Clinical Utility

Hereditary cholestatic liver disease is a heterogenous group of disorders with complex pathophysiology, often presenting with overlapping symptoms such as jaundice, pruritus, failure to thrive, hepatomegaly, and other liver abnormalities. At the molecular level, cholestasis is caused by a reduction of bile flow due to impaired hepatocyte secretion or obstruction of bile ducts as a result of defective hepatocyte transport, disorders of bile duct development, inborn errors of bile acid metabolism, and other metabolic disorders impacting the liver. Hereditary cholestasis often, but not always, presents in the neonatal period, and may present with extrahepatic manifestations as well as systemic disease. The estimated worldwide incidence of cholestasis ranges considerably depending on population. Pediatric cholestasis is estimated to affect about 1:2500 in newborns, while intrahepatic cholestasis of pregnancy is estimated to affect between ~0.1-5.2% of pregnancies worldwide, with up to ~9-25% of pregnancies affected in some South American populations. The prevalence of cholestasis among patients with inflammatory bowel disease is as high as 7%. Some hereditary forms of cholestatic liver disease are known to occur more frequently in ethnic groups where consanguineous marriage is prevalent or in some geographic regions due to founder effects.

Advantages of genetic testing for cholestasis include confirmation of diagnosis, identification of other health risks associated with syndromic disease, optimization of therapeutic management, allowing for targeted testing of other family members, and assistance with reproductive planning. This test especially aids in a differential diagnosis of similar phenotypes by analyzing multiple genes simultaneously that all include the clinical feature of cholestasis.