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  • Review Article
  • Published:

Neonatal cholestasis: emerging molecular diagnostics and potential novel therapeutics

Nature Reviews Gastroenterology & Hepatology volume 16, pages 346–360 (2019)Cite this article

Abstract

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.

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; these sites are potential targets for new pharmacological therapies.

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Fig. 1: Transport proteins involved in enterohepatic circulation of bile acids.
Fig. 2: Current and proposed emerging algorithms for evaluation of neonatal cholestasis.
Fig. 3: Imaging and histopathological findings of biliary atresia.
Fig. 4: A stage-based approach to the treatment of neonatal cholestasis.
Fig. 5: Targets for new therapies in development for the treatment of cholestasis.

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Acknowledgements

R.J.S. is supported in part by US National Institutes of Health (NIH) grants U01 DK062453 and UL1 TR002535. A.G.F. is supported by an NIH and National Center for Advancing Translational Sciences Clinical and Translational Science Award (KL2 TR002534) and a Children’s Hospital Colorado Research Scholar Award.

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Authors and Affiliations

  1. Pediatric Liver Center, Digestive Health Institute, Children’s Hospital Colorado, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, CO, USA

    Amy G. Feldman & Ronald J. Sokol

  2. Colorado Clinical and Translational Sciences Institute, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Ronald J. Sokol

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  1. Amy G. Feldman
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Both authors contributed equally to the preparation of this manuscript.

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Correspondence to Ronald J. Sokol.

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Glossary

Gilbert syndrome

A benign condition caused by a decrease in the activity of UGT1A1 that leads to intermittent elevations in serum unconjugated or indirect bilirubin levels.

Crigler–Najjar syndrome

An autosomal recessive disorder caused by mutations in UGT1A1 that lead to markedly elevated serum unconjugated or indirect bilirubin levels.

Galactosaemia

An autosomal recessive disorder caused by mutations in GALT that result in an inability to metabolize galactose normally, affecting the liver, brain and lens of the eye.

Choledochal cyst

Congenital dilatation of the biliary system.

Biliary atresia

A progressive sclerosing inflammatory process of the extrahepatic and intrahepatic bile ducts in infants under 3 months of age that leads to fibrosis and obliteration of the biliary tree.

Hepatoportoenterostomy (HPE) or Kasai procedure

A surgical procedure for treatment of biliary atresia in which a Roux-en-Y loop of jejunum is connected to the porta hepatitis, enabling bile to flow from the liver to the intestines.

Alagille syndrome

An autosomal dominant disorder in which a mutation in JAG1 or NOTCH2 results in phenotypic abnormalities including interlobular bile duct paucity.

Tyrosinaemia type 1

An autosomal recessive disorder caused by a defect in the enzyme fumarylacetoacetate hydrolase resulting in accumulation of toxic intermediates including succinylacetone in tissues and organs, leading to hepatocellular damage, hepatocellular carcinoma and neurotoxicity.

Biliary atresia splenic malformation syndrome

A phenotype of biliary atresia in which patients have a combination of laterality (left–right differentiation) defects, including asplenia or polysplenia, midline liver, preduodenal portal vein, interruption of the inferior vena cava, intestinal malrotation, situs inversus or cardiac malformations.

Posterior embryotoxon

A prominent Schwalbe’s line, in which the corneal endothelium and the uveal trabecular meshwork join, that is seen commonly in patients with Alagille syndrome.

Hepatobiliary scintigraphy

A diagnostic imaging technique that evaluates hepatocellular function and patency of the biliary system by following a radiolabeled tracer into the liver and out through the biliary system into the small intestine.

Dubin–Johnson syndrome

A benign autosomal recessive disorder caused by mutations in ABCC2 that result in isolated elevated serum conjugated or direct bilirubin levels and a dark coloured liver.

Niemann–Pick disease type C

A lysosomal storage disease associated with mutations in NPC1 and NPC2, which results in cholesterol and lipid accumulation in the lysosomes of hepatocytes, causing cholestasis, and affects the spleen and brain.

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Feldman, A.G., Sokol, R.J. Neonatal cholestasis: emerging molecular diagnostics and potential novel therapeutics. Nat Rev Gastroenterol Hepatol 16, 346–360 (2019). https://doi.org/10.1038/s41575-019-0132-z

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