Prolonged Unconjugated Hyperbilirubinemia Associated With Breast Milk and Mutations of the Bilirubin Uridine Diphosphate- Glucuronosyltransferase Gene

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Abstract
Objective. Breast milk jaundice is a common problem in nursing infants. It has been ascribed to various breast milk substances, but the component or combination of components that is responsible remains unknown. During our study of defects of the bilirubin uridine diphosphate-glucuronosyltransferase gene (UGT1A1) in patients with hereditary unconjugated hyperbilirubinemia (Crigler-Najjar syndrome and Gilbert9s syndrome) and neonatal hyperbilirubinemia, we encountered a prolonged case associated with breastfeeding; after cessation of breastfeeding, the infant9s bilirubin level became normal. Genetic analysis revealed a missense mutation identical to that found in patients with Gilbert9s syndrome, which usually causes jaundice after puberty. We analyzed the bilirubinUGT1A1 of infants with prolonged unconjugated hyperbilirubinemia associated with breast milk to ascertain whether genetic factors are involved. Patients and Methods. We analyzed 17 breastfed Japanese infants with apparent prolonged jaundice (total serum bilirubin concentrations above 171 μmol/L [10 mg/dL]) 3 weeks to 1 month after their birth. Except for jaundice, the infants were healthy and did not show evidence of hemolytic anemia, liver dysfunction, or hypothyroidism. After cessation of breastfeeding, the serum bilirubin concentration began to decrease in all cases. When breastfeeding was resumed, serum bilirubin concentration again became elevated in some infants, but the concentration fell to within normal by 4 months of age. We analyzed the polymerase chain reaction-amplified exon, promoter, and enhancer regions of UGT1A1 by direct sequencing. Results. Sixteen infants had at least one mutation of theUGT1A1. Seven were homozygous for 211G→A (G71R), which is the most common mutation detected in the East Asian population, and the mutant enzyme had one third of the normal activity. G71R is the most common missense mutation we found in our analyses in Japanese patients with Gilbert9s syndrome, and it corresponds to aUGT1A1 polymorphism in the Japanese population (the allele frequency is .16). One was heterozygous for 1456T→G (Y486D) and homozygous for 211G→A. Six were heterozygous for 211G→A. One was heterozygous for both 211G→A and a TATA box mutation (A(TA)7TAA). One had a heterozygous mutation in an enhancer region (C→A at −1353). We did not detect a homozygous A(TA)7TAA mutation, which was the most common cause of Gilbert9s syndrome in European population, in this study of Japanese infants with prolonged hyperbilirubinemia triggered by breast milk. Conclusions. The results indicate that defects ofUGT1A1 are an underlying cause of the prolonged unconjugated hyperbilirubinemia associated with breast milk. One or more components in the milk may trigger the jaundice in infants who have such mutations. The mutations we found were identical to those detected in patients with Gilbert9s syndrome, a risk factor of neonatal nonphysiologic hyperbilirubinemia and a genetic factor in fasting hyperbilirubinemia.