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 xv


Contributors xvii


Abbreviations xxi


Introduction: The Paradigm and Paradox of Liver Autoimmunity 1
M. Eric Gershwin


Section I Scientific Basis of Clinical Autoimmune Liver Diseases 3


1 Introduction to the Physiology, Immunology and Pathology of the Liver and Biliary Tree 5
Marco Carbone and Mario Strazzabosco


Key Points 5


Liver Cell Types and Organization 6


Hepatic Metabolism 7


Bilirubin Metabolism and Transport 7


Carbohydrate Metabolism 7


Lipid Metabolism 8


Protein Metabolism 8


Metabolic Zonation 8


Hepatic Transport Systems 9


Basolateral (Sinusoidal) Transporters 9


Apical (Canalicular) Transporters 11


Drug Metabolism 11


Bile Formation, Secretion and the Enterohepatic Circulation 12


Bile Acid Synthesis and Metabolism 13


Enterohepatic Bile Acid Circulation 13


Death and Regeneration of Hepatocytes 14


Cell Death 14


Liver Regeneration 15


Cholangiocyte Reaction to Biliary Damage 16


Protective Role of Biliary HCO3 Secretion 16


Cholangiocytes and Immunity 16


Biochemical Markers and Patterns of Hepatic Injury 17


Hepatocellular Necrosis 18


Cholestasis 18


References 20


2 Concepts of Autoimmunity Relevant to Autoimmune Liver Diseases 21
Isaiah G. Roepe and John M. Vierling


Key Points 21


Introduction 22


Role of Innate and Adaptive Immunity in Autoimmunity in the Context of the Liver as an Immune Organ 22


Overview 22


Innate Immunity 23


Liver as an Innate Immune Organ 25


Adaptive Immunity and Adaptive Immune Functions of the Liver 25


Role of the Liver as an Adaptive Immune Organ 28


Generation and Maintenance of Tolerance to Self?antigens 28


Overview 28


Central Tolerance 29


Central T?cell Tolerance 29


Central B?cell Tolerance 29


Peripheral Tolerance 30


T? and B?cell Clonal Anergy 30


T?cell Mediated Immune Regulation 30


Natural and Inducible T Regulatory Cells 30


Peripheral B?cell Regulatory Mechanisms 31


Regulatory Dendritic Cells 31


Immunoregulatory Interplay Between Treg and Th17 Cells 31


Risk Factors for Autoimmune Diseases 31


Genetics 31


Complex Genetic and Monogenic Diseases 31


HLA Risk Alleles 32


Non?HLA Gene Associations 32


Critical Role of Epigenetics 33


Transcription Factor Enhancers and Super Enhancers 33


MicroRNAs 33


Sex and Sex Hormones 33


Vitamin D and Sunlight Exposure 34


Loss of Immune Tolerance to Autoantigens and Perpetuation of Autoimmune Diseases 34


Overview 34


Role of the Microbiome 35


Mechanisms of Loss of Tolerance to Autoantigens 35


Bacterial and Viral Infections 35


Molecular Mimicry of Autoantigens 36


Neoantigens 36


Failure of Apoptosis to Conceal Autoantigens and Eliminate Autoreactive Cells 36


Immune Deviation of Activated T Cells 37


T?cell Receptor Revision in the Periphery 37


Perpetuation of Autoimmune Diseases 37


Epigenetics 37


Epitope Spreading 38


Tissue Memory T Cells 38


Cytokines Promoting Chronic Inflammation and Autoimmunity 38


Tertiary Lymphoid Structures and Germinal Centers 39


Epithelial Cell?induced Transformation of iTreg to Th17 Cells 39


Prevention of Autoimmunity and Therapeutic Control of Autoimmune Diseases 39


Overview 39


Strategies to Prevent Autoimmunity 39


Vitamin D3 39


Gut Microbiota Manipulation in Pregnancy and Infancy 39


Oral Tolerance 39


Strategies to Treat Established Autoimmune Diseases 40


Inducible T Regulatory T Cells 40


Epigenetic Enhancer Regulation 40


References 44


3 Genetics and Risk of Autoimmune Liver Diseases 47
George F. Mells


Key Points 47


Introduction 48


HLA Associations in Autoimmune Liver Disease 50


Non?HLA Associations in Autoimmune Liver Disease 53


Conclusion 61


References 62


4 Autoantibodies and Understanding of Autoimmune Liver Diseases 65
Benedetta Terziroli Beretta?Piccoli, Giorgina Mieli?Vergani, and Diego Vergani


Key Points 65


Introduction 66


Methods of Detection 66


Anti?nuclear Antibody 68


History 68


Immunofluorescence Reactivities and Antigenic Targets 68


Clinical Significance in Autoimmune Liver Disease 70


Anti?smooth Muscle and Anti?actin Antibodies 73


History 73


Immunofluorescence Reactivities, Antigenic Targets, and Clinical Significance 73


Anti?liver?kidney Microsomal Antibody 74


History 74


Immunofluorescence Reactivities, Antigenic Targets, and Clinical Significance 75


Anti?liver Cytosol Type 1 Antibody 76


History 76


Immunofluorescence Reactivities, Antigenic Targets, and Clinical Significance 76


Anti?soluble Liver Antigen Antibody 76


History 76


Immunofluorescence Reactivities, Antigenic Targets, and Clinical Significance 77


Anti?neutrophil Cytoplasmic Antibody 77


History 77


Immunofluorescence Reactivities, Antigenic Targets, and their Clinical Significance 77


Anti?mitochondrial Antibody 78


History 78


Immunofluorescence Reactivities, Antigenic Targets, and their Clinical Significance 78


Anti?asialoglycoprotein Receptor Antibody 79


History 79


Immunofluorescence Reactivities, Antigenic Targets, and their Clinical Significance 79


Indications for Autoimmune Liver Serology Testing 79


Concluding Remarks 81


References 82


5 Environmental Exposure and Risk in Autoimmune Liver Diseases 83
Ying Qi Li and Andrew L. Mason


Key Points 83


Introduction 84


Autoimmunity 84


Interaction of Genes and Environmental Triggers in Autoimmunity 85


Mechanisms for Triggering Autoimmunity 86


Primary Biliary Cholangitis 89


Geo?epidemiology, Clusters, and Case-Control Studies of PBC 92


Bacterial Infection and PBC 93


Xenobiotics and PBC 96


Viruses in PBC 97


Autoimmune Hepatitis 99


Prospectus 101


References 102


Section II Autoimmune Liver Diseases and Their Clinical Correlation 103


6 Autoimmune Hepatitis 105
Aliya Gulamhusein and Patrick McKiernan


Key Points 105


Introduction 106


Definition and Pathophysiology 106


Epidemiology 107


Presentation 108


Adult?onset AIH 108


Pediatric?onset AIH 109


Diagnosis 109


Autoimmune Sclerosing Cholangitis 112


Treatment 112


Therapeutic Approach in Adults 113


First-line Therapy 113


Withdrawal of Therapy 114


Second?line Options 114


Therapeutic Approach in Children 115


First-line Therapy 115


Withdrawal of Therapy 115


Second?line Options 115


Prognosis 116


Adulthood 116


Childhood 116


References 118


7 Primary Biliary Cholangitis 123
Alessio Gerussi and Marco Carbone


Key Points 123


Introduction and Definition 124


Epidemiology 124


Etiopathogenesis 125


Clinical Presentation 126


Asymptomatic Patients 126


Symptomatic Patients 126


Diagnosis 127


Biochemical Tests 127


Autoantibodies 128


Liver Biopsy 128


Imaging 130


Differential Diagnosis 130


Natural History 130


Disease Course in the UDCA Era 131


Risk Stratification 132


Treatment 134


Ursodeoxycholic Acid 134


Obeticholic Acid 135


Fibric Acid Derivatives 136


Budesonide 137


Liver Transplantation 137


Symptom Management 137


Complications of Liver Disease 139


Osteoporosis 139


Advanced Liver Disease 140


Varices 140


HCC 140


Useful Websites 141


References 141


8 Primary Sclerosing Cholangitis 143
Mette Vesterhus, Benedetta Terziroli Beretta?Piccoli, Kirsten Muri Boberg, and Giorgina Mieli?Vergani


Key Points 143


Introduction 144


Definition 145


Adult PSC 145


Epidemiology 145


Diagnosis 146


Diagnosis of Variant Phenotypes 147


Presentation 147


Malignancy 149


Cholangiocarcinoma 149


Gallbladder Cancer 150


Colorectal Cancer 150


Prognosis 150


Risk Stratification: Clinical Characteristics 150


Natural History Models 151


ALP and Bilirubin 151


Non?invasive Evaluation of Fibrosis 151


Treatment 152


Medical Treatment 152


Bile Acid Therapy 153


Microbiota Modulators 153


Anti-inflammatory Treatment 154


Antibiotic Therapy 154


Endoscopic Treatment 154


Surveillance for Malignancy 154


Colorectal Cancer: Colonoscopy 155


Gallbladder Cancer: Ultrasound 155


Hepatocellular Cancer: Ultrasound 155


Cholangiocarcinoma 155


Bone Mineral Density 155


Juvenile Sclerosing Cholangitis 155


Epidemiology in Pediatric Disease 155


Autoimmune Sclerosing Cholangitis 156


Diagnosis in Children 156


Clinical Features in Pediatric Disease 158


Treatment of Pediatric Disease (ASC and Juvenile PSC) 158


Prognosis in Pediatric Disease 159


Conclusion 159


References 160


9 IgG4?Related Liver and Biliary Disease 163
Eleanor Barnes and Emma L. Culver


Key Points 163


Introduction and Historical Perspective 164


Etiology and Pathogenesis of IgG4?RD 165


Development and Characteristics of an IgG4 Antibody Response 165


Antigens That May Drive an IgG4?RD Response 166


IgG4 Antibodies and Pathogenesis 167


Incidence and Prevalence of IgG4?RD 167


Clinical Characteristics of IgG4?related Hepatobiliary Disease 168


Hepatobiliary Disease 168


Disease Outside the Hepatobiliary System 168


Diagnostic Criteria, Histologic Features, and Approach to Diagnosis of IgG4?related Hepatobiliary Disease 168


Diagnostic Criteria for AIP and IgG4?RD 168


Histologic Diagnosis of IgG4?related Hepatobiliary Disease 170


Utility of Blood Tests, Including Serum IgG4 Levels in IgG4?RD Diagnostics 171


Common Alternative Diagnoses to Consider 172


Radiologic Characteristics of Hepatobiliary IgG4?RD 173


IgG4?RD and Relationship with Malignancy 173


Management and Treatment of Patients with IgG4?RD 174


Monitoring and Follow?up 175


Conclusions and Future Directions 175


References 177


Section III Specific Clinical Challenges 181


10 Managing Acute and Chronic Seronegative Liver Disease 183
Marcus C. Robertson and Peter C. Hayes


Key Points 183


Introduction 184


An Approach to Seronegative Acute Liver Failure 184


Potential Causes of Seronegative ALF and Features that Suggest an Autoimmune Pathogenesis 185


Clinical Features of Seronegative ALF 188


Risk Stratification in Seronegative ALF 188


Management of Seronegative ALF 189


N?Acetylcysteine 190


Corticosteroids 190


Emergency Liver Transplantation 191


An Approach to Cryptogenic Chronic Liver Disease 192


Potential Causes of Seronegative Chronic Liver Disease and Features that Suggest an Autoimmune Pathogenesis 192


Non?alcoholic Fatty Liver Disease 194


Wilson Disease 194


Seronegative Autoimmune Hepatitis 195


Seronegative Primary Biliary Cholangitis 197


Conclusion 197


References 198


11 Managing Pregnant Women with Autoimmune Liver Disease 201
Eleni Theocharidou and Michael A. Heneghan


Key Points 201


Introduction 202


Fertility in AIH 202


Pregnancy Outcomes in AIH 202


Liver?related Outcomes in Pregnancy 206


Pregnancy in Cirrhosis 209


Safety of Medication in Pregnancy 210


Summary 213


References 214


12 Bone Health in Patients with Autoimmune Liver Diseases 219
Albert Pares and Nuria Guanabens


Key Points 219


Introduction 220


Prevalence of Osteoporosis and Fractures 222


Primary Biliary Cholangitis 222


Primary Sclerosing Cholangitis 223


Autoimmune Hepatitis 223


Pathogenesis 224


Assessment of Bone Disease 226


Prevention and Treatment of Bone Loss 227


General Measures 227


Pharmacologic Agents 227


Bisphosphonates 227


Other Agents 229


Summary 230


References 231


Section IV Transplantation and Its Role in Autoimmune Liver Disease 233


13 Recurrent Autoimmune Liver Disease and Its Impact on Clinical Practice 235
Carlos Moctezuma?Velazquez and Aldo J. Montano?Loza


Key Points 235


Introduction 236


Primary Biliary Cholangitis 236


Recurrence of PBC After LT 236


Diagnosis of PBC After LT 236


Risk Factors Associated with PBC Recurrence After LT 237


Treatment of PBC Recurrence After LT 238


Prognostic Impact of PBC Recurrence After LT 239


Primary Sclerosing Cholangitis 239


Recurrence of PSC After LT 240


Diagnosis of Recurrence of PSC After LT 240


Risk Factors Associated with PSC Recurrence After LT 240


Treatment of PSC Recurrence After LT 241


Prognostic Impact of PSC Recurrence After LT 241


Autoimmune Hepatitis 241


Recurrence of AIH After LT 242


Risk Factors Associated with AIH Recurrence After LT 242


Treatment of AIH Recurrence After LT 243


Prognostic Impact of AIH Recurrence After LT 243


Conclusions 243


References 244


14 Recurrent Autoimmune Liver Disease and its Scientific Significance 247
Atsushi Tanaka, Patrick S.C. Leung, and M. Eric Gershwin


Key Points 247


Introduction 247


Recurrence of PBC 248


Incidence and Diagnosis of Recurrent PBC 249


Risk Factors of Recurrent PBC 250


Impact of Recurrent PBC on Long?term Outcomes 250


Recurrence of PSC 251


Incidence and Diagnosis of Recurrent PSC 252


Risk Factors of Recurrent PSC 253


Impact of Recurrent PSC on Long?term Outcomes 254


Recurrence of AIH 254


Incidence and Diagnosis of Recurrent AIH 254


Risk Factors of Recurrent AIH 255


Impact of Recurrent AIH on Long?term Outcomes 255


Concluding Remarks 256


References 257


Section V Controversies in Autoimmune Liver Diseases 263


15 Making Sense of Overlap and Crossover Syndromes 265
Olivier Chazouilleres


Key Points 265


Introduction 266


General Considerations 267


Liver Biopsy 268


AIH Scores 269


Genetics 269


PBC/AIH Overlap Syndrome 269


PSC/AIH Overlap Syndrome 272


Liver Transplantation 273


Conclusions 274


References 275


16 The Role of Extrahepatic Autoimmunity in Autoimmune Liver Disease 277
Ewa Wunsch and Piotr Milkiewicz


Key Points 277


Introduction 278


Epidemiology 278


Autoimmune Thyroid Disease 279


Sjogren Syndrome 279


Systemic Sclerosis 280


Systemic Lupus Erythematosus 281


Rheumatoid Arthritis 282


Celiac Disease 283


Inflammatory Bowel Disease 284


Conclusions 286


Guidelines for Clinicians 287


References 288


17 Symptoms, Chronic Disease, and Patient Management 289
David Jones


Key Points 289


Background 290


Goals of Treatment 290


Symptoms, Quality of Life, and Health Utility: Key Concepts 291


Symptoms 291


Health?related Quality of Life 292


Health Utility 292


Symptoms and Their Management in AILD 292


Impact of Disease?modifying Therapy on Symptoms in AILD 292


Stage?associated Symptoms 293


Stage?independent Symptoms 293


Pruritus 293


Fatigue and Cognitive Symptoms 295


Social Isolation Symptoms 298


Effective Care Delivery in AILD 299


References 300


Index 301