Circulating non-transferrin-bound iron after oral administration of supplemental and fortification doses of iron to healthy women: a randomized study

Abstract

Background: After the oral administration of iron, the production of circulating non-transferrin-bound iron may contribute to an increased risk of illness in malaria-endemic areas that lack effective medical services.

Objective: In healthy women with a range of body iron stores, we aimed to determine effects on the production of circulating non-transferrin-bound iron resulting from the oral administration of 1) a supplemental dose of iron (60 mg) with water, 2) a supplemental dose of iron (60 mg) with a standard test meal, and 3) a fortification dose of iron (6 mg) with a standard test meal.

Design: With the use of serum ferritin as the indicator, healthy women with replete iron stores (ferritin concentration >25 μg/L; n = 16) and reduced iron stores (ferritin concentration ≤25 μg/L; n = 16) were enrolled in a prospective, randomized, crossover study. After the oral administration of aqueous solutions of ferrous sulfate isotopically labeled with ⁵⁴Fe, ⁵⁷Fe, or ⁵⁸Fe, blood samples were collected for 8 h, and iron absorption was estimated by erythrocyte incorporation at 14 d.

Results: At 4 h, serum non-transferrin-bound iron reached peaks with geometric mean (95% CI) concentrations of 0.81 μmol/L (0.56, 1.1 μmol/L) for 60 mg Fe with water and 0.26 μmol/L (0.15, 0.38 μmol/L) for 60 mg Fe with food but was at assay limits of detection (0.1 μmol Fe/L) for 6 mg Fe with food. For the 60 mg Fe without food, the area under the curve over 8 h for serum non-transferrin-bound iron was positively correlated with the amount of iron absorbed (R = 0.49, P < 0.01) and negatively correlated with serum ferritin (R = -0.39, P < 0.05).

Conclusions: In healthy women, the production of circulating non-transferrin-bound iron is determined by the rate and amount of iron absorbed. The highest concentrations of non-transferrin-bound iron resulted from the administration of supplemental doses of iron without food. Little or no circulating non-transferrin-bound iron resulted from the consumption of a meal with a fortification dose of iron.

Trial registration: ClinicalTrials.gov NCT01404533.

© 2014 American Society for Nutrition.

Figures

FIGURE 1.

Mean (95% CI) transferrin saturation during 8 h after an oral dose of 6 mg Fe with a meal, 60 mg Fe with a meal, or 60 mg Fe without a meal as FeSO4. Curves display values at each time point for the respective meal for 25–29 subjects; transferrin saturation data were incomplete at some time points for 7 iron-replete subjects. Labeled legends indicate that the AUC for meals without a common letter differed, P < 0.0001 (repeated-measures ANOVA with Bonferroni correction).

FIGURE 2.

Geometric mean (95% CI) hepcidin concentrations during 8 h after an oral dose of 6 mg Fe with a meal, 60 mg Fe with a meal, or 60 mg Fe without a meal as FeSO4. Curves display values at each time point for the respective meal for all 32 subjects. P values for the linear mixed effects model were as follows: P-time × meal effect < 0.01, P-time < 0.001, and P-meal = 0.71. Note that hepcidin concentrations continued to increase after peaks of transferrin saturation (Figure 1) and non–transferrin-bound iron (Figure 3) had been reached at ∼4 h.

FIGURE 3.

Geometric mean (95% CI) increases in concentrations of non–transferrin-bound iron from baseline (Δ change) over 8 h after an oral dose of 6 mg Fe with a meal, 60 mg Fe with a meal, or 60 mg Fe without a meal as FeSO4. Curves display values at each time point for the respective meal for all 32 subjects. Labeled legends indicate that the AUC for meals without a common letter differed, P < 0.05 (repeated-measures ANOVA with Bonferroni correction).

FIGURE 4.

Correlation between the AUC for non–transferrin-bound iron increase from baseline (Figure 3) and the amount (mg) of iron absorbed for the test meal administering 60 mg without a meal (R = 0.49, P < 0.01; Pearson's correlation). Data for non–transferrin-bound iron increases and the amount of iron absorbed were analyzed on a log scale. Axis values are back transformed data presented on a log scale. Dotted lines indicate 95% CIs of the regression line.

FIGURE 5.

Mean (95% CI) increases in serum isotope appearance and serum iron from baseline (Δ change) during 8 h after an oral dose of 6 mg Fe with a meal, 60 mg Fe with a meal, or 60 mg Fe without a meal as FeSO4 in subjects with a serum ferritin concentration <25 μg/L. Curves display values at each time point for the respective meal for 16 subjects. Labeled legends indicate that the AUC for meals without a common letter differed, P < 0.05 (repeated-measures ANOVA with Bonferroni correction).