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

Research output: Contribution to journalReview articlepeer-review

Original languageEnglish
Pages (from-to)1628-1639
Number of pages12
JournalAlimentary Pharmacology and Therapeutics
Issue number11-12
Accepted/In press2020
PublishedDec 2020

Bibliographical note

© 2020 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

King's Authors


BACKGROUND: Children 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.

AIMS: To 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.

METHODS: A search of the literature on variants in specific cholestasis-related genes in adults was conducted.

RESULTS: The 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.

CONCLUSIONS: Individuals 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.

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