Clinical Genetics of Cholangiopathies


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.


Bacq Y, Sentilhes L, Reyes HB, et al. (2012) Efficacy of ursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: a meta‐analysis. Gastroenterology 143: 1492–1501.

Beuers U, Boberg KM, Chapman RW, et al. (2009) EASL Clinical Practice Guidelines: management of cholestatic liver diseases. Journal of Hepatology 51: 237–267.

Chalasani N, Bonkovsky HL, Fontana R, et al. (2015) Features and outcomes of 899 Patients with drug‐induced liver injury: the DILIN prospective study. Gastroenterology 148: 1340–1352.

Cordell HJ, Han Y, Mells GF, et al. (2015) International genome‐wide meta‐analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways. Nature Communications 22: 8019.

Degiorgio D, Colombo C, Seia M, et al. (2007) Molecular characterization and structural implications of 25 new ABCB4 mutations in progressive familial intrahepatic cholestasis type 3 (PFIC3). European Journal of Human Genetics 15: 1230–1238.

Delaunay JL, Durand‐Schneider AM, Dossier C, et al. (2016) A functional classification of ABCB4 variations causing progressive familial intrahepatic cholestasis type 3. Hepatology 63: 1620–1631.

Delaunay JL, Bruneau A, Hoffmann B, et al. (2017) Functional defect of variants in the adenosine triphosphate‐binding sites of ABCB4 and their rescue by the cystic fibrosis transmembrane conductance regulator potentiator, ivacaftor (VX‐770). Hepatology 65: 560–570.

Dixon PH, Wadsworth CA, Chambers J, et al. (2014) A comprehensive analysis of common genetic variation around six candidate loci for intrahepatic cholestasis of pregnancy. The American Journal of Gastroenterology 109: 76–84.

Ellinghaus D, Jostins L, Spain SL, et al. (2016) Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease‐specific patterns at shared loci. Nature Genetics 48: 510–518.

Engevik AC, Kaji I, Engevik MA, et al. (2018) Loss of MYO5B leads to reductions in Na+ absorption with maintenance of CFTR‐dependent Cl−secretion in enterocytes. Gastroenterology 155: 1883–1897.

Gilbert MA, Bauer RC, Rajagopalan R, et al. (2019) Alagille syndrome mutation update: Comprehensive overview of JAG1 and NOTCH2 mutation frequencies and insight into missense variant classification. Human Mutation 25: 2197–2220. DOI: 10.1002/humu.23879.

Gomez‐Ospina N, Potter CJ, Xiao R, et al. (2016) Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis. Nature Communications 18 (7): 10713.

Gonzales E, Taylor SA, Davit‐Spraul A, et al. (2017) MYO5B mutations cause cholestasis with normal serum gamma‐glutamyl transferase activity in children without microvillous inclusion disease. Hepatology 65: 164–173.

Gunaydin M, Tander B, Demirel D, et al. (2016) Different techniques for biliary diversion in progressive familial intrahepatic cholestasis. Journal of Pediatric Surgery 51: 386–389.

Jacquemin E, de Vree JM, Cresteil D, et al. (2001) The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood. Gastroenterology 120: 1448–1458.

Karlsen TH, Lammert F and Thompson RJ (2015) Genetics of liver disease: from pathophysiology to clinical practice. Journal of Hepatology 62: 6–14.

Lammert F, Marschall HU, Glantz A, et al. (2000) Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management. Journal of Hepatology 33: 1012–1021.

Lammert F, Wang DQ, Hillebrandt S, et al. (2004) Spontaneous cholecysto‐ and hepatolithiasis in Mdr2‐/‐ mice: a model for low phospholipid‐associated cholelithiasis. Hepatology 39: 117–128.

Liz JZ, Hov JR, Folseraas T, et al. (2013) Dense genotyping of immune‐related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nature Genetics 45: 670–675.

Lucena MI, Molokhia M, Shen Y, et al. (2011) Susceptibility to amoxicillin‐clavulanate‐induced liver injury is influenced by multiple HLA class I and II alleles. Gastroenterology 141: 338–347.

Manfredi C, Tindall JM, Hong JS, et al. (2019) Making precision medicine personal for cystic fibrosis. Science 365: 220–221.

Mells GF, Floyd JAB, Morley KI, et al. (2011) Genome‐wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis. Nature Genetics 43: 329–332.

Oda T, Elkahloun AG, Pike BL, et al. (1997) Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nature Genetics 16: 235–242.

Ovadia C, Seed PT, Sklavounos A, et al. (2019) Association of adverse perinatal outcomes of intrahepatic cholestasis of pregnancy with biochemical markers: results of aggregate and individual patient data meta‐analyses. Lancet 393: 899–909.

Pauli‐Magnus C, Stieger B, Meier Y, et al. (2005) Enterohepatic transport of bile salts and genetics of cholestasis. Journal of Hepatology 43: 342–357.

Pawlikowska L, Strautnieks S, Jankowska I, et al. (2010) Differences in presentation and progression between severe FIC1 and BSEP deficiencies. Journal of Hepatology 53: 170–178.

Poupon R, Rosmorduc O, Boëlle PY, et al. (2013) Genotype‐phenotype relationships in the low‐phospholipid‐associated cholelithiasis syndrome: a study of 156 consecutive patients. Hepatology 58: 1105–1110.

Reichert MC and Lammert F (2017) LPAC‐Syndrom (ABCB4‐Defizienz). Z Gastroenterol 55 (8): 736. Article in German.

Sambrotta M, Strautnieks S, Papouli E, et al. (2014) Mutations in TJP2 cause progressive cholestatic liver disease. Nature Genetics 46: 326–328.

Stieger B, Fattinger K, Madon J, et al. (2000) Drug‐ and estrogen‐induced cholestasis through inhibition of the hepatocellular bile salt export pump (BSEP) of rat liver. Gastroenterology 118: 422–430.

Strautnieks SS, Bull LN, Knisely AS, et al. (1998) A gene encoding a liver‐specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nature Genetics 20: 233–238.

Strautnieks SS, Byrne JA, Pawlikowska L, et al. (2008) Severe bile salt export pump deficiency. 82 different ABCB11 mutations in 109 families. Gastroenterology 134: 1203–1214.

Urban TJ, Yufeng S, Stolz A, et al. (2012) Limited contribution of common genetic variants to risk for liver injury due to a variety of drugs. Pharmacogenetics and Genomics 22: 784–795.

Van der Woerd WL, Wichers CG, Vestergaard AL, et al. (2016) Rescue of defective ATP8B1 trafficking by CFTR correctors as a therapeutic strategy for familial intrahepatic cholestasis. Journal of Hepatology 64: 1339–1347.

Vauthier V, Ben Saad A, Elie J, et al. (2019) Structural analogues of roscovitine rescue the intracellular traffic and the function of ER‐retained ABCB4 variants in cell models. Scientific Reports 30: 6653.

Wang KS, Tiao G, Bass LM, et al. (2017) Analysis of surgical interruption of the enterohepatic circulation as a treatment for pediatric cholestasis. Hepatology 65: 1645–1654.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Reichert, Matthias Christian, and Lammert, Frank(Jan 2020) Clinical Genetics of Cholangiopathies. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0028667]