Neonatal Cholestasis: Updates on Diagnostics, Therapeutics, and Prevention

Abstract

Cholestatic jaundice is a common presenting feature of hepatobiliary and/or metabolic dysfunction in the newborn and young infant. Timely detection of cholestasis, followed by rapid step-wise evaluation to determine the etiology, is crucial to identify those causes that are amenable to medical or surgical intervention and to optimize outcomes for all infants. In the past 2 decades, genetic etiologies have been elucidated for many cholestatic diseases, and next-generation sequencing, whole-exome sequencing, and whole-genome sequencing now allow for relatively rapid and cost-effective diagnosis of conditions not previously identifiable via standard blood tests and/or liver biopsy. Advances have also been made in our understanding of risk factors for parenteral nutrition-associated cholestasis/liver disease. New lipid emulsion formulations, coupled with preventive measures to decrease central line-associated bloodstream infections, have resulted in lower rates of cholestasis and liver disease in infants and children receiving long-term parental nutrition. Unfortunately, little progress has been made in determining the exact cause of biliary atresia. The median age at the time of the hepatoportoenterostomy procedure is still greater than 60 days; consequently, biliary atresia remains the primary indication for pediatric liver transplantation. Several emerging therapies may reduce the bile acid load to the liver and improve outcomes in some neonatal cholestatic disorders. The goal of this article is to review the etiologies, diagnostic algorithms, and current and future management strategies for infants with cholestasis.

Figure 1.

Evaluation of neonatal cholestasis. Biliary atresia, A1AT, and treatable causes of cholestasis (including choledochal cyst, infection, galactosemia, tyrosinemia, hypothyroidism) are excluded in a timely fashion through blood tests, imaging, potential liver biopsy, and intraoperative cholangiography to determine if biliary atresia is present. If there is a “red flag” based on maternal history, family history, or physical examination suggesting a specific diagnosis (Table 3), the infant should be promptly evaluated for that disease. If a cause is not identified, targeted gene panels, WES or WGS can be used to efficiently and effectively evaluate for both known genetic/metabolic causes of cholestasis as well as novel genetic causes. A1AT=α₁-antitrypsin, ALGS=Alagille syndrome, DB=direct bilirubin, IEOM=inborn errors of metabolism, TGP=targeted gene panel, WES=whole exome sequencing, WGS=whole genome sequencing.

Figure 2.

Hepatoportoenterostomy or Kasai portoenterostomy. A surgical procedure during which a Roux-en-Y loop of small intestine is connected to the hilum of the liver to create a new pathway for biliary drainage. (Image from National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.)