Are you sure?
This action might not be possible to undo. Are you sure you want to continue?
Liver Pathophysiology: Therapies and Antioxidants
Ratings:
914 pages
Summary
Liver Pathophysiology: Therapies and Antioxidants is a complete volume on morphology, physiology, biochemistry, molecular biology and treatment of liver diseases. It uses an integral approach towards the role of free radicals in the pathogenesis of hepatic injury, and how their deleterious effects may be abrogated by the use of antioxidants.
Written by the most prominent authors in the field, this book will be of use to basic and clinical scientists and clinicians working in the biological sciences, especially those dedicated to the study and treatment of liver pathologies.
Presents the most recent advances in hepatology, with a special focus on the role of oxidative stress in liver injury. Provides in vivo and in vitro models to study human liver pathology. Explains the beneficial effects of antioxidants on liver diseases. Contains the most recent and modern treatments of hepatic pathologies, including, but not limited to, stem cells repopulation, gene therapy and liver transplantation.Publisher: Academic PressReleased: Mar 2, 2017ISBN: 9780128043219Format: book
Book Preview
Liver Pathophysiology
Liver Pathophysiology
Therapies and Antioxidants
Editor
Pablo Muriel
Department of Pharmacology, CINVESTAV-IPN, Mexico City, Mexico
Table of Contents
Cover image
Title page
Copyright
Dedication
Hepatic Cirrhosis
List of Contributors
Foreword
Acknowledgments
Section I. Introduction
Chapter 1. The Liver: General Aspects and Epidemiology
Abbreviated History of Hepatology
Liver Anatomy and Physiology
Liver Cells
Liver Zonation Allows Functional Plasticity
Global Liver Epidemiology
Chapter 2. Structure and Ultrastructure of the Normal and Diseased Liver
Introduction
Normal Liver Cell Types
Pathology of the Diseased Liver
Concluding Remarks
Section II. Liver Pathophysiology
Chapter 3. Hepatic Apoptosis and Necrosis: Mechanisms and Clinical Relevance
Introduction of Hepatic Injury
Apoptosis and Necrosis
Mechanism of Liver Injury and Disease Relevance
Therapeutic Strategies for Liver Injury
Summary
Chapter 4. Autoimmune Hepatitis
Selection and Presentation of Indigenous Foreign Antigens
Breaking Immune Tolerance of Self-Antigens
Neoantigens and Epitope Spread
Implicated Self-Antigens
Cell Mediators of Liver Injury
Molecular Mechanisms of Immune-Mediated Liver Injury
Overview
Chapter 5. Pathogenesis of Idiosyncratic Drug Induced Liver Injury
Epidemiology of Idiosyncratic Drug Induced Liver Injury
Factors Contributing to the Development of Idiosyncratic Drug Induced Liver Injury
Individual Host Factors
Expression and Polymorphisms of Hepatocyte Transporters
Adaptive Immune System
Genetic Variations and Polymorphisms in Human Leukocyte Antigen
Defective Adaptation
Conclusion
Chapter 6. Acetaminophen
Introduction
Acetaminophen Metabolism
Mitochondrial Protein Adducts and Acetaminophen Hepatotoxicity
Mitochondrial Oxidative and Nitrosative Stress
Amplification of Mitochondrial Oxidative Stress: Role of c-Jun N-Terminal Kinase
Mitochondrial Permeability Transition and DNA Damage
Mode of Hepatocyte Cell Death After Acetaminophen Toxicity
Sterile Inflammation and Acetaminophen Hepatotoxicity
Clinical Biomarkers in Acetaminophen Hepatotoxicity
Chapter 7. Liver Regeneration
Introduction
Normal Turnover (Homeostasis) of the Liver
Liver Regeneration After Partial Hepatectomy
Molecular Mechanisms of Liver Regeneration After Partial Hepatectomy
Liver Regeneration After Different Models of Hepatic Injury
Nomenclature and Niche of Hepatic Progenitor Cells
Hepatic Progenitor Cells Activation in Human Liver Diseases
Oval Cells/Hepatic Progenitor Cells Contribution to Liver Regeneration
Signaling Pathways Regulating Hepatic Progenitor Cells Activation and Differentiation
TWEAK/Fn14 Signaling
Fibroblast Growth Factor 7
Stromal-Cell–Derived Factor 1
Hedgehog Signaling
Wnt and Notch Signaling
Contribution of Bone Marrow Cells to Liver Regeneration
Chapter 8. Nitric Oxide in Liver Ischemia–Reperfusion Injury
Introduction
Mechanisms of Liver Ischemia–Reperfusion Injury
Mechanisms of Nitric Oxide on Liver Ischemia–Reperfusion Injury
Potential Therapeutic Effect of Nitric Oxide on Liver Ischemia–Reperfusion Injury
Summary
Chapter 9. The Immune System and Viral Hepatitis
Introduction
Immune Response and Viral Hepatitis
Immune Response to Hepatitis A Virus and Hepatitis E Virus
Immune Response to Hepatitis C Virus and Hepatitis B Virus
Lipid Metabolism and Hepatitis C Virus: Immune Control
Heme Metabolism and Immune Modulation During Viral Hepatitis
Final Remarks
Chapter 10. The Pathophysiology of Alcoholic Liver Disease
Highlights
Introduction
Steatosis
Oxidative Stress
Inflammasomes
Macrophages
Neutrophilic Infiltration of the Liver
Role of Complement in Alcoholic Hepatitis Pathogenesis
Role of Hypoxia
The Effect of Nutrition on Alcoholic Liver Disease
Epigenetic Changes in Gene Expression in Alcoholic Liver Disease
Histone Acetylation and Methylation in Experimental Alcoholic Liver Disease
Microarray Analysis
Lipopolysaccharides and Toll-Like Receptor 4 and the Blood Alcohol Cycle
Balloon Cell Change and Mallory-Denk Body Formation
Cell Cycle Arrest in Alcoholic Hepatitis
Liver Fibrosis in Alcoholic Liver Disease
Chapter 11. Cytokines in Steatohepatitis
Introduction
Tumor Necrosis Factor
Interleukins
Interferons
Conclusive Remarks
Chapter 12. Redox Signaling in NASH
Introduction
Characteristics of the Pathogenesis of Nonalcoholic Fatty Liver Disease
Conclusion
Chapter 13. Amebic Liver Abscess
Introduction
Prevalence of Amebic Liver Abscess
Clinical Manifestations
Pathology
Experimental Hepatic Amebiasis
Humoral Response
Cellular Response
Diagnosis
Chemotherapy
Surgical Treatment
Vaccination
Chapter 14. Role of Cytokines and Reactive Oxygen Species in the Amebic Liver Abscess Produced by Entamoeba histolytica
Introduction
Animal Models of Amebiasis
Role of Cytokines in the Amebic Liver Abscess
Reactive Oxygen Species in the Pathogenesis of the Amebic Liver Abscess
Conclusions
Chapter 15. Epigenetics in Liver Disease: Involvement of Oxidative Stress
Introduction
Oxidative Stress, Alcohol, and Epigenetics
Nonalcoholic Fatty Liver Disease
Conclusions
Chapter 16. Role of Oxidative and Nitrosative Stress in Hepatic Fibrosis
Introduction
Oxidative Stress: Concept and Formation
Oxidative Stress and Redox Signaling in Liver Fibrosis
Nitrosative Stress in Liver Fibrosis
Conclusions
Chapter 17. Oxidative and Nitrosative Stress in Chronic Cholestasis
Introduction
Liver Injury
Oxidative Stress
Nitrosative Stress
Oxidative and Nitrosative Stress: An Interplay?
Mitochondrial Oxidative Changes
Conclusions
Chapter 18. Cholestasis, Contraceptives, and Free Radicals
Cholestasis
Liver Effects of Contraceptives: Cholestasis and Oxidative Stress
Other Hepatic Effects by Contraceptives
Conclusions
Chapter 19. Is Human Cirrhosis a Reversible Disease?
Introduction
Chronic Liver Disease
Fibrosis and Cirrhosis
Fibrosis and Cirrhosis Regression
Cirrhotic Hepatitis B
Cirrhotic Hepatitis C
Alcohol Cirrhosis
Reversibility of Fibrosis and Cirrhosis
Alcohol Cirrhosis
Nonalcoholic Liver Disease and Fibrosis
Autoimmune Cirrhosis
Antifibrotic Therapy
Chapter 20. Obesity and Hepatocellular Carcinoma
Introduction
Obesity and Hepatocellular Carcinoma Incidence
Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma Incidence
Hepatocellular Carcinoma in Noncirrhotic Liver With Nonalcoholic Fatty Liver Disease
Molecular Mechanisms of Hepatocarcinogenesis in Obesity-Related Hepatocellular Carcinoma
Adiponectin and Leptin
Endoplasmic Reticulum Stress
Oxidative Stress
Genetic Factor (Patatin-Like Phospholipase Domain–Containing 3)
Epigenetic Changes (HDAC8, MicroRNAs)
Peroxisome Proliferator–Activated Receptor Alpha
Farnesoid X receptor
Phosphatase and Tensin Homolog and P-Akt/Mammalian Target of Rapamycin Complex Pathway
Tumor Necrosis Factor Alpha and Interleukin-6
Insulin-Like Growth Factors
C-Jun Amino Acid-Terminal Kinases
Gut Microbiome
Toll-Like Receptor 4
Obesity-Related Hepatocellular Carcinoma Prevention and Therapy
Exercise
Statins
Metformin
Probiotics
Summary
Disclosure Statement
Chapter 21. Oxidative Stress as a Mechanism for Hepatocellular Carcinoma
Hepatocellular Carcinoma and Oxidative Stress
Chapter 22. Nuclear Factor-Kappa B Actions During the Development of Hepatocellular Carcinoma
Introduction
Nuclear Factor-Kappa B Activation and Function
Nuclear Factor-Kappa B Activation and Liver Carcinogenesis
Nuclear Factor-Kappa B Activation During Hepatocarcinogenesis in Animal Models
Conclusion
Chapter 23. The Role of Senescence in Hepatic Diseases
Introduction
Pathways of Senescence
Oxidative Stress and Liver Cell Senescence
Hepatic Diseases and Senescence
Conclusion
Chapter 24. Exercise, Liver Steatosis, and Free Radicals
The Role of Oxidative Stress in Nonalcoholic Fatty Liver Disease
Hepatic Redox Modulation Induced by Acute and Chronic Exercise
Exercise Mitigates Nonalcoholic Fatty Liver Disease-Induced Liver Oxidative Stress
Conclusions
Chapter 25. The Metabolic Syndrome, Oxidative Stress, and the Liver
Introduction
Definition of Metabolic Syndrome
Epidemiology of Metabolic Syndrome and Nonalcoholic Fatty Liver Disease
Oxidative Stress
The Metabolic Syndrome and Oxidative Stress
Nonalcoholic Fatty Liver Disease, Insulin Resistance, and Oxidative Stress
Conclusions
Chapter 26. Liver Diseases in the Elderly
Changes Found in the Aged Liver
Liver Diseases in the Elderly
Summary
Chapter 27. Cytokines in Hepatic Injury
Macrophage Heterogeneity, Cytokines, and Liver Injury
Cytokines and Basic Liver Pathophysiology
Cytokines in Various Hepatic Injuries
Conclusions
Chapter 28. Nrf2: A Key Regulator of Redox Signaling in Liver Diseases
Introduction
General Principles of Nrf2 Signaling
Role of Nrf2 in Liver Diseases
Conclusion
Chapter 29. Redox Regulation by HGF/c-Met in Liver Disease
Introduction
Hepatocyte Growth Factor/c-Met Redox Regulation and Liver Diseases
Conclusion
Section III. Liver Metabolism
Chapter 30. Hepatic Metabolism in Liver Health and Disease
Introduction
Hepatic Carbohydrates Metabolism
Hepatic Lipid Metabolism
Hepatic Protein Metabolism
Hepatic Drug Metabolism
Chapter 31. Cytochrome P450 and Oxidative Stress in the Liver
Introduction
Microsomal Mixed Function Oxidase and Cytochrome P450 Metabolism
Mixed Function Oxidase Activity
CYP2E1-Reactive Oxygen Species and Ethanol-Induced Liver Injury
Conclusions and Perspectives
Chapter 32. Drug Hepatic Clearance in Spinal Cord Injury
Background: Clinical and Experimental Observations on Pharmacokinetic Alterations Due to Spinal Cord Injury
Effects of Experimental Spinal Cord Injury on Phenacetin and Naproxen Clearance in Rats
What Do We Know About Spinal Cord Injury-Induced Changes in Liver Function and Drug Disposition
Section IV. Cirrhosis and Its Complications
Chapter 33. Complications of Cirrhosis: Introduction
Introduction
Complications of Cirrhosis
Concluding Remarks
Chapter 34. Portal Hypertension—Molecular Mechanisms
Introduction
Physiology of Portal Pressure
Pathophysiology of Portal Hypertension
Molecular Mechanisms of Portal Hypertension
Summary
Chapter 35. Gastroesophageal Varices
Definition and Clinical Significance
Pathophysiology of Portosystemic Collateral Circulation
Development of Portosystemic Collaterals: Preexistent and De Novo
Assessment of Varices
Rationale for the Management of Varices
Clinical Scenarios for the Treatment of Portal Hypertension
Chapter 36. Ascites
Pathogenesis
Pathophysiological Bases for the Treatment of Ascites
Management of Cirrhotic Ascites
Conclusions
Chapter 37. Reactive Nitrogen and Oxygen Species in Hepatic Encephalopathy
Introduction
Hepatic Encephalopathy
Manganese
Ammonia
Other Pathogenic Mechanisms Generating Reactive Nitrogen and Oxygen Species in the Brain
Conclusions
Chapter 38. Hepatorenal Syndrome
Introduction
Pathophisiology of HRS
Diagnosis
Differential Diagnosis
Precipitating Factors
Treatment of HRS
Chapter 39. Hepatopulmonary Syndrome and Portopulmonary Hypertension
Hepatopulmonary Syndrome
Portopulmonary Hypertension
Summary
Section V. Methods in Liver Disease
Chapter 40. Experimental Models of Liver Damage Mediated by Oxidative Stress
Introduction
Carbon Tetrachloride Is a Useful Model to Induce Acute and Chronic Liver Damage
Acetaminophen Intoxication as Model of Acute Liver Injury
Models of Cholestasis
Ischemia/Reperfusion Liver Injury Models Serve to Improve Liver Transplantation Surgery
Concanavalin A Is a Good Model That Mimics Autoimmune Hepatitis
Liver Damage Induced by Alcohol in Rats
d-Galactosamine and Lipopolysaccharides Induce Liver Damage Through Activating the Immune System
Thioacetamide Produces Chronic Liver Injury Through Free Radical Attack to Macromolecules
Dimethyl or Diethyl Nitrosamine Produces Necrosis, Fibrosis, and Cancer
Dietary Models Used to Acquire a Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis Phenotype
Gold Thioglucose+High-Fat Diet
Concluding Remarks
Chapter 41. Monitoring of Liver Fibrogenesis and Biochemical Diagnosis of Fibrosis
Introduction
Current Biomarkers of Hepatic Fibrogenesis
Class I Fibrosis Biomarkers
Class II Fibrosis Biomarkers
Development of Innovative Biomarkers
NX-Des-γ-carboxyprothrombin
Conclusion
Chapter 42. In Vitro Models of HCC
Introduction
General Overview and Traits of a Multistage Malignant Process
Cell Models for the Study of Hepatocellular Carcinoma Initiation Stage
Cell Models for the Study of Hepatocellular Carcinoma Promotion Stage
Cell Models for the Study of Hepatocellular Carcinoma Progression Stage
Comparative Analysis of Hepatocellular Carcinoma Cell Lines
Frequency of Use for Research Purposes
Pharmacological Studies in Hepatocellular Carcinoma Cell Lines
Studies With Antioxidants
Combination of Antioxidants With Different Drugs in Hepatocellular Carcinoma Cell Lines
Conclusions
Section VI. Therapies in Liver Disease
Chapter 43. The Liver, Oxidative Stress, and Antioxidants
Introduction
Oxidative Stress
The Overproduction of Free Radicals in Biological Systems
Antioxidants
Nuclear Erythroid 2-Related Factor 2/Antioxidant Response Element Pathway in Liver Diseases
Antioxidants From Natural Sources and Some of Its Hepatoprotective Effects
Conclusion
Chapter 44. Herbal Drugs on the Liver
Introduction
Plants as Hepatoprotective Agents
Polyherbal (Multiingredient) Formulations as Hepatoprotective Agents
Problems With Polyherbal Formulations
Chemistry of Hepatoprotective Herbal Drugs
The Mechanism(s) of Action
Active Phytochemicals as Hepatoprotective Agents
Development of Hepatoprotective Herbal Drugs
Chapter 45. Silymarin for Liver Disease
The History of Milk Thistle
Biochemistry
Pharmacokinetics
Pharmacological Studies
Alcohol-Induced Liver Disease
Nonalcoholic Fatty Liver Disease
Viral Hepatitis
Toxic and Iatrogenic Liver Disease
Mushroom Poisoning
Hepatocellular Carcinoma
Conclusion
Chapter 46. Naringenin and the Liver
Introduction
Knowing Naringenin
Pharmacokinetics of Naringenin
The Naringenin in Fibrogenic Signaling Pathways
Beneficial Effects of Naringenin in Liver Diseases
Pharmaceutical Technology of Naringenin
Safety and Toxicity of Naringenin
Conclusions and Perspectives
Chapter 47. Antioxidant, Antiinflammatory, and Antifibrotic Properties of Quercetin in the Liver
Introduction
Structure-Activity Relationship of Quercetin
Metal-Chelating Activity of Quercetin
Pharmacokinetics of Quercetin
Hepatoprotective Effects of Quercetin
Quercetin and Inflammation
Quercetin in the Treatment of Hepatocellular Carcinoma
Pharmaceutical Technology of Quercetin
Toxicological Effects
Conclusions and Perspectives
Chapter 48. Coffee and the Liver
Introduction
Chemical Composition of Coffee
Beneficial Effects of Coffee on Liver Disease
Chapter 49. Hepatoprotective Properties of Curcumin
Introduction
Antiinflammatory Properties of Curcumin in the Liver
Antifibrotic Properties of Curcumin in the Liver
Anticancer Properties of Curcumin in the Liver
Antiviral Properties of Curcumin in the Liver
Antiheavy Metal Properties of Curcumin in the Liver
Antisteatosis Properties of Curcumin in the Liver
Conclusions and Perspectives
Chapter 50. Retinoids in Liver Function
What Is a Retinoid?
Dietary Intake and Intestinal Absorption of Retinoids
Cellular Formation of Retinal and Retinoic Acid
Hepatic Retinoids and Liver Diseases
Effect of Retinoids on Iron Metabolism
Effect of Retinoids on Insulin Resistance in Liver
Activation of AMPK by Retinoids
Identification of the Responsive Genes of All-trans Retinoic Acid
Retinoid Metabolism in Nonalcoholic Fatty Liver Disease
Chapter 51. Stevia as a Putative Hepatoprotector
Introduction
Conclusions and Perspectives
Chapter 52. Are N-Acetylcysteine and Resveratrol Effective Treatments for Liver Disease?
Introduction
Overview of NAC and Resveratrol: Chemical Properties and Pharmacokinetic Aspects
Pharmacodynamic Properties and Clinical Applications
Effects of NAC and Resveratrol in Liver Diseases
Side-Effects and Toxicology of NAC and Resveratrol
NAC and Resveratrol Formulations
Conclusions and Perspectives
Chapter 53. Does Nutrition Matter in Liver Disease?
Introduction
Malnutrition as a Consequence of Liver Disease
Evaluation of Nutrition Status in Liver Disease
Nutritional Treatment of Liver Disorders
Conclusion and Perspectives
Chapter 54. One-Carbon Metabolism in Liver Health and Disease
Introduction
Hepatic One-Carbon Metabolism
S-Adenosylmethionine Treatment in Liver Disease
Chapter 55. Ursodeoxycholic Acid for the Treatment of Liver Diseases
History of Ursodeoxycholic Acid
Physicochemical Properties and Pharmacokinetics of UDCA
Pharmacological Activities of UDCA
Mechanisms of UDCA Action
Clinical Use and Efficacy of UDCA
Chapter 56. Current Treatment of Chronic Hepatitis C
Interferon-Free Treatment Regimens
Unresolved Issues
Conclusions
Chapter 57. An Adenosine Derivative Compound as a Hepatoprotective Agent
Introduction
Concluding Remarks and Perspectives
Chapter 58. Nitric Oxide and the Liver
Introduction
Sources and Regulation of NO in the Liver
NO Signaling in Liver
Pathophysiology
Conclusion: NO and the Liver
Chapter 59. Repopulation of Cirrhotic Liver by Hepatic Stem/Progenitor Cells: A Promising Strategy Alternative to Liver Transplantation
Introduction
Emergence of Cell Therapy for Liver Diseases
Hepatocytes Transplantation
Stem Cell–Based Therapy for Liver Cirrhosis
Stem Cells Repopulation in Cirrhotic Liver Through Different Routes/Sites
Immunobiology of hHSPCs Transplantation
Alternative Strategies for the Development of Bioartificial Liver Using hHSPCs Repopulation
Stem Cells Imaging and Tracking: From Bench to Bedside
Concluding Remarks
Chapter 60. Gene Therapy for Liver Disease
Introduction
Mechanisms of Liver-Directed Gene Therapy
Delivery Systems for Gene Therapy
Viral Vectors
Nonviral Vectors
Conclusions
Chapter 61. Role of Oxidative Stress in Liver Transplantation
Introduction
Role of Oxidative Stress in Ischemia-Reperfusion Associated With Liver Transplantation
Strategies to Decrease Oxidative Stress in I/R Associated With Liver Transplantation
Future Directions in Researching on Oxidative Stress in Ischemia-Reperfusion Injury Associated With Liver Transplantation
Index
Copyright
Academic Press is an imprint of Elsevier
125 London Wall, London EC2Y 5AS, United Kingdom
525 B Street, Suite 1800, San Diego, CA 92101-4495, United States
50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States
The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom
Copyright © 2017 Elsevier Inc. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.
This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.
Library of Congress Cataloging-in-Publication Data
A catalog record for this book is available from the Library of Congress
British Library Cataloguing-in-Publication Data
A catalogue record for this book is available from the British Library
ISBN: 978-0-12-804274-8
For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals
Publisher: Mica Haley
Acquisition Editor: Stacy Masucci
Editorial Project Manager: Samuel Young
Production Project Manager: Edward Taylor
Designer: Victoria Pearson
Typeset by TNQ Books and Journals
Dedication
Marcos Rojkind in his office at George Washington University Medical Center. Courtesy of Dr. Karina Reyes Gordillo.
Marcos Rojkind Matluk (July 29, 1935–September 10, 2011) was one of Mexico's most prominent scientists. Prof. Rojkind was recognized worldwide for his work on the molecular mechanisms involved in liver fibrosis. He shaped more than 70 distinguished researchers (some of them wrote a chapter in his memory in this book), published over 140 manuscripts in prestigious scientific journals and books, and held several patents as an inventor in the field of biotechnology.
Hepatic Cirrhosis
Every twenty-four weeks
—or when the doctor decides—
go to your preference lab,
do a liver function test
and check your levels of bilirubin.
Take into consideration
doing regular physical activity
and do not put salt on your food.
Otherwise
you can forget your slimmer abdomen
that has started to gather liquids:
the damages are irreversible.
Do not drink alcohol,
I repeat, do not drink alcohol.
It does not matter if your new girlfriend plans on leaving you.
It also does not matter
if it is impossible for you to be at a familiar reunion
without the ease
brought to you by a couple of drinks.
Perhaps you have forgotten to measure
your hepatic enzymes concentration?
Do not think of the properties
you lost in your divorce. The blood
must contain between three point four
and five point four—not more
nor less—
grams per deciliter of albumin.
Ignore your children that do not want to see you again,
but do not forget the magnetic resonance
and to program the regular check
with your primary care physician.
Do not be jealous of the firm erections
with which other men enjoy of your ex-wife.
The liver is the life-filtering organ.
It discharges toxic residues
and yours is wasted.
Concentrate on treating cirrhosis,
do not remember the blood stains,
the broken glass of the table,
the things you said —or they say you said—
the dry mouth the next day.
When you look in the mirror
do not stop feeling attractive
because of your yellow sclera.
Try not to think on the possible cancer
—hepatocellular carcinoma—
but do take care.
Do not smoke, do not drink alcohol,
do not have negative thoughts.
Do not worry
if you leave stains touching the napkins.
Loose fear of looking at life
only
through yellow-color shades.
Andrea Muriel [Translation by Carmen Amat]
Cirrosis Hepática
Cada veinticuatro semanas/–o cada que el médico lo señale–/vaya al laboratorio de su preferencia/hágase una prueba de función hepática/y compruebe sus niveles de bilirrubina./Tenga en cuenta/hacer actividad física regular/mantenga un peso adecuado/y no ponga sal a sus comidas./De lo contrario/usted podrá olvidarse de su esbelto abdomen/que ya empezó a acumular líquidos:/los daños son irreversibles./No beba alcohol/repito, no beba alcohol/no importa si su nueva novia piensa dejarlo/no importa tampoco/si le es imposible estar en una reunión familiar/sin la desenvoltura/que le permiten un par de copas./¿Acaso ha olvidado medir/su concentración de enzimas hepáticas?/No piense en las propiedades/que perdió con su divorcio. La sangre/debe contener entre tres punto cuatro/y cinco punto cuatro –no más/ni menos–/gramos por decilitro de albúmina./Ignore a sus hijos que no quieren volver a verlo/pero no olvide la resonancia magnética/y programar el chequeo periódico/con su médico de cabecera./No sienta celos de las erecciones firmes/con que otros hombres gozan de su exmujer./El hígado es el órgano filtrante de la vida/descarta los residuos tóxicos/y el suyo está deshecho./Concéntrese en tratar la cirrosis/no recuerde las manchas de sangre/el vidrio roto de la mesa/las cosas que dijo –o dicen que dijo–/la boca pastosa al día siguiente./Al verse al espejo/no deje de sentirse atractivo/por su esclerótica amarilla./Intente no pensar en el posible cáncer/–hepatocarcinoma–/pero cuídese/no fume, no beba alcohol/no tenga pensamientos negativos./No se preocupe/si deja huellas en las servilletas al tocarlas/pierda el miedo a ver la vida/solamente/en tonos de amarillo.
List of Contributors
L. Abenavoli, University Magna Graecia, Catanzaro, Italy
J.G. Abraldes, University of Alberta, Edmonton, AB, Canada
N.E. Aguilar-Olivos, Medica Sur Clinic & Foundation, Mexico City, Mexico
J. Aguirre-García, MIG Hospital, Mexico City, Mexico
P. Almeda-Valdés, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico
J. Arauz, Universidad Autónoma de Baja California, Mexicali, Mexico
R.N. Aravalli, University of Minnesota Medical School, Minneapolis, MN, United States
J. Arellanes-Robledo, Instituto Nacional de Medicina Genómica-INMEGEN, Mexico City, Mexico
A. Ascensão, University of Porto, Porto, Portugal
A. Bardia, Deccan College of Medical Sciences, Hyderabad, India
J. Beleza, University of Porto, Porto, Portugal
T.R. Billiar, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
L.D. Buendía-Montaño, Cinvestav-IPN, Mexico City, Mexico
J. Camacho, Cinvestav-IPN, Mexico City, Mexico
S. Casas-Grajales, Cinvestav-IPN, Mexico City, Mexico
A. Casillas-Ramírez
Hospital Regional de Alta Especialidad de Ciudad Victoria Bicentenario 2010
, Ciudad Victoria, Mexico
Universidad Autónoma de Tamaulipas, Matamoros, Mexico
G. Castañeda-Hernández, Cinvestav-IPN, Mexico City, Mexico
A.I. Cederbaum, Icahn School of Medicine at Mount Sinai, New York, NY, United States
V. Chagoya de Sánchez, Universidad Nacional Autónoma de México, Mexico City, Mexico
E. Chávez, Universidad Nacional Autónoma de México, Mexico City, Mexico
I. Colle, Ghent University, Ghent, Belgium
L. Cruz-Antonio, FES Zaragoza, Universidad Nacional Autónoma de México, Mexico City, Mexico
A. Cruz-Baquero, Escuela Superior de Medicina-IPN, Mexico City, Mexico
A.J. Czaja, Mayo Clinic College of Medicine, Rochester, MN, United States
L. Dara, University of Southern California, Los Angeles, CA, United States
M. del Pilar Cabrales-Romero, Universidad Nacional Autónoma de México, Mexico City, Mexico
M. Dhayal, CSIR-Centre for Cellular and Molecular Biology, Hyderabad, India
M. Espinosa-Cantellano, Centro de Investigación y de Estudios Avanzados, Mexico City, Mexico
V.M. Factor, National Cancer Institute, NIH, Bethesda, MD, United States
P. Ferenci, Medical University of Vienna, Vienna, Austria
E. Fernández-Martínez, Universidad Autónoma del Estado de Hidalgo (UAEH), Pachuca, Mexico
M. Fernandez
IDIBAPS Biomedical Research Institute, Barcelona, Spain
Instituto de Salud Carlos III, Madrid, Spain
N.A. Fierro
Civil Hospital of Guadalajara, Fray Antonio Alcalde
, Guadalajara, Mexico
University of Guadalajara, Guadalajara, Mexico
R.E. Flores-Beltrán, Cinvestav-IPN, Mexico City, Mexico
S.W. French
UCLA, Los Angeles, CA, United States
Harbor-UCLA Medical Center, Torrance, CA, United States
P. Fu, Zhongshan Hospital of Fudan University, Shanghai, China
H. Fukui, Nara Medical University, Kashihara, Japan
M. Galicia-Moreno, Universidad Autónoma de Baja California, Mexicali, Mexico
A. Galli, University of Florence, Florence, Italy
P. García-López, Instituto Nacional de Cancerología, Mexico City, Mexico
G. Garcia-Tsao
Yale University School of Medicine, New Haven, CT, United States
VA-CT Healthcare System, West Haven, CT, United States
M.C. García de León, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
P. Ginès
Hospital Clinic de Barcelona, Barcelona, Spain
University of Barcelona, Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
C. Girish, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, India
L.E. Gómez-Quiroz
Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico
National Cancer Institute, NIH, Bethesda, MD, United States
I.O. Gonçalves
University of Porto, Porto, Portugal
Higher School of Education of Fafe, Fafe, Portugal
K. Gonzalez-Aldaco
Civil Hospital of Guadalajara, Fray Antonio Alcalde
, Guadalajara, Mexico
University of Guadalajara, Guadalajara, Mexico
J. Gracia-Sancho, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS, CIBEREHD, Barcelona, Spain
I. Grattagliano
Italian College of General Practitioners, Bari, Italy
Aldo Moro
University Medical School, Bari, Italy
I. Graupera
Hospital Clinic de Barcelona, Barcelona, Spain
University of Barcelona, Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
O.A. Gressner, Wisplinghoff Medical Laboratories, Cologne, Germany
A.M. Gressner, Wisplinghoff Medical Laboratories, Berlin, Germany
R.J. Groszmann, Yale University School of Medicine, New Haven, CT, United States
G. Guízar-Sahagún, Proyecto Camina A.C., IMSS, Mexico City, Mexico
D.G. Gutiérrez-Reyes, UNAM, Mexico City, Mexico
M.C. Gutiérrez-Ruiz, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City, Mexico
M.A. Habeeb, Deccan College of Medical Sciences, Hyderabad, India
H. Hai, Osaka City University, Osaka, Japan
L. Hammerich, Icahn School of Medicine at Mount Sinai, New York, NY, United States
E. Hernández-Aquino, Cinvestav-IPN, Mexico City, Mexico
C. Hernández, Cinvestav-IPN, Mexico City, Mexico
H. Jaeschke, University of Kansas Medical Center, Kansas City, KS, United States
M.B. Jiménez-Castro, Transplant Biomedicals S.L., Barcelona, Spain
N. Kaplowitz, University of Southern California, Los Angeles, CA, United States
A. Katoonizadeh, Tehran University of Medical Sciences, Tehran, Iran
N. Kawada, Osaka City University, Osaka, Japan
D. Kershenobich, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
A.A. Khan, Deccan College of Medical Sciences, Hyderabad, India
S.H. Ki, Chosun University, Gwangju, Korea
K.M. Kim, Chosun University, Gwangju, Korea
M.R. Lakshman
Veterans Affairs Medical Center, Washington, DC, United States
The George Washington University, Washington, DC, United States
W. Li, China-Japan Union Hospital of Jilin University, Changchun, China
X. Liang, The University of Queensland, Brisbane, QLD, Australia
X. Liu, The University of Queensland, Brisbane, QLD, Australia
Z.-X. Liu, University of Southern California, Los Angeles, CA, United States
P.A. Loughran, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
S.C. Lu, Cedars-Sinai Medical Center, Los Angeles, CA, United States
S. Maeda, Yokohama City University, Yokohama, Japan
J. Magalhães, University of Porto, Porto, Portugal
J. Mann, Newcastle University, Newcastle upon Tyne, United Kingdom
J.U. Marquardt
Johannes Gutenberg University, Mainz, Germany
National Cancer Institute, NIH, Bethesda, MD, United States
M. Martínez-Castillo, Cinvestav-IPN, Mexico City, Mexico
M.L. Martínez-Chantar, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Derio, Spain
H.Y. Martínez-Padrón, Hospital Regional de Alta Especialidad de Ciudad Victoria Bicentenario 2010
, Ciudad Victoria, Mexico
A. Martínez-Palomo, Centro de Investigación y de Estudios Avanzados, Mexico City, Mexico
M.J. Martins, University of Porto, Porto, Portugal
J.M. Mato, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Derio, Spain
N. Méndez-Sánchez, Medica Sur Clinic & Foundation, Mexico City, Mexico
N. Milic, University of Novi Sad, Novi Sad, Serbia
G. Montes-Páez, Cinvestav-IPN, Mexico City, Mexico
S. Montes, National Institute of Neurology and Neurosurgery Dr. Manuel Velasco Suárez
, Mexico City, Mexico
P. Muriel, Cinvestav-IPN, Mexico City, Mexico
T. Nakamura, Kurume University School of Medicine, Kurume, Japan
M. Noureddin, Cedars-Sinai Medical Center, Los Angeles, CA, United States
P.J. Oliveira, University of Coimbra, Cantanhede, Portugal
R. Pacheco-Rivera, Cinvestav-IPN, Mexico City, Mexico
J. Pacheco-Yépez, Escuela Superior de Medicina-IPN, Mexico City, Mexico
A. Panduro
Civil Hospital of Guadalajara, Fray Antonio Alcalde
, Guadalajara, Mexico
University of Guadalajara, Guadalajara, Mexico
C. Peralta, Transplant Biomedicals S.L., Barcelona, Spain
J.I. Pérez-Carreón, Instituto Nacional de Medicina Genómica-INMEGEN, Mexico City, Mexico
P. Portincasa, Aldo Moro
University Medical School, Bari, Italy
S.C. Pradhan, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, India
S. Raevens, Ghent University, Ghent, Belgium
A. Ramachandran, University of Kansas Medical Center, Kansas City, KS, United States
E. Ramos-Tovar, Cinvestav-IPN, Mexico City, Mexico
K. Reyes-Gordillo
Veterans Affairs Medical Center, Washington, DC, United States
The George Washington University, Washington, DC, United States
S. Rivera-Mancía, Instituto Nacional de Cardiología Ignacio Chávez
, Mexico City, Mexico
M.S. Roberts
The University of Queensland, Brisbane, QLD, Australia
University of South Australia, Adelaide, SA, Australia
A.Y. Rocha-Sánchez, Hospital Regional de Alta Especialidad de Ciudad Victoria Bicentenario 2010
, Ciudad Victoria, Mexico
S. Roman
Civil Hospital of Guadalajara, Fray Antonio Alcalde
, Guadalajara, Mexico
University of Guadalajara, Guadalajara, Mexico
J. Serrano-Luna, Cinvestav-IPN, Mexico City, Mexico
R. Shah
Veterans Affairs Medical Center, Washington, DC, United States
The George Washington University, Washington, DC, United States
W. Shibata, Yokohama City University, Yokohama, Japan
M. Shibayama, Cinvestav-IPN, Mexico City, Mexico
Y. Shimizu, Nanto Municipal Hospital, Toyama, Japan
G. Shiota, Tottori University, Yonago, Japan
E. Solà
Hospital Clinic de Barcelona, Barcelona, Spain
University of Barcelona, Barcelona, Spain
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
F. Tacke, University Hospital Aachen, Aachen, Germany
K. Tajiri, Toyama University Hospital, Toyama, Japan
A. Takaki, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
M. Tarocchi, University of Florence, Florence, Italy
S.S. Thorgeirsson, National Cancer Institute, NIH, Bethesda, MD, United States
T.T.V. Thuy, Osaka City University, Osaka, Japan
T.T. Thuy le, Osaka City University, Osaka, Japan
T. Torimura, Kurume University School of Medicine, Kurume, Japan
L.A. Tristán-López, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez
, Mexico City, Mexico
V. Tsutsumi, Cinvestav-IPN, Mexico City, Mexico
G.R. Tsutsumi, Hospital General de Soledad, San Luis Potosí, Mexico
D. Uchida, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
T. Ueno
Kurume University School of Medicine, Kurume, Japan
Asakura Medical Association Hospital, Asakura, Japan
M. Uribe, Medica Sur Clinic & Foundation, Mexico City, Mexico
E.E. Vargas-Pozada, Cinvestav-IPN, Mexico City, Mexico
L.F. Vázquez-Flores, Escuela Nacional de Ciencias Biológicas-IPN, Mexico City, Mexico
G. Velasco-Loyden, Universidad Nacional Autónoma de México, Mexico City, Mexico
L. Vergani, University of Genova, Genova, Italy
S.K. Vishwakarma, Deccan College of Medical Sciences, Hyderabad, India
J.D. Vorobioff, Universidad Nacional de Rosario, Rosario, Argentina
J.-Y. Wang
Fudan University, Shanghai, China
Shanghai Institute of Liver Diseases, Shanghai, China
H. Wang, The University of Queensland, Brisbane, QLD, Australia
S.-D. Wu
Fudan University, Shanghai, China
Shanghai Institute of Liver Diseases, Shanghai, China
F. Xia, Southern Medical University, Guangzhou, China
W. Xu, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR
L. Xu, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
K. Yamamoto, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
X.R. Yao, Southern Medical University, Guangzhou, China
J. Yu, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR
L. Zeng, Nanchang University, Ganzhou, China
B.J. Zhou, Southern Medical University, Guangzhou, China
Foreword
Some weeks ago I received the generous invitation of Prof. Pablo Muriel to contribute an Introduction to the present collection of texts on various new (and not so new) aspects of liver pathophysiology. In reading the list of distinguished authors and their wide coverage of many different themes related to the liver that are to be included in the projected volume, I was tempted at first to decline the invitation, recognizing that on many of the subjects to be contained in the book to be published I really have little or no knowledge at all. Two circumstances, however, weighed against that first reaction: (1) for many years I have been interested in the liver and its diseases, and I am still actively working on two of them (amebiasis and liver cirrhosis, included in the book), and (2) the volume is to be dedicated to the memory of Prof. Marcos Rojkind, a former student and scientific collaborator of mine, and always a very close, admired, and dear friend.
How can one write an Introduction to a book as heterogeneous as this one? My first reaction was to consult the introductory chapters of all the books on the liver and its diseases in my library (which are many). I found that most of those chapters were unknown to me: I had never read them. Through many years, when consulting those books, I went directly to the chapters treating the specific topics of my interest; I seldom (or never), read their Prologue or Introductory chapters. The experiment confirmed what I had long suspected: the Prologue or Introductory Chapter of scientific books is the part that is less frequently or never read by their professional users. I see no reason why this will not be the fate of the lines I am now writing and you (a most unlikely but welcome reader) may now be reading. If this conclusion is right, I would like to know why it is the case, in order to explain such peculiar phenomenon and to try to avoid repeating it in this and the next times I am invited to write a Prologue or Introductory Chapter for scientific books.
I believe the simplest approach to the problem mentioned earlier is to try to answer the following two questions: (1) What should be the objective or goal of a Prologue or Introductory Chapter? and (2) How can such an objective or goal be best achieved? After reading many prologues in different scientific books (and writing a few myself) I can easily state which are the more frequent and less fortunate objectives displayed by prologue-writers: (1) a barely covered pretense to dominate all the contents of the volume, usually expressed with condescending authority; (2) a joyful reception to the timely appearance of such acutely needed text, accompanied by congratulations to editors and authors; (3) a nostalgic remembrance of past treatises on the same subject, which are now consigned to obsolescence. I decided to avoid such and other usual formats, and since this volume is dedicated to the memory of Prof. Marcos Rojkind, I shall limit this Prologue to a few comments on him.
I first met Marcos in the early fifties of the last century, as a medical student in my pathology course. One day he came to my office and asked me to recommend him to my older brother, who was a cardiologist, because Marcos wanted to study with him to eventually become a cardiologist. His interest was stimulated by his little sister, who was suffering with a disabling rheumatic heart disease. This was the time when Paul Klemperer introduced the concept of collagen diseases,
and in our laboratory my wife and I were then actively working on the regulation of connective tissues in several experimental animal models of human disease. I suggested that Marcos should first spend some time in our laboratory, getting acquainted with the basic general field of connective tissues, before going on to work with my brother in the clinical aspects of cardiovascular rheumatic diseases, and Marcos agreed. That was the beginning of our collaboration and friendship, which lasted for many years (he never went to work with my brother), until his untimely death. When the time came, Marcos went to continue his studies and research in connective tissues, in New York, with Paul Gallop and Sam Seifert, and then returned to Mexico, to head a laboratory in CINVESTAV. In his later years Marcos returned to the United States as a senior investigator. In our collaboration we wrote many papers, a couple of books, and had several common students, some of them authors in this volume. I remember Marcos as a serious scientist, a careful experimenter, a critical colleague, and an original thinker, respectful of his teachers and demanding (but generous) with his students. I also remember Marcos as a gentle husband, a loving father, and a faithful and constant friend, who remained the same lovely person throughout the different stages of his life. For these reasons, I celebrate that this book is dedicated to his memory.
Ruy Pérez-Tamayo, Emeritus Professor, National Autonomous University of Mexico, Director, Unit of Research in Experimental Medicine of the School of Medicine
Acknowledgments
I thank all authors for agreeing to contribute to this book with their best effort. Without their expertise, this dream would not have been possible. I specially acknowledge Erika Ramos Tovar for her help in all the editorial processes of this volume, including the organization of content, invitation to authors, and revision of manuscripts. Thank you very much Erika for your patience and effort, but mainly for your enthusiasm to work even on weekends and holidays! Thank you Andrea Muriel for your poem on the liver and María Fernanda Muriel for the front page design. I appreciate and acknowledge the editorial assistance of Elsevier, particularly Samuel Young.
To the memory of my mother who taught me how to fight against adversity and my daughters Andrea and María Fernanda.
Section I
Introduction
Outline
Chapter 1. The Liver: General Aspects and Epidemiology
Chapter 2. Structure and Ultrastructure of the Normal and Diseased Liver
Chapter 1
The Liver
General Aspects and Epidemiology
P. Muriel Cinvestav-IPN, Mexico City, Mexico
Abstract
Professor Marcos Rojkind considered the liver as an ecosystem that performs a plethora of essential functions for the preservation of homeostasis in the organism. Blood from the portal triad, rich in oxygen and nutrients, enters the sinusoids, where it drains into the central vein. The synthesis of proteins, bile acids, and hormones; the metabolism of nutrients and xenobiotics; the storage and usage of glucose; and the neutralization of foreign antigens and microbes from the gut are performed by different types of cells including hepatocytes, cholangiocytes, sinusoidal endothelial cells, Kupffer cells, natural killer cells, and hepatic stellate cells. Liver pathologies, as cancer, are the main causes of morbidity/mortality worldwide and the incidences are increasing due to obesity and other risk factors. In this chapter, the reader will find an introduction to modern hepatology and a general description of the sections and chapters that constitute the body of the present volume.
Keywords
Liver anatomy; Liver cells; Liver epidemiology; Liver history; Liver physiology; Liver zonation
The present chapter aims to point out the relevance and pertinence of this book and to introduce the reader to its content. The first part, consisting of history, anatomy, and physiology of this organ, tries to describe the liver seeking to motivate the interest in the study of modern hepatology. Once the vital importance of the liver is demonstrated, it is necessary to address the relevance of hepatic diseases as a cause of morbidity and mortality; thus the second section of this chapter Global liver epidemiology
demonstrates the impact of the various acute and chronic liver conditions on worldwide population. In addition, this review leads the reader to the various sections and chapters that constitute the body of this volume when necessary. The second chapter of this introductory section Structure and Ultrastructure of the Normal and Diseased Liver
by Prof. Tsutsumi and his colleagues is a collection of marvelous images that, in a beautiful way, illustrate and describe liver pathology.
The two chapters that constitute the introduction section are the basis to fully appreciate the rest of the book in which the most prominent hepatologists have put their best effort to present a review of their area of expertise in the field of hepatology.
Abbreviated History of Hepatology
Even in primeval times, the liver was well known as the most powerful and blood-rich organ of the body. Several processes were attributed to this impressive part of the entrails. It was even regarded as the seat of life
. The Indo-Germanic word lîp
meant both liver and life. There also exist similarities between the English words liver
live
and life
(Old English: lifer-līf
) and the German Leber-Leben
. In Old High German, the liver was termed leb (a) ra
. The Hebrew kábe (r), kábe (d)
(or cheber
) is the probable root of the Greek word hepar
(Kuntz and Kuntz, 2006).
In the middle ages, Mondino de Luzzi (Bologna) in his "Anatomia Mundini" that was published in 1316 recorded descriptions regarding the anatomy of the liver. This work is based on autopsies that were carried out for the first time in public in 1306 and 1315. This unprecedented textbook of anatomy served as a canon for almost two centuries. Fig. 1.1, taken from "Anatomia Mundini", shows the liver with several lobules (Kuntz and Kuntz, 2006).
Glisson published the first comprehensive monograph on the liver in 1654; his work served as an authoritative research of reference for the next two centuries (Glisson, 1654). The inner structure of the liver, characterized by its intrahepatic vascular vessels, the differentiation of liver segments through the portal vein, the terminal regions of the blood and bile capillaries as functional pathways, and the dynamics of the bile flow were described in detail in "Anatomia hepatis.
Glisson's capsule was recognized as branching, tree-like intrahepatic connective tissue. Fig. 1.2, by F. Glisson, depicts the blood and bile vessels from a liver. The portal vessels, which are surrounded by connective tissue, are termed portal trias (
Glisson's triangle) (1659). Glisson found nerves only in the liver capsule and not in the parenchyma. The role of the liver parenchyma was regarded as that of separating the bile from the blood by mechanisms of
affinity".
One of the earliest illustrations of the liver lobule was made by Kiernan in 1833, in which the hexagonal architecture of the parenchyma and the fine bile capillaries anastomoses can be appreciated (Fig. 1.3).
Figure 1.1 Visceral surface of the multiple-lobed liver (A), with the gall bladder (B), portal vein (D), and bile duct, bile system (C, E) (" Anatomia Mundini ", 1316) (Mondino de Luzzi, Bologna). Reproduced from Kuntz, E., Kuntz, H.D., 2006. History of Hepatology. Hepatology, Principles and Practice. History, Morphology, Biochemistry, Diagnostics, Clinic, Therapy, second ed. Verlag Berlin Heidelberg, Springer, pp. 1–13.
Liver Anatomy and Physiology
Because the liver is an ecosystem (Rojkind and Greenwel, 1988), it is mandatory to describe the components (anatomy) and their interactions and functions (physiology) before studying its pathophysiology (Section II of this book) and the possible treatments for the various hepatic illness (Section VI of this book). These are the two main subjects of this book. Also, the impact of liver diseases on worldwide morbidity/mortality needs to be addressed to highlight the relevance of this book. It is necessary to mention that the role of free radicals/oxidative/nitrosative stress is nowadays recognized and a fundamental factor in the development, establishment, and as a consequence in the prevention and treatment of these pathologies (Chapter 43). Moreover, several models (Chapters 40 and 42) and methods (Chapter 41) to evaluate the diverse hepatic pathologies are fundamental for the development of future strategies to fight acute or chronic liver disease that affect dozens of millions of people around the globe and constitute a major cause of global mortality (see the following).
Liver Anatomy
The liver is a triangular organ that extends across the abdominal cavity below the diaphragm. This organ is made of very soft and pinkish-brown tissues, encapsulated by a connective tissue capsule; it is the largest gland in the body and accounts for approximately 2.5% of the total human body weight (around 1500 g in the adult). The liver is divided into four lobules, the right and left lobules are divided by the falciform ligament. This organ is anatomically located to serve its dual role as a metabolic and biochemical transformation factory; it receives blood-containing substances from the portal vein and oxygen-rich blood from the hepatic artery. Then, the liver utilizes the substances from both blood sources to synthesize new chemicals. These are, in turn, returned to the blood stream through the hepatic vein or to bile for excretion by the biliary system (Fig. 1.4).
Figure 1.2 Illustration of the blood and bile vessels of the liver by F. Glisson (1654) [(A) dorsal region, (B) right aspect, (C) ventral region, (D) left aspect, (E) hepatic veins, (H) umbilical vein, (K) duct of Arantius, (G) gall bladder, (I) bile duct, (F) portal vein] (Univ. Library, Freiburg). Reproduced from Kuntz, E., Kuntz, H.D., 2006. History of Hepatology. Hepatology, Principles and Practice. History, Morphology, Biochemistry, Diagnostics, Clinic, Therapy, second ed. Verlag Berlin Heidelberg, Springer, pp. 1–13.
Figure 1.3 Illustration of liver lobules and vessels by F. Kiernan (1833) . (A, B) Interlobular veins, (C) intralobular vein plexus, (D) intralobular branch of the central hepatic vein. Reproduced from Kuntz, E., Kuntz, H.D., 2006. History of Hepatology. Hepatology, Principles and Practice. History, Morphology, Biochemistry, Diagnostics, Clinic, Therapy, second ed. Verlag Berlin Heidelberg, Springer, pp. 1–13.
Bile Ducts
The tubes that carry bile through the liver and gallbladder are known as bile ducts and form a branched structure known as the biliary tree. Bile produced by liver cells drains into microscopic canals known as bile canaliculi (Fig. 1.4). Bile canaliculi join into many bile ducts found throughout the liver to form the larger left and right hepatic ducts, which carry bile from both lobes of the liver. Then, hepatic ducts join to form the common hepatic duct that drains all bile away from the liver. The common hepatic duct finally joins with the cystic duct from the gallbladder to form the common bile duct that carries bile to the duodenum. Most of the bile produced by the liver is pushed back up the cystic duct by peristalsis to arrive in the gallbladder for storage, until it is needed for digestion.
Blood Vessels
Blood traveling to the spleen, stomach, pancreas, gallbladder, and intestines passes through capillaries in these organs and is collected into the hepatic portal vein. Then, the hepatic portal vein delivers this nutrient rich blood to the liver acinus where the contents of the blood are divided up into smaller vessels and processed before being passed on to the rest of the body. Blood leaving the tissues of the liver collects into the hepatic veins that lead to the vena cava and return to the heart. The liver also receives oxygenated blood from the hepatic artery (Fig. 1.4).
Liver Cells
The liver performs a wide variety of functions that are essential for the preservation of homeostasis in the organism. These functions include the synthesis of serum proteins and hormones, the extraction and metabolism of nutrients, xenobiotics and systemic waste products, the metabolism of lipids, bile acids and lipoproteins, the storage and usage of glucose, bile formation, and the neutralization of foreign antigens and microbes from the gut. All these tasks are performed by different types of cells, including: hepatocytes, cholangiocytes, liver sinusoidal endothelial cells (LSECs), Kupffer cells (KCs), natural killer (NK) cells, and hepatic stellate cells (HSC) (Fig. 1.5). The liver parenchyma is perfused by two sources of blood: portal venous blood, which is oxygen poor but rich in hormones, nutrients, and toxins coming from the gut, pancreas, and spleen and oxygenated blood from the hepatic artery (Fig. 1.4). These afferent blood vessels serially branch to form the smallest capillary-size vessels known as the sinusoids. Sinusoids connect with the efferent hepatic veins (central veins) that collect sinusoidal blood carrying metabolized products leading to the hepatic vein. Another network of conduits within the liver consists of the bile ducts that deliver bile to the gall bladder and the intestine, and together with the portal vein and the hepatic artery form the portal triad (Fig. 1.4). The hepatic lobule is the basic architectural unit of the liver, which is formed by hepatocytes, abundant polarized cells, arranged in single-cell thick cords lined by sinusoidal capillaries that extend from the portal triad to the central vein (Treyer and Müsch, 2013). Blood flows from the portal vein and hepatic artery to the centrilobular vein, whereas bile moves in the opposite direction; therefore, important metabolic and secretory functions are unevenly distributed along the porto–central axis in the liver cell plate, a phenomenon named liver zonation (Torre et al., 2010) (Fig. 1.4).
Figure 1.4 (Left) View of the liver showing the portal triad (portal vein, hepatic artery, and the bile duct). (Right) Schematic diagram of the liver lobule and zonated liver functions (metabolic areas); representation of the bile canaliculus and hepatic sinusoid, indicating the different cell types, blood vessels, and bile duct. Arrows indicate the blood flow.
Figure 1.5 Different types of liver cells.
The Hepatocyte and the Regenerative Capacity of the Liver
The metabolic and secretory capacity of the liver is a fundamental characteristic of this organ. The central position of the liver in systemic metabolism involves a prominent exposure to endogenous and exogenous damaging agents, including alcohol, viral infections, and dietary components, which can cause hepatocellular death and constitute the principal causes of liver disease (Blachier et al., 2013). To face these challenges, the liver has evolved an outstanding regenerative capacity mainly based on the proliferation of hepatocytes when a loss in functional parenchyma is detected and most importantly liver function needs to be maintained (Huch and Dollé, 2016; Michalopoulos, 2013).
The hepatic parenchymal cells possess a tremendous proliferative potential but they can lose their phenotype (Michalopoulos, 2013); unfortunately, increasing observations suggest that loss of hepatocellular differentiation and quiescence underlie liver malfunction in chronic liver disease and pave the way for hepatocellular carcinoma development. Therefore, identification of the key molecular factors involved in the preservation of hepatocellular homeostasis and potential strategies to preserve liver identity and functions are necessary to prevent chronic liver disease. Investigations are currently being performed on this subject with promising results (Avila and Moschetta, 2015; Berasain and Avila, 2015, 2016).
Pit Cells Exert Antitumor Functions
Pit cells are hepatic sinusoidal cells defined morphologically as large granular lymphocytes and functionally as liver-associated NK cells. They are situated inside the sinusoidal lumen, adhering to the LSECs and KCs. They contain multivesicular dense granules and rod-cored vesicles. NK cells recognize target cells with their receptors in their surface such as inhibitory and activating receptors. The most important feature of these cells is that they exert antitumor functions by exocytosis of perforin/granzyme-containing granules, induction of death receptor-mediated apoptosis in target cells, and production of several cytokines that increase the activity of other immune cells (Nakatani et al., 2004).
A variety of immunotherapies have been developed against malignant tumors, including biological response modifiers, cytokines, and adoptive transfer of activated dendritic cells and lymphokine-activated killer cells. NK cells act not only in the prevention of metastasis but also in the suppression of tumor initiation in hepatoma cells (Jinushi et al., 2003). Isolation and characterization of large granular lymphocytes from liver (Nakagawa et al., 2001), morphologically identified as Pit cells, should thus give important clues to the therapy of liver cancers and metastasis (Paschos et al., 2014).
LSECs Play a Prominent Role in Homeostasis
The LSECs comprise about 3% of the total liver volume, which makes 20% of the total number of liver cells. LSECs possess fenestrations, with diameters of about approximately 50–150 nm that are grouped together (Svistounov et al., 2012; Wisse, 1972). The sinusoidal endothelium lacks the basement membrane, which additionally constitutes its unique feature (Le Couteur et al., 2002) LSECs fenestrations allow for efficient transfer of lipoproteins, small chylomicron remnants, and other macromolecules between blood and the space of Disse, where they are taken up by hepatocytes (Fraser et al., 1978). LSECs have been shown to represent one of the most actively endocytosing cell types in the body mediating clearance of soluble waste macromolecules and colloid material, including blood-borne adenovirus (Ganesan et al., 2011; Simon-Santamaria et al., 2014). Also, LSECs express various scavenger receptors (SR) on their surface including SR-A (also known as macrophage SR), SR-B (SR-B1 and CD36), and the most important SR-H receptor [stabilin-1/FEEL-1 (fasciclin, EGF-like, laminin-type EGF-like, and link domain-containing scavenger receptor-1) and stabilin-2/FEEL-2 (fasciclin, EGF-like, laminin-type EGF-like, and link domain-containing scavenger receptor-2)/HARE (hyaluronic acid receptor for endocytosis)] (Sørensen et al., 2012). LSECs are professional pinocyting cells, clearing the blood of soluble macromolecules and small particles (<200 nm), whereas macrophages (KC) eliminate larger, insoluble particles by phagocytosis (Seternes et al., 2002). LSECs represent a structurally and functionally unique type of endothelium, which plays a fundamental role in maintaining liver homeostasis. LSEC dysfunction seems to have diagnostic, prognostic, and therapeutic significance in nonalcoholic fatty liver disease (NAFLD) and other liver diseases (Maslak et al., 2015). In addition, because LSECs are the main nitric oxide producing cells in the liver, their role in liver pathology and homeostasis is essential to this organ (Iwakiri and Kim, 2015; Iwakiri, 2015).
KCs Are the First Line of Defense of the Organism
KCs are liver-resident macrophages and represent 80–90% of all tissue macrophages in the body (Gregory and Wing, 2002), which play a crucial role in metabolic and immune functions in the liver (Jager et al., 2016). The origin of KCs in the liver and how these cells are maintained over time are controversial. The traditional view that KCs originate from circulating monocytes that migrate into the liver where they differentiate into tissue macrophages (Diesselhoff-Den Dulk et al., 1979) has indeed been challenged (Gomez Perdiguero et al., 2015; Schulz et al., 2012). It is now recognized that KCs come either from the yolk sac during embryogenesis and self-renew at the adult stage or from local intrahepatic progenitors independently of a contribution from hematopoietic stem cells (Dey et al., 2014; Yona et al., 2013; Zigmond et al., 2014).
The main function of KCs in healthy liver is to phagocytose bacteria, microorganisms, and toxic agents carried by the hepatic circulation and serve as antigen-presenting cells (Baffy, 2009). They are considered as the first line of defense of the organism (Baffy, 2009). KCs can migrate between the vessels (e.g., sinusoids) and the interstitial space (e.g., space of Disse) and mediate cross-talk between resident and recruited cells of the liver. Small KCs are situated in the centrilobular regions, whereas larger KCs are located in the periportal zone where they are directly exposed to incoming molecular signals (Baffy, 2009). Large KCs exhibit higher phagocytosis and lysosomal protease activity compared to the small KCs (Baffy, 2009). KCs are activated and release a variety of inflammatory mediators, including cytokines (e.g., tumor necrosis factor [TNF-α], interleukin [IL]-1β, and IL-6) and chemokines, as well as macrophage inflammatory proteins upon the recognition of a foreign substance (Kolios et al., 2006). These factors regulate the phenotype of KCs as well as that of neighboring cells, such as hepatocytes, HSCs, LSECs, and other immune cells that traffic through the liver (Bilzer et al., 2006). In turn, cytokines and chemokines secreted by KCs contribute to the recruitment of the liver cells, such as neutrophils, NKT cells, lymphocytes, NK cells, and blood monocyte-derived macrophages (Odegaard and Chawla, 2011; Swirski et al., 2007).
HSCs Are the Main Executors in Fibrogenesis
The knowledge of HSCs dates to 1876 when Kupffer identified them utilizing a gold chloride histochemical technic. In 1951, Ito suggested that HSCs and KCs were separate cell populations. When nonactivated, the most characteristic feature of HSCs is that their cytoplasm contains large amounts of retinoids. When the liver is injured, HSCs undergo activation, lose vitamin A storage sources, and express several smooth muscle markers, while the production of extracellular matrix (ECM) ensues, resulting in the fibrogenic process that eventually leads to cirrhosis (Yoneda et al., 2016).
Fibrogenesis is a multicellular response with HSCs constituting the main effectors contributing to approximately 90% of ECM-producing myofibroblasts (Mederacke et al., 2013) regulating many of the crucial cell–cell interactions as well as the recruitment of bone marrow–derived cells, through diverse signaling pathways. During this multicellular wound-healing response, HSCs interact closely with liver-resident cells, such as hepatocytes, KCs, cholangiocytes, LSECs, and infiltrating immune cells (Canbay et al., 2003; Deleve et al., 2008; Ding et al., 2014; Duffield et al., 2005; Pradere et al., 2013; Radaeva et al., 2006; Syal et al., 2012). These dynamic interactions are characteristic for both the development and the regression of liver fibrosis and control the activation status of HSCs and hepatic ECM content.
As the main executors of fibrogenesis, HSCs receive a wide range of signals from injured hepatocytes and the perturbed hepatic microenvironment, most of these mediated by cytokines (Jin et al., 2016; Seki and Schwabe, 2015). HSCs are highly responsive to cytokines and lipopolysaccharide, resulting in the activation of proinflammatory signaling pathways, such as nuclear factor kappa B (NF-κB) and activator protein 1, and further production of chemokines and cytokines (Seki et al., 2007). However, compared to the key role of KCs, HSCs probably make only minor contributions to overall hepatic inflammation in vivo; instead, it is likely that HSCs mainly act as recipients of inflammatory signals, and that inflammatory pathways regulate their activation and ensure the survival of activated HSCs, for example through NF-κB (Hellerbrand et al., 1998). HSCs may also provide specific chemotactic signals that regulate their interaction with inflammatory cell types, both during fibrogenesis (promoting the recruitment of cells that promote HSC activation) and during fibrosis regression by promoting recruitment of cells that degrade ECM and that kill HSCs. Also, HSCs provide a link between gut and liver through their high expression of Toll-like receptors, promoting HSC activation and fibrosis (Seki et al., 2007).
HSCs may be considered as a suitable target for the development of antifibrogenic strategies by disrupting the link between inflammation with the development of liver fibrosis, focusing on the role of inflammatory mediators during fibrogenesis and fibrosis regression (Zhang et al., 2016).
Liver Zonation Allows Functional Plasticity
The liver depicts a uniform anatomical structure composed of the regular arrangement of mainly hexagonal lobules in a honey comb-like pattern. Blood from the portal triad enters the sinusoids, the smallest capillaries of the liver, where the blood drains into the central vein. Fig. 1.4 shows that a gradient in oxygen and nutrients is formed in the sinusoid because blood from the portal triad is rich in these elements, as blood flows to the central vein, nutrients and oxygen are consumed, thus creating three zones (Z). As a consequence, hepatocytes lined up along the porto–central axis (ZI to ZIII) show a remarkable heterogeneity with respect to the biochemical and physiological functions they perform. This dynamic structural and functional heterogeneity, known as metabolic zonation, allows the plethora of functions necessary to maintain metabolic homeostasis of the body (Gebhardt and Matz-Soja, 2014; Lamers et al., 1989).
Regulation of Zonation of the Liver
Morphogens are signaling molecules that play a decisive role in embryogenesis, morphogenesis, and organogenesis (Tabata and Takei, 2004). Several researchers have pointed out that morphogen signaling pathways are involved in regulating metabolism in the liver. Although it is very likely that many morphogens are likewise involved in shaping liver zonation, this chapter will deal only with Wnt/β-catenin, hepatocyte growth factor (HGF), and Hedgehog (Hh) signaling for which most evidence is available.
The important role of Wnt/β-catenin signaling in regulating liver zonation in the liver is now well established and has been extensible reviewed (Cavard et al., 2008; Gebhardt and Hovhannisyan, 2010; Gebhardt et al., 2007; Monga, 2015; Torre et al., 2011). Its activity is highest around the central vein of the liver lobules; thus, it is particularly involved in the regulation of functions of this zone such as drug metabolism, glutamine, bile acid, and heme synthesis (Benhamouche et al., 2006; Burke et al., 2009; Sekine et al., 2006). However, the expression of certain periportal functions (e.g., gluconeogenesis and ureogenesis) is also influenced by the Wnt/β-catenin signaling pathway (Benhamouche et al., 2006). Usually, these portal functions are downregulated, if β-catenin signaling is induced (Torre et al., 2011; Vasilj et al., 2012). Because of the broad influence of the activity of this pathway on liver zonation, it seems appropriate to consider Wnt/β-catenin as a master regulator of zonation.
The role of HGF as a morphogen that is able to induce three-dimensional morphogenesis was identified in 1991 (Montesano et al., 1991). The contribution of HGF to the regulation of zonation was suggested on the basis of cell culture experiments using HGF as an inducer of rat sarcoma (RAS) signaling (Braeuning et al., 2007). Schwarz et al. developed the idea that opposing signaling pathways triggered by Ha-ras- and β-catenin-dependent factors determine zonation of gene expression in liver (Braeuning et al., 2007; Hailfinger et al., 2006). Interactions between RAS signaling and Wnt/β-catenin signaling as well as Hh signaling are of special interest and have been extensively reviewed mainly with respect to proliferation, differentiation, and tumorigenesis (Guardavaccaro and Clevers, 2012; Lauth, 2011; Zeller et al., 2013). It remains to be demonstrated whether they are relevant, at least partially, also for regulating zonation in adult liver especially as these interactions are highly context dependent.
Matz-Soja et al. (2013) have hypothesized that hepatocellular Hh signaling may contribute to liver zonation despite its low activity. In fact, using transgenic mice with conditional deletion of smoothened, they were able to demonstrate that even the very low activity of this pathway has a profound influence on mature liver function, consequently, on the level of insulin-like growth factor I (IGF-I) protein in the serum (Matz-Soja et al., 2014). Moreover, it was shown immunohistochemically that Indian Hh (Ihh) is expressed exclusively in the most distal pericentral area (Matz-Soja et al., 2014). This is in agreement with the known fact that Ihh is a target of Wnt/β-catenin signaling (Reed et al., 2008). The dependence of Ihh production on the activity of β-catenin signaling is further demonstrated by the extension of its pericentral distribution in transgenic mice with enhanced β-catenin signaling. This evidence indicates that expression of Ihh by pericentral hepatocytes is under the control of both Hh and Wnt signaling; however, the specific contribution of Hh signaling to the regulation of zonation remains to be established.
Metabolic Zonal Functions
Not all hepatic processes are strictly zonal. The synthesis of large amounts of serum proteins, such as the transthyretin and transferrin transporters, appears to occur in all hepatocytes. Albumin is also synthesized in all zones, with a higher concentration in the periportal area. Nowadays, the most studied zonated functions are glucose metabolism, ammonia detoxification, and the metabolism of drugs and xenobiotics. Other zonated processes include lipid metabolism (Behari et al., 2014) with lipogenesis occurring perivenously and periportal fatty acid degradation (Schleicher et al., 2015). Synthesis of bile acids derived from cholesterol shows clear perivenular (PV) zonation (Sasamoto et al., 2006); the metabolism of several amino acids (Shiue et al., 2014) such as the catabolism of histidine and serine shows mostly periportal zonation; glutamine synthesis (associated with ammonia detoxification) being found in zone III (Bartl et al., 2015; Qvartskhava et al., 2015). Glucose metabolism provides a historical example of compartmentalized metabolism. Gluconeogenesis is mostly performed in periportal zone (Hijmans et al., 2014), whereas glycolysis is mainly PV (Dasgupta et al., 2014). However, the concentration gradients of these enzymes differ depending on nutritional status, suggesting that nutrients and hormones play a role in the zonation of these components of glucose metabolism. One of the major roles of the liver is the removal of harmful ammonia arriving from the intestine via the portal vein. In mammals, three enzymes (or enzyme systems) are involved in this process: glutaminase, glutamine synthetase, and the urea cycle enzymes, represented by carbamoyl phosphate synthetase. The distribution of these enzymes for optimal ammonia detoxification was determined by numerical optimization; this in silico approach predicted that the enzymes have to be zonated to achieve maximal removal of toxic ammonia and minimal changes in glutamine concentration. It was found that glutamine synthetase is active only within a narrow pericentral zone, whereas glutaminase and carbamoyl phosphate synthetase are located in the periportal zone in a nonhomogeneous distribution (Bartl et al., 2015). Metabolism of drugs and xenobiotics also displays well-defined
You've reached the end of this preview. Sign up to read more!
Page 1 of 1