Co-inheritance of lithogenic ABCB4 and ABCG8 variants in a twin pair with juvenile onset gallstone disease and oral contraceptive and pregnancy aggravated cholestatic liver disease

Introduction: Rare variants of the ABCB4 gene encoding the phospholipid floppase MDR3 have been attributed to a wide spectrum of hepatobiliary syndromes spanning from neonatal cholestasis via gallstone disease (GD) and intrahepatic cholestasis of pregnancy (ICP) to liver cirrhosis. On the other hand, common polymorphisms within the genes encoding the heterodimeric cholesterol transporter ABCG5/8 have been associated with gallstone disease.

Case report: Here we report on two female monozygotic twins who both underwent cholecystectomy at 13 and 15 years of age, respectively, for symptomatic GD but showed constantly elevated laboratory markers of cholestasis thereafter. At that time, MRCP and ERCP as well as tests for viral or autoimmune hepatitis were negative. In both twins, liver biopsies showed vanishing of small bile ducts at 19 years of age and bridging fibrosis without inflammatory infiltrates two years later. Of note, the twins reported pruritus and jaundice upon oral contraceptives and moreover, one twin suffered severe intrahepatic cholestasis of pregnancy (ICP), resulting in premature delivery at 32 weeks of gestation. Ursodeoxycholic acid given at a dose of up to 20mg/kg per day had only moderate effect on itching and serum bile acid levels.

Results: Sequencing of ABCB4 revealed a novel heterozygous variant (c.2960C>T) that was not found in 300 healthy controls. Notably, this variant results substitutes leucine at position 987 in transmembrane domain 12, which is conserved among all species. In addition, the twins carry the ABCG8 D19H genotype, which is known to confer increased gallstone risk.

Conclusion: This is the first report on co-inheritance of ABCB4 and ABCG8 variants, indicating additive effects that lead to early and severe manifestation of hepatobiliary phenotypes.