Developmental, Genetic, Dietary, and Xenobiotic Influences on Neonatal Hyperbilirubinemia

Abstract

Hyperbilirubinemia, caused by the accumulation of unconjugated bilirubin, is one of the most common clinical diagnoses in both premature and term newborns. Owing to the fact that bilirubin is metabolized solely through glucuronidation by UDP-glucuronosyltransferase (UGT) 1A1, it is now known that immaturity of UGT1A1, in combination with the overproduction of bilirubin during the developmental stage, acts as a bottleneck to bilirubin elimination and predisposes the infant to high total serum bilirubin levels. Although neonatal jaundice is mostly benign, excessively high levels of serum bilirubin in a small percentage of newborns can cause bilirubin-induced neurologic dysfunction, potentially leading to permanent brain damage, a condition known as kernicterus Although a large portion of hyperbilirubinemia cases in newborns are associated with hemolytic diseases, we emphasize here the impaired ability of UGT1A1 to eliminate bilirubin that contributes to hyperbilirubinemia-induced neurotoxicity in the developmental stage. As a series of hereditary UGT1A1 mutations have been identified that are associated with UGT1A1 deficiency, new evidence has verified that delayed expression of UGT1A1 during the early stages of neonatal development is a tightly controlled event involving coordinated intrahepatic and extrahepatic regulation. This review recapitulates the progress that has been made in recent years in understanding the causes and physiopathology of severe hyperbilirubinemia, investigating molecular mechanisms underlying bilirubin-induced encephalopathy, and searching for potential therapies for treating pathologic hyperbilirubinemia. Several animal models have been developed to make it possible to examine bilirubin-induced neurotoxicity from multiple directions. Moreover, environmental factors that may alleviate or worsen the condition of hyperbilirubinemia are discussed.

Fig. 1.

Release of bilirubin into blood and transport to the liver. The rapid increase in oxygen after birth stimulates red blood cell production and senescence, resulting in the release of heme from hemoglobin by the reticuloendothelial system. Heme undergoes metabolism by heme oxygenase and biliverdin reductase, resulting in the production of bilirubin, which is released into the blood and bound to serum proteins. After its uptake into the liver, bilirubin undergoes glucuronidation by UGT1A1, located in the endoplasmic reticulum. Bilirubin-glucuronide exits the hepatocyte where it works its way through the biliary canaliculi into the lumen of the intestines.

Fig. 2.

The upper panel shows the genetic background of hUGT1A1*28 mice. The top diagram is a representation of the human UGT1A locus, which was inserted into the mouse genome (Tg-UGT1), and the bottom diagram shows the targeted disruption of the mouse Ugt1 locus with an insertion of the neoresistant gene into exon 4. Middle panel (left): The Ugt1^−/− neonate exhibits the phenotypic trait of jaundice with a yellow skin color compared with in Ugt1^+/− mice. Most of the Ugt1^−/− mice die before day 7. Middle panel (right): Expression of UGT1A1 in neonatal liver and small intestine tissues in hUGT1A1*28 mice. The bottom diagram shows comparisons of TSB between the Ugt1^−/− and hUGT1A1*28 mice during the developmental period.

Fig. 3.

Top: By using the Cre-loxP recombination technology, the hepatocyte- or intestinal enterocyte-specific deletion of the Ugt1a1 gene (Ugt1^ΔHep or Ugt1^ΔIE) was achieved. The bottom diagram shows the impact of the tissue-specific deletion of the Ugt1a1 gene on serum bilirubin levels.

Fig. 4.

Top: UFP mice carrying the target construct. Ugt1a1loxP[FRTneoFRT]loxP were bred into transgenic Albumin-Cre mice to generate UGT1a1F/F/Albumin-Cre mice (UAC mice). Middle (left): Comparisons of TSB levels between UFP and UAC mice during the developmental period. Middle (right): The Kaplan-Meier survival curves analyze the survival rates of UFP and UAC mice. Bottom: Excessively high levels of bilirubin penetrate to the brain of the 15-day-old UAC mouse.

Fig. 5.

Images from cerebellum, medulla, pons, and corpus callosum indicate reduced myelination, as shown by the reduction of the presence of myelin basic protein (MBP, green) in neurons (neurofilament, red).