The Cholangiopathies

doi:10.1016/j.mayocp.2015.03.017

Mayo Clinic Proceedings

Volume 90, Issue 6, June 2015, Pages 791-800

https://doi.org/10.1016/j.mayocp.2015.03.017 Get rights and content

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.

Section snippets

Cholangiocytes and the Cholangiopathies

Cholangiocytes line the biliary tree, a complex 3-dimensional network of conduits inside and outside the liver,⁴ and participate in the formation of bile via an array of transmembrane channels, transporters, and exchangers (Figure 1).⁵ These molecules are expressed on the apical or basolateral domain of cholangiocytes and facilitate movement of water, electrolytes and solutes, modifying bile volume and composition.4, 5 Cholangiocytes are also activated by interactions with endogenous and

Primary Biliary Cirrhosis

Primary biliary cirrhosis is characterized by nonsuppurative inflammation and destruction of the interlobular bile ducts; this condition progresses variably to biliary cirrhosis. The prevalence of primary biliary cirrhosis ranges broadly up to approximately 40 per 100,000 people.¹⁴ Reported prevalence rates have increased over time; however, whether this increase reflects heightened awareness or new environmental exposures is unclear.¹⁴ Established environmental triggers include smoking,

Primary Sclerosing Cholangitis

Primary sclerosing cholangitis is characterized by chronic inflammation of the intrahepatic and extrahepatic bile ducts, with resultant strictures (obliterative cholangitis) that ultimately progress to cirrhosis and end-stage liver disease.⁴² The prevalence of PSC is 0 to 16.2 per 100,000 people.¹⁴ The prevalence is rising¹⁴ due to either increased disease awareness or unidentified environmental factors leading to a true increase. The disease has a male preponderance, with a median age at

Cystic Fibrosis

Cystic fibrosis (CF) is a systemic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. It is the most common autosomal recessive genetic disease in white people, affecting 1 in 3000 births in the United States.⁵⁵ Cystic fibrosis involves several organs, including the lungs, reproductive tracts, pancreas, intestine, and liver. CFTR is a transmembrane protein expressed on epithelia that acts as an anion channel. Mutations of CFTR result in alterations of Cl^– and

Biliary Atresia

Biliary atresia is an infantile obstructive cholangiopathy of unknown etiology that accounts for approximately 50% of pediatric liver transplants.⁵⁹ Biliary atresia (incidence of 1 per 12,000 births in the United States) is characterized by persistent jaundice and acholic stools due to fibro-obliterative blocklage of the bile ducts.⁵⁹ It is postulated that a prenatal or perinatal viral infection may initiate cholangiocyte apoptosis, which causes the release of antigens that trigger an immune

Polycystic Liver Disease

The polycystic liver diseases are inherited disorders that occur alone (autosomal dominant polycystic liver disease) or in association with polycystic kidney disease (autosomal dominant or autosomal recessive polycystic kidney disease). Autosomal dominant polycystic liver disease has a prevalence of approximately 1 per 100,000 people and is due to a mutation of PRKCSH or Sec63 genes, both of which are expressed in cholangiocytes.⁶⁸ Autosomal dominant polycystic kidney disease, most often due to

Cholangiocarcinoma

Cholangiocarcinoma is a biliary malignancy that originates from oncogenic transformation of cholangiocytes and is classified as intrahepatic (10%), perihilar (50%), and distal (40%).⁷³ During the past 3 decades, the overall incidence of cholangiocarcinoma has increased,⁷⁴ and survival rates have not improved (5-year survival for R0-resected patients, ie, microscopically negative surgical margins, of 63% for intrahepatic, 30% for perihilar, and 27% for distal tumors).73, 75 Although most

Conclusion

The cholangiopathies continue to have high morbidity and mortality, pose substantial challenges for clinical management, and confer considerable economic burden on patients and society. Further understanding of the normal biology of cholangiocytes and elucidation of the genetic and nongenetic contributors associated with the cholangiopathies may result in more accurate prognostication and more effective therapies.

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ReviewThe Cholangiopathies

Abstract

Section snippets

Cholangiocytes and the Cholangiopathies

Primary Biliary Cirrhosis

Primary Sclerosing Cholangitis

Cystic Fibrosis

Biliary Atresia

Polycystic Liver Disease

Cholangiocarcinoma

Conclusion

Gastroenterology

Gastroenterology

Gastroenterology

J Hepatol

Cell

J Hepatol

Best Pract Res Clin Gastroenterol

J Hepatol

J Hepatol

Gastroenterology

Clin Res Hepatol Gastroenterol

Am J Transplant

Gastroenterology

Gastroenterology

Lancet

J Hepatol

J Hepatol

Gastroenterology

J Hepatol

Gastroenterology

J Hepatol

Gastroenterology

Cholangiocyte biology

Curr Opin Gastroenterol

Functional heterogeneity of cholangiocytes

Semin Liver Dis

Multipotent stem/progenitor cells in human biliary tree give rise to hepatocytes, cholangiocytes, and pancreatic islets

Hepatology

Biliary tree stem/progenitor cells in glands of extrahepatic and intraheptic bile ducts: an anatomical in situ study yielding evidence of maturational lineages

J Anat

Ductal plates in hepatic ductular reactions: hypothesis and implications, I: types of ductular reaction reconsidered

Virchows Arch

MicroRNAs and cholestatic liver diseases

Curr Opin Gastroenterol

Environmental factors in primary biliary cirrhosis

Semin Liver Dis

Primary biliary cirrhosis

Hepatology

Review article: controversies in the management of primary biliary cirrhosis and primary sclerosing cholangitis

Aliment Pharmacol Ther

Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants

N Engl J Med

Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis

Nat Genet

Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis

Nat Genet

Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis

Nat Genet

Breach of tolerance: primary biliary cirrhosis

Semin Liver Dis

Up-regulation of microRNA 506 leads to decreased Cl-/HCO3- anion exchanger 2 expression in biliary epithelium of patients with primary biliary cirrhosis

Hepatology

A biliary HCO3- umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes

Hepatology

Review
The Cholangiopathies

Up-regulation of microRNA 506 leads to decreased Cl^-/HCO3^- anion exchanger 2 expression in biliary epithelium of patients with primary biliary cirrhosis

A biliary HCO3^- umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes