Review article: liver disease in adults with variants in the cholestasis‐related genes ABCB11, ABCB4 and ATP8B1

Abstract

SummaryBackgroundChildren with intrahepatic cholestasis and genetic variants which result in the disruption of the formation and maintenance of bile (ABCB11, ABCB4 and ATP8B1) generally have a rapidly progressive clinical course. Adults with different phenotypes of cholestasis are increasingly being evaluated for variants in these genes associated with childhood diseases.AimsTo review the literature with respect to the presence of variants in cholestasis‐related genes in adults with various liver phenotypes, and provide clinical implications of the findings.MethodsA search of the literature on variants in specific cholestasis‐related genes in adults was conducted.ResultsThe common variant p.Val444Ala in ABCB11 confers increased risk of drug‐induced liver injury and intrahepatic cholestasis of pregnancy (ICP). Individuals with variants in ABCB4 are at risk of ICP and low phospholipid‐associated cholelithiasis. Variants in ABCB4, and possibly ABCB11 and ATP8B1, can be identified in up to a third of patients with cryptogenic chronic cholestasis.ConclusionsIndividuals with variants in ABCB11 rarely develop cholestasis until BSEP function dips below a threshold, which is also affected by other factors (e.g., drugs, hormones). However, variants in ABCB4 and consequent reduction in MDR3 protein, have a more linear dose‐response curve. In individuals with an ABCB11 variant, medications known to reduce BSEP activity should be used cautiously; they should be monitored during pregnancy for ICP; and first‐degree relatives should be counselled and screened. No proven management strategy exists, although ursodeoxycholic acid may be beneficial. Further work is needed to define the genotype‐phenotype correlation and natural history, and to evaluate the penetrance.