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Hyperbilirubinaemia presents as jaundice, occurs frequently in newborn babies, and is a leading cause of hospitalisation in the first weeks of life. In some infants, jaundice can progress to acute bilirubin encephalopathy and kernicterus, which may lead to neonatal mortality and neurodevelopmental impairments.1 The degree of hyperbilirubinaemia is one indicator of the severity of liver failure. High levels of bilirubin in plasma may predict short-term mortality in these patients.2 Four distinct steps of bilirubin metabolism were proposed.3 In health, unconjugated bilirubin is taken up along the sinusoidal surface of the hepatocyte by solute carrier family 21, member 6 (SLC21A6; AKA organic anion transporter 2, OATP2). Ligandin, a homodimer or heterodimer of glutathione-S-transferase (GST) A1 and A2, binds bilirubin with high affinity and increases its uptake. Bilirubin is then glucuronidated by bilirubin uridine diphosphate-5′-glucuronosyltransferase (UDP-glucuronosyltransferase 1A1, UGT1A1). The resulting hydrophilic bilirubin diglucuronide is then secreted across the bile-canalicular membrane of the hepatocytes by multidrug resistance-related protein 2 (MRP2) (cMOAT, ABCC2). Disrupting the pathway anywhere in this process can lead to several hyperbilirubinaemia syndromes. For example, complete OATP1B1 and OATP1B3 deficiency interrupts unconjugated bilirubin reuptake into the liver and leads to Rotor syndrome.4 Mild-to-severe deficiency of UGT1A1 results in two types of familial unconjugated hyperbilirubinaemia, Crigler-Najjar syndromes I and II, and Gilbert’s syndrome.5 Dubin-Johnson syndrome, a heritable loss of human MRP2 function, is characterised by hyperbilirubinaemia and pigment deposition in the liver. MRP2 is the rate-limiting step in hepatic bilirubin excretion. Ligands for farnesoid X-activated receptor (FXR), …
Contributors Both authors wrote and edited the manuscript.
Funding In preparing this manuscript, the author was supported by the Georgia and Irina Schaeffer Foundation, the John Hench Foundation, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK award R01DK124627) and the National Cancer Institute (NCI award 2R01CA139158).
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.