Hepcidin is the major predictor of erythrocyte iron incorporation in anemic African children

Abstract

Iron supplementation strategies in the developing world remain controversial because of fears of exacerbating prevalent infectious diseases. Understanding the conditions in which iron will be absorbed and incorporated into erythrocytes is therefore important. We studied Gambian children with either postmalarial or nonmalarial anemia, who were given oral iron supplements daily for 30 days. Supplements administered on days 1 and 15 contained the stable iron isotopes (57)Fe and (58)Fe, respectively, and erythrocyte incorporation was measured in blood samples drawn 14 days later. We investigated how the iron-regulatory hormone hepcidin and other inflammatory/iron-related indices, all measured on the day of isotope administration, correlated with erythrocyte iron incorporation. In univariate analyses, hepcidin, ferritin, C-reactive protein, and soluble transferrin receptor (sTfR) strongly predicted incorporation of (57)Fe given on day 1, while hepcidin, ferritin, and sTfR/log ferritin correlated with (58)Fe incorporation. In a final multivariate model, the most consistent predictor of erythrocyte isotope incorporation was hepcidin. We conclude that under conditions of competing signals (anemia, iron deficiency, and infection), hepcidin powerfully controls use of dietary iron. We suggest that low-cost point-of-care hepcidin assays would aid iron supplementation programs in the developing world.

Figure 1

Schedule of malarial treatment and iron supplementation, including administration of stable iron isotopes. A course of iron supplementation was initiated in anemic Gambian children. Supplementation was initiated on day 1. Children who had presented with P falciparum parasitemia 3 days previously had their parasitemias cleared by a 3-day course of chloroquine/fansidar. The stable iron isotopes ⁵⁷Fe and ⁵⁸Fe were administered as sulfate on days 1 and 15, respectively. Iron, 2 mg/kg/d, was given as liquid iron glycine sulfate on all other days of the supplementation course starting from day 2.

Figure 2

Scatterplots of oral iron incorporation versus hepcidin. (A) Serum hepcidin measured on day 1 is plotted against incorporation of ⁵⁷Fe (which was administered on day 1). (B) Serum hepcidin measured on day 15 is plotted against incorporation of ⁵⁸Fe (which was administered on day 15). ● indicates children admitted into the study with postmalarial anemia; and ○, children admitted into the study with nonmalarial anemia. Line depicts best-fit regression.