Severe neonatal hyperbilirubinemia and the brain: the old but still evolving story

Abstract

: The immature hepatic metabolism of bilirubin at birth is responsible for neonatal hyperbilirubinemia, present in more than 60% of otherwise healthy infants. Icterus (or jaundice), the most apparent features of the increased bilirubin level in the serum, testifies the entry of the pigment in the tissues and organs, brain included. The sensitivity of the central nervous system (CNS) to bilirubin toxicity is responsible for the potential neurologic damage, and even death. The symptoms in affected neonates suggest that selected brain areas are more specifically targeted by bilirubin, a hypothesis longer explained by the deposition of bilirubin in those areas, the “kern-icterus”. Most recently, a more complex picture and alternative explanations to the variability of the symptoms recapped by the terms bilirubin induced neurological dysfunction (BIND) or kernicterus spectrum disorder (KSD) are emerging, with pre-term neonates representing a new challenge. Here we will review what is known of the disease, from the dogma of the “kern-icterus” to the most recent findings bringing into play the stage of brain development at the time of bilirubin insult. Special emphasis will be given to the emerging population of pre-term neonates, especially sensitive to bilirubin toxicity. on the effect of free UCB on brain barriers integrity. A case report of a pre-term neonate with severe kernicterus indicates that signs of neurovascular network alteration was observed on autopsied brain tissue, possibly linked to an increase in vascular endothelial growth factor (VEGF) signaling (192). Given the comorbidities associated, whether UCB alone was responsible for these alterations remains to be understood. One study performed in Gunn rats, an animal model of jaundice characterized by a rapid postnatal increase in serum UCB evidenced a decrease in ABCC1 protein levels in CPs. This finding could be reproduced in vitro on choroidal epithelial cells chronically exposed to UCB, suggesting that ABCC1 downregulation results from a direct effect of UCB on the BCSFB