Aggravation of ABCB4 associated intrahepatic cholestasis of pregnancy due to coinheritance of functional ABCB11 and FXR variants

Introduction Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic disorder with a strong genetic background. Variants in hepatobiliary transporter genes, e.g. the phospholipid transporter ABCB4 and the bile salt export pump ABCB11, have been associated with ICP, as have functional variants of FXR (nuclear receptor 1H4), the central bile salt sensor. Herein, we report on an exceptional familial clustering of ICP related variants in three distinct genes and discuss putative implications. Case presentation A 36-years old primigravida was referred in her third trimester for severe pruritus and elevated liver enzymes, including γ-glutamyltransferase. After exclusion of alternative diagnoses, ICP was diagnosed based on elevated serum bile acid levels and relief of symptoms after delivery. Of note, the patient had been treated previously for bile duct and intrahepatic stones and chronically elevated liver function tests. Genetic analyses of ICP associated variants revealed a heterozygous ABCB4 mutation (p.S320F), homozygosity for the ABCB11 variant p.A444V, and heterozygosity for the FXR variant -1G>T. Genotyping of the remaining family members indicated paternal transmission of the FXR variant. Interestingly, the patient's sister, a nullipara, also suffered from juvenile cholelithiasis with hepatolithiasis, and biochemical evidence of cholestatic liver disease. Conclusions Aggregation of three disease-associated functional polymorphisms has never been reported before in ICP. Combining phenotypic and genetic data, we conclude that the accumulation of the defective FXR variant in the offspring generation might have resulted in a progressive cholestatic phenotype by cooperative negative interference with hepatobiliary transporter capacities. intrahepatic cholestasis of pregnancy - ABCB4 - ABCB11 - FXR