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Progressive familial intrahepatic cholestasis
1Department of Pediatrics and INSERM U 347, Bicêtre Hospital, Le Kremlin Bicêtre, France. emj@kb.inserm.fr
Insights
Progressive familial intrahepatic cholestasis (PFIC) is an inherited liver disease in children. Genetic discoveries now enable specific diagnoses and potential prenatal testing for PFIC, improving patient care.
Area of Science:
- Hepatology
- Genetics
- Pediatric Gastroenterology
Background:
- Progressive familial intrahepatic cholestasis (PFIC), or Byler disease, is a severe inherited childhood liver disorder.
- It presents with cholestasis of hepatocellular origin, often leading to liver failure before adolescence.
- PFIC exhibits heterogeneity, suggesting different types linked to bile acid secretion or metabolism defects.
Purpose of the Study:
- To review recent molecular and genetic findings in PFIC.
- To highlight the implications for diagnosis, prenatal testing, and targeted therapies.
Main Methods:
- Review of molecular and genetic studies identifying genes responsible for PFIC types.
- Analysis of genotype-phenotype correlations in PFIC patients.
Main Results:
- Identification of genes linked to PFIC, primarily mutations in hepatocellular transport system genes involved in bile formation.
- Demonstration that PFIC is related to defects in bile acid secretion or metabolism.
- Establishment of specific diagnostic tools and potential for prenatal diagnosis.
Conclusions:
- Genetic findings provide precise diagnostic tools for PFIC.
- Genotype-phenotype correlations aid in identifying patients who may benefit from ursodeoxycholic acid or biliary diversion.
- Future therapies like cell and gene therapies offer alternatives to liver transplantation.
Abstract:
Progressive familial intrahepatic cholestasis (PFIC), also known as Byler disease, is an inherited disorder of childhood in which cholestasis of hepatocellular origin often presents in the neonatal period and leads to death from liver failure before adolescence. The pattern of appearance of affected children within families is consistent with autosomal recessive inheritance. Several studies have provided support for the heterogeneity of this clinical entity suggesting the existence of different types due to different disorders affecting the hepatocyte and related to defects of bile acid secretion or bile acid metabolism. Recent molecular and genetic studies have identified genes responsible for three types of PFIC and have shown that PFIC was related to mutations in hepatocellular transport system genes involved in bile formation. These findings now provide specific diagnostic tools for the investigation of children with PFIC and should allow prenatal diagnosis in the future. Genotype-phenotype correlations performed in patients treated with ursodeoxycholic acid or biliary diversion should allow those PFIC patients who could benefit from these therapies to be precisely identified. In the future, other therapies, such as cell and gene therapies, might be considered and could also represent an alternative to liver transplantation.