden are placed on an elemental diet. In this type of diet, the child’s food intake is limited to an extensively hydrolyzed or aminoacid-based formula. Such diets can have significant adverse consequences and should only be pursued under the supervision of an allergist and nutritionist familiar with such diets. If the child’s symptoms abate following introduction of an oligoantigenic or elemental diet, other foods are added one by one into the diet with careful monitoring for the return of symptoms. In addition to the complexity of maintaining nutritional adequacy in a food elimination diet, reintroduction of foods after a long period of elimination poses a risk of increased severity of reaction to foods to which specific IgE is present or develops [90]. Consequently, care should be taken to avoid unnecessary elimination of foods.

Food Challenges A controlled oral food challenge is the gold standard for the diagnosis of food allergy. A food challenge is a physician-­supervised ingestion of a single serving of potential allergen performed to confirm or refute the diagnosis of food allergy to that food. This test is generally used when history and supporting tests fail to confirm or refute an allergy. The test may be used for diagnosis of food allergy from any pathophysiology, IgE mediated or not. A food challenge is performed for diagnostic purposes in the following scenarios:

In the case of acute IgE-mediated food allergy, eliminating the causative allergens prevents further reactions—this type • When several foods are being avoided, a food challenge of elimination diet represents treatment of the underlying can help determine foods that may be added back into the disorder. In the case of chronic food allergy in which no diet, particularly in the case of foods being avoided based causative food is identified on testing, particularly in cell-­ on allergy testing alone (rather than a history of reaction). mediated and mixed IgE- and cell-mediated food allergy, • When IgE testing is negative, but a particular food is elimination diets are pursued for both diagnostic and treatbeing avoided based on clinical history alone. ment purposes. There are three basic types of diagnostic • When a cell-mediated or mixed IgE- and cell-mediated elimination diets: focused elimination diets, oligoantigenic process is present (i.e., FPIES), a food challenge may be diets, and elemental formula diets. the only means of determining if an allergy is present.

26  Food Allergy

• In addition, if serum IgE and skin prick test results appear to indicate that a particular allergy has resolved, a negative (or nonreactive) food challenge confirms allergy resolution [91].

 ood Challenge Format F While a double-blind placebo-controlled food challenge is the gold standard for determining food allergy, in practice open food challenges and single-blind challenges tend to be more commonly pursued, as they reduce the amount of time required in clinic and overall cost of evaluation. A single-­ blind challenge, in which the observer, but not the child, is aware of which substance is placebo and which is the allergen, is useful in cases where a strong anxiety component is present. In an open food challenge, the child consumes the food in question in progressively increasing portion sizes every 10–15  min until the cumulative total of food given equals approximately one standard serving of the food. The patient is then observed for a predetermined period of time for delayed reactions prior to discharge home. If a reaction occurs, the challenge is halted, and the child treated for symptoms [91]. The physician performing the test, typically an allergist–immunologist, must be prepared to treat anaphylaxis.

Unproven Tests That Are Not Recommended Food-specific IgG/IgG4, lymphocyte activation tests, kinesiology, sublingual or intradermal provocation tests, cytotoxic tests, or vega testing are not supported by scientific validation and should not be performed as part of food allergy evaluation [1].

Prevention of Food Allergy A small body of evidence gathered at the beginning of the food allergy epidemic led to the recommendation to delay introduction of highly allergenic foods in order to try to prevent the development of food allergy. In 2008, due to lack of evidence and a continued increase in prevalence of food allergy, these recommendations were modified to acknowledge that data was insufficient to determine how timing of introduction of food allergens influenced the development of food allergy [92]. Finally, the LEAP (Learning Early About Peanut Allergy) study published in 2015 found that the early introduction of peanuts significantly decreased the frequency of the development of peanut allergy among children at high risk [93]. High-risk children were defined as those with severe eczema, egg allergy, or both. In this study, introduction of peanut was between 4  months and 11  months. Following this landmark trial, a consensus group recommended introducing peanut-containing products into the

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diets of “high-risk” infants early on in life (between 4 and 11 months of age) in countries where peanut allergy is prevalent because delaying the introduction of peanut can be associated with an increased risk of peanut allergy [94]. More recent guidelines for prevention encourage early incorporation of allergens in the infant diet [92, 95].

Dietary Treatment of Food Allergies Avoidance Food avoidance education is the cornerstone of food allergy management. Once it has been determined that a particular food must be eliminated from the diet, the child’s family and all caregivers must undertake what amounts to a complete readjustment of one of the most basic daily habits—that of partaking in meals and snacks. Food elimination entails a careful evaluation of food packaging labels, safety in food preparation both in the restaurant and at home, and working with everyone from restaurant chefs, other children’s parents, bakers, camp counselors, school cafeteria workers, and anyone else involved in the preparation of food to ensure that the allergen is not incorporated into any food consumed by the food-allergic child. Medications, vaccines, and cosmetics can also include food allergens. In highly sensitive individuals, less than a milligram of peanut, milk, or egg can cause a reaction [72–75].

Maternal Diet and Allergies in Breastfeeding Food proteins can be detected in breast milk, and several cases have been reported of children experiencing reactions ranging from chronic atopic dermatitis to anaphylaxis due to maternal transfer of allergens through breast milk [96–99]. However, a tolerizing effect has been hypothesized in at least one study [100]. For infants with a history of reacting to a protein in the breast milk, strict maternal avoidance of the allergen is recommended. Many children with food allergy will be able to continue consumption of breast milk without removal of the allergen from the maternal diet.

Nutritional Issues in Food Allergy When foods are being avoided due to allergy or potential allergy, care should be taken to assure that the nutritional needs of the affected child are addressed initially and revisited on a regular basis, as lower caloric intake and increased macro/micronutrient deficiency are more common in children with food allergy when compared with their age-­matched peers without food allergy [101, 102]. The greater the number of allergens being avoided, the

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greater the chance of a nutritional deficiency developing: Thus, greater diligence must be exercised to tailor food choices to ensure a well-balanced diet. In certain circumstances, this cannot be attained by incorporation of regularly available foods alone, and commercially prepared formulas may be necessary beyond the first year of life, particularly in children with cow’s milk and/or soy allergies. As children with food allergies are more likely to suffer from inadequate growth and poor nutrition than their peers, a consult with a dietitian well versed in food allergy elimination diets is necessary in most children with food allergies that significantly affect protein, fat, or carbohydrate intake [1, 101–104].

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Recent Advances in Food Allergy Management Immunotherapy is an emerging management approach to patients with IgE-mediated food allergy. An allergic individual is administered very small amounts of allergen (e.g., peanuts) below the threshold of reaction and the dose is incrementally increased over months. The goal of therapy is to raise the reaction threshold to protect the individual from accidental ingestion or make an individual “bite-safe.” These approaches have not been shown to be curative. Different routes of administration are being studied and developed, including oral (OIT), sublingual (SLIT), subcutaneous (SCIT), and epicutaneous (EPIT, or a skin patch) immunotherapy. Although most studies have focused on single antigen desensitization, multi-food oral immunotherapy, where multiple food items are combined into a single oral immunotherapy course, is also being investigated for its safety and efficacy [105]. Most of these approaches are still in their investigational stages [106–108]. Other approaches under investigation also include vaccines, microbiome modulating agents, and biologics, each used either in conjunction with immunotherapy or as a single treatment. Currently the only FDA-approved treatment for food allergy is a standardized OIT product for peanut allergy.

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Summary • A food allergy is “an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food” [1]. • The nine major food allergens (milk, egg, peanut, tree nuts, soy, wheat, sesame, fish, and crustacean shellfish) account for 90% of allergic reactions. • Food allergies may be IgE-mediated, cell-mediated, or “mixed” adverse immune responses. • IgE-mediated reactions are typically sudden in onset following exposure to a food allergen, whereas cell-­mediated

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responses may result in chronic inflammation or delayed symptoms. Acute IgE-mediated reactions can have cutaneous, ocular, gastrointestinal, respiratory, and/or cardiovascular symptoms. Anaphylaxis is defined as a serious allergic reaction that is rapid in onset and may cause death. Cell-mediated food-allergic reactions include FPIES, food-protein-induced enteropathy, food protein-induced proctitis and proctocolitis, and food-induced pulmonary hemosiderosis. FPIES is a cell-mediated gastrointestinal food allergy that typically manifests in infancy and generally resolves by 3 years of age. In the acute form, 1–3 h after ingestion of the causative food, infants present with profuse, repetitive vomiting and may experience dehydration and lethargy. Aggressive intravenous fluid administration, steroids, and ondansetron may be used to treat acute cases. Elimination of the causative food leads to chronic symptom resolution within 3–10 days. Food-protein-induced enteropathy is characterized by vomiting, diarrhea, malabsorption, failure to thrive, and anemia in an infant. Cow’s milk protein is the most likely causative agent, and symptoms usually spontaneously resolve by 2 years of age. Food-protein-induced allergic proctocolitis is characterized by blood and mucus in the stool of an otherwise healthy infant. Maternal dietary elimination of the causal agent (usually cow’s milk) leads to resolution of s­ ymptoms within 72 h. The problem generally resolves by 1 year of age. Atopic dermatitis, eosinophilic esophagitis, and eosinophilic gastroenteritis are disorders that can have both IgEand cell-mediated components. Elimination diets may be helpful in these disorders. Diagnostic evaluation of food allergy includes the history and physical examination, skin prick testing, serum-­ specific IgE testing, food elimination diets, and food challenges. The clinical history is paramount in diagnosing food allergy, as the pretest probability of food allergy determines what further testing is necessary. The history also discloses whether the illness is likely to be IgE antibody-­mediated or not. Skin prick testing and in vitro testing can determine the likelihood of an IgE-mediated systemic reaction to ingestion of a particular food, but they are unable to accurately predict the severity of that reaction should it occur. Positive predictive values for reaction during a food challenge have been established for in vitro testing to certain foods within certain age groups using a particular testing system. Food elimination diets play a treatment role in acute IgE-­ mediated food allergy and fulfill both diagnostic and

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359 ing, hydrolyzed formulas, and timing of introduction of allergenic complementary foods. Pediatrics. 2019;143(4):e20190281. 93. Du Toit G, Roberts G, Sayre PH, Bahnson HT, Radulovic S, Santos AF, et al. Randomized trial of Peanut consumption in infants at risk for Peanut allergy. N Engl J Med. 2015;372(9):803–13. 94. Togias A, Cooper SF, Acebal ML, Assa’ad A, Baker JR, Beck LA, et  al. Addendum guidelines for the prevention of peanut allergy in the United States: report of the National Institute of Allergy and Infectious Diseases-sponsored expert panel. J Allergy Clin Immunol. 2017;139(1):29–44. 95. Perkin MR, Togias A, Koplin J, Sicherer S.  Food allergy prevention: more than Peanut. J Allergy Clin Immunol Pract. 2020;8(1):1–13. 96. Des Roches A, Paradis L, Singer S, Seidman E.  An allergic reaction to peanut in an exclusively breastfed infant. Allergy. 2005;60(2):266–7. 97. Järvinen KM, Mäkinen-Kiljunen S, Suomalainen H.  Cow’s milk challenge through human milk evokes immune responses in infants with cow’s milk allergy. J Pediatr. 1999;135(4):506–12. 98. Lifschitz CH, Hawkins HK, Guerra C, Byrd N.  Anaphylactic shock due to cow’s milk protein hypersensitivity in a breast-fed infant. J Pediatr Gastroenterol Nutr. 1988;7(1):141–4. 99. Monti G, Marinaro L, Libanore V, Peltran A, Muratore MC, Silvestro L. Anaphylaxis due to fish hypersensitivity in an exclusively breastfed infant. Acta Paediatr. 2006;95(11):1514–5. 100. Frazier AL, Camargo CA, Malspeis S, Willett WC, Young MC. Prospective study of peripregnancy consumption of peanuts or tree nuts by mothers and the risk of peanut or tree nut allergy in their offspring. JAMA Pediatr. 2014;168(2):156–62. 101. Christie L, Hine RJ, Parker JG, Burks W.  Food allergies in children affect nutrient intake and growth. J Am Diet Assoc. 2002;102(11):1648–51. 102. Henriksen C, Eggesbø M, Halvorsen R, Botten G. Nutrient intake among two-year-old children on cows’ milk-restricted diets. Acta Paediatr. 2000;89(3):272–8. 103. Isolauri E, Sütas Y, Salo MK, Isosomppi R, Kaila M. Elimination diet in cow’s milk allergy: risk for impaired growth in young children. J Pediatr. 1998;132(6):1004–9. 104. Jensen VB, Jørgensen IM, Rasmussen KB, Mølgaard C, Prahl P. Bone mineral status in children with cow milk allergy. Pediatr Allergy Immunol. 2004;15(6):562–5. 105. Andorf S, Purington N, Block WM, Long AJ, Tupa D, Brittain E, et  al. Anti-IgE treatment with oral immunotherapy in multifood allergic participants: a double-blind, randomised, controlled trial. Lancet Gastroenterol Hepatol. 2018;3(2):85–94. 106. Kim EH, Yang L, Ye P, Guo R, Li Q, Kulis MD, et al. Long-term sublingual immunotherapy for peanut allergy in children: clinical and immunologic evidence of desensitization. J Allergy Clin Immunol. 2019;144(5):1320–1326.e1. 107. Fleischer DM, Greenhawt M, Sussman G, Bégin P, Nowak-­ Wegrzyn A, Petroni D, et  al. Effect of Epicutaneous immunotherapy vs placebo on reaction to Peanut protein ingestion among children with Peanut allergy: the PEPITES randomized clinical trial. JAMA. 2019;321(10):946–55. 108. Jongejan L, van Ree R, Poulsen LK.  Hypoallergenic molecules for subcutaneous immunotherapy. Expert Rev Clin Immunol. 2016;12(1):5–7.

Eosinophilic Gastrointestinal Disorders Beyond Eosinophilic Esophagitis

27

Eleni Koutri and Alexandra Papadopoulou

Introduction

Epidemiology

Eosinophilic gastrointestinal disorders (EGIDs) are chronic inflammatory disorders of the gastrointestinal (GI) tract characterized clinically by symptoms related to the dysfunction of the affected segment(s) of the GI tract and histologically, by dense eosinophilic infiltration, in the absence of an identifiable secondary cause [1]. EGIDs are classified according to the affected segment(s) of the GI tract to eosinophilic esophagitis (EoE), eosinophilic gastritis (EG), eosinophilic gastroenteritis, and eosinophilic colitis (EC) [1, 2]. It should be noted, however, that it is not uncommon that multiple parts of the GI tract are involved in the inflammatory process, either simultaneously or sequentially [3, 4]. Furthermore, EGIDs beyond EoE are subclassified according to the depth of the eosinophilic inflammation through the wall of the GI tract to mucosal, muscular, or subserosal disease. Due to the absence of biological markers, the diagnosis of EGIDs is based on clinical symptoms and on histological findings of eosinophilic inflammation, after the exclusion of a secondary cause of inflammation or a systemic disorder, which may be a challenging issue given the absence of strict histological criteria for EGIDs diagnosis (beyond EoE). Currently, the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN), and invited experts in the field have been working jointly on consensus guidelines on diagnostic criteria of EGIDs beyond the esophagus.

EGIDs are rare diseases. An electronic survey conducted by Spergel et  al. to 10,874 US pediatric and adult allergists, immunologists, and gastroenterologists including a total of 1836 responses (17%) revealed a prevalence of EGE or EC in 28/100,000 population based on patients assessed by gastroenterologists and 2/100,000 by allergists and immunologists [5]. Later, Jensen et al. [6] estimated that there are less than 50,000 total patients with EGIDs in the United States, with the prevalence of EG estimated about 6.3/100,000 population, of EGE 8.4/100,000 and of EC 3.3/100,000 persons, while in children, the prevalence was 4.4, 10.7, and 4.3/100,000, respectively. More recently, a population-based database, established by Mansoor et al. extracting information from electronic health records from 26 major healthcare systems in United States between 1999 and 2017, estimated a prevalence of EGE in 5.1 per 100,000 individuals and of EC in 2.1 per 100,000 individuals [7]. EGIDs are reported to be more prevalent in Caucasians compared to African-Americans and Asians [7]. With regard to sex, Mansoor et al. [7] reported an increased prevalence of all EGIDs in females, Jensen et al. [6] of only EG, but not of EGE or EC, while Mark et al., reported that EC had a higher incidence in males [8]. According to early reports, EGE can affect patients of any age, from infancy through the seventh decade, but typically presents with a peak age of onset in the third decade of life [9–11]. Newer studies [7] reported EGE be more prevalent in children and adolescents (under 18 years of age) than in adults, with the highest prevalence compared to the other EGIDs, among children below the age of 5 years [6]. With regard to EC, some studies report greater prevalence in adults (older than 18 years of age) [7] than in children and adolescents, while others showed no age or gender differences [6].

E. Koutri · A. Papadopoulou (*) Division of Gastroenterology and Hepatology, First Department of Pediatrics, University of Athens, Children’s Hospital “Agia Sofia’’, Athens, Greece e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 S. Guandalini, A. Dhawan (eds.), Textbook of Pediatric Gastroenterology, Hepatology and Nutrition, https://doi.org/10.1007/978-3-030-80068-0_27

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Esophageal involvement is not uncommon occurring in 10.6%, 12%, and 10.9% of patients with EG, EGE, and EC, respectively [6]. Furthermore, Jensen et  al. [6] reported a high frequency of atopic comorbidities in patients (particularly in children), occurring in 38.5%, 45.6%, and 41.8% of patients with EG, EGE, and EC, respectively [6].

Pathophysiology The eosinophils are present in all segments of the GI tract with the exception of esophagus [12], playing an important role in the immune homeostasis, while their absence is suggested to cause dysregulation of the mucosal barrier [13, 14]. The contribution of eosinophils to host defense is primarily based on the release of cationic proteins from cytoplasmic granules and various cytokines [12, 15]. However, the infiltration of the GI mucosa by an excessive amount of eosinophils, especially in association with changes in architecture and/or the presence of eosinophils in the deeper layers of the GI tract, is almost always pathologic. The eosinophilic infiltration of the GI mucosa may be enhanced by the exposure to a food or other antigen [16], possibly through a Th2 immune response [17]. Parasitic infections and other immune responses are also, likely to induce eosinophilic inflammation of the GI tract throughout important mediators like interleukin (IL)-5 [12]. In EGE, the recruitment and activation of eosinophils in the GI tract wall have been attributed to cytokine interleukins (IL)-3, IL-5 and granulocyte macrophage colony-stimulating factor [18], while the eotaxin family of chemokines has been reported to play a central role in regulating the accumulation of eosinophils in the lamina propria of the stomach and the small intestine, in response to antigen stimulation [19, 20]. The existing evidence suggests that a hypersensitivity reaction is involved in the pathogenesis of the disease [9, 21, 22], which is supported by the presence of peripheral eosinophilia, the elevated serum immunoglobulin E (IgE) levels [21, 23–25], and the prompt response to steroids [26, 27]. A study conducted at Mayo clinic revealed that 20 to 40% of patients with EGE had a history of an allergic diseases such as asthma, rhinitis, food allergy, drug allergy, and eczema [9]. Although the role of food allergy in the pathogenesis of EGE has not been well defined, the reports on improvement with an elemental or elimination diet [3, 28– 30] support an atopic component in some patients. Recently, Sato et al. [31] performed transcriptome analysis studies in children undergoing upper GI endoscopy for clinical symptoms suggestive of EGID between 2011 and 2016. The histological diagnosis of EG was based on find-

E. Koutri and A. Papadopoulou

ing of gastric mucosa eosinophilia ≥30 eosinophils per high power field (eos/hpf). The authors reported 1999 differentially expressed genes between patients with EG and the controls, including significant upregulation of eotaxin-3 (C-C chemokine ligand 26). More recently, Shoda et al. [32] showed in blood-based platforms from children with EG, increased eotaxin-3, thymus and activation-regulated chemokine, IL-5, and thymic stromal lymphopoietin levels. Upregulated gene cadherin 26 (CDH26), which is expressed by gastric epithelial cells, seems to play an important role in the pathogenesis of EG, as shown by other transcriptome analysis studies [33]. CDH26 binds to a4 and aE integrins regulating the adhesion and activation of the leukocytes, while, in vitro, it has been shown to inhibit CD4+ T cells, suggesting an important role as downregulating factor of inflammation [33]. Furthermore, other than eosinophils cells, such as mast cells and FOXP3-positive lymphocytes, seem to play also an important role in the disease’s pathogenesis as their counts in the gastric mucosa of patients with EG have been increased to be excessive compared to the controls [4]. The pathogenesis of EC is even less clear. Several studies have shown similarly increased eosinophilic infiltration of the colonic mucosa of patients with IBD [34–37], that was much greater compared to patients with allergic conditions [38], while children with ulcerative colitis showed in their colonic biopsies from the recto sigmoid segment elevated levels of eotaxin-1 [37]. Torrente [39] et  al. reported that patients with EC, but with IBD, had higher density of CD3+ T cells, eotaxin-2+ intraepithelial lymphocytes, and IgE+ cells in the lamina propria. The copresence in the colonic biopsies of inflammatory cell populations indicating chronic inflammation process in the absence of sheets of eosinophils is indicative of IBD, whereas the finding of degranulating eosinophils and mast cells in combination with IgE and tryptase deposits in perineural locations raise the suspicion for EC [39]. However, in some cases, the differential diagnosis of EC from IBD is challenging.

Clinical Manifestations (Table 27.1) The clinical presentation of EGIDs varies depending on the location of the arising inflammation in the GI tract and the specific layer of the GI tract (mucosal, muscular, serosal) that is involved. Gastrointestinal mucosa is most commonly affected by the eosinophilic inflammation, but muscular and/or serosal layers can also be involved with different symptomatology and diagnostic approach [1, 17, 23, 40].

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Table 27.1  Clinical manifestations of eosinophilic gastrointestinal disorders beyond eosinophilic esophagitis depending on the depth of inflammation through the GI tract wall Mucosal involvement

Muscular involvement Subserosal involvement

Clinical symptoms and signs EG: Nausea, vomiting, retrosternal or epigastric pain, dyspepsia, gastrointestinal bleeding (hematemesis and/or melena) EGE: Nausea, vomiting, abdominal pain, diarrhea, failure to thrive/weight loss, protein loss, gastrointestinal bleeding (hematemesis and/or melena) EC: Abdominal pain, tenesmus, diarrhea with mucus, and/or blood EG: Outlet obstruction mimicking pyloric stenosis EGE/EC: obstructive symptoms, intussusception, perforation EGE/EC: abdominal distention, ascites

EG Eosinophilic Gastritis, EGE Eosinophilic Gastroenteritis, EC Eosinophilic Colitis

Fig. 27.1  Endoscopic features of eosinophilic gastritis [2]. Gastric antral erosions and ulcers in a child with eosinophilic gastroenteritis presented with epigastric pain and iron deficiency anemia. (From Koutri and Papadopoulou [2]. Adapted with permission from Kurger AG Basel)

Mucosal Disease (Figs. 27.1, 27.2, 27.3, 27.4, and 27.5) [2, 41, 42] Mucosal EG presents with a variety of symptoms such as epigastric pain, nausea, vomiting, and early satiety [40], hematemesis and/or melena from gastric/duodenal erosions (Figs. 27.1 and 27.2) [2] or gastric/duodenal ulcers (Fig. 27.3) [2], while the laboratory findings include hypoalbuminemia, anemia, and peripheral blood eosinophilia [3, 4, 40, 43]. The presence of an isolated ulcer, not responding in proton pump inhibitor treatment, has also been described in adolescents [41, 44] (Fig. 27.4) [41] with possible perforation (Fig. 27.5) [42]. Jensen et  al. reported as most common symptoms of EG in 774 patients, abdominal pain, chest pain/throat pain,

Fig. 27.2 Endoscopic features of eosinophilic gastroenteritis [2]. Duodenal bulb erosions in a child with eosinophilic gastroenteritis presented with hematemesis. (From Koutri and Papadopoulou [2]. Adapted with permission from Kurger AG Basel)

Fig. 27.3 Endoscopic features of eosinophilic gastroenteritis [2]. Duodenal giant ulcer in a child with eosinophilic gastroenteritis presenting with hematemesis. (From Koutri and Papadopoulou [2]. Adapted with permission from Kurger AG Basel)

and nausea/vomiting, while 10.2% of these patients had concomitant EoE, which possibly explained the presence of throat pain [6]. Mucosal EGE presents with nonspecific symptoms. In a retrospective study of 40 patients with mucosal subtype of EGE, the most common symptoms appeared to be abdominal pain, nausea, vomiting, early satiety, diarrhea, and occasionally bleeding and weight loss [9, 17, 26, 45, 46]. Patients with diffuse small intestine mucosal disease can develop malabsorption, malnutrition, anemia, protein-losing enteropathy, and failure to thrive [1, 23, 40, 47–49]. In a study of 44 patients with EGE, conducted by Reed et  al., the most common symptoms were vomiting (71%) and abdominal

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Fig. 27.4 (a–d) Hemorrhagic duodenal ulcer on an adolescent with eosinophilic gastroenteritis [41]. (a) Marked mucosal edema was observed in the duodenal bulb. An ulcer with a thickened, deep, white, moss-like appearance, and marked edema at its edge was present at the superior duodenal angulus. (b) Upper gastrointestinal endoscopic find-

ings (approximately 1 week after the initial endoscopy). (c) Bleeding from an exposed vessel was noted. (d) Hemostasis was performed using a clip. (From Yamazaki et al. [41]. Reproduced with permission from Springer Nature)

Fig. 27.5 (a–b) Perforated duodenal ulcer in a 16-year-old boy [42]. (a) Intraoperative photo depicting the perforated duodenal ulcer in the

first portion of the duodenum. (b) Initial endoscopy showing residual duodenal ulceration after repair. (From Riggle et al. [42])

pain (62%) [48]. Jensen et al. reported abdominal pain, diarrhea, and nausea/vomiting as the most common symptoms among 954 patients with EGE [6]. Furthermore, it has been shown that approximately 80% of patients have symptoms for several years [50]. Mucosal EC manifests with abdominal pain, diarrhea, and even hematochezia although, in some circumstances, patients may be totally asymptomatic [6, 8, 34, 40].

Muscular Disease (Figs. 27.6, 27.7, 27.8, 27.9 and 27.10) [51–53] The eosinophilic infiltration of the muscle layer of the GI tract may cause wall thickening and impaired motility with symptoms suggestive of obstruction such as nausea, vomiting, and abdominal distention [9, 23, 47, 52, 54, 55]. Eosinophilic infiltration of the muscular layer may cause

27  Eosinophilic Gastrointestinal Disorders Beyond Eosinophilic Esophagitis

a

b

Fig. 27.6  Upper gastrointestinal follow through and gastric mucosal biopsy histology. (a) Minimal advancement of the contrast material through the pylorus (arrow). (b–c) Histologic images before and 5 d after steroid therapy. (b) Peripyloric antral sections showed prominent eosinophilic infiltration of the lamina propria (up to 30 eosinophils per single high-power field), with occasional degranulation (arrow) of

a

b

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c

eosinophilic content and infiltration of the muscularis mucosae. (c) Biopsies 5 d after intravenous steroid therapy demonstrated only a few eosinophils with a peak count of 2 eosinophils per high-power field (HE, ×40). (From Kellermayer et al. [52] Reproduced with permission by Baishideng Publishing Group Inc)

c

Fig. 27.7 (a–c) Gastric outlet obstruction on a 3-year-old girl with eosinophilic gastritis. (a) Barium meal X-ray showing absence of the duodenal bulb and the C-loop. Note that the distal stomach is also not visible. (b) Endoscopic visualization of the gastric mucosa showing for-

mation of multiple diverticuli, erosion, and ulceration. (c) Dense infiltrates of eosinophils in muscle layer of the stomach (hematoxylin and eosin stain, ×400). (From Katiyar et al. [53] Reproduced with permission from Springer Nature)

dilatation of the bile ducts [51] or result in obstruction (and even perforation) of the gastric outlet, small bowel, and rarely the colon [9, 21–23, 25, 47, 56–58]. It should be noted, however, that in EGIDs beyond the esophagus, the presence of strictures is not that common as in EoE [44, 59].

pancreatitis [62], acute appendicitis, and eosinophilic splenitis have also been reported in literature.

Serosal/Subserosal Disease (Figs. 27.11 and 27.12) [60, 61] In serosal/subserosal disease, patients may present with isolated ascites or ascites combined with symptoms of mucosal or muscular involvement [9, 60, 61]. An eosinophilic pleural effusion can also be present [47]. Features like cholangitis,

Laboratory Findings Peripheral blood eosinophilia occurs in 20–80% of patients [9] with eosinophil counts ranging from 5% to 35% with an average absolute eosinophil count of 1000 cells/μL [63]. Mucosal and serosal/subserosal EGE are usually associated with higher eosinophil counts compared to muscular EGE. EGE is often associated with iron deficiency anemia due to impaired iron absorption and/or occult gastrointestinal bleeding, especially in the mucosal subtype of the disease [23, 24, 47]. Hypoalbuminemia may occur due to the

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Fig. 27.8 (a–h) Contrast-enhanced computed tomography (CT) findings (a–c) and endoscopic ultrasound (EUS) findings of the duodenum (d–e). Upper gastrointestinal endoscopic examination findings (f–h). (a, b) CT revealed the thickening of the gastroduodenal mucosal wall (arrow). (d) EUS of the duodenum revealed extreme thickening of the mucosal and muscular walls. (c, e) Both findings were improved after

f

steroid therapy. In contrast, (b) dilation of the bile duct (arrow head) and (g) narrowing of the lumen of the second part of duodenum diminished before steroid therapy. (a, d, f) On admission, (b, g) 5 days before steroid administration and (c, e, h) 2 weeks after steroid administration. (From Hamamoto et al. [51]. Reproduced with permission from The Japanese Society of Internal Medicine)

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Fig. 27.8 (continued)

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Fig. 27.9 (a–e) Abdominal contrast-enhanced computed tomography (CT) and dynamic contrast-enhanced magnetic resonance imaging (MRI) findings. (a, b) CT showed the common bile duct dilatation and microabscesses in the left lobe of the liver (arrowhead). (c) Regarding MRI, the abscesses showed a positive signal on diffusion-weighted

imaging (arrowhead). (d) In the CT examination, invagination of the duodenal wall caused bile duct dilatation (arrow). (From Hamamoto et al. [51]. Reproduced with permission from The Japanese Society of Internal Medicine)

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Fig. 27.10  Changes in the invagination of the duodenal wall during the clinical course. The changes were observed by magnetic resonance cholangiopancreatography. Before steroid therapy (a); after half a year

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b

of steroid therapy (b). (From Hamamoto et al. [51]. Reproduced with permission from The Japanese Society of Internal Medicine)

increased mucosal permeability and protein-losing enteropathy that can be assessed measuring fecal alpha 1-antitrypsin in a 24-h feces collection. Low levels of immunoglobulins can present consequently to the protein loss [9, 21, 23]. The erythrocyte sedimentation rate is usually normal or modesty elevated in approximately 25% of patients [9, 47].

Gastrointestinal Endoscopy (Figs. 27.1, 27.2, 27.3, 27.4, and 27.5) [2, 41, 42] The endoscopy findings in EG or EGE may include nodular or polypoid appearance of the gastric mucosa, erythema, friability, and occasional ulcerative or erosive changes of either gastric (Fig. 27.1) [2] or duodenal mucosa (Fig. 27.2) [2], although not rare is the development of a giant ulcer that may cause severe abdominal bleeding and even perforation (Figs. 27.3, 27.4, and 27.5) [2, 41, 42], while in some circumstances, the mucosa may appear completely normal [2, 3, 4, 29, 43]. Newer reports in patients with EGE using wireless capsule endoscopy have shown salmon patch colored lesions with noticeable eosinophilic infiltration throughout their intestinal mucosa [65]. In patients with EC, the endoscopy findings include erythema, aphthous ulcers, erosions, whitish elevated lesions, or pale granular mucosa.

Fig. 27.11  CT scan findings on a 3-year-old boy with subserosal EGE [60]. CT scan shows a massive ascites displacing the intestine in the center of the abdomen in a 3-year-old patient with serosal subtype of EGE. (From Barabino et al. [60]. Reproduced with permission from Springer Nature)

It should be noted, however, that none of the above findings are specific for EGIDs. In patients with subserosal involvement, abdominal ultrasound (US), abdominal computed axial tomography (CT), or magnetic resonance imaging (MRI) may reveal the presence of ascites (Figs. 27.11 and 27.12) [60, 61].

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Fig. 27.12 (a–b) Abdominal computed axial tomography on an adult patient with subserosal EGE and histological examination of the ascitic fluid [61]. (a) Abdominal computed axial tomography showing ascites and gastric wall thickening. (b) Histological examination of ascitic fluid

showing abundant cellularity with inflammatory characteristics with a predominance of eosinophils (40× magnification). (From Ferreira et al. [61]. Reproduced with permission from SMC media Srl)

Histology (Figs. 27.13, 27.14, 27.15, 27.16, 27.17, and 27.18) [2, 66]

sity of the technical parameters of the commercially available microscopes may cause up to fivefold discrepancies in the eosinophil counts of the same biopsy sample. In our recent study [71] carried out in three major pediatric centers (Athens, Madrid, and Rome), histology slides (n  =  1014) from GI biopsies taken from 155 children who had no organic disease (based on an extensive work up due to GI symptoms and the GI endoscopy) were reviewed and the eosinophilic counts were expressed per different sizes of hpfs (0.196 mm2 and 0.306 mm2) and as eos/mm2 [71]. The study showed discrepancies in the peak counts of eosinophils in the same segments of the GI tract depending on the size of the hpf that was used for the calculation (Figs.  27.13 and 27.14) [71]. The above discrepancies highlight the importance of using eosinophil density (eos/m2) instead of eos/hpf, that is a universally accepted tool, independent of the size of hpf [71]. Furthermore, in the above study, we found a significant geographical distribution in eosinophilic counts of the GI mucosa of children with no organic disease, but not differences among children with and those without the diagnosis of functional GI disorders based on Rome IV criteria [71]. Other histological abnormalities found in patients with EGIDs (Figs. 27.15 and 27.16) [2] may include the findings of eosinophilic sheets in expanded lamina propria, abundant intraepithelial eosinophils, eosinophil cryptitis/pititis or abscesses, or the presence of eosinophils in the muscularis mucosa and submucosa. In some circumstances, complete loss of intestinal villi (Fig.  27.17) [66], multiple layers involvement, submucosal edema, and fibrosis may develop consequently to diffuse intestinal inflammation [24, 66, 72].

In contrast to EoE, consensus diagnostic histological criteria for EGIDs beyond the esophagus are lacking [17, 40]. Various studies have defined differently pathological eosinophilic infiltration of different parts of the GI mucosa to justify the diagnosis of EGIDs in the clinical context [35, 43, 67, 68]. With regard to eosinophilic infiltration of the mucosa of different segments of the GI tract, the following counts were considered by several authors to justify the diagnosis of EGIDs in the clinical context: ≥30 eosinophils per high power field (eos/hpf) in ≥5 hpfs or ≥70eos/hpf in ≥3 hpfs in the gastric mucosa, for the diagnosis of EG [3, 43, 69, 70]; ≥52 eos/hpf in duodenal mucosa and ≥56 eos/hpf in ileum for the diagnosis of EGE [17, 59, 69, 70]; ≥100 eos/hpf in cecum and ascending colon, ≥84 eos/hpf in transverse and descending colon, and ≥64 eos/hpf in the mucosa of rectosigmoid area, for the diagnosis of EC [70]. Debrosse et al., however, assessed the amount and location of eosinophils in the GI tract of healthy children and reported much lower peak numbers of eosinophils in the “healthy” GI mucosa: ≤26 eos/hpf in the duodenum; ≤50 eos/hpf in the ascending colon; and ≤30 eos/hpf more distally [69]. It is not easy to explain the discrepancies in the eosinophilic counts in the GI mucosa reported by different authors. An important issue is the calculation of eosinophil counts per high power field the size of which depends on the technical parameters of the microscope such as the magnification of the objective lens and the diameter of the ocular. The diver-

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a

hpf 0.196 mm2

hpf 0.306 mm2

b

mm2

hpf 0.306 mm2

mm2

400

Peak numbers of eosinophils

Peak numbers of eosinophils

250

hpf 0.196 mm2

200

150

100

50

0

300

200

100

0

Esophagus

Stomach

Duodenum

Fig. 27.13 (a, b) Peak numbers of eosinophils in the esophageal, gastric, duodenal, and ileal biopsies in children with no organic diseases [72]. (a) Median (IQR) of peak counts of eosinophils/high power field 0.196 mm2 and 0.306 mm2, and /mm2 in the esophagus (111 biopsies) and the stomach (111 biopsies) was as follows: esophagus: 0 (0–0), 0 (0–0), and 0 (0–0), respectively; stomach: 2 (0.6–3.0), 3.1 (1.0–4.7), and 10.2 (3.3–15.3), respectively. (b) Median (IQR) of peak counts of

hpf 0.196 mm2

lleum

eosinophils /high power field 0.196 mm2 and 0.306 mm2, and /mm2 in the duodenum (111 biopsies) and ileum (44 biopsies) was as follows: duodenum: 11.0 (5.1–17.0), 17.2 (8.0–26.5), and 56.1 (26.1–86.7), respectively; ileum: 12.0 (9.6–18.0), 18.7 (15.0–28.1), and 61.2 (49.0– 91.8), respectively (From Koutri et al. [71]. Reproduced with permission from Annals of Gastroenterology)

hpf 0.306 mm2

mm2

Peak numbers of eosinophils

250 200 150 100 50 0 Cecum

Ascending colon

Transverse colon

Fig. 27.14  Peak numbers of eosinophils in the colonic biopsies in the whole cohort of children. Median (IQR) of peak counts of eosinophils / high power field 0.196 mm2 and 0.306 mm2, and /mm2 in the cecum (37 biopsies), ascending colon (28 biopsies), transverse colon (44 biopsies), descending colon (31 biopsies), sigmoid colon (37 biopsies), and rectum (41 biopsies) was as follows: cecum: 15.0 (8.0–19.5), 23.4 (12.5– 30.5), and 76.5 (40.9–99.7), respectively; ascending colon: 14.5

Descending colon

Sigmoid colon

Rectum

(9.7–25.8), 22.8 (15.2–40.2), and 73.9 (49.5–131.4), respectively; transverse colon: 13.0 (8.0–17.9), 20.3 (12.5–28.0), and 66.3 (40.8– 91.5), respectively; descending colon: 13.0 (6.0–16.0), 20.3 (9.4–24.9), and 66.3 (30.6–81.6), respectively; sigmoid colon: 7.6 (5.4–10.0), 12.0 (8.5–15.6), and 39.2 (27.8–51.0), respectively; rectum: 5.0 (1.9–8.9), 7.8 (3.0–14.0), and 25.5 (9.8–45.8), respectively (From Koutri et  al. [71]. Reproduced with permission from Annals of Gastroenterology)

27  Eosinophilic Gastrointestinal Disorders Beyond Eosinophilic Esophagitis

Fig. 27.15 Histological features of eosinophilic gastritis [2]. Aggregates of eosinophils near the muscularis mucosa [small arrow]. Eosinophilic infiltration of pyloric glands [long arrow]. (From Koutri and Papadopoulou [2]. Adapted with permission from Kurger AG Basel)

Fig. 27.16 (a, b) Histological features of eosinophilic gastroenteritis (duodenal biopsies) [2]. (a) Erosion and aggregates of eosinophils [long arrow]. Eosinophilic infiltration of the Brunner glands [small arrow]. (b) Aggregates of eosinophils at the deep part of the crypts with degran-

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In patients with EC, the findings in colonic biopsies (Fig.  27.18) [2] may include apart from increased eosinophilic density, eosinophilic cryptitis/crypt abscesses, abnormalities in the architecture of the crypts, increased intraepithelial eosinophils, and the presence of eosinophils in the muscularis mucosa and submucosa [66]. In order not to miss the diagnosis, multiple biopsies should be taken from both normal- and abnormal-appearing mucosa since even a normal-appearing mucosa can be infiltrated by eosinophils and demonstrate inflammation [73]. In patients with muscular or subserosal type of EGE, mucosal biopsies can be normal [9, 73]. Thus, negative endoscopic mucosal biopsies do not definitively exclude muscular or subserosal disease. In that case, laparoscopic full-thickness biopsy should be performed to establish the diagnosis of EGID.  In patients with intestinal wall ­thickening and/or obstruction, laparoscopic full-thickness biopsy is important to exclude a possible underlying malignancy.

ulation [long arrow]. Eosinophilic infiltration of the crypts [small arrow]. (From Koutri and Papadopoulou [2]. Adapted with permission from Kurger AG Basel)

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Fig. 27.17  Eosinophilic gastroenteritis—duodenal biopsy [66]. This duodenal biopsy shows few preserved short villi (asterisk), elongated crypts (bar), and numerous eosinophils in the lamina propria (arrows), muscularis mucosa (shaded arrows), and submucosa (arrowheads). (From Collins et al. [66])

Fig. 27.18  Colonic biopsies histology on a child with eosinophilic colitis (histology) [2]. Aggregates of eosinophils at the deep part of the colonic crypts with degranulation [long arrow]. Eosinophilic infiltration of colonic crypts [small arrow]. (From Koutri and Papadopoulou [2]. Adapted with permission from Kurger AG Basel)

In conclusion, the location and depth of the obtained GI biopsies, the technical parameters of the microscope, and the analyses used for the examination of the histological samples, as well as the knowledge of the geographic variation in the normal amount of eosinophils in healthy GI tract, are all important factors to consider when interpreting the histological findings [1, 71]. Taking into account that there are no well-determined histological criteria for the diagnosis of EGIDs beyond EoE and until the consensus recommendations on diagnostic criteria of EGIDs by the ESPGHAN and NASPGHAN become available, the contribution of an expert gastrointestinal pathologist is extremely important.

Other Tests

Imaging Studies (Figs. 27.6, 27.7, 27.8, 27.9, 27.10, 27.11, and 27.12) [52, 53] In patients with mucosal disease, imaging studies of the GI tract may reveal thickening or nodularity in the antrum and thickening or “saw-tooth” appearance of the mucosa of the small bowel [56]. It should be noted, however, that the above findings lack of sensitivity and specificity regarding EGE. Imaging studies are particularly important tools for the diagnostic approach of muscular and subserosal subtype of EGIDs. Barium follow through (Figs.  27.6 and 27.7) [52, 53], abdominal ultrasound, abdominal computed tomography scan (Figs. 27.8 and 27.9) [51], or magnetic resonance imaging (Figs. 27.9 and 27.10) [51] may reveal in patients with muscular involvement, irregular narrowing of the lumen, especially in the area of the distal antrum and proximal small bowel [52, 53, 74].

In patients with subserosal disease and ascites, increased eosinophil counts have been reported in the ascitic fluid analysis (Fig. 27.12) [61]. The analysis of the ascitic fluid apart from cytology, it should also include Gram stain, acid-fast bacillus stain, fungal cultures, and mycobacterial cultures. Studies have documented a marked elevation of the eosinophil counts up to 88% in patients with subserosal subtype of EGE [23]. It should be noted, however, that no strict criteria to evaluate the eosinophilia of the ascitic fluid are available.

Differential Diagnosis (Table 27.2) The differential diagnosis of EGIDs includes infections, allergic conditions (such as drug allergy), hypereosinophilic syndrome, inflammatory bowel diseases, autoimmune diseases, connective tissue disorders, malignancy, chronic graft versus host disease, immunodysregulation, etc. [17, 35, 40, 59], while the differential diagnosis of EC should also include mastocytic enterocolitis [75, 76] or systemic mastocytosis [77, 78]. To exclude parasitic infections, it is necessary to check stool microscopy for ova and parasites and serology for Strongyloides and Toxocara species, while patients with a recent history of travel to (or residence in) endemic areas should be tested also, for antibodies to fungi and parasites such as Coccidioides, Echinococcus, Schistosoma, and Trichinella spiralis. Allergic colitis of infancy may also be associated with >20 eos/hpf in rectal biopsies [79], with patchy distribution [80], but the disease resolves clinically and histologically following the removal of the offending antigens (typically

27  Eosinophilic Gastrointestinal Disorders Beyond Eosinophilic Esophagitis

cow’s milk) from the diet of the affecting infant. Tissue eosinophilia can also be found in colon biopsies of patients in immunosuppression following transplantation, especially in those receiving tacrolimus [81–83]. Shoda et al. [32] tried recently to uncover likely molecular pathogenesis that accounts for the distinct endoscopic and histologic features of EG and developed tissue- and blood-based platforms for its diagnosing and monitoring. They enrolled 185 patients (74 patients with EG and 111 without) across nine Consortium of Eosinophilic Gastrointestinal Disease Researchers–associated sites. The researchers analyzed an EG Diagnostic Panel (EGDP; gastric transcript subset) and an EG blood biomarker panel (protein multiplex array). EGDP scores were derived from the expression of 18 highly dysregulated genes, while blood EG scores were derived from dysregulated cytokine/chemokine levels. The authors reported that the EGDP18 scores were inversely correlated with gastric peak eosinophil counts, periglandular circumferential collars, and endoscopic nodularity. With regard to blood-based platforms, the authors [32] reported significant increases in eotaxin-3, thymus, and activation-­regulated chemokine, IL-5 levels, as well as thymic stromal lymphopoietin levels. Blood EG scores were able to distinguish patients with EG from control subjects: They positively correlated with gastric eosinophil levels and inversely correlated with plasma and serum EGDP18 scores. The authors concluded that EGDP scoring based on tissue- and blood-based platforms is an important diagnostic tool for assessing EG. Further studies are required for the validation of the above platforms, assessment of their efficacy, and optimization for disease stratification.

Treatment Due to the rarity of EGIDs beyond the esophagus, there are no randomized controlled studies regarding standardized treatment options in children [17, 40]. Most evidence is based on case reports and case series and few randomized trials in adults. Corticosteroids are a mainstay of treatment for induc-

Table 27.2  Differential diagnosis of eosinophilic gastrointestinal disorders beyond eosinophilic esophagitis EG

EGE/EC

Helicobacter pylori infection Inflammatory bowel disease Connective tissue disorders Hypereosinophilic syndrome Infections (parasitic, amebic, fungal) Inflammatory bowel disease Connective tissue disorders Hypereosinophilic syndrome Vasculitis Malignancy

EG Eosinophilic Gastritis, EGE Eosinophilic Gastroenteritis, EC Eosinophilic Colitis

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ing remission, but there may be a subset of patients in whom elimination diet can be effective. In some occasions, the disease is not easily controlled [40, 48], while maintenance therapy is often required [29, 48, 67]. Additional therapies have been reported in case reports or small series of patients [84] with conflicting results, while novel drugs [85, 86] for treating refractory disease are currently under investigation. (i) Dietary Treatment In some pediatric patients with EGIDs beyond the esophagus, symptoms and tissue accumulation of eosinophils may be reduced by antigen restriction [3]. Ko et al. evaluated, retrospectively, the response to dietary treatment of 30 children with EG, 43% of whom had concomitant EoE and 21% EGE [3]. The dietary therapy included elemental diet, seven food elimination diet (milk, egg, wheat, soy, peanut/tree nuts, fish/ shellfish, and red meet) or empiric avoidance of one to three foods. Overall, 82% of patients achieved clinical remission. However, histological assessment was available in only up to five children per each dietary treatment group, 78% of whom achieved histological remission, making difficult to draw conclusions on efficacy [3]. Patients with concomitant esophageal eosinophilia appeared to be more resistant to dietary therapy since 6 of 16 patients were noted to have persistent esophageal eosinophilia despite resolution of findings in gastric biopsies. The above study showed also no correlation between response to dietary therapy and food sensitization, despite the fact that 86% of patients were found to be sensitized to several foods using skin prick tests or serum analyses [3]. In patients with EGE and symptoms of malabsorption, an initial therapeutic approach could involve an empiric six-­ food elimination diet or an elemental diet. Elemental diet eliminates all potential food allergens and has been reported to be beneficial in selected patients [28, 87]. Six-food elimination diet, excluding soy, wheat, egg, milk, peanut/tree nuts, and fish/shellfish, foods that most commonly cause hypersensitivity reaction in the general population, is the most commonly used diet, empirically, in such patients [88]. Reed et al. [48] reported that in 21 of 44 patients with EGE (13 being placed on an elemental formula, seven on a testing directed diet, and one not specified) 12 patients (57%) had resolution of symptoms. However, 15 of them received concomitant corticosteroids while histological response was not assessed [48]. Gonsalves et  al. carried out a prospective study published recently as Conference abstract [30], assessing the efficacy of elemental diet in 15 adults with EG/EGE, 87% of whom atopic comorbidities. The authors reported that elemental diet for 6  weeks was associated with histological remission in all patients, significant improvements in clinical symptoms, endoscopic findings, in depression and fatigue domains of the patient reported outcomes’ information measurement scores and also of the EGDP score [30]. A

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systematic review carried out by Lucendo et al. [88] assessed the efficacy of dietary interventions in children and adults with EGE.  The review included 30 studies, most of which were of low quality. Elemental diets were associated with clinical improvement in 75% of patients, but histological assessment was carried out in only six patients, five of which had achieved histological remission. Empiric elimination diets (6FED or 7FED that included the elimination also of red meat) were introduced to 34 patients and were associated with clinical improvement in 85% of them (histological response was not assessed), while single food (cow’s milk) elimination diet was introduced to 16 patients, 62% of whom improved clinically, without though, assessing histological response. In patients who were assessed for histological response, a significant reduction in gastric (but not duodenal) eosinophilic infiltration was reported [88]. More recently, a retrospective multicenter study [89] reported on treatment response of 109 patients with EGIDs beyond EoE who had a 6-month follow-up from the start of treatment. The authors reported that all types of elimination diets (6FED, elemental and targeted diet) were associated with clinical improvement. Furthermore, patients with EG showed a significant reduction in eosinophilic gastric infiltration, while those with EGE showed a significant decrease in gastric and a nonsignificant in duodenal eosinophilic infiltration [89]. Dietary therapy should be under the guidance and supervision of a dietician trained in EGIDs in order to assure the patient’s compliance and to avoid nutritional compromise. In patients with EGE and peripheral eosinophilia, a reduction of >50% could be considered as a response to dietary therapy. In all cases of uncertainty regarding the response to treatment and/or the degree of activity of the ongoing disease, a repeat endoscopy with biopsies should be performed. Once the dietary intervention is successful at reducing symptoms, peripheral and/or tissue eosinophilia, foods are reintroduced slowly, starting from the least allergenic to most allergenic. To conclude, some studies suggest that dietary treatment may be an alternative for inducing remission in patients with EGIDs beyond EoE, but data on histological response and on the long-term disease outcome are scarce, the possible food triggers have not been identified and the process of food ­reintroduction is not clear. Furthermore, although food allergens’ hypersensitivity plays an important role in the pathogenesis of EGIDs, there is no evidence to support the routine use of food allergy testing, in making clinical decision. (ii) Drug Treatment Corticosteroids Oral Corticosteroids Corticosteroids are known to decrease the recruitment of inflammatory cells including eosinophils, to decrease the release of eotaxins and other inflammatory mediators, and to

E. Koutri and A. Papadopoulou

reduce capillary permeability. Pineton et  al. demonstrated efficacy of oral corticosteroids in 18 out of 19 (95%) patients with EGE in whom it was used among a total number of 43 patients [67]. As fibrosis in EGE is much less common in EGE compared to EoE, the minimum dose of oral corticosteroids can improve EGE symptoms and control peripheral eosinophilia, avoiding the systemic side effects associated with high doses. Improvement in symptoms with the use of corticosteroids usually occurs within 2 weeks regardless of the layer which is involved [46, 47]. Prednisone is introduced at a dose of 1–1.5 mg/kg for 2 weeks, and subsequently, it is tapered rapidly over the next 2 to 4 weeks. Topical Corticosteroids Case reports have indicated that fluticasone improves gastric eosinophilia when used primarily to treat EoE [90], while others reported that the off-label use of formulations of budesonide in form of capsules, dissolved in water, may target the upper GI tract [59]. Treatment with topical steroids in the form of budesonide, as a budesonide capsule, has also been reported to be occasionally effective in patients with EGE involving the antrum and the small intestine [91–94]. In some circumstances, more prolonged therapy with glucocorticoids is needed in order to succeed complete resolution of symptoms [46, 95]. Patients who do not respond to oral glucocorticoids should undergo a course of equivalent intravenous glucocorticoids and in case of failure, a thorough reevaluation is needed in order to rule out other possible underlying conditions. Cromolyn, Ketotifen, and Montelukast Cromolyn is expected to prevent the release of mast cell mediators such as histamine, platelet-activating factor, and leukotrienes and reduce antigen absorption by the small intestine. Some case reports have documented its effectiveness for short- and long-term management of EGE, while others not [9, 96, 97]. Ketotifen is an H1-antihistamine and mast cell stabilizer which has been reported to improve clinical symptoms and tissue eosinophilia in small series of patients [98–100]. Montelukast is a leukotriene antagonist which has been reported to be effective in some case reports but not in others [64, 101–104]. Reed et  al. assessed the efficacy of various treatment options including dietary therapy, corticosteroids, mast cell inhibitors, H2 antagonists, and leukotriene receptor antagonists in 44 patients with EGE, including pediatric patients, for an average of 26.2 months, 76% of whom needing more than one treatment option [48]. None of the patients treated only with mast cells inhibitors, leukotriene receptor antagonists, or H2 antagonists achieved clinical or histological remission [48]. When all treatment modalities were considered, 60% of patients presented resolution of symptoms and

27  Eosinophilic Gastrointestinal Disorders Beyond Eosinophilic Esophagitis

51%, histological remission. Corticosteroids appeared to be the most effective treatment achieving resolution of symptoms in 22/36 (61%) patients, while dietary therapy in 12/21 (57%) patients, 71% of whom received also treatment with corticosteroids. Twenty-eight patients were assessed for histological response, 19 of whom demonstrated remission after treatment: 9/19 had received corticosteroids, 6/19 combination treatment with corticosteroids and dietary therapy, and 4/19 only dietary therapy [48]. In summary, although studies to date do not advocate the use of leukotriene receptor antagonists, cromolyn, or ketotifen as monotherapy in patients with EGIDs, in case of existing comorbidities for which they are indicated, evidence suggests that they are unlikely to be harmful. Biological Agents and Immunosuppressive Drugs Humanized anti-IL-5 antibody has been reported in a preliminary report of a small number of patients to reduce peripheral and tissue eosinophilia without improving symptoms [105, 106], while after the discontinuation of the treatment eosinophilia reappeared. Omalizumab, an anti-IgE monoclonal antibody, was reported in nine patients to be associated with improvement in symptoms and measures of IgE-mediated allergy, decrease in peripheral eosinophilia but no reduction in tissue eosinophilia [10], thus has no place in the treatment of EGIDs. In a recent study [107] on mouse model of food allergen induced GI eosinophilic inflammation, anti-CCR3 antibody significantly reduced the severity of eosinophilic inflammation, mucosal injury, and diarrhea. CCR3 may be a novel therapeutic target for treatment of EGE and other GI eosinophil-mediated diseases, but further studies are necessary to determine whether the above results can be extrapolated to humans. Suplatast tosilate, a novel antiallergic drug that seems to suppress the production of cytokines, including interleukin (IL)-4 and IL-5 from T helper 2 (Th2) cells, was reported to be effective in a single patient [108]. Thiopurines, such as azathioprine, have been reported to be effective in refractory cases [109]. A recent study [85] using an anti-integrin agent (Vedolizumab) in adult patients with steroid refractory EGE reported clinical and histological improvement in threefourths of steroid-­refractory patients receiving Vedolizumab, which is quite promising but more studies in children are necessary. Another agent that also seems promising is Siglec-8 blocker that was assessed recently in a double-­blind, placebo-controlled trial [86] in 65 patients with refractory EGE (AK002: 43, placebo: 22). The mean percentage change in gastrointestinal eosinophil count was -86% in the combined AK002 group, as compared with 9% in the placebo group. Treatment response occurred in 63% of the patients who received AK002 and in 5% of the patients who received placebo. The mean change in total symptom score was -48%

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with AK002 and -22% with placebo. Adverse events associated with AK002 were similar to those with placebo, with the exception of higher percentages of patients having mild-tomoderate infusion-related reactions with AK002 (60% in the combined AK002 group and 23% in the placebo group) [86]. In conclusion, although several novel drugs seem quite promising in treating EGIDs, more trials are required in adults and in children with EGIDs to assess their efficacy and safety. Due to limited number of randomized controlled trials on the efficacy of the above drugs, they cannot be recommended for routine use in pediatric patients with EGIDs, but they can be used in EGID centers either as part of research studies or for selected patients with refractory disease. Well-­designed randomized controlled trials are urgently needed to establish the best drug treatment option for refractory disease. (iii) Surgical Treatment Surgical treatment is limited only to highly selected cases of persistent pyloric or small bowel obstruction with increased percentage of recurrence [110, 111].

Natural History of EGIDs Beyond EoE Unfortunately, only few patients with EGE present complete long-term remission with treatment. In most patients, the disease is chronic, relapsing, with periodic flares months to years after the initial episode if long-term maintenance treatment is not applied. Chen et  al. noted that among 15 patients with EGE, 13 patients treated with oral corticosteroids, followed by a rapid tapering, manifested symptom remission within 2 weeks but five of them relapsed within 12 months from drug discontinuation [29]. Patients who have recurrent symptoms with periodic flares months to years after the first episode may undergo another short course of oral glucocorticoids, typically prednisone, followed by a rapid taper [46]. Pineton et al. assessed the long-term outcomes of 43 patients with EGIDs and noted that 18 of them (42%) had an initial flare without a relapse, 17 (37%) presented recurrent disease with multiple flares among periods of full remission and 9 (21%) had chronic disease. Among patients with recurring disease, an important variability of the intervals between flares was observed, ranging from months to years [67]. Similarly, Reed et al. noted that only one-third of the pediatric and adult EGE patients, enrolled in their study, underwent long-­term remission [48]. More studies are needed to better understand the pathogenesis and the natural history of various disease subtypes, their impact on patient’s growth, development and quality of life, and the effectiveness of various therapeutic approaches. Understanding this variance appears to be very important in educating patients and analyzing the outcomes of different

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therapeutic options, especially in patients who present refractory disease [32]. With all subtypes of EGIDs increasing more and more, emerging phenotypic data may facilitate the understanding of the complex pathogenetic mechanisms behind the disease, leading to an individualized short- and long-term management. Furthermore, international, consensus recommendations on diagnostic criteria for the diagnosis of the EGIDs beyond EoE are urgently needed to facilitate well-designed, randomized trials assessing the efficacy of various treatment modalities. ESPGHAN and NASPGHAN are about to produce such document to encourage high quality research, and to guide clinicians dealing with these disorders, decreasing variations in clinical practice and improving effectiveness and quality of care.

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28

Crohn’s Disease Marina Aloi and Salvatore Cucchiara

Introduction Crohn’s disease (CD) is a chronic, relapsing disorder of the gastrointestinal tract, belonging to the inflammatory bowel diseases (IBDs). Approximately 25% of IBD is present in childhood and adolescence, with recent studies suggesting that the prevalence is rising in both developed and developing countries [1–4]. The precise cause of IBD is still unsettled, but there is evidence that they develop as a consequence of an abnormal immune response to the intestinal microbiota in a genetically susceptible host [5, 6]. Although pediatricand adult-onset IBD seem to share many clinical aspects and pathogenetic pathways, however, some features characterize the pediatric form, such as the potential for linear growth impairment and pubertal delay, as complications of undertreated inflammation and malnutrition, the influence of nutritional treatment on the course, and the different phenotype expressions of the disease [7]. Finally, evidences from animal models of IBD and preliminary observations in children support the concept that IBD develops in distinct phases and that key mediators of the inflammation may play different roles, depending on the stage of the disease [8, 9]. These observations highlight the importance of taking into consideration the disease course when studying pediatric IBD and targeting appropriate treatments.

Epidemiology Although IBD can occur at any age, up to 25% of patients develop symptoms during childhood and adolescence [1–3]. Some epidemiological studies from the United States and Europe have shown a steady increase in the overall mean M. Aloi · S. Cucchiara (*) Pediatric Gastroenterology and Liver Unit, Department of Women’s and Children’s Health, Sapienza University of Rome, Rome, Italy e-mail: [email protected]; [email protected]

annual incidence of IBD around the world: the rising rate of pediatric IBD seems to be primarily due to an increase of the incidence of CD [1, 3, 10]. CD is unequally distributed all over the world, with highest rates occurring in Western and Northern countries, and with a decreasing gradient from North to South and from West to East [4]. The worldwide highest prevalence of pediatric IBD is reported from the Canadian Ontario region, with approximately 50 IBD patients per 100,000 inhabitants [3]. Recent epidemiological observations from two large claims databases in the United States reported an increased prevalence of IBD overall by 133%, from 33/100,000  in 2007 to 77/100,000  in 2016. Among children, CD was twice as prevalent as UC (45.9 vs 21.6). Prevalence was higher in boys than girls for all forms of IBD, in contrast to the adult population where the prevalence was higher in women than men [1]. In Europe, a recent study based on the Epidemiology of Inflammatory Bowel Diseases (EPIMAD) data of Northern France indicated a dramatic increase of both CD and UC in adolescents from 1988–1990 to 2009–2011: for CD, from 4.2 to 9.5/105 (+126%) and for UC, from 1.6 to 4.1/105 (+156%) [10]. Factors contributing to the evident increase in the global incidence could be a greater case ascertainment, the widening case definition, earlier onset in predisposed individuals, and greater access to health care; however, it is widely agreed that the rising incidence of pediatric IBD is due to a real increase in the number of affected children [11]. It has been postulated that the “Westernization” of different societies accounts for the progressive rise in the incidence of the disease also in previously low-incidence areas, including Japan [12], other Asian countries [13, 14], and some Eastern European countries [15]. Pediatric IBD present specific phenotypic and demographic differences when compared with the adult-onset disease. While CD and UC occur with an equal distribution in adults [4], it has been reported that in childhood CD is more frequently diagnosed than UC [1]; moreover, while in adults there is an equal male-to-female ratio (or a mild female

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 S. Guandalini, A. Dhawan (eds.), Textbook of Pediatric Gastroenterology, Hepatology and Nutrition, https://doi.org/10.1007/978-3-030-80068-0_28

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p­ redominance), all pediatric IBD cohort studies or registries indicate a male predominance [16]. In pediatric CD, most patients have an extensive disease, ileocolonic or colonic, and distinction of UC from colonic CD may not be uncommonly challenging [17]. Moreover, children with CD are more likely to have upper gastrointestinal involvement than their adult peers [18]. Pediatric CD also seems to have a different behavior than the adult-onset disease: children often present with an inflammatory or nonstricturing, nonpenetrating disease, while complicated disease is fairly unusual at presentation. However, even with treatment, many data demonstrate that inflammatory CD progresses to stricturing and penetrating disease in several children [18, 19]. Adult disease begins more often with a complicated behavior (stricturing or penetrating), with a lower trend of disease progression [20].

Etiopathogenesis The most accepted hypothesis for the pathogenesis of CD is that the interaction between luminal contents (i.e., the intestinal microbiota) and the mucosa leads to a dysregulated inflammation in a genetically predisposed host. Several microorganisms have been historically considered as potential causative agents for CD, including Mycobacterium paratuberculosis, Listeria monocytogenes, novel Burkholderiales, and Escherichia coli [21, 22]. Interestingly, strains of adherent-­invasive Escherichia coli (AIEC), capable of adhering to and invading epithelium, and to replicate in macrophages, have been described in adults and children with CD [23–25]. Nevertheless, there are no strong data to support a role for any of these microorganisms as the causative factor in the etiology of IBD. Some interesting findings in the pathogenesis of IBD come from genetics. The importance of genetics in CD was suggested by family, twin, and phenotype concordance studies. Monozygotic twins exhibit phenotypic concordance in 50–70% of CD patients, and their relative risk of developing CD is 800-fold greater compared to the general population [26–28]. Recently, the discovery of several susceptibility genes has further secured the importance of genetic predisposition in CD and UC [26]. After the pivotal study of Hugot et al., in 2001, who discovered the association of variants of the NOD2 gene with ileal CD [29], and the discovery of the correlation between variants of IL23 receptor (IL23R) gene and both CD and UC in 2006 [30], the number of IBD genetic associations is dramatically increased. More susceptibility loci have been quickly identified, such as autophagy genes, ATG16L1 and IRGM [31, 32]. In the last decade, the implementation of genome-wide association studies (GWAS) has significantly advanced our knowledge on the importance of genetic susceptibility in IBD [33]. To date, GWAS have identified more than 200 risk-conferring loci for IBD [34],

M. Aloi and S. Cucchiara

most of them shared by CD and UC. However, some genes are quite different for CD or UC, clearly denoting the genetic heterogeneity of the two forms of IBD, each one of them showing distinctive and shared genetic associations. For instance, NOD2 and autophagy genes, and ITLN1 (Intelectin 1) are unique for CD [34]. Despite the discovery of a massive number of susceptibility genes for IBD, we are still far from understanding the mechanism by which such genetic variants cause the uncontrolled intestinal inflammation. The challenge for basic IBD researchers is now to identify how genetic abnormalities influence pro-inflammatory pathways, providing information directly improving the clinical management. Some pro-­ inflammatory pathways have been partially or totally understood, in some cases this knowledge has enabled the development of specific interventions. For instance, NOD2 gene defected patients have an impaired ability to recognize and process bacterial products, and this may lead to an inappropriately innate immune response. Some CD patients with variants of the autophagy genes (ATG16L1 and IRGM) have a defective capacity to process cell degradation products, as well as bacteria, and therefore an insufficient ability to eliminate pro-inflammatory factors [23]. One of the most important discoveries in the field of genetics of pediatric IBD is the identification of impaired interleukin 10 (IL-10) signaling in some forms of very early onset (within the first months of life) CD [35]. The common characteristics of these patients are a very early onset of a severe form of CD (infantile colitis), with colonic involvement and presence of fistulae, in some patients associated with growth failure, resistant to conventional therapies. Allogeneic hematopoietic stem cell transplantation is effective in most patients [36]. This form of CD is due to homozygous mutations in either IL10RA or IL10RB, which encode subunits of the IL10 receptor, or for IL10 itself [37]. One could speculate that this form of IBD with a monogenetic inheritance could identify a subset of patients with a “more” Mendelian transmission, opening new horizons for research and also expectations to understand the definite mechanisms underlying these diseases. Since then, several other forms of monogenic chronic inflammatory conditions with an IBD phenotype have been discovered, sharing a disturbance of the intestinal epithelial barrier function or a dysfunction of the innate and adaptive immune system, with a wide spectrum of disease presentations and with different courses and medical and surgical treatments, although allogeneic hematopoietic stem cell transplantation is often the only effective therapy [36, 38, 39]. A correct diagnostic approach, including genetic analysis, is mandatory in children who develop a very early onset IBD, and possibly in general in those patients with a severe CD course [36]. Beyond the genetics, in the last two decades epidemiological and pathogenetic studies have been mainly focused on the role of environmental factors in the etiology of IBD. Indeed, the epidemiology of both CD and UC clearly

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addresses environment as the main factor that can determine such rapid changes. Moreover, the increasing incidence and prevalence of pediatric IBD worldwide, both in developed and in developing countries, seem to follow changes in the diet and lifestyle, with the adoption of a “Westernized” lifestyle [5]. Even though a causative role for a single factor has not been proven, several potential environmental influences have been studied so far. Smoking has been widely demonstrated to negatively affect the risk of developing CD and to exacerbate its disease course. The extensive use of antibiotics and gastrointestinal infections, particularly in the early ages of life, seem to increase the risk of developing IBD. Personal stress is recognized as a risk factor for disease exacerbations as well [40]. Among all, the spread of the “Western” diet, high in fat and protein but low in fruits and vegetables, is regarded by many researchers as a strong candidate, and its influence on gut inflammation is highly hypothesized [41].

Clinical Presentation CD is characterized by transmural inflammation that can be found everywhere in the gastrointestinal tract, from mouth to anus. The terminal ileum is the most common site of CD, however about 60% of children have an extensive ileocolonic involvement, and 20–30% an isolated colonic disease [17]. CD typically presents in any age group with a constellation of abdominal pain, diarrhea, weight loss, and poor appetite, however, short stature and predominant perianal disease are further significant features of presentation of pediatric CD. Impairment of linear growth and associated delay in sexual development can present before the onset of intestinal symptoms and can dominate the clinical presentation [42]. Growth failure is a unique characteristic of pediatric-­onset CD: it is defined as linear growth at or  5 mg/L (CRP > 0.5 mg/dL) was a criterion for treatment failure [51]. Several antibodies to microbial antigens have been identified in patients with IBD. The most extensively studied and commonly used are anti-Saccharomyces cerevisiae antibodies (ASCA) and perinuclear antineutrophil cytoplasmic autoantibodies (pANCA). ASCAs have initially been suggested as a marker for CD with a prevalence of 50–60%, compared with 10–15% in UC and 0–5% in healthy controls [52, 53]. Conversely, pANCAs have been proposed as a marker for

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 ecal Markers of Inflammation F The neutrophil-derived marker calprotectin is a noninvasive tool for the diagnosis and monitoring of the activity of IBD. Calprotectin is a calcium-binding protein that is excreted in the feces and can be readily measured using an ELISA (enzyme-linked immunosorbent assay). The protein is stable in stool specimens for up to a week at room temperature, allowing patients to collect a specimen at home without special precautions. Calprotectin is commonly used in the initial diagnostic approach to suspected IBD: a fecal calprotectin concentration of less than 40 μg/g in the presence of abdominal symptoms, suggestive of irritable bowel syndrome, is associated with only 1% chance of IBD, therefore reducing the number of negative endoscopies in both children and adults. Conversely, higher fecal calprotectin values (a cut-off of 100 μg/g has a good sensitivity for discriminating patients with suspected inflammation) help in identifying those patients who need investigation (i.e., endoscopy) and are most likely to have IBD [58]. Fecal calprotectin is, moreover, equally useful in the context of disease monitoring, due to its ability to confirm tissue healing and predict disease relapses. A few studies have evaluated this outcome, demonstrating a sensitivity of 89–90% and specificity of 82–83% for predicting disease relapse during a 12-month period, with a sensitivity and specificity to predict the absence of mucosal healing of 70–100% and 44–100%, respectively, depending on the calprotectin concentration threshold used [59]. Other fecal biomarkers, such as lactoferrin, neutrophil-derived S100A12 and High-­ Motility Group Box 1 (HMGB1), have shown promises as potential biomarkers for CD, but have been studied far less extensively [60, 61]. Ileocolonoscopy and Esophagogastroduodenoscopy (EGD) Traditional endoscopy has a pivotal role in the diagnosis of suspected CD.  According to the last European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines on the diagnosis of IBD, ileocolonoscopy and EGD should be recommended as the initial work-up for all children with suspected disease. Multiple biopsies should be obtained from all sections of the examined gastrointestinal tract, even in the absence of macroscopic lesions [46]. Beyond diagnostic aims, traditional endoscopy has an important role in staging disease severity, evaluating and treating strictures, detecting postoperative recurrences, surveilling neoplasms, and preoperative assessment. Moreover, endoscopy allows the monitoring of response to therapies, by evaluating mucosal healing (MH). In the last decade, MH has become the most rigorous endpoint in both adult and pediatric therapeutic trials. The so-­ called treat-to-target strategy for disease management and the importance of reaching MH will be further discussed at

383 Table 28.1  Endoscopic differentiation between typical CD and UC CD Throughout the entire GI tract Discontinuous lesions Rectal sparing or segmental inflammation Aphthous ulcers (may occur in normal mucosa) Linear ulcers common Cobblestoning Ileocecal valve stenotic and ulcerated

UC Confined to colon Usually continuous lesions Rectal involvement (in children may be absent) Mucosal granularity/friability Erosions/microulcers Loss of vascular pattern Ileocecal valve patulous and free from ulcerations (possible backwash ileitis)

Table 28.2  Histologic findings in CD and UC CD Focal crypt distortion Ulcers and/or aphthoid ulcers Mucin depletion absent or weak Pseudopyloric metaplasia Focal cryptitis Focal lympho-­ plasmacellular infiltration in the lamina propria Granulation tissue-like inflammation Epithelioid granulomas

UC Mucosal surface alteration Crypt distortion Atrophy Mucin depletion Cryptitis and/or crypt abscesses. Diffuse lympho-plasmacellular infiltration in the lamina propria Basal plasma cell infiltration

the end of this chapter. Tables 28.1 and 28.2 show the typical endoscopic and histologic findings differentiating CD and UC.

Small Bowel Evaluation Imaging Most CD patients, particularly those with a childhood-onset disease, present with a small bowel involvement. The revised PORTO criteria state the need of small bowel assessment at the diagnosis in all suspected CD cases, through magnetic resonance enterography (MRE) or wireless capsule endoscopy [62]. Furthermore, children with CD need frequent evaluations during the course of their disease, so noninvasive, radiation-free imaging tests, could be a valuable alternative to endoscopy for the definition of activity and complications of the disease. In the past, small bowel follow through (SBFT) was the “gold standard” for small bowel disease, but it no longer plays any role both in CD diagnosis and follow-up. In the last decade, due to considerable advances in technologies, other modalities, such as MRE, ultrasound (US), and computed tomography (CT), have taken its place [63, 64]. Computed tomography has the major disadvantage of the large radiation exposure, therefore limiting its use only to the

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emergency setting, when magnetic resonance (MR) is not available. Magnetic resonance with the administration of oral contrast (MRE) results in luminal distension, facilitating evaluation of bowel wall thickness, profile, and structure; MR enteroclysis (with contrast administered through a nasojejunal tube) seems to have the same sensitivity (88%) of MRE but a superior patient discomfort [63], and therefore it is not recommended in children with CD.  In comparison with endoscopy, MRE has a sensitivity of 84–96% and a specificity of 92–100% for the diagnosis of IBD [65]. MRE can also allow a detailed assessment of perianal fistulae, and it should be preferred as the imaging tool for perianal disease [66]. The last European Crohn’s and Colitis Organization (ECCO) and the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines on the management of pediatric CD recommend MRE as the imaging tool of choice for the diagnosis and follow-up of CD [67]. Abdominal US is a widely used technique in the evaluation of patients with CD because of its excellent safety profile, low cost, and recent advances in the equipment (Doppler and use of oral contrast) that allow high-resolution images [64, 68]. Recently, small intestine contrast ultrasonography (SICUS), performed after ingestion of an oral contrast material filling the small bowel lumen with anechoic fluid, has been developed for the study of the small bowel [68]. SICUS provides the opportunity to visualize and assess the entire small bowel by measuring the intestinal wall thickness and lumen diameter at different levels [63]. Ultrasound techniques have several advantages: they are cheap, noninvasive, well-tolerated and have a good correlation with MRE [69]. Their use is limited by local expertise and lack of validated score for grading inflammation [70].

drug ingestion as a diagnostic criterion, this has not been prospectively validated. Given the concerns about the specificity of SBCE in the diagnosis of IBD, but recognizing its good sensitivity, its utility is greater for monitoring established CD rather than for initial approach [71].

 mall Bowel Capsule Endoscopy S When there is a strong suspicion for small bowel inflammatory lesions, with normal features at ileocolonoscopy and imaging, small bowel capsule endoscopy (SBCE) represents a valuable and well-tolerated tool. It allows the evaluation of CD small bowel lesions, with no radiation. It is very sensitive for determining mucosal lesions: in comparison to traditional endoscopy, SBCE can evaluate the entire small bowel and is better tolerated from children. Regardless of its many advantages, SBCE also has some weaknesses: biopsy or intervention is not possible, it cannot detect extraluminal processes and there is no way to guide the capsule, so significant lesions may be missed because of a bad orientation of the camera, obscured visualization due to luminal bubbles or debris, or delayed intestinal transit resulting in an inaccurate examination. SBCE is contraindicated in patients with strictures because of the risk of capsule retention. Furthermore, there are no established diagnostic criteria for CD, although most studies have defined the presence of more than three ulcerations in the absence of nonsteroidal anti-inflammatory

Therapy

Balloon Enteroscopy Given the availability of the abovementioned noninvasive tools, the role of enteroscopy, especially balloon-assisted enteroscopy (BAE), remains limited to symptomatic patients in whom ileocolonoscopy, SBCE, and/or cross-sectional imaging are inconclusive for active disease, as well as to obtain mucosal samples to exclude potential malignancies and for therapeutic purposes [72]. Balloon-assisted enteroscopy was first introduced in 2001 as a device offering the possibility of a complete diagnostic and therapeutic access to the entire small bowel with an endoscope [73]. A single-­ balloon device has also been developed with a similar intention. The enteroscope can be inserted via the oral or anal route and, using the combination of these approaches, a complete examination of the entire small bowel can be achieved in many patients [74]. Several studies support the utility of BAE in established adult and pediatric CD with the potential to affect management in select populations of patients (small bowel disease) [75]. The main limitations of BAE are the invasive nature with the risk of bleeding and perforation (complication rate for diagnostic procedures is around 0.8% but can be as much as 4% for therapeutic interventions), prolonged duration, limited evaluation of the entire small bowel in a one-step approach, and requirement for specialized personnel [75].

The traditional management of CD based on achieving prolonged clinical remission has experienced a dramatic evolution in the last years, since the recognized paramount importance of MH, as the main outcome, and, possibly, transmural healing. The so-called treat-to-target (T2T) approach, adapted from rheumatoid arthritis and other chronic diseases, is now a consolidated strategy in the management of IBD: it is focused on an objective measure and monitoring of the intestinal damage at predefined time-­ points, and includes therapeutic adjustments in case of failure [76]. The introduction of these targets might be the best way to alter the natural course of IBD by preventing disability and bowel damage [77]. This may be of clinical relevance in children with CD, given the long-term consequences of an early-onset aggressive disease presentation. Pediatric CD therapy employs many of the same treatment regimens as its adult counterpart. There are only a few well-designed clinical trials performed in children, therefore much of the

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385

Fig. 28.2  Step-up approach in pediatric Crohn’s disease

ity

ctiv

a ase

e

Dis

TNFα antagonists Anti-IL 12/23 Anti-integrin Surgery

Systemic corticosteroids Immunomodulators Non-systemic corticosteroids Nutritional therapy

e­ vidence given is based on adult data. Conventional therapy is based on the escalation of drugs, from those with a better safety profile but a lower efficacy to those with improved efficacy but a greater risk of side effects (steroids, immunomodulators, biologicals, surgery). This “step up” approach is applied in some cases of pediatric IBD. The advantages of “step up” management are mainly to reserve more toxic drugs for those patients with a demonstrable “need” for more intensive therapy [78] (Fig. 28.2). However, potential disadvantages include the observation that conventional therapies have not altered the disease course toward disease complications (strictures and fistulae) or the need for surgical procedures. Hence, an “early aggressive” treatment (“top-down” approach) through the introduction of an early biologic therapy at the diagnosis is now a consolidated treatment strategy for CD patients at high risk of an aggressive disease course [79]. Several risk factors, which prompt this “top-down” treatment, have been identified and include the presence of deep colonic ulcerations on endoscopy, persistent severe disease despite adequate induction therapy, extensive (pan-­ enteric) disease, marked growth retardation, severe osteoporosis, stricturing and/or penetrating disease [80]. Increasing the knowledge of these markers (genetic, biochemical, or clinical) of poor prognosis or response to treatment will be the challenge in pediatric IBD research. Figure  28.3 shows the therapeutic pyramid applied in the management of pediatric CD.

Conventional Therapy Aminosalicylates There are no randomized controlled trials evaluating aminosalicylate (5-ASA) efficacy for the induction and maintenance of remission in children. Current data in adults do not support their use in ileal CD, showing any (or a slight)

improvement compared to placebo, thus their use in CD should not be supported.

Steroids Conventional corticosteroids (CS) are used for the induction of remission in moderate-to-severe CD.  CS are usually quickly weaned after the induction, due to their known adverse effects. Budesonide, an oral steroid preparation that is released in the distal ileum and proximal colon, can be used in patients with mild-to-moderate disease of those segments. It has less systemic side effects than conventional steroids but it is not completely without them, and a quick withdrawal can lead to an adrenal insufficiency [81]. Immunomodulators (Azathioprine, 6-Mercaptopurine, Methotrexate) Thiopurines, comprising azathioprine (AZA) and its active metabolite, 6-mercaptopurine (6-MP), are widely used maintenance agents in pediatric CD [67]. Their efficacy has been demonstrated in several trials both for induction and maintenance of remission in CD, however, due to their well-known slow onset of action (about 3 months), they are not used for induction of remission. Although the only pediatric prospective, multicenter, double-blind, placebo-controlled trial conducted in children, reported 91% of children receiving thiopurines to be in remission after 18  months of therapy [82], in routine clinical practice, a complete remission can be achieved in about 60% of patients 1 year after beginning the therapy [83]. Myelosuppression is a dose-dependent adverse event that can occur during AZA treatment. Complete blood count and liver tests should be monitored frequently during the therapy. Acute pancreatitis is a rare drug-related adverse event, typically occurring in the first month of treatment [84]. Genetic analysis for thiopurine S-methyltransferase (TPMT) deficiency can help to identify those patients at high risk for hematopoietic toxicity, although normal TPMT

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Nutritional support Surgery

Biologigs Immunomodulators (AZA/6-MP – MTX)

Prednisone

Exclusive enteral nutrition - Budesonide

Fig. 28.3  The therapeutic pyramid of pediatric Crohn’s disease. (Figure modified from Aloi et al. [78])

t­ esting does not exclude the possibility of leukopenia. Assays for 6-thioguanine (6-TGN) and 6-methylmercaptopurine (6-MMP) levels are commercially available and are related to therapeutic response and hepatotoxicity, respectively. While chronic thiopurine administration has been linked to a potential risk of developing non-Hodgkin (roughly, a fourfold increase in this risk compared to nontreated patients and the general population), AZA may have a role in the risk of developing the hepatosplenic T-cell lymphoma (HSTCL), an aggressive form of non-Hodgkin lymphoma, rapidly evolving and with a poor response and high mortality, mainly occurring in young male patients with IBD, who have received a long-lasting combination of AZA and anti-TNF alpha agents. Methotrexate is often regarded as a second-line immunomodulator in CD patients not responding or intolerant to thiopurines. Some data in adults have demonstrated its efficacy in inducing and maintaining remission [85]. To date, there have been no controlled trials of its use in pediatric CD, but reports from retrospective reviews and uncontrolled trials have shown good remission rates [86, 87].

Biologic Agents Monoclonal anti-TNF antibodies have revolutionized the treatment and management of IBD since their introduction more than 20  years ago. Infliximab (IFX), the first in this class to be approved in pediatric IBD, is a chimeric monoclonal immunoglobulin G1 (IgG1) antibody (part mouse and part human) that is given intravenously. Infliximab is effective in both inducing and maintaining remission in pediatric CD [88]. It reduces the need for corticosteroid, hospitalization, and surgery, is effective in perianal CD, and

induces mucosal healing [89]. In the main pediatric clinical trial, the Realizing Effectiveness Across Continents with Hydroxyurea (REACH) study, children with moderate-tosevere CD received a 3-dose induction of 5 mg/kg IFX at 0, 2, and 6 weeks, followed by 5 mg/kg maintenance infusions every 8 weeks. Remission rates were 60% at week 30 and 56% at week 54 [88]. Moreover, several studies have demonstrated that IFX is able to induce MH [90, 91] and its efficacy seems to be improved when used in combination with AZA, as clearly shown by the Study of Biologic and Immunomodulator Naive Patients in Crohn’s Disease (SONIC) trial, in which the combined therapy with IFX and AZA led to a 44% MH rate at week 26, compared to 30% in the IFX group and 17% in those patients treated with AZA monotherapy [59, 92]. In the last decade, therapeutic drug monitoring (TDM), based on the assessment of serum drug concentration and antidrug antibodies, has become an indispensable tool to optimize the use of anti-TNFs. Performed in the setting of active disease (“reactive” TDM) is helpful in elucidating the mechanism underlying the loss of response: an immune-mediated failure (which may benefit a “within-class” switch) is suggested in the presence of high titer of antidrug antibodies with low drug levels, while low drug concentrations in the absence of antibodies indicate nonimmune-mediated pharmacokinetic failure. In this case, treatment optimization through a dose increase or reduced intervals is likely successful. A mechanistic failure, and the need of switching to a non-anti-TNF agent, is implicated in the setting of adequate drug concentrations during active disease [93, 94]. “Proactive” TDM, performed in patients with quiescent disease, to maintain a target trough concen-

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tration was recently associated with favorable therapeutic outcomes [95–97]. Whether it should always be preferred to “reactive” TDM is still a matter of debate since the only prospective trials conducted in adults with the aim of evaluating the efficacy of a proactive approach in CD did not confirm its superiority [95, 98]. While it is clear that higher drug levels are associated with better response, IFX optimal serum drug concentration has not been clearly defined. It is suggested that postinduction concentrations greater than 7 μg/mL are more likely to be associated with MH, while during the maintenance phase, through concentrations should not be lower than 3  μg/mL when in remission [93]. Adalimumab is a humanized anti-TNF therapy that has been shown to be effective for induction and maintenance of remission for children with CD [99]. Its efficacy in luminal CD is comparable to that of IFX [100]. Its superiority over placebo in inducing and maintaining remission in patients with moderate-to-severe CD has been largely proven both in adults [101–103] and children [99, 104]. European guidelines on the medical management of pediatric CD recommend its use as an alternative to IFX (according to the availability, route of delivery, patient preference, cost, and local regulations) as the first treatment options for penetrating fistulizing CD, and in children with high risk for poor outcome [67]. TDM applies also to adalimumab: as for IFX, during maintenance therapy, at least 5 μg/mL is recognized as the optimal trough concentration threshold to target, but higher levels (>10 μg/mL) seem to be associated with better therapeutic outcomes [105]. Vedolizumab, an anti-α4β7-integrin humanized immunoglobulin G1 monoclonal antibody and ustekinumab, an anti-­ interleukin (IL)12/23p40 monoclonal antibody, are emerging as important rescue therapy for patients with moderate-to-­ severe CD, who fail to respond or lose response to anti-TNF (40% of cases) or, more recently, are biologic naϊve. GEMINI 2 and 3 trials of vedolizumab in moderately to severely active CD demonstrated only a partial benefit of vedolizumab on clinical outcomes with approximately 14% of 6-week clinical remission rate [106]. For ustekinumab, the UNITI study reported up to 30% of 6-week clinical remission rate, showing superiority to placebo, with percentage reaching 50% in those patients who were biologic naϊve [107].

Nutrition Exclusive enteral nutrition (EEN) is used as a therapy to achieve remission in children presenting with acute CD [67]. Nutritional therapy consists of using different milk formulas (elemental, semi-elemental, and polymeric) as the primary therapy to induce and maintain remission in CD, as a supplement to improve growth, or to replenish micronutrient defi-

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ciency. Although several evidence support the use of enteral nutrition as primary therapy, it has found favor in some parts of the world (mainly Europe and Canada), while it is less widely utilized in others (United States), and can be difficult to administer for long periods of time, mainly because of poor compliance by the patients. Several studies have shown the effectiveness of EEN in achieving clinical remission and mucosal healing in active CD [108–111]. Despite these data, there still remain a multitude of theories explicating the mechanisms of action of EEN. The most frequently advanced theory is that the microbiota of the gut lumen, or more probably products deriving from microbiota, are modified by enteral nutrition [112]; furthermore, the reduction in antigenic load associated with an exclusive enteral nutrition may also contribute to bowel rest [113]. The main drawback of enteral feeding is the poor compliance, most parents are reluctant to commit total enteral nutrition for their children for 6 to 8  weeks as required, and few children are able to consume adequate formula volume by mouth, thus requiring the insertion of a nasogastric tube. In the last years, new data have emerged about the efficacy of partial enteral nutrition with specific diets for both the induction and maintenance of remission of pediatric CD [114, 115]. Specifically, a few diets from different parts of the world have been evaluated in small prospective and retrospective studies with promising results [115, 116].

Surgery Up to 30% of children with CD require surgery within 10 years from the diagnosis [117]. The main indications are complications of the disease (especially strictures and fistulae), intestinal perforation or bleeding, failure of medical therapy, and complications of medical therapy (e.g., growth failure). Terminal ileal and colonic disease account for most of surgical interventions in children with CD. Primary goals of surgical treatment in CD are to preserve as much bowel as possible, relieve complications, and to help the patient to achieve the best possible quality of life. In children, the potential for bowel loss due to surgical resections must be weighed against the risk of poorly controlled disease, long-­ term steroid therapy, and growth failure. The surgical procedure depends on the clinical situation (urgent vs. elective) and the disease extent. Most of the procedures are bowel resections due to strictures, commonly located at the terminal ileum. Stricturoplasty can be an alternative to bowel resection in the case of multiple short segments or longer segments up to 20 cm in length [118, 119]. Another setting of surgical intervention is perianal CD. Several studies have shown that infliximab therapy combined with surgical treatment of fistulizing perineal disease results in significant improvement of perineal disease, which is superior to medical treatment alone [120, 121].

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29

Inflammatory Bowel Disease Unclassified (IBD-U)/Indeterminate Colitis Barbara S. Kirschner

Introduction The majority of patients with chronic IBD are diagnosed with either ulcerative colitis (UC) or Crohn’s disease (CD) on the basis of established clinical, endoscopic, histologic, and radiologic criteria [1–2]. However, in 5–23% of patients with chronic colitis, a definitive diagnosis of UC or CD cannot be established because the initial macroscopic appearance (either during ileo-colonoscopy or following colectomy) and histologic features overlap between UC and CD [1–9]. In this case, the diagnosis should be IBD-U if made prior to colectomy or indeterminate colitis (IC) if the pathology of the resected colon is not consistent with either UC or CD involving the colon [1–2, 8]. While many of these patients eventually evolve into patterns consistent with UC or CD, approximately 20–60% retain the diagnosis of IBD-U, over 5–10 years or longer post diagnosis [6–13]. This observation is increasingly suggestive that IBD-U represents a separate unique subtype within the spectrum of IBD [1–5, 8]. Updated information describing clinical, histologic, serologic, and newly described genetic features of IBD-U in pediatric patients has been added to this revised chapter.

I nflammatory Bowel Disease Unclassified (IBD-U) Clinical Presentation Several studies have estimated the percentage of patients with IBD-U among the patients with chronic IBD (See Table 29.1). A concurrent retrospective/prospective analysis B. S. Kirschner (*) Department of Pediatrics, Section of Gastroenterology, Hepatology & Nutrition, University of Chicago Medicine, Chicago, IL, USA e-mail: [email protected]

Table 29.1  Proportion of IBD-unclassified (IBD-U) cases in pediatric IBD reported studies Age group

Total no. IBD Pts

Everhov [31] Winter [24] Jose [17] Chandradevan [5] Castro [14] Gupta [7] Heikenen [9] Hildebrand [4] Malaty [32] Meucci [12]

4663 3461 1649 136 1576 420

Pediatric

IBD-U Mean age at diagnosis (years) No. Pts 839 266 171 136 131 51

91 132

Pediatric Pediatric Pediatric Pediatric Pediatric Pediatric 9 Pediatric 36

420 1113

Pediatric 78 Adult 50

(Percent) IBD-U v UC 18.0% 7.7% 12.3 12.9 – 10.3% 5.8% 5.3% 11.9% 10.0% 27.0%

7.8 –

18.6% 4.6%

9.2 –

9.7

of 1576 children and adolescents from the Italian Pediatric National IBD Register showed that 8% of their study population were diagnosed with IBD-U compared with 52% UC and 40% CD [14]. Presenting symptoms in IBD-U were more similar to UC (bloody diarrhea and abdominal pain) than CD (abdominal pain and diarrhea). Fever and weight loss occurred more frequently in CD than IBD-U and UC: fever in 40.5% CD, 12.9% in IBD-U, and 12.6% in UC; weight loss 50.1% in CD, 17.4% in IBD-U, and 20.6% in UC. The locations within the colon were also similar between IBD-U and UC (pancolitis 34% versus 39%; left colon 27% v. 23%; and rectum only 9% v. 7%). The male to female ratio was lowest in UC (0.82), intermediate in CD (1.18), and highest in IBD-U (1.42). Heyman et  al. [15], using the PediIBD Consortium Registry, reported that the prevalence of IBD-U in children with IBD-U was highest in those aged 0–2 years (33%) and decreased to 18% at 3–5 years, 12% at 6–12 years, and 9% in those aged 13–18 [15]. In young chil-

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 S. Guandalini, A. Dhawan (eds.), Textbook of Pediatric Gastroenterology, Hepatology and Nutrition, https://doi.org/10.1007/978-3-030-80068-0_29

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dren (less than 5 years of age), failure to thrive is more prominent than seen in UC [16]. Jose et al. [17] compared IBD disease type with the prevalence of extraintestinal manifestations (EIMs) at the time of diagnosis and during follow-up in pediatric patients with IBD [17]. That study, also from the PediIBD Registry, included 1649 patients: IBD-U (n = 171), UC (n = 471), and CD (n = 1007). With the exception of primary sclerosing cholangitis (PSC) being more prevalent in UC, the frequencies of the other EIMs did not differ between these disease types.

Epidemiologic Aspects Sykora et al. [18] noted a broad worldwide variation in the incidence of pediatric IBD with detailed numbers for many countries. For North America, it was highest for CD (0.7– 13.9/100,000 person years, 0.5–10.6 for UC, and lowest for IBD-U (0.2–2.1/100,000). A meta-analysis of 14 studies of pediatric patients with IBD and 18 studies in adult patients with IBD showed a higher frequency of IBD-U in children (12.7%) versus adults (6.0%) [19]. Gupta et al. [7] reviewed the medical records of 428 children with IBD followed at the University Chicago. Of those, 49 (11.4%) were diagnosed with IBD-U. Within the IBD-U group, 42.9% had histology “favored ulcerative colitis” (UC) but these patients also had features of CD including areas of focal colitis, focal gastric or duodenal inflammation, anal fissures or isolated granulomas adjacent to ruptured crypts. Features “favoring Crohn’s disease” (CD) were present in 20.4% of children with IBD-U, none of whom had granulomas, radiologic evidence of small bowel CD, or perianal findings. In the remaining 36.7%, there were no endoscopic and histologic findings favoring UC or CD. IBD-U was diagnosed after an X-ray study of the upper gastrointestinal tract with small bowel follow-through to exclude the possibility of Crohn’s disease. Heikenen et al. reported a prevalence of IBD-U (10%) in a pediatric population of IBD [9]. As a group, children with IBD-U were diagnosed at a younger age (7.8  years) than those with either UC (9.7 years) or CD (11.4 years).

Criteria for Histologic Diagnosis In establishing a diagnosis of IBD-U, it is essential to exclude other causes of colitis such as infections (Clostridium difficile, Yersinia, Mycobacterium tuberculosis, Entamoeba histolytica, E. coli 0157:B7 or other verocytotoxin-producing strains), drugs (NSAIDS), Behçet’s, malignancy, vasculitis, and certain immunologic disorders. Immune deficiency disorders which may include chronic intestinal inflammation

B. S. Kirschner

are: chronic granulomatous disease, Wiskott-Aldrich syndrome, common variable immunodeficiency disease (CVID), immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX), and glycogen storage disease type 1b [1–2, 8, 20]. Geboes and Van Eyken [8] published an in-depth description of the histologic features observed in normal intestinal mucosa as well as the changes seen in patients with IBD. Focal or diffuse plasmacytosis at the base of the mucosa and crypt architectural changes are strong predictors of IBD. However, it is important to recognize that these findings develop during the course of IBD.  Thus, while basal plasmacytosis was seen within 15 days of the onset of IBD, crypt distortion was observed at 16–30 days in only 25% of patients but increased to 75% after 4 months. By comparison with adults, children 20 intraepithelial lymphocytes per 100 colonocytes with mixed inflammation of the lamina propria and normal crypt architecture, CC features a thickened subepithelial collagen band in addition to the inflammatory changes seen in LC. MC affects patients of any age, including children, but most commonly presents in older adults and the elderly with a mean age of 60.7 years [1].

Epidemiology The reported prevalence of microscopic colitis ranges from 48 to 219 per 100,000 [3], and population-based studies in adults suggest a prevalence of 4–13% in patients investigated for chronic diarrhea [1]. Annual incidence of MC is estimated to be 2.6 to 10.0 per 100,000 person-years, with evidence for an increased incidence over time [4, 5]. The pediatric prevalence of MC remains unknown; however, the youngest reported case is a child 2 years of age [1]. In a pediatric retrospective study by Narla et al, LC was found to be more common than CC, which has also been reported in several adult population-based studies. Also, there was a slight female predominance of MC in this study

A. Rao · R. Gokhale (*) Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, IL, USA e-mail: [email protected]

with a ratio of 3:2, which is lower than what is described for both CC (7:1) and LC (2.4–2.7:1) in most adult reports [1]. Previous epidemiological studies have shown a marked age-dependent rise in the prevalence of MC, especially after the sixth decade of life. Additionally, there is a striking predilection of the disease for female patients [6, 7]. MC typically affects Caucasians, with patients of Indian, East Asian, and Hispanic ethnicity being significantly less affected. Jewish patients tend to be more affected than other ethnic groups [6].

Clinical Findings MC is characterized by chronic or intermittent watery diarrhea. The severity of diarrhea can range from mild to severe with dehydration and electrolyte abnormalities. Other common symptoms include vomiting, abdominal pain, fecal incontinence, anorexia, abdominal distension, weight loss, and arthralgias [8]. Unlike in adults, MC may manifest in children with atypical symptoms including constipation or alternating constipation and diarrhea [2]. Weight loss is typically mild but can be significant in some cases. MC is not associated with increased mortality, although symptoms can lead to impaired quality of life mostly due to abdominal pain, urgency, and incontinence [3]. Importantly, the symptoms of MC are nonspecific, and many patients with MC actually meet the diagnostic criteria for IBS. Therefore, histologic analysis of colonic biopsies is necessary to distinguish MC from IBS, which is a much more common disorder [9].

Associated Conditions Although the etiology of MC remains unknown, an autoimmune mechanism is a commonly proposed theory. This rationale is based on the female predominance, frequently

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 S. Guandalini, A. Dhawan (eds.), Textbook of Pediatric Gastroenterology, Hepatology and Nutrition, https://doi.org/10.1007/978-3-030-80068-0_31

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reported co-occurrence of other autoimmune diseases, possible autoimmune marker positivity, and response to steroid therapy [10, 11]. Concomitant autoimmune conditions, such as Type I diabetes mellitus, thyroid dysfunction, connective tissue disorders, and psoriasis, occur commonly in patients with MC.  However, the association between MC and celiac disease is clinically particularly important. In fact, as many as 33% of patients with celiac disease have colonic histologic changes that are consistent with MC. In a large cohort study of patients with celiac disease, 4.3% were diagnosed with MC, 72-fold greater than for patients without celiac disease. MC should therefore be considered in celiac patients who have continued or recurrent diarrhea despite a strict gluten-­ free diet [9, 10, 12]. Alternatively, celiac disease should be considered in patients with MC who have features of malabsorption, such as significant weight loss, steatorrhea, and unexplained iron deficiency anemia, as well as in those who do not respond to usual therapies. In children, additional associations with MC include collagenous gastritis, immunodeficiency, juvenile scleroderma, eosinophilic gastritis, Crohn’s disease, autism, and Aeromonas hydrophila infection [10]. There have been reports of patients with MC later developing inflammatory bowel diseases (IBDs) and of patients with IBD developing CC.  In a population-based study in Sweden by Khalili et al, there was a significant increase in the risk of incident IBD among adult patients with MC [13]. However, given the small number of cases, these reports could represent random associations of two different diseases [14]. Additionally, many of the histologic features of IBD such as Paneth cell metaplasia and crypt architecture distortion may occur in patients with MC who otherwise have no evidence of IBD [9]. According to two studies of women enrolled in the Nurses’ Health Study (NHS) and NHS II, certain lifestyle factors were associated with MC risk. Smoking has been identified as a risk factor for MC, with MC risk increasing with higher pack-years and diminishing following smoking cessation [15]. Surprisingly, unlike many other immune- and metabolic-related disorders, obesity and weight gain since early adulthood were associated with a lower risk of MC based on the results of NHS and NHS II [16].

Pathophysiology The pathophysiology of MC is not well understood. Several proposed etiologies include autoimmunity/immune dysregulation, reactions to luminal antigens, medications, or infectious insults. It may be that multiple different mechanisms result in similar clinical and histologic features that are labeled as MC [9]. Unfortunately, there is no established animal model available for MC and the current data on patho-

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genesis are mostly obtained from descriptive studies on patients [17]. Causes and associations of MC in the pediatric population are less clear, in part because of the relative paucity of cases in this age group [1].

Reactions to Luminal Antigens and Dysbiosis As noted previously, MC is strongly associated with autoimmune disorders such as celiac disease, polyarthritis, and thyroid disorders. In fact, up to 20–60% of patients with LC and 17%–40% of patients with CC have concomitant autoimmune disease [18]. LC-like changes can be induced in patients with celiac disease by a gluten enema [19]. One of the most plausible hypotheses for MC pathogenesis is on the basis of autoimmunity: MC is a chronic inflammatory process against self-antigens unleashed by an initial stimulation (infectious, chemical, or others) in a predisposed individual. Interestingly, symptoms and histologic changes of MC may resolve with diversion of the fecal stream, which also suggests abnormal immune responses to luminal antigens as well as dysbiosis playing a key role in MC [20]. According to a study by Morgan et al, dysbiosis is the defining feature of the gut microbiome in MC, similar to IBD.  However, larger-scale studies are needed to confirm this finding [21].

Genetic Predisposition In a large genetic study and meta-analysis, ancestral HLA haplotype 8.1 was identified as the major genetic risk factor for CC, and an HLA-DRB1∗04:01 susceptibility allele was identified as being protective. Multiple common susceptibility loci were significantly associated with CC risk, suggesting its polygenic nature [20]. Other studies that have investigated HLA associations have found conflicting results. One study reported an HLA pattern similar to that seen in celiac disease, while another found no HLA association. Abnormal HLA expression on colonocytes also has been described. However, given the conflicting results of these various studies, it is difficult to draw conclusions about the role of HLA haplotypes in MC.  Familial cases of MC have been reported, but the infrequency of these observations suggests that genetic predisposition is not a major factor in disease [9].

Infections Several lines of evidence suggest the possibility of an infectious cause for MC, with bacterial translocation in the gastrointestinal tract being theorized to be a mechanism. Bacterial antigens or toxins are suspected to increase inflam-

31  Microscopic Colitis

matory mediators in the colonic mucosa, leading to increased mucosal permeability, increased cytokines, degradation of the collagen matrix, and dysregulation of intestinal subepithelial myofibroblasts [18]. Also, many patients with MC have acute inflammation on biopsy and/or an acute onset of symptoms similar to gastroenteritis, and patients have been reported to respond to antibiotic therapy. Furthermore, MC has many features in common with “Brainerd diarrhea,” a chronic diarrhea thought to be infectious, which is characterized by mucosal lymphocytosis on colonic biopsies [9]. However, no causative organism has yet been identified for MC.

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response to chronic inflammation, whereas others suggest a primary abnormality of collagen synthesis. Pericryptal fibroblasts regulate the production and deposition of basement membrane collagen. In CC, they appear to be activated leading to excessive collagen production. However, another study found no evidence for increased collagen synthesis as measured by messenger RNA levels and others have not found elevated levels of fibroblast growth factor. Transforming growth factor β (TGF-β) may play a role in collagen deposition. This growth factor mediates collagen accumulation and, in one study, patients with CC had increased expression of TGF-β mRNA. Vascular endothelial growth factor (VEGF), another important mediator of fibrosis, appears to be upregulated in patients with Medication Side Effect CC. Furthermore, treatment with Budesonide reduces VEGF levels, at least in the lamina propria. An association between MC and the use of NSAIDs has been It has also been theorized that abnormal collagen deposireported in some studies but not in others and some patients tion may be a secondary process in response to ischemia or with MC improve with discontinuation of NSAIDs. Several another insult. However, this would not account for the other drugs also have been implicated as possible causes of inflammatory infiltrate that is seen. Also, the severity of MC, including proton pump inhibitors, histamine-2 receptor diarrhea is more strongly associated with the degree of blockers, selective serotonin reuptake inhibitors, beta-­ inflammation and not with the thickness of the collagen blockers, carbamazepine, and others [18]. One study assessed band [9, 22]. the strength of evidence that individual medications or classes of medications cause MC and concluded that several drugs had strong evidence. However, there are very few Laboratory Findings cases of positive drug rechallenge, and the number of cases for any specific drug is small, such that a chance association Routine laboratory work in patients with MC is typically cannot be excluded. Furthermore, some of the drugs thought normal. Some patients with MC have increased erythrocyte to cause MC may simply worsen diarrhea, bringing subclini- sedimentation rate (ESR), low albumin, or positive antinucal cases to diagnosis, but do not actually cause the colitis. clear antibodies (ANA) or other markers of autoimmunity, Regardless, if a potential case of drug-induced MC is identi- although these markers are neither sensitive nor specific for fied, discontinuation of the offending medication may lead to MC [9]. Small studies have demonstrated that fecal calprosymptom resolution [9]. tectin was slightly, albeit significantly, higher in those with MC compared to patients without organic causes of diarrhea such as IBS. However, the predictive value was low due to a Malabsorption of Biliary Acids large overlap of patients with active and quiescent disease as well as normal controls. Fecal calprotectin is not currently There is conflicting evidence on the role of biliary acids on the recommended for excluding or in monitoring MC [23]. pathogenesis of MC. Colonic infusion of biliary acids in animal models may predispose to colitis, and patients with ileal resection causing malabsorption of biliary acids may have Endoscopic and Histological Findings diarrhea. An association between atrophy of ileal villi and MC has also been described. However, small studies conducted In MC, the colonic mucosa generally appears endoscopically with bile acid breath tests have shown little or no evidence of normal, although occasionally mild findings such as edema malabsorption of biliary acids in patients with MC. Therefore, or erythema may be seen. Gross ulcerations suggest an alterthe validity of this etiology is still uncertain [9, 22]. nate diagnosis, although these can be seen in patients with MC who are taking nonsteroidal anti-inflammatory drugs (NSAIDs). Abnormal Collagen Metabolism The classic histologic finding in LC is intraepithelial lymphocytosis (IEL), defined as greater than 20 CD3+ lymphoCollagen typing studies have identified multiple potential cytes per 100 epithelial cells. The IEL density is usually abnormalities in patients with CC. Some studies suggest that more prominent in the surface than the crypt epithelium. In the abnormal collagen layer is part of a reparative process in addition, biopsies show a mixed infiltrate of acute and

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chronic inflammatory cells in the lamina propria (Fig. 31.1). CC has similar inflammatory findings on colonic biopsies, although the IEL infiltrate tends to be less prominent. Therefore, the main distinguishing feature of collagenous colitis is a subepithelial collagen layer thicker than 10 μm, compared with a normal band of approximately 5 μm or less (Fig. 31.2). In addition, biopsies often show surface epithelium damage including detachment of the epithelium in some cases. Biopsies can contain neutrophils, with active cryptitis being reported in a third of patients, although acute inflammation should not dominate the inflammatory infiltrate [9]. Although the histological features of the two subtypes may coexist simultaneously, most pathologists consider the presence of a thickened collagen band to be the major diagnostic determinant and, whenever present, indicate a diagnosis of CC [7]. Morphological abnormalities in MC can

be diffuse throughout the colon or can be restricted to one area [4]. There are reports of patients transitioning from one type of MC to the other over time or even having evidence for both types on biopsies from a single colonoscopy. This, in addition to the similar response to treatments, raises the question of whether lymphocytic and collagenous colitis are two separate entities or part of a single disorder. The current approach to these diagnoses is to consider them variants of the same condition [9]. At this time, there is no indication for histological monitoring of disease, as histological assessment of remission and relapse is not standardized and correlation between clinical disease activity and histology is weak. In a study of 283 patients, histological features persisted in postdiagnostic biopsies for up to 1 year in 77% with CC and 64% with LC [23].

Fig. 31.1  Increase of intraepithelial lymphocytes in lymphocytic colitis. H&E staining (upper panel) and CD3 immunostaining (lower panel) of the colonic tissue obtained from a lymphocytic colitis patient

are shown. Note that immunostaining of CD3 clearly demonstrates the increase of CD3-positive cells in the surface epithelial layer. (Reprinted with permission from Okamoto et al. [48])

Fig. 31.2  Subepithelial collagen band in collagenous colitis. H&E staining (upper panel) and Masson’s trichrome staining (lower panel) of the colonic tissue obtained from a collagenous colitis patient are

shown. Note that thickening of the collagenous layer is clearly observed at the subepithelial area. (Reprinted with permission from Okamoto et al. [48])

31  Microscopic Colitis

Treatment

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apy is recommended, starting at no more than 6  mg/day. Once remission is re-established, the dose is gradually Unlike other inflammatory colitides, there is no evidence that reduced to 3 mg/day, and then to 3 mg every other day. After the persistence of histological inflammation signifies long-­ 6 to 12 months of therapy, another attempt is usually made to term unfavorable outcomes such as colorectal cancer or the discontinue budesonide. If relapse occurs again, budesonide need for surgery. The goal of medical therapy is to relieve is restarted at the lowest effective dose [4, 9]. symptoms and improve quality of life while minimizing Recommendations for long-term therapy are based on studdrug-related adverse effects [3]. ies of budesonide in CC, because no long-term randomized The first step in managing patients with MC is to search trials of budesonide have been performed in LC [4]. Given for exacerbating factors, including a careful dietary history the limited systemic availability of budesonide, adverse searching for foods that might contribute to diarrhea, such as effects are minimal but may include headaches, nausea, and dairy in a patient with lactose intolerance or excessive con- dizziness. Prolonged steroid use may additionally cause sumption of artificial sweeteners that can lead to diarrhea. It osteoporosis; however, there is little scientific data on this is also important to review the patient’s medication list, being an issue in patients who are on the medication chroniincluding over-the-counter products and health food supple- cally [32]. ments, to search for drugs or other substances that might Treatment with 5-aminosalicylates such as mesalamine is cause MC or exacerbate diarrhea. In some patients, identifi- often considered as a second-line treatment for MC [3]. cation and elimination of these factors may lead to improve- However, several large uncontrolled studies have reported ment or even resolution of the diarrhea. that only a minority of patients respond to aminosalicylates, Nonspecific antidiarrheal medications such as loperamide and previous studies have shown that Mesalamine 3  g/day or diphenoxylate can be effective in patients with MC and administered for 8  weeks was not better than placebo in are often used empirically in patients with mild diarrhea. patients with CC [28] or LC [4]. Bismuth subsalicylate may additionally be effective at a dose For patients with steroid-resistant MC, treatment options of 3 tablets (262 mg each) 3 times per day [9]. One ­open-­label include bile acid–binding agents or an immunomodulator. study of 13 patients with MC showed clinical remission in Immunomodulators such as azathioprine, 6-mercaptopurine, 11/13 and histological remission in 9/13 patients with bis- or methotrexate can be helpful in steroid-dependent or muth treatment [24]. steroid-­refractory patients [33–37]. In one single-center retroFor patients with diarrhea who do not respond to antidiar- spective study of patients with severe treatment-resistant MC, rheals or those with severe symptoms, corticosteroids are azathioprine, and 6-mercaptopurine had a steroid-­ sparing typically used. Budesonide, a locally active steroid that effect and maintained improvement or remission of diarrhea undergoes extensive first-pass metabolism in the liver with over a median follow-up of 26 months, with a response rate of low systemic exposure, is the best-studied treatment for MC, 89% [34]. Cholestyramine can be effective, although many with four randomized, placebo-controlled induction studies patients do not tolerate it because of its texture. Bile-acid in collagenous colitis [25–28] and three in lymphocytic coli- binders in tablet form, such as colesevalam or colestipol, tis [4, 29, 30]. In all of these studies, budesonide was supe- might be better tolerated [9]. There have been a few reports of rior to placebo for inducing response, with response rates efficacy with the use of antitumor necrosis factor (TNF) thertypically in the 80% to 90% range. Budesonide has fewer apies such as adalimumab and infliximab in patients with side effects than prednisone, and unless cost is a significant severe steroid-refractory MC [38–40]. Several case series concern, it is commonly used when corticosteroid therapy is have additionally highlighted the efficacy of Vedolizumab in necessary. The efficacy of budesonide is due in part to its the treatment of steroid-refractory MC [41–44]. potent anti-inflammatory effect in the terminal ileum and proximal colon, [4] with its anti-inflammatory properties also extending to the left colon. Budesonide also improves Surgical Treatment Options and Prognosis bile acid malabsorption by upregulating bile acid transporter gene expression in the small intestine [31]. Despite the dem- Patients rarely require surgery for medically refractory onstrated efficacy of budesonide for induction of remission, MC.  Currently available operations include ileostomy crerelapse is common (∼70%) when it is discontinued [9]. ation with or without a proctocolectomy and ileal pouch anal The American Gastroenterological Association and the anastomosis (IPAA), as diversion of the fecal stream norEuropean Microscopic Colitis Group both recommend mally results in resolution of symptoms [45]. The reported budesonide 9 mg/day for 6–8 weeks as first-line therapy for natural history of MC varies considerably. The rate of sympactive MC. In patients who experience clinical relapse after tomatic remission ranges from 59% to 93% in patients with discontinuation of budesonide, low-dose maintenance ther- LC and 2% to 92% in those with CC.  One study reported

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spontaneous remission in 15% of patients with CC and treatment-­ induced remission in another 48% of patients. Only 22% of patients required prolonged therapy. In contrast, clinical trials have reported that only 12% to 40% of patients respond to placebo after 6 to 8 weeks, and an open-­ label study of steroid therapy reported that 90% of patients required maintenance therapy [46]. In addition, most patients have periods of clinical remission with relapses before lasting clinical remission is achieved [47].

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A. Rao and R. Gokhale 16. Liu PH, Burke KE, Ananthakrishnan AN, et al. Obesity and weight gain since early adulthood are associated with a lower risk of microscopic colitis. Clin Gastroenterol Hepatol. 2019;17(12):2523–2532. e2521. 17. Pisani LF, Tontini GE, Vecchi M, Pastorelli L.  Microscopic colitis: what do we know about pathogenesis? Inflamm Bowel Dis. 2016;22(2):450–8. 18. Park T, Cave D, Marshall C. Microscopic colitis: a review of etiology, treatment and refractory disease. World J Gastroenterol. 2015;21(29):8804–10. 19. Dobbins WO 3rd, Rubin CE. Studies of the rectal mucosa in celiac sprue. Gastroenterology. 1964;47:471–9. 20. Stahl E, Roda G, Dobbyn A, Hu J, Zhang Z, Westerlind H, Bonfiglio F, Raj T, Torres J, Chen A, Petras R, Pardi DS, Iuga AC, Levi GS, Cao W, Jain P, Rieder F, Gordon IO, Cho JH, D'Amato M, Harpaz N, Hao K, Colombel JF, Peter I. Collagenous colitis is associated with HLA signature and shares genetic risks with other immunemediated diseases. Gastroenterology. 2020;159:549–61. 21. Morgan DM, Cao Y, Miller K, et  al. Microscopic colitis is characterized by intestinal dysbiosis. Clin Gastroenterol Hepatol. 2020;18(4):984–6. 22. Ianiro G, Cammarota G, Valerio L, et al. Microscopic colitis. World J Gastroenterol. 2012;18(43):6206–15. 23. Miehlke S, Guagnozzi D, Zabana Y, et al. European guidelines on microscopic colitis: United European Gastroenterology (UEG) and European Microscopic Colitis Group (EMCG) statements and recommendations. United European Gastroenterol J. 2020;9:13–37. 2050640620951905 24. Fine KD, Lee EL.  Efficacy of open-label bismuth subsalicy late for the treatment of microscopic colitis. Gastroenterology. 1998;114:29–36. 25. Bonderup OK, Hansen JB, Birket-Smith L, et  al. Budesonide treatment of collagenous colitis: a randomized, double-blind, placebo controlled trial with morphometric analysis. Gut. 2003;52:248–51. 26. Miehlke S, Heymer P, Bethke B, Bastlein E, Meier E, Bartram HP, Wilhelms G, Lehn N, Dorta G, Delarive J, Tromm A, Bayerdorffer E, Stolte M.  Budesonide treatment for collagenous colitis: a randomized, double-blind, placebo- controlled, multicenter trial. Gastroenterology. 2002;123:978–84. 27. Baert F, Schmit A, D'Haens G, Dedeurwaerdere F, Louis E, Cabooter M, De Vos M, Fontaine F, Naegels S, Schurmans P, Stals H, Geboes K, Rutgeerts P.  Budesonide in collagenous colitis: a double blind placebo- controlled trial with histologic follow- up. Gastroenterology. 2002;122:20–5. 28. Miehlke S, Madisch A, Kupcinskas L, Petrauskas D, Bohm G, Marks HJ, Neumeyer M, Nathan T, Fernando-Banares F, Greinwald R, Mohrbacher R, Vieth M, Bonderup OK.  Budesonide is more effective than mesalamine or placebo in short- term treatment of collagenous colitis. Gastroenterology. 2014;146:1222–30. 29. Miehlke S, Madisch A, Karimi D, et al. Budesonide is effective in treating lymphocytic colitis: a randomized double-blind placebo-­ controlled study. Gastroenterology. 2009;136(7):2092–100. 30. Pardi DS, Loftus EV, Tremaine WJ, et al. A randomized, double-­ blind, placebo-controlled trial of budesonide for the treatment of active lymphocytic colitis. Gastroenterology. 2009;136:A519. 31. Bajor A, Kilander A, Galman C, et  al. Budesonide treatment is associated with increased bile acid absorption in collagenous colitis. Aliment Pharmacol Ther. 2006;24:1643–9. 32. Tangri V, Chande N. Use of budesonide in the treatment of microscopic colitis. Saudi J Gastroenterol. 2010;16(3):236–8. 33. Deslandres C, Moussavou-Kombilia JB, Russo P, Seidman EG.  Steroid-resistant lymphocytic enterocolitis and bronchitis responsive to 6-mercaptopurine in an adolescent. J Pediatr Gastroenterol Nutr. 1997;25:341–6.

31  Microscopic Colitis 34. Pardi DS, Loftus EV, Tremaine WJ, Sandborn WJ.  Treatment of refractory microscopic colitis with azathioprine and 6-­mercaptopurine. Gastroenterology. 2001;120:1483–4. 35. Vennamaneni SR, Bonner GF.  Use of azathioprine or 6-­mercaptopurine for treatment of steroid-dependent lymphocytic and collagenous colitis. Am J Gastroenterol. 2001;96:2798–9. 36. Pardi DS, Ramnath VR, Loftus EV, Tremaine WJ, Sandborn WJ.  Lymphocytic colitis: clinical features, treatment, and outcomes. Am J Gastroenterol. 2002;97:2829–33. 37. Riddell J, Hillman L, Chiragakis L, Clarke A.  Collagenous colitis: oral low-dose methotrexate for patients with difficult symptoms: long-term outcomes. J Gastroenterol Hepatol. 2007;22:1589–93. 38. Esteve M, Mahadevan U, Sainz E, Rodriguez E, Salas A, Fernández-Bañares F. Efficacy of anti-TNF therapies in refractory severe microscopic colitis. J Crohns Colitis. 2011;5:612–8. 39. Münch A, Ignatova S, Ström M.  Adalimumab in budesonide and methotrexate refractory collagenous colitis. Scand J Gastroenterol. 2012;47:59–63. 40. Pola S, Fahmy M, Evans E, Tipps A, Sandborn WJ. Successful use of infliximab in the treatment of corticosteroid dependent collagenous colitis. Am J Gastroenterol. 2013;108:857–8.

429 41. Casper M, Zimmer V, Hubschen U, et al. Vedolizumab for refractory collagenous colitis: another piece of the puzzle. Dig Liver Dis. 2018;50:1099–100. 42. Riviere P, Munch A, Michetti P, et  al. Vedolizumab in refractory microscopic colitis: an international case series. J Crohns Colitis. 2019;13:337–40. 43. Jennings JJ, Charbaty A.  Vedolizumab-induced remission in 3 patients with refractory microscopic colitis: a tertiary care center case series. Inflamm Bowel Dis. 2019;25:e97. 44. Wenzel AA, Strople J, Melin-Aldana H, Brown JB. Vedolizumab for the induction of remission in treatment-refractory microscopic colitis in a pediatric patient. J Pediatr Gastroenterol Nutr. 2020;71(1):e47–8. 45. Datta I, Brar SS, Andrews CN, et al. Microscopic colitis: a review for the surgical endoscopist. Can J Surg. 2009;52(5):E167–72. 46. Pardi DS, Kelly CP.  Microscopic colitis. Gastroenterology. 2011;140:1155–65. 47. Miehlke S, Verhaegh B, Tontini GE, Madisch A, Langner C, Münch A. Microscopic colitis: pathophysiology and clinical management. Lancet Gastroenterol Hepatol. 2019;4(4):305–14. 48. Okamoto R, Negi M, Tomii S, Eishi Y, Watanabe M.  Diagnosis and treatment of microscopic colitis. Clin J Gastroenterol. 2016;9(4):169–74.

Vasculitides Including IgA Vasculitis (Henoch–Schönlein Purpura)

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Karunesh Kumar, Jutta Köglmeier, and Keith J. Lindley

Introduction The vasculitides are a group of inflammatory disorders of the walls of blood vessels (usually the arteries). They are relatively rare in childhood with the exception of Henoch– Schӧnlein purpura (HSP) and Kawasaki disease (KD). Vasculitis might be primary or secondary to a number of causes including infections, drugs, hypersensitivity reactions, and connective-tissue disorders. The consequences of arterial inflammation include tissue ischemia and necrosis, giving rise to many of the gastrointestinal (GI) manifestations of vascular inflammation such as pain and bleeding. Vasculitis is usually classified based on the size of blood vessel(s) involved in the inflammatory process (Table 32.1 and Fig. 32.1). Not all of these are seen in the pediatric age group. The vasculitides associated with GI manifestations in childhood are listed in Table 32.2. These manifestations include abdominal pain (potentially due to bowel ischemia or bowel wall thickening and subacute obstruction), GI blood loss (due to GI ulceration, which can be aphthoid, undermined, or fissure like), diarrhea which is often bloody (due to nonspecific inflammation of the ileum or colon), and an acute abdomen as a consequence of a perforation K. Kumar Division of Neurogastroenterology and Motility, Department of Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK Division of Intestinal Rehabilitation and Nutrition, Department of Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK J. Köglmeier Division of Intestinal Rehabilitation and Nutrition, Department of Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK K. J. Lindley (*) Division of Neurogastroenterology and Motility, Department of Gastroenterology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK e-mail: [email protected]

Table 32.1  Classification of the vasculitides Large-vessel vasculitis (LVV)  Takayasu’s arteritis  Giant cell arteritis (GCA) Medium-vessel vasculitis (MVV)  Polyarteritis nodosa (PAN)  Kawasaki disease (KD) Small-vessel vasculitis (SVV)  (i) Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)    Eosinophilic granulomatosis with polyangiitis (Churg–Strauss)    Granulomatosis with polyangiitis (Wegener’s granulomatosis)    Microscopic polyangiitis  (ii) immune-complex SVV    IgA vasculitis (Henloch–Schӧnlein; IgAV)    Cryoglobulinemic vasculitis    Hypocomplementemic urticarial vasculitis    Antiglomerular basement membrane disease Variable-vessel vasculitis (VVV)  Behcet’s disease  Cogan’s syndrome Single-organ vasculitis (SOV) Vasculitis associated with systemic disease  Lupus  Rheumatoid Sarcoid Secondary vasculitis  Hepatitis B/hepatitis C  Drugs  Others Reprinted with permission John Wiley and Sons/Arthritis & Rheumatism, from Jennette et al. [49] IgA immunoglobulin A

[1]. Vasculitis subtypes have tendency to involve specific areas of the gastrointestinal tract: Kawasaki Disease (KD) along with Granulomatosis with polyangiitis (GPA) and Eosinophilic granulomatosis with polyangiitis (EGPA) commonly involve the esophagus and oral mucosae; SLEassociated vasculitis, polyarteritis nodosa (PAN), IgA vasculitis (IgAV), EGPA, and GPA may be implicated in

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 S. Guandalini, A. Dhawan (eds.), Textbook of Pediatric Gastroenterology, Hepatology and Nutrition, https://doi.org/10.1007/978-3-030-80068-0_32

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K. Kumar et al. Immune Complex Small Vessel Vasculitis Cryoglobulinemic Vasculitis IgA Vasculitis (Henoch-Schönlein) Hypocomplementemic Urticarial Vasculitis (Anti-C1q Vasculitis) Medium Vessel Vasculitis Polyarteritis Nodosa Kawasaki Disease

Anti-GBM Disease

ANCA-Associated Small Vessel Vasculitis

Large Vessel Vasculitis Takayasu Arteritis Giant Cell Arteritis

Microscopic Polyangiitis Granulomatosis with Polyangiitis (Wegener’s) Eosinophilic Geanulomatosis with Polyangiitis (Churg-Strauss)

Fig. 32.1  Distribution of vessel involvement by large-vessel vasculitis, medium-vessel vasculitis, and small-vessel vasculitis. Note that there is substantial overlap with respect to arterial involvement, and an important concept is that all three major categories of vasculitis can affect any size artery. Large-vessel vasculitis affects large arteries more often than other vasculitides. Medium-vessel vasculitis predominantly affects medium arteries. Small-vessel vasculitis predominantly affects small vessels, but medium arteries and veins may be affected, although

immune-complex small-vessel vasculitis rarely affects arteries. The diagram depicts (from left to right) aorta, large artery, medium artery, small artery/arteriole, capillary, venule, and vein. Anti-GBM—antiglomerular basement membrane; ANCA—antineutrophil cytoplasmic antibody. ANCA Antineutrophil cytoplasmic antibody. (Reprinted with permission John Wiley and Sons/Arthritis & Rheumatism, from Jennette et al. [49])

tion of immunoglobulin A1 (IgA1) immune complexes in vascular tissue, principally capillaries and postcapillary venules. The disease is predominantly seen in children aged Henoch-Schӧnlein purpura 3–10 years with the peak incidence aged 4–6 years. The clinKawasaki disease ical phenotype seems to change with age as older children Polyarteritis nodosa (PAN) have more joint symptoms (as in adult-onset IgAV) and ANCA-associated vasculitis (AAV) Behcet’s disease younger children more abdominal symptoms. IgAV is more Systemic disease (lupus and rheumatoid) frequent in the autumn/winter months and will commonly follow an infection [5]. Proposed infective triggers include stomach vasculitis; PAN, Anti-neutrophil cytoplasmic anti- group A beta-hemolytic streptococcus, Parvovirus B19, body–associated vasculitis (AAV), IgA vasculitis (IgAV), Staphylococcus aureus, and Coxsackie virus to name a few. SLE-associated vasculitis, Takayasu’s arteritis (TA), and It has been suggested that the pathogenesis involves the recGiant cell arteritis (GCA) have all been associated with ognition of galactose-deficient IgA1 by antiglycan antibodintestinal and mesenteric ischemia [2]. ies and the deposition of these immune complexes in small vessels. A recent large series suggests that 100% of patients have IgA Vasculitis (Henoch–Schönlein Purpura) skin involvement with 60–70% having “palpable purpura” of the lower limbs and buttocks, 66% have arthritis, which is IgA vasculitis (IgAV), formerly known as HSP, is an immune-­ usually symmetrical affecting the knees, ankles, and feet, and complex, nonthrombocytopenic, small-vessel vasculitis, 54% have GI involvement usually with lower GI bleeding or which typically presents acutely [3]. It is the most common abdominal pain but also intussusception, ileal perforation, vasculitis seen in childhood with an estimated annual inci- and pancreatitis [6]. Renal manifestations are seen in 30% dence of 3–27/100,000 children in the UK [4]. The disease is and include nephritic or nephrotic syndromes, which can lead characterized by a leukocytoclastic vasculitis with deposi- to chronic renal failure in a minority of cases. Rash in IgAV is

Table 32.2  Vasculitides associated with gastrointestinal manifestations in childhood

32  Vasculitides Including IgA Vasculitis (Henoch–Schönlein Purpura)

characteristic: it starts as macules, then these develop into petechiae, raised purpura, or larger ecchymoses in a symmetrical, gravity-dependent manner or on pressure points. The rash may last for up to a week and recur for few months. Diagnostic criteria include the presence of purpura or petechiae with lower-limb predominance with one of the following: diffuse abdominal pain, acute arthritis or arthralgia, hematuria or proteinuria and any biopsy showing predominant IgA deposition [7]. Described GI complications of HSP include intussusception, bowel ischemia and infarction, intestinal perforation, late stricturing, acute appendicitis, GI hemorrhage (occult and massive), pancreatitis, and gallbladder hydrops. One large series of patients reported abdominal pain in 58% of children and positive stool occult blood (SOB) in 18% [8]. Frank lower-GI bleeding was present in 3%. Plain abdominal radiology frequently showed dilated thickened bowel loops when the SOB was strongly positive, which was also visualized on ultrasound examination. Intussusception, perhaps the most serious GI complication of HSP, was rare (0.5%), although in other series a prevalence of up to 5% is described. The presence of thickened bowel wall on ultrasound might act as a prognostic marker for duration of hospitalization for HSP [9]. Endoscopic findings vary and can include the presence of circumscribed vascular lesions (rather similar to the palpable purpura seen on the skin) and segmental ischemic change (Fig. 32.2) [10]. Recently, it has been proposed that fecal calprotectin might be an early predictor of abdominal type of IgAV as well as a marker of disease severity [11].

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It is usual for children to make a complete recovery from HSP with only supportive treatment with the exception of HSP-associated nephritis, which is the cause of end-stage renal failure in up to 2% of children. Recurrence occurs in around 25% of patients, and they may be more common in older children. Most gastrointestinal manifestations are self-­limited, but severe abdominal pain, GI hemorrhage, and/or intussusception will require intervention. Corticosteroids as first line have been used: usually oral at 1–2 mg/kg/day for 2 weeks, and then weaned or pulsed IV methylprednisolone 10–30 mg/kg with a maximum of 1 g/ day for three consecutive days may be considered [12]. The use of steroids does not seem to protect against the development of nephritis.

Kawasaki Disease KD is the second commonest childhood vasculitis, which affects about 8/100,000 children younger than 5 years of age annually in the UK with twice as many cases occurring in the United States (25/100,000) and approximately 20 times the incidence in Japan (265/100,000). In common with IgAV, KD is more prevalent in the winter months [13]. The disease affects predominantly medium- and small-sized arteries and is normally self-limiting. However, coronary artery aneurysms are present in 25% of untreated patients and can lead to myocardial infarction or late coronary artery stenosis. In addition to involvement of the coronary arteries, systemic arterial injury can occur.

Fig. 32.2  Cutaneous purpura and small bowel hyperemia with ulceration in a young adult with HSP. (Reprinted from Hsu et al. [10], with permission from Elsevier)

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The seasonality and clustering of KD support an infectious trigger, although to date no single organism has been identified. The much higher prevalence of disease in Japanese and Korean children supports the notion that genetic predisposition is also an important factor and genome-wide association studies have identified a number of genes associated with disease susceptibility and disease phenotype [13]. Diagnosis of classic KD is clinical, comprising the presence of unremitting fever for 5 days or more plus 4/5 or more of the following features: conjunctivitis; lymphadenopathy; polymorphous rash; changes in lips, tongue or oral mucosa, and involvement of extremities including periungual desquamation (see Table 32.3). A careful history may reveal that ≥1 principal clinical features were present during the illness but resolved by the time of presentation. Patients lacking full clinical features of classic KD may be labeled incomplete or atypical KD and if coronary artery abnormalities are detected, the diagnosis of KD is considered confirmed in most cases [13]. Apart from disease defining coronary artery involvement, KD is characterized by inflammation in medium-sized arteries in other organs leading to varied systemic manifestations including hepatitis, pneumonitis, aseptic meningitis, myocarditis, pericarditis, pyuria, pancreatitis, and lymphadenopathy [13].Uncommon features of the disease include gallbladder hydrops, GI ischemia, mononeuritis, nephritis, seizures, and ataxia. Overall, abdominal symptoms, particularly diarrhea, which can be bloody or nonbloody, are a frequent early feature of KD. Abdominal pain is less frequent [14]. Vasculitic appendicitis, hemorrhagic duodenitis, paralytic ileus, and pseudo-obstruction are also described [15, 16]. Bowel wall edema may be evident as segmental thickening of the bowel wall as may gallbladder hydrops [17]. Inflammatory markers (erythrocyte sedimentation rate, ESR, and C-reactive protein, CRP) are inevitably elevated as is the peripheral blood white blood cell count. Thrombocytosis, which can be very marked, usually occurs in the second week of the disease. Table 32.3  Diagnostic criteria for Kawasaki disease Criterion Fever 1. Conjunctivitis 2. Lymphadenopathy 3. Rash 4. Changes in lips/mucus membranes 5. Changes in extremities

Description Duration of 5 days or more plus 4/5 of the following Bilateral nonpurulent with limbic sparing Cervical, often > 1.5 cm Polymorphous with no vesicles or crusts Red cracked lips, “strawberry” tongue, erythema of oropharynx Initially: Erythema and edema of palms and soles Later: Periungual desquamation

Early treatment of KD with aspirin and intravenous immunoglobulin (IVIG) reduces the occurrence of coronary artery aneurysms. A single infusion of 2 g/kg IVIG (within 10  days) and an anti-inflammatory dose of aspirin (30– 50 mg/kg/day in Europe/Japan and 80–100 mg/kg/day in the United States) will reduce the likelihood of developing coronary artery aneurysms in the majority of patients, although approximately 20% of children are IVIG resistant. The dose of aspirin should be reduced to an antiplatelet dose during the thrombocytosis phase of the illness. Patients who continue to have fevers and an ongoing systemic inflammatory response 48 h post IVIG are likely to be IVIG nonresponders and can be treated with intravenous methyl prednisolone for 5 days followed by 2 weeks of oral prednisolone or perhaps anti-tumor necrosis factor (TNF) antibodies [13].

Systemic Polyarteritis Nodosa Polyarteritis nodosa (PAN) is a necrotizing arteritis of medium and/or small arteries, which has been subclassified into systemic PAN and cutaneous polyarteritis. While systemic PAN is generally severe and cutaneous polyarteritis relatively benign, the cutaneous form can go on to develop features of multiorgan involvement. The presenting features of PAN can be very nonspecific and are known to affect a number of systems notably the skin, musculoskeletal system, kidneys, and GI tract. A recent pediatric series documents the most common presenting features of PAN as fever (87%), myalgia (83%), arthralgia/arthritis (75%), weight loss of > 5% of body weight (64%), fatigue (62%), livedo reticularis (49%), and abdominal pain (41%). In this series, 59% had GI symptoms comprising abdominal pain (49%), blood in the stools (10%), and bowel ischemia/perforation (8%) [18]. The diagnosis may be delayed as the symptoms are so nonspecific. GI bleeding can be massive, especially when it arises from a Dieulafoy lesion, a submucosal vascular abnormality with a prominent tortuous artery with/without aneurysm formation [19, 20]. Ulcers, which are circumscribed and well demarcated, may also be evident (Fig. 32.3a, b). Following remission induction in PAN, the onset of GI symptoms is a major clinical predictor of clinical relapse. Other symptoms seen in PAN less frequently include cardiac, respiratory, and neurological manifestations. GI symptoms are generally attributable to ischemia, which can lead to infarction, perforation, or stricture [21] [22]. The systemic vasculitides can also be associated with an ischemic colitis or a nonspecific colitis that can mimic inflammatory bowel disease [23]. The diagnosis of PAN is usually made through a combination of clinical, histopathological, and arteriographic features and relies on one mandatory criterion plus one of five secondary criteria. Mandatory criteria comprise fibrinoid

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a

Fig. 32.3 (a) Punched-out ulcers with well-demarcated edges in the colon in PAN. Ulcers are typically shallow and irregular often with surrounding erythema. (Reprinted from Vavricka SR et  al. Clin

necrosis of the walls of medium-sized arteries from an affected organ together with an inflammatory response in the adjacent vessel wall, which is characteristic of PAN or angiographic abnormalities (aneurysm, stenosis/segmental narrowing, or occlusion/pruning) of medium or small arteries. Secondary criteria include (i) characteristic skin involvement, (ii) myalgia or muscle tenderness, (iii) hypertension, (iv) peripheral neuropathy/mononeuritis, and (v) renal involvement. Renal, hepatic, and mesenteric arteriography is commonly used as a diagnostic tool in children which overall has a sensitivity of 94% for diagnosing PAN (Fig. 32.4). The microaneurysms that are the hallmark lesions of PAN can be frequently detected in hepatic, splenic, and mesenteric arteries as well as the renal arteries. There are many differential diagnoses of PAN in children; it is particularly important to exclude monogenic vasculitides such as deficiency of adenosine deaminase type 2 and other autoinflammatory syndromes [24]. ANCA is typically negative in PAN. A detailed discussion of treatment is beyond the scope of this chapter. Historically, this has involved remission induction with pulsed intravenous methyl prednisolone often with cyclophosphamide and antiplatelet agents followed by maintenance therapy with low-dose steroids and a steroid-sparing agent (usually azathioprine). Biologics may be considered in patients who fail to respond to standard therapy or where concern exists regarding cumulative cyclophosphamide dose; either TNF-alpha or IL-6 blockade or B cell-depleting agents may be considered [24].

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b

Gastroenterol Hepatol 2007; 5(11): A22, with permission from Elsevier). (b) Bleeding Dieulafoy lesion in the stomach in a case of PAN. (Reprinted from Maeda et al. [20], with permission from Elsevier)

Fig. 32.4  Inferior mesenteric artery angiogram showing vessel caliber changes and aneurysms characteristic of polyarteritis nodosa

Behçet Disease Behçet disease (BD) is rare in childhood (2/100,000  in Europe). Behçet described a triad of aphthous stomatitis, genital ulceration, and uveitis. It is a variable-vessel vasculitis, which can affect veins and arteries of any size. Three of six items are required to classify a patient as having pediatric

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BD: recurrent oral aphthosis (three attacks/year), genital ulceration or aphthosis, skin involvement (necrotic folliculitis, acneiform lesions, erythema nodosum), ocular involvement (anterior uveitis, posterior uveitis, retinal vasculitis), neurological signs (with the exception of isolated headaches), vascular signs (venous thrombosis, arterial thrombosis, arterial aneurysm) [25]. BD is extremely heterogeneous, affecting multiple organ systems with distinct geographical variations in symptoms. For example, GI manifestations are more prevalent in the Far East, while vascular manifestations are seen in the eastern Mediterranean. GI symptoms may be seen in up to 40%, and they are usually isolated abdominal pain or discomfort. Rare features are digestive aphthae, bleeding, and perforation [25]. Vascular manifestations include venous thromboembolism, arterial stenosis, aneurysms, and occlusions. Neuro-­ Behçets can present with headache, papilledema, central venous sinus thrombosis, and/or brain parenchymal disease causing seizures and focal neurological abnormalities [26].

ANCA-Associated Vasculitis (AAVs) ANCA-associated vasculitides (AAVs) are multisystemic diseases and include granulomatosis with polyangiitis (GPA, earlier Wegener’s granulomatosis), eosinophilic granulomatosis with polyangiitis (EGPA, earlier Churg-Strauss syndrome), and microscopic polyangitiis (MPA). Histopathologically, AAV is characterized by necrotizing changes (granulomatous lesions in GPA and eosinophil-rich granulomatous inflammation in EGPA) in small blood vessels (i.e., capillaries, venules, and arterioles), with few or no immune deposits, and associated with the presence of circulating ANCA autoantibodies that are usually directed against myeloperoxidase (MPO) or proteinase 3 (PR3) [27]. Tissue biopsies are crucial for diagnosis though may not be always necessary. Renal biopsy in case of renal involvement remains the gold standard for diagnosis. Treatment remains based on adult approach comprising remission-induction and remission-­maintenance phases. Combination of glucocorticoids and either cyclophosphamide (CYC) or rituximab (RTX) is recommended in induction. Maintenance is recommended with Azathioprine (AZA) or MTX in combination with glucocorticoid. Leflunomide (LEF) or MMF may also be considered as an alternative agent.

 ranulomatosis with Polyangiitis (GPA)— G Formerly Wegener’s Granulomatosis GPA is one of the antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides (AAV) and is a necrotizing granulomatous vasculitis of small blood vessels [27–29].

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The main features of the disease are due to a widespread small-vessel vasculitis with clinical manifestations of a necrotizing glomerulonephritis and respiratory tract granulomata dominating the clinical picture. GI involvement has been described in 6–36% of pediatric patients and may present with abdominal pain; mucosal ulceration of the esophagus, small or large bowel; GI perforation and rarely colitis and catastrophic GI hemorrhage or infarction of the gall bladder, intestine and colon. cANCA positivity is seen in up to 70% of these children.

Eosinophilic Granulomatosis with Polyangiitis (EGPA) This is another of the AAV, which is extremely rare. ANCA (usually pANCA) is positive in about 30% of cases. Histopathological features are those of a small-vessel (arteries and veins) granulomatous vasculitis with an eosinophil-­ rich inflammatory infiltrate. In addition, there is an eosinophil-rich granulomatous infiltrate of the respiratory tract and usually a history of asthma, allergic rhinitis, and peripheral blood eosinophilia. GI-tract involvement is seen in 40–60% of patients causing symptoms of pain (ischemic), ulceration, perforation, and bleeding [27–29]. Independently of vascular involvement, eosinophil-rich inflammation of the GI mucosa can result in symptoms such as diarrhea and perhaps pain. Forty percent of children have gastroenterological symptoms at presentation [30]. The pediatric disease is usually steroid responsive but subject to relapse.

Microscopic Polyangiitis (MPA) Microscopic polyangiitis is a necrotizing vasculitis of small vessels in which up to 65% of patients are perinuclear ANCA (pANCA) positive. It is uncommon in childhood [31]. The classical presentation is with rapidly progressive glomerulonephritis and alveolar hemorrhage [32]. In common with the other AAV, pain is a dominant GI symptom, although GI blood loss, cholecystitis, ischemic colitis, and bowel perforation are described. GI manifestations can be seen in 11–58% of pediatric patients [27–29].

Single-Organ Vasculitis (SOV) Systemic vasculitis occurs when vascular inflammation involves multiple territories or organs. In single-organ vasculitis (SOV), the inflammation is restricted to a single organ or part of that organ. By definition, there has to be a

32  Vasculitides Including IgA Vasculitis (Henoch–Schönlein Purpura)

lack of spread outside the single organ for at least 6 months. SOV is known to affect the GI tract and may affect small-, medium-, or large-sized arteries. The condition is not well described in children and is more commonly part of PAN (e.g., appendiceal vasculitis). Patients with gastrointestinal SOV may present with an acute abdomen, and diagnosis may be made based on histological findings after the surgery.

Takayasu Arteritis (TA) Takayasu arteritis (TA) is a vasculitis predominantly affecting large vessels (mainly the aorta and its main branches). It is most commonly seen in Asia and rarely encountered in the pediatric age group. Diagnosis is based on angiographic abnormalities showing aneurysm/dilatation (mandatory criterion) plus one of the five following criteria: pulse deficit or claudication, four limbs BP discrepancy, bruits, hypertension, and acute phase reactant [7]. Girls are more often affected than boys. Patients frequently complain about headache, abdominal pain, limb claudication, myalgia, arthralgia, and fever. Weight loss is said to occur in about 10% of affected individuals. GI manifestations are rare and occur mainly as ischemic changes due to large involvement in small or large intestine, spleen, or, more rarely, liver. Cases of TA coexisting with IBD have been reported in adult series. a

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 ystemic Lupus Erythematosus–Associated S Vasculitis Systemic lupus erythematosus (SLE) is a systemic autoimmune disease. The presence of anti–double-stranded DNA (anti-dsDNA) antibodies in the blood is a highly specific test for SLE being present in 70–80% with titers of antibody tending to mirror disease activity. Other pathogenic autoantibodies in SLE include antibodies to nucleosomes, Ro (a ribonucleoprotein component), La (an RNA-binding protein), C1q (complement), phospholipids, and the N-methyl-­ d-aspartic acid (NMDA) receptor. Many of these antigens are expressed on the cell surface during the process of apoptosis, and it has been hypothesized that abnormalities of the apoptotic pathway, which are ubiquitous in SLE, are important in the genesis of pathological autoantibodies [33]. Systemic lupus can affect the GI tract causing chronic, nonspecific mucosal inflammation, mucosal ulceration, or vasculitis resulting in mesenteric/GI ischemia (Fig.  32.5a, b). The three possible manifestations of lupus enteritis include lupus mesenteric vasculitis, intestinal pseudo-­ obstruction, and/or protein losing enteropathy [34]. Gastrointestinal manifestations directly attributable to SLE affect one-fourth of adult patients and vasculitis (usually cutaneous) can be seen in similar number of patients. Commonly, GI symptoms may be because of infection or drug side effects. GIS manifestations has been observed in up to 27.5% children in some series. b

Fig. 32.5 (a) Mucosal edema in association with nonspecific inflammation in SLE. (b) Colonic mucosal ulceration in SLE. (Reprinted from Lee CK et al. Gastrointest Endosc 2010;72(3): 618–9, with permission from Elsevier)

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Abdominal pain is present in 8–40% of published series of individuals with SLE; in children, it is most commonly (32%) due to lupus-associated mesenteric vasculitis [35]. Other causes of pain include pancreatitis (10%), appendicitis (7.5%), and cholecystitis (6%). Patients with vasculitis usually have high SLA disease activity scores (SLEDAI) but do not commonly have substantially elevated inflammatory markers. The clinical presentation of lupus-associated mesenteric vasculitis commonly mirrors an acute surgical abdomen. It is suggested that individuals with SLE, high SLEDAI, and an “acute abdomen” undergo imaging to look for evidence of vascular compromise before any surgical intervention (Fig. 32.6).

Juvenile Dermatomyositis (JDM) In juvenile dermatomyositis (JDM), vasculitis affects striated muscle, the skin, subcutaneous tissues, and the GI tract. Children develop weakness of the muscles of the neck, shoulders, and hips, leading to difficulties with swallowing, getting up from sitting, or climbing stairs. Gastrointestinal involvement occurs in 22% to 37% of JDM patients. GI manifestations include dysmotility (dysphagia), vasculitis with

associated malabsorption, and other more severe features of GI vasculopathy. Vasculopathy may present with abdominal pain, rectal bleeding, intestinal ischemia, pneumatosis, or life-threatening perforation [36]. GI bleeding and perforation can be catastrophic and are a major cause of death [37].

Rheumatoid-Associated Vasculitis Rheumatoid arthritis (RA) is another systemic inflammatory disorder with articular and extra-articular manifestations. Rheumatoid vasculitis (RV) is a systemic necrotizing vasculitis affecting small- and medium-sized arteries, which is clinically extremely heterogenous and can affect skin, nerves, and abdominal viscera. RV is usually seen in long-­ standing disease and when there are other extra-articular manifestations, and these patients are always rheumatoid factor positive. It is usual to find raised inflammatory markers (ESR and CRP), polyclonal hypergammaglobulinemia, and often hypocomplementemia. GI involvement is rare in children, but, in common with other vasculitides, can result in ischemia, perforation, and hemorrhage [38].

 ediatric Inflammatory Multisystem P Syndrome: Temporally Associated with SARS-CoV 2 (PIMS-TS) In the spring of 2020, the first wave of the COVID 19 pandemic, caused by the SARS-CoV 2 coronavirus, caused over a million deaths worldwide within 9  months. Children, in general, are not severely affected by SARS-CoV 2 infection but rarely children go on to develop a multisystem inflammatory response developing a syndrome, which shares features with Kawasaki disease and toxic shock syndrome. While not usually the presenting complaint abdominal symptoms / signs are prevalent within this group of children and can be a source of diagnostic confusion. The RCPCH (UK) has adopted the following definition in its guidance for health professionals [39]:

Fig. 32.6  CT scan of patient with PIMS-TS demonstrating mural thickening of the right colon and ascites

1. A child presenting with persistent fever, inflammation (neutrophilia, elevated CRP and lymphopenia), and evidence of single or multiorgan dysfunction (shock, cardiac, respiratory, renal, gastrointestinal, or neurological disorder) with additional features (Table 32.4). This may include children fulfilling full or partial criteria for Kawasaki disease. 2. Exclusion of any other microbial cause, including bacterial sepsis, staphylococcal or streptococcal shock syndromes, infections associated with myocarditis such as enterovirus. 3. SARS-CoV-2 PCR testing may be positive or negative.

32  Vasculitides Including IgA Vasculitis (Henoch–Schönlein Purpura) Table 32.4  Clinical and laboratory features of PIMS-TS Clinical: All:  Persistent fever >38.5 °C Most:  Oxygen requirement  Hypotension Some:  Abdominal pain  Confusion  Conjunctivitis  Cough  Diarrhea  Headache  Lymphadenopathy  Mucous membrane changes  Neck swelling  Rash  Respiratory symptoms  Sore throat  Swollen hands and feet  Syncope  Vomiting Laboratory findings: All:  Abnormal fibrinogen  Absence of potential causative organisms (other than SARS-CoV-2)  High CRP  High D-dimers  High ferritin  Hypoalbuminemia  Lymphopenia  Neutrophilia in most (normal in some) Some:  Acute kidney injury  Anemia  Coagulopathy  High IL-10  High IL-6  Proteinuria  Raised CK  Raised LDH  Raised triglycerides  Raised troponin  Thrombocytopenia  Transaminitis Imaging: Echo and ECG—Myocarditis, valvulitis, pericardial effusion, coronary artery dilatation Abdominal US—Colitis, ileitis, lymphadenopathy, ascites, hepatosplenomegaly Adapted from RCPCH Guidance (Ref. [39])

Other definitions have been adopted in other countries / continents although all are broadly similar. For example, the Centers for Disease Control and Prevention (CDC) in the United States has termed the condition as multisystem inflammatory syndrome in children (MIS-C) [40]. The reader

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is referred elsewhere for further information regarding this rapidly evolving field [41]. Notably KD and PIMS-TS have quite a different epidemiology. For example, KD is seen most commonly in children aged 60 and the identification of 2 CF-causing mutations (defined by CFTR2) with symptoms of CF, or positive family history is consistent with a diagnosis of CF. A monosymptomatic clinical entity (CBAVD/pancreatitis/bronchiectasis) associated with CFTR dysfunction that does not fulfill the diagnostic criteria for CF is defined as CFTR-related disorder. Individuals who had a positive newborn screening but do not fulfill the diagnostic criteria of CF are defined: CFTR-­ related metabolic syndrome (CRMS) or CF screen positive, inconclusive diagnosis (CFSPID). They should receive a clinical evaluation by CF specialist in order to identify any possible clinical symptoms [45]. With newborn screening, diagnosis is often made before obvious clinical manifestations such as failure to thrive and chronic cough show up. Screening consists of a combination of immunoreactive trypsinogen results and limited DNA testing on blood spots, which are then coupled with confirmatory sweat analysis, and it is ≈95% sensitive [50]. Sweat test, which is considered the gold standard in the diagnosis of CF, is based on the determination of Na + and Cl- concentration in sweat collected after local stimulation with pilocarpine. Levels 60  mmol/L are considered pathological. Between 35 mmol/L and 60 mmol/L, results are considered borderline; in this scenario, sweat test must be repeated with an extensive CFTR gene mutation analysis, and this patient should receive a clinical evaluation by CF specialist. A positive sweat test alone does not allow to make a diagnosis and, on the other hand, it does not allow to exclude CF if negative: some mutations are associated with a negative sweat test [43, 46, 47]. Generally, sweat tests are not performed in subjects younger than 2 weeks of age and that weigh less than 3  kg. The test is contraindicated in babies younger than 48 hours of age, because high concentrations of sweat electrolytes can be found on the first day of life. If the patient is acutely unwell, dehydrated, edematous, or receiving corticosteroids, the test should be delayed [36]. Another important diagnostic test is the search for genetic mutations of the CFTR gene. Several commercial laboratories test for 30–96 of the most common CFTR mutations. These tests identify ≥90% of individuals who carry 2 CF mutations. These tests are used to confirm but not to exclude the dubious diagnosis, because a lot of mutations have not yet been identified. The genetic study can identify four different mutations categories: CF-causing mutation, mutation of varying clinical consequence, uncharacterized mutation, non-CF-causing mutation. In individuals with a positive newborn screen but with unchar-

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acterized or mutation of varying clinical consequence CFTR mutations (40%

Fig. 44.2  World map of overweight or obese among children 2–4 years of age, 2016. (Source: Institute of Health Metrics and Evaluation (IHME). Available from https://ourworldindata.org/how-­to-­use-­our-­world-­in-­data (Used with permission))

with inadequate zinc intake are also often those with higher stunting prevalence. Though considerable progress has been made in the last few decades, the world is still not on track to meet the 2025 global nutrition targets related to maternal, infant, and young child nutrition. The global exclusive breastfeeding rate of

infants under 6  months stands at 42.2%, and substantial efforts will be needed to meet the target of a rate of 50% within the next 5  years. For under-five stunting, the global annual rate of reduction will need to be accelerated from the current 2.2% to at least 4.0% to achieve the 2025 target [5]. Alarmingly, many countries in Africa and Western Asia are

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dealing with the double burden of malnutrition, with childhood stunting and overweight coexisting at the individual level, highlighting the importance of understanding and addressing the determinants of poor nutritional outcomes [5]. The impact of the COVID-19 pandemic will further impede and, even, reverse progress in many regions. With disrupted health systems, inconsistent access to food, and reduced coverage of interventions, childhood wasting is expected to increase during COVID and may account for 18–23% of additional under-five deaths [6].

School-Age and Adolescence School-age (5–10 years old) is a phase of continued physical growth and rapid development. Nutritional deprivation and disease are common in this group and can manifest as wasting, underweight, stunting, and micronutrient deficiencies. Overweight and obesity are also a rising issue among this group. Adolescence (10–19  years) is a period of increased nutrient and energy needs for critical biological and psychosocial changes taking place. Importantly in this age group, adolescent girls, especially in low-resource settings, are at higher risk of undernutrition and iron deficiency anemia owing to menstrual losses, poor diets, and early pregnancies. Every year 12 million women aged 15–19 years give birth and nearly 800,000 more give birth before they are even 15 years old [7]. These young girls are at even greater risk of nutritional deficiencies, morbidity, and mortality. Unfortunately, there are gaps in the nutritional data of these two groups, especially school-age children. Recognizing this evident gap, researchers are increasingly prioritizing the 5–19-year group. Though school-age children are at less risk of morbidity and mortality as compared to the first 5  years of life, poverty, increased nutritional needs, limited access to nutritious food, and frequent worm infestation lead to many nutritional issues such as stunting, iron deficiency anemia, and iodine deficiency in 5–10-year-­ olds. Iron deficiency is the primary cause of DALYs in school-age children and nearly 25% of all school-age children are anemic [8]. Further, evidence indicates that nearly 37% of all school-age children do not consume sufficient iodine which leads to impaired cognitive development. Evidence indicates that in many countries nearly half of all adolescents are stunted, reflecting chronic undernutrition and growth retardation over the years. Data on the prevalence of underweight in adolescent females (13–17  years) shows it to be less than 5% in most countries with some exceptions such as Maldives, Vietnam, Sudan, and Cambodia where nearly 18%, 16%, 14%, and 13% of young girls (13– 15  years) are underweight, respectively. Importantly, overweight and obesity are rising in this group with nearly 28% of adolescent females in the Eastern Mediterranean region

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being overweight, followed by Western Pacific (25%) and the Americas (25%) [9]. Iron deficiency remains the most common micronutrient deficiency in adolescents. Females, predictably, bear the greater burden of iron insufficiency and the consequent anemia, with South Asia and sub-Saharan Africa having the highest rates of iron deficiency in adolescents. Insufficiency of iodine is also a critical cause of DALYs lost in adolescent females and males especially in South Asia, sub-Saharan Africa, the Middle East, and North Africa. Other important micronutrient deficiencies in this age group include vitamin A, zinc, calcium, and vitamin D. There is growing evidence of vitamin D insufficiency in adolescents especially females, in many regions of the world including Europe, North America, and the Middle East. However, accurate data on the prevalence of micronutrient deficiencies in adolescents is limited.

Risk Factors Risk factors for undernutrition and overweight range from broad national-scale determinants to individual specific and factors that affect various ages and periods of life. While there are factors distinct to specific age groups, many risk factors overlap. Undernutrition is more than just a consequence of not eating enough food or illness. Numerous basic and underlying causes contribute to the development of undernutrition in under-five and school-age children and adolescents. National socioeconomic and political determinants have an impact and include political stability, economics, food security, poverty, and literacy among others. Natural disasters including famine, floods, and other emergencies have detrimental effects. Several social factors such as poor socioeconomic conditions, unstable contexts, limited access to care, poor living conditions, and household food insecurity exacerbate the issue of undernutrition. At a more intermediate level, suboptimal feeding practices including delayed initiation of breastfeeding, lack of exclusive breastfeeding, formula feed, delayed and inadequate complementary feeding, as well as poor WASH practices can all contribute to the poor nutritional status of under-five children. Maternal factors such as maternal stunting, undernutrition, lack of education, poor nutrition during pregnancy, and consequent intrauterine growth restriction are associated with increased odds of stunting in the children [10]. Important to note is that lack of maternal education is associated with both increased childhood undernutrition and overweight, illustrating the significance of maternal education and awareness for optimal child nutrition. Worrisome food insecurity is critical, but a factor that is potentially even more important in children is the inability to

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absorb what they do take in because of repeated or persistent intestinal infections. Severe infectious diseases in early childhood, such as measles, diarrhea, pneumonia, meningitis, and malaria, can cause acute wasting and have long-term effects on linear growth. The most important of these infections is diarrhea, hence the need for understanding the impact and mechanisms of malnutrition and diarrhea, which form a vicious cycle of enteric infection worsening and being worsened by malnutrition. Several recognized processes by which enteric infections cause malnutrition range from well-­ recognized anorexia and increased catabolic or caloric demands to direct protein and nutrient loss or impaired absorptive function [11]. In older children, the same social factors also influence diets and nutrition status. Additionally, inadequate intake, nutrient-poor diets, unhealthy food choices, and repeated infections can lead to undernutrition and micronutrient deficiencies. Parasitic infections, most common in school-age children, also increase the risk of micronutrient deficiencies, particularly iron deficiency. Importantly, there are many common personal, lifestyle, environmental, and macrolevel factors and determinants that can lead to contrasting suboptimal nutritional outcomes, whether undernutrition or overweight and obesity, as illustrated in the causal factor framework (Fig. 44.3). Adolescence is a period of rapid growth when maximum height and bone length is achieved. During the growth spurt, nutrient requirements may be double what they are during the rest of the adolescent period. These increased require-

ments put this group at a higher risk of undernutrition. Inadequate nutrition can affect physical growth and reproductive maturation. Nutrient-poor diets, such as junk food popular in this age group, and a lack of dietary diversity can lead to micronutrient deficiencies. Importantly, ongoing blood loss during menstruation puts adolescent girls at a higher risk of iron deficiency. Early marriages and pregnancies put them at even greater risk of undernutrition and micronutrient deficiencies. The risk factors for being overweight and obese in childhood and adolescence are multifactorial. With suboptimal infant and young child feeding and increased consumption of processed and energy-dense food, the risk of overweight and obesity even in children under 5 years of age is increasing. Mixed feeding, use of formula milk, inclusion of processed foods in complementary diet, and a rising trend of giving sugar-laden drinks and snacks have increased the risk of obesity in infants and toddlers. Less physical activity and increased screen time escalate the probability of young children being overweight. Maternal obesity and gestational diabetes are also recognized as risk factors for infant obesity. School-age and adolescent periods are formative years of life and habits formed during this time have lifelong implications. Children start becoming independent with many lifestyle influences outside the home environment, such as school, friends, and social media. Globally, in urban and rural communities, diets increasingly comprise high-fat, high-sugar, and high-sodium foods including fast food, ready-to-eat snacks, and soft drinks. Such foods are often

Malnutrition, micronutrient malnutrition, obesity, and other nutrition-related chronic diseases

Malnutrition during fetal life/infancy/childhood; Low body stores

Dietary inadequacies

Livelihood factors: Sedentary lifestyle (or heavy physical work) Alcohol Smoking

Early pregnancy

Psychological factors Eating patterns

Typical eating styles of adolescents

Eating disturbances

Infectious diseases & other health problems

Socioeconomic factors Access to food; Food supplies

Cultural patterns & practices

Changes in processed food supplies

Lack of access to nutritious & safe food (poverty)

Fig. 44.3  Conceptual framework of nutritional problems and causal factors in adolescence. (Adapted from: WHO [12])

Food supply deficit

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COVID-19 and Malnutrition:  The impact of the COVID pandemic and the consequent response will undoubtedly affect the nutritional status of women and children in the long term. Modeling exercises estimate that with disrupted coverage of maternal and child health interventions and reduced food access wasting could increase by 10–50% leading to additional under-five deaths and maternal mortality. Additionally, experts predict a rise in micronutrient deficiencies, maternal undernutrition, and intrauterine growth retardation that would ultimately impact growth and increase childhood stunting [13]. Figure 44.4 summarizes the impact of COVID-19 on various drivers of maternal and child nutrition. Multiple factors, from basic drivers including diverted policies and redirected resources to poverty, limited food access, altered care-­ seeking behaviors, and unhealthy household environments, will most likely lead to poor nutritional intake and increased disease in populations. As studies have shown, the effect of COVID-19 on household food security is not only an issue for low-income settings, with high-income settings also reporting nearly a 30% BASIC RISK DRIVERS DEPRIORITIZED CONTEXT & COMPROMISED ENABLERS

increase in household food insecurity, especially in vulnerable communities [14, 15]. Unemployment and suspension of school meal programs have led to an increased demand for food banks and food distribution programs.

 hort- and Long-Term Consequences S of Malnutrition on Growth and Development Serious consequences of malnutrition can cause immediate disability but also long-term consequences that may manifest at later life stages. Additionally, cognitive, developmental, social, mental health, and economic consequences threaten the future economic productivity of these individuals impacted by malnutrition. As we have seen, the global burden of malnutrition is serious, with its impact potentially persisting throughout the life course for individuals, communities, and countries [16, 17]. In this section, the consequences are discussed for being underweight, overweight/ obese, and having nutrient deficiencies.

Underweight Being underweight is associated with impaired linear growth, impaired cognitive and motor function, weakened immunity, mortality, and various morbidities, sarcopenia, cardiac and renal dysfunction, and immunological defects. Childhood undernutrition may cause as many as 3.1 million deaths annually [18]. Adolescent undernutrition is also harmful to the health and wellbeing of individuals and societies and is also the beginning of one’s reproductive life [19]. Being

UNDERLYING RISK DRIVERS REDUCED INCOME & LIMITED RESOURCES

POOR FEEDING PRACTICES & FOOD INSECURITY

Policy diversion to urgent care

Increased poverty and reduced spending power

Limited or interrupted food supply chain, driving food insecurity

Reduced social sector spending or diversion to COVID response

Limited / interrupted social safety nets

Interrupted school & communtiy nutrition programming / counseling

Increased inequity

Interrupted / discontinued education

IMMEDIATE RISK DRIVERS POOR DIETARY INTAKE

LIMITED CARE & RESTRICTED HEALTH SERVICES Reduced care seeking Limited access to modern contraceptives and family planning – driving high-risk pregnancies

HIGHER DISEASE INCIDENCE WITH LONGER DURATIONS

Reduced coverage of antenatal care services Limited service and supplies for regular maternal and childcare delivery e.g. immunizations

UNHEALTHY HOUSEHOLD ENVIRONMENT

HIGHER RISK OF INTERGENERATIONAL TRANSFER

(COMPROMISED MATERNAL HEALTH)

COMPROMISED MATERNAL & CHILD NUTRITION

readily available and relatively cheap, making them tempting options, particularly for low-income families. Unhealthy diets, physical inactivity, and poor sleeping habits put older children at greater risk of overweight and obesity. A family history of overweight further increases the risk. The adolescent period is critical in terms of psychosocial development, and many adolescents face stress and depression which can lead to disordered eating such as binge eating, fad diets, skipping meals, and not eating at home – all behaviors that increase the risk of being overweight and unhealthy.

STUNTING

WASTING

UNDERWEIGHT

SMALL FOR GESTATIONAL AGE

MATERNAL & CHILD MICRONUTRIENT DEFICIENCIES

Limited access / proximity to available services (e.g., clean water, safe sanitation)

Fig. 44.4  Direct effects of COVID-19 on basic, underlying, and immediate drivers of acute and chronic malnutrition. (Source: Akseer et al. [13] (Used with permission))

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underweight during adolescence may progress the burden of undernutrition into further generations [19].

 hildren Under 5 Years of Age C Underweight has negative effects on an individual possibly starting from before birth and lasting throughout the whole life course [20]. Birth weight is an important indicator for child health, and about 80% of newborns who die every year are low birth weight (LBW). This is because they were either born preterm, small for gestational age, or both [21]. LBW newborns who survive have a greater risk of both short- and long-term adverse health consequences than their normal-­ weight counterparts [21]. LBW has been associated with neonatal death, lower academic performance, long-term neurologic disability, impaired language development, reduced cognitive abilities, and increased risk of disease including cardiovascular disease (CVD) and diabetes [22]. Fetal conditions may also affect development and result in children being born SGA.  Improper nourishment from the placenta during fetal development may result in intrauterine growth restriction (IUGR). IUGR places stress on the developing fetus and may result in metabolic syndrome later in life; however, not all SGA infants experienced IUGR.  SGA infants, in general, may have more abdominal fat later in life and are at an increased risk of metabolic syndrome later in life, possibly due to catch-up growth and rapid refeeding in early life [23]. It has been suggested that early catch-up growth is needed for preterm infants to allow for proper neurodevelopmental outcomes, but this rapid weight gain is likely to affect the long-term health of LWB (and normal weight) infants [24]. Low birth weight, childhood stunting, and wasting all deplete components of metabolic capacity [25]. After birth, infant and child mortality is the most serious consequence of undernutrition. According to the WHO, 45% of all child deaths are linked to malnutrition [26]. A major driving force of infant mortality is the decreased immune function in underweight infants and children [27]. This immune dysfunction may result in illness from communicable diseases such as diarrhea and pneumonia and increase the risk of mortality [27]. Undernourished children may also have impaired liver, kidney, and thyroid function [28]. Furthermore, gastrointestinal changes in undernourished children include a stunted microbiome which may cause gut dysbiosis and increase the risk of intestinal infection [29]. Major cognitive, motor, and behavioral consequences are also important as brain development in early childhood may also be affected by proteinenergy malnutrition. This includes a smaller brain size in malnourished children. The developmental abnormalities are likely to affect the infant socially, personally, and economically beyond infancy. In the long term, underweight children are also at risk of metabolic syndrome, central fat distribution, and obesity. This outcome is thought to be a major driver

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of the double burden of malnutrition. Although they are the most serious forms of undernutrition, even mild forms of undernutrition can have developmental effects as well as increase the risk of metabolic syndrome later in life [30].

 chool-Age Children (6–9 Years) S Undernutrition in school-age children also has serious longand short-term consequences. Stunting is a marker of multiple pathologies associated with increased morbidity and mortality, loss of physical growth potential, reduced neurodevelopmental and cognitive function, and an elevated risk of chronic disease in adulthood [31]. The growth failure as well as being underweight may contribute to an increased lifetime risk of osteoporosis. As in infancy and early childhood, undernutrition puts an excess metabolic strain on the body which may increase the risk of metabolic syndrome and CVD later in life. The catch-up growth and rapid refeeding early in life may contribute to metabolic syndrome later in life [32, 33]. The immune system is also weakened with undernutrition, and these children may be more susceptible to communicable diseases and have more difficulties in recovering. Cognitive, motor, and behavioral delays persist into school-age if proper nutrition is not obtained. This undoubtedly has negative implications for school, learning, and academic achievement. This, in turn, has long-term economic consequences. Impaired intellectual development may be ameliorated when the malnutrition is resolved. Adolescents (10–19 Years) Significant gaps exist in the literature regarding adolescent malnutrition. Puberty which occurs during early adolescence increases nutritional requirements due to the period of rapid growth known as the pubertal growth spurt [34]. Adolescents may not reach their linear growth potential as this required increased nutrition to fuel a growth spurt [19]. Being underweight may also delay puberty [35]. The consequences for adolescent girls may persist into future generations as undernutrition and stunted growth may increase the risk for low birth weight in offspring [36]. Underweight adolescents also have an increased risk of osteoporosis [37]. Reduced cognitive capabilities and reduced work outputs may lower the academic achievement and work output of these adolescents as well. Collectively, these consequences may seriously reduce the economic productivity of individuals entering the workforce [38].

Overweight/Obesity Excess body fat and overweight or obesity are important risk factors for many adult diseases. Being overweight in infancy, childhood, and adolescence is likely to persist for whole life [39]. Not only does this pose a significant risk to health, but

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it also contributes to social, behavioral, and mental health problems. Collectively, these consequences contribute to a large economic burden in HIC and LMIC [40]. Obesity during childhood increases the risk for abnormalities in cardiovascular function, glucose homeostasis, pulmonary function, and cognition during childhood, as well as risk for obesity (and therefore mortality) in adulthood [18].

cancer. In boys, obesity may delay puberty but there is less evidence than in girls [50]. There are also important mental health and behavioral consequences in this period of change including anxiety, depression, lack of self-esteem, lower quality of life, as well as social problems that include bullying and a lower lifetime earning potential [19].

 hildren Under 5 Years of Age C The most important risk factors for being overweight or obese in children under 5 years of age are those that occur early in life. High birth weight has been associated with an increased metabolic load which may increase the risk of metabolic syndrome later in life [41] and a higher risk of hypoglycemia after birth and birth defects [42]. High birth weight has also been suggested as a risk factor for developing leukemia, obesity in childhood and adulthood, and later CVD [43]. Although high birth weight may have negative consequences, low birth weight remains a more important risk factor for many morbidities and all-cause mortality [43].

Nutrient Deficiencies

 chool-Age Children (6–9 Years) S Arguably, the most important consequence of childhood obesity is the increased disease risk in adulthood. Overweight children often remain overweight adults [44]. Aside from long-term, chronic disease risk, there are also immediate consequences in childhood. These include early type 2 diabetes or prediabetes, fatty liver disease, sleep apnea, type 2 diabetes, asthma, hepatic steatosis (fatty liver disease), CVD, high cholesterol, cholelithiasis (gallstones), glucose intolerance and insulin resistance, skin conditions, menstrual abnormalities, gastrointestinal reflux, impaired balance, and orthopedic problems [45]. The social and psychological health effects add to the burden as obese children are at risk of depression, anxiety, bullying, and low self-esteem [46]. Because low birth weight and catch-up growth may contribute to childhood overweight, the double burden of malnutrition is rapidly increasing across the globe. Adolescents (10–19 Years) Adolescent obesity, as with childhood obesity, leads to an increased risk of morbidity and mortality due to cancer, CVD, and metabolic diseases in adulthood. In this period that encompasses puberty, overweight can influence the progression of pubertal milestones [35]. Multiple studies have shown that the secular trend of puberty timing in girls is related to the increasing trend of childhood obesity [47, 48]. This may be related to catch-up growth in infancy and childhood [49]. Obesity in peripubertal girls may also be associated with hyperandrogenemia and a high risk of adolescent polycystic ovary syndrome, which is the leading cause of infertility in women, and also increases the risk of metabolic syndrome, diabetes mellitus type 2, CVD, and endometrial

Micronutrient deficiencies are a major problem across the globe and can pose a threat to the long-term health of infants, children, and adolescents. Micronutrient deficiencies may be associated with stunted growth, cognitive delays, weakened immunity, and other morbidities [51]. For pregnant women, the lack of essential vitamins and minerals can increase the risk of low birth weight, birth defects, stillbirth, and even death. Clinical manifestation of micronutrient deficiencies can be devastating.

 hildren Under 5 Years of Age C Micronutrient deficiencies can start in fetal life if the mother is malnourished. Zinc, iron, and iodine deficiencies are very prevalent in pregnant women [52]. These deficiencies can result in abnormal fetal development [52, 53] and increase the infant’s risk of chronic disease due to altered organ development, size, and function. Vitamin A deficiency in pregnancy may cause preterm birth which is a risk for child mortality. Iron, iodine, and vitamin A deficiencies in infancy and childhood have serious and lifelong consequences and remain common in many LMICs. In early development, vitamin A and iodine are crucial for brain development. Iodine deficiency remains the most important cause of avoidable brain damage [54]. Iodine deficiency can cause abnormal myelination of neurons, hearing impairment, and hypothyroidism. This deficiency is of crucial importance as there are long-term economic impacts when a child fails to meet intellectual capacity. Iron deficiency causes impaired reactivity and coordination in infants: psychomotor and mental development [55] may persist with iron therapy which is why preventing deficiency is needed. A lack of sufficient iron intake may significantly delay the development of the central nervous system as a result of alterations in morphology, neurochemistry, and bioenergetics [56]. Vitamin A deficiency increases the risk of respiratory and diarrheal infections, growth failure, night blindness, and permanent blindness. Vitamin A deficiency can contribute to stunting and infant mortality [57, 58]. Additionally, retinoic acid is critical for brain development, and a deficiency is associated with learning and memory problems and decreased plasticity of the hippocampus. Zinc deficiency impairs immune, nervous, and endocrine functions, increases the susceptibility to infection, and restricts physical growth [59]. Vitamin D deficiency pre-

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vents bone mineralization and causes rickets which may cause permanent changes to bone structure. In this period of rapid growth, adequate vitamin D is needed. Vitamin D is also needed for optimal nerve, muscle, and immune function [60]. Micronutrient deficiencies threaten health in the long and short term and hurt the economy of countries with widespread micronutrient deficiency [61].

 chool-Age Children (6–9 Years) S Children in this age group share the consequences for micronutrient deficiencies observed in early childhood. Iron is important for cognitive development. It is also needed for proper musculoskeletal growth. The most common cause of anemia is iron deficiency, and anemia can decrease school performance, productivity in adult life, quality of life, and the general income of affected individuals [62]. Vitamin A is still needed in school-age children for immune function and preventing night blindness [63]. Furthermore, iodine deficiency may affect cognition by disturbing normal brain development, and it may affect cognition by altering brain function possibly due to altered thyroid function [64]. The maturation of brain regions responsible for higher cognitive function continues to mature in childhood and adolescence.

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sensitive or nutrition-specific interventions [69]. Some examples of nutrition-specific interventions for malnutrition include food fortification and supplementation, while nutrition-­ sensitive interventions include education, clean water, sanitation, agriculture programs, regulatory interventions, and deworming [70]. Generally, interventions appear most successful where there is a strong political commitment along with collaboration between government, nongovernment, national, and international organizations [71].

Age Group 0–5 Years

Neonatal Interventions Widespread interventions to reduce the risk of LBW, SGA, and preterm birth involve improving women’s pre-­ conception/conception nutritional status. Anti-malarial drugs and maternal nutrition education have also been shown to benefit neonatal outcomes [72, 73]. The benefits of pre-­ conception/conception supplementation are nuanced, but a few systematic reviews have demonstrated that oral supplementation with vitamin A, low-dose calcium, zinc, or MMN (multiple micronutrients) can have a considerable effect in decreasing LBW, SGA, and preterm birth (PTB) [73–75]. Vitamin A with other micronutrients (iron plus folate) Adolescents (10–19 Years) Delayed growth, goiter, increased risk of infection, blind- reduced LBW by 33% versus micronutrient supplements ness, anemia, and inadequate bone mineralization, along without vitamin A [74]. However, vitamin A alone did not with other psychological, social, and economic conse- reduce LBW compared with placebo or no treatment. Oral quences, remain a concern in adolescents with micronutrient low-dose calcium supplementation (less than 1  g/day) sigdeficiency. Iron deficiency, especially common in adolescent nificantly reduced LBW by 80% but did not affect the risk of girls, has adverse effects on productivity and cognition in the SGA [76]. Oral zinc supplementation in adolescent preggeneral population and is the leading cause of anemia during nancy reduced the likelihood of LBW by 61% as evidenced pregnancy, contributing to 20% of all maternal and perinatal by a systematic review of five RCTs [77]. A significant mortality and low birth weight [65]. Zinc deficiency in ado- reduction of LBW in the range of 11–14% and a significant lescence may alter sex hormone metabolism and impair reduction of SGA in the range of 10–17% were observed folgrowth and immunity [38]. Vitamin D is needed in this lowing multiple micronutrient (MMN) supplementation period of growth for bone growth, strength, and develop- [75]. However, when comparing MMN containing iron and ment. Vitamin D deficiency may reduce bone density and folic acid versus placebo, the effect was not statistically sigincrease the lifetime risk of osteoporosis, fractures, and nificant. In the aforementioned trials, the effect on PTB was decreased quality of life during later life stages [66]. Iodine unaffected or not statistically significant. A systematic and vitamin A continue to be needed for brain development, review by Muanda et al. (2015) suggests that women receiving anti-malarial drugs have also been shown to have a immunity, growth, and eye health [67]. reduced risk of LBW 27% compared with women not receiving these drugs during pregnancy [78]. The intervention did not affect the risk of PTB and other outcomes were not Interventions reported. Finally, nutrition education LBW was reduced by The causes of malnutrition are complex and multifaceted; 96% and PTB by 54% for women receiving nutritional edutherefore, improving childhood malnutrition requires double-­ cation to increase energy and protein intake compared with duty actions to address the double burden of malnutrition no nutritional education in pregnancy as evidenced by a syswhich occurs when undernutrition coexists with overweight, tematic review [72]. No effect on SGA was seen for this obesity, and diet-related non-communicable diseases [68]. intervention. Other interventions did not have a meaningful Such interventions have also been categorized as nutrition-­ effect on these neonatal outcomes.

44 Malnutrition

Breastfeeding Interventions In children 0–5  years of age, breastfeeding and effective complementary feeding are of paramount importance to ensure optimal nutrition and thus proper growth and development. All-cause mortality, as well as infection-related mortality, was lower in exclusively breastfed infants (0–5 months of age) as opposed to predominantly, partially, and non-breastfed infants [79]. Additionally, children 6–11 and 12–23 months of age who were not breastfed had 1.8and 2.0-fold higher risk of mortality, respectively, when compared to those who were breastfed. The risk of infection-­ related mortality was double in non-breastfed children when compared to breastfed children aged 6–23 months. Fortified breast milk interventions improved short-term growth in weight, length, and head circumference in preterm infants compared to unfortified or micronutrient fortified breast milk, while not increasing the risk of necrotizing enterocolitis or feed intolerance [80]. In preterm and LBW children unable to obtain breast milk from their mother, a systematic review by Quigley and colleagues demonstrated that feeding with formula compared with donor breast milk resulted in higher rates of weight gain, linear growth, and head growth but had no effect on all-cause mortality or on long-term growth or neurodevelopment [81]. Breastfeeding rates are far from optimal despite its clear benefits [82–85]. Breastfeeding interventions can be effective and have higher improvements in breastfeeding rates when delivered in a combination of settings [85]. Greatest improvements in early initiation of breastfeeding were achieved when counseling or education was provided in home and community, exclusive breastfeeding in health systems and community, and continued breastfeeding rates in health systems and home settings with the most effective interventions being support at the health system such as level baby-friendly hospital environments [85]. Interestingly, a 2015 systematic review and meta-analysis found no significant effect of breastfeeding promotion interventions on child growth on length or height z-scores [86].  omplementary Feeding Interventions C The WHO complementary feeding guidelines recommend that infants at about 6 months should be introduced to nutritional foods in addition to breastfeeding [87]. Improving complementary diets of children aged 6–23 months is a recommended approach for reducing stunting in children under 5 years old, but the potential of these interventions to prevent wasting is inconclusive [88]. Complementary foods containing iron (naturally or fortified) help prevent iron deficiency and maintain iron status in the first year among infants at risk of insufficient iron stores (but not infants with already low iron stores) [89]. A recent Cochrane review [90] was unable to confirm any benefit of a meat-based intervention com-

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pared to a dairy-based intervention or fortified cereals on linear growth and weight gain.

Stunting, Wasting, and Underweight Interventions Interventions most commonly implemented for childhood stunting, wasting, and underweight include supplementation, nutrition education and counseling, growth monitoring and promotion, immunization, water, sanitation and hygiene, and social safety nets [71]. As evidenced by a systematic review of children 6–24  months of age in LMICs [91], iron plus folic acid supplementation and multiple micronutrients improve height-for-age z-score (HAZ) but only MMN reduces the risk of stunting. This review also found that flour in the caloric range of 270–340 kcal and fortified lipid-based nutrient supplements containing 220–285 kcal decreased the risk of stunting compared to standard of care, but these interventions and other food supplements did not show improvements for HAZ [91].  ater, Sanitation, and Hygiene (WASH) W Interventions Hygienic conditions prevent diarrhea and parasitic infections which could cause reduced absorption and nutrient losses, reduced appetite, and diversion of energy and nutrients from growth to the immune system [92, 93]. Repeated intestinal infection may also cause environmental enteropathy which increases the small intestine’s permeability and reduces nutrient absorption [94]. WASH interventions alone improved HAZ when delivered over 18–60 months and for children under 2 years of age as evidenced by a systematic review [95]. This review also showed that interventions combining WASH with nutrition had a strong effect on stunting and underweight (weight for age z-score) and a modest effect on wasting. Thus, a synergistic effect of WASH and nutritional interventions is of interest. Another systematic review [96] also linked WASH interventions to increased mean HAZ. Additionally, a systematic review that studied results in LMICs [97] showed diarrhea risk reductions between 27% and 53% in children 0–5 years old, depending on the WASH intervention type.  icronutrient Deficiency Interventions M Interventions for stunting, wasting, and underweight overlap with many micronutrient deficiency interventions. Micronutrient supplementation is the most popular intervention for both single micronutrient and multiple micronutrient deficiencies. According to a 2019 review of systematic reviews, the most effective strategies with the clearest evidence for addressing micronutrient deficiencies in children 0–5 include optimal cord clamping, anthelmintic treatment, anti-malarial treatment, and supplementation of single or

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multi-micronutrients [98]. Delayed cord clamping is an effective intervention for reducing anemia in early life. In helminth endemic areas, iron status can be improved by anthelmintic treatment, and anti-malarial treatment can improve ferritin. In deficient populations, single iron, vitamin A, and MMN supplementation can improve iron, vitamin A, and multiple micronutrient status, respectively. While the impact of home fortification on multiple micronutrient status remains questionable, commercial iron fortification may improve iron status [98].

 ood Fortification Interventions F Food fortification may be one of the most cost-effective and safe strategies to reach populations at large as deemed by the Copenhagen consensus [99]. Home fortification is preferred over commercial fortification from a cost perspective [100]. However, evidence from a review of systematic reviews indicates that multi-micronutrient home and commercial fortification did not significantly increase HB, serum ferritin, zinc, or vitamin A consistently [98]. Another systematic review [101] does not show a clear benefit of point-of-use multiple micronutrient fortification for a child or maternal anemia and hemoglobin. I ron Supplementation and Fortification Interventions Iron supplementation and fortification have been widely proven at the systematic review level to improve ferritin and hemoglobin concentration [98]. Delayed cord clamping has been shown to improve the hematological and iron status of both preterm and term infants after the neonatal period, as evidenced by a systematic review [102]. Systematic review evidence shows that malaria treatment increases serum ferritin but does not decrease the risk of anemia after 12 weeks [103]. A systematic review by Neuberger and colleagues (2016) found that iron status was improved the most in malaria-endemic areas when iron supplementation was combined with anti-malarial treatment [104].  itamin A Supplementation and Fortification V Interventions Vitamin A supplementation interventions not only reduce the risks associated with vitamin A deficiency but have also been associated with a reduction in the risk of all-cause mortality [105].  inc Supplementation and Fortification Z Interventions Zinc supplementation and fortification have been shown to increase serum zinc concentration in several reviews [106– 108]. Petry and colleagues (2016) found that low-dose daily iron and zinc use during 6–23 months of age has a positive effect on child iron and zinc status [109].

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I ntervention to Decrease Bodyweight In children under 5 years of age, feeding is influenced and, in most cases, controlled by parents, school, and other authorities making community and family interventions important for preventing childhood overweight and obesity. Breastfeeding, along with its aforementioned benefits, also may lower rates of obesity later in life. Other chronic diseases that are reduced by breastfeeding include diabetes (both type 1 and type 2), obesity, hypertension, cardiovascular disease, hyperlipidemia, and some types of cancer [110]. There is no conclusive evidence, at a systematic review level, of when the best time to introduce complementary foods to reduce the risk of overweight [111]. A systematic review [112] found home-based interventions with family involvement, preschool/early childhood settings, multicomponent interventions across multiple settings, and healthcare settings as possible options. A 2019 Cochrane review by Bown and colleagues suggests that interventions that include diet combined with physical activity interventions can reduce the risk of obesity in children aged 0–5  years, while physical activity interventions only do not have a significant effect [80]. A community approach to these interventions was shown to be the most useful for the overweight. This review also suggests a promising role for increasing the accessibility of education on diet and physical activity for disadvantaged families to prevent childhood obesity while making the interventions culturally acceptable. Another systematic review [113] found that school-based interventions are effective in reducing excessive weight gain of children. This review found significant results for the effectiveness of single-­ component intervention (physical activity), but emphasizing the enjoyment of physical activity sessions was critical for the interventions. Preschool interventions should be an avenue of intervention as food choices are shaped at this early age.

School-Age Children (6–10 Years) Antihelminthic Interventions Malnutrition research is abundant regarding children under 5 years; however, school-age children are an important group of interest to reduce the burden of malnutrition. An intervention for school-age children is routine treatment with antihelminthic drugs. One systematic review [114] shows evidence of an association between helminth infections and micronutrients (mostly iron and vitamin A) in school-age children. However, evidence from two systematic reviews, one by Taylor-Robinson and colleagues [115] and one by Welch and colleagues [116], does not justify treating all schoolchildren at regular intervals with deworming drugs in areas where helminth infection is common. Although deworming has not demonstrated meaningful improvements in height, hemoglo-

44 Malnutrition

bin, cognition, school performance, or mortality, it has demonstrated modest increases in weight; nevertheless, the WHO recommends widespread deworming [117].

Supplementation Interventions Iron supplementation safely improves hematologic and nonhematologic outcomes among primary-school-age children in low- or middle-income settings and is well-tolerated [118]. A systematic review of studies among children 0–10 years of age [119] showed that zinc supplementation may modify fat-free mass among children with pre-existing growth failure.

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tently shown to have a beneficial effect on weight loss and obesity prevention. Evidence on the use of multicomponent interventions in the treatment of childhood overweight and obesity was shown in a 2017 systematic review [126].

Adolescence (10–19 Years)

 nderweight and Micronutrient Deficiency U Nutrition interventions specifically for adolescents seem to be less important for boys, whereas iron and MMN supplementation may have meaningful benefits for adolescent girls. A systematic review by Salam and colleagues [127] Fortification Interventions identified the most pertinent interventions for adolescent Large-scale food fortification (LSFF) of staple foods to pre- nutrition. This study primarily found evidence suggesting an vent micronutrient deficiencies has been shown to have sig- overall significant reduction in anemia with iron/iron-folic nificant improvements in the micronutrient status of children acid supplementation (primarily in females) alone or in despite programmatic and implementation limitations [120]. combination with other micronutrient supplementation. Other hematologic markers also improved following food Furthermore, nutrition strategies, mainly consisting of calfortification among children with vitamin A, iron, and MMN, cium and zinc supplementation, among “pregnant adolessuggesting some conjoint benefits. MMN fortification, when cents” showed statistically significant improved birth weight, compared to placebo/no intervention, has demonstrated decreased low, and preterm birth. Other interventions that reductions in anemia, iron deficiency anemia, and micronu- studied the effect of various micronutrient supplementation/ trient deficiencies (iron, vitamin A, vitamin B2, and vitamin fortification on body mass index (BMI) and MMN fortificaB6), but MMN fortification was not associated with any sig- tion did not provide certain evidence. Secondarily, iron supnificant benefits on HAZ, WAZ, and WHZ [121]. The fortifi- plementation irrespective of folic acid may improve cation of foods with vitamin D has also been associated with hemoglobin concentrations, and calcium/vitamin D suppleimprovements in the vitamin D status of children aged mentation may improve serum vitamin D levels, and body 2–11 years [122]. Additionally, vitamin D food fortification bone mineral density may be marginally improved with calhas also been associated with improved blood concentra- cium-only supplementation and calcium and vitamin D suptions, deficiency prevention, and improved IQ levels [123]. plementation. These results mirrored a systematic review by Lassi and colleagues [67] that suggested that iron alone, iron plus folic acid, zinc, and MMN supplementation in adolesIntervention to Decrease Bodyweight A recent Cochrane review highlighted the importance of this cents can significantly improve serum hemoglobin concenage group for overweight and obesity interventions [124]. tration [67]. It also suggested that zinc supplementation in This review found that interventions with physical activity pregnant adolescents showed improvements in preterm birth alone or in combination with diet can decrease the risk of and low birth weight. Regarding underweight adolescents, obesity for this age group (no evidence was found for the there was limited evidence on food/protein energy suppleeffectiveness of diet only). Multicomponent behavior-­ mentation in adolescents. Overall, studies have found limchanging interventions that incorporate diet, physical activ- ited evidence supporting micronutrient supplementation/ ity, and behavior change may be beneficial in achieving fortification among adolescents on health and nutritional small, short-term reductions in BMI, BMI z-score, and status [67, 127]. weight in children aged 6–11 years as evidenced by a systematic review [125]. However, sustained reduction in these Intervention to Decrease Bodyweight parameters is necessary to reduce the burden of overweight Adolescent obesity is multifaceted with a lack of guidelines in children. Interventions for overweight and obesity in this for proven weight loss success interventions. Multidisciplinary age group primarily target diet and physical activity and are interventions which include family support and guided typically school-based, community-based, or home-based behavior modification appear to be one type of effective interventions. School-based interventions with combined method to combat adolescent overweight and obesity [128]. diet and physical activity components and a home element Additionally, a recent Cochrane review suggested the benefihad the greatest effectiveness in a systematic review of chil- cial impacts from programs that combine the promotion of dren of preschool and school-age children [17]. healthy dietary habits with physical activity on preventing Multicomponent lifestyle interventions have been consis- obesity in children and adolescents, especially school-based

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programs [124]. The absence of clearly proven strategies to prevent or treat obesity demonstrates the complexity of the etiology of obesity [129].

Conclusions Commitments made by countries to the Millennium Development Goals (MDGs) have significantly helped decrease maternal and infant mortality and childhood stunting. The Sustainable Development Goals (SDGs) aimed to build on those successes while expanding goals to adolescents who were largely ignored in the MDGs [130]. Supporting adolescent policies in addition to childhood nutrition policies and strategies represent important targets to improve malnutrition among children and adolescents. For almost two decades, reports have highlighted the need for expanded global health programs and policies targeting adolescents [131, 132]. In response to this call for action, the SDGs included 90 youth-related indicators [130]. The latest Sustainable Development Report, however, only identifies two SDG goals that are on track to achieve Goal 1 (No Poverty) and Goal 13 (Climate Action) [133]. Adolescent nutrition guidelines in many LMIC are limited in scope as they focus on school feeding, obesity, and supplementation for some micronutrients [134]. Continued gains in decreasing childhood and adolescent malnutrition will be negatively impacted by COVID 19. Concerted efforts will require greater national nutrition programs and enhanced intersectoral approaches among government and nongovernment agencies to overcome these new challenges.

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45

Enteral Nutrition Mora Puertolas and Timothy A. Sentongo

Introduction Enteral nutrition (EN) or enteral tube feeding (ETF) as currently practiced is a technique for nutritional support which delivers a homogeneous, liquid nutrition admixture into the digestive tract by tube, into the stomach, duodenum, or the proximal jejunum. The inception of enteral feeding dates back to 3500 years ago in ancient Egypt, when practitioners used rectal enemas to administer wine, milk, broth, and other nutrients to the ill [1, 2]. The first documented delivery of EN through a tube inserted into the esophagus was by Capivavacceus of Venice in 1598, who constructed a device from animal bladder. Recognition of the importance of nutrition therapy during injury and recovery from disease rapidly grew in the 1930s and 1940s and led to development of specialized commercial enteral feeding products in the 1950s and modern EN formulas in the 1970s [1, 2]. In 1980, Guaderer and colleagues at Rainbow Babies and Children’s Hospital in Cleveland, Ohio, USA, were the first to describe the technique of inserting feeding gastrostomy tubes (GT) without requirement for laparotomy, that is, percutaneous endoscopic gastrostomy (PEG) tube [3]. EN may be administered via oral, nasal, gastrostomy, or jejunal routes (Fig. 45.1). EN is used to preserve nutritional status, support normal growth, and treat malnutrition when oral feeding is inadequate or not possible. EN is more physiologic, usually safer, easier to administer, and less costly compared to parenteral nutrition (PN). Therefore, EN should be preferred to PN in infants, children, and adolescents with malnutrition and/or nutritional risk, when the intestinal tract is usable to provide sufficient nutrients for achieving optimal growth or catch-up growth [4]. EN may be administered rapidly as a bolus into M. Puertolas · T. A. Sentongo (*) Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, IL, USA e-mail: [email protected]

the stomach, or more slowly over several hours as a continuous infusion into the stomach, duodenum, or jejunum. The underlying disease and patient tolerance are what determines whether to use bolus or continuous feeds. The physiological basis of continuous EN makes it of great interest in pediatric patients with feeding intolerance and other gastrointestinal (GI) disorders [4]. EN may be used as the sole source of nutrition or to just supplement a patient’s oral and/or PN intake. Also, depending on the indication, EN may be used daily or just on a periodic basis. While EN is normally initiated in the hospital, continuing it at home has become a common option. Home EN may be used long term or just as a temporary bridge until children achieve oral food intakes that support adequate growth and nutritional status. Even though home EN is an effective method of meeting a child’s growth and nutritional requirements, health practitioners should not disregard the mixed acceptance by families and sometimes negative impact on quality of life [5–7].

 hysiological Basis of Continuous Enteral P Feeding Gastrointestinal Motility The rate of gastric emptying, and secretion of pancreatic biliary fluids, is regulated by the infusion rate, calorie density, and osmolality of the enteral feeds [8]. In the case of gastric administration of continuous feeds, a rate of continuous gastric emptying related to the infusion rate can be achieved if the infusion rate, calorie density, and osmolality of the mixture are not excessive. Steady-state gastric emptying of 1  kcal/mL formula can be maintained at infusion rates of ≤3 mL/min. When the infusion rate is excessive and higher than the gastric emptying rate, the risk of vomiting increases. As caloric load and/or osmolality of the formula increases, the gastric emptying rate is reduced to maintain a constant calorie load delivered into the duodenum. Thus, EN

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 S. Guandalini, A. Dhawan (eds.), Textbook of Pediatric Gastroenterology, Hepatology and Nutrition, https://doi.org/10.1007/978-3-030-80068-0_45

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Fig. 45.1  Possible routes for EN Nasogastric/Orogastric Nasoduodenal Nasojejunal

PEG, PEJ; PEG/J Button Gastrostomy

Jejunostomy

PEG: Percutaneous endoscopic gastrostomy tube PEJ: Percutaneous endoscopic jejunostomy tube PEG/J: Percutaneous endoscopic gastrostomy jejunal tube

c­ onsisting of very calorie-dense formulas should initially be administered very cautiously. The individual nutrient composition of the formula has a lesser effect on gastric emptying function than the caloric density, except for the type of triglyceride: long-chain triglycerides (LCTs) cause greater delays in gastric emptying than medium-chain triglycerides (MCTs). Gastric emptying is dependent on duodenal function. The effects of continuous enteral nutrition (CEN) on intestinal motility can be analyzed by manometry. Motor migrating complexes are observed in adults during CEN, as during fasting state [9]. In small preterm infants, duodenal motor activity is higher following slower infusion of gastric feeds than with rapid boluses, and this is associated with lower postprandial gastric contents [10]. During administration of jejunal feeds, energy loads at rates within the physiologic range of gastric emptying (≤4  kcal/min) initiate normal-­ motor small-bowel motor responses; however, increasing the osmolality (>600 mosmol) has a significant inhibitory effect on small-bowel contractile and propagative activity [11] and thus greater likelihood for intolerance. Very few data are available about the changes of colonic motility induced by CEN; however, the continuous gastric infusion of nutritive

formula modifies the gastrocolic reflex. Gallbladder motility is maintained during CEN as assessed by increased serum cholecystokinin (CCK) and ultrasonography [11, 12]. Emulsified LCTs delivered to the duodenum have a potent stimulating effect on CCK release and gallbladder contraction [13]. Conversely, whereas dietary MCTs are more efficiently absorbed and rapidly metabolized compared to LCTs [14], they are very weak stimulants for CCK release, gallbladder contractility, and hence luminal postprandial bile acid concentrations. Biliary complications such as sludge or cholelithiasis are rare during long-term CEN.

Digestive Secretion and Hormonal Response Gastric secretion depends mostly on protein intake and, in the case of elemental diet, on amino-acid composition. Gastric secretory response is reduced by lipids and not influenced by carbohydrates. It has not been demonstrated whether or not the type of diet (i.e., elemental, semi-­ elemental, or polymeric) modifies gastric acid secretion [15]. Secretion of CCK and pancreatic polypeptide (PP) is maintained during CEN [12]. All forms of oral and enteral feeding

45  Enteral Nutrition

stimulate pancreatic synthesis and secretion of fluids and enzymes through CCK, secretin, and PP.  Pancreatic secretions can be reduced by 50% if a low-fat elemental formula is used for duodenal feeding. Stimulation of pancreatic trypsin synthesis or secretion can be inhibited by delivering EN into the mid-distal jejunum [16]. The mechanism involves increased secretion of the “ileal-brake” hormones glucagon-­ like peptide-1 (GLP-1) and peptide YY (PYY) [17, 18] which inhibit production of pancreatic secretions and motility in the proximal GI tract. Gastrin secretion is also maintained during CEN, but its response to protein load is decreased. Gastric or duodenal CEN stimulates insulin secretion depending on the type of infused nutrients. The glycemic and insulinemic response induced by EN parallels that of oral feeds and is significantly lower than PN [16]; therefore, less risk for steatosis.

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enterocutaneous fistula, or proximal enterostomy. CEN has been associated with better feeding tolerance, nutrient absorption, and growth than boluses or oral feeds in infants and adult patients with intestinal disease [24, 25].

Indications Indications for EN are different from indications for PN, since the use of EN as nutritional support is based on normal or at least partially preserved gut functions. The decision tree for the route of feeding is determined based on aspiration risk, motility function of the stomach, and anticipated duration of need for EN support. See Fig. 45.2. EN can be used on any patient with normal GI absorptive function but unable to adequately be fed by mouth. The conditions commonly encountered are listed in Table 45.1.

Effects of CEN on Mucosal Trophicity

 onditions with Normal Intestinal C The effects of elemental formulas (totally absorbed in the Absorptive Function upper GI tract and providing minimal residue to the distal bowel) on small-bowel mucosal trophism remain controversial. In studies comparing intestinal trophicity and function in animals fed elemental diets versus regular chow, there was similar digestive function but significantly decreased mucosal mass in the distal bowel of animal-fed elemental diets. These changes could be the consequence of the almost complete absorption of nutrients within the proximal part of the small bowel, leading to lack of stimulation of the distal segment [19, 20]. This suggests an ability of EN to achieve bowel rest in the distal part of the bowel, providing efficient treatment for ileocolic inflammatory diseases.

 ffects of CEN on Energy Expenditure E and Feeding Tolerance Thermogenic effect of feeding is related to the increase of energy expenditure for synthesis and secretion of digestive enzymes following ingestion of food. The increase in energy expenditure induced by CEN in normal subjects is lower than when the same nutrients are administered by bolus feed [21]. Finally, the slow and continuous administration of nutrients into the GI tract through CEN allows the achievement of optimal utilization despite intestinal illness. In fact, by changing the conditions of flow and of contact between the nutritive formula and the digestive tract, CEN may increase the capacity for intraluminal digestion and intestinal absorption. This feeding technique does not appear to provide benefit in patients without intestinal disease [22, 23]; however, it seems logical and efficient when the absorptive surface is reduced, for example, short bowel syndrome (SBS), villous atrophy,

EN is required in cases of inability to eat normally, that is, in those situations that are secondary to structural or functional abnormalities of the upper GI tract or neurological impairment of the processes involved in sucking and/or swallowing (see also Chap. 20). Esophageal diseases including esophageal atresia, fistula, or stenosis, often resulting from sequel of epidermolysis bullosa, are among the conditions that can benefit from EN, usually through gastrostomy or duodenal tubes [26, 27]. The choice of feeding through gastrostomy versus transpyloric tube must be assessed according to the patient age, disease, and condition (Fig. 45.2). Children with chronic diseases inducing immaturity or inability to feed orally, especially with sucking and swallowing troubles as seen in neurologically impaired children, with neuromuscular chronic diseases or cerebral palsy, also require EN, using GTs.

Premature Infants EN via nasogastric or orogastric tube is routinely used in premature infants younger than 32 weeks’ gestation because of uncoordinated suck, swallow, and breathing related to immaturity [28]. Human milk is the preferred feed because of its immunological benefits. Preterm infant formulas come fortified with protein, calcium/phosphorous, and a calorie density of 22–24 kcal/oz. to meet the high nutritional requirements of infants. A Cochrane systematic review of treatment trials did not provide evidence of any beneficial effect from transpyloric feeding over gastric feeding on feeding ­tolerance, growth, and development in preterm infants [29].

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M. Puertolas and T. A. Sentongo Patient unable to adequately feed by mouth

Functional GI Tract (normal absorption/motility

Low Aspiration risk

Dysfunctional GI Tract (impaired absorption/motility)

High aspiration risk; GER

Short term (3 m)

Nasogastric tube

PEG; Gastrostomy

Short term (3 m)

Nasoduodenal/jejunal tube

Functional stomach (normal motility)

G-tube/Fundoplication

Dysfunctional stomach (delayed emptying)

Gastrojejunal tube; PEG/s direct jejunal tube

Fig. 45.2  Decision tree for the route of EN. GER gastroesophageal reflux, PN parenteral nutrition, GI gastrointestinal, PEG percutaneous endoscopic gastrostomy, PEG/J percutaneous endoscopic gastrostomy/jejunostomy, G-tube gastrostomy tube

Therefore, gastric feeding administered by bolus or continuously is the preferred approach for EN in preterm infants, where its use appears to also have a role in preventing necrotizing enterocolitis [30] (see also Chaps. 6 and 7).

 estrictive Eating Disorders: Anorexia R Nervosa and Avoidant Restrictive Food Intake Disorder Anorexia nervosa (AN) is a life-threatening psychiatric condition characterized by disordered eating behaviors, significantly lower than expected body weight, intense fear of becoming overweight, and a distorted body image. It is man-

aged by a multidisciplinary team of health providers including psychiatrists, child and adolescent medicine pediatricians, nutritionists, and social workers. Indications for inpatient therapy include presence of suicidal or aggressive behaviors; severe bradycardia, hypotension, electrolyte imbalance, dehydration, and hypothermia; and medical complications, for example, seizures and pancreatitis [31]. Weight restoration is one of the major predicators for favorable short- and long-term outcomes in patients with AN [32]. Also, restoration of body weight is associated with improvements in malnutrition-­induced cognitive impairments, thus facilitating psychological and psychiatric therapy [33]. Nutritional support in AN and avoidant resrictive food intake disorder (ARFID)  remains very controversial. The

45  Enteral Nutrition Table 45.1  Conditions commonly managed with EN Conditions with normal intestinal absorptive function Preterm infants Critically ill patients Nonorganic FTT Anorexia Inborn errors of metabolism Glycogen storage diseases, urea cycle defects Chylothorax Hypermetabolic states Head injury, graft versus host disease (GVHD), renal failure, congenital heart disease Digestive disorders Protracted diarrhea of infancy/childhood Short bowel syndrome Intestinal pseudo-obstruction Crohn’s disease Malabsorption disorders Cystic fibrosis Chronic liver disease FTT failure to thrive

oral feeding route is preferred; however, patients are given the option of voluntary or forced EN if resistant to therapy and/or severe malnutrition, that is, body mass index (BMI) < 13  kg/m2 or z-score ≤−3  in adolescents [34, 35] and weight-for-height z score 1900 kcal/day with progressive increase during the course of hospitalization [31, 32]. The main complication of nutritional management is risk for developing re-feeding syndrome: hypophosphatemia, hypokalemia, edema, and increased hepatic transaminases. The risk factors associated with re-feeding syndrome include food intake 1 month [38], greater severity of malnutrition, abnormal electrolytes prior to re-feeding, use of EN or PN, and weight loss >15% within the preceding 3 months [31, 32]. Patients may be preemptively treated with phosphate and thiamine supplements during the early phases of nutritional management.

Inborn Errors of Metabolism EN is part of the standard therapy used to prevent biochemical abnormalities, metabolic decompensation, and catabolism in patients with inherited disorders of metabolism, for example, hepatic glycogen storage disease (GSD) and

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enzyme deficiencies of the urea cycle. Patients with GSD type 1 (glucose-6-phosphatase deficiency) develop hypoglycemia and compensatory biochemical abnormalities of lactic acidosis, hyperuricemia, hyperlipidemia, and platelet dysfunction all stemming from the primary defect of inability to dephosphorylate glucose-6-phposphate to free glucose. Managing GSD type 1 involves overnight continuous high-­ carbohydrate feedings and frequent daytime feedings supplemented with uncooked cornstarch [39, 40]. EN consisting of a glucose/glucose polymer solution or a sucrose-free, lactose-free/low formula enriched with maltodextrin may be used. EN should be started within 1  h after the last meal. Likewise, an oral or EN should be given within 15 min after discontinuation of the continuous EN because of the risk for hypoglycemia. Gastrostomy is contraindicated in patients with GSD type 1b because of complications in case development of inflammatory bowel disease and local infections [40]. Continuous EN should provide a glucose infusion rate of 7–9 mg/kg/min in children younger than 6 years, 5–6 mg/ kg/min in children aged 6–12 years, and 5 mg/kg/min in adolescents [40]. Intermittent feedings of uncooked cornstarch may be used if continuous nighttime EN is not an option. No significant differences in biochemical parameters or growth have been found between patients with GSD type 1 receiving overnight continuous EN compared to scheduled feeds of uncooked cornstarch [41, 42]. The starting dose for uncooked cornstarch is 0.25 g/kg and optimal dose is 1.75–2.5 g/kg of ideal body weight every 6 h [40, 41, 43]. Patients with GSD type 3 (debrancher enzyme deficiency) have impeded glycogenolysis; however, gluconeogenesis is endogenously enhanced to maintain adequate glucose production. Therefore, nutritional management of patients with GSD type 3 involves frequent high-protein feedings during the day and a high-protein snack at night. Patients with GSD IV (brancher enzyme deficiency), GSD VI (phosphorylase deficiency), and GSD IX (phosphorylase kinase deficiency) respond to the high-protein diets similar to what is recommended for patients with GSD type 3 [44]. Inherited defects in urea synthesis are inborn errors of nitrogen detoxification and arginine synthesis due to defects in the urea cycle enzymes, namely, carbamoyl phosphate synthetase 1, ornithine transcarbamylase, argininosuccinate synthetase, argininosuccinate lyase, and arginase [45]. They may present at any age with symptoms ranging from poor feeding to coma shock and death. Other clinical symptoms may include lethargy, vomiting, ataxia, confusion, behavior changes, hypotonia or spasticity, hyperventilation (leading to respiratory alkalosis), and seizures. The main biochemical abnormalities are hyperammonemia and increased plasma concentrations of glutamine [46]. The symptoms of metabolic crisis are usually precipitated by protein intake in excess of what the patient can metabolize,

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catabolism of lean body mass resulting from intercurrent infection, trauma, inadequate energy intake, or inadequate intake of protein or essential amino acids. Management of patients with urea cycle defects involves a combination of carefully restricting protein intake and therapy with nitrogen-scavenging drugs, for example, sodium benzoate, sodium phenyl acetate, or sodium phenyl butyrate [45]. The nutritional management includes (1) administration of sufficient energy to support anabolism, (2) restriction of protein intake to that tolerated by the patient without producing excess NH3, (3) provision of essential amino acids in adequate amounts to support growth, (4) supplementation of “conditionally” essential arginine or citrulline in all except arginase deficiency, and (5) provision of all required minerals and vitamins in amounts appropriate for age [47]. During hyperammonemic metabolic crisis, the nutritional management consists of providing high-energy low-protein intakes [48]. Successful long-term management requires a dedicated metabolic dietician and physician to make frequent dietary adjustments while closely monitoring progress. Patients with neurological handicaps or developmental delays, feeding difficulties, poor appetite/refusal of food, compliance problems with the diet, and/or medications will require use of nasogastric or gastrostomy feeding tubes to ensure adequate intake [45, 49]. Patients in metabolic crisis with symptomatic hyperammonemia (>500μM/L) and/or lack of response despite 3–6 hours of appropriate medical treatment should have management escalated to hemodialysis [45].

Hypermetabolic States Hypermetabolic states include patients with burns, cancer, and head injury. Much of the morbidity and mortality in severely burned patients is connected to the prolonged hypermetabolism and catabolism, impaired wound healing, and sepsis. Whenever GI function permits, EN is superior to PN in patients with burns [50]. EN results in better regulation of the postburn catabolic hormones and inflammatory cytokine responses than PN [50, 51]. Furthermore, early EN support of patients with severe burns helps maintain gut mucosal integrity, which has the beneficial effect on reducing risk for gut-derived endotoxemia and infections [52].

M. Puertolas and T. A. Sentongo

Graft Versus Host Disease Traditionally, PN is given as the first option for nutrition support in children undergoing chemotherapy and/or bone marrow/stem cell transplant. The reasons cited range from intestinal injury and poor GI tolerance secondary to conditioning and myeloablative therapy, intestinal graft versus host disease (GVHD), oral mucositis, epistaxis, and parental refusal of EN. However, whenever GI function permits, EN is equally as effective as PN, associated with lower risk for infection, and more cost-effective [53–56]. A prospective study comparing EN and PN in children with bone marrow transplants had poor enrolment into the EN group. Initiation of EN prior to transplant was associated with better overall tolerance. The EN group was also less likely to develop cholestasis [55]. A more recent Cochrane database review of nutrition support in patients of all ages with bone marrow or stem cell transplants failed to find evaluable data that properly compared efficacy and superiority of EN versus PN. However, the overall findings suggested that in patients without GI symptoms, intravenous fluids and oral diet should be considered as preference to PN [57].

Renal Failure Supplemental nutrition should be given to children with renal failure to promote positive nitrogen balance and meet energy needs [4]. Children with chronic renal failure are at risk for malnutrition and growth retardation from persistent anorexia, inadequate protein calorie intake, chronic metabolic acidosis, azotemia, hormonal and metabolic disturbances, and catabolic diseases associated with uremia, for example, infections. Long-term EN is effective in preventing growth retardation in children with chronic renal disease and persistent anorexia, especially if started before the age of 2 years [58, 59], but singly may not lead to catch-up growth [60]. There is a positive correlation between efficacy of dialysis and linear growth of children with chronic renal failure [61]. Therefore, the combination of aggressive nutrition support with whey protein-based formulas in children age 1 yr 30 keal/oz

GER Whey protein thickened feeds

Carbohydrate Malabsorption

Fat Malabsorption

Lactofree Carboydrate-free formala

↑MCT ↓LCT

Milk-soy Allergy protein hydrolysates dipeptide or crystalline amino acid formula

Cholestaris & protein intolerance ↑MCT ↓LCT Protein hydrolysate or crystalline amino acid formula

Short-gut Protein hydrolysates dipeptide or Crystalline amino acid formala

Fig. 45.3  Algorithm for selection of formula. GER gastroesophageal reflux, MCT medium-chain triglycerides, LCT long-chain triglycerides, EN enteral nutrition

protein sensitivity, motility status, and tolerance to fluid intake, all obviously dependent on the age and on the underlying disease (Fig. 45.3). In preterm, newborns, and young infants with normal intestinal function, human milk or standard infants formulas supplemented with long-chain polyunsaturated fatty acids (LCPUFA) may be used. Formulas for preterm infants are unique in being more calorically dense (72–90  kcal/100  mL) with increased protein (1.8– 2.3 g/100 mL), calcium (70–108 mg/100 mL), and phosphorus [160]. The preterm formulas are continued after hospital discharge in preterm or small for gestation-age infants when discharge growth parameters are below appropriate post-­ conception growth, and continued until achievement of catch-up growth [160]. Breast milk and standard infant formulas have a calorie density of 0.67 kcal/mL with lactose as the carbohydrate source and fat source compromised of LCTs and LCPUFA (DHA and EPA). Commercial polymeric formulas are available for older children (age >1 year), and blenderized diets can be prepared using food from the kitchen and may be used in the nonstressed patients with normal gut function. The calorie density of formulas used in older children (age >1  year) ranges from 1  kcal/mL (standard) to 1.5–2.0 kcal/mL (calorically dense).

In the case of GI disease, the choice of the nutritive solution must take into account not only the child’s age and nutritional status but also the underlying digestive disease, for example, the presence of anatomical and functional changes in the intestine, whether due to an extensive reduction of the absorptive surface, to enteropathy, or to pancreatic insufficiency. Limiting factors in such cases are impairment of gastric, biliary, and pancreatic secretions, disturbances of the intestinal flora, and malabsorption. Most standard (1  kcal/ mL) polymeric formulas have osmolality within the range of 300–360  mosmol/kg. Oligomeric (hydrolysate/semi-­ elemental) and elemental (crystalline amino acid based) enteral formulas are designed for use in patients with malabsorption such as in short bowel syndrome, CF, cholestasis, food allergy, or intolerances. These diets include dipeptides, tripeptides, and a few free amino acids, combined with LCTs and MCTs, and carbohydrates including glucose polymers and maltodextrins. The osmolality of a solution is determined by the number of particles within it. Likewise, the osmolality of enteral formulas is directly influenced by the calorie density and whether it is made up of intact protein, peptides, or amino acids. Therefore, free amino-acid-based formulas tend to have a

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higher osmolality. Children with severe malabsorption or short bowel syndrome unable to tolerate peptide-­based formulas (protein hydrolysates) might benefit from the free amino-acid-based formulas [161, 162]. Nutritional formulas in which each of the constituents is modified independently are mostly used in special conditions, for example, selective malabsorption. In that case, glucose may be given initially as calorie source, the amount being increased progressively and controlled according to the stool volume, pH, and absence of reducing substances in the stools. In the first days of feeding, at least a molar ratio of glucose and sodium is maintained.

 egulation of Intakes and Rhythm of EN R Delivery EN should be progressively introduced depending on the child’s nutritional status and the indications for EN. In the case of digestive disease, CEN can be used after a brief or prolonged period of PN. The first step includes the progressive reduction of the parenteral intake and the stepwise increase of EN according to the digestive tolerance. The rhythm of EN delivery depends on the underlying disease. Intermittent feeding using bolus is more physiological and well tolerated when the digestive function is normal. Continuous cyclic nocturnal EN is better tolerated in some patients who do not tolerate bolus feeding and provides less interference with daytime oral intake. On the other hand, continuous 24/24  h rhythm of delivery is indicated in the case of impaired digestive function. The weaning period varies from few days to several weeks or months. Eating disorders can be avoided by the maintenance of sucking and swallowing functions during the period of CEN. On the other hand, it has been demonstrated that nonnutritive sucking intervention during CEN in preterm infants resulted in faster transition from feeding tube to oral feeds, better bottle feeding performance, enhanced growth and intestinal maturation, and decreased duration of hospital stay compared to preterm infants without the intervention [163, 164]. In older children, weaning from EN may include a period of continuous nighttime feeding supplemented by several meals in the daytime until the latter account for 50% of the total intake. Oral feeding must be carefully increased because of the relatively low intestinal activity due to long-term CEN.

Complications of Enteral Nutrition Therapy Although complications occur rarely, they can be quite serious. Strict adherence to the procedure is indicated and careful supervision is essential to prevent them. See Table 45.2.

M. Puertolas and T. A. Sentongo Table 45.2  Complications of enteral feeding tubes and therapy Nasogastric PEG/gastrostomy Complications during tube insertion Arrhythmias Aspiration Pyriform sinus perforation Hemorrhage Esophagus perforation Peritonitis Tube in pulmonary tree/pulmonary Necrotizing fasciitis intubation (rare) Pneumothorax Ileus Empyema Fistulous tracts Gastric perforation Perforation of viscera Duodenal perforation – Complications when in situ Otitis media Peristomal infection Sinusitis Stomal leakage Epistaxis Buried bumper Nasal mucosal ulceration Gastric ulcer Pulmonary aspiration Inadvertent removal Gastroesophageal reflux – Tube dislodgement – Functional complications Diarrhea Clogging Knotted tubes Contaminated feeds: Cronobacter spp. (formally Enterobacter sakazakii), E. cloacae Re-feeding syndrome Feeding aversions

Functional Complications of Feeding Tubes The functional complications of enteral feeding tubes include tendency to clog, which occurs 18–45% of the time [165]. The risk is higher in smaller-diameter tubes, and the cause of occlusion includes interaction of proteinbased formulas with an acidic environment and medications, and complete obstruction from knotting of the feeding tube [165–167]. Clogged NGTs should be readily replaced without the need to apply extraneous efforts to unclog. However, a good effort should be made to unclog blocked nasojejunal and gastrojejunal tubes because they are more difficult to insert. Clogging and occlusion can be minimized by frequently flushing the tube before and after administration of feeds. Water is more effective than carbonated beverages for flushing and unclogging occlusions. Sterile water is preferred for flushing because several published cases of infection were traced to tap water [145]. Persistently clogged tubes despite water flushes may respond to installation of one crushed tablet of Viokase (pancreatic enzyme) in 5  mL water and pH raised to 7.9 using NaOH instilled into the tube using a 50 mL syringe under manual pressure for 1 min, then clamping the tube for 5 min [167]. Other options include trial of meat tenderizer or use of mechanical devices such as Fogarty balloon and biopsy brush. Failure to unclog the tube requires replacement of the tube [145].

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Gastrointestinal Complications Risks and complications start with passage of NGTs, which can be hazardous in any patient, especially those with poor or impaired gag reflex, absent cough reflex, or altered consciousness. Furthermore, presence of a cuffed endotracheal tube is not guaranteed protection against pulmonary intubation. Therefore, feeding should not begin until proper placement of the tube is verified [146]. The bedside assessment tools of visually inspecting for color and testing for pH of aspirates may be inaccurate because small bore tubes may collapse resulting in failure to drawback aspirates, and therapy with gastric acid suppressants may affect the measured pH.  The auscultation method is also problematic because sounds may be transmitted to the epigastrium regardless of tube placement in the lung, esophagus, or stomach. Some protocols call for the first feed to be water to ensure tolerance [146]. Overall, abdominal X-ray is the gold standard for establishing location of the NGT tip [150]. Aspiration pneumonia is the most threatening complication associated with NGT feeding [146]. Irregular flow rate of infusion, delayed gastric emptying due to the underlying disease or to medications, GER, tube placement or migration into the distal esophagus, behavioral vomiting, and formula intolerance are risk factors for vomiting and aspiration. The general prevalence of feeding-tube-related aspiration pneumonia is unknown; however, the incidence in critically ill patients ranges from 25% to 40% [163] with both oropharyngeal and gastropharyngeal contents implicated. The risk factors in critically ill patients include decreased level of consciousness, vomiting, malpositioned feeding tube, larger-­ diameter NGT, and bolus feeding. The preventative measures include keeping the patient in a semi-recumbent position, continuous aspiration of subglottic secretions, and change from bolus/intermittent to continuous EN [168, 169]. Tubes placed past the third portion of the duodenum are associated with decreased risk of aspiration [146]. Diarrhea is the most common complication of EN and is reported in up to 68% of patients [146]. Increased stool losses occur when the combined absorptive capacity of the small bowel and the salvaging capacity of the colon are exceeded (see Ref. [170] for a review of the role of the colon in short bowel syndrome) and may result in dehydration and hypoglycemia. The causes include inappropriate composition of the formula for the underlying disease, high formula osmolality and rate of infusion, intraduodenal infusion, hypoalbuminemia, and bacterial contamination of the formula. The volume of endogenous fluid flux into the jejunum is directly proportional to the osmolality and rate of infusion of the EN [171]. Therefore, since higher osmolality

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(>300  mosmol/kg) feeds will induce greater endogenous fluid flux into the bowel, their rates of infusion should be increased cautiously.

 echanical, Infectious, and Metabolic M Complications NGT-related mechanical complications include nasal trauma, laryngeal ulceration, or stenosis, and esophageal or gastric perforations. Duodenal perforations have been reported in association with transpyloric feeding tubes in preterm infants, neonates, and critically ill children regardless of whether they are polyvinyl, silicone, or polyurethane feeding tubes [172–174]. In one series of 526 critically ill children receiving transpyloric EN, the prevalence of GI complications was 11.5%. These included abdominal distension and/ or excessive gastric residue (6.2%), diarrhea (6.4%), GI bleeding, necrotizing enterocolitis, and duodenal perforation (0.9%). The major factors associated with risk for developing these complications were shock, epinephrine dose >0.3μg/kg/min, and hypophosphatemia [175]. Therefore, frequent re-evaluation and a high index of suspicion are required in this patient population. Complications from PEG placement may occur during the immediate postoperative period and/or delayed for several days. The postoperative complications include aspiration, hemorrhage, peritonitis, necrotizing fasciitis, peristomal infections, prolonged ileus, fistulous tracts, and inadvertent removal. The delayed complications include site infections, persistent peristomal leakage/irritation, buried bumper syndrome, gastric ulcer, fistulous tracts, inadvertent tube removal, and fungal tube infections, especially affecting silicone tubes leading to tube degradation and malfunction [145]. Children without ­fundoplication may go through a period of worsened reflux symptoms [176–178] that may respond to slower advancement of EN or necessitate a brief period of change to continuous feeding schedule. Patients with PEGs placed too close to the pylorus, and 24–30% of children with fundoplication, may develop metabolic dumping characterized by postprandial tachycardia, diaphoresis, lethargy, refusal to eat, gas bloat, and water diarrhea in association with bolus feeds [179–181]. Establishing a screening protocol for postprandial hypoglycemia in patients with history of fundoplication is important because approximately 46% of affected children fail to exhibit symptoms [181]. The diagnosis of dumping is confirmed by a glucose tolerance test showing postprandial hypoglycemia preceded by postprandial hyperglycemia. The management options include initial avoidance of boluses, change to continuous feeding schedule, modification of the EN to avoid

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lactose, change to a complex carbohydrate source, supplementation of bolus feedings with uncooked cornstarch [182– 185], and in refractory cases, therapy with ascorbate (disaccharidase inhibitor) [186].

M. Puertolas and T. A. Sentongo

delivered into the stomach, there is a protective effect from gastric acid. Therefore, the risk of bowel contamination is theoretically higher when EN is delivered distal to the pylorus. Since necrotizing enterocolitis (NEC) may occur in premature infants and neonates suffering from hypoxia and infections, the abdomen must be checked daily very careInfectious Complications fully. Because of the risk of infectious complications and NEC, using gastric route, avoidance of duodenal infusions, EN has been associated with outbreaks of antimicrobial-­ and utilization of ready-to-use preterm formulas are recomresistant organisms. Cronobacter sp. (formally Enterobacter mended in preterm infants. sakazakii) is a rare but one of the most important worldwide causes of outbreaks of neonatal sepsis and meningitis associated with non-sterile powdered infant formula or human Re-feeding Syndrome milk fortifier, and has a mortality of 40% [187]. Ninety-nine percent of affected patients were infants aged 10% in the preuse  formula [190]. Microbial contamination of the enteral ceding 1–2 months, severe malnutrition as defined by 14 days, use a mixed lipid emulsion  In cholestasis avoid pure soya lipid even if PN is only needed for a few days  Limit the lipid infused or stop completely if patient is tolerating some enteral nutrition or unlikely to need the PN for > a further 14 days  Reduce the number of lipid infusions/week to, e.g. alternate days or just 2–3 times/week at the earliest opportunity 4. Treat any underlying infection promptly:  Even with appropriate treatment, there may be a temporary increase in liver enzymes with CRBSI or other intercurrent infections 5. Consider ursodeoxycholic acid at 10 mg/kg TDS 6. If there is evidence of intestinal bacterial overgrowth, investigate and treat

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Enteral feeding even if less than 10% of the total energy intake is an important factor in preventing/reversing cholestasis [29]. Ursodeoxycholic acid may be beneficial although it is not always well tolerated. Small intestinal stasis can be associated with bacterial overgrowth and if present should be treated [30]. Copper and manganese are usually excreted in the bile and can become hepatotoxic in cholestatic patients. Please see Table 46.5 for management strategies for limiting IFALD. If IFALD is persistent and worsening, early referral for assessment by an intestinal transplant centre is recommended [2].

Enteral Nutrition and Weaning from PN Enteral autonomy is usually achieved in four stages: 1. On starting PN aim to stabilise the patient. 2. Aim for appropriate weight gain on PN—usually ‘catch up’ weight gain required. 3. Maintain weight centile appropriate for patient’s length/ height. 4. Withdraw/wean PN and give increasing volume of oral food or liquid enteral nutrition. The aim is to give a mixed diet by mouth with the range of foods and amount eaten tailored to the patient’s enteral tolerance with the ultimate aim of weaning off PN and onto diet alone. Enteral nutrition is given alongside PN in two contexts: 1. Early introduction of oral food or EN as trophic feeds should be given alongside PN treatment if at all possible [3]. The major benefits of minimal/trophic enteral nutrition include: • Prevention of intestinal mucosal atrophy • Maintenance of the enterohepatic circulation (see Table 46.5) • If given by mouth, retention of feeding skills However enteral nutrition will need to be limited if there are significant adverse consequences such as excessive fluid losses, vomiting or abdominal pain associated with its introduction. 2. Secondly, once a child is tolerating EN well, the possibility of increasing EN and weaning from PN is considered. At this stage the child should be in an improved nutritional state. The aim should be to reduce the PN and give the maximum EN tolerated. It is important to be purposeful when weaning. There are a variety of weaning strategies that can be used. Please see Table 46.6.

46  Parenteral Nutrition in Infants and Children Table 46.6  Strategies for weaning PN [3, 33] The speed of weaning from PN varies widely:  If severe IF, feed volumes may need to be increased slowly, according to the digestive tolerance, e.g. an increase of 1 ml/h every 24 h  Some other children can abruptly return to full nutrition over a few days  Children with chronic IF on PN at home will often need gradual introduction of enteral nutrients over weeks or even months, e.g. severe SBS The weaning plan should be made with the MDT Ensure parents are aware of the risk of continuing PN versus the benefit of weaning Involve the parents/carers in drawing up the weaning strategy The smaller infant will almost certainly need an artificial feeding device: the volume of feed needed to wean is usually so great that the child will not willingly ingest sufficient orally Maximise absorptive ability with a liquid enteral feed given continuously via tube feeding with a volumetric infusion pump or 2 hourly boluses in a small infant Allowing the older infant to breast/bottle-feed and have solid food and the child to eat and drink rather than giving a liquid enteral feed is usually more successful If oral feeding is contraindicated, a liquid enteral feed should be given  Make one change at a time  In the first instance, avoidance of common dietary antigens can be beneficial, e.g. avoidance of cow’s milk, egg, wheat and soya. Slow onset/non-IgE-mediated food allergy is common in infants with an enteropathy and in SBS secondary to NEC or volvulus probably subsequent to ischaemic damage  Prioritise the weaning rather than risking setbacks by introducing a new food that precipitates symptoms that interfere with the weaning process. Once the PN has stopped, the diet can be expanded again  Offer food little and often. A child with ultra-SBS may not tolerate a full meal  It is usually possible to stop a night of PN if clinically stable on about 50% requirements enterally  If the child is lethargic the day after a night without PN, the most common problem is sodium deficiency [33]:    1. Check urine sodium the a.m. after the night off PN    2. Give oral/enteral NaCl (1 mmol/ml) usually starting with 1–2 mmol/kg    3. If larger amounts Na needed 30% NaCl (5 mmol/ml) can be used  If the child has large intestinal fluid losses and poor fluid intake, oral rehydration solution may be more appropriate than a concentrated sodium solution  If high output, proximal stoma/jejunostomy trial double concentration Dioralyte/oral rehydration solution [34]  Never be complacent about the child’s safety on PN even if they have not had any significant complications such as CRBSI. There is always a risk whilst the CVC is in place

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in a good nutritional state, it will not harm them to lose weight at the time of weaning. When weaning the older infant or child, it is usually best to reduce the volume of the PN first, and the child will then hopefully start to eat and drink more (or if on a liquid enteral feed, tolerate an increase in volume). The PN is often best reduced gradually, e.g. by 10% increments initially. Once the child is managing about 50% of requirements enterally, a whole night without PN can be considered in a child who can eat and drink. If the child is dependent on a liquid feed, the reduction might be continued more gradually.

Failure to Wean from PN as Expected When it is not possible to wean a child from PN who appears clinically ready to do so, the following investigations should be considered: 1. Re-check urine Na since this is a good indicator of total body sodium (unless on diuretic treatment) + urine specific gravity. Check the first sample after disconnecting  PN in the morning. If low, start an oral/enteral Na supplement. A child with a low total body sodium is unlikely to thrive [23]. 2. Dietary assessment by a dietitian with IF experience. 3. Faecal reducing substances for sugar malabsorption if watery diarrhoea/high stoma losses. 4. Stool elastase for pancreatic malabsorption. 5. Intestinal endoscopy with mucosal biopsies for histological (and in certain cases electron microscopy) examination. 6. Urine organic acids should be checked for bacterial metabolites and blood for D-lactate and consider H2 breath test since intestinal bacterial overgrowth may present with worsening gastrointestinal symptoms and lethargy. 7. Consider a radiological contrast study to exclude strictures and other abnormalities particularly in the child who has had previous intestinal surgery. 8. Consider the possibility of fabricated or induced illness. If suspected, one-to-one 24 h nursing care may be needed as well as limiting the mother’s involvement in the child’s care.

Preparation for Home PN: Care in Hospital The child’s weight needs to be checked regularly, for example, twice weekly in the hospitalised child and once a month in the child weaning slowly from PN at home. It is important to be aware whether the child can afford to lose weight during the weaning process. Many children on PN are kept on a centile that is above their height/length centile. It is acceptable for their weight to fall to the equivalent centile to their height when weaning. As long as the child was initially

Whilst most patients wean from PN regaining intestinal function within days or weeks of starting PN treatment, there are a small number who become dependent on PN for longer. These children should be considered for discharge home on treatment with PN if after extensive investigation and treatment by a specialist multidisciplinary paediatric gastroenterology service, it is not possible to significantly improve the

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underlying disease, and the IF is expected to persist for at least two further months. Every attempt should have been made to wean the child from PN using the most appropriate type of feed given via the most suitable feeding device. The patient should be assessed by the IF rehabilitation service for home PN if not already under their care. Many services will discharge an infant home from about 4 months of age at which stage the infant should tolerate several hours off the PN infusion. However, some services discharge even younger infants once they are stable, even when still on continuous PN [35]. The use of portable pumps has improved mobility for children when connected to PN. Most infants are able to tolerate a 10-h period without PN from about 4.5 kg (if weight is in the normal centile range for age), depending on their enteral tolerance and nutritional state. The aetiology of chronic IF requiring long-term/home PN is most commonly short bowel syndrome (SBS). Infants with ultra-SBS, i.e. with < 10 cm in length of post-duodenal small intestinal remnant after surgical resection will almost certainly require long-term/home PN. Home PN is also needed for children with other PDD and for some PNDD such as life-limiting severe immunodeficiency, chronic graft versus host disease post bone marrow transplant and IF secondary to severe neurological impairment, please see Table 46.1. Treatment at home with care by parent(s)/carer(s) who have been formally trained to administer PN and instructed what to do if complications arise gives the child the best chance of long-term survival with minimal complications [18]. It has been clear for some years that the advantages of homecare include improved quality of life, reduced incidence of CRBSI [36] and IFALD, improved psychosocial circumstances and reduced cost of treatment [18]. The aim of PN at home should be to incorporate the child’s care into the family’s lifestyle and not to have a ‘hospital at home’. The child can attend school and participate in other childhood activities including swimming. It is also possible to enjoy family holidays again. Most parents will return to their previous employment. However, the home environment needs to be a safe place for PN administration. Ideally there should be running water easily accessible from the child’s bedroom, reliable electricity supply and sufficient space to connect/disconnect PN. At least one parent/caregiver (and if at all possible two) should to be formally trained. In certain circumstances a nurse may visit the home to connect and disconnect PN, twice daily. Appropriate social support should be organised (including financial support in many countries) and arrangements for appropriate home equipment including a portable pump. In many countries a homecare company supplies the PN and related equipment. Ideally PN should be supplied in a single bag that includes the lipid with the vamin-dextrose to simplify care with only one infusion pump needed. Shared care should be set up with the most local hospital to the child’s home and the specialist centre (if the specialist centre is not close to the families’ home) in order to ensure treatment can be started promptly for emergencies such as suspected CRBSI [18].

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The current UK guidelines recommend that a viable home PN service should manage at least 10–20 patients with an MDT [37]. The composition is similar to the hospital MDT described above. Table 46.7 gives details of the steps needed to arrange transition from hospital to homecare. Good communication is essential for successful management of PN at Table 46.7  Preparation for discharge home [18] 1. The patient’s hospital team and the IF rehabilitation team need to meet to ensure treatment is rationalised to the simplest possible management plan 2. The IF rehabilitation doctor and nurse should meet with both parents (unless the father is unknown), even if they live apart  It is important to establish the need for both parents to be involved in the child’s care  It also gives the home PN team the opportunity to explain the child’s condition and future care plan and prognosis to both parents  It is best to train both parents even if one of them will lead on care  The other parent should aim to do at least one connection/ disconnection each week to maintain skills 3. If there is only one parent available, a second relative may be prepared to be trained in order to support the single parent. If parents are physically unable to perform the procedure, a community-based nurse may do so 4. Aim to reduce PN infusion time to a minimum of 12–14 h overnight if possible 5. Ensure good venous access with single-lumen tunnelled CVC. A PICC line can be used at home if functioning well. Doble lumen CVC may be used if other intravenous infusions also required. 6. Arrange a home visit to check facilities for managing PN:  Running water easily accessible from the child’s bedroom  Reliable electricity supply  Sufficient space to connect/disconnect PN  Space for a dedicated fridge to store PN bags (may be outside the house) 7. Arrange funding and source a home PN supplier:  Arrangements vary from country to country. Currently, in the UK, there is a national framework for home PN with central government funding  In many countries (including the UK), a commercial homecare company manufactures and delivers the PN, and ancillary equipment including the fridge to the patient’s home  The PN formulation should have a minimum of 7 days of stability and preferably 21–28 days  Deliveries limited to twice monthly if sufficient stability available 8. A specialist nurse should undertake the training programme with the parent(s) or carer(s) to cover the process of connecting and disconnecting PN and a plan of what to do when complications arise:  The parent/carers need to be available for a 30-h training programme over a 10-day period  Training may be completed sooner or in some cases take longer  In the unlikely event that a parent fails to train, they may be offered a second training period after discharge home and watching their partner or a nurse connecting/disconnecting for a few weeks  A one-person aseptic non-touch technique (ANTT) for connecting and disconnecting the catheter enables just one parent/carer to perform the connections and disconnections in the simplest manner possible 9. Shared care needs to be formally set up with the most local hospital for acute medical emergencies (e.g. suspected CRBSI or CVC displacement):  Parents would usually continue to connect and disconnect the PN and connect other infusions/antibiotics to limit risk when in hospital

46  Parenteral Nutrition in Infants and Children Table 46.7 (continued) 10. A discharge date should be set and a pre-discharge meeting arranged via video, telephone or face to face with parents present  Attendees include the IF rehabilitation team specialist doctor and nurse, a community nurse, a local hospital consultant, parents and other professionals as needed. Please see Table 46.8 for meeting agenda.  Minutes should be sent to all participants including parents 11. The child should be discharged home as soon as the parent/carer training has been completed (unless intercurrent medical problems arise) and if feasible after a 48-h period of self-care in hospital Table 46.8  Points for discussion in the discharge meeting [33] 1. Patient’s clinical history 2. Patient’s current medical needs 3. Date of local hospital and IF rehabilitation team first out-patient clinics 4. Background information about the home PN service (non-­ specialist professionals may have never dealt with home PN before) 5. Create an action plan for parents to follow if/when problems arise:  Fever or other symptoms suggestive of CRBSI  Blocked, broken or displaced CVC To discuss any psychosocial concerns and plan for support if needed To ensure the different professionals and the family know how to contact the specialist centre To arrange a date for a follow-up meeting 3–6 months after discharge should it be needed

home. A pre-discharge planning meeting is instrumental in setting up good homecare. Please see Table  46.8 for the meeting agenda.

Management at Home Once established on PN at home, the focus is to ensure the child thrives with appropriate weight gain. At the same time, there are two main aims of treatment: firstly, to wean off PN by introducing enteral nutrition (EN) at the earliest opportunity and, secondly, to ensure that the child has the best possible quality of life whilst on PN. Regular monitoring is essential to ensure treatment is given in the most efficient manner possible, to prevent complications (and if any do occur to detect them at the earliest opportunity) and to document changes in the patient’s overall clinical condition [18]. Monitoring needs to include the patient’s weight gain and growth, any metabolic abnormalities, infection, and liver and thromboembolic disorders [18]. Routine blood tests can be done as infrequently as once every 3  months in the stable child on PN at home.

 omplications of Long-Term/Home PN C and Their Management Children at home are susceptible to the same complications as children on short-term hospital PN but are less likely to

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have certain metabolic problems and have some additional longer-term issues. The most common longer-term PN complications are CRBSI, displacement, breakage or blockage of the CVC, metabolic bone disease and IFALD [38]. Parents/carers should have the details of the nearest acute paediatric centre to take the child to have a blood sample taken for culture and two broad-spectrum antibiotics commenced if CRBSI is suspected. Treatment should be rationalised once a positive blood culture is available and stopped if the culture is negative after 48 h (see CRBSI above) after discussion with the specialist IF rehabilitation service. In patients who have > one CRBSI at home, prophylactic anti-bacterial line locks such as taurolidine [39], ethanol or EDTA [40] should be considered. The local acute paediatric service would usually manage a blocked CVC with an alteplase or urokinase infusion [2]. They should also manage treatment of infection of the CVC insertion site or subcutaneous infection along a tunnelled CVC. The local service would also be expected to stabilise a child with a displaced or fractured CVC prior to transfer to the specialist centre for CVC repair or replacement. Treatment should be discussed with the specialist service. Other complications of long-term PN treatment are poor bone mineralization [41], abnormal body composition [42], gallstones [43] and rarely thrombotic complications such as pulmonary emboli [28]. Monitoring for potential bone disease includes blood ALP, Ca, P04 levels every 3 months if stable, vitamin D and parathyroid hormone every 6 months and bone age annually. From the age of 5  years (when there is a normal range to compare), bone density can be checked annually [18]. Management of IFALD has already been described under ‘optimising PN management in hospital’. Additional investigations at home include an annual ultrasound scan to investigate for gallstones as well as liver parenchymal disease. Early referral to a hepatology transplant service is necessary if liver disease develops.

Specific Features of PN at Home In the same way as in hospital, the hours that the PN is infused should be limited to the minimum possible, usually 12 h overnight. The child and family can participate in usual daytime activities. It can be difficult for the family to pursue a reasonably normal lifestyle if a child is connected for more than 14–16 h, although portable pumps facilitate improved mobility.  Every effort should be made to supply all PN requirements in a single bag for each infusion night in order to have one giving set and infusion pump. Most children will have two separate formulations to be used on different nights of the week since the lipid-containing infusion is usually limited to two or three nights/week, with the dextrose and amino acid preparation without lipid given on intervening nights.

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The PN bag for home use is usually made with extra volume/‘overage’ in case the child’s requirements increase. In smaller infants, the rate of infusion should be reduced/ wound down for the final hour or so (usually 50% of the full hourly rate for 30 min and 25% rate for the final 30 min prior to disconnection) in order to minimise the risk of rebound hypoglycaemia when the infusion is stopped. When a child on PN at home is clinically stable and has at least some enteral tolerance, an attempt should be made to increase enteral intake and reduce PN.  Points to consider when weaning PN at home are [18]: • In order to improve quality of life, the PN should be reduced to the minimum possible number of nights/ week at the earliest opportunity. • If the child only tolerates a liquid enteral feed via an infusion rather than drinking it and is unlikely to gain enteral autonomy, the hours of infusion should be limited to just one or two per day. • As soon as an infant can tolerate about 50% of requirements enterally, PN can be reduced to a maximum of five nights and possibly less. • Rather than going straight to a night off PN, the parents/ carers can halve the infusion volume one night a week and check if the child is well the next day. If successful they can stop the PN one night, the following week. • If a night without PN can be tolerated, reduce the PN infusions to five nights/week with the two nights off spread through the week. • If excess weight loss ensues when infusions are reduced, first increase the PN on the nights it is given, and review weight gain rather than immediately increasing the number of infusions. • Enteral sodium supplements are often required the evening before and the morning after a night off PN. • Growth and development should be monitored and PN adjusted as necessary. Dietetic input is essential to ensure earliest possible introduction of EN. Dietitians will usually contact families between face-to-face consultations when actively weaning. When discharged, the child should be sufficiently stable to cope with the same PN formulation being given for a week, in order to give the homecare pharmacy a reasonable time to make changes to the formulation. If changes to the PN are required more frequently, the volume should be increased/ reduced and supplemented enterally if extra electrolytes required. A portable infusion pump should be supplied to enable the child to be mobile in the evenings after connecting the PN. Many portable pumps have a rucksack to help support mobility when the child is connected to the infusion. In certain circumstances, for example, when using a commercially available standard bag, the vitamins may be added

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at home. When patients have residual intestinal function, most vitamins (especially water soluble) can be adequately absorbed from the gastrointestinal tract. The IF rehabilitation team should regularly audit the homecare service. The family should have ease of access to contact the specialist centre by electronic messaging and phone calls. Face-­ to-­face review by the specialist MDT intestinal rehabilitation service is usually only necessary on a 3-month basis when the child is stable [18]. Laboratory investigations/monitoring are also only needed 3 monthly when stable. Appropriate investigations include blood urea, electrolytes, urine sodium, full blood count, vitamin A and E, ferritin, copper, zinc and selenium. Vitamin D, manganese [13] and thyroid function should be checked annually. Other annual investigations include abdominal ultrasound to review the liver and kidneys and chest x-ray to assess position of the CVC (if in situ >12 months). Children aged over 5 years should have annual measurement of bone age and bone density [18]. The underlying intestinal disease predisposing the child to IF should be reviewed regularly and treatment appropriately adjusted.

Quality of Life in Children on PN at Home Children who remain on PN into adult life can have a good quality of life [18]. Adolescents can do well at school and progress to higher education [44]. Children who remain on PN into adult life can gain employment [45].

 egaining Enteral Autonomy and Weaning PN R Treatment Weaning a child from PN to oral/enteral nutrition can be one of the most complex aspects of management. Even with extensive investigation and assessment of intestinal function, it is only certain whether a child has adequate intestinal function by reducing the PN and either allowing the child to eat or increasing infused liquid EN accordingly. Please see Table 46.7. Weaning from PN to EN at home usually takes place with: • Dietetic support from the specialist unit. • The main aim is to reduce the number of PN infusions/ week. • PN reduction can be done safely at home with support from the multidisciplinary IF rehabilitation team.

 ransition to Adult Care T A small proportion of children remain on PN throughout childhood and need to transition from paediatric to adult care

46  Parenteral Nutrition in Infants and Children

on PN treatment [44]. Transition needs to be arranged on an individual basis since there are a limited number of patients on long-term care and each will have their individual needs. Although issues relating to transition are the same as for other chronic conditions, transfer needs to be performed between specialist IF units with the experience and resources to ensure the child complies with the process.

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The two major changes are as follows: (1) the adolescent takes on ‘ownership’ of the condition, and (2) the parent relinquishes responsibility. The experienced units have the ability to provide a bespoke service for each patient with a professional (usually a specialist nurse) to provide support. The transition process can take 2 years for such complex patients.

Other treatment strategies : when long - term / home PN is inappropriate.

Intestinal Transplant Despite a marked improvement in outcome in specialist IF rehabilitation centres with current PN management, there are still a small number of children who ‘fail’ PN treatment. Children who cannot continue with long-term PN and are not weaning from PN should be assessed for intestinal transplant. The indications for transplant are loss of vascular access, end-stage liver disease, unstable fluid balance and poor quality of life [27]. The transplant can range from small intestine alone to inclusion of the stomach and/or colon and if required the liver and other abdominal organs, multi-organ transplant. The outcome for long-term PN, despite the risk of potentially life-threatening complications such as CRBSI, can be up to 95% long-term/5-year survival [18, 46]. In contrast the 5-year survival for intestinal transplant according to the 2016 Scientific Registry of Transplant Recipients was 68% with 60% graft survival [47].

Withdrawing PN Treatment Home PN was originally set up for otherwise healthy children with IF to be discharged home for a good quality of life. However, children with co-existing major organ failure are now referred for PN treatment at home. In some of these children, the burden of care is so great that long-term home treatment might prolong suffering when the child has no hope of eventual recovery and will never be capable of an independent life. In such situations ethical issues need to be addressed. For example, children with severe neurological impairment can develop intestinal dysmotility and hyperaesthesia with increasing age. The PN has often been started for what was thought to be an acute self-limiting illness that has progressed, and it has not been possible to wean the child off treatment. Early assessment by the hospital palliative care team should be arranged. If it is agreed that a child with a life-limiting condition is started on PN, an ‘end of life plan’ should be discussed at an

early stage. The plan is a guide, and parents can ask for it to be altered in a crisis if they change their minds. In other cases the child’s condition may deteriorate when already on PN treatment. An MDT meeting can be held, and if appropriate a plan made for withdrawing PN treatment if it is considered inappropriate (for example appears to be causing rather than relieving suffering if continued). Psychosocial support and review should be made available.

Outcome Management of PN is now so successful that a child can grow and develop normally on PN treatment throughout childhood and into adult life even when unable to tolerate little/no enteral nutrition. In children with a primary digestive disorder, life expectancy is good. As long ago as 2012, a European survey reported a 2-year survival rate of 97%, 5-year survival rate of 89% and 10-year rate of 81% [46]. Outcome of different series varies according to the severity and diagnoses of patients discharged home [18]. Children can grow and develop normally on PN. IFALD usually improves in children discharged home. The number of intestinal transplants has been falling since 2008 [47] as IF rehabilitation management has improved.

Summary A good nutritional state is a prerequisite for normal growth and development in childhood and a sense of well-being. The effects of inadequate nutrition in childhood may have lifelong consequences with stunted growth and intellectual development in addition to worsening any systemic illness. The child who develops IF today can expect to survive into adult life with a good quality of life with the support of PN managed by a multidisciplinary IF rehabilitation team.

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References 1. Barclay A, Henderson P, Gowen H, et  al. The continued rise of paediatric home parenteral nutrition use: implications for service and the improvement of longitudinal data collection. Clin Nutr. 2015;34:1128–32. 2. Goulet O, Jan D. Intestinal failure: causes and management in children. Curr Opin Organ Transplant. 2004;9:192–200. 3. Puntis JWL, Hojsak I, Ksiazyk J.  ESPGHAN/ESPEN/ESPR/ CSPEN guidelines on pediatric parenteral nutrition: organisational aspects. Clin Nutr. 2018;37:2392–400. 4. Pironi L, Arends J, Baxter J, et  al. ESPEN endorsed recommendations. Definition and classification of intestinal failure in adults. Clin Nutr. 2015;34:171–80. 5. Barsoum N, Kleeman C. Now and then, the history of parenteral fluid administration. Am J Nephrol. 2002;22:284–9. 6. Dudrick SJ, Wilmore DW, Vars HM, Rhoads JE. Long-term total parenteral nutrition with growth, development, and positive nitrogen balance. Surgery. 1968;64:134–42. 7. Hallberg D, Holm I, Obel AL, Schuberth O, Wretlind A.  Fat emulsions for complete intravenous nutrition. Postgrad Med J. 1967;43:307–16. 8. Mesotten D, Joosten K, van Kempen A, Verbruggen S. ESPGHAN/ ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: carbohydrates. Clin Nutr. 2018;37:2337–43. 9. Lapillonne A, Fidler Mis N, Goulet O, van den Akker CHP, Wu J, Koletzko B. ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: lipids. Clin Nutr. 2018;37:2324–36. 10. Van Goudoever JB, Carnielli V, Darmaun D, Sainz de Pipaon M, ESPGHAN/ESPEN/ESPR/CSPEN Working Group on Pediatric Parenteral Nutrition. ESPGHAN/ESPEN/ESPR guidelines on pediatric parenteral nutrition: amino acids. Clin Nutr. 2018;37:2315–23. 11. Joosten K, Embleton N, Yan W, ESPGHAN/ESPEN/ESPR/CSPEN Working Group on Pediatric Parenteral Nutrition, et al. ESPGHAN/ ESPEN/ESPR guidelines on pediatric parenteral nutrition: energy. Clin Nutr. 2018;37:2309–14. 12. Mihatsch W, Fewtrell M, Goulet O, ESPGHAN/ESPEN/ESPR/ CSPEN Working Group on Pediatric Parenteral Nutrition, et  al. ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: calcium, phosphorus and magnesium. Clin Nutr. 2018;37:2360–5. 13. Domellof M, Szitanyi P, Simchowitz V, et al. ESPGHAN/ESPEN/ ESPR, CSPEN guidelines on pediatric parenteral nutrition: iron and trace minerals. Clin Nutr. 2018;37:2354–9. 14. Bronsky J, Campoy C, Braegger C, et  al. ESPGHAN/ESPEN/ ESPR/CSPEN guidelines on pediatric parenteral nutrition: vitamins. Clin Nutr. 2018;37:2366–78. 15. Jochum F, Moltu SJ, Senterre T, Nomayo A, Goulet O, Iacobelli S, ESPGHAN/ESPEN/ESPR/CSPEN Working Group on Pediatric Parenteral Nutrition. ESPGHAN/ESPEN/ESPR guidelines on pediatric parenteral nutrition: fluid and electrolytes. Clin Nutr. 2018;37:2344–53. 16. Clayton PT, Whitfield P, Iyer K.  The role of phytosterols in the pathogenesis of liver complications of pediatric parenteral nutrition. Nutrition. 1998;14:158–64. 17. Riskin A, Picaud JC, Shamir R. ESPGHAN/ESPEN/ESPR guidelines on pediatric parenteral nutrition: standard versus individualized parenteral nutrition. Clin Nutr. 2018;37:2409–17. 18. Hill S, Ksiazyk J, Prell C, et al. ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: home parenteral nutrition. Clin Nutr. 2018;37:2401–8. 19. Fivez T, Kerklaan D, Mesotten D, et al. Early versus late parenteral nutrition in critically ill children. N Engl J Med. 2016;374:1111–22. 20. Kolaček S, Puntis JWL, Hojsak I.  ESPGHAN/ESPEN/ESPR/ CSPEN guidelines on pediatric parenteral nutrition: venous access. Clin Nutr. 2018;37:2379–91.

S. Hill 21. https://www.rcpch.ac.uk/sites/default/files/2018-­03/standards_for_ paediatric_gastroenterology_hepatology_and_nutrition.pdf 22. NCEPOD.  Parenteral nutrition: a mixed bag. 2010. https://www. ncepod.org.uk/2010report1/downloads/PN_report.pdf 23. Mansour F, Petersen D, De Coppi P, Eaton S. Effect of sodium deficiency on growth of surgical infants: a retrospective observational study. Pediatr Surg Int. 2014;30:1279–84. 24. Hartman C, Shamir R, Simchowitz V.  ESPGHAN/ESPEN/ ESPR/CSPEN guidelines on pediatric parenteral. Clin Nutr. 2018;37:2418–29. 25. Pichler J, Soothill J, Hill S. Reduction of blood stream infections in children following a change to chlorhexidine disinfection of parenteral nutrition catheter connectors. Clin Nutr. 2014;33(1):85–9. 26. Baskin JL, et al. Management of occlusion and thrombosis associated with long-term indwelling central venous catheters. Lancet. 2009;374:159–69. 27. Kaufman SS, Atkinson JB, Bianchi A, et al. Indications for pediatric intestinal transplantation: a position paper of the American Society of Transplantation. Pediatr Transplant. 2001;5(2):80–7. 28. Pichler J, Biassoni L, Easty M, Irastorza I, Hill S.  Reduced risk of pulmonary emboli in children treated with long-term parenteral nutrition. Clin Nutr. 2016;35:1406–13. 29. Pichler J, Simchowitz V, Macdonald S, Hill S. Comparison of liver function with two new/mixed intravenous lipid emulsions in children with intestinal failure. Eur J Clin Nutr. 2014;68(10):1161–7. 30. Norsa L, Nicastro E, DiGiorgio A, Lacaille F, D’Antiga L.  Prevention and treatment of intestinal failure-associated liver disease in children. Nutrients. 2018;10:664. 31. Goulet O, Antebi H, Wolf C, Talbotec C, Alcindor LG, Corriol O, et  al. A new intravenous fat emulsion containing soybean oil, medium-chain triglycerides, olive oil, and fish oil: a single-center, double-blind randomized study on efficacy and safety in pediatric patients receiving home parenteral nutrition. JPEN J Parenter Enteral Nutr. 2010;34(5):485–95. 32. Gura KM, Calkins KL, Puder M. Use of fish oil intravenous lipid emulsion as monotherapy in the pediatric intestinal failure patient; beyond the package insert. Nutr Clin Pract. 2020;35:108–18. 33. Hill S.  Practical management of home parenteral nutrition in infancy. Early Hum Dev. 2019;138:104876. 34. https://www.bapen.org.uk/pdfs/bifa/bifa-­top-­tips-­series-­1.pdf 35. Fredriksson F, Nyström N, Waldenvik K, et al. Improved outcome of intestinal failure in preterm infants. J Pediatr Gastroenterol Nutr. 2020;71:223–31. 36. Melville CA, Bisset WM, Long S, Milla PJ. Counting the cost: hospital versus home central venous catheter survival. J Hosp Infect. 1997;53:197–205. 37. https://www.bapen.org.uk/images/pdfs/news/bifa-­p osition-­ statement-­about-­hpn.pdf 38. Duggan CP, Jacsik T.  Pediatric intestinal failure. NEJM. 2017;377:666–75. 39. Chu HP, Brind J, Tomar R, Hill S.  Significant reduction in central venous catheter related bloodstream infections in children on HPN after starting treatment with taurolidine line lock. J Pediatr Gastroenterol Nutr. 2012;55(4):403–7. 40. Quirt J, Belza C, Pai N, et al. Reduction of central line-associated bloodstream infections and line occlusions in pediatric intestinal failure patients receiving long-term parenteral nutrition using an alternative locking solution, 4% tetrasodium ethylenediaminetetraacetic acid [published online ahead of print, 2020 Aug 7]. JPEN J Parenter Enteral Nutr. 2020; https://doi.org/10.1002/jpen.1989. 41. Pichler J, Chomtho S, Fewtrell M, Macdonald S, Hill S.  Growth and bone health in paediatric intestinal failure patients receiving long-term parenteral nutrition. Am J Clin Nutr. 2013;97:1260–9. 42. Pichler J, Chomtho S, Fewtrell M, Hill S.  Body composition in paediatric intestinal failure patients receiving long-term parenteral nutrition. Arch Dis Child. 2014;99:147–53.

46  Parenteral Nutrition in Infants and Children 43. Pichler J, Watson T, McHugh K, Hill S.  Prevalence of gallstones compared in children with different intravenous lipids. J Pediatr Gastroenterol Nutr. 2015;61:253–9. 44. Kyrana E, Beath SV, Gabe S, Small M, Hill S.  Current practices and experience of transition of young people on long term home parenteral nutrition. Clin Nutr ESPEN. 2016;14:9–13. 45. Ashworth I, Wilson A, Aquilina S, Parascandalo R, Mercieca V, Gerada J, Macdonald S, Simchowitz V, Hill S.  Reversal of intestinal failure in children with tufting enteropathy supported

661 with parenteral nutrition at home. J Pediatr Gastroenterol Nutr. 2018;66:967–71. 46. Pironi L, Goulet O, Buchman A, et  al. Outcome on home parenteral nutrition for benign intestinal failure: a review of the literature and benchmarking with the European prospective survey of ESPEN. Clin Nutr. 2012;31:831–45. 47. Smith JM, Weaver T, Skeans MA, et al. OPTN/SRTR 2016 annual data report: intestine. Am J Transplant. 2018;18(Suppl. S1):254–90.

47

Intussusception Rachael Essig, Brian A. Jones, and Mark B. Slidell

Introduction

Incidence and Demographics

Intussusception is a common cause of abdominal pain in children under 3 years of age. At the time of John Hunter’s description of intussusception in 1793 [1], it was a nearly uniformly fatal diagnosis. In 1836 the very first therapeutic air enema was completed using a bellows followed in 1876 by Hirschsprung’s development of a hydrostatic reduction technique [1, 4]. There were some improvements in patient outcomes following the introduction of these mechanical reduction techniques in the late 1800s; however, Frederick Treves still reported a case fatality rate greater than 70% in an operative series from 1885 [2, 3]. The first reports of fluoroscopic guided reduction with enemas were reported in 1927 [5], and the current success rate of radiologic reduction techniques should be greater than 80% to 90% in most centers [6, 7]. With advances in modern medicine, this disease is now consistently diagnosed and treated with minimal morbidity or mortality. In the current day and age, the mortality rate is   G) and E297G (c.890A  >  G) [21, 23]. BSEP deficiency leads to accumulation of bile salts within hepatocytes and has a subsequent effect on hepatocellular function. As anticipated, it has also been shown to have significant affinity for some of the main bile salts in human bile, such as glycocholate, taurocholate and chenodeoxycholate [25]. Severe BSEP deficiency presents within the first year of life, and, although variable, it is usually a non-relapsing severe progressive cholestasis and pruritus leading to fibrosis. Birth weight can be below normal range especially in the non-D482G > E patients [22]. Serum bilirubin levels are not necessarily reflective of the degree of cholestasis as bilirubin is transported separately from bile salts. Like FIC1 deficiency, BSEP-deficient patients demonstrate low γ-glutamyltransferase (GGT) activity but with a trend to higher cholesterol, significantly raised transaminases (>threefold higher compared to FIC1 deficiency), alpha-­ fetoprotein and serum bile acid concentrations. Other biochemical indices include fat-soluble vitamin deficiencies manifesting with coagulopathy and rickets. Gallstones have been reported in up to 32% of patients [22]. Serum bile acid profiles demonstrate a high cholic acid-to-chenodeoxycholic acid ratio as reported in FIC1 patients. Reduced biliary bile salt concentration in BSEP patients is similar to that in PFIC1 and in direct contrast to MDR3 deficiency patients [3, 26, 27]. Severe phenotypes have been associated with mutations leading to protein truncation or failure of protein production.

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In a series by Strautnieks et  al., missense mutations were identified in 79% of patients, many affecting protein processing and trafficking or protein structure [28]. Previous reports of ABCB11 missense mutations and single nucleotide polymorphisms showed pre-mRNA splicing subsequently causing reduction in mRNA levels in a significant number of cases. These defects at the protein or mRNA level can have a detrimental impact in BSEP function [28]. Liver histology features consist of increased lobular inflammation and portal fibrosis, giant cell transformation of hepatocytes and neonatal hepatitis with finely filamentous bile. The absence of liver immunohistochemistry for BSEP can assist in the diagnostic process [23, 29] (Fig.  61.4). Immunohistochemically detectable BSEP expression does not exclude functional BSEP deficiency [30]. In a previous series, 28% of BSEP patients analysed exhibited some degree of BSEP staining, and in a small minority expression was even considered normal [23]. Hepatocellular carcinoma (HCC) or cholangiocarcinoma has been reported in a number of children on the background of severe neonatal hepatitis [31, 32] or proven BSEP deficiency [23, 32]. The risk appears to be higher in patients with two protein-truncating mutations (38% vs. 10%) compared to other genotypes. The exact mechanism of malignancy remains unclear, though further insight to the development of these tumours has been gained recently [33]. Treatment options for BSEP deficiency include antipruritic agents such as UDCA, rifampicin, liver enzyme inducers (phenobarbitone), nutritional support and fat-soluble vitamin supplementation, where indicated. Partial external

T. Grammatikopoulos

biliary diversion, ileal exclusion and liver transplantation are all recommended surgical treatment options [16, 20, 34, 35]. Hepatocellular malignancy remains an indication for early liver transplantation in BSEP patients. Patients with biallelic truncating mutations warrant close monitoring with liver ultrasonography and serum alpha-fetoprotein levels. Overall, in terms of prognosis, patients with D482G mutation developed portal hypertension less frequently, developed fibrosis at an older age and underwent liver transplantation at an older age as well [22]. Recurrence of symptoms after LT has been described in BSEP-deficient patients, in contrast to other FIC syndromes. Jara et al. reported recurrence of cholestasis and pruritus following LT in BSEP patients with no evidence of cellular rejection on liver biopsy in 2009 [36]. In the same year, BSEP antibodies in the serum and at the hepatocyte canalicular membrane of a single patient who underwent two liver transplants were described [37]. The mechanism of action is thought to be that anti-BSEP antibodies form, which bind to an epitope in the intracanalicular domain of BSEP and subsequently block the function of the bile acid transporter. A multicentre series of six patients with recurrence of disease [38] was reported in 2010. In all of these patients, treatment was extremely problematic, four underwent a repeat LT and various management protocols were suggested. All reports have identified mutations (splice site, missense, truncating) leading to the absence of BSEP protein expression on immunostaining. Modifications in immunosuppression, plasmapheresis, intravenous immunoglobulin courses and single pass albumin dialysis were used in isolation or jointly with limited effect on patients’ symptoms. Following the identification of BSEP antibodies in post-LT BSEP deficiency patients with cholestasis in the absence of rejection, an antibody-­based treatment was suggested as potentially beneficial. Two cases of patients with BSEP deficiency that, following LT, had demonstrated evidence of functional BSEP deficiency treated successfully with two repeated 4-week courses of anti-CD20 monoclonal antibodies were subsequently reported [39, 40].

TJP2 Deficiency

Fig. 61.4  Liver biopsy from a 7-month-old patient with ABCB11 disease/BSEP deficiency. There is bridging fibrosis and partial nodular transformation of the parenchyma (not shown). Hepatocytes show giant cell change and canalicular cholestasis. Lobular inflammation is present. BSEP immunostaining shows the absence of canalicular expression, whilst canalicular GGT expression is preserved (not shown) [H&E stained slide at ×200 magnification]

Since in one third of patients with normal-GGT cholestasis mutations in either ABCB11 or ATP8B1 have not been identified [26], a cohort of 33 cholestatic children with relatively low serum GGT levels were studied recently by Sambrotta et al. [41]. From eight consanguineous families with novel protein-truncating mutations in the tight junction protein-2 gene (TJP2), located in chromosome 9q21.11, 12 patients were identified. The phenotype of these patients consists of early presentation within the first couple of months of life with low serum GGT, and nine of

61  Familial Intrahepatic Cholestasis

811

them underwent liver transplantation by their first decade of life. Patients can develop portal hypertension, persistent pruritus and malabsorption. A single patient died at 13 months. Liver immunohistochemical findings consist of lack of TJP2 and reduced staining of claudin-1 (CLDN1) with normal distribution of claudin-2 (CLDN2), both proteins essential to cellular tight junctions (Figs. 61.5, 61.6, and 61.7). On transmission electron microscopy, elongation of the tight junctions with sparsity of the zona occludens (ZO) is also seen. Extrahepatic involvement is present in some cases and consists of chronic respiratory disease or neurological complications such as subdural haematomas. Mutations in the TJP2 gene have been previ-

Fig. 61.7  With expression of canalicular BSEP [×400 magnification]

Fig. 61.5  Liver biopsy from a 4-year-old patient with TJP2 disease. There is extensive bridging fibrosis (not shown). Hepatocytes are oedematous and show rosetting. Canalicular cholestasis is present. [H&E ×200 magnification]

ously associated with familial hypercholanaemia (FHC), a nonprogressive cholestatic disorder, described in the Amish population [42]. In that report, out of all 17 individuals with FHC screened, 11 patients in eight families were found homozygous for an incompletely penetrant missense mutation in TJP2, with alterations in the cellular bile acid concentration gradient. Mutations in the TJP2 gene are also known to cause intrahepatic cholestasis of pregnancy (ICP) [43], BRIC [44], cirrhosis in adults and hepatocellular carcinoma [43, 45, 46] and deafness [47, 48]. Treatment consists of supportive choleretic agents, fat-­ soluble vitamin supplementation, nutritional support, partial external biliary diversion (PEBD) and subsequently liver transplantation. No liver malignancy has been so far described in this newly defined PFIC group.

MDR3 Deficiency

Fig. 61.6 Absence magnification]

of

canalicular

TJP2

expression.

[×400

This type of FIC is caused by a variety of mutations in the ATP-binding cassette subfamily B member 4 (ABCB4), the gene encoding multidrug resistance protein 3 (MDR3) [49]. It is also inherited in an autosomal recessive pattern. ABCB4 has been mapped to the 7q21-36 region, and it codes for a floppase responsible for phosphatidylcholine [50] translocation across the canalicular membrane. Defective PC translocation leads to a lack of PC in bile. The absence of PC inhibits the chaperoning of bile acids through micelle formation, leading to damage to the biliary epithelium and cholangiopathy. Biliary phospholipid levels are significantly reduced, and biliary bile salt-to-phospholipid and cholesterol-­ to-­ phospholipid ratios are significantly higher in affected individuals when compared with wild-type bile [51].

812

MDR3 deficiency causes a spectrum of liver diseases such as cholesterol cholelithiasis, adult biliary cirrhosis, low-phospholipid-associated cholelithiasis syndrome (LPAC), transient neonatal cholestasis, intrahepatic cholestasis of pregnancy (ICP) and drug-induced cholestasis [52–58]. In severe MDR3 deficiency, symptoms can manifest within the first year, but not usually as neonatal jaundice, and gradually progress towards liver cirrhosis and end-stage liver disease within the first few years of life [1, 59, 60]. Patients with a single affected copy of the gene can develop symptoms under particular circumstances, such as pregnancy, whilst otherwise they may remain asymptomatic [61, 62]. Liver histology demonstrates expansion of portal tracts, bile duct proliferation, bile plugs and portal fibrosis with mixed inflammatory infiltrate (Fig. 61.8). Cytokeratin immunostaining can be confirmatory of the ductular proliferation, and MDR3 immunohistochemistry can be absent or markedly reduced at the canalicular membrane in affected individuals [63]. MDR3 deficiency is differentiated from the other three FIC types at a biochemical level by an elevated serum of γ-glutamyltransferase (GGT). Biochemical profile also consists of normal serum cholesterol and moderately raised concentration of serum primary bile salts [27]. The first-line management, as in the other FIC types, is with UDCA and other antipruritic and choleretic agents. UDCA seems to be very effective in milder cases, and it may also prevent disease progression in these cases. Liver transplantation remains the treatment of choice for the nonresponders.

Fig. 61.8  Liver biopsy from a 1-year-old child with MDR3 deficiency/ ABCB4 disease. There is a cholangiopathy manifested by cholangiocyte disarray and vacuolation. Immunohistochemistry demonstrated an absence of canalicular MDR3 expression (not shown) [H&E ×200 magnification]

T. Grammatikopoulos

Farnesoid X-activated receptor Another molecule regulating bile acid homeostasis is the farnesoid X-activated receptor (FXR). FXR belongs to a subclass of metabolic receptors within the intracellular ligandactivated nuclear receptor (NR). FXR is encoded by the nuclear receptor subfamily 1, group H, member 4 (NR1H4) gene, located in chromosome 12q23.1 [64, 65]. Bile acids are ligands for the nuclear hormone receptor FXR, which together with its heterodimeric partner, the RXR, acts as a transcription factor for several bile salt transporters, including the hepatic BSEP and the ileal bile acid binding protein (I-BABP) [66, 67]. The expression of short heterodimeric protein (SHP)-1 in the liver, which acts as a transcriptional repressor, is itself regulated by FXR and can downregulate the expression of several genes including Ntcp and cholesterol-7a-hydroxylase CYP7A1, which is a rate-limiting enzyme in bile salt synthesis [68]. Conversion of cholesterol to bile salts by CYP7A1 is stimulated by the oxysterol-activated liver X receptor (LXR). Bile salts have a negative effect on their synthesis by activation of the FXR-dependent short heterodimeric protein 1 (SHP-1), which in turn suppresses CYP7A1 and 8B1 transcription. The activation of FXR by bile salt production stimulates the transcription of Mrp2, Bsep and OATP8 [69, 70]. Bile salt synthesis is also regulated by a feedback mechanism between FXR and other nuclear receptors including RXR, LXR and LRH-1. FXR is expressed in the liver, intestine and kidney, and its activation has been shown to be activated by both conjugated and free bile salts such as chenodeoxycholate, deoxycholate, lithocholate and cholate [67]. There are similarities in the activation of FXR by bile salts in hepatocytes and terminal ileum enterocytes which in essence controls the entire enterohepatic circulation of bile salts [71]. The presence of bile salts in the terminal ileum activates FXR which reduces bile salt uptake and promotes their secretion via the basolateral membrane reducing the intracellular concentration and increasing their excretion via the faecal route [72, 73]. FXR has been shown to activate an endocrine feedback mechanism via the fibroblast growth factor 19 (FGF19). FGF19 is secreted from the ileum to the portal venous system whereby once it reaches the liver it supresses bile salt production by activation of the FGF receptor 4 [74]. FGF19 can also activate hepatic glycogen synthesis and inhibits gluconeogenesis [75, 76]. Gomez-Ospina et al. reported the first small series of four individual patients from two unrelated families with homozygous loss-of-function variants in NR1H4 [65]. All patients presented at a very early age. Three presented with neonatal cholestasis and one presented with ascites, pleural effusions and intraventricular haemorrhage at birth. At the time of initial evaluation, all patients had conjugated hyperbilirubinemia, raised liver transaminases, low-to-normal GGT activity

61  Familial Intrahepatic Cholestasis

and refractory to vitamin K coagulopathy. Two patients underwent successfully LT, one died on the waiting list for LT and another patient died at 5 weeks of age from an acute vascular event. Chen et al. identified one patient with a single heterozygous nonsense variant in NR1H4 from a large cohort of children with early-onset normal GGT activity cholestasis [64]. Their patient underwent biliary surgery and T-tube drainage for refractory to medical treatment cholestasis with minimal effect. Subsequently, this case developed cirrhosis and ascites. So far, the phenotype of patients affected with FXR-associated liver disease seems of early-onset cholestasis leading to cirrhosis and LT. Liver histology can show ductular reaction, giant cell transformation with hepatocyte ballooning and intralobular cholestasis. Biopsy material from explanted livers had features of micronodular cirrhosis and fibrosis. Liver immunohistochemistry showed lack of canalicular BSEP expression with preservation of MDR3. More recently, FXR agonists, such as the bile salt derivative obeticholic acid, have been shown to improve alkaline phosphatase (ALP), a disease marker in primary biliary cirrhosis [77, 78], but with minimal effect on pruritus. In recent years, there have been studies suggestive of FXR’s potential therapeutic role also in lipid and glucose metabolism [79, 80], immunomodulation in inflammatory bowel disease [81, 82] and colorectal cancer [83]. Further reports are required to expand our knowledge of the disease, understand genotype-phenotype associations and investigate potential therapeutic options.

813

there has been a clearer distinction in this type of cholestatic syndrome, now called MVID-associated cholestasis [89, 90]. Recent evidence shows that the effects of mutations on MYO5B (OMIM 606540) are not limited to the small intestine but can also involve other organs such as the stomach, colon, pancreas and more importantly the liver [84]. Interestingly, a small group of children can present with MVID-like disease, but although they recover from their gastrointestinal disease with histologically normal small intestine, they suffer from recurrent cholestasis and troublesome pruritus [91]. Patients can present with cholestasis and pruritus at an early age but some at a much later stage. The biochemical profile is that of low GGT activity with preserved synthetic function and evidence of cholestasis with raised bilirubin or serum bile acids and limited parenchymal inflammation (AST/ALT) and gallstones. The difference in the disease phenotype between MVID- and MYO5B-associated cholestasis has not been yet clearly defined though, and further functional studies are required. It has been recognised that deficiency of MYO5B impairs the BSEP in the canalicular membrane contributing to cholestasis [92]. BSEP is a liver-specific transporter and crucial to bile acid transport at the canalicular membrane [93]. An alternative mechanism for the cholestasis in these patients has also been attributed to impairment of MYO5B/RAB11A interaction [92, 94, 95]. The degree of jaundice or cholestasis can be variable amongst patients with MYO5B-associated cholestasis but somewhat comparable to other low-GGT cholestatic syndromes such as FIC1 and BSEP deficiency [5, 96]. There are often clinical similarities between their MYO5B Myosin 5B Cholestasis cohort and patients with other low-/normal-GGT cholestatic syndromes but also differences in their histological/immuMYO5B is a motor protein-mediating membrane transport nostaining findings. Liver histology findings are those of mild and recycling in polarised cells, found in all epithelia [84] and nonspecific portal inflammation with minimal, focal loband encoded by the gene MYO5B, located in 18q21.1. ular cholestasis and fibrosis. BSEP expression has been variMYO5B binds selected small guanosine triphosphatase able amongst different case series from preserved and (GTPase) rab proteins, including the trans-Golgi network localised to the canalicular membrane to ­distortion with low (TGN)-associated and the recycling endosome-associated GGT expression mainly identified in periportal areas [94]. rab11a and rab8, and has been implicated in protein traffickCroft et al. reported a unique case, where the patient preing across the apical plasma membrane [85]. sented with severe gastrointestinal symptoms, typical of Functional deficiency or loss of MYO5B results in aber- MVID, which resolved over childhood. The GI histology rant cell polarity and is the major cause of microvillus inclu- showed MYO5B expression at the microvillus brush border, sion disease (MVID), an autosomal recessive disorder and ultrastructural studies confirmed the absence of microcausing watery diarrhoea presenting in early infancy that villus inclusions, with intact normal-sized microvilli in the requires parenteral nutrition. The condition can also lead to brush border [91, 96]. This case subsequently developed intestinal failure and small bowel transplantation [86, 87]. cholestasis and pruritus. Perry et al. reported some atypical Loss of the motor function causes the formation of inclu- cases of MVID in whom one patient had transient intestinal sions and retention in brush border enzymes that lead to failure but was on full enteral feeds at time of reporting [97]. early-onset watery diarrhoea and failure to thrive [88]. Both these reports highlight the clinical diversity of GI Cholestasis when reported in patients with MVID is often involvement in patients with MYO5B cholestasis in whom a considered identical to the typical intestinal failure-­ convincing pathophysiologic explanation remains to be associated liver disease phenotype. More recently though, established.

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The clinical progression of the disease demonstrates a variable response to medicinal antipruritic agents and surgical interventions. Some centres reported good response to medicinal agents (bile acid modifiers); others explored the potential role of surgical interruption of the enterohepatic circulation (external or internal biliary diversion) and nasobiliary drainage with limited effect on pruritus and quality of life and a minority progress to LT [98–100]. The clinical progression of the disease demonstrates a variable response to medicinal antipruritic agents (UDCA, cholestyramine, rifampicin, naltrexone, chlorphenamine) and surgical interventions. Some patients require biliary diversion with limited effect on pruritus and quality of life, but only two reported cases so far progressed to LT. Despite the various treatment modalities, patients do not become completely asymptomatic. Clinical trials currently underway in other cholestatic conditions interfering with the bile acid homeostasis may have a beneficial effect on children with MYO5B-­ associated cholestasis. The long-term prognosis of patients with MYO5B-­ associated liver disease should be addressed with caution on the basis of the uncertainty whether these patients will remain free of GI symptoms in the future and their liver disease outcome in adulthood.

 biquitin-Specific Peptidase 53-Associated U Liver Disease In the last 2 years, another type of progressive familial intrahepatic cholestasis with normal GGT has been described in association with variants in the ubiquitin-specific peptidase 53 gene [101–104]. To date, there have been three case series reported describing a limited number of patients with USP53-related cholestasis. The USP53 gene, located in chromosome 4q26, encodes a non-protease protein homologue of the ubiquitin-specific peptidase family [105] important for the regulation of protein degradation, but due to lack of a histidine residue, this function is lost [106]. The USP53 protein is expressed in the kidney, inner ear, liver and brain. USP53, a tight junction (TJ) protein, co-localises and interacts at the cellular TJs with other tight junction proteins 1 and 2 (TJP1 and TJP2). In a mouse model, Usp53 is interacting with TJs and more specifically with TJP2. The missense variant c.682T  >  A; p.Cys288Ser seems though to not alter the co-localisation with TJP2, and it has been reported to cause progressive hearing loss [107]. The biallelic variants described so far include mostly homozygous or compound heterozygous forms with variations though amongst reports. Bull et al. and Alhebbi et al. reported in all but one homozygous changes in USP53 variants causing loss of function unlike the series by Zhang et al.

T. Grammatikopoulos

where all cases were compound heterozygous in variants causing either nonsense, frameshifting, canonical splicing or missense changes. In view of the limited cases reported, it remains challenging to extract meaningful phenotype-­ genotype associations and more so about the long-term prognosis. Clinical presentation can include relapsing normal-GGT cholestasis varying from early infancy to adolescence, pruritus and signs of fat-soluble vitamin deficiency such as hypocalcaemia, tetany and intracranial bleeding due to vitamin D and K deficiency, respectively. Hypertrophic cardiomyopathy, heart failure, hypothyroidism, unilateral kidney enlargement, developmental/speech delay and hearing loss requiring cochlear implants have also been reported. The biochemical profile of patients with USP53-associated liver disease consists of high serum bilirubin and ALP, mildly elevated ALT/ AST and normal GGT [101–104]. Liver histopathology shows hepatocyte giant cell changes, canalicular and hepatocellular cholestasis with mild lobular activity and in a single case [101] cholangiopathy with florid duct proliferation and inflammation. Of interest, there is also porto-septal and porto-portal fibrosis and parenchymal nodularity hinting towards the chronic nature of the liver disease. Immunohistochemistry confirms canalicular protein GGT and BSEP expression in a pan-lobular distribution in all patients. TJP2 can be expressed albeit decreased and less crisp with challenges in USP53 immunostaining from reports [102, 104]. In ultrastructural studies, Bull et al. reported variations in bile retention (granular or finely filamentous) with preservation of tight junctions, but changes in TJ’s length and orientation were described by Zhang et al. Patients reportedly respond well to UDCA and/or cholestyramine and rifampicin with relapse in pruritus after temporarily stopping treatment. In the majority of patients with USP53-associated cholestasis, the disease phenotype may be relatively mild albeit relapsing, but one patient has already undergone LT. There is also variability in onset of hearing deficit, and further reports will enhance our knowledge and understating of this newly described condition.

Conclusion Over the last few years, our understanding of paediatric cholestatic disorders has significantly improved. Through the latest gene sequencing techniques (targeted resequencing and/or whole exome sequencing) and careful patient selection, we have managed to identify causative genes for cholestatic syndromes in most patients and highlight the mechanism of action of the encoded proteins at a cellular level. This enables physicians to characterise and treat these patients more efficiently. A number of clinical trials are cur-

61  Familial Intrahepatic Cholestasis

rently underway in some of the above-mentioned cholestatic conditions interfering with the bile acid homeostasis, and yet there is to be established the application of possible gene therapies. Whether such treatment options would be beneficial to children with FIC1, BSEP deficiency or other cholestatic syndromes requires further interrogation. Additionally, new clinical challenges are appearing such as recurrence of BSEP deficiency after liver transplantation.

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T. Grammatikopoulos 105. Quesada V, Diaz-Perales A, Gutierrez-Fernandez A, Garabaya C, Cal S, Lopez-Otin C.  Cloning and enzymatic analysis of 22 novel human ubiquitin-specific proteases. Biochem Biophys Res Commun. 2004;314(1):54–62. 106. Hu M, Li P, Li M, Li W, Yao T, Wu JW, et al. Crystal structure of a UBP-family deubiquitinating enzyme in isolation and in complex with ubiquitin aldehyde. Cell. 2002;111(7):1041–54. 107. Kazmierczak M, Harris SL, Kazmierczak P, Shah P, Starovoytov V, Ohlemiller KK, et al. Progressive hearing loss in mice carrying a mutation in Usp53. J Neurosci. 2015;35(47):15582–98.

62

Alagille Syndrome Shannon M. Vandriel and Binita M. Kamath

Introduction

Clinical Manifestations

Alagille syndrome (ALGS) is an autosomal dominant phenotypically heterogeneous disorder. The defining clinical features of ALGS as described by Daniel Alagille include cholestatic liver disease classically with bile duct paucity, cardiac disease, posterior embryotoxon, butterfly vertebrae, and characteristic facial features [1]. The diagnostic criteria have since been expanded to encompass vascular and renal anomalies [2, 3]. ALGS stems from heterozygous mutations in one of two genes in the Notch signaling pathway: JAGGED1 (JAG1) mutations are reported in up to 94% of clinically diagnosed cases, and mutations in the NOTCH2 receptor are found in 2.5% [4]. De novo mutations account for approximately 60% of ALGS cases. Historically, the prevalence of ALGS has been estimated to be approximately 1  in 70,000 live births. However, advances in molecular diagnostics have revealed that the true burden of ALGS is likely closer one in 30,000 [5]. This increase in prevalence is partially attributable to the growing availability and use of genetic testing and capturing individuals who present with partial or subclinical disease expression. There is remarkable variability in both disease severity and organ system involvement among ALGS patients, even within families harboring the same pathogenic variant. The following sections will describe the hallmark features of ALGS and provide evidence-based management considerations and strategies.

Hepatic

S. M. Vandriel Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON, Canada B. M. Kamath (*) Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON, Canada Department of Pediatrics, University of Toronto, Toronto, ON, Canada e-mail: [email protected]

The majority of ALGS patients who are symptomatic with liver disease present in the first year of life with cholestasis, classically with conjugated hyperbilirubinemia and high γ-glutamyltransferase (GGT). During childhood, elevations of serum bilirubin up to 30 times normal and serum bile salt elevations of 100 times normal are common. Cholesterol levels can be staggering and may exceed 1000–2000  mg/ dL. However, this high level of plasma cholesterol is largely associated with lipoprotein-X [10]. Lipoprotein-X is in the low-density lipid range and resists oxidation, thereby protecting against atherosclerosis. Thus, the hypercholesterolemia of ALGS does not appear to carry an increased risk of cardiovascular disease [6, 11]. Hepatic synthetic function is usually well preserved in ALGS. Physical examination findings in children with ALGS and liver disease include hepatomegaly early on and splenomegaly in the majority over time. The pruritus seen is among the most severe of any liver disease. It rarely is present before 3–5 months of age but is seen in most children by the second year of life, even in some who are anicteric. Multiple xanthomas are common sequelae of severe cholestasis associated with ALGS and correlate with a serum cholesterol level greater than 500  mg/dL.  Xanthomas typically form on the extensor surfaces of the fingers, the palmar creases, the nape of the neck, the ears, the buttocks, and around the inguinal creases (Fig. 62.1a, b). Xanthomas are disfiguring and occasionally interfere with fine motor function when they occur on the fingers and feet. Bile duct paucity is the histopathologic hallmark of ALGS and is defined as a ratio of interlobular bile ducts to portal tract ≤0.5 in at least five portal tracts (normal ratio 0.9–1.8). Other histological features of ALGS include giant cell transformation and, occasionally, biliary obstruction in patients with a biliary atresia (BA) phenotype. Notably, bile duct

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 S. Guandalini, A. Dhawan (eds.), Textbook of Pediatric Gastroenterology, Hepatology and Nutrition, https://doi.org/10.1007/978-3-030-80068-0_62

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Fig. 62.1 (a, b) Xanthomas on the hands of a child with Alagille syndrome

p­ aucity is not always present in early infancy and has been reported to increase in frequency with age [6]. Large regenerative hepatic nodules are observed in up to 30% of ALGS patients and are postulated to occur in response to abnormal vascular perfusion of the liver [7, 8]. These lesions are typically solitary and centrally located close to the right portal vein. On radiological evaluation, these lesions have normal hepatic vessels and are relatively stable on follow-­up imaging studies, with a mean interval of 33 months [8]. There is general consensus that the mechanisms leading to hepatic nodules in ALGS are reactive in nature as opposed to neoplastic. Hepatocellular carcinoma (HCC) is considered a rare complication of ALGS. A recent case series and review of the literature described 21 children with ALGS who developed HCC [9]. The median age of HCC diagnoses was 4  years old (range 1–16  years), with the youngest case reported being a 1.5-year-old child. Cirrhosis was reported in all cases except for one at the time of HCC diagnosis. Although ALGS patients are not considered a high-risk group for HCC, monitoring of serum alpha-fetoprotein levels and an ultrasound examination is recommended every 12 months.

There is considerable variation in the clinical course and ultimate prognosis of liver disease in ALGS. For those children with significant hepatic involvement in infancy, the clinical picture is dominated by cholestasis and follows a severe course in the first 5 years of life, after which it appears to improve for many patients. This spontaneous improvement is poorly understood but well documented. In approximately 10–20%, the cholestasis persists unabated or progresses to end-stage liver disease (ESLD) with the onset of portal hypertension later in childhood. It is difficult to predict early on which ALGS children with cholestasis in early childhood will eventually require liver transplantation (LT) and which will spontaneously improve. There are no known genotypic or radiologic predictors of liver disease progression in ALGS. A review of laboratory data of ALGS patients showed that bilirubin and cholesterol levels before the age of 5 may aid in distinguishing patients at high and low risk of problematic cholestasis in later childhood. More specifically, mean levels of total bilirubin (TB) >6.5 mg/dL (111μmol/L), conjugated bilirubin (CB) >4.5 mg/dL (77μmol/L), and cholesterol >520 mg/dL (13.3 mmol/L) are strongly associated with severe liver disease in later life, whereas levels lower than this are associated with a more favorable hepatic

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­outcome [10]. These data may assist the clinician in predicting which children might go on to resolve their cholestasis and therefore avoid unnecessary LT in young children with ALGS. The overall hepatic prognosis in ALGS was previously regarded as favorable, with reportedly only 20–30% requiring LT [6, 11]. However, these data represent mixed cohorts of children with ALGS and those with and without significant liver disease. Recently, Kamath et al. recently reported on the outcomes of 293 ALGS patients with cholestasis in a prospective observational multicenter North American study [12]. Native liver survival in ALGS probands with cholestasis was only 24% at 18.5 years. As described above, in early childhood, LT  in ALGS typically occurs due to complications of cholestasis, and this study revealed an additional burden of liver disease in later childhood due to fibrosis and portal hypertension [6, 11, 13].

Cardiac Cardiac anomalies are a hallmark feature of ALGS, with a reported prevalence of 94% [14]. The extent and pattern of cardiac involvement is highly variable, ranging from an asymptomatic murmur or peripheral pulmonary artery stenosis (PPS) to more complex intracardiac anomalies such as tetralogy of Fallot with or without pulmonary atresia. PSS accounts for approximately 73% of reported cardiac anomalies in ALGS and can lead to pressure or volume overload of the right ventricle (RV), RV hypertrophy, and, in severe cases, right-sided heart failure. The most common serious intracardiac defect is tetralogy of Fallot (TOF), which occurs in 7–12% [6, 14]. Approximately 40% of patients with ALGS demonstrating TOF have pulmonary atresia, representing a more severe phenotype. Cardiac disease accounts for nearly all of the early deaths in ALGS.  Patients with intracardiac disease have approximately a 40% rate of survival to 6 years of life, compared with a 95% survival rate in patients with ALGS without intracardiac lesions [6].

Characteristic Facies Individuals with ALGS often have a characteristic facial appearance that may include a high forehead with frontal bossing, deep-set eyes with moderate hypertelorism, saddle or straight nose with a bulbous tip, and/or pointed chin (Fig. 62.2). Together, these features give the face an inverted triangle appearance. This facial appearance is one of the most penetrant findings in ALGS and is reported in up to 90% of patients with a JAG1 variant [6]. In early infancy, characteristic ALGS facial features may be difficult to recognize; however, this feature  becomes increasingly evident

Fig. 62.2  Facial features of Alagille syndrome

with age. In one study, a series of photographs from patients with ALGS and patients with other known early-onset liver diseases were evaluated by clinical dysmorphologists to determine the diagnostic sensitivity and specificity of ALGS facies. The study authors found clinical dysmorphologists were able to correctly identify ALGS facial features in 79% of pediatric cases [15]. Interestingly, in adults, ALGS facial features were more difficult to identify and were correctly identified in only 67% of cases. The author’s clinical experience is consistent with this finding, which suggests the forehead becomes less prominent after puberty, while the protruding chin is more noticeable, thus losing the overall triangle appearance. Recognition of ALGS-specific facies may aid in diagnoses, particularly in adult ALGS patients who present with idiopathic cardiac or renal disease and little or no hepatic involvement. It should be noted that the presence of ALGS facial features might be less evident among individuals with ALGS and Vietnamese heritage [16]. When evaluated by North American dysmorphologists, characteristic ALGS facies was only identified correctly in 24% of Vietnamese children with ALGS and a JAG1 variant. A higher sensitivity was reported by the referring pediatric gastroenterologist in Vietnam, who identified ALGS facies in 61% of children. Furthermore, a notably lower incidence of characteristic facial features has been described in ALGS patients with a NOTCH2 variant (20%) in comparison to those with a JAG1 variant (79%) [17]. These findings were recently confirmed in a congress abstract by the Global Alagille Alliance (GALA) Study Group, which describes the largest cohort of NOTCH2-­ associated ALGS to date [18]. These data indicate that

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c­ linicians should evaluate these patient populations for other extrahepatic involvement instead of relying on the characteristic facies.

Ophthalmologic The ocular abnormalities of patients with ALGS do not generally affect vision but are important as diagnostic tools. A large and varied number of ocular abnormalities have been described, though posterior embryotoxon is the most important diagnostically. Posterior embryotoxon is a prominent, centrally positioned Schwalbe’s ring (or line) at the point at which the corneal endothelium and the uveal trabecular meshwork join and is visible on slit-lamp examination. Posterior embryotoxon occurs in 56–88% of patients with ALGS and was also detected in 22% of children evaluated in a general ophthalmology clinic [19]. Posterior embryotoxon is seen in other multisystem disorders such as chromosome 22q deletion, as well. The Axenfeld anomaly, seen in 13% of patients with ALGS, is a prominent Schwalbe’s ring with attached iris strands and is associated with glaucoma. Optic disk drusen identified using ocular ultrasonography has been described in ALGS patients with high prevalence, but this test is not routinely performed [20].

Skeletal Involvement Vertebral abnormalities are described in the initial reports of this syndrome. The most characteristic finding is the sagittal cleft or butterfly vertebrae, which is found in 33–87% of patients with ALGS [1, 13, 21, 22]. This relatively uncommon anomaly may occur in normal individuals and is also seen in other multisystem abnormalities, such as 22q deletion syndrome and VATER (vertebral defects, anal atresia, tracheoesophageal fistula, radial and renal defect) syndrome. The affected vertebral bodies are split sagittally into paired hemivertebrae because of a failure of the fusion of the anterior arches of the vertebrae. The mildly affected vertebrae have a central lucency. A fully affected vertebra has a pair of separate triangular hemivertebrae whose apices face each other like the wings of a butterfly. Generally, these anomalies are asymptomatic and of no clinical significance. Other associated skeletal abnormalities include an abnormal narrowing of the adjusted interpedicular space in the lumbar spine, a pointed anterior process of C1, spina bifida occulta, fusion of the adjacent vertebrae, hemivertebrae, the absence of the 12th rib, and the presence of a bony connection between ribs. In addition, supernumerary digital flexion creases have been described in one-third of patients [23]. Severe metabolic bone disease with osteoporosis and pathologic fractures is common in patients with ALGS. Recurrent fractures, particularly of the femur, have

S. M. Vandriel and B. M. Kamath

been cited as an indication for LT. Preliminary survey data suggests that there is a propensity toward pathologic lower extremity long bone fractures in ALGS [24]. A number of factors may contribute to osteopenia and fractures, including severe chronic malnutrition, vitamin D and vitamin K deficiency, chronic hepatic, and renal disease. It is not yet known whether there is an intrinsic defect in cortical or trabecular structure of the bones in patients with ALGS. Olsen evaluated bone status in prepubertal children with ALGS and identified significant deficits in bone size and bone mass that were related to fat absorption but not dietary intake [25]. In a study from the Childhood Liver Disease Research Network (ChiLDReN), 49 ALGS patients and 99 children with other inherited chronic liver diseases underwent dual-energy X-ray absorptiometry (DXA) scans [26]. In ALGS, DXA measures were found to be low but improved after adjustment for weight and height. Of note, DXA Z-scores in the ALGS population correlated negatively with measures of cholestasis including TB and serum bile acid levels. These data support multifactorial influences on bone density in ALGS, with possible contribution of impaired Notch signaling. ALGS patients are frequently found to have short stature, and this is likely multifactorial in origin, resulting from cholestasis and malabsorption, congenital heart disease, and genetic predisposition. A validated growth curve for ALGS individuals is not yet available.

Renal Involvement Renal involvement in ALGS has been widely reported on an individual case basis or as part of a larger report on general features of ALGS.  The prevalence of renal involvement in larger series ranges from 40% to 70% such that it has been proposed that renal anomalies now be considered a disease-­ defining criterion in ALGS.  In a large retrospective study, there was a prevalence of 39% of renal anomalies or disease. The most common renal involvement was renal dysplasia (59%), followed by renal tubular acidosis (10%), vesicoureteric reflux (8%), and urinary obstruction (8%) [3]. Hypertension in patients with ALGS can be of cardiac, vascular, or renal etiology. Functional and structural evaluation of the kidneys should be undertaken in all patients. Renal function should be ­reassessed during the evaluation for  LT (see Management below).

Vascular Involvement Cerebrovascular anomalies are a well-known feature of ALGS and are a significant contributor to morbidity and

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early mortality [2]. Three distinct clinical phenotypes have emerged in ALGS, including (1) cerebral aneurysms, (2) syndromic moyamoya, and (3) anomalies of the internal carotid artery. The main clinical complication of these anomalies in ALGS is stroke, either ischemic or hemorrhagic. Ischemic stroke is typically associated with moyamoya, while cerebral aneurysms represent the most common cause of hemorrhagic stroke among patients with ALGS. The presence of a vasculopathies in ALGS is consistent with the intrinsic role of the Notch signaling pathway in vascular formation and morphogenesis. Retrospective studies in small cohorts of ALGS patients have reported wide ranges for the prevalence of cerebrovascular anomalies [2]. In one study, Emerick et al. retrospectively reviewed neuroimaging reports in 26 children with ALGS and identified anomalies in 38% of patients [27]. In this series, 100% of symptomatic ALGS patients and 23% of clinically asymptomatic patients had vascular anomalies detected by imaging studies. However, most concerning, cerebral angiography failed to detect any vascular anomaly in two asymptomatic patients, who both subsequently suffered fatal intracranial events several years after their baseline screening. These findings suggest the progression of underlying cerebrovascular disease. A more recent retrospective analysis by Carpenter et al. evaluated arterial and venous abnormalities in 19 children and young adults with ALGS [28]. The study authors reported cerebral arterial disease in 32% (N = 6/19) of ALGS patients, while venous anomalies were present in 21% (N = 4/19). Like Emerick et al., most patients were clinically asymptomatic at the time of neurovascular imaging, suggesting a high prevalence of silent cerebral vasculopathies. It is now recognized that vasculopathies in ALGS extend beyond the central nervous system (CNS). Reported systemic vascular abnormalities include aortic aneurysms and coarctations and celiac, hepatic, and renal arterial anomalies. In a large retrospective chart review of 268 patients with ALGS, 25 patients had vascular complications (9%), including three patients with aortic aneurysms, two with aortic coarctations, and one patient with bilateral renal artery stenosis [2]. The frequency of intra-abdominal vascular anomalies has particular significance for LT in ALGS [29].

Bleeding Tendency in ALGS Intracranial bleeding events are a concerning and potentially life-threatening complication of ALGS. Clinical series have reported cerebrovascular events in up to 16% of ALGS patients, with 30–50% of events resulting in mortality [2, 21]. Bleeding events in ALGS do not follow a distinct or predictable pattern and may occur spontaneously or with minimal trauma. An increased susceptibility to systemic bleeding events has also been observed in ALGS and appears

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to be unrelated to coagulopathy. In a retrospective chart review of 174 ALGS patients, 22% (n = 38/174) of individuals had one or more bleeding episodes, in the absence of coagulopathy [30]. The majority of the reported bleeding events occurred spontaneously or during a surgical or other invasive procedure. Concerningly, bleeding events accounted for 14% of deaths in the cohort. The underlying processes responsible for the heightened risk of spontaneous bleeding, particularly intracranial bleeding, among individuals with ALGS remain unclear. Impaired integrity of blood vessels due to an underlying developmental defect, particularly within the CNS, has been cited as a possible explanation. Moreover, as discussed in the preceding section, underlying cerebral vascular anomalies, including cerebral aneurysms, are known to contribute to some cases [31–33].

Infections and Immune Dysregulation It has been suggested that some individuals with ALGS may exhibit an immune-deficient phenotype characterized by recurrent episodes of otitis media with effusion (OME) and upper respiratory tract infections (URTIs). Serious, recurrent bacterial infections have not been reported in ALGS. Recurrent OME and URTIs have been described in up to 35% of children with ALGS, and it is hypothesized that this stems from an intrinsic defect in Notch signaling, specifically in CD46-Jagged1 interactions [13, 34]. CD46 is a complement and immune regulator that plays a critical role in mediating NOTCH expression during T cell activation. CD46 also mediates innate and adaptive immune responses. In a small case series, Shamouna et al. demonstrated increased Jagged1 expression on resting T cells in four immune-deficient ALGS patients. Furthermore, CD4+ T cells in these patients failed to elicit an efficient Th1 response to sustain induction of interferon (IFN)-γ production, both in vitro and in vivo. Similar findings have been described in CD46-deficient patients. The study authors also speculate that the molecular mechanisms leading to immune defects in ALGS may predispose patients to asthma, eczema, and food allergies [35, 36]. However, further studies are needed to understand how dysfunction in Notch signaling contributes to immune dysregulation in children with ALGS and the clinical significance of this problem.

Hearing Loss Children with ALGS are at greater risk for both conductive and sensorineural hearing loss (SNHL). ALGS-specific features may be a contributing factor to OME (as described

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above) and conductive hearing loss. Structural anomalies in the middle and inner ear have been described in ALGS, including partial or a complete absence of the bony and membranous structures of the posterior semicircular canals and hypoplasia of the anterior semicircular canals [37–39]. In one series, Teng and colleagues conducted hearing tests in 44 children with ALGS, of whom 13 had hearing loss in at least one ear [40]. Conductive hearing loss (27% of left ears, 30% of right ears) was the most common hearing impairment, followed by mixed hearing loss (14% of left ears, 9% of right ears) and SNHL (4% of left ears, 11% of right ears). More recently, in large multicenter cohort, Kamath et  al. investigated audiological manifestations in 110 children with ALGS and cholestatic liver disease. Air conduction testing was performed and revealed 38% (n = 42) of participations failed at least one frequency in one or both ears [12]. Tympanometry was subsequently performed in those who failed the air conduction test and identified 67% (n = 28/42) of participants failed in one or both ears. These data indicate a high prevalence of hearing impairment among ALGS patients and the need for ongoing surveillance and hearing screening.

Arthritis The number of reported cases of arthritis in ALGS has increased in recent years and may be more common than initially appreciated. In 1993, Jacobs and colleagues reported the first case of a child with ALGS and severe, refractory juvenile idiopathic arthritis (JIA) [41]. Two subsequent case reports have also described JIA in a child and an adult with ALGS [42, 43]. More recently, in an international, multicenter study, Ferrara et al. described ten children with ALGS and features of JIA [44]. The median age of onset was 6.5 years (range 2–10 years), and the median number of joints with active arthritis was 2 (IQR 0–4). The most commonly affected joints were the knees (90%) and ankles (70%), followed by the small joints of the hands or feet (50%). Notably, only 33% (n = 2/6) of ALGS children had positive antinuclear antibody (ANA) titers. The study authors pooled together all ALGS cases from their seven centers with and without JIA and reported a combined prevalence rate of 5% (n = 10/195). Strikingly, the estimated prevalence rate of JIA is 1 in 1000 children ( 105 virions/ml

10% replicating viruses in serum, 30-80% in liver

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negative hepatitis B.  However, reactivation rarely occurs during childhood and adolescents. Another particular condition warrants mention: occult HBV infection. It is defined as the existence of HBV DNA in serum among HBsAg-negative patients and can be classified into seropositive and seronegative with respect to the presence of anti-HBs or antibody against HBcAg (anti-HBc) antibodies. Possible explanations are low levels of viral replication activity or the emergence of HBV variants in the a-determinant of the S-gene. Occult hepatitis B is most common in endemic regions and seems rare with 1.4% [22]. However, prevalence may rise considerably in immunized children from HBsAg-positive mothers. One study reported a prevalence of 28% in this special group [23].

Long-Term Prognosis Individuals with chronic HBV infection are at risk to develop long-term sequelae such as end-stage liver disease including liver cirrhosis, hepatic failure, and HCC.  Progression strongly correlates with the disease activity in terms of viral replication level, inflammatory activity, HBsAg levels, HBV genotypes, and HBeAg/anti-HBe status. Strong risk factors for developing liver cirrhosis and HCC are higher age, male, presence of HBeAg, HBV DNA levels >104 copies/ml, HBsAg serum concentrations >103 IU/ml, and alanine aminotransferase (ALT) > 45 IU/l [24, 25]. Progression to liver cirrhosis in children is under 5% until adulthood, and data of the Asian region report 0.01–0.003% of individuals with chronic hepatitis B to be expected developing HCC in childhood [26, 27]. In general, anti-HBe seroconversion significantly reduces the risk of developing HCC.  The time at which anti-HBe seroconversion occurs is important. A study in adults investigating the 15-year cumulative incidences of HBeAg-negative hepatitis demonstrated that cirrhosis and HCC increased with increasing age of HBeAg seroconversion [28]. The lowest risk was observed in patients with anti-­ HBe seroconversion under the age of 30 (cirrhosis 7%, HCC 2.1%) and highest in individuals older than 40 years (cirrhosis 42.9%, HCC 7.7%). The hazard ratio for HBeAg-negative hepatitis, cirrhosis, and HCC was 2.95, 17.6, and 5.22, respectively, in the older compared with the younger group. The authors concluded that patients with HBeAg seroconversion before age 30 have an excellent prognosis, whereas patients with delayed HBeAg seroconversion after age 40 have significantly higher incidences of HBeAg-negative hepatitis, cirrhosis, and HCC. An additional precondition is persistently normal ALT levels [29]. Since children have a high probability to experience anti-HBe seroconversion until adulthood, the overall risk of developing severe liver disease in later life seems limited. Nevertheless, there remain a considerable number of patients with immune tolerance or

S. Wirth

inflammatory activity that needs careful and professional monitoring.

Relevance of Genotypes and Mutants During the replication cycle, HBV polymerase is acting as a reverse transcriptase without proofreading function. Therefore, mutant viral genomes are regularly emerging in a considerable number particularly during the high replicative status. Peculiar requirements such as replication modalities, selection pressure, and changing immunological conditions may select variants and strongly influence the predominant HBV quasispecies in an infected individual. Generally, a change of the primarily determined genotype is possible during long-term course and ranges between 2.8% and 19% usually associated with anti-HBe seroconversion [26, 30]. It is not yet known if there is any clinical impact at all. In adults, genotype C infection rather than genotype B is associated with a delayed anti-HBe seroconversion and a higher risk of developing HCC. Genotype D tends to proceed more severely and shows delayed anti-HBe seroconversion compared with genotype A.  Precore and basic core promotor (BCP) mutants are frequently associated with HBeAg-­ negative hepatitis, and HBsAg escape mutants are now increasingly observed in association with primarily vaccinated children. The typical precore point mutant is the G1896A stop codon preventing the production of HBeAg. It emerges typically around the time of anti-HBe seroconversion and may be associated with a decreased risk of developing HCC compared with the wild type. But it can also be found in patients with HBeAg-negative hepatitis. Depending on European or Asian regions, precore mutants have been detected between 8% and 50% in HBeAg-negative children. The BCP mutants A1762T/G1764A prevail to be associated with an increased risk for HCC. But, finally, the data remain controversial [7, 16, 31, 32].

Treatment Since there is no definite curative medical treatment available to date, it has to be defined what the aim of antiviral treatment should be in dependence on age group and phase of chronic hepatitis B. There is no doubt that one major goal is to reduce the risk of progressive liver disease and long-­ term sequelae such as liver cirrhosis, hepatic decompensation, and HCC and eventually to achieve the same life expectancy compared with healthy individuals of the same age. Unfortunately, anti-HBs seroconversion can only be reached in 5–10% at the most under current medical treatment strategies. Thus, the most important task in the treatment of children and adolescents is to achieve anti-HBe

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seroconversion at the earliest possible time associated with suppressed viral replication and decreased liver inflammation followed by persistent presence of anti-HBe, undetectable HBV DNA, and preferably aminotransferase values less than half of the upper limit of normal. Children with HBeAg-­ positive hepatitis should be monitored every 6 months with physical examination, measurement of laboratory parameters such as aminotransferases, hepatitis B serology, alpha-­ fetoprotein, and ultrasound of the liver. After anti-HBe seroconversion, follow-up visits can be performed for lifetime on an annual basis [15, 17, 33]. The decision to treat should be based on age, phase of HBV infection determined by ALT level, HBeAg/anti-HBe status, liver histology, coexisting diseases, and expectable compliance. The response rate in patients in the immune-­ tolerant phase is very low. Thus, treatment of children with normal aminotransferases is not recommended. Recently published clinical trials in immune-tolerant children and adults combining a nucleoside analogue and peg-alpha interferon did not achieve a higher anti-HBe seroconversion rate compared to the control group [34, 35]. However, treatment should be considered when aminotransferases rise and transition to the immune-active phase is recognized. Children and adolescents who have persistently elevated ALT levels for more than 6  months should be offered treatment. Currently, seven treatment options are approved for hepatitis B in adults, including two formulations of conventional and pegylated interferon as an immunomodulatory therapy and five nucleos(t)ide analogues (lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil) with strong reduction of viral replication. Approval for children and adolescents depends on the region. Large trials have been performed in children for lamivudine, adefovir, entecavir, and tenofovir. Entecavir has been authorized from 2  years onward, and adefovir and tenofovir disoproxil have been approved for subjects older than 12 years of age in the USA and Europe [36–38]. Predictors of response may be increased ALT levels, relatively low HBV DNA levels, and infection with genotype A or B. The main problem of all clinical trials with nucleos(t)ide analogues is the duration of medical treatment of not more than 96 weeks. Although a high proportion of treated patients will experience a significant decrease of viral load, the anti-HBe seroconversion rate cannot be expected to exceed 25%. After ceasing treatment, a reactivation of viral replication to baseline levels can be observed. A 24-week course of alpha interferon yields an approximately 10% higher anti-HBe seroconversion rate. Anti-HBs seroconversion rate is limited to single cases with nucleos(t)ide analogues and may range between 6% and 10% in patients with alpha interferon. There is no doubt that these results are dissatisfying with respect to our primary goal of anti-HBe seroconversion. Another interesting fact is that alpha interferon treatment only accelerates anti-HBe seroconversion in

837

successfully treated individuals but does not enhance the absolute number of responders [39]. Extending the treatment with nucleos(t)ide analogues for several years will result in an anti-HBe seroconversion rate of 40–50% [33]. However, there are no long-term data in children with regard to side effects. In the case of anti-HBe seroconversion, treatment should be maintained for 12 months, because the treatment-­ induced anti-HBe-positive status may be instable and reactivation may occur [40, 41]. In view of the present data and experience, there is a remarkable counseling conflict between the choice of drug and the duration of treatment, given that anti-HBe seroconversion remains the essential goal. Antiviral drug resistance is a major limitation to the long-term success of antiviral treatment. For this reason, lamivudine with a 5-year resistance rate of 70% has been considered obsolete just as adefovir which does often not sufficiently suppress viral replication. Nevertheless, at least for smaller children, lamivudine can be used as an approved drug for a limited time. Telbivudine has also a considerable resistance risk and is not approved. Entecavir and tenofovir do not show significant resistances after years of treatment. Tenofovir disoproxil may be associated with an increase in serum creatinine levels after 3–5 years of therapy. Decrease of bone mineral density has also been reported. These side effects might occur less frequent with the new tenofovir alafenamide. Oral treatment with nucleos(t)ide analogues is quite comfortable but needs a real true commitment to the treatment, and alpha interferon may have sometimes restrictive side effects but with the advantage of a defined duration. Thus, the decision which treatment option to choose is not that easy and has to be achieved in agreement with the patient and the parents. Alpha interferon is particularly appropriate for those children and adolescents who are reluctant to commit to a long duration of treatment and are not in the pubertal growth spurt. Nowadays, peg-alpha interferon should be recommended for 48 weeks. Nucleos(t)ide analogues are most appropriate for patients with contraindications to interferon, after liver transplantation with an anti-HBc-positive donor or under immune suppressive treatment. It is most important that they are willing to commit to a treatment for several, probably 3–5, years, maybe longer. Entecavir and tenofovir have the best profile in terms of safety, efficacy, and drug resistance. For younger patients, entecavir seems actually the preferable option. Children and adolescents with a HBeAg-negative hepatitis should be treated with a nucleos(t)ide analogue if ALT levels are elevated, and HBV DNA concentration is above 20,000  IU/ml to prevent progressive liver disease [42]. During long-term treatment with nucleos(t)ide analogues, HBV DNA, HBeAg/anti-HBe status, and aminotransferase levels should be monitored every 3 months. Very low or negative HBV DNA concentrations are important preconditions to avoid drug resistance.

838

Prevention Vaccination is the most effective procedure in order to prevent infection with the HBV. Active and passive immunization is well established in newborns of HBsAg-positive mothers. The first injections have to be administered within 12–24  h after birth to achieve a seroprotective response in 90–95% when two monthly follow-up active vaccinations are completed. Very-low-birth-weight preterm infants should receive a total of four doses. HBeAg-positive mothers can be treated with a nucleoside analogue (telbivudine, tenofovir) during the last trimester of pregnancy to reduce the risk of vertical transmission [14]. In many countries, routine active HBV vaccination is implemented in the vaccination schedule of all infants. Postvaccination testing for a protective anti-HBs concentration (> 100 IU/l) is not routinely recommended. If indicated, the best time would be approximately 2–3 months after the last vaccination. Revaccination is indicated in subjects with an anti-HBs titer 12 years of age a Yes Yes Not intended

Approved >3 years of age a Yes Yes Not intended

Daklinza, Sovaldi Zepatier Epclusa Vosevi Maviret

1, 4 1–6 1–6 1–6

Yes Yes Yes Yes Yes

Not intended In question Yes Not intended Yes

Not intended In question Yes, > 6 years Not intended Yes

Approval by FDA and EMA No longer in use in adults c Duration of treatment 8 weeks in non-cirrhotic patients a

b

Experiences with the treatment of children with chronic hepatitis C started in the early 1990s. Nineteen studies using recombinant alpha interferon were published between 1992 and 2003. A meta-analysis of trials with alpha interferon monotherapy showed a wide range of viral response (0–76%). Based on an increasing number of trials in adults, ribavirin was also added to alpha interferon treatment trials for children. Between the years 2000 and 2005, six studies were published showing a sustained viral response rate from 27% to 64% [52]. It became clear that genotype-2- and genotype-­ 3-­infected individuals responded much better. Alpha interferon-­2b in combination with ribavirin was then approved by the FDA. Trials with peg-alpha interferon and ribavirin followed in the next years, and both peg-alpha interferon-2b and peg-alpha interferon-2a have been approved by FDA and EMA 2008/2009 and 2011/2012 in combination with ribavirin for children. Peg-alpha interferon and ribavirin therapies in treatment-naïve children and adolescents yield a sustained viral response rate in approximately 50% of adequately treated genotype-1-infected patients. Thus, this option could theoretically be offered to all interested individuals. In patients infected with genotype 2 or 3, treatment for 24 weeks has a response rate of more than 90% [62–64]. It could be used in children from 3  years and peg-alpha interferon-2a from 5 years onward, but it is also no longer recommended. Since spontaneous viral elimination in vertically infected subjects may occur within the first 3 to 4 years, the start of therapy was agreed after the age of three. Treatment management of children with chronic hepatitis C infection is formed by the attitude of the medical attendant regarding the need of therapeutic intervention with respect to a generally slow progressive disease. In general, also for children and adolescents, interferon-based treatment options are considered obsolete, despite approval. Adverse events during treatment were frequent, and the duration was 24 to 48 weeks in dependence on the genotype. Under the aspect of health prevention for a long lifetime, all children with a measureable level of HCV RNA should be treated. The level

neither of aminotransferases nor of HCV RNA predicts the long-term outcome of the disease. Also, liver histology is not a helpful entry criterion for indicating treatment, because children generally do not have severe lesions. With the development of the new DAAs, there is no reason not to treat children and adolescents after diagnosis of chronic hepatitis C from 3 years of age onward [65, 66]. The drugs are well tolerated and have only an exceptionally low rate of side effects. Three groups of DAAs were differentiated in three groups: NS3/4A protease inhibitors, NS5a inhibitors, and polymerase inhibitors. Protease inhibitors have the ending “previr,” NS5a inhibitors have the ending “asvir,” and polymerase inhibitors are ending with “buvir.” Sofosbuvir is one of the most potent polymerase inhibitors. It is important to combine at least two of different groups to avoid developing rapid drug resistance. For the pediatric population, several clinical trials have been performed. Due to the approval regulations, the first groups included were between 13 and 18 years of age, followed by the younger ages. The combination of sofosbuvir and ledipasvir is approved from 3 years onward and suitable for the treatment of genotypes 1 and 4. It is administered for 12 weeks [67–69]. For genotypes 2 and 3, sofosbuvir and ribavirin are approved. Genotype 2 has to be treated for 12 weeks and genotype 3 for 24 weeks [70, 71], which can now be considered second line. The most recent approval is the combination of glecaprevir and pibrentasvir, which is pangenotypic (genotypes 1–6) and has the additional advantage of an 8-week treatment duration [72]. With Sofobuvir/Velpatasvir there are now two pangenotypic active drugs available. This panel seems sufficient to successfully addressing the pediatric chronic HCV infections. The overall sustained viral response rate was extremely high and achieved in most of the trials 100%. That was also true for individuals who were treatment experienced with a previous interferon-based therapy. Relapses were observed only in few isolated cases. It is recommended to determine HCV RNA 4 weeks after the start of treatment. Most patients are already negative at that time. The most important checkpoint is SVR

63  Chronic Viral Hepatitis B and C

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17. Sokal EM, Paganelli M, Wirth S, et  al. Management of chronic hepatitis B in childhood: ESPGHAN clinical practice guidelines: consensus of an expert panel on behalf of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition. J Hepatol. 2013;59(4):814–29. 18. Hui CK, Leung N, Yuen ST, et al. Natural history and disease progression in Chinese chronic hepatitis B patients in immune-tolerant phase. Hepatology. 2007;46:395–401. 19. Bortolotti F. Treatment of chronic hepatitis B in children. J Hepatol. 2003;39(Suppl 1):S200–5. 20. Popalis C, Yeung LT, Ling SC, Ng V, Roberts EA. Chronic hepatitis B virus (HBV) infection in children: 25 years’ experience. J Viral Hepat. 2013;20:e20–6. 21. Iorio R, Giannattasio A, Cirillo F, D’Alessandro L, Vegnente A.  Long-term outcome in children with chronic hepatitis B: a 24-year observation period. Clin Infect Dis. 2007;45:943–9. 22. Minuk GY, Sun DF, Uhanova J, et al. Occult hepatitis B virus infection in a North American community-based population. J Hepatol. 2005;42:480–5. 23. Shahmoradi S, Yahyapour Y, Mahmoodi M, et al. High prevalence of occult hepatitis B virus infection in children born to HBsAg-­ References positive mothers despite prophylaxis with hepatitis B vaccination and HBIG. J Hepatol. 2012;57:515–21. 1. Nel E, Sokol RJ, Comparcola D, et al. Viral hepatitis in children. J 24. Lee MH, Yang HI, Liu J, et  al. Prediction models of long-term Pediatr Gastroenterol Nutr. 2012;55:500–5. Cirrhosis and hepatocellular carcinoma risk in chronic hepatitis B 2. McMahon BJ, Alward WL, Hall DB, et  al. Acute hepatitis B patients: risk scores integrating host and virus profiles. Hepatology. virus infection: relation of age to the clinical expression of dis2013;58:546–54. ease and subsequent development of the carrier state. J Infect Dis. 25. Tseng TC, Liu CJ, Yang HC, et al. Serum hepatitis B surface anti1985;151:599–603. gen levels help predict disease progression in patients with low 3. Chatzidaki V, Kouroumalis E, Galanakis E. Hepatitis B virus acquihepatitis B virus loads. Hepatology. 2013;57:441–50. sition and pathogenesis in childhood: host genetic determinants. J 26. Ni YH, Chang MH, Wang KJ, et al. Clinical relevance of hepatitis Pediatr Gastroenterol Nutr. 2011;52:3–8. B virus genotype in children with chronic infection and hepatocel 4. Trautwein C. Mechanisms of hepatitis B virus graft reinfection and lular carcinoma. Gastroenterology. 2004;127:1733–8. graft damage after liver transplantation. J Hepatol. 2004;41:362–9. 27. Chang MH, You SL, Chen CJ, et al. Decreased incidence of hepa 5. Levrero M, Pollicino T, Petersen J, et al. Control of cccDNA functocellular carcinoma in hepatitis B vaccines: a 20-year follow-up tion in hepatitis B virus infection. J Hepatol. 2009;51:581–92. study. J Natl Cancer Inst. 2009;101:1348–55. 6. Bonilla Guerrero R, Roberts LR. The role of hepatitis B virus inte 28. Chen JD, Yang HI, Iloeje UH, et al. Carriers of inactive hepatitis B grations in the pathogenesis of human hepatocellular carcinoma. J virus are still at risk for hepatocellular carcinoma and liver-related Hepatol. 2005;42:760–77. death. Gastroenterology. 2010;138:1747–54. 7. Shi YH, Shi CH.  Molecular characteristics and stages of 29. Tai DI, Lin SM, Sheen IS, et al. Long-term outcome of hepatitis B chronic hepatitis B virus infection. World J Gastroenterol. e antigen-negative hepatitis B surface antigen carriers in relation to 2009;15:3099–105. changes of alanine aminotransferase levels over time. Hepatology. 8. Hadziyannis SJ.  Natural history of chronic hepatitis B in Euro-­ 2009;49:1859–67. Mediterranean and African countries. J Hepatol. 2011;55:183–91. 30. Wirth S, Bortolotti F, Brunert C, et al. Hepatitis B virus genotype 9. Jefferies M, Rauff B, Rashid H, Lam T, Rafiq S. Update on global change in children is closely related to HBeAg/anti-HBe seroconepidemiology of viral hepatitis and preventive strategies. World J version. J Pediatr Gastroenterol Nutr. 2013;57:363–6. Clin Cases. 2018;6:589–99. 31. Kao JH. Hepatitis B viral genotypes: clinical relevance and molecu 10. Mahtab MA, Rahman S, Khan M, Karim F. Hepatitis B virus genolar characteristics. J Gastroenterol Hepatol. 2002;17:643–50. types: an overview. Hepatobiliary Pancreat Dis Int. 2008;7:457–64. 32. Alavian SM, Carman WF, Jazayeri SM. HBsAg variants: diagnostic-­ 11. Lee C, Gong Y, Brok J, Boxall EH, Gluud C. Effect of hepatitis B escape and diagnostic dilemma. J Clin Virol. 2013;57:201–8. immunisation in newborn infants of mothers positive for hepati 33. Kwon H, Lok AS.  Hepatitis B therapy. Nat Rev Gastroenterol tis B surface antigen: systematic review and meta-analysis. BMJ. Hepatol. 2011;8:275–84. 2006;332:328–36. 34. Feld JJ, Terrault NA, Lin HS, et al. Entecavir and Peginterferon 12. Lee C, Gong Y, Brok J, Boxall EH, Gluud C. Hepatitis B immunialfa-2a in adults with hepatitis B e antigen-positive immunesation for newborn infants of hepatitis B surface antigen-positive tolerant chronic hepatitis B virus infection. Hepatology. mothers. Cochrane Database Syst Rev. 2006;2:CD004790. 2019;69:2338–48. 13. Han GR, Cao MK, Zhao W, et  al. A prospective and open-label 35. Rosenthal P, Ling SC, Belle SH, et al. Combination of Entecavir/ study for the efficacy and safety of telbivudine in pregnancy for the Peginterferon alfa-2a in children with hepatitis B e antigen-positive prevention of perinatal transmission of hepatitis B virus infection. J immune tolerant chronic hepatitis B virus infection. Hepatology. Hepatol. 2011;55:1215–21. 2019;69:2326–37. 14. Aslam A, Campoverde Reyes KJ, Malladi VR, Ishtiaq R, Lau 36. Murray KF, Szenborn L, Wysocki J, et al. Randomized, placebo-­ DTY.  Management of chronic hepatitis B during pregnancy. controlled trial of tenofovir disoproxil fumarate in adolescents with Gastroenterol Rep (Oxf). 2018;6:257–62. chronic hepatitis B. Hepatology. 2012;56:2018–26. 15. Paganelli M, Stephenne X, Sokal EM. Chronic hepatitis B in chil 37. Jonas MM, Little NR, Gardner SD.  Long-term lamivudine treatdren and adolescents. J Hepatol. 2012;57:885–96. ment of children with chronic hepatitis B: durability of therapeutic 1 6. Wai CT, Fontana RJ. Clinical significance of hepatitis B virus genoresponses and safety. J Viral Hepat. 2008;15:20–7. types, variants, and mutants. Clin Liver Dis. 2004;8:321–52. vi

24, 24 weeks after cessation of treatment, as HCV RNA negativity is associated with long-term elimination. The safety and tolerability profile of the DAAs is also excellent. The vast majority of adverse events were mild and unrelated to the medication. Headache, fatigue, or signs of upper respiratory tract infections were registered up to about 15% [72]. In adult trials, there was no difference to the side effects of the placebo arm. Treatment does not appear to have an impact on growth and development. Overall, early treatment of the pediatric population with chronic hepatitis C will decrease the pool of infected individuals and not only alleviate the development of a progressive liver disease but also prevent further transmission in the hope to eradicate the disease in this age group.

842 38. Jonas MM, Mizerski J, Badia IB, et  al. Clinical trial of lamivudine in children with chronic hepatitis B.  N Engl J Med. 2002;346:1706–13. 39. Bortolotti F, Iorio R, Nebbia G, et al. Interferon treatment in children with chronic hepatitis C: long-lasting remission in responders, and risk for disease progression in non-responders. Dig Liver Dis. 2005;37:336–41. 40. Sokal EM, Kelly DA, Mizerski J, et  al. Long-term lamivudine therapy for children with HBeAg-positive chronic hepatitis B. Hepatology. 2006;43:225–32. 41. EASL clinical practice guidelines: management of chronic hepatitis B virus infection. J Hepatol. 2012;57:167–85. 42. Papatheodoridis GV, Manesis EK, Manolakopoulos S, et al. Is there a meaningful serum hepatitis B virus DNA cutoff level for therapeutic decisions in hepatitis B e antigen-negative chronic hepatitis B virus infection? Hepatology. 2008;48:1451–9. 43. Robinson JL, Doucette K. The natural history of hepatitis C virus infection acquired during childhood. Liver Int. 2012;32:258–70. 44. Bartenschlager R, Cosset FL, Lohmann V. Hepatitis C virus replication cycle. J Hepatol. 2010;53:583–5. 45. Mack CL, Gonzalez-Peralta RP, Gupta N, et al. NASPGHAN practice guidelines: diagnosis and management of hepatitis C infection in infants, children, and adolescents. J Pediatr Gastroenterol Nutr. 2012;54:838–55. 46. Ruiz-Extremera A, Munoz-Gamez JA, Salmeron-Ruiz MA, et  al. Genetic variation in interleukin 28B with respect to vertical transmission of hepatitis C virus and spontaneous clearance in HCV-­ infected children. Hepatology. 2011;53:1830–8. 47. Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:1335–74. 48. Wirth S, Kelly D, Sokal E, et  al. Guidance for clinical trials for children and adolescents with chronic hepatitis C.  J Pediatr Gastroenterol Nutr. 2011;52:233–7. 49. Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology. 2013;57:1333–42. 50. Mok J, Pembrey L, Tovo PA, Newell ML.  When does mother to child transmission of hepatitis C virus occur? Arch Dis Child Fetal Neonatal Ed. 2005;90:F156–60. 51. Bortolotti F, Indolfi G, Zancan L, et  al. Management of chronic hepatitis C in childhood: the impact of therapy in the clinical practice during the first 2 decades. Dig Liver Dis. 2011;43:325–9. 52. Bortolotti F, Verucchi G, Camma C, et  al. Long-term course of chronic hepatitis C in children: from viral clearance to end-stage liver disease. Gastroenterology. 2008;134:1900–7. 53. Wirth S. Current treatment options and response rates in children with chronic hepatitis C. World J Gastroenterol. 2012;18:99–104. 54. Batsis ID, Wasuwanich P, Karnsakul WW.  The management of hepatitis B and hepatitis C in children. Minerva Pediatr. 2019;71:59–75. 55. Rodrigue JR, Balistreri W, Haber B, et  al. Impact of hepatitis C virus infection on children and their caregivers: quality of life,

S. Wirth cognitive, and emotional outcomes. J Pediatr Gastroenterol Nutr. 2009;48:341–7. 56. McAndrews MP, Farcnik K, Carlen P, et al. Prevalence and significance of neurocognitive dysfunction in hepatitis C in the absence of correlated risk factors. Hepatology. 2005;41:801–8. 57. Omland LH, Krarup H, Jepsen P, et al. Mortality in patients with chronic and cleared hepatitis C viral infection: a nationwide cohort study. J Hepatol. 2010;53:36–42. 58. Sangiovanni A, Prati GM, Fasani P, et  al. The natural history of compensated cirrhosis due to hepatitis C virus: a 17-year cohort study of 214 patients. Hepatology. 2006;43:1303–10. 59. Aghemo A, De Francesco R. New horizons in hepatitis C antiviral therapy with direct-acting antivirals. Hepatology. 2013;58:428–38. 60. Afdhal N, Zeuzem S, Kwo P, et  al. Ledipasvir and sofosbu vir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370:1889–98. 61. Cornberg M, Honer zu Siederdissen C, Maasoumy B, Manns MP. New direct-acting antiviral agents for the treatment of chronic hepatitis C in 2014. Internist (Berl) 2014;55:390–400. 62. Druyts E, Thorlund K, Wu P, et al. Efficacy and safety of pegylated interferon alfa-2a or alfa-2b plus ribavirin for the treatment of chronic hepatitis C in children and adolescents: a systematic review and meta-analysis. Clin Infect Dis. 2013;56:961–7. 63. Sokal EM, Bourgois A, Stephenne X, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in children and adolescents. J Hepatol. 2010;52:827–31. 64. Wirth S, Ribes-Koninckx C, Calzado MA, et  al. High sustained virologic response rates in children with chronic hepatitis C receiving peginterferon alfa-2b plus ribavirin. J Hepatol. 2010;52:501–7. 65. Clemente MG, Antonucci R, Sotgiu G, et  al. Present and future management of viral hepatitis B and C in children. Clin Res Hepatol Gastroenterol. 2020;44:801–9. 66. Karnsakul W, Schwarz KB. Management of Hepatitis C Infection in children in the era of direct-acting antiviral agents. J Viral Hepat. 2019;26:1034–9. 67. Balistreri WF, Murray KF, Rosenthal P, et al. The safety and effectiveness of ledipasvir-sofosbuvir in adolescents 12-17 years old with hepatitis C virus genotype 1 infection. Hepatology. 2017;66:371–8. 68. Schwarz KB, Rosenthal P, Murray KF, et al. Ledipasvir-Sofosbuvir for 12 weeks in children 3 to   95th percentile and overweight as a BMI between the 85 and 95th centile. The ‘normal’ BMI varies with age and sex, and different centile charts are available for different populations. More than 370 million children and young people aged 0–19  years are now overweight or obese (http://globalnutritionreport.org) and are likely to remain so in adulthood, and thus more likely to develop NAFLD and type 2 diabetes. Variation in reports of prevalence of NAFLD is partly due to the different methods of detection and a lack of clarity regarding the definition of the disorder [7, 12, 13]. Liver biopsy is the criterion standard for diagnosis of NAFLD, but clearly this is not feasible as an epidemiological tool and proxy markers such as abnormal transaminases and/or the presence of an echogenic liver on ultrasound are often used

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 S. Guandalini, A. Dhawan (eds.), Textbook of Pediatric Gastroenterology, Hepatology and Nutrition, https://doi.org/10.1007/978-3-030-80068-0_69

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to define the disorder. The true sensitivity, specificity and predictive value of these proxy markers are unknown, and it is well recognised that an elevation of transaminases may only occur in 60% of cases of fibrotic NAFLD [14]. As the reference range for AST and ALT is derived from population data including those with undiagnosed NAFLD, the use of these markers as a proxy for NAFLD is flawed [4, 15]. In addition, there is considerable variation in the normal ranges for laboratory values across different institutions. Nevertheless, in the absence of a more robust noninvasive diagnostic test, population studies have used an elevated ALT (in the absence of other diagnoses) as definition of the disorder. In one US-based study, an elevated ALT was found in 8% of 5586 adolescents aged 12–19 years [16]. Park et al. reported a prevalence of 3.2% in 1543 Korean teenagers using ALT >40 [17]. In Japan a population-based study found 2.6% of children to have NAFLD based on ultrasound [18]. In a study from Italy of 268 obese children, 44% had NAFLD using ultrasound and elevated ALT [19]. Studies of liver biopsy findings give a more accurate reflection of prevalence as NAFLD is a histological diagnosis. One of the most useful studies reporting prevalence in the general paediatric population is an autopsy study of 800 children and young people who died of accidental injury. Schwimmer et al. reported fatty liver in 9.3% of this cohort, with NASH present in 3% [5]. The prevalence of NAFLD appears to increase with age, and in general, boys are more at risk [5, 20, 21]. Ethnic variations also exist; Hispanic children and adolescents have a greater risk of NAFLD compared to Caucasian children. Black, non-Hispanic children are less susceptible despite a higher incidence of insulin resistance [5, 21, 22]. This mirrors findings in adults [6, 23, 24]. Both genetic and environmental factors are likely to be involved in ethnic distribution. Familial clustering is also seen [25, 26] with a strong heritability in first-degree relatives [27]. The advent of genome-wide association studies (GWAS) and candidate gene studies has significantly advanced our understanding of genetic susceptibility to NAFLD. Though a smaller body of evidence exists in genetic variation in susceptibility of children with NAFLD than in adults with the condition, children are arguably most likely to demonstrate the effects of genetic variation. We now understand that single nucleotide polymorphisms (SNPs) in DNA (resulting in the altered expression of a gene or altered protein function) and other epigenetic modification influence the phenotype of this polygenic disease [28]. In both GWAS and candidate gene studies, variants in certain genes, namely, patatin-like phospholipase domain-containing protein (PNPLA3; adiponutrin) variant I148M, the transmembrane superfamily 2 (TM6SF2) variant E167K and variants in GCKR (glucokinase regulatory protein) and MBOA7 (membrane-bound O-acyltransferase domain containing 7), amongst others,

E. Fitzpatrick

most consistently convey a susceptibility to NAFLD in both adults and children [29–32]. Perhaps best described and most frequently cited is the variant within PNPLA3, where the mutated protein accumulates on the surface of lipid droplets in the hepatocyte, altering lipid remodelling, and also promotes retinol release prompting inflammation and fibrogenesis [33, 34]. The coexistence of obesity amplifies the effect of the variants [35], and the cumulative risk of genetic variants is also of importance. In a study of 450 children, the combination of variants in PNPLA3, TM6SF2, GCKR and MBOAT7 explained 19% of hepatic fat fraction (HFF%) variance as quantified by MRI. There is amplification of this effect in the presence of obesity and overweight [36]. Understanding the genetic variation contributing to disease in an individual may allow more targeted prevention and reversal of disease. Epigenetic factors, particularly microRNA, have been implicated in pathogenesis of NAFLD. Epigenetic modification is unrelated to changes in DNA sequence. MicroRNAs are small soluble RNAs which influence the translation of certain genes. The relative underexpression of microRNA-122 has been described in NAFLD [37]. The importance of the antenatal environment on metabolic programming has been well established since the reports of Barker [38, 39]. Antenatal programming of a child’s liver to injury due to lipid accumulation, oxidative stress and innate immune dysfunction may play a role in the susceptibility to NAFLD [40]. In rodent models, the effect of a high-fat diet (HFD) in dams can be seen in the predisposition to developing fatty liver in offspring. A cumulative effect can be seen when the pup offspring of HFD dams are fed with a methionine choline-­deficient (MCD) diet, a well-established model for NAFLD [41]. An alteration of DNA methylation and a decrease of microbiome diversity in the gut were found possibly to mediate the effect. In mice, maternal obesity and a postweaning high-fat diet were independent risk factors for steatosis and steatohepatitis and fibrosis at 12  months with a significant increase in liver injury when both risk factors were present [40]. A macaque model of HFD prior to breeding and during pregnancy showed similar findings with increased steatosis in the offspring of treated mothers [42]. The equivalent antenatal priming of the liver in humans, which may then be exposed to decades of excess nutrition and sedentary behaviour, may result in a more severe phenotype or progressive disease. The early effects of maternal metabolic control on the infant liver have been investigated. Stillborn infants of mothers with gestational diabetes mellitus (GDM) were found to have steatotic livers in 78.8% of cases versus 17% of those born to nondiabetic mothers [43]. Live-born infants to ­mothers with GDM in another study demonstrated a higher

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liver fat content on MRI in those born to mothers with GDM than controls [44]. As adipose tissue deposition does not occur until the third trimester, there is foetal hepatic accumulation of excess substrate together prior to this point with an increase in de novo lipogenesis due to a high transplacental glucose supply in infants of diabetic mothers [38]. This is in the context that up to 60% mothers are now obese at the time of conception and thus at high risk of GDM [45]. Further evidence of the importance of a healthy pregnancy is that birth weight is associated with the development of NAFLD in childhood in a large cohort [46]. Early nutrition is likely also important in modification of the risk of later NAFLD. Nobili and colleagues have studied breast feeding habits in a cohort of children with NAFLD and concluded that breast feeding is protective against progression of the disease from simple steatosis to steatohepatitis and fibrosis [47]. The role of maternal obesity and the method of delivery and of early infant feeding may all be mediated in part via the microbiome and a decrease in diversity conveyed to the infant microbiome which is associated with later obesity. Soderberg et al. demonstrated this effect in mice by colonising germ-free mice with microbiota from 2-week-old pups born to obese mothers or to normal weight mothers. Mice colonised with the microbiota from infants of obese mothers demonstrated increased liver injury with a histological pattern similar to paediatric patients with NAFLD [48]. Nutrition and physical activity are critically important environmental factors determining risk of NAFLD, with lifestyle modification as the primary recommendation in the prevention and management of the disease [49, 50]. Excess food intake and lack of exercise contribute to weight gain and contribute to the progression of liver fibrosis and inflammation in patients with NAFLD [51, 52]. Specific dietary factors either protect against or exacerbate the development and progression of NAFLD.  Food-­ based analyses have suggested that higher meat and fructose [53–55] and higher consumption of low-nutrient, high-­ calorie, high-salt food [56] are associated with NAFLD. Fructose has been identified as a particular culprit in increasing fat, inflammation and fibrosis [57, 58]. Fewer paediatric studies of dietary composition have been undertaken in NAFLD; however, a large study from Australia compared Western/health diet in 993 14-year-olds to later development of NAFLD on ultrasound and found a significant association of Western diet and development of steatosis at 17  years [59]. A study in 82 obese Greek children revealed that a diet higher in carbohydrates and saturated fatty acids and lower in omega-3 was associated with NAFLD [60]. Dietary chemical composition of fatty acids may be an important factor in lipotoxicity observed in insulin resis-

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tance. Palmitic acid rather than oleic acid results in lower steatosis but in higher cell death and impaired insulin signalling [61]. A study of fish intake and omega-3 fatty acid intake in children with NAFLD revealed a dietary deficiency of both was associated with increased portal and lobular inflammation [62]. Vos et al. described an association of dietary vitamin E insufficiency and increased steatosis in children with NAFLD [63].

Pathophysiology NAFLD can be thought of as the hepatic manifestation of the metabolic syndrome (linking obesity, insulin resistance, hypertension and hyperlipidaemia). The pathogenesis of the condition is still incompletely understood. Insulin resistance (IR) is a finding in up to 80% of children with NAFLD and has a similarly high prevalence in adults with the condition [22, 24, 64, 65]. It is widely accepted that IR and the resulting hyperinsulinemia seem to play a major role in the development of hepatic steatosis and steatohepatitis. The molecular mechanism leading to the involvement of IR in the development of NAFLD is complex however, and has not yet been fully elucidated. The ‘two-hit hypothesis’ proposed in 1998 consisting of a first hit of liver fat accumulation followed by a trigger for inflammation and fibrosis, was first thought of as a model of liver injury in NAFLD. We now know there are likely multiple ‘hits’ including oxidative stress, intestinal dysbiosis, bile acid dysregulation [66, 67] and adipocytokines from a high visceral fat mass or saturated free fatty acids (FFA) [68–70]. Figure 69.1 demonstrates the interplay of the multiple hits.

Steatosis Macrovesicular steatosis is characterised by the accumulation of triglycerides (formed of glycerol esterified to three fatty acids) in the hepatocyte. Steatosis is conventionally thought to arise from increased hepatic supply of FFA as a result of obesity and associated extrahepatic insulin resistance. Normally adipocytes store fat after meals and release fat during fasting by lipolysis. In the liver, carbohydrate is stored as glycogen, and when the liver is saturated, de novo lipogenesis occurs via acetyl coenzyme A and fatty acid synthetase. The third source of fatty acids as a substrate for the liver is dietary. In the setting of normal insulin sensitivity, fatty acids undergo esterification to triglycerides in the hepatocyte and are then exported from the cell as very low-density ­lipoproteins (VLDL) via apolipoprotein B enzyme activity

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Obesity

Dyslipidemia

Bile acids

Insulin resistance Adipokines

Increased lipogenesis Decreased lipolysis XS FFA supply

Proinflammatory pathways

Cytokines / chemokines

Oxidative stress

TLRs

NASH / Fibrosis Gut – liver axis

Fig. 69.1  Interplay of multiple hits involved in the pathogenesis NAFLD

[71]. Alternatively they may undergo β-oxidation in the mitochondria or oxidation in the peroxisomes or microsomes. Uptake of FFA into the mitochondria requires carnitine palmitoyl acyl-transferase which is inhibited by insulin and malonyl coenzyme A. The net retention of lipids is the primary problem in steatosis. The most consistent predisposing factor to hepatic fatty acid accumulation is insulin resistance, though other factors may be involved. In normal physiological circumstances, the role of insulin includes glycogen synthesis, glycolysis and protein and lipid synthesis. In the postprandial state, insulin promotes lipogenesis and suppresses lipolysis and gluconeogenesis. The normal fall in insulin with the fasting state, which is accompanied by an increase in glucagon and catecholamines, mediates glycogenolysis and gluconeogenesis. These processes are accompanied by lipolysis and increased lipid oxidation. Sensitivity to insulin is increased by adiponectin and decreased by TNFα [72]. In the setting of insulin resistance, fat-laden and insulin-­ resistant adipocytes continue to release glycerol and FFA into the circulation, and deliver increased free FFA to the liver [73–75]. This in itself may then induce hepatic IR [76].

Hyperinsulinemia and hyperglycaemia promote de novo lipogenesis via upregulation of the transcription factors sterol regulatory element-binding protein 1c (SREBP1c) and peroxisome proliferator-activated receptor γ (PPARγ) [73]. In addition, insulin increases malonyl coenzyme A (an intermediate of FA synthesis) and inhibits carnitine palmitoyl transferase, thereby inhibiting the passage of long-chain fatty acids (LCFA) into mitochondria for β-oxidation [77]. SREBP1c can also be upregulated by glucose and saturated fats, whereas polyunsaturated fatty acids (PUFAs) lead to decreased expression [78]. Increased glucose levels also stimulate lipogenesis through the activation of carbohydrate response element-binding protein (ChREBP), a transcription factor activating the expression of key enzymes of glycolysis and lipogenesis [79, 80]. Hyperinsulinemia also results in decreased triglyceride secretion as VLDL by lowering apolipoprotein B synthesis and stability [81, 82]. Hence, hepatic FFA uptake and lipogenesis outweigh FA oxidation and triglyceride secretion leading to hepatic fat accumulation [83]. In the setting of peripheral insulin resistance, some hepatic insulin sensitivity may be preserved with continuing de novo lipogenesis as a consequence. This is mixed and thought to be medicated

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through a functioning insulin receptor substrate 1 (IRS-1) which blocks lipid oxidation, but aberrant IRS-2 serine phosphorylation which fails to suppress gluconeogenesis [71].

Oxidative Stress Mitochondrial FA oxidation and ketogenesis are increased, and the transcription factor PPARα is activated as a result of fatty acid accumulation [84]. This results in reactive oxygen species (ROS) which lead to oxidative stress and lipid peroxidation. Cell membranes are damaged, and cytochrome c is released from the mitochondrial intermembrane space. In turn, this leads to an imbalance in the flow of electrons over the respiratory chain (RC) creating overreduction of RC complexes which can react with oxygen to form further ROS [85]. ROS may then propagate liver inflammation and injury. Mitochondrial function has been shown to be impaired in patients with severe steatosis and steatohepatitis [86]. Ultrastructural abnormalities of mitochondria have been demonstrated in patients with NASH [87, 88]. It is not clear if this is a primary or secondary phenomenon however. Mitochondrial abnormalities could be a pre-existing condition enabling the excessive production of ROS in the setting of enhanced FFA ß-oxidation [87]. This could explain why for the same amount of obesity, or for the same degree of IR, certain patients just have steatosis, whilst others develop NASH and cirrhosis. Genetic polymorphisms could also at least partially explain this difference in susceptibility as some could favour mitochondrial dysfunction [89]. Alternatively the overload of the mitochondrial RC, the resulting formation of ROS and subsequent lipid peroxidation products may give rise to mitochondrial damage. There is an inverse correlation of peripheral TNFα levels and measures of insulin resistance with RC enzyme levels suggesting that insulin resistance and cytokine activity may be important in impairment of the mitochondrial RC [90]. Enhanced ROS formation in the vulnerable steatotic liver subsequently triggers lipid peroxidation and the formation of reactive aldehydes such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA). These give rise to further mitochondrial damage and ROS formation, resulting in a vicious cycle [85]. Hepatic stellate cells may be activated by these molecules, thus leading to fibrosis [91].

Cytokines and Inflammation Much of the progression from simple steatosis to steatohepatitis is characterised by an inflammatory response [92]. It is clear from both rodent and human studies that hepatic steatosis is associated with a state of chronic inflammation [93– 95]. More specifically, hepatic steatosis in this context is associated with nuclear factor κB (NFκB) activation. FFA can directly activate the pathway via a lysosomal cathepsin

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B-dependent mechanism [96], as can mitochondrial and ER stress [94, 97]. NFκB is a sequence-specific transcription factor that functions as a pro-inflammatory master switch during inflammation. It upregulates the transcription of a wide range of inflammatory mediators including TNFα, IL6 and IL1β. Increased production of inflammatory cytokines by hepatocytes leads to Kupffer cell activation with subsequent inflammatory mediator release and hepatic and systemic insulin resistance [98]. Animal studies have shown that translocation of bacteria from the gut to the liver via the mesenteric circulation can activate Kupffer cells (via CD14/Toll-like receptor 4 (TLR4) binding) and induce a local and systemic inflammatory response [99]. There has been a great deal of interest in gut microbiota and the innate immune response in the context of obesity and insulin resistance [100]. There is evidence that intestinal bacterial overgrowth exacerbates NAFLD and that the prevalence of bacterial overgrowth is higher in those who are obese [101], the portal circulation providing a direct route from the gut to the liver. Manipulation of gut microbiota and elimination of intestinal bacterial overgrowth may thus be promising ways to halt the progression of steatosis to steatohepatitis and fibrosis. Finally, visceral fat is a highly inflammatory tissue and the source of many inflammatory mediators known as adipocytokines which have an important role in insulin resistance and, most likely, in NAFLD [102, 103]. These adipocytokines, including leptin, adiponectin, TNFα and IL6, are polypeptides produced by both adipocytes and macrophages which infiltrate adipose tissue [104]. Adipokines are involved in the various injury patterns in NASH such as cell death, inflammation and fibrosis [85]. Leptin is a 16 kDa protein, a product of the ob gene, and has important roles in appetite suppression and regulation of energy metabolism [105], with high levels in obese individuals though this is thought to be a result of leptin resistance. The role of leptin in NAFLD is not yet clear though it is thought to contribute as a pro-inflammatory, profibrogenic mediator [106, 107]. Adiponectin is a polypeptide adipokine with a collagen-­ like domain and globular domain produced in white adipose tissue. It has an important role in insulin sensitivity; as part of their action, thiazolidinediones are known to increase levels of adiponectin [108]. It is also hepatoprotective with anti-­ inflammatory and anti-fibrogenic properties [109–111].

Hepatocyte Apoptosis Hepatocyte apoptosis is recognised as an important event in the development of chronic liver disease and has particular prominence in NAFLD [112]. The initiating event in apoptosis may be extrinsically mediated hepatocyte injury (e.g. in autoimmune liver disease, viral hepatitis and ischaemia per-

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fusion injury). This is usually directed through pathways involving Fas ligand, TNFα, and TRAIL.  Alternatively, intrinsic injury and death may occur via organelle dysfunction when cells are subjected to excessive oxidative stress (ER or mitochondrial), e.g. with drugs/toxins, fatty acids, and iron. This results in altered membrane permeability and RNA damage with cytochrome C release [113]. The injurious mechanism in NAFLD/NASH appears to be due to a combination of extrinsic and intrinsic insults [114, 115]. Though apoptosis is classically thought to be a silent event without provoking an inflammatory response, this is not the case in the liver [114]. Apoptotic bodies can activate stellate cells and Kupffer cells inducing an inflammatory response and leading to the progression of steatohepatitis and fibrosis [116, 117].

ised by septae and nodule formation. Several different injurious processes will result in fibrosis. Hepatocyte injury, inflammation, apoptosis and death initiate the process which involves a cascade of inflammatory cells, the release of cytokines and the activation of fibrogenic effector cells (mainly stellate cells) [118]. Thus, a number of different processes and mechanisms are involved in the progression of steatosis to NASH: oxidative stress, inflammation, apoptosis and fibrosis (Fig. 69.2). The exact sequence of development of obesity, fatty liver and NAFLD remains unclear. Whether IR causes hepatic steatosis or whether the accumulation of fat in the liver is the primary event leading to hepatic and peripheral IR is also yet to be elucidated [119].

Diagnosis and Histology

Fibrosis

Children with NAFLD are often asymptomatic or may present with vague nonspecific symptoms such as abdominal pain and fatigue. The majority are overweight (gender- and age-specific BMI >85th centile) or obese (>95th centile) [120]. Hepatomegaly may be present, and acanthosis nigricans (a black pigmentation of the skinfolds, axillae and

The final common pathway of inflammation, oxidative stress and hepatocellular damage is the development and progression of fibrosis in NAFLD. The process of fibrosis involves the deposition of extracellular matrix within the parenchyma. Cirrhosis, the end stage of the fibrotic process, is character-

a

b

Fig. 69.2  Histology of NAFLD. (a) Haematoxylin and eosin staining showing steatosis, inflammation and ballooning. (b) Reticulin stain showing fibrosis

69  Nonalcoholic Fatty Liver Disease

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neck), often seen in children with insulin resistance (IR), is found in 30–50% of children with NAFLD [22, 121]. The majority of children with NAFLD have insulin resistance as measured by homeostasis model assessment-insulin resistance (HOMA-IR: [fasting glucose (mmol/l) x fasting insulin (IU/l)]/22.5) [22]. A normal HOMA-IR (20–30% steatosis as increased echogenicity, though this is not specific for fat [128]. Magnetic resonance imaging/magnetic resonance spectroscopy (MRI/MRS) is more sensitive and can detect >5% steatosis [129]. However, neither technique can assess presence of inflammation or fibrosis. Schwimmer et  al. used MRI PDFF (proton density fat fraction) to diagnose NAFLD with a cutoff of 5% steatosis. The corresponding cutoff levels for ALT in boys were 42 IU/l and 30 IU/L for girls [130]. Liver biopsy remains the gold standard in differentiation of steatosis from steatohepatitis. The diagnosis of NASH is based on a specific pattern of histopathological findings including macrovesicular steatosis, mixed or polymorphonuclear lobular inflammation, ballooning degeneration with Mallory hyaline and a perivenular distribution of fibrosis in adults (type 1 NASH) [131] (Fig. 69.3). Children often have a different pattern of disease with greater degree of steatosis, less prominent ballooning and portal rather than pericentral accentuation of inflammation and fibrosis (type 2 NASH) [132] (Fig. 69.4). Children and young people may demonstrate type 2 NASH or NAFLD which is a more periportal tract-based pattern [133]. Fifty to seventy percent have a type 2 pattern or a crossover between type 1 and type 2 [127, 134, 135]. Type 2 NASH has been studied in the context of severity, and both adults and children with histology are more

E. Fitzpatrick

Fig. 69.3  Liver biopsies showing type 1 NASH with pericentral disease. Type 2 NASH is more common in children and type 1 in adults. (Picture kindly provided by Dept. Liver Histopathology, King’s College Hospital)

Fig. 69.4  Type 2 NASH with more periportal disease. Type 2 NASH is more common in children and type 1 in adults. (Picture kindly provided by Dept. Liver Histopathology, King’s College Hospital)

likely to have higher stage of fibrosis [136, 137]. It is not clear if this pattern is due to a separate pathophysiological mechanism, though it certainly seems to be a marker of more advanced NASH.

69  Nonalcoholic Fatty Liver Disease

A possibility which may in part explain the preferential distribution of disease is the concept of zonation. Along the liver lobe, the hepatocytes have different functions depending on their location in the lobule. For example, periportal hepatocytes are functionally specialised in Krebs cycle amongst other tasks, and those in the area of the central vein are rich in cytochrome P450 enzymes. The exposure of the liver to dietary components is more marked in zone 1 than in zone 3 (pericentral) [138]. Africa et  al. studied the biopsies of 813 children with NAFLD and found that the presence of periportal (zone 1) steatosis was associated with a younger age and more severe fibrosis. Interestingly, those with zone 3 fibrosis (the more classical adult type 1 pattern) were more likely to have significant inflammation or NASH [137]. The presence of fibrosis in the absence of significant inflammation is now well described leading to the term steatofibrosis as a more accurate reflection of disease stage. The occurrence of portal inflammation was reviewed as a distinct entity in NASH by the NASH Clinical Research Network (CRN) [136]. A study of biopsies from 728 adults and 205 children found that the presence of portal inflammation in adults was associated with older, female patients with a higher BMI and insulin resistance. There was a clear association with amount and location of steatosis, ballooning and advanced fibrosis. In the paediatric group, portal inflammation was associated with younger age, azonal location of steatosis and more advance fibrosis (bridging). In both groups it was associated with diagnosis of definitive NASH.  There was no association with lobular inflammation in either group. It is not clear if this pattern is due to a separate pathophysiological mechanism, though it certainly seems to be a marker of more advanced NASH. The periportal pattern mirrors that of the ductular reaction which has been reported in NAFLD. The possible epithelial-mesenchymal transition of biliary cells in this process may relate to the pattern of fibrosis seen [139]. Though the classic description of fat in NAFLD is macrovesicular, the presence of microvesicular steatosis has been described. In one study approximately 10% biopsies of those in NAFLD revealed microvesicular steatosis [140]. The study found that the presence of microvesicular steatosis was strongly associated with cellular injury and cytoskeletal damage. Microvesicular steatosis has the appearance of distended hepatocytes with foamy cytoplasm; the nucleus is usually central rather than pushed peripherally as in macrovesicular steatosis. Oil red O staining is sometimes needed to identify microvesicular steatosis if it is not visible in haematoxylin and eosin staining. Classically this type of steatosis has been associated with mitochondrial disease, acute fatty liver of pregnancy and some drug effects (e.g. steroids and valproate) which can cause β-oxidation impairment [141]. Taken together, microvesicular steatosis in NAFLD is

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a likely indicator of mitochondrial damage. It is not yet understood if this is a feature of advanced disease per se or if the pathogenesis of disease in those with microvesicular steatosis is different. Caldwell et al. reported on the significance of ballooning in NAFLD [142]. These are classically enlarged cells with rarefied cytoplasm. Using ultrastructural analysis this group reported on the multiple small fat lipid droplets seen with degree of ER dilatation and Mallory-Denk bodies and cytoskeletal disarray. Fugii et  al. have demonstrated altered expression of FFA-associated protein on the surface of fat droplets which also stain for oxidised phosphatidylcholine (a marker of oxidative damage) [143]. They concluded that oxidative injury to the fat droplet surface may impair its safe disposal and contribute to lipotoxicity. The Pathology Committee of the NASH CRN proposed a histological scoring system that could be useful in studies of NAFLD [144]. The scoring system includes the evaluation of steatosis (0–3), lobular inflammation (0–2), hepatocellular ballooning (0–2) and fibrosis (0–4). The NAFLD activity score (NAS) is the unweighted sum of steatosis, lobular inflammation and hepatocellular ballooning scores. NAS of 5 or more correlates with the diagnosis of NASH, whilst NAS less than 3 is defined as ‘not NASH’. As this system is typically developed for type 1 NASH, the interobserver agreement for type 2 NASH is not as strong (only 18 children were included in the study cohort used for development of the score). The CRN also emphasised that the scoring system was developed as a tool for use in trials and is not a surrogate for a histological diagnosis of NASH [145]. Despite these shortcomings this is the best available tool to standardise the description of the entire spectrum of NAFLD in both adults and children across different centres for research purposes. It is important, however, to consider the paediatric pattern of disease as a separate entity, particularly when investigating the pathophysiological mechanisms or putative biomarkers of disease severity/progression.

Noninvasive Biomarkers in NAFLD Though the criterion standard for diagnosis and assessing progression of disease is liver histology, the decision ‘if or when’ to perform a liver biopsy in children with suspected NAFLD remains controversial. Liver biopsy in children requires admission to hospital and sedation. Risks include bleeding and very rarely death [146]. Repeated biopsy is not a suitable tool for regularly monitoring progression of disease or response to treatment. In addition, biopsy samples only 1/50,000 of the liver, raising the possibility of sampling error [147].

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There has been much focus on the development and validation of noninvasive biomarkers of NAFLD in recent years. There is an urgent need for a less invasive method than biopsy of screening the population, stratifying disease severity and following disease progression. The pathophysiology and evolution of the condition under scrutiny is an important consideration in the development and evaluation of biomarkers. In the case of NAFLD, first is the identification of disease and second the progression. Most longitudinal cohort studies in NAFLD have shown that prognosis is determined by stage and rate of progression of fibrosis rather than the presence of necro-inflammation [52, 148, 149]. Clinical importance lies with being able to differentiate between no/minimal fibrosis (F0/F1), significant fibrosis (F2), severe fibrosis (F3) and cirrhosis (F4).

Serum Biomarkers and NASH Large adult series have suggested scoring systems using age, BMI, insulin resistance, AST/ALT, platelet count and albumin to differentiate mild from severe disease [150–153]. These simple markers are neither sensitive nor specific enough in isolation [6, 14]. A growing understanding of the pathophysiology of the disease has allowed the investigation of more specific, mechanism-based biomarkers [154–156]. Markers of apoptosis/cell death have been shown to be very useful in differentiating simple steatosis from NASH [112]. CK18-M30 fragments have been shown by a number of studies including paediatric studies to correlate well with severity of NASH [157–160]. Numerous other biomarkers of inflammation, oxidative stress and apoptosis are currently under investigation.

Noninvasive Markers of Fibrosis in NAFLD Simple tests derived from regression analysis of a large series of patients include the AST to platelet ratio index [161] and the AST to ALT ratio [162], which have been validated in the NAFLD population with AUROC between 0.67 and 0.86 for differentiation of severity of fibrosis [163–165]. Algorithms specifically derived from NAFLD cohorts include the BAAT score (consisting of BMI, ALT, age and triglyceride levels) [166], the BARD score (BMI, AST/ALT ratio, diabetes) [152, 167] and the NAFLD fibrosis score (incorporating age, glucose, AST, ALT, BMI, platelets and albumin) [150, 163, 164, 168, 169]. These markers do not perform particularly well in children however. In children, Nobili et  al. developed and internally validated the paediatric NAFLD fibrosis index (PNFI) in 136 children with NAFLD [170]. Logistic regression analysis of gender, age, BMI, waist circumference, ALT, AST, γGT,

E. Fitzpatrick

albumin, prothrombin time, glucose, insulin, cholesterol and triglycerides gave a predictive model with an AUROC for detection of fibrosis was 0.85. Again this study was limited in view of small numbers in fibrosis groups F2–F4. The European Liver Fibrosis (ELF) test combining hyaluronic acid, procollagen III N-terminal peptide (P3NP) and TIMP1 was first derived by Rosenberg et al. in a cohort of over 1000 patients with chronic liver disease including NAFLD [171] and has since been validated in other NAFLD cohorts with the addition of several simple markers to improve accuracy [172]. Importantly this test has been shown to correlate well with outcome [173]. The ELF test was evaluated by Nobili et al. in 122 children with NAFLD [174]. Simple markers including age, waist circumference and triglycerides were added to improve diagnostic accuracy. Excellent AUROC for any (0.92), significant (0.98) and advanced (0.99) disease was achieved. In this cohort 37 (30%) had no fibrosis; 58 (48%) scored as F1, 9 (7%) as F2, and 8 (6.5%) as F3–F4. Alkhouri et al. developed this further and validated both the PNFI and ELF in a cohort of 111 children with NAFLD (69% with fibrosis) [175]. The area under the curve for presence of fibrosis was 0.76 for PNFI, 0.92 for ELF and when the two indices were combined: 0.94. The major issue in both studies was the skew towards no or minimal disease, potentially overestimating the accuracy of the test.

Noninvasive Biomarkers and Imaging Ultrasound, CT and MRI Ultrasound (US) has a high sensitivity and specificity for diagnosis of steatosis >30%, but is not good at detecting fibrosis. Because of the low cost, the absence of radiation exposure and the wide availability, US is often used in screening for NAFLD.  The accumulation of fat causes the liver to appear hyperechoic compared with the kidney. This finding is nonspecific and does not differentiate fat from other substances such as glycogen. When compared with ­histological findings, the sensitivity of US to detect fat infiltration below 30% of the liver is low [176]. Computed tomography (CT) is rarely used for the assessment of NAFLD in children because of its ionising radiation exposure. Magnetic resonance imaging (MRI) and spectroscopy are the imaging techniques with the greatest accuracy to determine hepatic fat content in studies of both adults and children [129, 177–179]. MRI proton density fat fraction has been validated to liver biopsy with the mean PDFF in those with grade 1 steatosis 9.2%, 15.1% for grade 2 and 26.8% for grade 3 with an acceptable ability to distinguish between stages. Aside from liver fat, however, other features of NASH cannot be assessed. Other methods include MR elastography

69  Nonalcoholic Fatty Liver Disease

which visualises and measures propagating shear waves and has a high sensitivity (>85%) and specificity (>90%) for fibrosis [180]. Cost of this technique may be preclusive however. For diagnosis of NASH, Iijima et al. have reported on the use of contrast ultrasound with Levovist with an AUC of 1.0 [181]. The decreased accumulation of microbubbles with advancing degree of fibrosis is unique to NAFLD. There is an emerging literature examining the use of acoustic radiation force-based shear stiffness in NAFLD, an ultrasound-based investigation which uses short bursts of high-intensity acoustic pulses that produce shear waves through the liver tissue, the velocity of which correlates with liver stiffness to correlate well with the stage of fibrosis in the condition [182, 183].

Transient Elastography Transient elastography (FibroScan) has been shown to be a useful method for detection of liver fibrosis. In NAFLD, a small number of studies have demonstrated the efficacy of TE in distinguishing severity of fibrosis. In a study of 246 adults with NAFLD, TE had an AUROC of 0.84, 0.93 and 0.95 in distinguishing significant fibrosis, severe fibrosis and cirrhosis, respectively [184]. A Japanese study demonstrated similar results [185]. A recent report of 52 children with NAFLD has shown an AUROC of 0.977, 0.992 and 1 for distinguishing any, significant and severe fibrosis [186]. Feasibility and reproducibility of transient elastography is an issue when patients have a BMI > 30 [187]. An XL probe is available for better accuracy in this scenario [188].

 on-hypothesis-Driven Search for Novel N Biomarkers Using New Technologies The use of relatively new techniques such as proteomics [189–192], glycomics [193, 194], lipidomics and metabolomics in the derivation of panels of biomarkers associated with a disease may also give an insight into pathophysiology of the condition.

Natural History and Management The natural history of paediatric NAFLD has not yet been well described. Case series including one of 20 years describe occasional need for transplantation in young adulthood [195, 196], but the rate of progression is not known [197]. Paired liver biopsies undertaken in 122 children who had enrolled in the placebo arm of two randomised clinical trials in NAFLD were studied. Over time, fibrosis progressed in 23% and

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improved in 34% [198]. In children who present in the pre-­ teenage years with already established with stage 2–3 fibrosis, the rate of progression may be accelerated [199]. The heterogeneity within the population is not yet well understood, but variability in phenotype may be due to underlying genetic susceptibility rather than environmental exposure. The relative histological severity at presentation in children with this disease and the fact that alcohol is an unlikely confounding factor mean that paediatric NAFLD serves as an excellent disease model in evaluating pathophysiological mechanisms of development and thus targeting intervention in predisposed individuals. Cirrhosis secondary to NASH has been reported in children as young as 10  years [121, 196]. A recent study by Feldstein et al. describes the long-term outcome of 66 children with NAFLD followed for up to 20 years [200]. Of five children who underwent follow-up biopsy, four showed progression of fibrosis. During the study period, two patients required liver transplantation for decompensated end-stage disease. Both had recurrence of NASH in the allograft and one required retransplantation. In adult studies, the variables most commonly associated with fibrosis are presence of diabetes, increasing age and high BMI [151]. Similarly in children, severity of obesity and insulin resistance seem to be predictors of advanced fibrosis [22]. The difference between the natural history of type 1 and type 2 NASH has not yet been characterised and is an important subject for future research. Management of NAFLD encompasses lifestyle modification, medication or both. NAFLD is largely the consequence of imbalanced nutrition and sedentary behaviour on the background of genetic predisposition. Primary prevention is the ideal. In adults, weight reduction of 5–10% body weight often leads to normalisation or improvement of serum transaminases and reduced hepatic steatosis, inflammation and fibrosis [201–203]. In children, weight maintenance as the child crosses the height centiles may achieve the same effect. In a meta-analysis of adults with NAFLD, weight loss of 5% or more results in improvement in steatosis, whereas ≥7% weight loss resulted in improvement in steatohepatitis, and in those with ≥10% weight loss, all features of NAFLD were reversed or stabilised [204]. In a prospective study again in adults, these outcomes were confirmed [205]. Only 50% of the cohort were able to achieve 7% of weight loss or more though of note in 94% of those who achieved ≥5% weight loss, fibrosis stabilised or reversed. A small number of trials in children have demonstrated similar outcomes. In a trial of 84 children, weight loss (average 4 kg) over a 12-month period achieved an improvement in ALT and steatosis on ultrasound [135]. Of the cohort, 57 (70%) children completed the 12-month intervention with a mean 8% (SD 4.7%) decrease in weight in the 52 who were overweight or obese. In the remaining five children who

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completed the study and had a BMI 3 y 100 g)

Protein Carbohydrate (g) (g) Fat (g) 2 11.6 3.6 1.8 7.2 3.4

Protein type Whole Peptide

MCT (%) Comments 49 Supplemented with BCAA 50 Clinically lactose-free (12 years: Colecalciferol 9600 IU daily (maximum 40,000 IU daily) 0–12 years: Alpha tocopheryl 10 mg/kg up to 100 mg/kg (maximum 200 mg/kg per day) >12 years: Alpha tocopheryl 286 mg (maximum 200 mg/kg/day) 12 years: Menadiol tablets 10 mg

dren who have gastrointestinal-related aversive experiences such as abdominal discomfort and vomiting [12] or extended periods with no oral feeding [13], all of which may occur with chronic liver disease. With infants, it is especially important to encourage age-appropriate weaning practices, to avoid missing the ‘window of opportunity’ to introduce tastes and textures [14]. This can be especially difficult when there is ascites or organomegaly or when the child is being tube fed. The emotional and social benefits of eating and drinking for the child and family are also important, and eating should be encouraged, even if oral intake is minimal.

Tube Feeding Tube feeding may be required in children who are unable to take sufficient nutrition orally. Nasogastric tube feeding has been associated with improved body composition [15] and growth [16] in children with liver disease. Tube feeding may have a positive impact on quality of life as it can remove the pressure on both the child and family to meet requirements orally. The tube can be used to administer unpalatable feeds and medicines, and continuous or frequent feeds can minimise periods of fasting, thus helping to maintain blood sugars and preserve body stores. Gastrostomy feeding is preferred in children with long-­ term feeding problems but is rarely possible in children with chronic liver disease. Portal hypertension and intra-­ abdominal varices increase the risk of bleeding during placement of the tube, while ascites may prevent adequate tract formation around the gastrostomy [17]. Gastrostomy feeding has been used successfully in children with no portal hypertension, varices or ascites [18].

Parenteral Nutrition

Due to the risks associated with parenteral nutrition (PN), PN should only be used when it is not possible or effective to Fat-Soluble Vitamin Supplementation feed enterally [19]. For example, PN may be used when NG placement is not possible (e.g. due to large, bleeding varices) Table 75.5 shows how fat-soluble vitamins are supplemented or where there is significant and persistent malabsorption for cholestasis at the author’s institution. It should be noted impacting on growth. Wendel et al. [20] found that there was that these are suggested starting doses, and prescribed an improvement in nutritional status in children with end-­ amounts should be adjusted according to serum levels of fat-­ stage liver disease awaiting transplant who were on PN as soluble vitamins. If serum vitamin levels are particularly they were unable to tolerate enteral nutrition. low, they may be given intra-muscularly.

Methods of Feeding

 he Management of Common Liver T Conditions

Oral Feeding

Conjugated Hyperbilirubinaemia

All children should be encouraged to feed orally where possible. Behavioural feeding difficulties are common in chil-

Infants presenting with conjugated hyperbilirubinaemia will generally require MCT supplementation. If galactosaemia

75  Nutritional Management of Children with Liver Disease

has not been excluded, breast feeding should be stopped and replaced with an MCT feed containing only trace amounts of galactose (e.g. Pregestimil®). The mother should be encouraged to express breast milk as it is usually possible to restart breast feeding once galactosaemia is excluded. If cholestasis persists with accompanying symptoms of malabsorption and suboptimal growth, MCT supplementation will continue to be required. This can be given as 2–5 ml of a fat emulsion with every breast feed or as an MCT-containing formula (Table  75.2) either exclusively or alongside some breast feeding.

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Treatment is primarily through chelating agents that bind dietary copper for excretion. Foods with very high concentrations of copper such as offal, shellfish, nuts, dried fruit, chocolate and mushrooms may need to be avoided [25] although this is usually only necessary in patients who are unresponsive or non-compliant with drug therapy [26].

Progressive Familial Intrahepatic Cholestasis

Progressive familial intrahepatic cholestasis (PFIC) refers to a group of autosomal recessive disorders that interfere with the secretion of bile and often present in infancy with choBiliary Atresia lestasis [27]. The major problem from a nutritional point of view is fat malabsorption, necessitating MCT supplementaBiliary atresia presents in infancy with jaundice due to bili- tion. Fat malabsorption may occur without jaundice due to ary duct obstruction and is managed surgically with a Kasai the inability of patients with PFIC to produce bile salts. Poor portoenterostomy to restore bile flow [21]. The nutritional intake and appetite may also occur as a result of intractable intervention is as described for conjugated hyperbilirubinae- pruritis. Short stature is common, though may improve folmia. Close monitoring is important as BA progresses to end-­ lowing liver transplantation [28]. Supplementary nutrition stage liver disease at some point in the majority, with 50% of support via nasogastric tube or gastrostomy is often required. infants requiring a liver transplant before age two and 75% by age 20 [21]. Standard weaning practices are advised, with age-appropriate solids. MCT supplementation continues Alagille’s Syndrome until jaundice has cleared or if jaundice does not resolve, MCT supplementation may continue until transplant. Alagille’s syndrome can be particularly challenging from a nutrition point of view. It is characterised by cholestasis and malabsorption, poor growth, selective eating, intractable Non-alcoholic Fatty Liver Disease pruritis, renal acidosis [29] and pancreatic insufficiency in some patients [30]. The nutritional management is as Non-alcoholic fatty liver disease (NAFLD) exists as a spec- described for conjugated hyperbilirubinaemia. Intervention trum ranging from benign hepatic steatosis to more aggres- through specialist feeding clinics may be beneficial to sive forms that can potentially progress to cirrhosis in address selective eating. Supplementary nutrition support via childhood [22]. It is the most common liver abnormality in nasogastric tube or gastrostomy is often required. the paediatric population [23]. Weight reduction through dietary modification and physical activity is the cornerstone of management. The aims are to reduce insulin resistance Intestinal Failure-Associated Liver Disease and visceral obesity to decrease oxidative stress [24]. A study of 84 children with NAFLD, who underwent a 12-month diet Intestinal failure-associated liver disease (IFALD) is seen in and lifestyle programme, demonstrated a significant reduc- 40–60% of children with intestinal failure on parenteral tion in BMI, fasting glucose levels, insulin, lipids and liver nutrition [31]. It can progress from cholestasis to fibrosis and enzyme activity [22]. Evidence for other treatments includ- cirrhosis and result in the need for liver and/or small bowel ing vitamin E, metformin and ursodeoxycholic acid have transplantation. It may result because of physiological abnorproduced equivocal results. Lifestyle changes remain the malities associated with intestinal failure or from the toxic mainstay of treatment. effects of PN [32]. Risk factors include prematurity, short bowel syndrome, sepsis, intestinal bacterial overgrowth and a lack of enteral nutrition [33]. Strategies to reduce the risk Wilson’s Disease of IFALD include early implementation of enteral feeding, a specialised, multidisciplinary approach and techniques Wilson’s disease is an autosomal disorder of copper metabo- focused on avoiding sepsis [34]. The use of the lipid formulism and may present at almost any age. Copper accumulates lation SMOF (soybean oil, MCT, olive oil, fish oil) in place in the liver during childhood but may also deposit in other of soybean oil has been a significant advancement and has parts of the body such as the brain, eyes, joints and kidneys. been shown to reduce IFALD-related cholestasis [35].

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S. Mancell

Liver Transplantation

Transplant-Acquired Food Allergy

Feeding post-transplant usually starts within 3–5  days, via nasogastric tube and then progresses fairly quickly to a normal oral diet. High energy feeds are used for patients with poor nutritional status with catch-up growth typically seen in the 2  years following transplant. However, many children may achieve a final height below their genetic potential [36]. Where there are gastrointestinal complications (e.g. bowel perforation) or severe undernutrition at the time of transplant, parenteral nutrition may be required. Pre-existing behavioural feeding difficulties are common and may mean that tube feeding continues for an extended period. In cases where children are likely to continue to require long-term tube feeding post-transplant, the aim will be to keep the current gastrostomy or place a new one during transplant where possible. Following liver transplant, Seville oranges and grapefruit should be avoided as they may interfere with immunosuppressant medication. It is important to adhere to food safety guidelines and avoid foods that may contain bacteria such as listeria, E. coli or salmonella as there is an increased vulnerability to food poisoning when on high dose immunosuppressant medication.

Transplant-acquired food allergy (TAFA) is present in as many as 17% of transplanted children [37]. The cause of TAFA is not known but may be due to increased permeability of the intestine due to immunosuppressants or the transfer of lymphocytes or IgE as a result of the transplant [38]. Some children may need a long-term dietary restriction, whereas others do appear to develop tolerance over time [39].

Chylous Ascites Chylous ascites is a potential complication post liver transplant. It usually occurs as a result of damage to the lymph vessels during surgery and results in a loss of chyle, a milky, triglyceride-rich fluid, into the peritoneal cavity. This is often evident in the intra-abdominal drain. Treatment for chylous ascites involves the dietary restriction of long-chain triglycerides (LCT) to reduce the flow of lymph in the disrupted lymphatic system. Dietary restriction generally lasts for at least 3 weeks. A feed or formula with high levels of MCT may be used (Table 75.6) alongside low LCT foods. As MCTs are not a source of essential fatty acids (EFAs), supplementation with EFAs may be required (e.g. with walnut oil).

 he Nutritional Management of Acute Liver T Failure The nutritional consequences of acute liver failure (ALF) include catabolism, hypoglycaemia, hyperammonaemia, hepatic encephalopathy, electrolyte, acid base and fluid disturbance and conjugated hyperbilirubinaemia. Catabolism results from impaired glycogen storage and gluconeogenesis with protein and fat stores broken down to meet energy demands [9]. The catabolic effect is increased by a rise in insulin and glucagon, driving the need for gluconeogenesis to maintain blood sugars [40] and an increase in resting energy expenditure [41]. Hypoglycaemia can worsen the neurological prognosis [42] and is associated with poor outcomes and mortality [43]. Hyperammonaemia occurs due to impaired detoxification of ammonia to urea with increased aromatic and decreased BCAAs in circulation [9]. Management is based on preventing hypoglycaemia, managing metabolic disturbances such as hyperammonaemia, maintaining nutritional status despite fluid restrictions imposed in the critical care setting and supplementing the diet with MCT where there is jaundice (Table 75.2). Metabolic disorders are a frequent cause of ALF and require specific dietary therapy to prevent accumulation of toxic by-products. The ideal dietary therapy cannot begin until the diagnosis is determined, which can take time.

Table 75.6  MCT feeds which are suitable for chylous ascites Feed per 100 ml Monogen Low Fat Module Lipistart Emsogen

Standard Age dilution (%) From birth 17.5 From birth 18

Energy (Kcal) 74 67

Protein (g) 2.2 1.6

Carbohydrate (g) 11.6 14.9

Fat (g) 2.2 0.14

Protein type Whole Whole

0–10 years 15 >1 year 20

70 88

1.8 2.5

8.7 12

3.2 3.3

Whole Amino acid

MCT (%) Comments 82 100 Contains no essential fatty acids. 74 83

For cow’s milk allergy or when amino acid required

75  Nutritional Management of Children with Liver Disease

Summary Optimal nutrition support which is individually tailored and responsive to the changing clinical picture is essential for children with liver disease. Nutrition therapy should focus not only on correcting nutritional deficits and managing the complications of liver disease but also promoting normal growth, development and quality of life.

References 1. Mouzaki M, Bronsky J, Gupte G, Hojsak I, Jahnel J, et al. Nutrition and the European Society for Pediatric Gastroenterology Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2019;69:498–511. 2. Yang CH, Perumpail BJ, Yoo ER, Ahmed A, Kerner JA. Nutritional needs and support for children with chronic liver disease. Nutrients. 2017;9(10):1–16. 3. Turnpenny PD, Ellard S. Alagille syndrome: pathogenesis, diagnosis and management. Eur J Hum Genet. 2012;20(3):251–7. 4. Taylor RM, Bjarnason I, Cheeseman P, Davenport M, Baker AJ, et al. Intestinal permeability and absorptive capacity in children with portal hypertension. Scand J Gastroenterol. 2002;37(7):807–11. 5. Nightingale S, Ng VL.  Optimizing nutritional management in children with chronic liver disease. Pediatr Clin N Am. 2009;56(5):1161–83. 6. Mager DR, Wykes LJ, Roberts EA, Ball RO, Pencharz PB. Branched-­ chain amino acid needs in children with mild-to-moderate chronic cholestatic liver disease. J Nutr. 2006;136(4):133–9. 7. Sultan MI, Leon CD, Biank VF.  Role of nutrition in pediatric chronic liver disease. Nutr Clin Pract. 2011;26(4):401–8. 8. Chin SE, Shepherd RW, Thomas BJ, Cleghorn GJ, Patrick MK, et  al. The nature of malnutrition in children with end stage liver disease awaiting orthotopic liver transplantation. Am J Clin Nutr. 1992;56(1):164–8. 9. Plauth M, Bernal W, Dasarathy S, Merli M, Plank L, et  al. ESPEN guideline on clinical nutrition in liver disease. Clin Nutr. 2019;38(2):485–521. 10. Greer R, Lehnert M, Lewindon P, Cleghorn GJ, Shepherd RW. Body composition and components of energy expenditure in children with end-stage liver disease. J Pediatr Gastroenterol Nutr. 2003;36(3):358–63. 11. Kyrana E, Williams JE, Wells JC, Dhawan A.  Resting energy expenditure of children with end-stage chronic liver disease before and after liver transplantation. J Pediatr Gastroenterol Nutr. 2019;69(1):102–7. 12. Meyer R, Rommel N, Van Oudenhove L, Fleming C, Dziubak R, et  al. Feeding difficulties in children with food proteininduced gastrointestinal allergies. J Gastroenterol Hepatol. 2014;29(10):1764–9. 13. Mancell S, Meyer R, Hind J, Halter M. Factors impacting on eating in pediatric intestinal-transplant recipients: a mixed methods study. Nutr Clin Pract. 2019 (published online ahead of print 13 Nov). Available at: https://onlinelibrary.wiley.com/doi/pdf/10.1002/ ncp.10439. Accessed 21 July 2020. 14. Hopkins J, Cermak SA, Merritt RJ.  Oral feeding difficulties in children with short bowel syndrome: a narrative review. Nutr Clin Pract. 2017;20(10):1–7. 15. Holt R, Miell J, Jones J, Mieli-Vergani G, Baker A.  Nasogastric feeding enhances nutritional status in paediatric liver disease but does not alter circulating levels of IGF-I and IGF binding proteins. Clin Endocrinol. 2000;52(2):217–24.

1031 16. Macias-Rosales R, Larrosa-Haro A, Ortiz-Gabriel G, Trujillo-­ Hernandez B.  Effectiveness of enteral versus oral nutrition with a medium-chain triglyceride formula to prevent malnutrition and growth impairment in infants with biliary atresia. J Pediatr Gastroenterol Nutr. 2016;62(1):101–9. 17. Baltz JG, Argo CK, Al-Osaimi AMS, Northup PG. Mortality after percutaneous endoscopic gastrostomy in patients with cirrhosis: a case series. Gastrointest Endosc. 2010;72(5):1072–5. 18. Sullivan JS, Sundaram SS, Pan Z, Sokol RJ.  Parenteral nutrition supplementation in biliary atresia patients listed for liver transplantation. Liver Transpl. 2012;18(1):120–8. 19. Baker A, Stevenson R, Dhawan A, Goncalves I, Socha P, et  al. Guidelines for nutritional care for infants with cholestatic liver disease before liver transplantation. Pediatr Transplant. 2007;11(8):825–34. 20. Wendel D, Mortensen M, Harmeson A, Shaffer ML, Hsu E, et  al. Resolving malnutrition with parenteral nutrition before liver transplant in biliary atresia. J Pediatr Gastroenterol Nutr. 2018;66(2):212–7. 21. Bezerra JA, Wells RG, Mack CL, Karpen SJ, Hoofnagle J, et  al. Biliary atresia: clinical and research challenges for the 21st century. Hepatology. 2018;68(3):1163–73. 22. Nobili V, Marcellini M, Devito R, Ciampalini P, Piemonte F, et al. NAFLD in children: a prospective clinical-pathological study and effect of lifestyle advice. Hepatology. 2006;44(2):458–65. 23. Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, et al. Prevalence of fatty liver in children and adolescents. Pediatrics. 2006;118(4):1388–93. 24. Alisi A, Carpino G, Nobili V. Paediatric nonalcoholic fatty liver disease. Curr Opin Gastroenterol. 2013;29(3):279–84. 25. Roberts EA, Schilsky ML. Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008;47(6):2089–111. 26. Socha P, Janczyk W, Dhawan A, Baumann U, D’Antiga L, et  al. Wilson’s disease in children: a position paper by the hepatology committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2018;66(2):334–44. 27. Jankowska I, Socha P.  Progressive familial intrahepatic cholestasis and inborn errors of bile acid synthesis. Clin Res Hepatol Gastroenterol. 2012;36(3):271–4. 28. Aydogdu S, Cakir M, Arikan C, Tumgor G, Yuksekkaya HA, et al. Liver transplantation for progressive familial intrahepatic cholestasis: clinical and histopathological findings, outcome and impact on growth. Pediatr Transplant. 2007;11(6):634–40. 29. Kronsten V, Fitzpatrick E, Baker A.  Management of choles tatic pruritus in paediatric patients with Alagille syndrome: the King’s College Hospital experience. J Pediatr Gastroenterol Nutr. 2013;57(2):149–54. 30. Kamath BM, Piccoli DA, Magee JC, Sokol RJ. Pancreatic insufficiency is not a prevalent problem in Alagille syndrome. Childhood Liver Disease Research and Education Network. J Pediatr Gastroenterol Nutr. 2012;55(5):612–4. 31. Raphael BP, Duggan C.  Prevention and treatment of intesti nal failure-associated liver disease in children. Semin Liver Dis. 2012;32(4):341–7. 32. Lacaille F, Gupte G, Colomb V, D’Antiga L, Hartman C, et  al. Intestinal failure-associated liver disease: a position paper of the ESPGHAN working group of intestinal failure and intestinal transplantation. J Pediatr Gastroenterol Nutr. 2015;60(2):272–83. 33. Kelly DA. Preventing parenteral nutrition liver disease. Early Hum Dev. 2010;86(11):683–7. 34. Goulet O, Dabbas-Tyan M, Talbotec C, Kapel N, Rosilio M, et al. Effect of recombinant human growth hormone on intestinal absorption and body composition in children with short bowel syndrome. J Parenter Enteral Nutr. 2010;34(5):513–20.

1032 35. Muhammed R, Bremner R, Protheroe S, Johnson T, Holden C, et al. Resolution of parenteral nutrition-associated jaundice on changing from a soybean oil emulsion to a complex mixed-lipid emulsion. J Pediatr Gastroenterol Nutr. 2012;54(6):797–802. 36. Scheenstra R, Jan Gerver W, Odink RJ, van Soest H, Peeters PMJG, et  al. Growth and final height after liver transplantation during childhood. J Pediatr Gastroenterol Nutr. 2008;47(2):165–71. 37. Mavroudi A, Xinias I, Deligiannidis A.  Long term outcome of acquired food allergy in pediatric liver recipients: a single center experience. Pediatr Rep. 2012;4(1):e6. 38. Hosakoppal SS, Bryce PJ.  Transplant-acquired food allergy: current perspectives. J Asthma Allergy. 2017;10:307–15.

S. Mancell 39. Ozdemir O.  New developments in transplant-acquired allergies. World J Transplant. 2013;3(3):30–5. 40. Cochran JB, Losek JD.  Acute liver failure in children. Paediatr Emerg Care. 2007;23(2):129–35. 41. Walsh TS, Wigmore SJ, Hopton P, Richardson R, Lee A.  Energy expenditure in acetaminophen-induced fulminant hepatic failure. Crit Care Med. 2000;28(3):649–54. 42. Figuera E, Filho J, Nacif L, D’Albuqerque L, Waizberg D. Nutritional support for fulminant hepatitis. Nutr Hosp. 2015;32(6):2427–32. 43. Berger M, Reintam-Blaser A, Calder P, Casaer M, Hiesmayr M, et al. Monitoring nutrition in the ICU. Clin Nutr. 2019;38(2):584–93.

Paediatric Liver Transplantation

76

Annalisa Dolcet and Nigel Heaton

Introduction Liver transplantation continues to be the only effective treatment for children with end-stage liver disease. Thomas Starzl performed the first liver transplant in a child in March 1963 [1]; however, it was not until 1967 that he reported the first recipient with significant survival [2]. Following his early series of 7 children aged between 13 months and 16 years [2], more than 15,000 paediatric liver transplants have been carried out in the USA and 10,000  in Europe, with 3- and 5-year survival of 80% and 75%, respectively. There have been continued improvements in all aspects of care of the child with liver disease coming to liver transplantation including surgical, anaesthetic, intensive care and postoperative management and long-term graft, and patient survivals are now exceptionally good with improved quality of life (QOL) for recipients. The advent of reduced size and split LT in the 1980s led to a significant decrease in waiting list mortality for children. The paediatric overall waiting list mortality is about 10% and appears to be highest in children younger than 6  years. The change in donor demographics over the past 25 years has resulted in a reduction in the number of brain-dead donor livers suitable for splitting, which is the commonest graft for young children in the West. Living donor liver transplantation (LDLT) was first performed in 1989; and subsequently developed as perhaps the most common form of organ donation in the East [3, 4]. Most recently, liver perfusion machine has been utilized to try to improve the condition of marginal donor livers. To date this has not impacted on paediatric liver transplantation, but with increasing experience, this is likely to change.

The large numbers of recipients currently surviving beyond 20 years are informing clinical practice and providing more information for families currently facing transplantation. As the majority of children are transplanted at a young age and have little memory of the events surrounding their transplant, continuing patient and family education is increasingly recognized as important. There has been a change of emphasis in care from a focus on survival to long-­ term outcomes centred on well-being, psychosocial and physical development and educational attainment. It is clear that adolescence and transition to adulthood and follow-up within an adult environment pose further significant challenges and late death due to non-adherence to medication and follow-up are significant problems. The emergence of models of care to manage these challenges will hopefully help lead to further improvement in long-term outcomes. In addition, the timing of transplant and its influence on subsequent development and outcome is coming under increasing scrutiny.

Pre-transplant Historically children have been listed for liver transplantation based on criteria adopted from adult experience. However, children present with a different spectrum of diseases, with two-thirds of children coming to liver transplantation in the first 5 years of life, and consideration has to be given to their emotional, social, intellectual and physical development. The timing of liver transplantation has to be considered with the long-term development of the child in mind, and there remains a lack of data regarding this topic.

A. Dolcet Institute of Liver Studies, Denmark Hill, London, UK

Indications for Liver Transplantation

N. Heaton (*) King’s Healthcare Partners, Kings College Hospital FT NHS Trust, Institute of Liver Studies, Denmark Hill, London, UK e-mail: [email protected]

Liver transplantation should be considered for any child with end-stage liver disease with a predicted prognosis of less

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 S. Guandalini, A. Dhawan (eds.), Textbook of Pediatric Gastroenterology, Hepatology and Nutrition, https://doi.org/10.1007/978-3-030-80068-0_76

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than 18  months, acute liver failure (ALF), unresectable hepatic tumours and liver-based metabolic defects. Indications for liver transplantation are in general derived from adult liver transplant experience but are modified for children and include: • Liver decompensation (prolonged INR, low serum albumin, ascites) • Disordered metabolism (jaundice, loss of muscle mass, osteoporosis) • Portal hypertension (variceal bleeding, severe hypersplenism, intractable ascites) • Encephalopathy • Spontaneous bacterial peritonitis • Hepatopulmonary syndrome, hepatorenal syndrome • Pulmonary hypertension • Recurrent cholangitis and intractable pruritus • Quality of life (failure to growth, poor concentration, lethargy) • Tumours Extrahepatic biliary atresia is the most common indication for liver transplantation and accounts for 40–50% of cases listed worldwide. Common indications for liver transplantation are listed in Box 76.1. The majority of paediatric recipients under 2 years old have cholestatic diseases, particularly biliary atresia, which accounts for 74% of cases in this age group. Metabolic disorders and ALF are less common indications and account for 9% each of the overall number [5]. However, metabolic diseases, although individually rare, collectively are becoming a more common indication for transplantation.

Box 76.1 Indications for liver transplantation in children

• Traditional –– Cholestatic conditions Biliary atresia Sclerosing cholangitis Parenteral nutrition-associated cholestasis Alagille syndrome Progressive familial intrahepatic cholestasis (BSEP and MDR3 deficiency) –– Metabolic disease Alpha 1 antitrypsin deficiency Cystic fibrosis Gestational alloimmune liver disease Urea cycle defects Tyrosinemia Wilson disease Primary hyperoxaluria Glycogen storages disorders

A. Dolcet and N. Heaton

–– Tumours Hepatoblastoma Haemangioendothelioma Hepatocellular carcinoma –– Acute liver failure –– Cryptogenic cirrhosis Budd-Chiari syndrome –– Propionic acidaemia • Controversial –– Mitochondrial hepatopathy –– Metastatic liver tumours –– Progressive familial intrahepatic cholestasis (PFIC1 deficiency)

Box 76.2 Contraindications to liver transplantation

• Absolute –– Extrahepatic malignancy –– Irreversible “severe” neurological injury –– Multisystem organ failure –– Active uncontrolled sepsis –– Uncorrectable life-limiting defects in other critical organs – Kidney – Heart – Lungs

Chronic Liver Diseases Biliary Atresia Extrahepatic biliary atresia (BA) is a destructive inflammatory obliterative cholangiopathy that affects the intrahepatic and extrahepatic bile tree. Type 3 BA is the most frequent form of the disease accounting for 90% of cases and is the most severe form with a solid porta hepatis, microscopic ductules and a solid gallbladder or mucocele [6]. The majority of children coming to transplant have undergone Kasai porto-enterostomy within the first 3 months of life. Early porto-enterostomy and expertise of the multidisciplinary team have a significant impact on outcome and the need for liver transplantation in early life [7, 8]. The results of concentrating expertise in a small number of centres each performing more than 5 cases per year in the UK have led to a 4-year survival with the native liver intact of 41–51% and an overall survival of 87–89%. More recently survival of 96% at 10 years has been reported for the UK with an integrated programme of Kasai porto-enterostomy and liver transplantation [6]. Mortality is distributed equally between deaths on waiting list for liver transplant and in the post-transplant period. By the age of 18 years, approximately 80% of children with BA will have been treated by liver transplantation. Outcomes have been reported for 5- and 10-year actuarial graft and patient sur-

76  Paediatric Liver Transplantation

vival of 76.2% and 72.7% and 87.2% and 85.5% for cadaveric [7] and 84.9% and 76.6% and 86.7% and 80.8% for LDLT [9], respectively. The majority of young children (under 5  years of age) with BA will come to transplant with jaundice and synthetic failure. In a small number of children (6% of cases), acute decompensation secondary to ischaemic hepatitis may occur following a viral illness or infection. Children at risk of ischaemic hepatitis and liver decompensation are those with a hepatic artery resistance index of greater than 1 on Doppler ultrasound where the liver is dependent on arterial inflow [10]. An episode of systemic hypotension will lead to arterial insufficiency, and the liver will take an ischaemic “hit” and precipitate acute liver decompensation. Urgent liver transplantation will rescue these children if recognized in time. Children older than 5 years of age may present with failure to grow and a falling serum albumin (synthetic failure), but without jaundice. Adolescents coming to transplantation will invariably have portal hypertension as a dominating feature, which in association with adhesions from previous surgery can make for a difficult surgical challenge. The presence of portosystemic collaterals, particularly in the presence of a small or thrombosed portal vein, requires surgical ligation at the time of surgery to maintain PV flow postoperatively. Congenital anomalies associated with “syndromic” BA (15% of all cases) include polysplenia/asplenia, absent inferior vena cava, portal hypoplasia, preduodenal portal vein, malrotation and situs inversus and may complicate surgery and influence graft choice. Cholestatic and Metabolic Disorders Cholestatic liver diseases excluding BA account for 10% of liver transplants in children. These include Alagille syndrome, progressive familial intrahepatic cholestasis and sclerosing cholangitis. Liver transplantation is often used to treat symptoms, such as severe pruritus. Children with Alagille syndrome are at risk of growth failure and morbidity from pruritus, xanthomas and complications of vitamin deficiency. Progressive familial intrahepatic cholestasis (PFIC) defines a group of disorders characterized by chronic, unremitting cholestasis and autosomal recessive inheritance with a shared pattern of biochemical, clinical and histological features. Liver transplantation is reserved for those with severe symptoms including pruritis or progressive liver disease. Earlier transplant may lessen future growth and developmental impairment in some, but not all of these conditions [11]. In Alagille syndrome, the biliary hypoplasia is associated with other congenital malformations, the most important of which is pulmonary artery stenosis. This needs to be assessed preoperatively due to the risk of mortality post reperfusion if cardiac output is limited by the pulmonary stenosis. Dobutamine stress testing has

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been used to identify at risk children who are unable to increase their cardiac index by 50%. Inborn errors of metabolism, collectively as a group, form a relatively common indication for LT accounting for 9% and 26% of children under and over 2 years of age at the time of transplant, respectively. Metabolic diseases resulting in cirrhosis include alpha-1-antitrypsin deficiency, tyrosinemia, Wilson’s disease, neonatal haemochromatosis, respiratory chain disorders, fatty acid oxidation defect and glycogen storage disease type IV, among many others. Metabolic diseases without structural liver disease include Crigler-Najjar syndrome type 1, glycogen storage disease type 1, propionic acidaemia, primary hyperoxaluria type 1, hereditary tyrosinemia, factor VII deficiency, ornithine transcarbamylase deficiency, familial hypercholesterolemia and protein C deficiency. Two series from the USA from the Scientific Registry of Transplant Recipients of 551 transplants [12] and Europe from King’s College Hospital of 112 transplants reported excellent outcomes for this group [11]. Although the presence of cirrhosis did not appear to be a risk factor for worse outcomes, recipient black race, combined organ transplantation, ALF, hospitalization before transplant and age less than or equal to 1 year were predictors. The study from Sze et al. reported 11 ALTs with similar outcomes to whole liver replacement for noncirrhotic liver disease with an absent enzyme/gene product such as Crigler-Najjar type 1 [11]. Tumours Liver transplantation for liver tumours in children accounts for 2–6% of all cases in European and American series. The most common indication is unresectable hepatoblastoma (following appropriate chemotherapy). Other tumours treated by LT include hepatocellular carcinoma, haemangioma, infantile haemangioendothelioma, rhabdomyosarcoma and epithelioid haemangioendothelioma. Angiosarcomas should not be transplanted as they invariably recur early. However, differentiation from more benign vascular tumours can be difficult even on histological examination of a biopsy. Clinical features such as pain, rapid deterioration or disease progression indicate sarcoma. The outcome of LT for unresectable hepatoblastoma is excellent with long-term patient and graft survival rates for cadaveric transplantation of 91%, 77.6%, and 77.6%, at 1, 5, and 10 years, respectively [13]. Patient and graft survival for children undergoing LDLT is 100%, 83.3%, and 83.3%, at 1, 5, and 10 years, respectively. Two North American series of 25 (HCC, 10 cases and hepatoblastoma, 15 cases) and 12 patients (HCC, 6 cases and hepatoblastoma, 6 cases) reported similar medium- and long-term survival rates for both tumours [14, 15]. Salvage transplantation for recurrent hepatoblastoma after conventional liver resection is less satisfactory with 5-year survival of 40% with a high rate of further recurrence. An analysis of

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UNOS data of 336 patients with liver tumours which included 237 hepatoblastomas, 58 HCC and 35 haemangioendotheliomas noted that patient survival for the latter was inferior to that of hepatoblastoma (5-year survival of 72%) and rare liver tumours (5-year survival of 78.9%), but better than HCC (5-year survival of 53.5%) [16]. Tumour recurrence was the major cause of death in hepatoblastoma and HCC patients, but not haemangioendothelioma. The development of hepatocellular carcinoma has been reported in BA, Alagille syndrome and progressive intrahepatic cholestasis, particularly BSEP (bile salt export pump) caused by a mutation in ACBC II gene. Children with tyrosinemia have a high risk of hepatocellular carcinoma before 2 years of age which appears to be markedly reduced by the use of 2-(2-nitro-4-3 trifluoromethylbenzoyl)-1,3- cyclohexanedione (NBTC) therapy [17]. For HCC, there are no criteria for selection comparable to the Milan criteria in adult patients. Macrovascular invasion of the portal vein trunk and first divisions continues to be a contraindication to transplantation due to the high risk of recurrence.

 cute Liver Failure A Acute liver failure (ALF) is defined by the onset of severe impairment of liver function in the absence of previous liver disease. Coagulopathy is always present, but in young children hepatic encephalopathy may be absent and is a late feature associated with a poor outcome. ALF is an indication for LT in 9% of under and 16% of over 2-year-olds in Europe and 15% of children in America. The cause of ALF cannot be determined in the majority of children (49% of all children and 54% of those aged 1 year) [18]. Potential causes include metabolic, paracetamol intoxication, autoimmune hepatitis, viral hepatitis, drugs, Wilson’s disease, vascular disease and Amanita phalloides poisoning. The risk of death or liver transplantation is highest in children under 3  years of age. Logistic regression analysis has identified total serum bilirubin >5 mg/dL, INR >2.55 and hepatic encephalopathy as risk factors for death or liver transplantation. Of note, grade IV hepatic encephalopathy on admission was associated with higher rate of spontaneous recovery than those children who progressed to grade IV during the course of admission (50% vs 20%). Indications for LT are different from adults and an INR >4 (in the absence of disseminated intravascular coagulopathy) identifies the at-risk population. Two recent series reported 5-year patient survival of 70% in children with ALF [19, 20]. Farmer et al. identified 4 factors which predicted graft or patient survival in 122 children with ALF which included cCrCl 25 (graft), recipient age 1 year and growth [24]. The introduction of MELD (and subsequently PELD) significantly decreased death or removal from the waiting list for being too sick within 2  years for both adults and children [25]. Cowles et al. [26] in reviewing a cohort of 71 children transplanted for BA (61, KP before LT; 10, primary LT) considered that PELD monitoring identified those in need of transplantation. Children with a PELD greater than 12 (n = 47) had a higher rate of post-LT mortality and retransplantation than those with a PELD of 10 or less. The authors suggested that a PELD score approaching 10 should trigger discussion of LT. PELD is the only scoring system currently used in children, and although helpful in advanced liver dysfunction, it is of limited value in the very young (under 1 year of age) and in older recipients, particularly with complications such as recurrent cholangitis, severe portal hypertension, pulmonary hypertension and hepatopulmonary syndrome [27–31]. Because of these limitations, PELD use has been largely restricted to North America. More research is needed to define optimal timing of transplantation in children to gain most benefit in terms of survival, growth and intellectual and social development.

Graft Allocation Organs from deceased donors are mainly allocated depending on the blood group and organ size. Children will generally receive a liver from donors with the same blood group with certain exceptions. Children below 2  years old have received organs from mismatch blood group donors, but this is usually undertaken in circumstances when it is difficult to find a size match and good quality organ within a limited time such as in very sick patients or in countries where the only source of organs is live donors. The size of the graft will also be important at the moment of organ allocation; it is generally difficult to have a whole size match organ for a small child; therefore, the main source of livers comes from adult donors, which are reduced or split to provide grafts that fit the children (generally left lateral segment (LLS)).

Graft Type The type of graft used in children in need of an LT has also been in evolution. In order to match the graft-to-recipient

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body weight ratio, surgeons have developed techniques to resect segments of the liver from either a live or cadaveric donor. In case of a live donor, this requires estimating the required graft size and the liver remnant volume to ensure both donor and recipient have adequate function post surgery for it to be performed with compatible outcomes to cadaveric liver transplantation. For the youngest and smallest of the recipients, typically a LLS is utilized, while for a larger school-age child one may need the entire left lobe (LL). If the recipient is adult-sized, then a right lobe (RL) graft is required. For deceased adult donor, defined as suitable for routine use in children (