M. Eric Gershwin John M. Vierling Michael P. Manns Editors Liver Immunology Principles and Practice Second Edition 123 Liver Immunology M. Eric Gershwin (cid:129) John M. Vierling Michael P. Manns Editors Liver Immunology Principles and Practice Second Edition Editors M. Eric Gershwin John M. Vierling Division of Rheumatology, Medicine and Surgery Allergy and Clinical Immunology Baylor College of Medicine University of California School of Medicine Houston , TX , USA Davis , CA , USA Michael P. Manns Department of Gastroenterology, Hepatology and Endocrinology Medical School of Hannover Hannover, Germany ISBN 978-3-319-02095-2 ISBN 978-3-319-02096-9 (eBook) DOI 10.1007/978-3-319-02096-9 Springer New York Heidelberg Dordrecht London Library of Congress Control Number: 2013952928 © Springer Science+Business Media New York 2014 This work is subject to copyright. 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Linie is one of a kind and is a true star in the struggle to fi nd a cure for autoimmune disease. “ Gutta cavat lapidem ” Foreword Meeting the Challenge of Patients with Immune-Mediated Liver Disease Medicine, health, and health care are in a period of rapid evolution. As expenses continue to soar, societal pressure will push us to provide better health for less money to more people. These lofty aims are achievable, although not likely with our present delivery system. New systems will require even more data-driven decisions and a more tailored, personal- ized approach to individuals. This personalized approach will in part depend on understanding data available in the individual genetic code which can help direct risk assessment as well as help us make better diagnostic and treatment decisions. Our new, data-driven approach will be based on a better understanding of underlying mech- anisms, with an increased focus on more directed or targeted therapy. This new edition of this textbook will help set the stage for those exciting changes. Advances in liver disease include the emergence of imaging modalities to assess liver fi bro- sis (magnetic resonance elastography and ultrasound elastography) improved imaging of liver masses and noninvasive methods to assess the biliary tree and vascular structures. Immunohistochemical staining allows differentiation of tumors and infections as well as char- acteristics of some immune-mediated diseases. The understanding of the genetic code has led to genome-wide association studies which hold the promise of new insights into potential pathogenetic pathways that can be then explored with more directed, functional studies. These associations are already being used to target therapies designed to ameliorate the infl ammatory response. In cancer therapy, whole genome sequencing of tumors has now allowed specifi cally targeted therapy which may yield greater effi cacy with fewer adverse side effects. Genetic polymorphisms have also been used to predict treatment responses and predict development of steatosis, among other uses. Therapy for liver disease has emerged quickly in the past decade. Hepatitis B is suppressed long term with excellent clinical results while the vast majority of patients with Hepatitis C may soon be curable. Primary biliary cirrhosis is now treatable with ursodeoxycholic acid while primary sclerosing cholangitis is still lacking the effective therapy. Our understanding of the basic and clinical aspects of immune-mediated liver disease is rapidly progressing and an excellent update, such as provided in the second edition of this clas- sic textbook, is timely. There has been increased attention on immune diseases of the liver because of a rising increase in prevalence in some cases, in others because of new discoveries that may give us clues to pathogenesis, while in other instances improved management has been established. Several diseases among this collection of illnesses remain without effective therapy, spurring further research to fi nd sorely needed treatment options. Furthermore, several of these diseases are accompanied by increased risk of malignancy, adding more to the urgency to better understand and treat these conditions. This second edition begins with important information about the epidemiology and mortal- ity of liver disease worldwide. These are followed by chapters related to basic immunology, application of liver immunology for diagnosis, and several excellent chapters that provide a vii viii Foreword solid foundation for understanding immune-mediated liver disease including those associated with the biliary tree. A chapter on non-hepatic manifestations of immune-mediated liver dis- ease helps provide context for how these diseases affect the patient overall. There are chapters that discuss various discrete immunologically mediated infectious liver disorders including those related to bacteria, parasites, and all of the classic viruses. Chapters on the traditional autoimmune liver diseases; primary biliary cirrhosis, autoimmune hepatitis, primary sclerosing cholangitis as well as overlap syndrome are included. The breadth of this second edition is highlighted by chapters on alcoholic liver disease, nonalcoholic fatty liver disease, and drug-induced liver disease among others, which have potentially immunologic features, yet are not usually included among the immune-mediated liver diseases. More classic immune-mediated liver disease occurring in the setting of transplantation, whether graft vs. host disease or liver transplantation, are also included. The edition ends with a forward-looking view of future directions and how we might meet the challenge of refractory patients, written by the editors jointly. The editors of this second edition have consolidated an outstanding group of authors who are responsible for the various chapters. The book will serve as a comprehensive textbook for many liver diseases, especially those that have an immune-related pathogenesis. The text does not cover malignant, vascular, congenital, or cystic diseases. It leverages the focus on immune- mediated diseases to provide an in-depth and comprehensive overview of this important aspect of liver disease. This book will serve as an excellent overview for this rapidly evolving fi eld and should add to our understanding of the pathogenesis of these diseases, as well as provide insights that can be harnessed into helping improve the care of patients affl icted with these various immune- mediated diseases. This book will be valued by those learning about this fi eld in training as well as by established experts in the fi eld. The editors are to be congratulated for this important contribution. Rochester , MN , USA Keith D. Lindor, MD Pref ace Recognition of the importance of the liver to health by Babylonians in the nineteenth century BCE stands in stark contrast to the relative obscurity of the liver in the minds of most educated adults today. Medical appreciation of the vital nature of the liver’s diverse functions continues to evolve along with our efforts to better understand a multitude of hepatobiliary diseases caused by alcohol, xenobiotics, viruses, autoimmunity, and genetic diseases. The unantici- pated success of liver transplantation in the absence of histocompatibility matching between donor and recipient showed that the hepatic environment is immunosuppressive. Further stud- ies proved that liver transplantation also protected other transplanted organs from being rejected, indicating that the liver is truly an immunologic organ. Recent data provide new insights into the physiological roles of hepatocytes, sinusoidal lining cells, activated macro- phages (Kupffer cells), cholangiocytes and stellate cells, and their modulation of T cells, natu- ral killer (NK) cells, and NKT cells. Concurrently, studies of the pathogenetic mechanisms involved in hepatobiliary diseases have provided unequivocal evidence that the pathogenesis of virtually all hepatobiliary diseases involves infl ammation involving the innate and/or adap- tive immune responses. Progress in our understanding of the liver as an immune organ and immunopathogenesis of diverse hepatobiliary diseases provides hope that this knowledge will rapidly be translated into more effective therapies in the near future. These factors were the impetus for the third edition of Liver Immunology: Principles and Practice, which is directed to clinicians, investigators, and students. The editors are indebted to all of the authors who have donated their talents, intellects, and expertise to provide “state-of-the-art” contributions. All of us hope that this book will provide new perspectives of hepatobiliary physiology and pathophysiology and stimulate creative approaches to accelerate the pace of research progress in the fi eld. Time has validated our belief that continued studies of immunology of the liver will ultimately improve the care and the prognosis of patients affl icted with a diverse array of hepatobiliary diseases. The editors have many people to thank, not the least of which are the contributors, all of whom worked very hard to have their manuscripts delivered on time and in the style we requested. However, we especially want to thank Nikki Phipps and Kathy Wisdom, our assistants at UC Davis, who worked so hard to make this book a reality. Davis , CA , USA M. Eric Gershwin, MD, FACP Houston , TX , USA John M. Vierling, MD, FACP Hannover , Germany Michael P. Manns, MD ix