Liver Diseases. A Multidisciplinary Textbook

Preface
Contents
Part I: Overview
	1: Anatomy and Embryology of the Liver
		1.1	 Introduction
		1.2	 Clinical Anatomy of the Liver
		1.3	 Gross Anatomy and Surfaces of the Liver
		1.4	 Peritoneum and Ligaments of the Liver
		1.5	 Vessels and Nerves
		1.6	 Segmental Anatomy of the Liver
		1.7	 Extrahepatic Biliary Tract
		1.8	 Liver Development
			1.8.1	 Hepatic Competence
			1.8.2	 Hepatic Induction
			1.8.3	 Liver Bud Formation and Growth
			1.8.4	 Hepatoblasts Fate and Function
			1.8.5	 Differentiation of Hepatocytes and Biliary Epithelial Cells
			1.8.6	 Hepatic Vascular Development
			1.8.7	 Morphogenetic Events Accompanying the Liver Growth
		1.9	 Conclusions
		Self Study
			Questions
			Answers
		References
	2: Liver Histology
		2.1	 Introduction: The Microstructure of the Liver
		2.2	 Hepatic Morpho-functional Units: Hepatic Lobule, Portal Lobule, Hepatic Acinus
		2.3	 Hepatic Cytotypes
			2.3.1	 Hepatocytes
			2.3.2	 Endothelial Cells
			2.3.3	 Hepatic Stellate Cells
			2.3.4	 Kupffer Cells
			2.3.5	 Lymphocytes or Pit Cells
		2.4	 Cholangiocytes and the Intrahepatic Bile Ducts
		2.5	 Hepatic Microcirculation
		2.6	 Microstructure of the Extrahepatic Biliary Tract
		2.7	 Conclusions
		Self Study
			Questions
			Answer
		References
	3: Hepatic Progenitor Cells and Biliary Tree Stem Cells
		3.1	 Hepatic Progenitor Cells: Embryology Derivation and Anatomical Location
		3.2	 Role of Hepatic Progenitor Cells and Regeneration Pathways in Human Liver Pathologies
		3.3	 HPCs Activation Is Driven by a Specialized Niche and Signaling Pathways
		3.4	 Biliary Tree Stem Cells and Peribiliary Glands
		3.5	 Stem Cells in Regenerative Medicine for Liver Diseases
		3.6	 Conclusions
		Self Study
			Questions
			Answers
		References
	4: Hepatocellular Death: Apoptosis, Autophagy, Necrosis and Necroptosis
		4.1	 Introduction
		4.2	 Apoptosis
		4.3	 Autophagy
		4.4	 Necrosis
		4.5	 Necroptosis
		4.6	 The Crosstalk Between Apoptosis, Autophagy, Necrosis and Necroptosis
		4.7	 Conclusions
		Self Study
			Questions
			Answers
		References
	5: Liver Inflammation: Short Uptodate
		5.1	 Introduction
		5.2	 Liver Inflammation
			5.2.1	 Macrophages
			5.2.2	 Dendritic Cells (DCs)
			5.2.3	 Lymphocytes
			5.2.4	 Mucosal-Associated Invariant T (MAIT)
			5.2.5	 Leukocytes
			5.2.6	 HMGB1 (High Mobility Group Box 1) Protein
		5.3	 Pathological Liver Inflammation
			5.3.1	 Cholangiocyte Immune Response
			5.3.2	 Steatosis and Steatohepatitis
			5.3.3	 Inflammation in NASH
			5.3.4	 Metaflammation
		5.4	 Conclusions
		Self Study
			Questions
			Answers
		References
	6: Molecular Basis of Fibrogenesis and Angiogenesis During Chronic Liver Disease: Impact of TGF-β and VEGF on Pathogenic Pathways
		6.1	 Introduction
		6.2	 Biology of TGF-β Signaling Pathway
		6.3	 Apoptotic and Fibrotic Effects of TGF-β on Hepatocytes
		6.4	 Molecular Basis for Phenotypic Changes of HSCs to MyoFBs
		6.5	 Linkage of VEGF-Induced Angiogenesis with TGF-β-Induced Fibrogenesis
		6.6	 Endothelial to Mesenchymal Transition (EndoMT) for LC
		6.7	 Summary and Perspective
		Self Study
			Questions
			Answers
		References
	7: Hepatotoxicity: Mechanisms of Liver Injury
		7.1	 Introduction
		7.2	 Hepatic Injury
		7.3	 Hepatic Function
		7.4	 Hy’s Law
		7.5	 Detecting and Assessing Hepatotoxicity
		7.6	 Morphologic Pathology
		7.7	 Direct Hepatotoxins
		Self Study
			Questions and Answers
		References
	8: Crosstalk of Molecular Signaling in Hepatocellular Carcinoma
		8.1	 Introduction
		8.2	 Receptor Tyrosine Kinases Signaling
		8.3	 MAPK/ERK Pathway
		8.4	 PI3K/Akt/mTOR Pathway
		8.5	 Crosstalk of ERK/MAPK and PI3K/Akt/mTOR Pathway
		8.6	 Wnt/β-Catenin Signaling
		8.7	 Crosstalk of Wnt/β-Catenin Pathway with Other Pathways
		8.8	 TGF-β Signaling
		8.9	 Crosstalk of TGF-β Signaling with Other Pathways
		8.10	 JAK/STAT Pathway
		8.11	 Crosstalk of JAK/STAT Pathway with Other Pathways
		8.12	 MDM2-p53 Pathway
		8.13	 Crosstalk of MDM2-p53 Pathway with Other Pathways
		8.14	 Other Signaling Pathways
		8.15	 Conclusions and Perspectives
		Self Study
			Questions
			Answers
		References
	9: Drug Induced Liver Injury: Mechanisms, Diagnosis, and Clinical Management
		9.1	 Introduction
		9.2	 Definitions
			9.2.1	 Idiosyncratic Versus Intrinsic Toxicity
		9.3	 DILI Mechanisms and Hypothetical Cascade of Events
		9.4	 Clinical Aspects
			9.4.1	 Most Implicated Drugs
			9.4.2	 Genetic and Non-genetic Risk Factors
			9.4.3	 DILI Signatures for Specific Drugs
			9.4.4	 Demographics and DILI Characteristics
			9.4.5	 Clinical Spectrum
			9.4.6	 Alternative Causes
		9.5	 Biomarkers
		9.6	 RUCAM-Based Causality Assessment
			9.6.1	 Principles
			9.6.2	 Alternative Approaches of Causality Assessment
			9.6.3	 Global Usage
		9.7	 Practical Example
		9.8	 Conclusions
		Self Study
			Questions
			Answers
		References
			Further Reading
			Related Links/Journals/Book
	10: Acquired Metabolic Disorders
		10.1	 Introduction
		10.2	 Ornithine Transcarbamylase Deficiency
			10.2.1	 Brief Historical Overview
			10.2.2	 Definition of the Disorder
			10.2.3	 Diagnosis
			10.2.4	 Treatment
		10.3	 Porphyria
			10.3.1	 Brief Historical Overview
			10.3.2	 Definition of the Disorder
			10.3.3	 Diagnosis
			10.3.4	 Treatment
		10.4	 Hemochromatosis
			10.4.1	 Brief Historical Overview
			10.4.2	 Definition of the Disorder
			10.4.3	 Diagnosis
			10.4.4	 Treatment
		10.5	 Alpha 1 Antitrypsin Deficiency
			10.5.1	 Brief Historical Overview
			10.5.2	 Definition of the Disorder
			10.5.3	 Diagnosis
			10.5.4	 Treatment
		10.6	 Wilson Disease
			10.6.1	 Brief Historical Overview
			10.6.2	 Definition of the Disorder
			10.6.3	 Diagnosis
			10.6.4	 Treatment
		10.7	 Conclusions and Future Perspectives
		Self Study
			Questions
			Answers
		References
			Further Readings
			Ornithine Transcarbamylase Deficiency
			Porphyria
			Hemochromatosis
			Alpha 1 Antitrypsin Deficiency
	11: Vascular Disorders of the Liver
		11.1	 Introduction
		11.2	 Budd-Chiari Syndrome or Hepatic Venous Outflow Tract Obstruction
		11.3	 Portal Vein Thrombosis
		11.4	 Sinusoidal Obstruction Syndrome
		11.5	 Congenital Vascular Malformations Affecting the Liver
			11.5.1	 Isolated Congenital Liver Shunts
		11.6	 Conclusions
		Self Study
			Questions
			Answers
		References
	12: Liver Ischaemia-Reperfusion Injury
		12.1	 Introduction
			12.1.1	 Definitions
		12.2	 Aetiology
			12.2.1	 Liver Surgery
			12.2.2	 Liver Transplantation
		12.3	 Risk Factors
			12.3.1	 Liver Surgery
			12.3.2	 Liver Transplantation
		12.4	 Pathophysiology
			12.4.1	 Intracellular Events
			12.4.2	 Innate Immune Response
			12.4.3	 Cellular Response
			12.4.4	 Inflammatory Mediators
			12.4.5	 Microcirculatory Failure
		12.5	 Clinical Manifestation
			12.5.1	 Direct Injury to the Liver
			12.5.2	 Remote Injury to Other Organs
				12.5.2.1	 Post-reperfusion Syndrome (PRS)
		12.6	 Prevention and Treatment
			12.6.1	 Liver Surgery
				12.6.1.1	 Intermittent Clamping
				12.6.1.2	 Ischaemic Preconditioning (IPC)
				12.6.1.3	 Remote Ischaemic Preconditioning (RIPC)
				12.6.1.4 Pharmacological Agents
		12.7	 Liver Transplantation
		12.8	 Donor Strategies
			12.8.1	 Donor Optimisation
			12.8.2	 Normothermic Regional Perfusion (NRP)
		12.9	 Preservation and Resuscitation
			12.9.1	 Preservation Solutions
			12.9.2	 Hypothermic Machine Perfusion (HMP)
			12.9.3	 Normothermic Machine Perfusion (NMP)
		12.10	 Recipient Strategies
			12.10.1 Washout Techniques
			12.10.2 Remote Ischaemic Preconditioning (RIPC)
			12.10.3 Pharmacological Agents
		12.11	 Future Perspectives
		Self Study
			Questions
			Answers
		References
	13: Autoimmune Hepatitis
		13.1	 Introduction
		13.2	 Diagnostic Criteria
		13.3	 Autoantibody Serology
		13.4	 Aetiology
		13.5	 Pathogenesis
		13.6	 Natural History
		13.7	 Epidemiology
			13.7.1	 Histopathological Features
			13.7.2	 Diagnostic Work Up
		13.8	 Disease Treatment and Management
			13.8.1	 Standard Treatment
		Self Study
			Questions
			Answers
		References
	14: Primary Sclerosing Cholangitis
		14.1	 Introduction
		14.2	 Diagnostic Criteria
		14.3	 Epidemiology
		14.4	 Natural History
		14.5	 Serological Features
		14.6	 Imaging Features
		14.7	 Histopathological Features
		14.8	 Autoimmune Hepatitis in PSC
		14.9	 Extrahepatic Manifestations
		14.10	 Pathogenesis
		14.11	 Medical Treatment
		Self Study
			Questions
			Answers
		References
	15: Parasitic Liver Diseases
		15.1	 Introduction
			15.1.1	 Parasitic Liver Diseases: Helminths
				15.1.1.1	 Schistosomiasis
			15.1.2	 Echinococcosis
			15.1.3	 Clonorchiasis and Opisthorchiasis
			15.1.4	 Fascioliasis
			15.1.5	 Ascariasis
			15.1.6	 Visceral Larva Migrans
			15.1.7	 Hepatic Capillariasis
			15.1.8	 Ectopic Pinworm Infection
			15.1.9	 Strongyloidiasis
			15.1.10	 Fasciolopsiasis
			15.1.11	 Dicrocoeliasis
			15.1.12	 Visceral pentastomiasis
		15.2	 Parasitic Liver Diseases: Protozoa
			15.2.1	 Amoebiasis
			15.2.2	 Giardiasis
			15.2.3	 Cryptosporidiosis
			15.2.4	 Malaria
			15.2.5	 Visceral Leishmaniasis
			15.2.6	 Toxoplasmosis
			15.2.7	 Babesiosis
			15.2.8	 Chagas’ Disease (Trypanosomiasis)
		15.3	 Concluding Remarks and Future Directions
		Self Study
			Questions
			Answers
		References
			Further Reading
	16: Viral Hepatitis B
		16.1	 Introduction
		16.2	 HBV Genome
		16.3	 HBV Genotypes
		16.4	 HBV Mutation
		16.5	 HBV Transmission
		16.6	 Acute Infection
		16.7	 Chronic Infection
		16.8	 Genetic Factors Predisposing to Chronic Persistent Infection
		16.9	 Serological Diagnosis of HBV
		16.10	 Immune Response
		16.11	 Fulminant Hepatic Failure
		16.12	 Chronic Hepatitis, Liver Cirrhosis and Massive Hepatic Necrosis
		16.13	 Hepatocellular Carcinoma
		16.14	 HBV Vaccination
		16.15	 Anti-HBV Therapy
		16.16	 Pegylated Interferon Alpha (IFN-α) Therapy
		16.17	 Nucleos(t)ide Analogues Therapy
		16.18	 Combination Therapy
		16.19	 Future Perspectives
		16.20	 Conclusion
		Self Study
			Questions
			Answers
		References
	17: Viral Hepatitis C
		17.1	 Introduction
		17.2	 Virology
			17.2.1	 Taxonomic Classification and Genotypes
			17.2.2	 Viral Structure
			17.2.3	 Viral Life Cycle
		17.3	 Epidemiology
		17.4	 Transmission
		17.5	 Diagnosis
			17.5.1	 Anti-HCV Antibodies
			17.5.2	 Nucleic Acid Detection
			17.5.3	 Genotyping
			17.5.4	 Point of Care and Rapid Tests
		17.6	 Clinical Manifestations
			17.6.1	 Acute Hepatitis
			17.6.2	 Chronic Hepatitis
			17.6.3	 Hepatic Steatosis
			17.6.4	 Cirrhosis
				17.6.4.1	 Ascites
				17.6.4.2	 Esophageal Varices
				17.6.4.3	 Hepatic Encephalopathy
		17.7	 HCC
		17.8	 Extrahepatic Manifestations
			17.8.1	 Mixed Cryoglobulinemia
			17.8.2	 Lymphoproliferative Disorders
			17.8.3	 Cardiovascular Manifestations
			17.8.4	 Neurologic and Psychiatric Diseases
			17.8.5	 Endocrine Diseases
		17.9	 Natural History
		17.10	 Treatment
			17.10.1	 Objectives of Therapy
			17.10.2	 Direct Antiviral Drugs
				17.10.2.1	 NS3/4A Protease Inhibitors
				17.10.2.2	 NS5A Inhibitors
				17.10.2.3	 NS5B RNA Polymerase Inhibitors
			17.10.3	 DAA Therapeutic Regimens and Their Clinical Use
				17.10.3.1	 DAA Treatment and Drug-to-Drug Interaction
				17.10.3.2	 Post-Treatment Follow-Up
		17.11	 Treatment of HCV Acute Hepatitis
		17.12	 Treatment of Particular Patients with HCV
			17.12.1	 HBV and HIV Co-Infected
			17.12.2	 End-Stage Liver Disease
			17.12.3	 Patients with Renal Insufficiency
			17.12.4	 Non-hepatic Solid Organ Transplantation Patients
			17.12.5	 Re-treatment of Non-SVR to DAA
		17.13	 Prevention of HCV Infection
		Self Study
			Questions
			Answers
		References
		Glossary
	18: Non-B, Non-C Viral Hepatitis
		18.1	 Introduction
		18.2	 Epidemiology of Non-B/Non-C Viral Hepatitis
			18.2.1	 HAV Infection
			18.2.2	 HDV Infection
			18.2.3	 HEV Infection
		18.3	 Clinical Presentation and Management of Non-B/Non-C Viral Hepatitis
			18.3.1	 HAV Infection
			18.3.2	 HDV Infection
			18.3.3	 HEV Infection
		18.4	 Global Burden of Non-B/Non-C Viral Hepatitis
		18.5	 Summary and Perspectives
		Self Study
			Question
			Answer
		References
	19: The Microbiome in Liver Diseases
		19.1	 Introduction
		19.2	 The Intestinal Microbiome in Liver Diseases
		19.3	 Summary and Perspectives
		Self Study
			Question
			Answer
		References
	20: Polycystic Liver Diseases
		20.1	 Introduction
		20.2	 Pathogenesis
		20.3	 Epidemiology
		20.4	 Signs and Symptoms
		20.5	 Diagnosis
		20.6	 Establishing Diagnosis
		20.7	 Differential Diagnosis
		20.8	 Natural History and Complications
		20.9	 Classifications
		20.10	 Treatment
		Self Study
			Questions
			Answers
		References
	21: Hepato- and Porto-pulmonary Hypertension
		21.1	 Introduction
		21.2	 Porto-Pulmonary Hypertension
			21.2.1	 Definition
			21.2.2	 Epidemiology
			21.2.3	 Pathology
			21.2.4	 Pathophysiology
			21.2.5	 Clinical Manifestations
			21.2.6	 Workup
			21.2.7	 Pharmacological Treatment
			21.2.8	 Liver Transplantation in Patients with POPH
			21.2.9	 Prognosis
		21.3	 Hepato Pulmonary Syndrome (HPS)
			21.3.1	 Definition
			21.3.2	 Epidemiology
			21.3.3	 Risk Factors
			21.3.4	 Pathology
			21.3.5	 Pathophysiology (Fig. 21.1)
			21.3.6	 Workup
			21.3.7	 Echocardiography
			21.3.8	 HPS Classification
			21.3.9	 HPS Prognosis
			21.3.10 HPS Treatment
			21.3.11 Pharmacological Treatment
			21.3.12 Conclusions
		Self Study
			Questions
		Answers
		Future Perspectives
		References
			Further Reading
	22: Hepatic Abscesses
		22.1	 Definition
		22.2	 History
		22.3	 Incidence
		22.4	 Classification
		22.5	 Aetiopathogeny
		22.6	 Diagnosis
			22.6.1	 Clinical Manifestations
			22.6.2	 Imaging Explorations
			22.6.3	 Laboratory Tests
			22.6.4	 Differential Diagnosis
		22.7	 Evolution
		22.8	 Treatment
		22.9	 Amoebaean Abscesses
		Self Study
			Questions
			Answers
		References
	23: Liver Cirrhosis
		23.1	 Introduction
		23.2	 Epidemiology
		23.3	 Etiology
			23.3.1	 Viral Hepatitis
			23.3.2	 Alcoholic Liver Disease
			23.3.3	 Non-alcoholic Fatty Liver Disease
			23.3.4	 Cholestasis
			23.3.5	 Circulation Disorders
			23.3.6	 Drugs and Industrial Poisons
			23.3.7	 Others
		23.4	 Pathology
		23.5	 Clinical Stages and Presentations
		23.6	 Laboratory Tests
		23.7	 Imaging
		23.8	 Diagnosis
		23.9	 Treatment
			23.9.1	 Antiviral Treatment
			23.9.2	 Ascites
			23.9.3	 Variceal Bleeding
			23.9.4	 Hepatic Encephalopathy
			23.9.5	 Hepatorenal Syndrome
		23.10	 Prognosis
		Self Study
			Questions
			Answers
	24: Primary Biliary Cholangitis
		24.1	 Introduction
		24.2	 Epidemiology of PBC
		24.3	 Pathogenesis of PBC
			24.3.1	 Genetic Factors
			24.3.2	 Epigenetics
			24.3.3	 Environmental Factors
			24.3.4	 The Role of AMA, T Cells and BECs in the Pathogenesis of PBC
		24.4	 Clinical Presentation
		24.5	 Diagnosis
			24.5.1	 Biochemical Findings
			24.5.2	 Autoantibodies
			24.5.3	 Histology
			24.5.4	 Non-invasive Methods for Monitoring Disease Stage
		24.6	 Natural History of PBC and Treatment
			24.6.1	 Natural History of PBC in the Pre-UDCA Era
			24.6.2	 Natural History and Treatment of PBC
				24.6.2.1	 Medications to Delay Disease Progression
					UDCA
					Obeticholic Acid
					Other Treatment Modalities
					Liver Transplantation
				24.6.2.2	 Active Management of Disease-Related Symptoms
		24.7	 Variant Syndromes of PBC
			24.7.1	 AMA Negative PBC
			24.7.2	 PBC-AIH Variant
			24.7.3	 Premature Ductopenic Variant
		24.8	 Staging and Surveying of PBC Patients
		24.9	 Conclusion/Summary
		Self Study
			Questions
			Answers
		References
	25: The Paucity of Interlobular Bile Ducts
		25.1	 Introduction
		25.2	 Cholangiocyte
		25.3	 Ductal Plate Remodeling of the Liver
		25.4	 The Paucity of Interlobular Bile Ducts
		25.5	 Alagille Syndrome (AGS)
		25.6	 Williams-Beuren Syndrome (WBS)
		25.7	 Ivemark Syndrome (IS)
		25.8	 Zellweger Syndrome
		25.9	 Major Karyotype Abnormalities
		25.10	 Alpha-1-Antitrypsin Deficiency
		25.11	 Cystic Fibrosis
		25.12	 Virus-Related PIBD
		25.13	 Sclerosing Cholangitis
		25.14	 Conclusion
		Self Study
			Questions
			Answers
		References
	26: Nonalcoholic Fatty Liver Disease: A Wide Spectrum Disease
		26.1	 Introduction
		26.2	 Epidemiology
			26.2.1	 Prevalence and Incidence of NAFL/NASH
			26.2.2	 Natural History and Risk Factors for NAFL and NASH
			26.2.3	 Genetic and Epigenetic Factors
			26.2.4	 Environmental Factors
			26.2.5	 Lean NAFLD
		26.3	 Pathogenesis
		26.4	 Experimental Models
		26.5	 Diagnosis
			26.5.1	 Diagnosis of NAFLD
			26.5.2	 Diagnosis of NASH and Fibrosis
		26.6	 Treatment
		26.7	 Conclusions
		Self Study
			Questions
			Answers
		References
			Related Published Articles
	27: Alcoholic Liver Disease
		27.1	 Introduction
		27.2	 Malnutrition and Metabolic Dysfunction
		27.3	 Oxidative Stress
		27.4	 Genetics/Epigenetics
		27.5	 Gut Permeability and Endotoxemia
		27.6	 Treatment of Alcoholic Liver Disease
		27.7	 Conclusion/Summary
		Self Study
			Questions
			Answers
		References
			Further Reading and Additional Resources
	28: Liver Disease in Pregnancy
		28.1	 Introduction
		28.2	 Normal Pregnancy
		28.3	 Pre-existing or Coincidental Liver Disease During Pregnancy
			28.3.1	 Acute Viral Hepatitis
			28.3.2	 Herpes Simplex Virus
			28.3.3	 Hepatitis B
			28.3.4	 Hepatitis C
			28.3.5	 Other Chronic Liver Diseases
			28.3.6	 Benign Liver Lesion
		28.4	 Liver Diseases Specific to Pregnancy
			28.4.1	 Hyperemesis Gravidarum
			28.4.2	 Intrahepatic Cholestasis of Pregnancy
			28.4.3	 Preeclampsia/Eclampsia
			28.4.4	 Acute Fatty Liver of Pregnancy
			28.4.5	 HELLP
			28.4.6	 Hepatic Venous Outflow Obstruction (Budd Chiari)
		28.5	 Special Liver Related Considerations in Pregnancy
			28.5.1	 Imaging
			28.5.2	 Liver Biopsy
			28.5.3	 Endoscopy/ERCP/EUS/Sedation
			28.5.4	 ERCP
		28.6	 Cirrhosis and Portal Hypertension
		28.7	 Liver Transplant
		28.8	 Conclusion
		Self Study
		Questions
		Answers
		References
			Normal Pregnancy
			Pre-existing or Coincidental Liver Disease During Pregnancy
			Liver Diseases Specific to Pregnancy
			Special liver Related Considerations in Pregnancy
			Cirrhosis and Portal Hypertension
	29: Cirrhotic Cardiomyopathy
		29.1	 Introduction
		29.2	 Definition
		29.3	 Epidemiology
		29.4	 Pathophysiology
		29.5	 Diagnostic Tests
			29.5.1	 Echocardiography
			29.5.2	 Systolic Dysfunction
			29.5.3	 Diastolic Dysfunction
			29.5.4	 Cardiac Scintigraphy
			29.5.5	 Cardiac Magnetic Resonance
			29.5.6	 Electrophysiological Changes
			29.5.7	 Cardiac Biomarkers
		29.6	 Prognosis and Correlation with Liver Disease Severity
		29.7	 Management Options
		29.8	 Conclusions
		Self Study
			Questions
			Answers
		References
			Further Reading
	30: Benign Liver Tumours
		30.1	 Introduction
		30.2	 Focal Nodular Hyperplasia
			30.2.1	 Introduction and Epidemiology
			30.2.2	 Pathogenesis
			30.2.3	 Pathology
			30.2.4	 Clinical Features
			30.2.5	 Diagnosis
			30.2.6	 Treatment
		30.3	 Hepatocellular Adenoma
			30.3.1	 Introduction and Epidemiology
			30.3.2	 Etiology and Incidence
			30.3.3	 Pathology
			30.3.4	 Genotype and Phenotype Classification
			30.3.5	 Clinical Features
			30.3.6	 Diagnosis
			30.3.7	 Treatment
		30.4	 Hepatic Hemangioma
			30.4.1	 Introduction and Epidemiology
			30.4.2	 Pathogenesis
			30.4.3	 Pathology
			30.4.4	 Clinical Features
			30.4.5	 Diagnosis
			30.4.6	 Treatment
		30.5	 Cystic Liver Lesions
			30.5.1	 Introduction
		30.6	 Simple Hepatic Cysts
			30.6.1	 Epidemiology and Pathogenesis
			30.6.2	 Pathology
			30.6.3	 Clinical Features
			30.6.4	 Diagnosis
			30.6.5	 Treatment
		30.7	 Polycystic Liver Disease
			30.7.1	 Epidemiology and Pathogenesis
			30.7.2	 Clinical Features
			30.7.3	 Diagnosis
			30.7.4	 Treatment
		30.8	 Benign Biliary Cystic Tumours (Cystadenoma)
			30.8.1	 Epidemiology and Pathogenesis
			30.8.2	 Pathology
			30.8.3	 Clinical Features
			30.8.4	 Diagnosis
			30.8.5	 Treatment
		30.9	 Conclusions
		References
	31: Liver Cancer
		31.1	 Introduction
		31.2	 Hepatocellular Carcinoma
			31.2.1	 Epidemiology and Risk Factors
			31.2.2	 Prevention
			31.2.3	 Pathogenesis
			31.2.4	 Diagnosis
			31.2.5	 Surveillance
			31.2.6	 Staging
			31.2.7	 Pathology
			31.2.8	 Clinical Features
			31.2.9	 Treatment
				31.2.9.1 Liver Surgery
				31.2.9.2 Local Ablation
				31.2.9.3 Liver Resection vs Local Ablation
				31.2.9.4 Transarterial Chemoembolization
				31.2.9.5 Radiation Therapy
				31.2.9.6 Systemic Therapy
		31.3	 Intrahepatic Cholangiocellular Carcinoma
			31.3.1	 Epidemiology and Risk Factors
			31.3.2	 Molecular Pathogenesis
			31.3.3	 Pathology and Classification
			31.3.4	 Clinical Features
			31.3.5	 Diagnosis
			31.3.6	 Staging
			31.3.7	 Treatment
				31.3.7.1 Liver Resection and Liver Transplantation
				31.3.7.2 Locoregional Therapies
				31.3.7.3 Systemic Therapy
		31.4	 Combined Hepatocellular-Cholangiocarcinoma
		Self Study
			Questions
			Answers
		References
	32: Acute Liver Failure
		32.1	 Introduction
		32.2	 Definition
		32.3	 Etiology
			32.3.1	 Etiologies with Possible Indication for Emergency LT
				32.3.1.1	 Drug-Related Hepatotoxicity
				32.3.1.2	 Acetaminophen (Paracetamol) Toxicity
				32.3.1.3	 Idiosyncratic Drug Reaction
				32.3.1.4	 Toxin-Related Hepatotoxicity
				32.3.1.5	 Viral Hepatitis
				32.3.1.6	 Hepatitis B Virus (HBV)
				32.3.1.7	 Hepatitis A Virus (HAV)
				32.3.1.8	 Hepatitis E Virus (HEV)
				32.3.1.9	 Hepatitis D Virus (HDV)
				32.3.1.10	 Hepatitis C Virus (HCV)
				32.3.1.11	 Other Viral Infection
				32.3.1.12	 Autoimmune Hepatitis
				32.3.1.13	 Wilson Disease
				32.3.1.14	 Budd-Chiari Syndrome
				32.3.1.15	 Pregnancy: Acute Fatty Liver of Pregnancy and HELLP Syndrome
			32.3.2	 Etiologies with No Indication of LT
				32.3.2.1	 Malignancies
				32.3.2.2	 Vascular Causes
				32.3.2.3	 Portal Vein Thrombosis (PVT)
		32.4	 Epidemiology
		32.5	 Pathophysiology
		32.6	 Diagnosis
			32.6.1	 Laboratory Evaluation
			32.6.2	 Imaging Study
		32.7	 Treatment
			32.7.1	 General Principles and Organ Specific Management
			32.7.2	 Treatment for Specific Etiology of ALF
			32.7.3	 Specific Treatment of ALF
				32.7.3.1	 Measures to Prevent ICP Elevation
			32.7.4	 Experimental Therapies
			32.7.5	 Artificial Liver Support Devices
			32.7.6	 Liver Transplantation
		32.8	 Prognosis
		32.9	 Conclusions
		Self Study
			Questions
			Answers
		References
	33: Chronic Liver Failure and Acute-on-Chronic Liver Failure
		33.1	 Introduction
		33.2	 Pathogenesis of Chronic Liver Failure
			33.2.1 Portal Hypertension and Hyperdynamic Circulation
			33.2.2 Dysbiosis, Bacterial Translocation and Systemic Inflammation
		33.3	 Clinical Manifestations
			33.3.1 Gastrointestinal Bleeding Secondary to PH
			33.3.2 Ascites
			33.3.3 Renal Impairment
			33.3.4 Immune Dysfunction
			33.3.5 Infections
			33.3.6 Neurological Manifestations
			33.3.7 Cardiopulmonary Complications
			33.3.8 Nutrition and Muscle Mass
			33.3.9 Bone Disease
			33.3.10 Endocrinopathies
			33.3.11 Haematological Alterations
			33.3.12 Skin Manifestations
			33.3.13 Hepatocellular Carcinoma
			33.3.14 Acute-on-Chronic Liver Failure
		33.4	 Conclusions/Summary
		Self Study
			Questions
			Answers
		References
			Further Reading and Related Links
Part II: Diagnostic Methods
	34: History and Physical Examination
		34.1	 Introduction
		34.2	 Symptoms of Liver Disease
		34.3	 Clinical Examination in Liver Disease
			34.3.1	 Auscultation
			34.3.2	 Inspection
			34.3.3	 Palpation
			34.3.4	 Percussion
		34.4	 Conclusions/Summary
		Self Study
			Questions
			Answers
		References
			Further Reading
	35: Assessment of Liver Function
		35.1	 Introduction: Standard Liver Panel
			35.1.1 Total Bilirubin
			35.1.2 Transaminases
			35.1.3 AST/ALT Ratio
			35.1.4 Alkaline Phosphatase
			35.1.5 Gamma Glutamyl Transpeptidase
			35.1.6 Albumin
			35.1.7 Other Tests
				35.1.7.1 5′-Nucleotidase
				35.1.7.2 Ceruloplasmin
				35.1.7.3 Alpha-Fetoprotein
				35.1.7.4 Coagulation Studies
				35.1.7.5 Serum Glucose
			35.1.8 Lactate Dehydrogenase
				35.1.8.1 Elevated Transaminases
		35.2	 Viral Hepatitis
			35.2.1 Hepatitis A
			35.2.2 Hepatitis B
			35.2.3 Hepatitis C
			35.2.4 Hepatitis D
			35.2.5 Hepatitis E
			35.2.6 Alcohol-Induced Liver Disease
			35.2.7 Drug-Induced Liver Injury
			35.2.8 Ischemic Hepatitis
			35.2.9 Acute Liver Failure
			35.2.10 Autoimmune Hepatitis
		35.3	 Metabolic Liver Disease
			35.3.1 Nonalcoholic Fatty Liver Disease
			35.3.2 Hereditary Hemochromatosis
			35.3.3 Alpha-1 Antitrypsin Deficiency
			35.3.4 Wilson Disease
		35.4	 Cholestatic Liver Diseases
			35.4.1 Primary Biliary Cholangitis
			35.4.2 Primary Sclerosing Cholangitis
		35.5	 Complications of Chronic Liver Disease
			35.5.1 Cirrhosis
		35.6	 Complications of Cirrhosis
			35.6.1 Portal Hypertension
			35.6.2 Esophageal Varices
			35.6.3 Gastric Varices and Portal Hypertensive Gastropathy
			35.6.4 Hepatic Encephalopathy
			35.6.5 Hepatopulmonary Syndrome
			35.6.6 Portopulmonary Hypertension
			35.6.7 Ascites
			35.6.8 Spontaneous Bacterial Peritonitis
			35.6.9 Hepatorenal Syndrome
			35.6.10 Hepatocellular Carcinoma
		35.7	 Determining Prognosis
			35.7.1 MELD
			35.7.2 Child-Turcotte-Pugh
		35.8	 Future Directions
			35.8.1 Cytokeratin 18
			35.8.2 MicroRNA
			35.8.3 Extracellular Vesicles
		Self Study
			Questions
			Answers
		References
	36: Noninvasive Biomarkers for Liver Fibrosis
		36.1	 Introduction
		36.2	 Extracellular Matrix (ECM) from Normal to Fibrotic Liver
		36.3	 Liver Biopsy
		36.4	 Noninvasive Biomarkers of Liver Fibrosis
		36.5	 Characteristics of Ideal Marker
			36.5.1 Indirect Markers
				36.5.1.1	 Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) Ratio (AAR)
				36.5.1.2	 APRI
		36.6	 Immune Fibrosis Index (IFI) Score
			36.6.1 Prothrombin Time
			36.6.2 The FIB-4 Score
		36.7	 Fibrofast; FIB-5
			36.7.1 The NAFLD Fibrosis Score
			36.7.2 Fibro Index
			36.7.3 FibroTest (FibroSURE in USA)
		36.8	 Fibro Test Is Calculated as Below
			36.8.1 FibroMax
		36.9	 Serum Leptin and Homeostasis Model Assessment-IR Model
			36.9.1 Neutrophil to Lymphocyte Ratio
			36.9.2 The PGA Index
			36.9.3 The Forns Index
		36.10	 Forns Index
			36.10.1 HepaScore
			36.10.2 Platelet Volume and Neutrophil to Lymphocyte Ratio
			36.10.3 FibroMeter
			36.10.4 SteatoTest
			36.10.5 The Proteomics Based Tests
		36.11	 Direct Noninvasive Biomarkers (NIBMs) for Assessing Liver Fibrosis
			36.11.1 Direct Markers Related to Matrix Deposition
				36.11.1.1	 Procollagen I Carboxy Peptide and Procollagen III Amino Peptide
				36.11.1.2	 Type IV Collagen
				36.11.1.3	 Laminin
				36.11.1.4	 Hyaluronic Acid (HA)
				36.11.1.5	 YKL-40 (Chondrex)
			36.11.2 Direct Markers Linked to Matrix Degradation [Metalloproteinases (MMPs) and Tissue Inhibitors of Matrix Metalloproteinases (TIMPs)]
			36.11.3 Cytokines
				36.11.3.1	 Transforming Growth Factor (TGF)-β1 and TGFα
				36.11.3.2	 Connective Tissue Growth Factor (CTGF)
				36.11.3.3	 Platelet-Derived Growth Factor-Beta
				36.11.3.4	 Microfibrillar-Associated Protein 4
				36.11.3.5	 Cytokeratin-18 Fragments
			36.11.4 Genetic Markers for Liver Fibrosis
		36.12	 Combined Direct and Indirect Markers
			36.12.1 The Fibrometer Test
			36.12.2 Enhanced Liver Fibrosis Test (ELF)
			36.12.3 TGF-ß1, HA, PIIINP and TIMP-1 Panel
			36.12.4 Combination of sFas with TGF-ß1, HA, PIIINP
			36.12.5 Fibrospect II Test
			36.12.6 SHASTA Index
			36.12.7 European Liver Fibrosis Panel (ELF) Test
			36.12.8 Hyaluronic Acid Vascular Score
		36.13	 Consensus Guidelines on Non-invasive Assessment of Hepatic Fibrosis
		36.14	 Conclusions/Summary
		36.15	 Future Perspectives for Liver Fibrosis Markers
		Self Study
			Questions
			Answers
		References
	37: Peritoneal Fluid Analysis
		37.1	 Introduction
		37.2	 Ascitic Fluid Analysis: “When and How”
		37.3	 Ascites in Cirrhosis vs. Other Conditions: Differential Diagnosis
			37.3.1	 Ascites with SAAG ≥1.1 g/dL
			37.3.2	 Ascites with SAAG <1.1 g/dL
		37.4	 Conclusion/Summary
		Exercises
			Case 1
			Case 2
		References
	38: Measurement of the Hepatic Venous Pressure Gradient (HVPG)
		38.1	 Introduction
		38.2	 How and Why to Perform HVPG Measurements
		38.3	 Methodological Considerations
		38.4	 Summary and Conclusions
		Self Study
			Questions
			Answers
		References
	39: Liver Biopsy for Histopathology
		39.1	 Introduction
		39.2	 Indications
			39.2.1	 Parenchymal Liver Diseases
			39.2.2	 Focal Liver Lesions
				39.2.2.1	 Benign Lesions
				39.2.2.2	 Malignant Lesions
					Metastases
					Primary Liver Tumors
		39.3	 Contraindications
		39.4	 Biopsy Technique
			39.4.1	 Percutaneous Liver Biopsy (PLB)
				39.4.1.1	 Ultrasound-Guided Percutaneous LB
				39.4.1.2	 CT-Guided and MRT-Guided Percutaneous LB
				39.4.1.3	 Fusion Technique
			39.4.2	 Transjugular Liver Biopsy (TJLB)
			39.4.3	 Surgical/Laparoscopic biopsy (SLB)
		39.5	 Post-biopsy Monitoring
		39.6	 Complications
		Self Study
			Questions
			Answers
		References
	40: Liver Ultrasonography
		40.1	 Principles of Liver Ultrasonography
		40.2	 Normal Liver Ultrasonography
			40.2.1	 Liver Size
			40.2.2	 Liver Echostructure
			40.2.3	 Liver Surface
			40.2.4	 Liver Vascularization
		40.3	 Pathologic Aspects in Liver Ultrasonography
			40.3.1	 Diffuse Liver Disease
				40.3.1.1	 Fatty Liver
				40.3.1.2	 Acute Hepatitis
				40.3.1.3	 Chronic Hepatitis
				40.3.1.4	 Hepatic Congestion
				40.3.1.5	 Fibrosis and Cirrhosis
			40.3.2	 Focal Liver Lesions
				40.3.2.1	 Benign Focal Liver Lesions
					Liver Cysts
					Hemangiomas
					Liver Cell Adenoma
					Focal Nodular Hyperplasia (FNH)
				40.3.2.2	 Malignant Focal Liver Lesions
					Hepatocellular Carcinoma (HCC)
					Cholangiocarcinoma (CCC)
					Liver Metastases
			40.3.3	 Vascular Related Pathologies of the Liver
				40.3.3.1	 Portal Hypertension and Portal Thrombosis
				40.3.3.2	 Budd-Chiari Syndrome
				40.3.3.3	 Veno-Occlusive Disease
				40.3.3.4	 Osler-Weber-Rendu Disease
		Self Study
			Questions
			Answers
		References
	41: Endoscopy in Hepatic Diseases
		41.1	 Introduction
		41.2	 Gastro Esophageal Varices
		41.3	 Primary Prophylaxis
		41.4	 Acute Variceal Bleeding
		41.5	 Endoscopic Therapy for Gastric Varices
		41.6	 Secondary Prophylaxis
		41.7	 PHG and GAVE
		41.8	 Capsule Endoscopy and Enteroscopy
		41.9	 Endoscopic Retrograde Cholangiopancreatography
		41.10	 Biliary Complications After Liver Transplantation
		41.11	 Metabolic and Bariatric Endoscopy for NASH
		41.12	 Conclusions
		Self Study
			Questions
			Answers
		References
	42: Dynamic and Multi-phase Contrast-Enhanced CT Scan
		42.1	 Introduction
		42.2	 CT Technology Developments
		42.3	 Hounsfield Units
		42.4	 Liver Scanning Protocol
		42.5	 Benign Focal Liver Lesions
			42.5.1	 Hepatic Cystic Lesions
			42.5.2	 Benign Hepatic Tumors
		42.6	 Malignant Hepatic Tumours
			42.6.1	 Hepatocellular Carcinoma (HCC)
			42.6.2	 Cholangiocarcinoma
			42.6.3	 Hepatic Metastases
		42.7	 Conclusions
		Self Study
			Questions
			Answers
		References
	43: Patient-Specific 3D Printing in Liver Disease
		43.1	 Introduction
		43.2	 Image Post-processing and Segmentation
		43.3	 3D Printed Liver Models: Dimensional Accuracy
		43.4	 3D Printed Liver Models: Pre-surgical Planning and Simulation
			43.4.1	 3D Printed Liver Models in Pre-surgical Planning of Hepatic Tumours
			43.4.2	 3D Printed Liver Models in Pre-surgical Planning of Liver Transplantation
		43.5	 3D Printed Liver Models: Medical Education
		43.6	 3D Printed Liver Models: Limitations and Future Directions
		43.7	 Summary
		Self Study
			Questions
			Answers
		References
		Glossary
	44: Dynamic Contrast-Enhanced Ultrasonography of the Liver
		44.1	 Introduction
			44.1.1	 General Considerations
			44.1.2	 Safety Considerations
			44.1.3	 Terminology
			44.1.4	 CEUS Phases: Examination Technique
		44.2	 Characterization of Focal Liver Lesions
			44.2.1	 Benign Liver Lesions
				44.2.1.1	 Hemangioma
				44.2.1.2	 Focal Nodular Hyperplasia
				44.2.1.3	 Hepatocellular Adenoma
				44.2.1.4	 Focal Fatty Change
				44.2.1.5	 Liver Abscess
				44.2.1.6	 Liver Cyst
				44.2.1.7	 Other Benign Liver Lesions
			44.2.2	 Malignant Liver Lesions
				44.2.2.1	 Hepatocellular Carcinoma
				44.2.2.2	 Cholangiocarcinoma
				44.2.2.3	 Liver Metastases
				44.2.2.4	 Lymphoma
		44.3	 Characterization of Portal Vein Thrombosis
		Self Study
			Questions
			Answers
		References
	45: Ultrasound Elastography
		45.1	 Introduction
		45.2	 Basic Technology of Ultrasound Elastography
			45.2.1	 Transient Elastography
			45.2.2	 Point SWE
			45.2.3	 2D-SWE
			45.2.4	 Strain Elastography
		45.3	 Clinical Studies of Ultrasound Elastography
		45.4	 US Elastography Is Reliable?: Quality Criteria of Ultrasound Elastography
		45.5	 US Elastography: Limitations and Promises
		45.6	 Need to Know When Doing US Elastography
		45.7	 Conclusion
		Self Study
			Questions
			Answers
		References
	46: MR Elastography and Functional MRI of the Liver
		46.1	 Magnetic Resonance Elastography
			46.1.1	 Introduction
			46.1.2	 Principles
			46.1.3	 Technical Aspects
		46.2	 Clinical Applications of MRE
			46.2.1	 MRE in Staging of Liver Fibrosis
			46.2.2	 Nonalcoholic Steatohepatitis (NASH) and Nonalcoholic Fatty Liver Disease (NAFLD)
			46.2.3	 Primary Sclerosing Cholangitis
			46.2.4	 MRE Potential Role in Liver Tumors
			46.2.5	 Limitations and Pitfalls of MRE
		46.3	 Functional MRI of the Liver
			46.3.1	 Introduction
			46.3.2	 DWI Definition
			46.3.3	 Principles and Applications of DWI
		46.4	 Liver-Specific Gadolinium (Gd) Based Contrast Agents
			46.4.1	 Introduction
			46.4.2	 Definition and Mechanism
			46.4.3	 Contrast MR Acquisitions
			46.4.4	 Indications
			46.4.5	 Advantage
			46.4.6	 Pitfalls Using Primovist
			46.4.7	 Limitations
		46.5	 Conclusions: Future Perspectives
		Self Study
			Questions
			Answers
		References
	47: Contrast Enhanced MR imaging of Liver
		47.1	 Introduction
		47.2	 Contrast Medium
			47.2.1	 Extracellular Agents
				47.2.1.1	 Toxic Effects
				47.2.1.2	 MR Technical Considerations
				47.2.1.3	 Dosage
			47.2.2	 Reticuloendothelial Agents
				47.2.2.1	 MR Technical Considerations
				47.2.2.2	 Dosage
			47.2.3	 Hepatobiliary Agents
				47.2.3.1	 MR Technical Considerations
				47.2.3.2	 Dosage
			47.2.4	 Blood Pool Agents
			47.2.5	 Combined Agents
				47.2.5.1	 MR Technical Considerations
				47.2.5.2	 Dosage
		47.3	 Diagnosis of Diffuse Liver Diseases with Contrast Enhanced MR
		47.4	 Diagnosis of Focal Liver Lesions with Contrast Enhanced MR
			47.4.1	 Hemangiomas
			47.4.2	 Focal Nodular Hyperplasia (FNH)
			47.4.3	 Hepatic Cyst
			47.4.4	 Hepatocellular Adenoma
			47.4.5	 Malignant Metastatic Tumors
			47.4.6	 Hepatocellular Carcinoma (HCC)
			47.4.7	 Intrahepatic Cholangiocarcinoma (ICC)
			47.4.8	 Diagnostic Pitfalls of Focal Hepatic Disease
		47.5	 Conclusions/Summary
		Self Study
			Questions
			Answers to the Questions
		References
	48: Transient Elastography in Chronic Liver Diseases
		48.1	 Introduction
		48.2	 Advantages of Transient Elastography
		48.3	 Limitations of Transient Elastography
			48.3.1	 Operator Skill
			48.3.2	 Obesity
			48.3.3	 Cholestasis
			48.3.4	 Alanine Aminotransferase Flares
			48.3.5	 Narrow Intercostal Space
			48.3.6	 Hepatic Congestion
			48.3.7	 Food Intake
			48.3.8	 Steatosis
			48.3.9	 Ascites
				48.3.9.1	 Validation of Transient Elastography in Liver Fibrosis Assessment
		48.4	 Normal Values of Liver Stiffness on TE
		48.5	 Transient Elastography in Chronic Liver Diseases
		48.6	 Transient Elastography and HCV
		48.7	 Transient Elastography and CHB
		48.8	 Transient Elastography and Portal Hypertension
		48.9	 Transient Elastography and Autoimmune Hepatitis
		48.10	 Transient Elastography and NAFLD
		48.11	 Transient Elastography and Hepatocellular Carcinoma
		48.12	 Transient Elastography and Acute Cellular Rejection Following Liver Transplantation
		48.13	 Transient Elastography and Alcoholic Liver Disease
		48.14	 Controlled Attenuation Parameter (CAP)
		48.15	 Transient Elastography and Postoperative Outcomes
		48.16	 Conclusions/Summary
		48.17	 Future Perspectives for Liver FibroScan
		Self Study
			Questions
			Answers
		References
	49: Portal Venography
		49.1	 Introduction
		49.2	 Noninvasive Imaging of the Portal System
			49.2.1	 Ultrasonography (US)
			49.2.2	 Computed Tomography
			49.2.3	 Magnetic Resonance Imaging
		49.3	 Invasive Imaging of the Portal System
			49.3.1	 Wedged Hepatic Venography
			49.3.2	 Percutaneous Splenoportography
			49.3.3	 Transhepatic Portography
			49.3.4	 Arterial Portography
		49.4	 Conclusion
		Self Study
			Questions
			Answers
		References
	50: Minilaparoscopy and Conventional Laparoscopy
		50.1	 Introduction
		50.2	 Indications
		50.3	 Surgical technique
			50.3.1	 Access to the Abdominal Cavity, Pneumoperitoneum, Exposition of the Operative Field
			50.3.2	 Parenchymal Transection
		50.4	 Procedures
		50.5	 Comparison of Single Incision and Multi Port Laparoscopic Surgery
		50.6	 Future Perspectives
		50.7	 Conclusion
		Self Study
			Questions
		Answers
		References
Part III: Treatment
	51: Medical Nutrition Therapy in Liver Disease
		51.1	 Introduction
			51.1.1	 General Principles of Nutritional Medical Intervention in Liver Diseases (LDs)
		51.2	 Nutrition Assessment
			51.2.1	 Anthropometric and Body Composition Assessment
				51.2.1.1	 Measurement of Height and Weight
				51.2.1.2	 Determination of Body Mass Index (BMI)
				51.2.1.3	 Other Anthropometric Evaluations
				51.2.1.4	 Determination of the Energetic Balance
				51.2.1.5	 The Composite Score
			51.2.2	 Biochemical Data
				51.2.2.1	 Biochemical Data Regarding the Nutritional Status
				51.2.2.2	 Specific Lab Determinations for Liver Disease
			51.2.3	 Nutrition: Physical Evaluation
			51.2.4	 Patient’s History
		51.3	 Nutritional Intervention in LD
			51.3.1	 Related Issues Regarding Liver Physiopathology
			51.3.2	 Nutritional Intervention in Acute Liver Diseases
			51.3.3	 Nutritional Intervention in CLD
				51.3.3.1	 Nutritional Intervention in ALD
				51.3.3.2	 Nutritional Intervention in NAFLD, NASH
				51.3.3.3	 Nutritional Intervention in Cirrhosis
					Sodium Restriction in the Diet and the Management of Ascites
					Portal Hypertension
					Hyponatremia
						Glucose Alteration
						Hepato-Renal Syndrome
						Osteopenia
				51.3.3.4	 Nutritional Intervention in Liver Transplantation
		51.4	 Conclusions
		Self Study
			Questions
			Answers
		References
	52: Molecular Targets in Liver Disease
		52.1	 Protein Kinases
			52.1.1	 Receptor Tyrosine Kinases
				52.1.1.1 Vascular Endothelial Growth Factor Receptors
				52.1.1.2 Platelet-Derived Growth Factor Receptors
				52.1.1.3 Hepatocyte Growth Factor Receptor c-MET
				52.1.1.4 c-MET Structure and Activation
				52.1.1.5 c-MET Downstream Signaling
				52.1.1.6 c-MET Regulation
			52.1.2	 Intracellular Serine/Threonine Kinases: RAF Kinases
				52.1.2.1 RAF Activation and Regulation
				52.1.2.2 RAF Signaling
			52.1.3	 Drugs Targeting Protein Kinases in HCC
		52.2	 Nuclear Receptors
			52.2.1	 General Structure and Activation
				52.2.1.1 Structure
				52.2.1.2 Activation
			52.2.2	 Farnesoid X Receptors
				52.2.2.1 Structure and Activation
				52.2.2.2 FXRs in Cholestasis
				52.2.2.3 FXRs in Non-alcoholic Fatty Liver Disease (NAFLD)/Non-alcoholic Steatohepatitis (NASH)
				52.2.2.4 Drugs Targeting FXRs
			52.2.3	 Peroxisome Proliferator-Activated Receptors
				52.2.3.1 Structure and Activation
				52.2.3.2 Drugs Targeting PPARs
			52.2.4	 Glucocorticoid Receptors
		52.3	 Novel Therapeutic Targets
			52.3.1	 Takeda G Protein-Coupled Receptor 5 (TGR5, Gpbar-1, M-BAR)
			52.3.2	 Cell Death Protein-1 Checkpoint Inhibitors
			52.3.3	 Metabotropic Glutamate Receptors
		52.4	 Summary
		Self Study
			Questions
			Answers
		References
			Further Reading
	53: Specific Medications for Chronic Viral Hepatitis
		53.1	 Introduction
		53.2	 Hepatitis B Virus (HBV) Infection
			53.2.1	 Treatment Strategies for HBV
				53.2.1.1	 Interferon (IFN)
				53.2.1.2	 Nucleos(t)ide Analogues (NAs)
				53.2.1.3	 HBV in Pregnancy
				53.2.1.4	 HBV in Children
		53.3	 Hepatitis C Virus (HCV) Infection
			53.3.1	 Treatment Strategies for HCV
				53.3.1.1	 Ribavirin
				53.3.1.2	 Direct-Acting Antivirals (DAAs)
					Sofosbuvir
					Combination Regimens
						Sofosbuvir and Ledipasvir
						Sofosbuvir and Velpatasvir
						Sofosbuvir, Velpatasvir and Voxilaprevir
						Ritonavir-Boosted Paritaprevir, Ombitasvir and Dasabuvir
						Grazoprevir and Elbasvir
						Glecaprevir and Pibrentasvir
		53.4	 Future Perspectives for Hepatitis Treatment
			53.4.1	 Future Treatment Options for HBV
			53.4.2	 Future Perspectives for the Treatment of HCV
		Self Study
			Questions
			Answers
		References
	54: Portal Vein Embolization (PVE) and Partial TIPE ALPPS: Beyond the Limitations of PVE
		54.1	 Introduction
		54.2	 History
		54.3	 Mechanism of PVE-Induced Hypertrophy
		54.4	 Approaches to the Portal Vein for PVE
			54.4.1	 TIPE Technique
			54.4.2	 PTPE Technique (Fig. 54.1)
		54.5	 Embolic Materials
		54.6	 Potential Complications of PVE
			54.6.1	 Bleeding
			54.6.2	 Portal Thrombosis and Coil Migration
			54.6.3	 Bile Leakage
		54.7	 Outcomes of PVE
		54.8	 Beyond the Limitations of PVE: Associating Liver Partition and Portal Vein Embolization for Staged Hepatectomy
		Self Study
			Question
			Answers
		References
	55: Endoscopic and Pharmacological Treatment of Esophageal Varices
		55.1	 Introduction
		55.2	 Pathophysiology and Endoscopic Characteristics of Esophageal Varices
		55.3	 Screening of EVs in Cirrhotic Patients
		55.4	 Pharmacological Treatment in the Prevention and Management of Variceal Bleeding
			55.4.1	 Non-selective Beta-Blockers (NSBBs)
			55.4.2	 Carvedilol
			55.4.3	 Terlipressin
			55.4.4	 Somatostatin and Its Analogues
			55.4.5	 Simvastatin
		55.5	 Endoscopic Treatments of Esophageal Varices
			55.5.1	 Sclerotherapy
			55.5.2	 Endoscopic Variceal Band Ligation (EVBL)
			55.5.3	 Other Endoscopic Treatments
		55.6	 Overall Management of Esophageal Varices
			55.6.1	 Primary Prophylaxis
			55.6.2	 Acute Bleeding
			55.6.3	 Secondary Prophylaxis
		55.7	 Conclusions
		Self Study
			Questions
			Answers
		References
	56: Procedure for Gastric Variceal Bleeding: From BRTO to PARTO to CARTO, Three Decades of Progress
		56.1	 Introduction
		56.2	 Techniques and Outcomes of BRTO
			56.2.1	 Patients
			56.2.2	 Outcomes of BRTO
			56.2.3	 BRTO vs. Endoscopic Treatment
			56.2.4	 Conventional BRTO: Technique
			56.2.5	 The Occlusion-Balloon: Dwell-Time and Rupture
			56.2.6	 Sclerosants and Transvenous Obliteration
		56.3	 Modified BRTO
			56.3.1	 PARTO
			56.3.2	 CARTO
		56.4	 More Indications for BRTO
			56.4.1	 BRTO, PARTO, CARTO: Hepatic Encephalopathy and Synthetic Function
		56.5	 Summary
		Self Study
			Questions
			Answers
		References
	57: Endoscopy and Endoscopic Ultrasound for the Evaluation and Treatment of Gastric and Ectopic Varices
		57.1	 Introduction
		57.2	 Gastric Varices
			57.2.1	 Endoscopic Treatment
			57.2.2	 The Role of Endoscopic Ultrasound
		57.3	 Ectopic Varices
			57.3.1	 Duodenal and Jejunal Varices
			57.3.2	 Choledochal Varices
			57.3.3	 Rectal and Colonic Varices
		57.4	 Conclusions
		Self Study
			Questions
			Answers
		References
	58: Portacaval Shunting for Portal Hypertension
		58.1	 Overview of Portal Hypertension
		58.2	 Current Treatment Options
			58.2.1	 Surgical Shunts
			58.2.2	 Percutaneous Shunts
				58.2.2.1	 Transjugular Intrahepatic Portosystemic Shunt (TIPS)
				58.2.2.2	 Direct Intrahepatic Portacaval Shunt (DIPS)
				58.2.2.3	 Percutaneous Mesocaval Shunt
		58.3	 Comparison of Available Portocaval Shunting Procedures (Table 58.1)
		58.4	 Future Directions
		Self Study
			Questions
			Answers
		References
	59: Systemic Therapy of Advanced Liver Cancer
		59.1	 Introduction
		59.2	 Conventional Chemotherapy for Advanced HCC
		59.3	 Molecularly Targeted Therapy
		59.4	 Immunotherapy
		59.5	 Future Perspective and Biomarkers
		Self Study
			Questions
			Answers
		References
	60: Embolization Therapy for Liver Cancer
		60.1	 Introduction
		60.2	 Indications
		60.3	 Technique
		60.4	 Technical Advances
		60.5	 Methods
			60.5.1	 cTACE
			60.5.2	 DEB-TACE
			60.5.3	 Comparison of DEB-TACE and cTACE
			60.5.4	 DSM-TACE
		Self Study
			Questions
			Answers
		References
	61: Ablation of Hepatocellular Carcinoma
		61.1	 Introduction
		61.2	 Indications
			61.2.1	 At-Risk Localizations and Adverse Events
			61.2.2	 Tumor Size
		61.3	 Technical Aspects
			61.3.1	 Radiofrequency-Ablation (RFA)
			61.3.2	 Microwave Ablation (MWA)
			61.3.3	 Irreversible Electroporation (IRE)
		Self-Study
			Questions
			Answers
		References
	62: Laparoscopic Liver Resection
		62.1	 Introduction
		62.2	 Indications
			62.2.1	 Benign Disease
				62.2.1.1	 Simple Liver Cyst
			62.2.2	 Primary Malignant Disease
				62.2.2.1	 Hepatocellular Carcinoma
				62.2.2.2	 Intrahepatic Cholangiocarcinoma
			62.2.3	 Metastatic Disease
		62.3	 Preparation
		62.4	 Surgical Technique
			62.4.1	 Wedge Resection
			62.4.2	 Anatomical Segmentectomy
			62.4.3	 Left Lateral Lobectomy
			62.4.4	 Left Hepatectomy
			62.4.5	 Right Hepatectomy
		62.5	 Peri-operative Management
			62.5.1	 Pain Management
			62.5.2	 NG Tubes, Abdominal Drains
		62.6	 Conclusion
		Self Study
			Questions
			Answers
		References
	63: New Loco Regional Approaches to Treat Liver Cancer
		63.1	 Introduction
		63.2	 Ablative Techniques
			63.2.1	 Radiofrequency Ablation
			63.2.2	 Microwave Ablation
			63.2.3	 Cryoablation
			63.2.4	 Irreversible Electroporation (IRE)
			63.2.5	 Chemical Ablation
		63.3	 Endovascular Techniques
			63.3.1	 TACE
			63.3.2	 Bland Embolization
			63.3.3	 Y-90
			63.3.4	 Stereotactic Body Radiotherapy (SBRT)
		63.4	 Immunotherapy
		63.5	 Conclusion
		Self Study
			Questions
			Answers
		References
	64: Hepatic Encephalopathy
		64.1	 Developments in Pathophysiologic Understanding
			64.1.1	 The Role of Ammonia in the Pathogenesis of HE Occurring in ALF, Cirrhosis and Chronic Porto-Systemic Shunting
				64.1.1.1	 In ALF
				64.1.1.2	 In Cirrhosis and Chronic Porto-Systemic Shunting
			64.1.2	 The Role of Inflammation in the Pathogenesis of HE Occurring in ALF, Cirrhosis and Chronic Porto-Systemic Shunting
			64.1.3	 The Two-Phase Roles of Ammonia and Inflammation in the Pathogenesis of HE Occurring in ACLF
		64.2	 Management
			64.2.1	 Treatment of HE in ALF (Table 64.3)
			64.2.2	 Treatment of HE in Cirrhosis (Table 64.4)
				64.2.2.1	 Reducing the Intestinal Production and Systemic Absorption of Ammonia
				64.2.2.2	 Increasing the Systemic Metabolism of Ammonia
				64.2.2.3	 Reducing Systemic Inflammation by Modulation of the Intestinal Microbiome
			64.2.3	 HE in Chronic Portal-Systemic Shunting
			64.2.4	 HE in Acute on Chronic Liver Failure (ACLF)
		Self Study
			Question
			Answers
		References
	65: Management of Ascites
		65.1	 Introduction
		65.2	 Classification and Management of Ascites
			65.2.1	 Uncomplicated Ascites
				65.2.1.1	 Sodium Intake Restriction
				65.2.1.2	 Diuretics
				65.2.1.3	 Complications of Diuretic Therapy
			65.2.2	 Large Ascites
			65.2.3	 Refractory Ascites
				65.2.3.1	 Liver Transplantation (LT)
				65.2.3.2	 Vasoconstrictors
				65.2.3.3	 Other Treatments
				65.2.3.4	 Transjugular Intrahepatic Portosystemic Shunts (TIPS)
		65.3	 Hyponatremia
			65.3.1	 Management of Hyponatremia
		65.4	 Spontaneous Bacterial Peritonitis (SBP)
			65.4.1	 Management of SBP: Antibiotic Treatment
			65.4.2	 Prophylaxis of SBP
		65.5	 Hepatorenal Syndrome (HRS)
			65.5.1	 Management of HRS
		65.6	 Conclusions/Summary
		Self-Study
			Questions
			Answers
		References
	66: Extracorporeal Non cellular Liver Assisted Devices
		66.1	 Introduction
		66.2	 Types of Extracorporeal Liver Assisted Devices
		66.3	 Molecular Adsorbent Recirculating Systems (MARS)
		66.4	 Prometheus System
		66.5	 Single Pass Albumin Dialysis (SPAD)
		66.6	 Selective Plasma Filtration Therapy (SEPET)
		66.7	 Discussion
		66.8	 Conclusion
		Self Study
			Questions
			Answers
		References
	67: Extracorporeal Cellular Liver Assisted Devices
		67.1	 Introduction
		67.2	 Bioartificial Liver Support (BALS)
		67.3	 Extracorporeal Liver Assist Device
			67.3.1	 Extracorporeal Circuit
			67.3.2	 Studies
		67.4	 HepatAssist™
			67.4.1	 Extracorporeal Circuit
			67.4.2	 Studies
		67.5	 Modular Extracorporeal Liver Support System (MELS)
			67.5.1	 Extracorporeal Circuit
			67.5.2	 Studies
		67.6	 Bioartificial Liver Support System (BLSS)
			67.6.1	 Extracorporeal Circuit
			67.6.2	 Studies
		67.7	 Conclusions
		Self Study
			Question
			Answer
		References
	68: Liver Transplantation for Acute and Chronic Liver Failure
		68.1	 Introduction
		68.2	 Liver Allocation
		68.3	 Orthotopic Liver Transplantation
		68.4	 Indications for Liver Transplantation
		68.5	 Transplantation Evaluation and Listing
		68.6	 Important Medical Concerns for Listing
			68.6.1	 Age
			68.6.2	 Obesity
			68.6.3	 Coronary Artery Disease
			68.6.4	 Porto-Pulmonary Hypertension
			68.6.5	 Hepatopulmonary Syndrome
			68.6.6	 Renal Dysfunction
			68.6.7	 Tobacco Use
			68.6.8	 Absolute Contraindications to Transplantation
		68.7	 Early Post-Liver Transplant Complications
		68.8	 Immunosuppression
		68.9	 Acute and Chronic Rejection
			68.9.1	 Long-Term Outcomes and Reoccurrence of Disease
			68.9.2	 Long-Term Concerns After Liver Transplantation
		68.10	 Hypertension
		68.11	 Obesity
		68.12	 Diabetes Mellitus
		68.13	 Dyslipidemia
		68.14	 Kidney Disease
		68.15	 Osteopenia
		68.16	 Malignancy
		68.17	 Conclusion
		Self Study
			Questions
			Answers
		References
	69: Surgical Complications Following Liver Transplant and Their Management
		69.1	 Introduction
		69.2	 Surgical Complications
			69.2.1	 Haemorrhage
				69.2.1.1	 Methods of Ensuring Haemostasis During Transplant
				69.2.1.2	 Post transplant Monitoring of Clotting and Administration of Clotting Factors
				69.2.1.3	 Detection, Quantifying and Treating Post op Haemorrhage
			69.2.2	 Vascular Complications
				69.2.2.1	 Hepatic Artery Thrombosis (HAT)
					Incidence and Presentation
					Diagnosis and Treatment of Early HAT
					Diagnosis of HAT
					Treatment of Early HAT
					Treatment of Late HAT
				69.2.2.2	 Hepatic Artery Stenosis
					Diagnosis
					Treatment
				69.2.2.3	 Hepatic Artery Pseudoaneurysms
				69.2.2.4	 Portal Vein Thrombosis (PVT)
				69.2.2.5	 Portal Vein Stenosis
				69.2.2.6	 Concurrent Hepatic Artery and Portal Vein Thrombosis
				69.2.2.7	 Vena Cava Complications
			69.2.3	 Biliary Complications
				69.2.3.1	 Biliary Reconstruction Techniques
				69.2.3.2	 Diagnosis of Biliary Complications
				69.2.3.3	 Bile Leaks
				69.2.3.4	 Biliary Strictures
					Anastomotic Strictures
					Nonanastomotic Biliary Strictures
			69.2.4	 Intra-abdominal Infections
			69.2.5	 Wound Complications
		69.3	 Conclusion
		Self Study
			Questions
			Answers
		References
	70: Anaesthesia for Liver Transplantation
		70.1	 Introduction
		70.2	 Preoperative Considerations
			70.2.1	 Frailty, Sarcopenia and Poor Functional Capacity
			70.2.2	 Cardiorespiratory Pathology
			70.2.3	 Diabetes Mellitus
			70.2.4	 Chronic Kidney Disease
			70.2.5	 Coagulopathy and Anaemia
		70.3	 Intraoperative Care
			70.3.1	 Anaesthetic Choice
			70.3.2	 Vascular Access
			70.3.3	 Haemodynamic Monitoring
			70.3.4	 Point of Care Testing
			70.3.5	 Induction and Maintenance
			70.3.6	 Fluid Management and Transfusion
		70.4	 Key Intraoperative Priorities
			70.4.1	 Dissection Phase
			70.4.2	 Anhepatic Phase
			70.4.3	 Reperfusion Phase
		70.5	 Immediate Postoperative Care
		70.6	 Discussion of Adjuvant Drugs
		70.7	 Living Donor Liver Transplantation in Adults
			70.7.1	 LDLT Recipients
			70.7.2	 Donor Preoperative Assessment
			70.7.3	 Intraoperative Care of the Living Donor
			70.7.4	 Recipient and Donor Outcomes
		Self Study
			Questions
			Answers
		References
	71: Surgery in Liver Disease
		71.1	 Introduction
		71.2	 Surgical Anatomy of the Liver
			71.2.1	 Avoiding Blood Loss During Liver Surgery
		71.3	 Physiological Changes of Liver Disease and Implications for Surgery
			71.3.1	 Altered Circulation
			71.3.2	 Drug Clearance and Hepatic Encephalopathy
			71.3.3	 Clotting and Blood Loss
			71.3.4	 Nutrition, Obesity and Sarcopenia
			71.3.5	 Hepato-Renal Syndrome (HRS)
			71.3.6	 Sepsis in Cirrhotic Patients, Particularly SBP
		71.4	 Pre-operative Management for Cirrhotic Patients
			71.4.1	 Auto-Transfusion and Cell Salvage
			71.4.2	 Pre-operative TIPPS
		71.5	 Classifying Severity of Liver Disease
			71.5.1	 CTP Score
			71.5.2	 MELD Score
		71.6	 Emergency Surgery in Cirrhotic Patients
		71.7	 Elective Surgery in Patients with Abnormal Liver Function
		71.8	 Hepatic Resection in Cirrhotic Patients
			71.8.1	 Selection of Surgical Procedure
			71.8.2	 Evaluation of Liver Function and Functional Reserve
			71.8.3	 Other Methods of Predicting Postoperative Liver Failure
			71.8.4	 Importance of AFP Levels in Patients with Suspected HCC
		71.9	 Non-hepatic Surgery in Cirrhotic Patients
			71.9.1	 Umbilical Hernia Repair (UHR)
				71.9.1.1	 Emergency UHR
				71.9.1.2	 Elective
			71.9.2	 Cholecystectomy
				71.9.2.1	 Emergency
				71.9.2.2	 Elective
			71.9.3	 Colorectal Surgery
			71.9.4	 Cardiac Surgery
		71.10	 Avoiding Futile Operations
		71.11	 Summary
		Self Study
			Questions
			Answers
		References
	72: Robotic Liver Resection
		72.1	 Introduction
		72.2	 Indications
		72.3	 Operative Technique
			72.3.1	 Patient Positioning and Port Placement
			72.3.2	 Lobectomy (Right and Left Hepatectomy)
			72.3.3	 Segmentectomy (Follow Segmental Anatomy)
			72.3.4	 Wedge Resection
			72.3.5	 Near-Infrared Fluorescence Imaging
		72.4	 Outcomes of Robotic Liver Resection
			72.4.1	 Post-operative Outcomes
			72.4.2	 Long-Term Oncologic Outcomes
			72.4.3	 Comparative Outcomes: Robotic vs. Open
			72.4.4	 Comparative Outcomes: Robotic vs. Laparoscopic
			72.4.5	 Learning-Curve
			72.4.6	 Financial Impact
		72.5	 Conclusion
		Self Study
			Questions
			Answers
		References
	73: Cardiac Surgery Risks in Liver Dysfunction
		73.1	 Introduction
		73.2	 Advanced Liver Dysfunction Physiopathological Changes Relevant for Cardiac Surgery
			73.2.1	 Haemostasis and Coagulation Disorders
			73.2.2	 Renal Function Impairment
			73.2.3	 Cardiovascular Alterations
			73.2.4	 Disorders of the Immune System
			73.2.5	 Pulmonary Disorders
			73.2.6	 Liver Function Deterioration
		73.3	 Cardiac Surgery Risks and Outcome in Patients with Advanced Liver Dysfunction
		73.4	 Preoperative Preparation of Cirrhotic Patients Prior to Major Cardiac Surgery
		73.5	 Anaesthetic Management of Patients with Advanced Liver Dysfunction Undergoing Cardiac Surgery
		73.6	 Operative Management of Cirrhotic Patients Undergoing Major Cardiac Surgery. Cardiopulmonary Bypass and Liver Dysfunction
		73.7	 Postoperative Care of Cirrhotic Patients After Major Cardiac Surgery
		73.8	 Endovascular Procedures in Cirrhotic Patients
		73.9	 Early Ischemic Liver Injury After Cardiac Surgery
		73.10	 Conclusion
		Self Study
			Questions
			Answers
		References
	74: Future Approaches in Liver Disorders: Regenerative Medicine
		74.1	 Introduction
		74.2	 Liver Architecture and Its Regeneration
			74.2.1	 Cell Therapy
			74.2.2	 Human Primary Hepatocytes
			74.2.3	 Hepatocyte Like-Cells (HLCs)
			74.2.4	 Cellular Reprogramming
			74.2.5	 Pluripotent Stem Cells (PSCs)
			74.2.6	 Mesenchymal Stem Cells (MSCs)
			74.2.7	 Embryonic Stem Cells (ESCs)
			74.2.8	 Hematopoietic Stem Cells (HSCs)
			74.2.9	 Human Fibroblasts
		74.3	 Liver Tissue/Organ Engineering
			74.3.1	 Scaffold-Based Systems
			74.3.2	 Organoid Technology
			74.3.3	 Microencapsulation Technique
			74.3.4	 Bioprinting in the Fabrication of 3D Liver Tissues (Bioprinted Liver Tissues)
		74.4	 Bioartificial Liver (BAL)
		74.5	 Gene Therapy
		74.6	 Conclusions
		Self Study
			Questions
			Answers
		References