Project Details

The influence of hepcidin on benefits and risks of iron supplementation in Bangladeshi children

Leila Larson, PhD, MPH

Summary

BACKGROUND: Hepcidin is the best predictor of iron absorption from food or supplements, and hepcidin concentrations may indicate which individuals are responsive to iron supplementation. In individuals with high hepcidin, absorption of iron is reduced which may lead to more iron progressing to the colon where it can feed pathogenic activity and increase diarrhea. GAP: Studies to examine the influence of hepcidin on the benefits and risks of iron supplementation in various forms are needed to inform public health interventions. HYPOTHESES: (1) Compared to placebo, effects of 3 months of supplementation with iron syrup and iron-containing multiple micronutrient powders (MNPs) on hemoglobin and ferritin concentration at end of intervention and 9 months later will be larger in children with lower compared to higher baseline hepcidin concentrations. (2) Compared to placebo, effects of 3 months of supplementation with iron syrup and iron-containing MNPs on incidence of diarrhea will be smaller in children with lower compared to higher baseline hepcidin concentrations. (3) Effect modification from baseline hepcidin will be larger for children receiving MNPs compared to those receiving iron syrup. METHODS: Serum hepcidin was measured in a subsample of 1281 8 month-old children enrolled in a three-arm, double-blind, double-dummy, individually randomized controlled trial examining the efficacy of 3 months of universal supplementation with daily iron syrup (12.5mg iron), MNPs (containing 12.5mg iron), or placebo in children living in Bangladesh. Venous blood was collected from all participants at baseline, immediately post-intervention (month 3) and after a further 9 months of follow-up (month 12). Serum hepcidin concentrations were measured by ELISA (ILS), hemoglobin concentration was measured using venous blood on a HemoCue 301, and caregiver-reported incidence of diarrhea was collected weekly during the 3-month intervention period and monthly during the 9-month follow-up period. We used a likelihood-based longitudinal data analysis model that included hepcidin-by-treatment and hepcidin-by-visit interaction terms, to examine effect modification from baseline hepcidin on the effects of iron syrup or MNPs on hemoglobin concentration, ferritin concentration, and incidence of diarrhea at months 3 and 12. RESULTS: The proportion of children with low (<10ng/mL) hepcidin concentration was 9.6% and was comparable between arms. Mean baseline hemoglobin was lower in children with low compared to high baseline hepcidin concentration (104.1g/L [95% CI: 102.2, 106.0] among children with hepcidin <10ng/mL; 111.4g/L [95% CI: 110.9, 111.9] among children with hepcidin ≥10ng/mL). Baseline hepcidin modified the effect of MNPs, but not iron syrup, compared to placebo on hemoglobin and ferritin concentration immediately post intervention. The difference between children who received MNPs vs placebo in the change from baseline to month 3 in hemoglobin and ferritin concentrations was larger among children with low vs high baseline hepcidin (hemoglobin: mean difference 11.6g/L [95% CI: 7.2, 15.9] vs 4.3 [95% CI: 2.9, 5.6], p-interaction=0.002; ferritin: geometric mean ratio difference 2.4 [95% CI: 1.6, 3.6] vs 1.5 [95% CI: 1.3, 1.7], p-interaction=0.023). However, effect modification from baseline hepcidin was not sustained at month 12. Baseline hepcidin did not modify effects of either intervention on incidence of diarrhea. IMPACT: The immediate effects of MNP supplementation on hemoglobin and iron status of young children in this setting is larger among children with low vs high hepcidin concentrations, indicating that pre-intervention screening may be useful in identifying those children who would benefit most from MNP supplementation. The effects of supplementation with iron syrup, on the other hand, are not influenced by hepcidin and suggest that the benefits from this form of supplementation are independent of hepcidin status.