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

J. Watchko
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引用次数: 6

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.
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遗传因素对新生儿高胆红素血症和kernicterus风险的影响:一项有针对性的更新
新生儿高胆红素血症的发生具有病因异质性、环境调节和多基因位点的相互作用等特点。除了遗传性溶血性疾病外,常见的黄疸基因变异也可能是高胆红素血症和核黄疸风险的调节剂。本综述针对Gilbert综合征的生物学性别、尿苷二磷酸葡萄糖醛酸糖基转移酶同酶UGT1A1基因变异的影响,包括它们在母乳黄疸中的作用,以及黄疸等位基因的共同表达对新生儿高胆红素血症风险的增强作用。值得注意的是,在过去二十年中,来自全球各地的证据证实,母乳黄疸是新生儿中普遍存在的吉尔伯特综合征表型。此外,来自人源化小鼠模型的新数据表明,母乳低聚糖对肠道(而不是肝脏)UGT1A1表达的重要抑制作用导致母乳黄疸风险。更具体地说,人乳低聚糖阻断肠道toll样受体激活和下游IĸB激酶磷酸化。这反过来又抑制新生肠道UGT1A1的活性。相比之下,配方饲料激活IĸB并诱导肠道(而非肝脏)UGT1A1活性,从而降低血清总胆红素(TSB)。这种现象是否适用于人类新生儿尚不清楚。虽然UGT1A1在成人肠道中表达,但在人类胎儿或新生儿肠道中UGT1A1的表达尚无可比的发育数据,这一知识空白为临床研究提供了成熟的条件。
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