Clinical Genetics of Cholangiopathies

Abstract

Cholestasis can be caused by various liver diseases. In the recent years, genetic factors for cholestatic liver diseases have been identified. In the case of rare cholestatic liver diseases such as progressive familial intrahepatic cholestasis, genetic tests are already an indispensable part of the diagnostic algorithm. Frequently the causative gene mutations lead to the dysfunction of hepatocanalicular transporters. The further development of genetic testing (gene panels, exome sequencing) will help to tailor the treatment of patients with inherited cholestatic liver diseases.

Key Concepts

  • For ‘classic’ cholestatic liver diseases such as PBC and PSC or drug‐induced cholestasis, genetic risk factors have been identified, but these are not yet helpful for clinical routine.
  • In monogenic cholestasis syndromes, causative mutations in genes coding for hepatocanalicular transporter can be identified in many patients by gene sequencing.
  • Clinical phenotypes, γ‐GT and liver biopsy are helpful in the differential diagnosis of the different FIC subtypes.
  • ABCB4 deficiency due to variants in this gene encoding the hepatocanalicular phosphatidylcholine transporter is characterised by a broad clinical spectrum, ranging from ICP to LPAC to the severe phenotype PFIC.
  • Through genetics‐based diagnosis (gene panel, exome sequencing), previously unknown gene variants can be identified in individual patients with cholestatic liver diseases of unknown aetiology. However, the interpretation of the results and the functional relevance can be challenging.

Keywords: byler syndrome; cholestasis; complex disease; liver; molecular genetics

Figure 1. Key transport proteins for hepatocellular uptake of bile constituents from sinusoidal blood and secretion into bile canaliculi.
Figure 2. Phenotypic disease spectrum of ABCB4 deficiency. Abbreviations: GT, glutamyl‐transpeptidase; LPAC, low phospholipid‐associated cholelithiasis; PFIC, progressive familial intrahepatic cholestasis.
Figure 3. Intrahepatic stone in the right bile duct and gallbladder stone in a 24‐year‐old female patient with LPAC syndrome and two heterozygous ABCB4 gene variants. Reichert and Lammert . Reproduced with permission of Georg Thieme Verlag KG.
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Reichert, Matthias Christian, and Lammert, Frank(Jan 2020) Clinical Genetics of Cholangiopathies. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0028667]