Molecular Advances in Cholestatic Liver Diseases

The list of genetically defined causes of cholestatic liver diseases continues to expand; it currently includes mutations affecting bile acid synthesis, basolateral and apical membrane transporters, bile duct development, canalicular tight junctions, and bile acid conjugation, among others. The most frequently identified mutations in large multi-institutional studies of cholestasis occur in JAG1, ATP8B1, ABCB11, ABCB4, SERPINA1 , and CFTR . Mutations in JAG1 , SERPINA1, and CFTR cause Alagille syndrome, alpha-1 antitrypsin deficiency, and cystic fibrosis, respectively. Mutations in ATP8B1 , ABCB11, and ABCB4 cause a spectrum of diseases that range from the episodic, nonprogressive benign recurrent intrahepatic cholestasis and intrahepatic cholestasis of pregnancy to the severe and rapidly progressive familial intrahepatic cholestasis. These cholestatic disorders present a wide range of symptoms and overlapping clinical features. However, in contemporary practice, diagnosis is often easily and rapidly established by clinically available comprehensive gene panels. In addition to diagnosis, these panels also aid in the discovery of novel genes or variants as potential causes of cholestasis. Genetic mutations may also be responsible for drug-induced cholestasis, as the liver plays a vital role in metabolism of drugs and xenobiotics. Uptake into hepatocytes and elimination into the bloodstream or bile of drugs and xenobiotics involve transporters across the basolateral and apical hepatocellular membranes, respectively. Therefore, mutations in any of the transporters lead to impaired metabolism and/or elimination of these substances. Furthermore, a large number of drugs and xenobiotics have a transcriptional or functional inhibitory effect on transporters such as BSEP and MDR3, setting the stage for the all-too-common drug-induced cholestasis.