The contribution of genetic factors to hyperbilirubinemia and kernicterus risk in neonates: a targeted update

Abstract

The genesis of neonatal hyperbilirubinemia is characterized by etiologic heterogeneity, environmental modulation, and the interaction of multiple gene loci. In addition to inherited hemolytic conditions, common icterogenic gene variants may act as modifiers of hyperbilirubinemia and kernicterus risk. The current review targets the effect of biologic sex, uridine diphosphate glucuronosyltransferase isoenzyme UGT1A1 gene variants of Gilbert syndrome, including their role in breastmilk jaundice, and the co-expression of icterogenic alleles have on potentiating hyperbilirubinemia risk in neonates. Notably, evidence accrued during the past two decades, from around the globe, confirm that breastmilk jaundice is a prevalent Gilbert syndrome phenotype in neonates. Moreover, novel data from humanized murine models suggest an important repressive effect of breastmilk oligosaccharides on intestinal (as opposed to hepatic) UGT1A1 expression in driving breast milk jaundice risk. More specifically, human milk oligosaccharides block intestinal Toll-like receptor activation and downstream IĸB kinase phosphorylation. This in turn represses newborn intestinal UGT1A1 activity. Formula feeding, by contrast, activates IĸB and induces intestinal (but not hepatic) UGT1A1 activity thereby lowering the total serum bilirubin (TSB). Whether this phenomenon is operative in human neonates is unclear. Although UGT1A1 is expressed in adult intestine, there are no comparable developmental data on intestinal UGT1A1 expression in the human fetus or neonate, a knowledge gap that is ripe for clinical investigation.