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Review
. 2015 Jun;90(6):791-800.
doi: 10.1016/j.mayocp.2015.03.017. Epub 2015 May 6.

The Cholangiopathies

Affiliations
Review

The Cholangiopathies

Konstantinos N Lazaridis et al. Mayo Clin Proc. 2015 Jun.

Abstract

Cholangiocytes (ie, the epithelial cells that line the bile ducts) are an important subset of liver cells. They are actively involved in the modification of bile volume and composition, are activated by interactions with endogenous and exogenous stimuli (eg, microorganisms, drugs), and participate in liver injury and repair. The term cholangiopathies refers to a category of chronic liver diseases that share a central target: the cholangiocyte. The cholangiopathies account for substantial morbidity and mortality given their progressive nature, the challenges associated with clinical management, and the lack of effective medical therapies. Thus, cholangiopathies usually result in end-stage liver disease requiring liver transplant to extend survival. Approximately 16% of all liver transplants performed in the United States between 1988 and 2014 were for cholangiopathies. For all these reasons, cholangiopathies are an economic burden on patients, their families, and society. This review offers a concise summary of the biology of cholangiocytes and describes a conceptual framework for development of the cholangiopathies. We also present the recent progress made in understanding the pathogenesis of and how this knowledge has influenced therapies for the 6 common cholangiopathies-primary biliary cirrhosis, primary sclerosing cholangitis, cystic fibrosis involving the liver, biliary atresia, polycystic liver disease, and cholangiocarcinoma-because the latest scientific progress in the field concerns these conditions. We performed a search of the literature in PubMed for published papers using the following terms: cholangiocytes, biliary epithelia, cholestasis, cholangiopathy, and biliary disease. Studies had to be published in the past 5 years (from June 1, 2009, through May 31, 2014), and non-English studies were excluded.

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Figures

FIGURE 1
FIGURE 1
Cholangiocytes serve several functions in health and disease with the contribution of several important molecules. For example, bile formation is achieved with the participation of transmembrane molecules expressed on cholangiocytes like channels (ie, water channels [aquaporins]), transporters (ie, SGLT1: Na+-glucose transporter), and exchangers (ie, SLC4A2: Cl/HCO3 exchanger). Dysfunction of these molecules could lead to cholestasis. Moreover, cholangiocytes interact with resident and nonresident cells of the bile ducts via inflammatory and fibrotic mediators, such as tumor necrosis factor α and interleukin-6, which in disease states results in biliary inflammation and fibrosis. Finally, cholangiocytes contribute to cell-cycle phenomena that are key to maintaining tissue homeostasis in the bile ducts. These functions are achieved through modulators of apoptosis (ie, AkT1: protein kinase B α) senescence (ie, N-RAS transforming protein), and proliferation (ie, platelet-derived growth factor), whereas their malfunction leads to ductopenia, dysplasia, and malignant transformation of the bile ducts.
FIGURE 2
FIGURE 2
The putative initial insult to cholangiocytes may be an interaction with an endogenous or exogenous substance, a microorganism, or an unidentified environmental exposure. The initial host response is the development of a reactive cholangiocyte phenotype and a bile duct proinflammatory microenvironment. The balance of the host response to this insult, likely dependent on genetic susceptibility, epigenetics, posttranscriptional regulation, or other yet unknown mechanisms, may result in repair/resolution of the cholangiocyte injury or in perpetuation of the initial inflammatory response, leading to chronic inflammation of the bile ducts and ultimately to cholestasis, bile duct proliferation, ductopenia, fibrosis, and potential malignant transformation of cholangiocytes.

References

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    1. Lazaridis KN, Strazzabosco M, Larusso NF. The cholangiopathies: disorders of biliary epithelia. Gastroenterology. 2004;127(5):1565–1577. - PubMed
    1. Bogert PT, LaRusso NF. Cholangiocyte biology. Curr Opin Gastroenterol. 2007;23(3):299–305. - PubMed

MeSH terms