Autoimmune Liver Disease: Management and Clinical Practice

Autoimmune Liver Disease: Management and Clinical Practice
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ISBN: 9781119532606
Anul publicării: 2020
Pagini: 336


A practical guide to autoimmune liver diseases through pathogenesis, diagnosis, and management

In Autoimmune Liver Disease Management and Clinical Practice, practitioners will learn about the current state of autoimmune liver disease and how to focus on their diagnosis and treatment. The four-part book begins with a thorough investigation of current immunological thinking as it relates to the autoimmunity of the liver. It also covers the four major hepatic autoimmune liver diseases in both adults and children, their management and the role of liver transplantation, and learned approaches to patient management and empowerment.

Expert authors in the field have come together to provide a thorough examination of autoimmune liver disease to help support clinicians assisting patients. The text provides an in-depth look at topics including:

●      The four major hepatic autoimmune liver diseases, their diagnosis, and potential disease management

●      The use (and misuse) of autoantibodies in diagnosis and treatment

●      The role and timing of liver transplantation and the impact of recurrent autoimmune liver disease as well as de novo autoimmune hepatitis

●      Optimal approaches to managing patients and keeping care personalised

With breadth, depth and current-day relevance, Autoimmune Liver Disease sheds light on recent developments in management of liver disease for practitioners, nurses, and health care professionals.


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 HCO 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 Parés and Núria Guañabens

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‐Velázquez 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 Chazouillères

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


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.


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