The Pathophysiology of Biliary Epithelia

Gianfranco Alpini

• Publisher: CRC Press
• Year: 2020
• eBook ISBN: 9781000724660
• Topic: Medicine
• Subtopic: Dentistry

This book is a comprehensive review of the biliary epithelia pathophysiology. Biliary epithelial cells (also referred to as cholangiocytes) line the intra- and extrahepatic bile ducts. Cholangiocytes have immerged in the last several years as one of the more important epithelial cells in the gastrointestinal system due to their large contribution to bile formation and tendency to be involved in human diseases.

The book's 35 chapters represent a nearly complete review of the function and disease of bile ducts. The gestational development of bile ducts is shown to be a complex interaction between hepatocyte and biliary precursors. The structure of bile ducts can be defined by ultrastructural studies and by 3D reconstruction studies which show that the bile duct system resembles a tree. The array of membrane transporters and channels involved in ductal absorption and secretion of water and electrolytes is reviewed. Like other gastrointestinal epithelial cells, the physiologic responses of cholangiocytes are regulated by hormones, nerve input, cytokines, factors in bile and intracellular signals (e.g., cyclic AMP and intracellular calcium). The potential role of the cholangiocyte in production of collagen in cholestatic liver disease is discussed. A number of important models used in the study of cholangiocyte physiology and reactions to injury are reviewed. Finally the relationships between the cholangiocyte responses and human liver diseases are discussed.

While many basic scientists and hepatologists who devote their careers to the study of the liver will find this book useful, the intended audience of this book is the more heterogeneous group of individuals who study clinical and/ or basic science digestive physiology and due to their interest in epithelial function will find the cutting edge information in this book both enlightening and useful to their progression of their work.

CHAPTER 1

Normal and Abnormal Development of the Biliary Tree

James M. Crawford

Introduction

The liver primordium buds off the ventral aspect of the embryonic foregut very early during development of the abdominal organs, at about 18 days of gestation. By week 16, the architectural organization of the hepatic parenchyma and vasculature is well-established, and the extrahepatic biliary tree is substantively formed. However, development of the intrahepatic biliary tree continues throughout gestation and after birth, owing in part to the massive growth of the liver that occurs throughout gestation and into the first years of childhood. The extrahepatic biliary tree forms directly from the embryonic bud of tissue off the foregut. The intrahepatic biliary tree forms out of the interplay between the early hepatic endodermal cells, the hepatoblasts, and the mesenchyme of the primitive liver. The anatomical sequence giving rise to the biliary tree will be discussed in this chapter, drawing especially on a recent review on this same topic.¹ Liver microarchitecture overall will not be discussed. Literature on this latter topic spans two centuries dating back to Kiernan in 1833,² and excellent reviews of liver development and microarchitecture are given by Roskams et al³ and Ekataksin et al,⁴ respectively.

Anatomy

It is worth considering first the anatomy of the mature biliary tree. The extrahepatic biliary tract consists of the common bile duct, cystic duct and gallbladder, and the common hepatic duct. Approximately 60% to 70% of the time, the common hepatic duct bifurcates into the right and left hepatic ducts before entering the liver.⁵ The predominant anatomic variation is absence of the right hepatic duct. Instead, posterior and anterior branches of bile ducts supplying the right portion of the liver arise from a hilar confluence with the left hepatic bile duct. This occurs in the form of a three-way branch point with the left hepatic bile duct, or variations of two-way confluences of the anterior or posterior branches with the left hepatic duct.⁵ Finally, while the common hepatic duct and its branches lie ventral to the portal vein system, the right posterior bile duct may wrap in an inferior/ventral or a superior/dorsal fashion around the right portal vein. This last variation must be kept in mind when performing surgery in the region of the liver hilum, so as to avoid transecting the portal vasculature.

The large intrahepatic bile ducts are defined as follows:⁶ right and left hepatic ducts (with origin just outside the liver corpus); segmental ducts (the first major branches of each hepatic duct: left medial and lateral, right anterior and posterior); and area ducts (the first major branches of each segmental duct: superior and inferior). The segmental bile ducts of the caudate lobe of the liver drain directly into the right or left hepatic duct or their major branches.⁷ These large ducts – right and left hepatic, segmental, and area – are grossly visible and are characterized by association with intrahepatic mucin-secreting peribiliary glands.⁶ Smaller biliary branches within the liver arise from nondichotomous branching, in that radial trees of bile ducts do not divide symmetrically.^8,9 As a result, there are considerable variations in the branching of the biliary tree within the liver as well as at its hilum.⁶

Table 1. Glossary of recommended terms*

		Generation
Major bile ducts	Grossly visible branches of the biliary system (common hepatic; right/left hepatic; segmental; area)	0–3
Conducting bile ducts	Ramify through liver, supply terminal bile ducts	3-~17
Terminal bile ducts	Smallest branches of portal tract-based biliary system	≥~17
Bile ductule Canal of Hering	Tubular channel linking terminal bile duct to canal of Hering A biliary channel lined partially by biliary epithelium (cholangiocytes) and partially by hepatocytes: -situated at the peripheral rim of portal tracts or -penetrating the parenchyma in the periportal region
NOTE: “conducting” bile duct = “septal” bile duct = “sublobular” bile duct “terminal” bile duct = “interlobular” bile duct “Generation” refers to branch number. * From reference 1.

The finer branches of the biliary system are identifiable by microscopy only, and are not associated with peribiliary glands. By convention, conducting bile ducts are all branches down to the last bifurcation of the biliary system. The most terminal branches are commonly called interlobular bile ducts, based on the concept that it is these branches which supply the lobules of the liver. Saxena et al¹⁰ recommended calling these smallest branches terminal bile ducts, in part to recognize the fact that the microarchitectural units of the hepatic parenchyma go by many names other than “lobule”, and to refocus the terminology on the architecture of the biliary tree rather than on the hepatic parenchyma. However, within the lexicon of histopathology, ‘interlobular’ remains the term in common usage.

Bile ductules are those channels branching off the terminal bile ducts that collect bile directly from the hepatocellular parenchyma via the canals of Hering. To the best of current knowledge,¹⁰ these structures are a single unit that drains bile from within the parenchyma to the biliary tree, and so for this chapter will be referred to as bile ductule:canal of Hering units. They will be discussed in a separate section below. The recommended terminology for the biliary tree is given in (Table 1).

The relationship between bile ductule: canal of Hering units and the liver parenchyma raises the issue of the microarchitectural organization of the liver, which is not the subject of this chapter. The 170-year old debate over the microarchitectural subdivision of the liver is reviewed by Ekataksin et al⁴ and many other authors. However, it is useful to consider how many terminal bile ducts and bile ductule:canal of Hering units are needed to supply the liver parenchyma. First, based on microanatomic study it appears that one terminal bile duct is to be expected for every 2 to 3 mm³ of the liver.¹¹ In an exhaustive analysis of the intrahepatic biliary tree of a single adult liver filled in a retrograde fashion by contrast medium, Ludwig et al¹² demonstrated 10 orders of branching of the intrahepatic biliary tree in the adult human, 3 of which are external to the hepatic corpus and 7 of which are intrahepatic. Post-mortem cholangiograms in children have shown as many as 17 branch points in evaluable biliary “rays”.¹¹ However, most identifiable ducts do not exhibit 16 to 17 branch points, but instead exhibit a gaussian distribution of branches with a mode of 10. This matches the 10 orders of branching enumerated by Ludwig.¹² However, Ludwig also alludes to smaller biliary radicles extending beyond the 10^th order of branching. The fact that both Ludwig¹² and Landing and Wells inconsistently observe biliary branches beyond the 10^th order may be due to the technical challenge of retrograde filling of the biliary tree—it is a dead-end compartment.

Table 2. Development of the human intrahepatic biliary tree*

18 day embryo:	liver bud arises as thickened endodermal epithelium from foregut
22 day embryo:	hepatic diverticulum protrudes into mesenchyme of septum transversum
23 day embryo:	endodermal “cords” of hepatoblasts invade mesenchyme
23-24 days:	hepatoblasts express a-fetoprotein, albumin
3-8 weeks:	hepatoblasts express CK4, CK18, CK19, CK14; hepatic duct becomes patent
8-12 weeks:	"ductal plate” develops, from hilum outwards (centrifug...

Table of contents

• Cover
• Title Page
• Copyright Page
• Table of Contents
• Editors
• Contributors
• Preface
• 1. Normal and Abnormal Development of the Biliary Tree
• 2. Human Liver Stem Cells: Recent Developments
• 3. Vascularization of the Intrahepatic Biliary Tree and Its Role in the Regulation of Cholangiocyte Growth
• 4. Ultra-Structural Analysis of the Intrahepatic Bile Duct System
• 5. Three-Dimensional Reconstruction of the Rat Intrahepatic Biliary Tree: Physiological Implications
• 6. Cholangiocyte Ion Channels: Targets for Drug Development
• 7. Effects of Cytokines and Nitric Oxide on Bicarbonate Secretion by Cholangiocytes
• 8. Hormonal Regulation of Cholangiocyte Secretion
• 9. Purinergic Regulation of Bile Ductular Secretion
• 10. Calcium Signaling in Cholangiocytes
• 11. Bile Acid Interactions with Cholangiocytes
• 12. Aquaporin-Mediated Water Transport in Intrahepatic Bile Duct Epithelial Cells
• 13. ABC Transporters, Organic Solute Carriers and Drug Metabolising Enzymes in Bile Duct Epithelial Cells
• 14. Regulation of Secretion in Human Gallbladder Epithelial Cells
• 15. Ductal Bicarbonate Secretion in Human Cholestatic Liver Diseases
• 16. Participation of Cytokines and Growth Factors in Biliary Epithelial Proliferation and Mito-Inhibition during Ductular Reactions
• 17. Estrogen Regulation of Cholangiocyte Proliferation
• 18. Nerve Regulation of Cholangiocyte Functions
• 19. Cholestasis and Fibrogenesis
• 20. Apoptosis of Biliary Epithelial Cells
• 21. Cytokine Regulation of Cholangiocyte Growth
• 22. Fas-Mediated Cholangiopathy in a Murine Model of Graft-versus-Host Disease
• 23. Functional Heterogeneity of the Intrahepatic Biliary Epithelium
• 24. In Vitro Systems for the Study of the Intrahepatic Biliary Epithelium
• 25. Mouse Knockout Models of Biliary Epithelial Cell Formation and Disease
• 26. Drug-Induced Vanishing Bile Duct Syndromes
• 27. Biliary Atresia
• 28. Primary Biliary Cirrhosis Bench to Bedside
• 29. Immunopathogenesis of Vanishing Bile Duct Syndromes
• 30. Cryptosporidium and Bile Duct Injury
• 31. Liver Disease in Cystic Fibrosis
• 32. Medical Treatment of Vanishing Bile Duct Syndrome in Adults
• 33. Ursodeoxycholic Acid Treatment of Vanishing Bile Duct Syndromes
• 34. Liver Transplantation for Adult Vanishing Bile Duct Syndromes
• 35. Pathology of the Intrahepatic Biliary Tree after Liver Transplantation
• Index