Genetische Prädisposition der intrahepatischen Schwangerschaftscholestase : Mutationsanalyse des Phospholipidtransporters ABCB4 und der Gallensäurenexportpumpe ABCB11

Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder with a complex aetiology: Hormonal factors, exogenous influence and, in patients with high gamma-glutamyl transferase (GGT), heterozygous mutations in the ABCB4 gene encoding the hepatic canalicular phospholipid transport protein MDR3 play a role in pathogenesis. Mutations in the ABCB11 encoding the bile salt export pump BSEP may as well predispose for ICP. In 28 Swedish and German patients suffering from MSUD a mutational analysis was accomplished, furthermore clinical and biochemical data were obtained and correlations were calculated. There was a clear correlation between GGT and bilirubin concentrations indicating a severe clinical course in patients with elevated gamma-GT levels. In patients with elevated GGT (21%) the coding regions of the ABCB4 gene were searched for mutations. Patients presenting with normal gamma-GT levels were screened for mutations in the promotor region and the exons of ABCB11. In the ABCB11 gene no divergence from the published wild type sequence could be detected. In 1 patient with elevated GGT levels suffering from ICP and cholesterine cholelithiasis the heterozygous missense mutation S320F in exon 9 of ABCB4 was detected. The mutation results in the substitution of serine by phenylalanine in the conserved position 320 of the 5th segment of the first transmembrane domain of MDR3. A BamHI site of cleavage is deleted in the mutated sequence. This restriction fragment length polymorphism was used to rule out the existence of the mutation in 166 control chromosomes. The heterozygous missense mutation S320F was likewise detected in the mother and the sister of the patient. Impaired function of MDR3 can thus manifest as cholestasis or cholelithiasis. Patients suffering from ICP and elevated GGT represent a subgroup of patients in whom mutations in the ABCB4 gene can be existent. These patients may benefit from a therapy with the hydrophilic bile acid ursodeoxycholic acid (UDCA) substituting endogenous hydrophobic bile acids. Thereby the cytotoxic action of endogenous bile acids on cholangiocytes can be lowered below a critical threshold.