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This research investigates the genetic and immunological factors contributing to cholestatic liver disease.

January 1, 2013

Cholestatic Liver Disease

Key Points

This research investigates the genetic and immunological factors contributing to cholestatic liver disease.
Genome-wide association studies identified susceptibility loci for primary biliary cirrhosis and primary sclerosing cholangitis.
Diagnostic evaluations included patient history, imaging, serological studies, and liver biopsy when necessary.
Consideration of genetic testing for mutations in hepatobiliary transporters ATP8B1, ABCB11, and ABCB4 for familial intrahepatic cholestasis.
Identification of significant associations with the major histocompatibility complex in cholestatic diseases.
Discovery of causal mutations in hepatobiliary transporters leading to varying disease severity.
Emerging therapeutic options involving nuclear receptor ligands and bile salt modifications are under investigation.

Abstract

Cholestasis develops as a consequence of impaired bile formation and/or bile flow and can be classified as intra- or extrahepatic. Chronic cholestatic diseases are mostly intrahepatic with the exception of primary and secondary sclerosing cholangitis affecting intra- and extrahepatic bile ducts. Recent genome-wide association studies have confirmed major histocompatibility complex associations and discovered multiple susceptibility loci in primary biliary cirrhosis and primary sclerosing cholangitis, providing new insights into disease pathogenesis, which may translate into more precise therapeutic prevention and intervention in the future. Diagnostic steps in cholestatic conditions comprise a thorough patient history, abdominal imaging and distinct serological studies including antimitochondrial antibodies and IgG4 levels; if the diagnosis remains unclear, liver biopsy is warranted. Genetic testing should also be considered, as mutations in the hepatobiliary transporters ATP8B1, ABCB11 and ABCB4 are causative for three different forms of familial intrahepatic cholestasis. Disease severity is dependent on the genotypic variants of these transporters, ranging from mildly elevated liver enzymes in adults to cirrhosis in early childhood. Ligands of nuclear receptors, which represent important regulators of hepatobiliary transporters, and modified bile salts are new promising therapeutic options in cholestatic liver disease and are currently being investigated in clinical trials.

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