Genetic Determinants of Drug-induced Cholestasis and Intrahepatic Cholestasis of Pregnancy

Christiane Pauli-Magnus, M.D.; Peter J. Meier, M.D.; Bruno Stieger, Ph.D.

Disclosures

Semin Liver Dis. 2010;30(2):147-159. 

In This Article

Genetics of Cholestasis of Pregnancy

Besides hormonal and most likely environmental factors, genetic susceptibility constitutes a risk factor to develop ICP. A genetic predisposition has been suspected based upon the strong regional clustering, the higher prevalence in female family members of patients with ICP, and the susceptibility of ICP patients to develop intrahepatic cholestasis under other hormonal challenges such as oral contraception.[57] In the last decade, mutations and polymorphisms in the canalicular transporter proteins BSEP and MDR3 have both been associated with the development of ICP. A pathogenic role of genetically determined MDR3 dysfunction was first discussed upon the observation that female members of a large consanguineous family with one family member suffering from progressive intrahepatic cholestasis experienced typical recurrent episodes of ICP.[98] These observations were subsequently verified in pedigree and case-control studies, investigating the pathogenic role of heterozygous ABCB4 mutations in different populations. Strong evidence for a role of ABCB4 genetic variation came from a Swiss cohort, where the extent of ABCB4 genetic variation in 21 unrelated Caucasian women with ICP was compared with that observed in healthy pregnant women as controls.[66] In this collective, 47% of ICP patients had elevated GGT levels and 77% of these patients carried ICP-specific ABCB4 mutations, including three splicing consensus mutations. These findings were later confirmed by a Swedish study, reporting the association of specific ABCB4 haplotypes and severe cholestasis in 12% of 52 observed ICP cases compared with 0% in the control group.[99] Furthermore, a large Italian study of 80 women found heterozygous ABCB4 mutations in 4% of cases.[100] A ABCB4 splicing site mutation was detected as causative locus for the development of ICP in a large consanguineous family of Mennonite kinship.[101] Interestingly, the same genetic locus was associated with the development of gallstone disease, which makes it tempting to think that the higher prevalence of gallstone disease observed in ICP women could also be related to MDR3 dysfunction. In contrast, a study in Finland failed to demonstrate a pathogenic role of ABCB4 mutations in ICP, pointing toward the heterogenous pathogenic nature of this disease.[102]

In contrast to ABCB4, the pathogenic role of ABCB11 genetic variation in ICP has only recently emerged. Biochemical workup of ICP patients subsequently allowed the differentiation between high and low GGT forms of ICP, suggesting the involvement of different transporter pathways. Although high GGT values were present in the majority of ICP patients with an ABCB4 mutation, genetic ABCB11 dysfunction was postulated in low GGT cases.[98,103] Two Swiss studies conducted in independent ICP collectives first suggested the BSEP p.V444A polymorphism as the ICP susceptibility factor, with the homozygous and heterozygous state for the alanine in position 444 being significantly more frequent in ICP women than in healthy pregnant controls.[66,104] Very interestingly, the ABCB11 genotype in position 444 also correlated with serum bile acid levels, with carriers of the alanine showing higher serum bile acid levels than carriers of the valine allele. These findings were recently confirmed in two independent ICP cohorts of more than 400 patients: alanine homo- and heterozygotes were significantly more frequent in the ICP collectives. In the same study, heterozygosity for the BSEP mutations p.E297G, p.D482G, and p.N591S formerly associated with benign and progressive forms of familial intrahepatic cholestasis type 2 were found in four, one, and two ICP patients, respectively, allowing the extrapolation that 1% of European ICP cases are caused by these mutations.[105] Although the molecular and mechanistic basis for p.V444A and p.N591S were not apparent, in silico structural and functional analysis suggests that p.E297G and p.D482G destabilizes the protein fold of BSEP, leading to decreased taurocholate transport in case of p.E297G.[105,106] In addition, decreased hepatic BSEP expression,[107,108] and very recently, significantly reduced hepatic mRNA levels[109] was reported in healthy human liver tissue carrying the alanine allele in position 444 of BSEP, which could predispose to the development of ICP by way of decreased canalicular availability of BSEP. Furthermore, four novel heterozygous variants (c.-1G> T, p.M1V, p.W80R, and p.M173T[110]) of the farnesoid X receptor (FXR), a key transcription factor driving the expression of ABCB11 and ABCB4,[111,112] were recently identified in a British cohort of 92 women with ICP. Of these variants, p.M173T, which is located in the nucleotide-binding domain of the second zinc finger significantly associated with ICP and was shown to have a markedly reduced capacity to activate the ABCB11 promoter in vitro.[110] Although the effect of this variant on MDR3 expression has not been studied, it is likely that activation of the ABCB4 promoter is also reduced. In line with this, a recent report of an ICP patient suffering from alterations in three genes: p.S320F in ABCB4 (previously described in a patient with ICP[113]), p.A444V in ABCB11, and c.-1G> T in FXR,[114] again highlights the role of FXR as a factor associated with ICP.

These observations in intrahepatic cholestasis of pregnancy can be translated to other estrogen-related forms of cholestasis, such as cholestasis seen with the use of oral contraceptives. Specifically, a heterozygous p.G855R mutation in BSEP leading to highly impaired taurocholate transport was associated with noninflammatory cholestasis and highly elevated serum bile acid levels in a young patient under the first use of an oral ethinylestradiol/gestodene combination for contraception.[115] Interestingly, the mother and the maternal grandmother of the patient, who carried the same mutation had a history of ICP. In another study, homozygosity for the alanine phenotype in position 444 of BSEP was seen in four individuals with cholestasis under oral contraceptives.[104] It is therefore tempting to think that genetically determined impairment of canalicular transporter function not only predisposes to ICP, but constitutes a risk factor to the development of bland cholestasis observed with the use of female sex hormones. It can only be speculated whether the same genetic events are also involved in cholestasis associated with the use of anabolic steroids.

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