Challenges in the diagnosis and treatment of genetic cholestasis in adults

Disorders of bile formation and bile flow along the intra- and extrahepatic bile ducts are summarised under the term cholestasis. Clinically, conditions resulting in retention of biliary constituents such as bile acids within hepatocytes (termed primary cholestasis) need to be distinguished from diseases characterised by bile duct injury (termed cholangiopathies). Some cholangiopathies may also cause retention of biliary constituents within hepatocytes, resulting in secondary cholestasis. Genetic variants in a multitude of genes can contribute to the development of both primary cholestasis and cholangiopathies. Assessing the contribution of identified genetic variants to the clinical presentation in adults is complicated by factors such as environmental exposure, comorbidities, and medication intake. The diagnostic workup in adults with cholestasis should first consider common causes of primary cholestasis and cholangiopathies. If the aetiology remains unclear, liver histology and/or genetic testing should be pursued. Until recently, treatment for these conditions was largely supportive. However pharmacological interruption of the enterohepatic circulation of bile acids now offers the possibility of more specific intervention. Moreover, for those conditions in which the bile duct epithelium is the main site of injury, ursodeoxycholic acid remains essential. Multidisciplinary case discussions can help facilitate diagnosis and guide management.