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Neonatal hyperbilirubinemia in glucose-6-phosphate dehydrogenase-deficient heterozygotes
M Kaplan1, E Beutler, H J Vreman
1Department of Neonatology, Shaare Zedek Medical Center, Jerusalem, Israel. kaplan@cc.hujiac.il
Insights
Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency heterozygotes face a higher risk of neonatal hyperbilirubinemia. The variant UGT1A1 gene also increases this risk, while standard screening tests miss most G-6-PD heterozygotes.
Area of Science:
- Neonatal Medicine
- Medical Genetics
- Biochemistry
Background:
- Neonatal hyperbilirubinemia is a common condition, particularly in at-risk populations.
- Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency is an inherited condition that can affect red blood cells.
- The UGT1A1 gene plays a crucial role in bilirubin metabolism.
Purpose of the Study:
- To assess the incidence of hyperbilirubinemia in Sephardic Jewish female neonates with G-6-PD deficiency, focusing on heterozygotes.
- To investigate the roles of hemolysis and the UGT1A1 gene variant in the pathogenesis of neonatal hyperbilirubinemia.
Main Methods:
- Clinical observation and serum bilirubin evaluations for hyperbilirubinemia in term female neonates.
- Screening for G-6-PD deficiency and analysis of DNA for G-6-PD Mediterranean563T mutation and UGT1A1 gene variants.
- Blood carboxyhemoglobin (COHb) determinations to assess hemolysis.
Main Results:
- G-6-PD-deficient heterozygotes (22%) and homozygotes (26.3%) had a higher incidence of hyperbilirubinemia compared to normal homozygotes (9.8%).
- Neonates with both G-6-PD deficiency and the variant UGT1A1 gene showed a significantly greater incidence of hyperbilirubinemia.
- Standard G-6-PD deficiency screening tests failed to identify most heterozygotes (only 20.4% detected).
Conclusions:
- G-6-PD-deficient heterozygotes are at increased risk for neonatal hyperbilirubinemia.
- The presence of the variant UGT1A1 gene confers an additional risk for hyperbilirubinemia.
- Current screening methods are inadequate for detecting G-6-PD heterozygotes effectively.
Objectives:
We assessed the incidence of hyperbilirubinemia, defined as serum total bilirubin >/=15 mg/dL (256 micromol/L), in a cohort of Sephardic Jewish female neonates at risk for glucose-6-phosphate dehydrogenase (G-6-PD) deficiency with especial emphasis on the heterozygotes. We studied the roles of hemolysis by blood carboxyhemoglobin (COHb) determinations and of the variant promoter of the gene for the bilirubin-conjugating enzyme uridine 5'-diphosphate glucuronosyltransferase 1 (UGT1A1) seen in Gilbert's syndrome in the pathogenesis of the hyperbilirubinemia.
Methods:
Consecutively born, healthy, term, female neonates were screened for G-6-PD deficiency and observed clinically with serum bilirubin evaluations as indicated for hyperbilirubinemia. On day 3, blood was sampled for COHb, total hemoglobin (tHb), and a mandatory serum bilirubin determination. COHb, determined by gas chromatography, was expressed as percentage of tHb and corrected for inspired carbon monoxide (COHbc). DNA was analyzed for the G-6-PD Mediterranean563T mutation and for the variant UGT1A1 gene.
Results:
The cohort included 54 G-6-PD-deficient heterozygotes, 19 deficient homozygotes, and 112 normal homozygotes. More heterozygotes (12/54, 22%; relative risk: 2.26; 95% CI: 1.07-4.80) and deficient homozygotes (5/19, 26.3%; relative risk: 2.68; 95% CI: 1.05-6.90) developed hyperbilirubinemia, than did normal homozygotes (11/112, 9.8%). Third-day serum bilirubin values that were obtained from 144 neonates were significantly higher in both heterozygotes (11.2 +/- 3. 7 mg/dL [192 +/- 64 micromol/L]) and G-6-PD-deficient homozygotes (12.0 +/- 3.0 mg/dL [206 +/- 52 micromol/L]) than in the G-6-PD normal homozygotes (9.4 +/- 3.4 mg/dL [160 +/- 58 micromol/L). In contrast, COHbc values were higher only in G-6-PD-deficient homozygotes (0.74% +/- 0.14%) and not in heterozygotes (0.69% +/- 0. 19%, not statistically significant), compared with control values (0. 63% +/- 0.19%). High COHbc values were not a prerequisite for the development of hyperbilirubinemia in any of the G-6-PD genotypes. A greater incidence of hyperbilirubinemia was found among the G-6-PD-deficient heterozygotes, who also had the variant UGT1A1 gene, in both heterozygous (6/20, 30%) and homozygous (4/8, 50%) forms, than was found in their counterparts with the normal UGT1A1 gene (2/26, 7.7%). This effect was not seen in the G-6-PD normal homozygote group. A color reduction screening test for G-6-PD deficiency identified only 20.4% (11/54) of the heterozygotes.
Conclusions:
We showed that G-6-PD-deficient heterozygotes, categorically defined by DNA analysis, are at increased risk for neonatal hyperbilirubinemia. The screening test that was used was unable to detect most heterozygotes. Increased bilirubin production was not crucial to the development of hyperbilirubinemia, but presence of the variant UGT1A1 gene did confer increased risk.