Prolonged unconjugated hyperbilirubinemia associated with breast milk and mutations of the bilirubin uridine diphosphate-glucuronosyltransferase gene

Objective. Breast milk jaundice is a common problem in nursing infants. It has been ascribed to various breast milk substances, but the component or c ombination of components that is responsible remains unknown. During our st udy of defects of the bilirubin uridine diphosphate-glucuronosyltransferase gene (UGT1A1) in patients with hereditary unconjugated hyperbilirubinemia (Crigler-Najjar syndrome and Gilbert's syndrome) and neonatal hyperbilirubi nemia, we encountered a prolonged case associated with breastfeeding; after cessation of breastfeeding, the infant's bilirubin level became normal. Ge netic analysis revealed a missense mutation identical to that found in pati ents with Gilbert's syndrome, which usually causes jaundice after puberty. We analyzed the bilirubin UGT1A1 of infants with prolonged unconjugated hyp erbilirubinemia associated with breast milk to ascertain whether genetic fa ctors are involved. Patients and Methods. We analyzed 17 breastfed Japanese infants with appare nt prolonged jaundice (total serum bilirubin concentrations above 171 mu mo l/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, liv er dysfunction, or hypothyroidism. After cessation of breastfeeding, the se rum bilirubin concentration began to decrease in all cases. When breastfeed ing was resumed, serum bilirubin concentration again became elevated in som e infants, but the concentration fell to within normal by 4 months of age. We analyzed the polymerase chain reaction-amplified exon, promoter, and enh ancer regions of UGT1A1 by direct sequencing. Results. Sixteen infants had at least one mutation of the UGT1A1. Seven wer e homozygous for 211G-->A (G71R), which is the most common mutation detecte d 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 Gilbert's syndrome, and it corresponds t o a UGT1A1 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)7 TAA mutation, which was the most common cause of Gilbert's syndrome in Euro pean population, in this study of Japanese infants with prolonged hyperbili rubinemia triggered by breast milk. Conclusions. The results indicate that defects of UGT1A1 are an underlying cause of the prolonged unconjugated hyperbilirubinemia associated with brea st milk. One or more components in the milk may trigger the jaundice in inf ants who have such mutations. The mutations we found were identical to thos e detected in patients with Gilbert's syndrome, a risk factor of neonatal n onphysiologic hyperbilirubinemia and a genetic factor in fasting hyperbilir ubinemia.