The cholangiopathies: disorders of biliary epithelia

The intrahepatic bile ducts comprise a complex 3-dimensional network of conduits within the liver lined by specialized epithelial cells called cholangiocytes. A majorfunction of cholangiocytes is bile formation (Figure 1). Hepatocytes, the other epithelial cell type of the liver, produce primary or hepatic bile, which percolates through the intrahepatic bile ducts; during this journey, bile is modified by cholangiocytes via a series of secretory and absorptive processes that provide additional bile water (cholangiocytes secrete _40% of daily bile production in humans) and alkalinity (Figure 2).1,2 To perform this task, biliary epithelia express an array of “flux molecules” (i.e., proteins involved in transport, such as channels, exchangers, transporters) on their plasma membranes (see Strazzabosco et al.3–5 for reviews on structure, topography, and function of cholangiocyte flux molecules). Cholangiocytes also proliferate in response to endogenous or exogenous signals/stimuli and actively participate in inflammatory and reparative processes within the liver. Furthermore, cholangiocytes interact with the immune system and microorganisms and are involved in drug metabolism (Figure 1). To accomplish these multifaceted functions, cholangiocytes display morphologic and functional heterogeneity along the biliary tree. As shown on Figure 2, cholangiocytes lining large bile ducts (300–800 _m) participate in hormone-regulated bile secretion, whereas cholangiocytes lining small bile ducts (15–300 _m) possess proliferative capabilities and display considerable plasticity, being able to assume a “reactive phenotype” in disease conditions (see Marzioni et al.6 and Kanno et al.7 for recent reviews on cholangiocytes heterogeneity). Cholangiocytes represent the primary cell target of a diverse group of genetic and acquired biliary disorders, which we have called collectively “cholangiopathies” (Table 1). Many of the cholangiopathies are, at their early stages, site restricted along the biliary tree. For instance, primary biliary cirrhosis (PBC), drug-induced cholangiopathies, and graft vs. host disease (GVHD) involving the liver affect primarily the small bile ducts. In contrast, primary sclerosing cholangitis (PSC) and cholangiocarcinoma mainly involve the large intra- and extrahepatic bile ducts. Thus, recognition of cholangiocyte heterogeneity along the biliary tree is necessary to understand better the cholangiopathies and, potentially, to devise novel, effective therapies.6,7 Because of their morbidity, mortality, need for liver transplantation, and overall cost to society, cholangiopathies are now recognized as an important group of liver diseases. Most cholangiopathies display a progressive course leading to cirrhosis and liver failure. To date, the cause of most cholangiopathies remains obscure. In this review, we summarize possible pathogenetic mechanisms involved in the cholangiopathies.