Neonatal cholestasis: emerging molecular diagnostics and potential novel therapeutics

Neonatal cholestasis is a group of rare disorders of impaired bile flow characterized by conjugated hyperbilirubinaemia in the newborn and young infant. Neonatal cholestasis is never physiological but rather is a sign of hepatobiliary and/or metabolic disorders, some of which might be fatal if not identified and treated rapidly. A step-wise timely evaluation is essential to quickly identify those causes amenable to treatment and to offer accurate prognosis. The aetiology of neonatal cholestasis now includes an expanding group of molecularly defined entities with overlapping clinical presentations. In the past two decades, our understanding of the molecular basis of many of these cholestatic diseases has improved markedly. Simultaneous next-generation sequencing for multiple genes and whole-exome or whole-genome sequencing now enable rapid and affordable molecular diagnosis for many of these disorders that cannot be directly diagnosed from standard blood tests or liver biopsy. Unfortunately, despite these advances, the aetiology and optimal therapeutic approach of the most common of these disorders, biliary atresia, remain unclear. The goals of this Review are to discuss the aetiologies, algorithms for evaluation and current and emerging therapeutic options for neonatal cholestasis. Neonatal cholestasis is a group of disorders of impaired bile flow characterized by conjugated hyperbilirubinaemia that can be fatal if not treated rapidly. In this Review, aetiologies, algorithms for evaluation and current and emerging therapeutic options for neonatal cholestasis are discussed. Key points Early recognition and expedited evaluation of an infant with cholestasis are of utmost importance, as neonatal cholestasis is never physiological and often requires immediate treatment or intervention. Cost-effective methods to reliably screen for biliary atresia in the first month of life are needed to improve age at diagnosis and Kasai hepatoportoenterostomy for infants with biliary atresia. New genetic causes of neonatal cholestasis are being discovered at a rapid rate owing to the advent of next-generation gene-sequencing technologies and sophisticated bioinformatics. Use of genetic testing might enable us to rapidly identify genetic causes of cholestasis without the need for invasive procedures and might lead to new precision treatments. Multiple sites exist within the hepatobiliary tree where bile formation or flow can be impaired, resulting in neonatal cholestasis; thes