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.

Maternal liver-related symptoms during pregnancy in primary sclerosing cholangitis

“…ICP has been identified as a risk factor for future fibrosis/cirrhosis (HR 5.11, 95% CI 3.29-7.96), although this may be primarily influenced by chronic hepatitis C infection, 17 it is also likely to related to genetic factors that confer susceptibility to ICP and cirrhosis. 18 , 19 Although we demonstrated a poorer transplant-free survival from time of pregnancy in our cohort, there was no difference in transplant-free survival from time of PSC diagnosis ( Fig. S2B ) and this is likely to be related to a lead time bias and a shorter interval to PSC diagnosis.…”

Hepatic Dry Copper Weight in Pediatric Autoimmune Liver Disease

“…PFIC are a group of disorders characterized by severe early onset cholestasis, and elevated hepatic dry copper weight has been reported as a result of secondary copper overload from cholestasis in patients with PFIC3 (MDR3 deficiency) and ABCB4 variants (17–19). Although elevated tissue copper has not been described in ABCB4 heterozygous patients, they may have reduced functional MDR3 protein and can develop chronic cholestatic liver disease (20). It is therefore possible that the genetic variants in these patients have contributed to their elevated tissue copper.…”

UK guideline on the transition and management of childhood liver diseases in adulthood

“…102 There is an increasing recognition that individuals who are heterozygotes for variants in the genes seen in PFIC, particularly ABCB11 and ABCB4, can present with milder liver disease phenotypes in adulthood. 103 Although this is considered milder, it still may lead to end-stage liver disease and liver cancer, [104][105][106][107] and therefore it is important that when first-degree relatives undergo genetic screening, they are also offered genetic counselling.…”