Bioavailability of iron, zinc, folic acid, and vitamin A from fortified maize.

Several strategies appear suitable to improve iron and zinc bioavailability from fortified maize, and fortification per se will increase the intake of bioavailable iron and zinc. Corn masa flour or whole maize should be fortified with sodium iron ethylenediaminetetraacetate (NaFeEDTA), ferrous fumarate, or ferrous sulfate, and degermed corn flour should be fortified with ferrous sulfate or ferrous fumarate. The choice of zinc fortificant appears to have a limited impact on zinc bioavailability. Phytic acid is a major inhibitor of both iron and zinc absorption. Degermination at the mill will reduce phytic acid content, and degermed maize appears to be a suitable vehicle for iron and zinc fortification. Enzymatic phytate degradation may be a suitable home-based technique to enhance the bioavailability of iron and zinc from fortified maize. Bioavailability experiments with low phytic acid-containing maize varieties have suggested an improved zinc bioavailability compared to wild-type counterparts. The bioavailability of folic acid from maize porridge was reported to be slightly higher than from baked wheat bread. The bioavailability of vitamin A provided as encapsulated retinyl esters is generally high and is typically not strongly influenced by the food matrix, but has not been fully investigated in maize.

Iron deficiency up-regulates iron absorption from ferrous sulphate but not ferric pyrophosphate and consequently food fortification with ferrous sulphate has relatively greater efficacy in iron-deficient individuals.

Fe absorption from water-soluble forms of Fe is inversely proportional to Fe status in humans. Whether this is true for poorly soluble Fe compounds is uncertain. Our objectives were therefore (1) to compare the up-regulation of Fe absorption at low Fe status from ferrous sulphate (FS) and ferric pyrophosphate (FPP) and (2) to compare the efficacy of FS with FPP in a fortification trial to increase body Fe stores in Fe-deficient children v. Fe-sufficient children. Using stable isotopes in test meals in young women (n 49) selected for low and high Fe status, we compared the absorption of FPP with FS. We analysed data from previous efficacy trials in children (n 258) to determine whether Fe status at baseline predicted response to FS v. FPP as salt fortificants. Plasma ferritin was a strong negative predictor of Fe bioavailability from FS (P < 0·0001) but not from FPP. In the efficacy trials, body Fe at baseline was a negative predictor of the change in body Fe for both FPP and FS, but the effect was significantly greater with FS (P < 0·01). Because Fe deficiency up-regulates Fe absorption from FS but not from FPP, food fortification with FS may have relatively greater impact in Fe-deficient children. Thus, more soluble Fe compounds not only demonstrate better overall absorption and can be used at lower fortification levels, but they also have the added advantage that, because their absorption is up-regulated in Fe deficiency, they innately 'target' Fe-deficient individuals in a population.

A micronutrient powder with low doses of highly absorbable iron and zinc reduces iron and zinc deficiency and improves weight-for-age Z-scores in South African children.

Micronutrient powders (MNP) are often added to complementary foods high in inhibitors of iron and zinc absorption. Most MNP therefore include high amounts of iron and zinc, but it is no longer recommended in malarial areas to use untargeted MNP that contain the Reference Nutrient Intake for iron in a single serving. The aim was to test the efficacy of a low-iron and -zinc (each 2.5 mg) MNP containing iron as NaFeEDTA, ascorbic acid (AA), and an exogenous phytase active at gut pH. In a double-blind controlled trial, South African school children with low iron status (n = 200) were randomized to receive either the MNP or the unfortified carrier added just before consumption to a high-phytate maize porridge 5 d/wk for 23 wk; primary outcomes were iron and zinc status and a secondary outcome was somatic growth. Compared with the control, the MNP increased serum ferritin (P < 0.05), body iron stores (P < 0.01) and weight-for-age Z-scores (P < 0.05) and decreased transferrin receptor (P < 0.05). The prevalence of iron deficiency fell by 30.6% (P < 0.01) and the prevalence of zinc deficiency decreased by 11.8% (P < 0.05). Absorption of iron from the MNP was estimated to be 7-8%. Inclusion of an exogenous phytase combined with NaFeEDTA and AA may allow a substantial reduction in the iron dose from existing MNP while still delivering adequate iron and zinc. In addition, the MNP is likely to enhance absorption of the high native iron content of complementary foods based on cereals and/or legumes.

Revised recommendations for iron fortification of wheat flour and an evaluation of the expected impact of current national wheat flour fortification programs.

BACKGROUND: Iron fortification of wheat flour is widely used as a strategy to combat iron deficiency. OBJECTIVE: To review recent efficacy studies and update the guidelines for the iron fortification of wheat flour. METHODS: Efficacy studies with a variety of iron-fortified foods were reviewed to determine the minimum daily amounts of additional iron that have been shown to meaningfully improve iron status in children, adolescents, and women of reproductive age. Recommendations were computed by determining the fortification levels needed to provide these additional quantities of iron each day in three different wheat flour consumption patterns. Current wheat flour iron fortification programs in 78 countries were evaluated. RESULTS: When average daily consumption of low-extraction (< or = 0.8% ash) wheat flour is 150 to 300 g, it is recommended to add 20 ppm iron as NaFeEDTA, or 30 ppm as dried ferrous sulfate or ferrous fumarate. If sensory changes or cost limits the use of these compounds, electrolytic iron at 60 ppm is the second choice. Corresponding fortification levels were calculated for wheat flour intakes of < 150 g/day and > 300 g/day. Electrolytic iron is not recommended for flour intakes of < 150 g/day. Encapsulated ferrous sulfate or fumarate can be added at the same concentrations as the non-encapsulated compounds. For high-extraction wheat flour (> 0.8% ash), NaFeEDTA is the only iron compound recommended. Only nine national programs (Argentina, Chile, Egypt, Iran, Jordan, Lebanon, Syria, Turkmenistan, and Uruguay) were judged likely to have a significant positive impact on iron status if coverage is optimized. Most countries use non-recommended, low-bioavailability, atomized, reduced or hydrogen-reduced iron powders. CONCLUSION: Most current iron fortification programs are likely to be ineffective. Legislation needs updating in many countries so that flour is fortified with adequate levels of the recommended iron compounds.

Plasma hepcidin is a modest predictor of dietary iron bioavailability in humans, whereas oral iron loading, measured by stable-isotope appearance curves, increases plasma hepcidin.

BACKGROUND: Plasma hepcidin appears to be a major regulator of iron absorption and homeostasis, but there are few data in humans. OBJECTIVES: With the use of iron stable isotopes, we aimed to determine whether circulating hepcidin predicts dietary iron bioavailability, to quantify the amount of absorbed iron after oral iron loading, and to measure the plasma hepcidin response. DESIGN: In the first study, young women (n = 98) with an iron status varying from iron deficiency anemia to iron sufficiency (women with serum ferritin concentrations 25-40 microg/L were not included) were given stable isotope-labeled test meals (n = 196) containing ferrous sulfate, ferrous fumarate, or ferric pyrophosphate, after which plasma hepcidin and iron bioavailability were measured. In the second study, iron-sufficient men (n = 4) were given 3.8- and 60-mg oral doses of labeled ferrous sulfate. The stable isotope appearance curve was determined, and the plasma hepcidin response was measured over 6 h. RESULTS: In study 1, plasma hepcidin and plasma ferritin were strongly correlated (r = 0.79, P < 0.001). Plasma hepcidin significantly, but modestly, predicted iron bioavailability from ferrous sulfate and ferrous fumarate (r = -0.51 and -0.46, respectively; P < 0.0001) but not from ferric pyrophosphate (r = -0.30, P = 0.056, respectively). In study 2, the 3.8-mg dose increased mean circulating absorbed iron to a peak of 0.42 micromol/L at 60 min but did not increase plasma hepcidin, The 60-mg dose increased mean circulating absorbed iron to a peak of 5.9 micromol/L at 120 min and produced an approximately 30% increase in mean plasma hepcidin at 6 h (P < 0.01). CONCLUSIONS: Plasma hepcidin is only a modest predictor of dietary iron bioavailability in humans. Oral iron loading, measured by stable-isotope appearance curves, increases circulating hepcidin.

Efficacy of wheat-based biscuits fortified with microcapsules containing ferrous sulfate and potassium iodate or a new hydrogen-reduced elemental iron: a randomised, double-blind, controlled trial in Kuwaiti women.

Adverse sensory changes prevent the addition of highly bioavailable ferrous sulfate (FeSO4) to most wheat flours. Poorly absorbable reduced Fe powders are commonly used. Encapsulation of FeSO4 can overcome these sensory changes, but the particle size of commercial compounds is too large to be used by flour mills. The first objective of the study was to measure the efficacy in wheat flour of two newly developed Fe compounds, an H-reduced Fe powder (NutraFine RS; North America Höganäs High Alloys LLC, Johnstown, PA, USA) and small particle-sized (40 microm) encapsulated FeSO4. As a second objective, the microcapsules were evaluated as a vehicle for iodine fortification. A randomised, double-blind controlled intervention trial was conducted in Kuwaiti women (n 279; aged 18-35 years) with low body Fe stores (serum ferritin (SF) < 25 microg/l) randomly assigned to one of three groups (20 mg Fe as NutraFine RS, 10 mg Fe as encapsulated FeSO4 and 150 microg iodine, or no fortification Fe) who consumed wheat-based biscuits 5 d per week. At baseline and 22 weeks, Hb, SF, transferrin receptor, urinary iodine and body Fe stores were measured. Relative to control, mean SF in the encapsulated FeSO4 group increased by 88 % (P < 0.001) and body Fe stores increased from - 0.96 to 2.24 mg/kg body weight (P < 0.001), while NutraFine RS did not significantly increase SF or body Fe stores. The median urinary iodine concentration increased from 140 to 213 microg/l (P < 0.01). NutraFine RS added at double the amount of Fe as FeSO4 was not efficacious in improving Fe status. The newly developed microcapsules were highly efficacious in improving both Fe stores and iodine status.

Vitamin A supplementation in iodine-deficient African children decreases thyrotropin stimulation of the thyroid and reduces the goiter rate.

BACKGROUND: Vitamin A (VA) deficiency (VAD) and iodine deficiency (ID) often coexist in children in Africa. VAD may affect thyroid function and the response to iodine prophylaxis. OBJECTIVE: The aim was to investigate the effects of supplementation with iodine or VA alone, and in combination, in children with concurrent VAD and ID. DESIGN: A 6-mo randomized, double-blind, 2 x 2 intervention trial was conducted in 5-14 y-old South African children (n = 404), who, on average, had mild-to-moderate VAD and ID. At baseline and after 3 mo, children received 1) iodine (191 mg I as oral iodized oil) + placebo (IS group), 2) VA (200000 IU VA as retinyl palmitate) + placebo (VAS group), 3) both iodine and VA (IS+VAS group), or 4) placebo. At baseline, 3 mo, and 6 mo, urinary iodine (UI), thyroid volume, thyrotropin (thyroid-stimulating hormone; TSH), total thyroxine (TT(4)), thyroglobulin, serum retinol (SR), and retinol-binding protein (RBP) were measured. RESULTS: SR and RBP increased significantly with VA supplementation (P < 0.05). For UI, SR, and RBP, there were no significant treatment interactions between iodine and vitamin A. The 3-factor and all three 2-factor interactions were significant for thyroid volume, TSH, and thyroglobulin (P < 0.001), whereas none of these interactions were significant for TT(4). There was a clear effect of VAS without IS on TSH, thyroglobulin, and thyroid volume; all 3 variables decreased significantly (P < 0.05). CONCLUSIONS: Iodine prophylaxis is effective in controlling ID in areas of poor vitamin A status. VA supplements are effective in treating VAD in areas of mild ID and have an additional benefit-through suppression of the pituitary TSHbeta gene, VAS can decrease excess TSH stimulation of the thyroid and thereby reduce the risk of goiter and its sequelae.

Serum retinol-binding protein 4 concentration and its ratio to serum retinol are associated with obesity and metabolic syndrome components in children.

CONTEXT: Although retinol-binding protein (RBP)-4 concentrations are elevated in animal models of obesity and insulin resistance (IR), the link between RBP4 and IR in humans is less clear. There are few published data on RBP4 levels in overweight children, and most previous studies did not control for vitamin A (VA) status and/or subclinical inflammation. OBJECTIVE: The objective of the study was to measure serum RBP4, serum retinol (SR), the RBP4-to-SR molar ratio, and dietary VA intakes in normal-weight and overweight children and investigate the relationship of these variables to IR, subclinical inflammation, and the metabolic syndrome in this age group. DESIGN: This was a cross-sectional study. SETTING: The study was conducted in Northern Switzerland. PATIENTS: Patients included 6- to 14-yr-old normal-weight, overweight, and obese children (n = 79). MAIN OUTCOME MEASURES: Body mass index, body fat percentage, waist-to-hip ratio, dietary VA intakes, serum RBP4, and SR were determined. IR was assessed using fasting insulin and the quantitative insulin sensitivity check index, and components of the metabolic syndrome and indices of subclinical inflammation were measured. RESULTS: Only 3% of children had low VA status. Independent of age, VA intakes, and C-reactive protein, body mass index, body fat percentage, and waist-to-hip ratio were significant predictors of RBP4, SR, and RBP4/SR. Independent of adiposity, RBP4 and RBP4/SR were significantly correlated with serum triglycerides, and RBP4/SR was correlated with fasting insulin. The RBP4-to-SR ratio more strongly correlated with components of the metabolic syndrome than serum RBP4. CONCLUSION: Independent of subclinical inflammation and vitamin A intakes, serum RBP4 and the RBP4-to-SR ratio are correlated with obesity, central obesity, and components of the metabolic syndrome in prepubertal and early pubertal children.

Vitamin A repletion in rats with concurrent vitamin A and iodine deficiency affects pituitary TSHbeta gene expression and reduces thyroid hyperstimulation and thyroid size.

Concurrent vitamin A (VA) deficiency (VAD) and iodine deficiency (ID) are common in developing countries. VAD has effects on thyroid metabolism that may be dependent on iodine status. The aim of this study was to investigate the effect of VA supplementation (VAS) and/or dietary iodine repletion, alone and in combination, on the thyroid-pituitary axis in rats with concurrent VAD and ID. Weanling rats (n = 96) were fed diets deficient in VA and iodine or sufficient in both (control), for 30 d. Subsequently, deficient rats were repleted with iodine and/or single VAS or remained deficient for 10 d. Serum retinol (SR), thyroid hormones, serum thyrotropin (TSH), pituitary TSHbeta mRNA expression level, and thyroid weight were measured. High-dose VAS restored SR concentrations to normal in both iodine-deficient and iodine-sufficient rats. Despite continuing VAD, provision of the iodine-sufficient diet entirely reversed the abnormalities of the pituitary-thyroid axis produced by VAD and ID. In iodine-sufficient rats, VAS had no discernible effects on the pituitary-thyroid axis; in iodine-deficient rats, VAS reduced pituitary production of TSH and thyroid stimulation but had no discernible effects on circulating thyroid hormone concentrations. Primary hypothyroidism in rats with concurrent VAD and ID does not reduce the efficacy of VAS, nor does VAD reduce the efficacy of dietary iodine to correct pituitary-thyroid axis dysfunction due to ID. In concurrent VAD and ID, VAS, independent of iodine repletion, reduces thyroid hyperstimulation and size, an effect likely mediated through the effects of VA on pituitary TSHbeta gene expression.

Synthesis, characterization, and bioavailability in rats of ferric phosphate nanoparticles.

Particle size is a determinant of iron (Fe) absorption from poorly soluble Fe compounds. Decreasing the particle size of metallic Fe and ferric pyrophosphate added to foods increases Fe absorption. The aim of this study was to develop and characterize nanoparticles of FePO(4) and determine their bioavailability and potential toxicity in rats. Amorphous FePO(4) nanopowders with spherical structure were synthesized by flame spray pyrolysis (FSP). The nanopowders were characterized and compared with commercially available FePO(4) and FeSO(4), including measurements of specific surface area (SSA), structure by transmission electron microscopy, in vitro solubility at pH 1 and 2, and relative bioavailability value (RBV) to FeSO(4) in rats using the hemoglobin repletion method. In the latter, the potential toxicity after Fe repletion was assessed by histological examination and measurement of thiobarbituric acid reactive substances (TBARS). The commercial FePO(4) and the 2 FePO(4) produced by FSP (mean particle sizes, 30.5 and 10.7 nm) had the following characteristics: SSA: 32.6, 68.6, 194.7 m(2)/g; in vitro solubility after 30 min at pH 1: 73, 79, and 85% of FeSO(4); and RBV: 61, 70, and 96%, respectively. In the histological examinations and TBARS analysis, there were no indications of toxicity. In conclusion, nanoparticles of FePO(4) have a solubility and RBV not significantly different from FeSO(4). Reducing poorly soluble Fe compounds to nanoscale may increase their value for human nutrition.

Treatment of iodine deficiency in school-age children increases insulin-like growth factor (IGF)-I and IGF binding protein-3 concentrations and improves somatic growth.

CONTEXT: Iodine deficiency in utero impairs fetal growth, but the relationship between iodine deficiency and postnatal growth is less clear. OBJECTIVE: The objective of the study was to determine whether iodine repletion improves somatic growth in iodine-deficient children and investigate the role of IGF-I and IGF binding protein (IGFBP)-3 in this effect. DESIGN, PARTICIPANTS, AND INTERVENTIONS: Three prospective, double-blind intervention studies were done: 1) in a 10-month study, severely iodine-deficient, 7- to 10-yr-old Moroccan children (n = 71) were provided iodized salt and compared with children not using iodized salt; 2) in a 6-month study, moderately iodine-deficient, 10- to 12-yr-old Albanian children (n = 310) were given 400 mg iodine as oral iodized oil or placebo; 3) in a 6-month study, mildly iodine-deficient 5- to 14-yr-old South African children (n = 188) were given two doses of 200 mg iodine as oral iodized oil or placebo. At baseline and follow-up, height, weight, urinary iodine (UI), total T4 (TT4), TSH, and IGF-I were measured; in Albania and South Africa, IGFBP-3 was also measured. RESULTS: In all three studies, iodine treatment increased median UI to more than 100 microg/liter, whereas median UI in the controls remained unchanged. In South Africa, iodine repletion modestly increased IGF-I but did not have a significant effect on IGFBP-3, TT4, or growth. In Albania and Morocco, iodine repletion significantly increased TT4, IGF-I, IGFBP-3, weight-for-age z scores, and height-for-age z scores. CONCLUSION: This is the first controlled study to clearly demonstrate that iodine repletion in school-age children increases IGF-I and IGFBP-3 concentrations and improves somatic growth.

Effect of concurrent vitamin A and iodine deficiencies on the thyroid-pituitary axis in rats.

OBJECTIVE: Deficiencies of vitamin A and iodine are common in many developing countries. Vitamin A deficiency (VAD) may adversely affect thyroid metabolism. The study aim was to investigate the effects of concurrent vitamin A and iodine deficiencies on the thyroid-pituitary axis in rats. DESIGN: Weanling rats (n = 56) were fed diets deficient in vitamin A (VAD group), iodine (ID group), vitamin A and iodine (VAD + ID group), or sufficient in both vitamin A and iodine (control) for 30 days in a pair-fed design. Serum retinol (SR), thyroid hormones (FT(4), TT(4), FT(3), and TT(3)), serum thyrotropin (TSH), pituitary TSHbeta mRNA expression levels, and thyroid weights were determined at the end of the depletion period. MAIN OUTCOME: Compared to the control and ID groups, SR concentrations were about 35% lower in the VAD and VAD + ID groups (p < 0.001), indicating moderate VA deficiency. Comparing the VAD and control groups, there were no significant differences in TSH, TSHbeta mRNA, thyroid weight, or thyroid hormone levels. Compared to the control group, serum TSH, TSHbeta mRNA, and thyroid weight were higher (p < 0.05), and FT4 and TT4 were lower (p < 0.001), in the VAD + ID and ID groups. Compared to the ID group, TSH, TSHbeta mRNA, and thyroid weight were higher (p < 0.01) and FT(4) and TT(4) were lower (p < 0.001) in the VAD + ID group. There were no significant differences in TT3 or FT3 concentrations among groups. CONCLUSION: Moderate VAD alone has no measurable effect on the pituitary-thyroid axis. Concurrent ID and VAD produce more severe primary hypothyroidism than ID alone.

Vitamin A supplementation in children with poor vitamin A and iron status increases erythropoietin and hemoglobin concentrations without changing total body iron.

BACKGROUND: Vitamin A deficiency impairs iron metabolism; vitamin A supplementation of vitamin A-deficient populations may reduce anemia. The mechanism of these effects is unclear. In vitro and in animal models, vitamin A treatment increases the production of erythropoietin (EPO), a stimulant of erythropoiesis. OBJECTIVE: We measured the effect of vitamin A supplementation on hemoglobin, iron status, and circulating EPO concentrations in children with poor iron and vitamin A status. DESIGN: In a double-blind, randomized trial, Moroccan schoolchildren (n = 81) were given either vitamin A (200,000 IU) or placebo at baseline and at 5 mo. At baseline, 5 mo, and 10 mo, hemoglobin, indicators of iron and vitamin A status, and EPO were measured. RESULTS: At baseline, 54% of children were anemic; 77% had low vitamin A status. In the vitamin A group at 10 mo, serum retinol improved significantly compared with the control group (P < 0.02). Vitamin A treatment increased mean hemoglobin by 7 g/L (P < 0.02) and reduced the prevalence of anemia from 54% to 38% (P < 0.01). Vitamin A treatment increased mean corpuscular volume (P < 0.001) and decreased serum transferrin receptor (P < 0.001), indicating improved iron-deficient erythropoiesis. Vitamin A decreased serum ferritin (P < 0.02), suggesting mobilization of hepatic iron stores. Calculated from the ratio of transferrin receptor to serum ferritin, overall body iron stores remained unchanged. In the vitamin A group at 10 mo, we observed an increase in EPO (P < 0.05) and a decrease in the slope of the regression line of log10(EPO) on hemoglobin (P < 0.01). CONCLUSION: In children deficient in vitamin A and iron, vitamin A supplementation mobilizes iron from existing stores to support increased erythropoiesis, an effect likely mediated by increases in circulating EPO.

Triple fortification of salt with microcapsules of iodine, iron, and vitamin A.

BACKGROUND: In many developing countries, children are at high risk of goiter, vitamin A deficiency, and iron deficiency anemia. OBJECTIVE: We aimed to develop a stable, efficacious salt fortified with iodine, iron, and vitamin A. DESIGN: A novel spray-cooling technique was used with hydrogenated palm oil to package potassium iodate, micronized ferric pyrophosphate, and retinyl palmitate into microcapsules (mean particle size: 100 mum). We used the microcapsules to create triple-fortified salt (TFS) with 30 mug I, 2 mg Fe, and 60 mug vitamin A/g salt. After storage trials, we compared the efficacy of TFS with that of iodized salt in a 10-mo, randomized, double-blind trial in goitrous schoolchildren (n = 157) who had a high prevalence of vitamin A deficiency and iron deficiency anemia. RESULTS: After storage for 6 mo, losses of iodine and vitamin A from the TFS were approximately 12-15%, and color was stable. In the TFS group, mean hemoglobin increased by 15 g/L at 10 mo (P < 0.01), iron status indexes and body iron stores improved significantly (P < 0.05), and mean serum retinol, retinol-binding protein, and the ratio of retinol-binding protein to prealbumin increased significantly (P < 0.01). At 10 mo, prevalences of vitamin A deficiency and iron deficiency anemia were significantly lower in the TFS group than in the iodized salt group (P < 0.001). CONCLUSION: Newly developed microcapsules containing iodine, iron, and vitamin A are highly stable when added to local African salt. TFS was efficacious in reducing the prevalence of iron, iodine, and vitamin A deficiencies in school-age children.