RESUMO
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.
Assuntos
Colestase Intra-Hepática/genética , Heterogeneidade Genética , Complicações na Gravidez/etiologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/genética , Adulto , Ácidos e Sais Biliares/sangue , Colestase Intra-Hepática/epidemiologia , Saúde da Família , Feminino , Finlândia/epidemiologia , Genes Dominantes/genética , Ligação Genética/genética , Genótipo , Haplótipos/genética , Humanos , Incidência , Linhagem , Gravidez , Complicações na Gravidez/epidemiologia , Estudos Prospectivos , Transaminases/sangueRESUMO
We report three sisters with intrahepatic cholestasis of pregnancy (ICP) and the pedigree of the family, including six generations. ICP was observed in five successive generations; most of the patients also had cholelithiasis. The uniform expression, the complete penetrance of the trait and the direct parent-to-child transmission support the Mendelian dominant mode of inheritance. Determination of HLA A, B and C haplotype was made in five ICP patients, without any findings of HLA type common to everyone. X-linked inheritance cannot be excluded in this study.
Assuntos
Colestase Intra-Hepática/genética , Antígenos HLA/genética , Complicações na Gravidez , Adulto , Colestase Intra-Hepática/imunologia , Feminino , Haplótipos , Humanos , Linhagem , Gravidez , Complicações na Gravidez/imunologiaRESUMO
OBJECTIVE: To investigate whether dexamethasone suppression of fetoplacental oestrogen production can reduce obstetric cholestasis. DESIGN: Observational study. SETTING: Department of Obstetrics and Gynaecology, University of Tampere, Finland. SUBJECTS: 10 women, at between 28 and 37 weeks gestation, with intrahepatic cholestasis of pregnancy. INTERVENTIONS: Treatment with 12 mg oral dexamethasone daily for 7 days, after which the therapy was gradually discontinued over 3 days. MAIN OUTCOME MEASURES: Serum oestriol, oestradiol, total bile acids and ALAT were measured before and during therapy and on days 4 and 7 and ALAT also on day 12. Differences were tested by paired t test. RESULTS: Itching disappeared or was relieved in all patients. Serum oestriol level fell significantly by day 1 of treatment, serum oestradiol and total bile acid levels by day 4 and ALAT by day 12 from the beginning of the therapy. CONCLUSION: Dexamethasone is a drug of choice in the treatment of intrahepatic cholestasis of pregnancy.