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.

Progressive Familial Intrahepatic Cholestasis (PFIC) in Indian Children: Clinical Spectrum and Outcome

“…ICP has been described in heterozygous mothers of affected children with PFIC. 20 Implicating family screening, 40% of the patients of PFIC had an affected sibling or family member. Previous studies 17,18 have reported affected sibling in 15-25% of PFIC.…”

Gestational Intrahepatic Cholestasis: Etiology, Maternal Outcome, Fetal Outcome and Management: Review

“…9 Avrupa'da, en sık İskandinav ülkelerinde (İsveç'te %1,5) olmakla beraber %0,1-0,2 sıklığında izlenmektedir. 3 Son zamanlarda Şili'de GİK'nin insidansının azaldığı (%1,4-4,0) rapor edilmiştir. 13,14 Aynı zaman diliminde İskandinavya'da da prevalansın %0,1-1,5 değerlerine düştüğü rapor edilmiştir.…”

“…1 Hastalık, coğrafi konum ve etnik orijine göre %0,1-15,6 arasında değişen sık-lıkla görülmektedir. [2][3][4][5] Gebelikte viral hepatit tanısından sonra en sık görülen sarılık sebebidir. 6 Özellikle gebeliğin ikinci yarısından sonra maternal kanda artmış safra asit düzeyleri ve bozulmuş karaciğer fonksiyon testleri (KFT) ile seyretmektedir.…”

Sequence variation in the ATP8B1 gene and intrahepatic cholestasis of pregnancy

“…1,2 In Scandinavian countries, ICP occurs in 0.5 -1.5% of pregnancies. 3,4 The genetic etiology of ICP is largely unknown, and likely to be heterogenous. Currently, investigation of the genetic background of ICP is focused mainly on candidate genes, particularly those causing cholestatic diseases.…”