Iron availability: An updated review

Iron is an essential trace element in human nutrition and its deficiency is a world nutritional problem. Due to the high prevalence of anaemia in developing and industrialized countries, it is necessary to maintain a suitable iron intake through diet in order to achieve an appropriate status of this element in the body. For this reason, accurate knowledge of iron availability of foods is essential in order to plan intervention strategies that improve deficient situations of this nutrient. Regarding to the two forms of iron present in foods, heme iron has greater availability than non-heme iron. Beside this, non-heme iron availability is conditioned by several dietary factors, such as classic factors (meat, ascorbic acid, fibre, phytic acid, polyphenols) and new factors (caseinophosphopeptides and fructo-oligosaccharides with prebiotic characteristics).For that reason, the aim of this paper is to accurately review all investigations reported in the past decade related to dietetic factors that influence the bioavailability of different iron forms.     

Nutritional aspect of zinc availability

Zinc is an essential trace element in human nutrition and its deficiency is a world nutritional problem. However, the zinc content of foods is low and its availability is conditioned by several physiologic and dietary factors. For that reason, the objective of the present work is to compile past and present information about the influence of these factors on zinc availability to try to improve this availability.     

Intestinal iron absorption: regulation by dietary & systemic factors

Iron is an essential trace metal in human metabolism. However, imbalances in iron homeostasis are prevalent worldwide and have detrimental effects on human health. Humans do not have the ability to remove excess iron and therefore iron homeostasis is maintained by regulating the amount of iron entering the body from the diet. Iron is present in the human diet in number of different forms, including heme (from meat) and a variety of non-heme iron compounds. While heme is absorbed intact, the bioavailability of non-heme iron varies greatly depending on dietary composition. A number of dietary components are capable of interacting with iron to regulate its solubility and oxidation state. Interestingly, there is an emerging body of evidence suggesting that some nutrients also have direct effects on the expression and function of enterocyte iron transporters. In addition to dietary factors, body iron status is a major determinant of iron absorption. The roles of these important dietary and systemic factors in regulating iron absorption will be discussed in this review.     

A food-group based algorithm to predict non-heme iron absorption

OBJECTIVE: To develop an algorithm to predict the percentage non-heme iron absorption based on the foods contained in a meal (wholemeal cereal, tea, cheese, etc.). Existing algorithms use food constituents (phytate, polyphenols, calcium, etc.), which can be difficult to obtain. DESIGN: A meta-analysis of published studies using erythrocyte incorporation of radio-isotopic iron to measure non-heme iron absorption. METHODS: A database was compiled and foods were categorized into food groups likely to modify non-heme iron absorption. Absorption data were then adjusted to a common iron status and a weighted multiple regression was performed. RESULTS: Data from 53 research papers (3,942 individual meals) were used to produce an algorithm to predict non-heme iron absorption (R(2) =0.22, P < 0.0001). CONCLUSIONS: The percentage non-heme iron absorption can be predicted from information on the types of foods contained in a meal with similar efficacy to that of food-constituent-based algorithms (R(2) = 0.16, P= 0.0001).     

Animal Models for Studying the Effect of Fibre on Gastrointestinal Function

Objective To develop an algorithm to predict the percentage non-heme iron absorption based on the foods contained in a meal (wholemeal cereal, tea, cheese, etc.). Existing algorithms use food constituents (phytate, polyphenols, calcium, etc.), which can be difficult to obtain.

Design A meta-analysis of published studies using erythrocyte incorporation of radio-isotopic iron to measure non-heme iron absorption.

Methods A database was compiled and foods were categorized into food groups likely to modify non-heme iron absorption. Absorption data were then adjusted to a common iron status and a weighted multiple regression was performed.

Results Data from 53 research papers (3,942 individual meals) were used to produce an algorithm to predict non-heme iron absorption (R²=0.22, P<0.0001).

Conclusions The percentage non-heme iron absorption can be predicted from information on the types of foods contained in a meal with similar efficacy to that of food-constituent-based algorithms (R²=0.16, P=0.0001).     

Heme, ferritin and vegetable iron absorption in humans from meals denatured of heme iron during the cooking of beef

The iron absorption from heme, ferritin and vegetable foods was tested in 63 humans (10 males and 53 females). The iron absorption from heme in beef exposed to prolonged heating was markedly reduced, following the degree of denaturation of the heme. The iron absorption from ferritin was about 31% of the absorption of the reference dose when administered with meat alone, falling to 11% of the reference dose when administered in a meal containing meat and vegetable foods. The absorption of ferritin iron was less than half that of vegetable iron. The data confirm a previous proposal that ferritin forms part of a subgroup of the non-heme iron pool.     

Dietary Iron Intake and Availability in Hill Tribe and Urban Women,Chiang Rai Province,Northern Thailand

ABSTRACT

Data were collected as part of a cross-sectional study. The objectives were to compare dietary intakes of iron and enhancers and inhibitors of non-heme iron absorption in hill tribe and urban women of Chiang Rai province, northern Thailand, and compare iron- and vitamin C- containing foods sold in markets in both settings. Dietary data were collected using three 24- hour recalls from 128 women aged 19–50 years (hill tribe: n = 65; urban n = 63), and proportions of low-, medium- and high-iron/vitamin C containing foods were surveyed in local markets. Hill tribe women consumed less iron, animal protein, vitamin C and calcium, but market availability of iron/vitamin C foods was similar. Future interventions should focus on food choice modification, to improve intakes of iron and foods that enhance its absorption, especially among hill tribe women.     

Statistical model for predicting non-heme iron bioavailability from vegetarian meals

Availability of non-heme iron has been extensively discussed when meals comprise heme as well as non-heme iron, but seldom so for exclusively vegetarian meals. The present study aimed to develop a statistical model for predicting non-heme iron availability from a composite vegetarian meal. Radioisotopic measurements of in vitro iron dialyzability of 208 out of 274 meals representing vegetarian diets from Asia, Africa, Europe and Latin America and the meal contents of iron, zinc, copper, ascorbic acid, beta-carotene, riboflavin, thiamin, folic acid, tannic acid, fiber and degraded phytate forms (IP6-IP1) were used for development of the model. A multiple regression model weighted for calorie contents was developed for the percentage iron dialyzability with the possible predictors as meal contents along with plausible interaction terms. The model was validated with in vitro iron dialyzability of 66 meals and in vivo iron absorption in five ileostomized adults. Application of the model was demonstrated using data on the daily dietary intake of 215 young adults whose hemoglobin levels were estimated twice in 3 weeks. Weighted multiple regression model was: ln(% Fe dialyzability)=1.340-0.259xln(IP2 [mg])+0.188xln(IP3 [mg])-0.278xln(IP5 [mg])+0.0912xln(ascorbic acid [mg])+0.06693xln(tannins [mg])+0.09552xln(beta-carotene [microg])+0.137xln(hemicellulose [g]) (P<0.01, R2=0.51). Good agreement was seen between observed and predicted dialyzability (r=0.90) and human absorption (r=0.89). The model would be useful to estimate bioavailable iron intakes of vegetarian populations and to identify at-risk individuals.     

The precision of in vitro methods and algorithms for predicting the bioavailability of dietary iron

Three factors determine how much iron will be absorbed from a meal. They are the physiological mechanisms that regulate uptake by and transfer through the enterocytes in the upper small intestine, the quantity of iron in the meal, and its availability to the cellular iron transporters. Established methods exist for predicting the effect of physiological regulation and for measuring or estimating meal iron content. Three approaches to estimating bioavailability have been advocated. Two are in vitro screening procedures: measurement of dialyzable iron and Caco-2 cell uptake, both carried out after in vitro simulated gastric and pancreatic digestion. The third is the use of algorithms based on the predicted effects of specific meal components on absorption derived from isotopic studies in human volunteers. The in vitro procedures have been very useful for identifying and characterizing factors that affect non-heme iron absorption, but direct comparisons between absorption predicted from the in vitro tests and measurements in human volunteers have only been made in a limited number of published studies. The available data indicate that dialysis and Caco-2 cell uptake are useful for ranking meals and single food items in terms of predicted iron bioavailability, but may not reflect the magnitudes of the effects of factors that influence absorption accurately. Algorithms based on estimates of the amounts of heme iron and of enhancers and inhibitors of non-heme iron absorption in foods make it possible to classify meals or diets as being of high, medium, or low bioavailability. The precision with which meal iron bioavailability can be predicted in a population, for which a specific algorithm has been developed, is improved by measuring the content of the most important enhancers and inhibitors. However, the accuracy of such predictions appears to be much lower when the algorithm is applied to meals eaten by different populations.     

The importance and bioavailability of phytoferritin-bound iron in cereals and legume foods

Ferritin is present in several types of plants in low concentrations, but it is possible to enhance this content by plant breeding, or by inserting the gene for ferritin into staple foods. Since each ferritin molecule can bind thousands of iron atoms, this may be a sustainable means to increase the iron content of plants. Before launching such efforts it is important to determine whether ferritin-bound iron is bioavailable. We assessed this in vitro using Caco-2 cells and in vivo using radiolabeled ferritin and whole body counting in human subjects. In Caco-2 cells, we found that dietary factors affecting iron absorption, such as ascorbic acid, phytate, and calcium, had very limited effect on iron uptake from intact ferritin, suggesting that ferritin-bound iron is absorbed via a mechanism different from that of non-heme iron. Using in vitro digestion, we found that ferritin was relatively resistant against proteolytic enzymes. Binding of ferritin to Caco-2 cells was found to be saturable and the kinetics for binding characteristic for a receptor-mediated process. In human subjects, we found that iron absorption from animal ferritin was similar to that from ferrous sulfate, suggesting that iron is well absorbed from ferritin. We did not find any significant difference between iron absorption from ferritin reconstituted with high-phosphate (plant-type) and low-phosphate (animal-type) ferritin mineral, suggesting that plant ferritin-iron is bioavailable. In a subsequent human study we also found that iron from purified soybean ferritin given in a meal was as well absorbed as ferrous iron. In conclusion, iron is well absorbed from phytoferritin and may represent a means of biofortification of staple foods.     

Statistical model for predicting non-heme iron bioavailability from vegetarian meals

Availability of non-heme iron has been extensively discussed when meals comprise heme as well as non-heme iron, but seldom so for exclusively vegetarian meals. The present study aimed to develop a statistical model for predicting non-heme iron availability from a composite vegetarian meal. Radioisotopic measurements of in vitro iron dialyzability of 208 out of 274 meals representing vegetarian diets from Asia, Africa, Europe and Latin America and the meal contents of iron, zinc, copper, ascorbic acid, β-carotene, riboflavin, thiamin, folic acid, tannic acid, fiber and degraded phytate forms (IP6–IP1) were used for development of the model. A multiple regression model weighted for calorie contents was developed for the percentage iron dialyzability with the possible predictors as meal contents along with plausible interaction terms. The model was validated with in vitro iron dialyzability of 66 meals and in vivo iron absorption in five ileostomized adults. Application of the model was demonstrated using data on the daily dietary intake of 215 young adults whose hemoglobin levels were estimated twice in 3 weeks. Weighted multiple regression model was: ln(% Fe dialyzability)=1.340–0.259×ln(IP2 [mg])+0.188×ln(IP3 [mg])–0.278×ln(IP5 [mg])+0.0912×ln(ascorbic acid [mg])+0.06693×ln(tannins [mg])+0.09552×ln(β-carotene [µg])+0.137×ln(hemicellulose [g]) (P<0.01, R²=0.51). Good agreement was seen between observed and predicted dialyzability (r=0.90) and human absorption (r=0.89). The model would be useful to estimate bioavailable iron intakes of vegetarian populations and to identify at-risk individuals.     

An in vitro method for estimation of iron availability from meals

An in vitro method for estimating food iron availability is described. The method involves simulated gastrointestinal digestion followed by measurement of soluble, low molecular weight iron. Mixtures of foods (meals) were homogenized and exposed to pepsin at pH 2. Dialysis was used to adjust the pH to intestinal levels and digestion was continued after the addition of pancreatin and bile salts. Iron from the digestion mixture which diffused across a 6 to 8000 molecular weight cutoff semipermeable membrane was used as an indicator of available iron. Results were similar when intrinsic food iron or added extrinsic radioiron was measured. Availability estimates were made on meals formulated to contain known iron availability enhancing and inhibiting factors. Relative availabilities determined for a series of meals containing ascorbic acid, eggs, orange juice, tea, coffee, cola, or whole wheat bread show that the method accurately reflects actual food iron availability.     

Iron and ascorbic Acid: proposed fortification levels and recommended iron compounds

An adequate supply of dietary iron during the 1st 24 mo of life is essential for preventing iron deficiency with its attendant negative effects on mental, motor and emotional development as well as later cognitive performance. Iron reserves and the small amount of highly bioavailable iron in human milk are adequate to satisfy the iron requirements of breast-fed infants of adequate birth weight for the 1st 6 mo of life. Thereafter, complementary foods, iron supplements or both are needed to meet this requirement. Complementary foods should not displace the consumption of human milk. The quantities eaten, particularly by younger infants, may therefore be quite small. As a consequence it is essential that the iron be supplied in a highly bioavailable form. This can be achieved by fortifying complementary foods with ferrous sulfate and ascorbic acid provided that the ascorbic acid is not lost during storage or meal preparation. Suggested fortification levels for ferrous sulfate and ascorbic acid for some types of complementary foods are given. The use of ferrous fumarate or an elemental iron powder instead of ferrous sulfate has not been evaluated adequately. There is a need to develop alternative strategies for improving iron bioavailability in complementary foods because it may not be possible to preserve ascorbic acid activity in many of them.     

Enhancing the absorption of fortification iron. A SUSTAIN Task Force report

Iron deficiency remains a major global health problem affecting an estimated 2 billion people. The World Health Organization ranked it as the seventh most important preventable risk for disease, disability, and death in 2002. Since an important factor in its causation is the poor bioavailability of iron in the cereal-based diets of many developing countries, SUSTAIN set up a Task Force, consisting of nutritional, medical, industry, and government experts to consider strategies for enhancing the absorption of fortification iron. This paper summarizes the findings of this Task Force. Detailed reviews of each strategy follow this overview. Highly soluble compounds of iron like ferrous sulfate are desirable food fortificants but cannot be used in many food vehicles because of sensory issues. Thus, potentially less well-absorbed forms of iron commonly are used in food fortification. The bioavailability of iron fortificants can, however, be enhanced with innovative ingredient technologies. Ascorbic acid, NaFeEDTA, ferrous bisglycinate, and dephytinization all enhance the absorption of fortification iron, but add to the overall costs of fortification. While all strategies cannot be recommended for all food fortification vehicles, individual strategies can be recommended for specific foods. For example, the addition of ascorbic acid is appropriate for dry blended foods such as infant foods and other dry products made for reconstitution that are packaged, stored, and prepared in a way that maximizes retention of this vitamin. NaFeEDTA can be recommended for fortification of fish sauce and soy sauce, whereas amino acid chelates may be more useful in milk products and beverages. With further development, dephytinization may be possible for low-cost, cereal-based complementary foods in developing countries. Encapsulation of iron salts in lipid coatings, while not an iron absorption-enhancing strategy per se, can prevent soluble forms of iron from interacting undesirably with some food vehicles and hence broaden the application of some fortificants. Research relevant to each of these strategies for enhancing the bioavailability or utility of iron food fortificants is reviewed. Individual strategies are evaluated in terms of enhancing effect and stability, organoleptic qualities, cost, and regulatory issues of interest to the nutrition community, industry, and consumers. Recommendations are made on potential usages and further research needs. Effective fortification depends on the selection of technically feasible and efficacious strategies. Once suitable strategies have been identified, cost becomes very important in selecting the best approach to implement. However it is essential to calculate cost in relation to the amount of bioavailable iron delivered. An approach to the calculation of cost using a conservative estimate of the enhancing effects of the innovative technologies discussed in the supplement is given in the final section.     

An in vitro method for predicting the bioavailability of iron from foods.

An in vitro method for the determination of availability of nonheme iron from foods and diets was investigated. Food was extracted with pepsin-HCl at pH 1.35 and subsequently the pH was adjusted to pH 7.5 and filtered. Ionizable iron was determined in the pH 7.5 filterate by the alpha, alpha-dipyridyl method. The percent iron absorption from the same diets observed in the adult males. Ionizable iron at pH 7.5 was shown to increase in presence of ascorbic acid and meat extract while it decreased in presence of phytate and tannins, similar to the effects of these factors on iron absorption in human subjects. Based on these observations it is proposed that ionizable iron at pH 7.5 determined as described in this study can be used as a reliable measure of bioavailability of nonheme iron in foods.     

Enhancers of iron absorption: ascorbic acid and other organic acids

Ascorbic acid (AA), with its reducing and chelating properties, is the most efficient enhancer of non-heme iron absorption when its stability in the food vehicle is ensured. The number of studies investigating the effect of AA on ferrous sulfate absorption far outweighs that of other iron fortificants. The promotion of iron absorption in the presence of AA is more pronounced in meals containing inhibitors of iron absorption. Meals containing low to medium levels of inhibitors require the addition of AA at a molar ratio of 2:1 (e.g., 20 mg AA: 3 mg iron). To promote absorption in the presence of high levels of inhibitors, AA needs to be added at a molar ratio in excess of 4:1, which may be impractical. The effectiveness of AA in promoting absorption from less soluble compounds, such as ferrous fumarate and elemental iron, requires further investigation. The instability of AA during food processing, storage, and cooking, and the possibility of unwanted sensory changes limits the number of suitable food vehicles for AA, whether used as vitamin fortificant or as an iron enhancer. Suitable vehicles include dry-blended foods, such as complementary, precooked cereal-based infant foods, powdered milk, and other dry beverage products made for reconstitution that are packaged, stored, and prepared in a way that maximizes retention of this vitamin. The consumption of natural sources of Vitamin C (fruits and vegetables) with iron-fortified dry blended foods is also recommended. Encapsulation can mitigate some of the AA losses during processing and storage, but these interventions will also add cost. In addition, the bioavailability of encapsulated iron in the presence/absence of AA will need careful assessment in human clinical trials. The long-term effect of high AA intake on iron status may be less than predicted from single meal studies. The hypothesis that an overall increase of dietary AA intake, or fortification of some foods commonly consumed with the main meal with AA alone, may be as effective as the fortification of the same food vehicle with AA and iron, merits further investigation. This must involve the consideration of practicalities of implementation. To date, programs based on iron and AA fortification of infant formulas and cow's milk provide the strongest evidence for the efficacy of AA fortification. Present results suggest that the effect of organic acids, as measured by in vitro and in vivo methods, is dependent on the source of iron, the type and concentration of organic acid, pH, processing methods, and the food matrix. The iron absorption-enhancing effect of AA is more potent than that of other organic acids due to its ability to reduce ferric to ferrous iron. Based on the limited data available, other organic acids may only be effective at ratios of acid to iron in excess of 100 molar. This would translate into the minimum presence/addition of 1 g citric acid to a meal containing 3 mg iron. Further characterization of the effectiveness of various organic acids in promoting iron absorption is required, in particular with respect to the optimal molar ratio of organic acid to iron, and associated feasibility for food application purposes. The suggested amount of any organic acid required to produce a nutritional benefit will result in unwanted organoleptic changes in most foods, thus limiting its application to a small number of food vehicles (e.g., condiments, beverages). However, fermented foods that already contain high levels of organic acid may be suitable iron fortification vehicles.     

Micronutrient deficiencies in developing and affluent countries

Micronutrient deficiencies, also known as 'hidden hunger', are determining and aggravating factors for health status and quality of life. Three nutritional problems that have serious consequences are deficiencies of iron, vitamin A and iodine. It is estimated that in today's world, iron deficiency anemia affects two billion people, mostly women and children. Blindness due to vitamin A deficiency affects 2.8 million children under 5 years of age. Iodine deficiency disorders affect 740 million people. Cuba is employing various programs to deal with these micronutrient deficiencies. Dietary diversification, fortification of foods and supplementation with pharmaceutical preparations are included in Cuba's response to these deficiencies. Urban agriculture is one strategy to increase dietary diversity. The aim is to increase both the availability and consumption of vegetables and fruits. Food fortification takes many forms in Cuba today and various supplementation programs are carried out. The most common supplemental program in the country is the prenatal program. This program provides four essential nutrients: iron, ascorbic acid, vitamin A and folic acid. At present, iodination covers more than 90% of the total amount of salt used for human consumption. Results of research carried out in Cuba have shown that vitamin A deficiency is nonexistent in children up to 7 y of age. Foods and preparations for these programs are delivered gratuitously or at very low prices.     

Duodenal Cytochrome b (DCYTB) in Iron Metabolism: An Update on Function and Regulation

Iron and ascorbate are vital cellular constituents in mammalian systems. The bulk-requirement for iron is during erythropoiesis leading to the generation of hemoglobin-containing erythrocytes. Additionally, both iron and ascorbate are required as co-factors in numerous metabolic reactions. Iron homeostasis is controlled at the level of uptake, rather than excretion. Accumulating evidence strongly suggests that in addition to the known ability of dietary ascorbate to enhance non-heme iron absorption in the gut, ascorbate regulates iron homeostasis. The involvement of ascorbate in dietary iron absorption extends beyond the direct chemical reduction of non-heme iron by dietary ascorbate. Among other activities, intra-enterocyte ascorbate appears to be involved in the provision of electrons to a family of trans-membrane redox enzymes, namely those of the cytochrome b₅₆₁ class. These hemoproteins oxidize a pool of ascorbate on one side of the membrane in order to reduce an electron acceptor (e.g., non-heme iron) on the opposite side of the membrane. One member of this family, duodenal cytochrome b (DCYTB), may play an important role in ascorbate-dependent reduction of non-heme iron in the gut prior to uptake by ferrous-iron transporters. This review discusses the emerging relationship between cellular iron homeostasis, the emergent “IRP1-HIF2α axis”, DCYTB and ascorbate in relation to iron metabolism.     

A quantitative model for prediction of iron bioavailability from Indian meals: An experimental study

The major goal of the study was to explore the possibility of developing an updated model that integrates the effect of various enhancers and inhibitors for predicting the potential availability of iron from typical Indian vegetarian meals. The interaction effects of four constituents namely ascorbic acid, citric acid, tannic acid and calcium phosphate was studied using a standard cereal meal (STD meal) providing 3 mg non-heme iron/250 ml homogenate. Based on the data, a regression equation was evolved which was tested for its predictive power as applied to a set of 10 typical Indian meals. Regression analysis of the data revealed that both ascorbate and citrate emerged as equally strong enhancers while tannate and calcium phosphate demonstrated strong inhibitory effect on iron availability in the STD meal. Further, when the prediction equation, generated on the basis of the interaction effect data was applied to the typical Indian meals, it showed a high correlation coefficient (r = 0.76) between the analysed values for iron availability vs the values computed using the enhancer and inhibitor contents of the meals. Comparison with the only other model available in the literature namely that of Monsen & Balintfy (1982) revealed that the present model was far better in predicting iron availability from cereal based Indian meals (r = 0.76) than Monsen's model (r = 0.19). The findings of the present study substantiated the hypothesis that a regression model, evolved from a cereal meal, by integrating the effect of enhancers as well as inhibitors, rather than only enhancers, provides a more precise estimate of iron availability from typical Indian meals. A limitation of the model however, was that phytate could not be incorporated into the equation.     

Dietary Determinants of and Possible Solutions to Iron Deficiency for Young Women Living in Industrialized Countries: A Review

Iron deficiency is a concern in both developing and developed (industrialized) countries; and young women are particularly vulnerable. This review investigates dietary determinants of and possible solutions to iron deficiency in young women living in industrialized countries. Dietary factors including ascorbic acid and an elusive factor in animal protein foods (meat; fish and poultry) enhance iron absorption; while phytic acid; soy protein; calcium and polyphenols inhibit iron absorption. However; the effects of these dietary factors on iron absorption do not necessarily translate into an association with iron status and iron stores (serum ferritin concentration). In cross-sectional studies; only meat intake has consistently (positively) been associated with higher serum ferritin concentrations. The enhancing effects of ascorbic acid and meat on iron absorption may be negated by the simultaneous consumption of foods and nutrients which are inhibitory. Recent cross-sectional studies have considered the combination and timing of foods consumed; with mixed results. Dietary interventions using a range of focused dietary measures to improve iron status appear to be more effective than dietary approaches that focus on single nutrients or foods. Further research is needed to determine optimal dietary recommendations for both the prevention and treatment of iron deficiency.