Genetic determinants of cholangiopathies: Molecular and systems genetics |
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Authors: | Matthias C. Reichert Rabea A. Hall Marcin Krawczyk Frank Lammert |
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Affiliation: | 1. Department of Medicine II, Saarland University Medical Center, Homburg, Germany;2. Laboratory of Metabolic Liver Diseases, Centre for Preclinical Research, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland;3. Chair of Internal Medicine II, Saarland University, Saarbrücken, Germany |
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Abstract: | Familial cholangiopathies are rare but potentially severe diseases. Their spectrum ranges from fairly benign conditions as, for example, benign recurrent intrahepatic cholestasis to low-phospholipid associated cholelithiasis and progressive familial intrahepatic cholestasis (PFIC). Many cholangiopathies such as primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC) affect first the bile ducts (“ascending pathophysiology”) but others, such as PFIC, start upstream in hepatocytes and cause progressive damage “descending” down the biliary tree and leading to end-stage liver disease. In recent years our understanding of cholestatic diseases has improved, since we have been able to pinpoint numerous disease-causing mutations that cause familial cholangiopathies. Accordingly, six PFIC subtypes (PFIC type 1–6) have now been defined. Given the availability of genotyping resources, these findings can be introduced in the diagnostic work-up of patients with peculiar cholestasis. In addition, functional studies have defined the pathophysiological consequences of some of the detected variants. Furthermore, ABCB4 variants do not only cause PFIC type 3 but confer an increased risk for chronic liver disease in general. In the near future these findings will serve to develop new therapeutic strategies for patients with liver diseases. Here we present the latest data on the genetic background of familial cholangiopathies and discuss their application in clinical practice for the differential diagnosis of cholestasis of unknown aetiology. As look in the future we present “system genetics” as a novel experimental tool for the study of cholangiopathies and disease-modifying genes. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen. |
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Keywords: | AP alkaline phosphatase ASBT apical sodium bile acid transporter BRIC benign recurrent intrahepatic cholestasis CC collaborative cross DILI drug-induced liver injury ?-GT ?-glutamyl transpeptidase GRP genetic reference populations GWAS genome-wide association studies HCC hepatocellular carcinoma ICP intrahepatic cholestasis of pregnancy LPAC low phospholipid-associated cholelithiasis PBC primary biliary cirrhosis PBED partial biliary external diversion PFIC progressive familial intrahepatic cholestasis PSC primary sclerosing cholangitis RIL recombinant inbred lines UDCA ursodeoxycholic acid Cholestasis Complex disease Genetic test Phosphatidylcholine translocator Quantitative trait locus |
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