Genetics of cholestatic liver disease in 2010

Many of the cholestatic diseases show similar clinical features, despite underlying differences in the genetic etiology. The present review aims to present recent insight into this etiological heterogeneity.

Mutations in the genes causing progressive familial intrahepatic cholestasis are also involved in less severe phenotypes like benign recurrent intrahepatic cholestasis, gallstone disease, intrahepatic cholestasis of pregnancy and drug-induced cholestasis. This probably represents a continuum of severity of the mutations involved, but also complex patterns of inheritance ranging from monogenic autosomal recessive disorders to heterozygosity only conferring a moderate increase in disease risk, where additional genetic or environmental factors are needed to acquire a disease phenotype. Recent genome-wide association studies in the inflammatory cholestatic diseases primary biliary cirrhosis and primary sclerosing cholangitis have revealed susceptibility genes involved in autoimmunity and inflammatory bowel disease, whereas the genetic risk factors for the biliary preference of these diseases remain unknown.

The complexity of the genetic contribution to cholestatic liver disease needs to be accounted for to fully understand the pathogenesis of these conditions.