The wide spectrum of multidrug resistance 3 deficiency: From neonatal cholestasis to cirrhosis of adulthood

Background & Aims: We have specified the features of progressive familial i ntrahepatic cholestasis type 3 and investigated in 31 patients whether a de fect of the multidrug resistance 3 gene (MDR3) underlies this phenotype. Me thods: MDR3 sequencing liver MDR3 immunohistochemistry, and biliary phospho lipid dosage were performed, Results: Liver histology showed a pattern of b iliary cirrhosis with patency of the biliary tree. Age at presentation rang ed from the neonatal period to early adulthood. Sequence analysis revealed 16 different mutations in 17 patients. Mutations were identified on both al leles in 12 patients and only on 1 allele in 5, Four mutations lead to a fr ame shift, 2 are nonsense, and 10 are missense, An additional missense muta tion probably representing a polymorphism was found in 5 patients, MDR3 mut ations were associated with abnormal MDRB canalicular staining and a low pr oportion of biliary phospholipids, Gallstones or episodes of cholestasis of pregnancy were found in patients or parents. Children with missense mutati ons had a less severe disease and more often a beneficial effect of ursodeo xycholic acid therapy. Conclusions: At least one third of the patients with a progressive familial intrahepatic cholestasis type 3 phenotype have a pr oven defect of MDR3, This gene defect should also be considered in adult li ver diseases.