Systemic regulation of bilirubin homeostasis: Potential benefits of hyperbilirubinemia

Neurotoxic bilirubin is the end product of heme catabolism in mammals. Bilirubin is solely conjugated by UDP-glucuronosyltransferase (UGT) 1A1, which is a membrane-bound enzyme that catalyzes a transfer of glucuronic acid. Due to low function of hepatic and intestinal UGT1A1 during the neonatal period, human neonates develop mild to severe physiological hyperbilirubinemia. The accumulation of bilirubin in the brain leads to the onset of irreversible brain damage, kernicterus. Breastfeeding is one of the most significant factors that increase the risk of developing kernicterus in infants. Why does this most natural way of feeding increase the risk of brain damage or even death? This question leads to the hypothesis that breast milk-induced hyperbilirubinemia might bring certain benefits that outweigh those disadvantages. While bilirubin is neuro- and cytotoxic, it is also a potent antioxidant. There are studies showing improved clinical conditions in patients with hyperbilirubinemia. Accumulating evidence also shows that genetic polymorphisms linked to hyperbilirubinemia are beneficial against various diseases. In this review article, we first introduce the production, metabolism, and transport of bilirubin. We then discuss the potential benefits of neonatal and adult hyperbilirubinemia. Finally, epigenetic factors as well as metabolomic information associated with hyperbilirubinemia are included. This review article advances the understanding of the physiological importance of the paradoxical compound bilirubin. This article is protected by copyright. All rights reserved.