Table Of ContentMEDICAL
INTELLIGENCE
UNIT
The Pathophysiology
of Biliary Epithelia
Gianfranco Alpini, Ph.D.
Depanment of Internal Medicine and Medical Physiology
Texas A&M University System Health Sciences Center College of Medicine
and Central Texas Veterans Health Care System
Scott & White Hospital
Temple, Texas, U.S.A
Domenico Alvaro, M.D.
Depanment of Clinical Medicine
Division of Gastroenterology
University of Rome "La Sapienza"
Rome, Italy
Marco Marzioni, M.D.
Department of Gastroenterology
Universita Politecnica delle Marche School of Medicine
Ancona, Italy
Lesage:
Gene M.D.
Depanment of Internal Medicine
Division of Gastroenterology, Hepatology and Nutrition
University of Texas Houston Medical School
Houston, Texas, U.S.A
Nicholas La.Russo, M.D.
Depanment of Internal Medicine
Division of Gastroenterology and Hepatology
Center for Basic Research in Digestive Diseases
Mayo Medical School, Clinic and Foundation
Rochester, Minnesota, U.S.A
Boca Raton London New York
CRC Press is an imprint of the
Taylor & Francis Group, an informa business
THE
PATHOPHYSIOWGY OF BIIJARY EPITHEllA
Medical Intelligence Unit
First published 2004 by Landes Bioscience and Eurekah
Published 2019 by CRC Press
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ISBN 13: 978-1-58706-171-4 (hbk)
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Library of Congress Cataloging-in-Publication Data
The pathophysiology ofbiliary epithelia / [edited by] Gianfranco Alpini ... [et al.].
p.;cm.
Includes bibliographical references and index.
ISBN 1-58706-171-6
1. Biliary tract--Pathophysiology. 2. Epithelial cells. I. Alpini, Gian&anco.
[DNLM: 1. Biliary Tract--ultrastructure. 2. Biliary Tract Diseases--physiopathology. 3. Epithelial
Cells--physiology. 4. Llver--ultrastructure. 5. Liver Diseases--physiopathology. 6. Signal Transduc-
tion-physiology. WI 700 P2978 2004]
RC849.P36 2004
616.3'607--dc22
2003027905
^ = ^ = CONTENTS
Preface xix
1. Normal and Abnormal Development of the Biliary Tree 1
James M. Crawford
Anatomy 1
The Hepatic Primordium 3
The Intrahepatic Biliary Tree 4
Three-Dimensional Architecture of the Intrahepatic Biliary Tree 8
Bile Ductules and the Canals of Hering 10
Peribiliary Glands 12
Abnormal Development of the Biliary Tree 13
2. Human Liver Stem Cells: Recent Developments 28
AlastairJ. Strain
Liver Regeneration 28
Hematopoietic-Derived Stem Cells 30
In Vitro Studies 33
Factors Which Control Stem Cell Differentiation 36
3. Vascularization of the Intrahepatic Biliary Tree and Its Role
in the Regulation of Cholangiocyte Growth 41
Eugenio Gáudio, Paolo Onori, Antonio Franchitto, Roberta Sferra,
Antonella Vetuschi, Sergio Morini, Gianfranco Alpini
and Domenico Alvaro
Background and Experimental Approach 41
Rearrangement of PBP during Cholangiocyte Proliferation 42
Role of VEGF in the Regulation of Vascular Proliferation
during Cholangiocyte Growth 45
4. Ultra-Structural Analysis of the Intrahepatic Bile Duct System 51
Luca Marucci, Anne Marie Jezequel and Antonio Benedetti
Ultrastructure of Bile Ducts 51
5. Three-Dimensional Reconstruction of the Rat Intrahepatic
Biliary Tree: Physiological Implications 60
Tatyana V. Masyuk, Anatoliy I. Masyuk Erik L. Ritman
y
and Nicholas F. LaRusso
Micro-CT 61
Quantitative Assessment of the Intrahepatic Biliary Tree 61
Segment-by-Segment Analysis of the Reconstructed Biliary Tree 61
Number and Length of the Bile Duct Interbranch Segments 61
Diameter of Bile Duct Segment 62
Biliary Tree Volume 63
Heterogeneity of Bile Flow along the Biliary Tree Axis 64
Type of Anatomic Remodeling 65
Origin and Fate of the Newly Formed Bile Ducts 66
Inducers of Cholangiocyte Proliferation 67
6. Cholangiocyte Ion Channels: Targets for Drug Development 72
/. Gregory Fitz
Mechanisms of Ion Transport—Properties of Ion Channels 72
Cellular Strategies for Secretion—Transepithelial CI" Transport 75
Cyclic AMP-Independent Regulation of Secretion 76
Regulation of the Number and Types of Ion Channels
in the Plasma Membrane 78
7. Effects of Cytokines and Nitric Oxide on Bicarbonate
Secretion by Cholangiocytes 81
Carlo Spirlï, Lajos Okolicsanyi and Mario Strazzabosco
Inflammatory Cytokines and Cholangiocyte Secretory Function 82
Nitric Oxide and Cholangiocyte Secretory Function 84
8. Hormonal Regulation of Cholangiocyte Secretion 89
Alessandro Gigliozzi, Flavia Fraioli and James L. Boyer
Secretin 90
Acetylcholine 91
Vasoactive Intestinal Peptide (VIP) 92
Bombesin 92
Somatostatin 92
Gastrin and Insulin 93
Estrogens 93
Corticosteroids 94
9. Purinergic Regulation of Bile Ductular Secretion 96
Jonathan A. Dranoff
Introduction to P2 Receptors and Purinergic Signaling 96
P2Y Receptor Actions in Epithelia 97
Identification of P2Y Receptors in Isolated Cell Models
of Biliary Epithelia 98
Use of Polarized Cholangiocyte Cell Models to Study
Nucleotide-Mediated Signaling in Biliary Epithelia 99
Use of in Vitro Tissue Culture Models to Study
Nucleotide-Mediated Signaling in Biliary Epithelia 99
Potential Roles of Nucleotide Release to Mediate Paracrine
Signaling between Hepatocytes and Biliary Epithelia 100
10. Calcium Signaling in Cholangiocytes 105
Erick Hernandez and Michael H. Nathanson
Molecular Basis for Calcium Signaling in Bile Duct Cells 105
Calcium Signaling Patterns in Cholangiocytes 107
Ca2+Agonists in Bile Duct Cells 108
Effects of Ca2+ on Cholangiocyte Secretion 109
11. Bile Acid Interactions with Cholangiocytes 112
Gianfranco Alpini, Shannon Gloser, Heather Francis, Marco Marzioni,
Julie Venter, JoLynne Phinizy and Gene LeSage
Overview 112
Cholangiocyte Bile Acid Uptake 114
Intracellular Bile Acid Movement in Cholangiocytes 114
Bile Acid Efflux in Cholangiocytes 114
Cholehepatic Shunting of Bile Acids 115
Overview of the Regulation of ASBT Expression
in Cholangiocytes 116
Bile Acid Signaling in Cholangiocytes 119
Bile Acid Synthesis and Conjugation in Cholangiocytes 122
Gallbladder Epithelial Cells 122
Bile Acid Effects on Cholangiocyte Function or Dysfunction
in Humans 122
12. Aquaporin-Mediated Water Transport in Intrahepatic
Bile Duct Epithelial Cells 127
Anatoliy I. Masyuk and Nicholas F. LaRusso
Molecular Biology of Mammalian AQPs 127
AQPs in Cholangiocytes 130
13. ABC Transporters, Organic Solute Carriers and Drug
Metabolising Enzymes in Bile Duct Epithelial Cells 136
Peter L.M. Jansen
Transporters in Hepatocytes 137
Transporters and Drug Metabolizing Enzymes in Cholangiocytes 140
Cholehepatic Shunt 143
Gallstones 143
14. Regulation of Secretion in Human Gallbladder Epithelial Cells 149
Nicolas Chignard, Laura Fouassier, Annick Paul and Chantai Housset
Regulation of Mucin Secretion in the Gallbladder 150
Regulation of Fluid and Ion Transport in the Gallbladder 151
Bile Salt Transport and Regulating Functions
in the Gallbladder Epithelium 155
15. Ductal Bicarbonate Secretion in Human Cholestatic
Liver Diseases 159
Juan F. Medina and Jesus Prieto
Biliary Transport of HC0 '/H+ 159
3
Altered Biliary Transport of HC0 " / H+ in Primary
3
Biliary Cirrhosis 160
In Vivo Imaging of Ductal Bicarbonate Secretion in Health
and Disease 162
16. Participation of Cytokines and Growth Factors
in Biliary Epithelial Proliferation and Mito-Inhibition
during Ductular Reactions 167
Anthony J. Demetris, J. G. Lunz III, Vladimir Subbotin, Tong Wu,
Isao Nozaki, Sarah Contrucci andXia Yin
Conceptual Approach to Hepatic Responses to Injury 167
Ductular Reactions 168
Factors That Stimulate Biliary Epithelial Cell Proliferation
in Vitro and Correlation with Ductular Reactions in Vivo 168
The Effect of Growth Factors on BEC Growth 171
Mito-Inhibitors and Cell Cycle Regulation 180
Gene Transfer in Vivo 182
17. Estrogen Regulation of Cholangiocyte Proliferation 192
Domenico Alvaro, Gianfranco Alpini, Paolo Onori, Antonio Franchitto,
Maria Grazia Mancino, Shannon Glaser, Veronica Drudi-Metalli,
Alessandro Gigliozzi, Adolfo Franco Attili and Eugenio Gáudio
Estrogens Modulate Cholangiocyte Proliferation:
Experimental Evidences 193
Role of Endogenous Estrogens in the Modulation
of Cholangiocyte Proliferation 194
Intracellular Signaling Pathways Activated by Estrogens
in Cholangiocytes 195
18. Nerve Regulation of Cholangiocyte Functions 199
Barbara Bárbaro, Shannon Glaser, Heather Francis, Silvia Taffetani,
Marco Marzioni, Gene LeSage and Gianfranco Alpini
Anatomical and Morphological Features of the Biliary Epithelium .... 199
Experimental in Vivo and in Vitro Models for Studying the Role
of Nerves in the Regulation of Cholangiocyte Functions 199
Brief Overview of Cholangiocyte Functions 200
Innervation of the Liver 200
Cholinergic Regulation of Cholangiocyte Functions 201
Adrenergic and Dopaminergic Regulation of Cholangiocyte
Functions 202
19. Cholestasis and Fibrogenesis 210
Massimo Pinzani
Liver Fibrosis: Definition and General Mechanisms 210
Cholestasis and Fibrogenesis: A Common Association 212
Cholangiopathies As Chronic Fibrogenic Disorders 212
Liver Fibrosis Associated with Bile Duct Damage/Ductopenia:
Primary Biliary Cirrhosis As a Paradigm of Inflammatory
Cholangiopathy 214
Liver Fibrosis Associated with Bile Duct Proliferation 214
20. Apoptosis of Biliary Epithelial Cells 219
Natalie J. Tõrõk and Gregory J. Gores
Molecular Regulation of Apoptosis in the Bile Duct
Epithelial Cells 221
Regulators of Apoptosis in the Biliary Epithelium 222
Dysregulation of Apoptosis in Biliary Carcinogenesis 223
21. Cytokine Regulation of Cholangiocyte Growth 227
Yoko Yamagiwa and Tushar Patel
Cytokines and Biliary Epithelia 227
Cytokine Mediated Growth Regulation in Pathophysiological
Processes 229
Biliary Tract Inflammation 229
Cytokine Regulation of Biliary Epithelial Proliferation 230
22. Fas-Mediated Cholangiopathy in a Murine Model
of Grafi-versus-Host Disease 235
Yoshiyuki Ueno
Fas Receptor Is Expressed by Cholangiocyte in Situ and in Vitro 236
Alloreactive Lymphocytes Are Cytotoxic to Cultured
Cholangiocytes 238
23. Functional Heterogeneity of the Intrahepatic Biliary Epithelium 245
Shannon S. Gloser, Heather Francis, Marco Marzioni,
Silvia Taffetani, Jo Lynne Phinizy, Gene LeSage
and Gianfranco Alpini
Overview of Biliary Anatomy and Morphology 245
Cholangiocyte Functions 246
In Vivo and in Vitro Experimental Models 247
Functional Heterogeneity Found in Other Epithelia 247
Heterogeneity of Cholangiocytes 247
Proliferative Heterogeneity and Apoptotic Susceptibility
of Small and Large Cholangiocytes in Response
to Injury and Toxins 251
24. In Vitro Systems for the Study of the Intrahepatic
Biliary Epithelium 255
Ruthjoplin, Shahnaz Gill, Sarah Ward and Stivelia Kachilele
Source of Intrahepatic Biliary Epithelial Cells for in Vitro Studies 255
Maintenance of Intrahepatic Biliary Epithelial Cells in Vitro 257
Other Potential Models for Culture of Intrahepatic Biliary
Epithelial Cells 263
25. Mouse Knockout Models of Biliary Epithelial Cell Formation
and Disease 268
Lopa Mishra
Smads Soxl7 Foxa Proteins 269
Hex Proxl Cell-Cell Interactions and ECM Remodeling 272
Hepatic Growth Signals from the Cardiac Mesoderm 272
FGF Bmp Signaling and Hepatic Induction 272
ELF Smad Signaling in Liver and Biliary Tree Development 272
Smad2/3 Hlx HGF c-Met and TGF-beta 273
Apoptosis Necrosis and Generation of Tissue Architecture 273
Coordination with Vascular Development 274
Division of Hepatocyte and Biliary Lineages 274
Extrahepatic Bile Ducts and the Gall Bladder Formation 274
Fetal Liver Cell Lines to Study the Hepatic-Biliary Split 274
Hepatocyte Differentiation after Hematopoiesis 274
HNF4 Control of Hepatocyte Differentiation 275
Genetic Defects in Hepatobiliary Transport 275
Alagille Syndrome and Jagged 1 275
ATP8B1 ABCB11 ABCB4 Deficiency 275
26. Drug-Induced Vanishing Bile Duct Syndromes 279
Tania A. Roskams and ValeerJ. Desmet
Drug-Induced Vanishing Bile Duct Syndrome 280
Histopathologic^ Features 282
Toxin-Induced Bile Duct Injury 285
Iatrogenic Sclerosing Cholangitis 285
27. Biliary Atresia 289
David H. Perlmutter
History 289
Embryology/Morphogenesis 290
Clinical Manifestations 291
Natural History 293
Diagnosis 293
Treatment 295
Pathogenesis 299
28. Primary Biliary Cirrhosis Bench to Bedside 311
Shinji Shimoda, Akiyoshi Nishio, Hiromi Ishibashi
andM. Eric Gershwin
Clinical Features 311
Natural History 313
Pathology 314
Autoantibodies 316
Antigens in Biliary Epithelium 318
Genetics 318
T Cell Response in PBC 319
Etiology 321
29. Immunopathogenesis of Vanishing Bile Duct Syndromes 330
John M. Vierling Marius Braun and Hairnet Wang
Biliary Anatomy 331
Immune Responses 331
Immunobiology of Biliary Epithelial Cells: Implications
for Autoimmunity and Alloimmunity 335
Non-Suppurative Destructive Cholangitis 336
Immunopathogenesis of Non-Suppurative Destructive
Cholangitis 337
Alloimmune Mechanisms 341
Immunopathogenesis of Non-Suppurative Destructive
Cholangitis 344
Fibrous Obliterative Cholangitis 345
30. Cryptosporidium and Bile Duct Injury 357
Xian-Ming Chen and Nicholas F. LaRusso
Biology of Cryptosporidium and Epidemiology
of Human Infection 357
Etiology of AIDS-Cholangiopathy 358
Immune Response to Cryptosporidiosis 360
Clinical Features 361
Pathophysiology of Cryptosporidiosis and AIDS-Cholangiopathy 363
Diagnosis 364
Treatment 365
31. Liver Disease in Cystic Fibrosis 368
Carla Colombo, Pier Maria Battezzati, Clara Fredella
and Andrea Crosignani
Clinical Picture of Liver Disease in CF 370
Pathogenesis of Liver Disease in CF 370
Prevalence, Risk Factors and Natural History of Liver
Disease in CF 373
Other Hepatobiliary Manifestations of CF 375
Diagnosis and Clinical Follow Up 376
Management of Patients with Liver Disease 377
32. Medical Treatment of Vanishing Bile Duct Syndrome in Adults 382
C Squarcia Giussani, Andrea Crosignani and Mauro Podda
Treatment of Symptoms of Long-Standing Cholestasis 383
Treatment of Complications of Long-Standing Cholestasis 386
Treatment of the Underlying Liver Disease 389
33. Ursodeoxycholic Acid Treatment of Vanishing
Bile Duct Syndromes 404
Christian Rust and Ulrich Beuers
Mechanisms of Action of UDCA 405
Role of UDCA in Vanishing Bile Duct Syndromes 409
