Autoimmune Liver Disease

JAMES NEUBERGER studied at Oxford and trained at the Liver Unit, Kings College Hospital, in London. He has researched and written about liver disease and liver transplantation for over 35 years, including editing five books and serving as the editor of Transplantation and associate editor of The Journal of Hepatology. He is currently a consultant physician in the Liver Unit, Queen Elizabeth Hospital, Birmingham, UK. GIDEON M. HIRSCHFIELD is a clinician-scientist and expert in autoimmune liver disease practice and science. His experience spans many years in transplant Hepatology in North America and the United Kingdom, including numerous published works. He currently has a practice at the University of Toronto, Ontario, Canada.

• Preface xvContributors xviiAbbreviations xxiIntroduction: The Paradigm and Paradox of Liver Autoimmunity 1M. Eric GershwinSection I Scientific Basis of Clinical Autoimmune Liver Diseases 31 Introduction to the Physiology, Immunology and Pathology of the Liver and Biliary Tree 5Marco Carbone and Mario StrazzaboscoKey Points 5Liver Cell Types and Organization 6Hepatic Metabolism 7Bilirubin Metabolism and Transport 7Carbohydrate Metabolism 7Lipid Metabolism 8Protein Metabolism 8Metabolic Zonation 8Hepatic Transport Systems 9Basolateral (Sinusoidal) Transporters 9Apical (Canalicular) Transporters 11Drug Metabolism 11Bile Formation, Secretion and the Enterohepatic Circulation 12Bile Acid Synthesis and Metabolism 13Enterohepatic Bile Acid Circulation 13Death and Regeneration of Hepatocytes 14Cell Death 14Liver Regeneration 15Cholangiocyte Reaction to Biliary Damage 16Protective Role of Biliary HCO3 − Secretion 16Cholangiocytes and Immunity 16Biochemical Markers and Patterns of Hepatic Injury 17Hepatocellular Necrosis 18Cholestasis 18References 202 Concepts of Autoimmunity Relevant to Autoimmune Liver Diseases 21Isaiah G. Roepe and John M. VierlingKey Points 21Introduction 22Role of Innate and Adaptive Immunity in Autoimmunity in the Context of the Liver as an Immune Organ 22Overview 22Innate Immunity 23Liver as an Innate Immune Organ 25Adaptive Immunity and Adaptive Immune Functions of the Liver 25Role of the Liver as an Adaptive Immune Organ 28Generation and Maintenance of Tolerance to Self‐antigens 28Overview 28Central Tolerance 29Central T‐cell Tolerance 29Central B‐cell Tolerance 29Peripheral Tolerance 30T‐ and B‐cell Clonal Anergy 30T‐cell Mediated Immune Regulation 30Natural and Inducible T Regulatory Cells 30Peripheral B‐cell Regulatory Mechanisms 31Regulatory Dendritic Cells 31Immunoregulatory Interplay Between Treg and Th17 Cells 31Risk Factors for Autoimmune Diseases 31Genetics 31Complex Genetic and Monogenic Diseases 31HLA Risk Alleles 32Non‐HLA Gene Associations 32Critical Role of Epigenetics 33Transcription Factor Enhancers and Super Enhancers 33MicroRNAs 33Sex and Sex Hormones 33Vitamin D and Sunlight Exposure 34Loss of Immune Tolerance to Autoantigens and Perpetuation of Autoimmune Diseases 34Overview 34Role of the Microbiome 35Mechanisms of Loss of Tolerance to Autoantigens 35Bacterial and Viral Infections 35Molecular Mimicry of Autoantigens 36Neoantigens 36Failure of Apoptosis to Conceal Autoantigens and Eliminate Autoreactive Cells 36Immune Deviation of Activated T Cells 37T‐cell Receptor Revision in the Periphery 37Perpetuation of Autoimmune Diseases 37Epigenetics 37Epitope Spreading 38Tissue Memory T Cells 38Cytokines Promoting Chronic Inflammation and Autoimmunity 38Tertiary Lymphoid Structures and Germinal Centers 39Epithelial Cell‐induced Transformation of iTreg to Th17 Cells 39Prevention of Autoimmunity and Therapeutic Control of Autoimmune Diseases 39Overview 39Strategies to Prevent Autoimmunity 39Vitamin D3 39Gut Microbiota Manipulation in Pregnancy and Infancy 39Oral Tolerance 39Strategies to Treat Established Autoimmune Diseases 40Inducible T Regulatory T Cells 40Epigenetic Enhancer Regulation 40References 443 Genetics and Risk of Autoimmune Liver Diseases 47George F. MellsKey Points 47Introduction 48HLA Associations in Autoimmune Liver Disease 50Non‐HLA Associations in Autoimmune Liver Disease 53Conclusion 61References 624 Autoantibodies and Understanding of Autoimmune Liver Diseases 65Benedetta Terziroli Beretta‐Piccoli, Giorgina Mieli‐Vergani, and Diego VerganiKey Points 65Introduction 66Methods of Detection 66Anti‐nuclear Antibody 68History 68Immunofluorescence Reactivities and Antigenic Targets 68Clinical Significance in Autoimmune Liver Disease 70Anti‐smooth Muscle and Anti‐actin Antibodies 73History 73Immunofluorescence Reactivities, Antigenic Targets, and Clinical Significance 73Anti‐liver‐kidney Microsomal Antibody 74History 74Immunofluorescence Reactivities, Antigenic Targets, and Clinical Significance 75Anti‐liver Cytosol Type 1 Antibody 76History 76Immunofluorescence Reactivities, Antigenic Targets, and Clinical Significance 76Anti‐soluble Liver Antigen Antibody 76History 76Immunofluorescence Reactivities, Antigenic Targets, and Clinical Significance 77Anti‐neutrophil Cytoplasmic Antibody 77History 77Immunofluorescence Reactivities, Antigenic Targets, and their Clinical Significance 77Anti‐mitochondrial Antibody 78History 78Immunofluorescence Reactivities, Antigenic Targets, and their Clinical Significance 78Anti‐asialoglycoprotein Receptor Antibody 79History 79Immunofluorescence Reactivities, Antigenic Targets, and their Clinical Significance 79Indications for Autoimmune Liver Serology Testing 79Concluding Remarks 81References 825 Environmental Exposure and Risk in Autoimmune Liver Diseases 83Ying Qi Li and Andrew L. MasonKey Points 83Introduction 84Autoimmunity 84Interaction of Genes and Environmental Triggers in Autoimmunity 85Mechanisms for Triggering Autoimmunity 86Primary Biliary Cholangitis 89Geo‐epidemiology, Clusters, and Case–Control Studies of PBC 92Bacterial Infection and PBC 93Xenobiotics and PBC 96Viruses in PBC 97Autoimmune Hepatitis 99Prospectus 101References 102Section II Autoimmune Liver Diseases and Their Clinical Correlation 1036 Autoimmune Hepatitis 105Aliya Gulamhusein and Patrick McKiernanKey Points 105Introduction 106Definition and Pathophysiology 106Epidemiology 107Presentation 108Adult‐onset AIH 108Pediatric‐onset AIH 109Diagnosis 109Autoimmune Sclerosing Cholangitis 112Treatment 112Therapeutic Approach in Adults 113First-line Therapy 113Withdrawal of Therapy 114Second‐line Options 114Therapeutic Approach in Children 115First-line Therapy 115Withdrawal of Therapy 115Second‐line Options 115Prognosis 116Adulthood 116Childhood 116References 1187 Primary Biliary Cholangitis 123Alessio Gerussi and Marco CarboneKey Points 123Introduction and Definition 124Epidemiology 124Etiopathogenesis 125Clinical Presentation 126Asymptomatic Patients 126Symptomatic Patients 126Diagnosis 127Biochemical Tests 127Autoantibodies 128Liver Biopsy 128Imaging 130Differential Diagnosis 130Natural History 130Disease Course in the UDCA Era 131Risk Stratification 132Treatment 134Ursodeoxycholic Acid 134Obeticholic Acid 135Fibric Acid Derivatives 136Budesonide 137Liver Transplantation 137Symptom Management 137Complications of Liver Disease 139Osteoporosis 139Advanced Liver Disease 140Varices 140HCC 140Useful Websites 141References 1418 Primary Sclerosing Cholangitis 143Mette Vesterhus, Benedetta Terziroli Beretta‐Piccoli, Kirsten Muri Boberg, and Giorgina Mieli‐VerganiKey Points 143Introduction 144Definition 145Adult PSC 145Epidemiology 145Diagnosis 146Diagnosis of Variant Phenotypes 147Presentation 147Malignancy 149Cholangiocarcinoma 149Gallbladder Cancer 150Colorectal Cancer 150Prognosis 150Risk Stratification: Clinical Characteristics 150Natural History Models 151ALP and Bilirubin 151Non‐invasive Evaluation of Fibrosis 151Treatment 152Medical Treatment 152Bile Acid Therapy 153Microbiota Modulators 153Anti-inflammatory Treatment 154Antibiotic Therapy 154Endoscopic Treatment 154Surveillance for Malignancy 154Colorectal Cancer: Colonoscopy 155Gallbladder Cancer: Ultrasound 155Hepatocellular Cancer: Ultrasound 155Cholangiocarcinoma 155Bone Mineral Density 155Juvenile Sclerosing Cholangitis 155Epidemiology in Pediatric Disease 155Autoimmune Sclerosing Cholangitis 156Diagnosis in Children 156Clinical Features in Pediatric Disease 158Treatment of Pediatric Disease (ASC and Juvenile PSC) 158Prognosis in Pediatric Disease 159Conclusion 159References 1609 IgG4‐Related Liver and Biliary Disease 163Eleanor Barnes and Emma L. CulverKey Points 163Introduction and Historical Perspective 164Etiology and Pathogenesis of IgG4‐RD 165Development and Characteristics of an IgG4 Antibody Response 165Antigens That May Drive an IgG4‐RD Response 166IgG4 Antibodies and Pathogenesis 167Incidence and Prevalence of IgG4‐RD 167Clinical Characteristics of IgG4‐related Hepatobiliary Disease 168Hepatobiliary Disease 168Disease Outside the Hepatobiliary System 168Diagnostic Criteria, Histologic Features, and Approach to Diagnosis of IgG4‐related Hepatobiliary Disease 168Diagnostic Criteria for AIP and IgG4‐RD 168Histologic Diagnosis of IgG4‐related Hepatobiliary Disease 170Utility of Blood Tests, Including Serum IgG4 Levels in IgG4‐RD Diagnostics 171Common Alternative Diagnoses to Consider 172Radiologic Characteristics of Hepatobiliary IgG4‐RD 173IgG4‐RD and Relationship with Malignancy 173Management and Treatment of Patients with IgG4‐RD 174Monitoring and Follow‐up 175Conclusions and Future Directions 175References 177Section III Specific Clinical Challenges 18110 Managing Acute and Chronic Seronegative Liver Disease 183Marcus C. Robertson and Peter C. HayesKey Points 183Introduction 184An Approach to Seronegative Acute Liver Failure 184Potential Causes of Seronegative ALF and Features that Suggest an Autoimmune Pathogenesis 185Clinical Features of Seronegative ALF 188Risk Stratification in Seronegative ALF 188Management of Seronegative ALF 189N‐Acetylcysteine 190Corticosteroids 190Emergency Liver Transplantation 191An Approach to Cryptogenic Chronic Liver Disease 192Potential Causes of Seronegative Chronic Liver Disease and Features that Suggest an Autoimmune Pathogenesis 192Non‐alcoholic Fatty Liver Disease 194Wilson Disease 194Seronegative Autoimmune Hepatitis 195Seronegative Primary Biliary Cholangitis 197Conclusion 197References 19811 Managing Pregnant Women with Autoimmune Liver Disease 201Eleni Theocharidou and Michael A. HeneghanKey Points 201Introduction 202Fertility in AIH 202Pregnancy Outcomes in AIH 202Liver‐related Outcomes in Pregnancy 206Pregnancy in Cirrhosis 209Safety of Medication in Pregnancy 210Summary 213References 21412 Bone Health in Patients with Autoimmune Liver Diseases 219Albert Parés and Núria GuañabensKey Points 219Introduction 220Prevalence of Osteoporosis and Fractures 222Primary Biliary Cholangitis 222Primary Sclerosing Cholangitis 223Autoimmune Hepatitis 223Pathogenesis 224Assessment of Bone Disease 226Prevention and Treatment of Bone Loss 227General Measures 227Pharmacologic Agents 227Bisphosphonates 227Other Agents 229Summary 230References 231Section IV Transplantation and Its Role in Autoimmune Liver Disease 23313 Recurrent Autoimmune Liver Disease and Its Impact on Clinical Practice 235Carlos Moctezuma‐Velázquez and Aldo J. Montano‐LozaKey Points 235Introduction 236Primary Biliary Cholangitis 236Recurrence of PBC After LT 236Diagnosis of PBC After LT 236Risk Factors Associated with PBC Recurrence After LT 237Treatment of PBC Recurrence After LT 238Prognostic Impact of PBC Recurrence After LT 239Primary Sclerosing Cholangitis 239Recurrence of PSC After LT 240Diagnosis of Recurrence of PSC After LT 240Risk Factors Associated with PSC Recurrence After LT 240Treatment of PSC Recurrence After LT 241Prognostic Impact of PSC Recurrence After LT 241Autoimmune Hepatitis 241Recurrence of AIH After LT 242Risk Factors Associated with AIH Recurrence After LT 242Treatment of AIH Recurrence After LT 243Prognostic Impact of AIH Recurrence After LT 243Conclusions 243References 24414 Recurrent Autoimmune Liver Disease and its Scientific Significance 247Atsushi Tanaka, Patrick S.C. Leung, and M. Eric GershwinKey Points 247Introduction 247Recurrence of PBC 248Incidence and Diagnosis of Recurrent PBC 249Risk Factors of Recurrent PBC 250Impact of Recurrent PBC on Long‐term Outcomes 250Recurrence of PSC 251Incidence and Diagnosis of Recurrent PSC 252Risk Factors of Recurrent PSC 253Impact of Recurrent PSC on Long‐term Outcomes 254Recurrence of AIH 254Incidence and Diagnosis of Recurrent AIH 254Risk Factors of Recurrent AIH 255Impact of Recurrent AIH on Long‐term Outcomes 255Concluding Remarks 256References 257Section V Controversies in Autoimmune Liver Diseases 26315 Making Sense of Overlap and Crossover Syndromes 265Olivier ChazouillèresKey Points 265Introduction 266General Considerations 267Liver Biopsy 268AIH Scores 269Genetics 269PBC/AIH Overlap Syndrome 269PSC/AIH Overlap Syndrome 272Liver Transplantation 273Conclusions 274References 27516 The Role of Extrahepatic Autoimmunity in Autoimmune Liver Disease 277Ewa Wunsch and Piotr MilkiewiczKey Points 277Introduction 278Epidemiology 278Autoimmune Thyroid Disease 279Sjogren Syndrome 279Systemic Sclerosis 280Systemic Lupus Erythematosus 281Rheumatoid Arthritis 282Celiac Disease 283Inflammatory Bowel Disease 284Conclusions 286Guidelines for Clinicians 287References 28817 Symptoms, Chronic Disease, and Patient Management 289David JonesKey Points 289Background 290Goals of Treatment 290Symptoms, Quality of Life, and Health Utility: Key Concepts 291Symptoms 291Health‐related Quality of Life 292Health Utility 292Symptoms and Their Management in AILD 292Impact of Disease‐modifying Therapy on Symptoms in AILD 292Stage‐associated Symptoms 293Stage‐independent Symptoms 293Pruritus 293Fatigue and Cognitive Symptoms 295Social Isolation Symptoms 298Effective Care Delivery in AILD 299References 300Index 301