Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy

Abstract

Background and aims: The aim of this study was to investigate the genetic aetiology of intrahepatic cholestasis of pregnancy (ICP) and the impact of known cholestasis genes (BSEP, FIC1, and MDR3) on the development of this disease. Patients and methods: Sixty nine Finnish ICP patients were prospectively interviewed for a family history of ICP, and clinical features were compared in patients with familial ICP (patients with a positive family history, n=11) and sporadic patients (patients with no known family history of ICP, n=58). For molecular genetic analysis, 16 individuals from two independently ascertained Finnish ICP families were genotyped for the flanking markers for BSEP, FIC1, and MDR3. Results: The pedigree structures in 16% (11/69) of patients suggested dominant inheritance. Patients with familial ICP had higher serum aminotransferase levels and a higher recurrence risk (92% v 40%). Both segregation of haplotypes and multipoint linkage analysis excluded BSEP, FIC1, and MDR3 genes in the studied pedigrees. Additionally, the MDR3 gene, previously shown to harbour mutations in ICP patients, was negative for mutations when sequenced in four affected individuals from the two families. Conclusions: These results support the hypothesis that the aetiology of ICP is heterogeneous and that ICP is due to a genetic predisposition in a proportion of patients. The results of molecular genetic analysis further suggest that the previously identified three cholestasis genes are not likely to be implicated in these Finnish ICP families with dominant inheritance.

Intrahepatic cholestasis of pregnancy: the severe form is associated with common variants of the hepatobiliary phospholipid transporter ABCB4 gene

“…However, it is possible that as yet unidentified rare variants of the ABCB11 gene might play a part in ICP pathogenesis, as a recent study on 57 Finnish patients with ICP 30 linked two intragenic ABCB11 SNPs to ICP. Our findings are in line with a recent Finnish family study, 31 in which segregation of haplotypes and multipoint linkage analysis excluded ABCB11 as being responsible for the pathogenesis of ICP in two families with dominant inheritance. ABCB11 haplotype structure has also been investigated in patients with primary biliary cirrhosis, primary sclerosing cholangitis 20 or gallstone disease, without any specific findings.…”

Estrogen Receptor α Mediates 17α-Ethynylestradiol Causing Hepatotoxicity

“…Mutations in the BSEP gene are not implicated in sporadic cases of ICP in Swiss patients (36). In addition, common mutations in MDR3 are not found in familial and sporadic cases of ICP in Finnish patients (37). Although mutations in these genes may raise the susceptibility to ICP, the results of these studies do not confirm a direct correlation between mutational events in these candidate genes and ICP.…”

Reduced Antidiabetic Effect of Metformin and Down-regulation of Hepatic Oct1 in Rats with Ethynylestradiol-Induced Cholestasis

“…Estrogen has long been known to cause intrahepatic cholestasis in susceptible women during pregnancy (0.5-1.8% of pregnant women suffer from intrahepatic cholestasis, (13)(14)(15), after the administration of oral contraceptives, or during postmenopausal hormone replacement therapy (16). Experimental intrahepatic cholestasis induced by 17α-ethynylestradiol (EE) is a widely used in vivo animal model used to examine the molecular mechanisms involved in estrogen-induced cholestasis (17).…”