Bilirubin Uridine Diphosphate-Glucuronosyltransferase Variation Is a Genetic Basis of Breast Milk Jaundice

Abstract

Objective To evaluate the role of bilirubin UDP-glucuronosyltransferase family 1, polypeptide A1 (UGT1A1) gene variations on prolonged unconjugated hyperbilirubinemia associated with breast milk feeding (breast milk jaundice [BMJ]). Study design UGT1A1 gene allelic variation was analyzed in 170 Japanese infants with BMJ with polymerase chain reaction-direct sequencing, and their genotypes compared with serum bilirubin concentrations. In 62 of 170 infants, serum bilirubin concentration was followed after 4 months of life. Genotypes were examined in 55 infants without BMJ. Results Of 170 infants with BMJ, 88 (51.8%) were homozygous UGT1A1*6. Serum bilirubin concentrations (21.8 ± 3.65 mg/dL) were significantly greater than in infants with other genotypes (P < .0001). The Gilbert UGT1A1*28 allele was not detected in infants with BMJ, except in an infant who was compound heterozygous with UGT1A1*6. At 4 months of age, serum bilirubin concentration improved to >1 mg/dL, except in 2 infants who were homozygous UGT1A1*7. Homozygous UGT1A1*6 was not detected in the control group. Conclusion One-half of the infants with BMJ were homozygous UGT1A1*6 and exhibited a serum bilirubin concentration significantly greater than other genotypes. This finding indicates that UGT1A1*6 is a major cause of BMJ in infants in East Asia. Previous finding have demonstrated that 5β-pregnane-3α,20β-diol present in breast milk inhibits p.G71R-UGT1A1 bilirubin glucuronidation activity. Thus, prolonged unconjugated hyperbilirubinemia may develop in infants with UGT1A1*6 who are fed breast milk.

Genotype of UGT1A1 and phenotype correlation between Crigler–Najjar syndrome type II and Gilbert syndrome

“…UGT1A1*28 enhancer-promoter reduces the expression of hepatic UGT1A1 but not intestinal UGT1A1 at neonatal period. 33 However, UGT1A1*28 does not only affect hyperbilirubinemia in the neonatal period; 5,21 in this study, it was clinically revealed that UGT1A1*28 plays a role in GS after puberty, similar to UGT1A1*6, in the Japanese population.…”

“…Our recent and previous studies on the association between neonatal jaundice revealed that UGT1A1*6 is also a risk factor for neonatal hyperbilirubinemia in early neonatal period and a genetic cause for BMJ. 4,5,21 However, UGT1A1*28 does not contribute to neonatal hyperbilirubinemia and BMJ. The reason why the contribution of UGT1A1*28 to generate hyperbilirubinemia is different in neonatal period and thereafter was estimated as follows.…”

Healthy Newborn Jaundices: Causes, Course, Prognosis

“…В течение последних 5 лет представлены доказа-тельства того, что имеется связь между желтухой есте-ственного вскармливании и вариантами гена, кодирую-щего синтез фермента уридин-дифосфат-глюкуронил-трансферазы (UDP-glucuronosyl-transferase family 1, polypeptide A1 [UGT1A1]), участвующего в конъюгации непрямого билирубина [11]. При желтухе от материнского молока в неонатальном периоде наиболее часто встреча-ется аллель UGT1A1*6.…”

A Modern Look at Breastfeeding in Neonatal Hyperbilirubinaemia

“…Один или несколько компонен-тов в молоке могут вызвать желтуху именно у младенцев, у которых имеются такие мутации. Таким образом, дли-тельная неконъюгированная гипербилирубинемия может развиваться у младенцев с UGT1A1 * 6, которые получа-ют грудное молоко [22,23]. При желтухе, связанной с составом грудного молока, наблюдается более высокая концентрация НБ в крови к 4-6-му дню жизни, которая продолжает нарастать, достигая пика к 10-15-му дню жизни.…”