The amount of radioiron released from rat peritoneal macrophages after phagocytosis of 59Fe labelled erythrocytes can be enhanced by addition of desferrioxamine. The effect is dose dependent and the iron chelated by desferrioxamine appears to be at the expense of ferritin. However, desferrioxamine does not appear to chelate iron already incorporated into ferritin. It seems likely that the iron comes from a labile chelatable pool through which the iron from haemoglobin catabolism passes before being incorporated into ferritin. The desferrioxamine appears to enter the macrophage and chelate iron to form ferrioxamine which subsequently leaves the macrophage. In vivo it was not possible to show substantial iron chelaton by desferrioxamine in rats when 59Fe labelled non-viable red cells were injected intravenously. This suggests that in vivo mobilization of reticuloendothelial iron by desferrioxamine may be of limited significance.

59 patients with active pulmonary tuberculosis were evaluated in terms of haematological indices, iron-related measurements and markers of inflammation. The variables evaluated included the Hb, mean cell volume (MCV), serum iron, total iron-binding capacity, percentage saturation, serum ferritin, erythrocyte sedimentation rate (ESR) and C-reactive protein. In addition, marrow iron stores were assessed both histologically and chemically. Among the changes noted was a raised S-Ferritin, which appeared in part to be a component of the acute phase response, since it correlated with C-reactive protein concentration (r 0.59, p less than 0.0001). In addition, there was a good correlation between the S-Ferritin and the concentrations of non-haem iron in the marrow, as assessed chemically on trephine biopsies (r 0.78, p less than 0.0001) and histologically on aspirated and biopsy material (rS 0.78, p less than 0.0001 and rS 0.68, p less than 0.0001, respectively). Furthermore, the quantitative relationship between the S-Ferritin and the chemical concentrations of non-haem iron in the marrow was similar to that found previously in a heterogeneous group of subjects without infections. While the present findings confirm that iron is diverted into reticuloendothelial stores in active pulmonary tuberculosis, no evidence was found to suggest that the anaemia which was present in 45 of the 59 patients was secondary to iron-deficient erythropoiesis; the percentage saturations in the 2 groups were 30.3 and 31.1 respectively. In a final analysis, the present findings were compared with previous ones obtained in a group of patients with Hodgkin's disease. The degree of rise in the S-Ferritin for a given marrow non-haem iron concentration was significantly less in the patients with tuberculosis (p less than 0.0001).

Elemental iron powders are widely used to fortify staple foods. Experimental evidence indicates that there is considerable variation in the bioavailability of different products. For some powders, it may be too low to permit a significant impact on iron status. This study was designed to evaluate possible approaches to screening commercial iron powders for predicted bioavailability, to identify products that have the potential to improve iron status, and to ascertain whether bioavailability is related to the method of manufacture. Nine commercial iron powders were allocated to one of five types based on the production process; carbonyl, electrolytic, hydrogen-reduced (H-reduced), carbon monoxide-reduced (CO-reduced), and other reduced. Structure by scanning electron microscopy and physical properties (pycnometric and apparent density, particle size distribution, Fisher subsieve size, and surface area) were determined on all samples. Selected samples (one or more of each type depending on the cost of the assay) were then subjected to five screening procedures that have previously been advocated for predicting bioavailability in humans--issolution rate in 0.1 mol/L HCl, dialyzability and Caco-2 cell iron uptake, both after simulated in vitro gastrointestinal digestion, relative bioavailability (RBV) with respect to ferrous sulfate by the AOAC rat hemoglobin repletion method, and plasma iron tolerance tests in human volunteers. The results for particle size distribution, surface area, Fisher subsieve size, dissolution rate in 0.1 mol/L HCl, and RBV in rats were significantly correlated and consistent for powders of the same type. However, values for different powder types were significantly different. There was no correlation between either dialyzability or Caco-2 cell uptake and the predicted bioavailability estimates based on the physical properties, dissolution rates, RBV in rats, or human efficacy data. Although human plasma iron tolerance tests were in general agreement with the other measures of predicted bioavailability, they did not provide information that would have improved the precision of bioavailability estimates based on physical properties, dissolution in HCl and/or RBV in rats. Our observations indicate that the dissolution rate in 0.1 mol/L HCI under standardized conditions is highly predictive of potential bioavailability and that it would be the most practical approach to developing a reliable and sensitive screening procedure for predicting and monitoring the bioavailability of commercial elemental iron powder products. Some, but not all, of the carbonyl and electrolytic iron powders had the highest predicted bioavailability values. The predicted bioavailability for the reduced iron products was lower and variable, with the lowest values being recorded for the carbon monoxide and other reduced iron products. Two powder types were selected for a human efficacy trial, electrolytic (because it is the iron powder type recommended by WHO) and hydrogen-reduced (because of its widespread use). Electrolytic/A131 and H-reduced/AC-325 had relative efficacies compared with ferrous sulfate monohydrate of 77% and 49%, respectively, based on the change in body iron stores in Thai women with low iron stores, who received an additional 12 mg iron per day, six days per week for 35 weeks in wheat-based snacks. We conclude that there is significant variability in the bioavailability of the commercial iron powders that we evaluated (those used for food fortification at the time that our studies were initiated), and that bioavailability is related in part to production method. The bioavailability of some carbonyl and electrolytic iron powders may be adequate for effective food fortification. The reduced iron powders that we tested are unlikely to have an adequate impact on iron nutrition at the fortification levels currently employed, although preliminary analysis of a new H-reduced product indicates that it may be possible to improve the bioavailability of individual powders of this type of product. We did find significant differences among products in both the electrolytic and carbonyl categories. Therefore, all products should be screened rigorously.

The full-term infant receives a generous and relatively fixed iron supply from the mother. As a result, iron absorption in the early postnatal period is lower than at any later time in childhood; the amount and availability of dietary iron are therefore less important before 2 months of age. The infant then enters a period during which body growth rapidly outstrips the maternal supply of iron, and by 4 to 6 months of age the iron status of the infant becomes almost totally dependent on dietary iron supply. Iron balance in the infant is characterized not only by this sudden change in iron requirement but by an equally dramatic alteration in the nature of the dietary iron consumed. It is convenient to review dietary iron availability during infancy in relation to three overlapping periods (Fig. 1). Initially, when the infant's iron needs are lowest, dietary iron is derived largely from milk or milk products. Weaning or transitional foods, mainly processed cereals, are then introduced. In addition, in poor socioeconomic segments of the populations of developing countries there are often programs to enhance caloric and protein intake at this age using so-called infant food supplements. It is during this period in infancy that iron needs are not only the highest but the prospect for meeting these needs by manipulating dietary intake is also greatest. During the latter part of infancy there is an increasing dependence on solid foods, so that by 1 year of age the diet approaches that of other members of the household.

The role of the exocrine secretions of the pancreas in the absorption of iron has been the subject of extensive investigation. There is a considerable body of evidence indicating that deficiency of the pancreatic secretions leads to excessive absorption of iron, and consists of observations both in experimental animals and in human subjects. The animal evidence includes the increase in carcass iron observed after pancreatectomy (Taylor, Stiven, and Reid, 1931), after ligation of the pancreatic duct (Taylor, Stiven, and Reid, 1935; Gillman, Gillman, Mandelstam, and Gilbert, 1947; Kinney, Finch, Kaufman, Hegsted, and Partington, 1950), and after pancreatic necrosis induced by ethionine (Kinney, Kaufman, and Klavins, 1955; Brozovic, Popovi6, Obradovic, and Pendid, 1966), or by protein malnutrition (Kaufman, Klavins, and Kinney, 1958). Similar observations have been reported in patients with pancreatic disease. An increase in tissue iron has been noted at necropsy in some subjects with fibrocystic disease of the pancreas (Andersen, 1938) and chronic pancreatitis (Banwell, Hutt, Marsden, and Blackman 1964). Furthermore, iron absorption has been reported to be increased in a proportion of patients with fibrocystic disease of the pancreas (Tonz, Weiss, Strahm, and Rossi, 1965) and chronic pancreatitis (Davis, 1961; Davis and Badenoch, 1962; Ball, 1964; Deller, 1965). It has even been suggested that idiopathic haemochromatosis is the consequence

Ethylene diamine tetraacetic acid (EDTA) is a hexadentate chelator, which can combine with virtually every metal in the periodic table. CaNa2EDTA and Na2EDTA (ADI 2.5 mg EDTA/kg body weight/day) are widely used as sequestering agents in canned products, while NaFeEDTA is a promising iron fortificant. Binding of EDTA with iron is favored in the acid milieu of the stomach, irrespective of whether the EDTA is administered as CaNa2EDTA, Na2EDTA, or NaFeEDTA, but in the more alkaline medium of the duodenum the iron is exchanged, in part, with other metals. The iron released from EDTA is absorbed by the normal physiological mechanisms. When NaFeEDTA is present in a meal, the iron moiety exchanges with the intrinsic food iron and the EDTA partially protects the iron in this common non-heme iron pool from the effects of inhibitors of iron absorption, such as phytates and polyphenols. When iron is added as NaFeEDTA to an inhibitory meal, it is two to three times better absorbed than is iron added as ferrous sulfate. It also has a similar effect on the intrinsic food iron in the meal. Fortification with NaFeEDTA is most efficacious when administered with cereal- and legume-based diets but offers no advantages over other fortificants when added to meals of high bioavailability. Its potential as a fortificant has been confirmed in five extended fortification trials carried out in developing countries. There is no evidence that NaFeEDTA in the dose range proposed for food fortificants (5 to 10 mg iron daily) will have any direct toxic effects. Na2EDTA and CaNa2EDTA have proved safe over a number of years, while the Joint FAO/WHO Expert Committee on Food Additives concluded in 1999 that NaFeEDTA "could be considered safe when used in supervised fortification programs". Animal and human studies, including the results of two fortification trials, suggest that NaFeEDTA has little or no effect on overall zinc metabolism. Indeed, if anything, it increases zinc and possibly copper absorption. Data on potentially toxic metals, such as lead mercury, aluminum, and manganese, are limited but the evidence that is available is uniformly negative thus far. Further studies in this field are desirable. The long-term potential of NaFeEDTA fortification to cause iron overload is conjectural but the available evidence suggests that homeostatic controls would prevent excess iron accumulation in the normal population. NaFeEDTA, which is pale yellow in color, causes fewer organoleptic changes in a number of stored vehicles, including cereals, than do other soluble iron salts. Other potential vehicles include condiments, several of which have been successfully used in fortification trials. What is currently lacking is a consolidated body of published evidence on the stability of NaFeEDTA during processing, storage, and household cooking in widely consumed food vehicles, coupled with standardized testing of consumer acceptance of each fortified vehicle. While NaFeEDTA seems to be an appropriate fortificant for developing countries, its cost is about six to eight times that of ferrous sulfate in terms of equivalent amounts of iron. Its better absorption (a factor of 2-3) might make it possible to halve the daily fortification level but, it still remains expensive and there is a pressing need for food grade NaFeEDTA at more affordable prices. Another possible option is the use of other salts of EDTA (Na2EDTA or Ca Na2EDTA) together with a soluble source of iron, such as ferrous sulfate. The combination has been shown to be as effective as NaFeEDTA when the EDTA:Fe molar ratio is between 1:2 and 1:1. This approach is, however, only feasible with vehicles that are stored for short periods because of ferrous sulfate's propensity to cause organoleptic changes. The search for an iron source that is more stable but at the same time available to combine with EDTA has been unsuccessful thus far. Target populations for fortification with NaFeEDTA include all those that subsist on cereal- and legume-based diets, with the most appropriate vehicles being cereal products and condiments. The fortification of infant milk and cereal formulas with NaFeEDTA does not seem appropriate, since the amounts of NaFeEDTA required for effective fortification would be close to the acceptable daily intake (ADI) of 2.5 mg EDTA/kg body weight/day.

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.

Original CommunicationA Model for Calculating the Cost of Employing Iron Absorption Enhancement Strategies in Fortification ProgramsMoore, Grant, Kratky, Bothwell, Rodenstein, Streekstra, Turner, and WreesmannMoore SUSTAIN, Washington, DC, USA Search for more papers by this author, Grant SUSTAIN, Washington, DC, USA Search for more papers by this author, Kratky Nestlé, New Milford, Connecticut, USA Search for more papers by this author, Bothwell Department of Medicine, University of Witwatersrand, Johannesburg, South Africa Search for more papers by this author, Rodenstein Unilever Health Institute, Englewood Cliffs, New Jersey, USA Search for more papers by this author, Streekstra DSM Food Specialties, Delft, Netherlands Search for more papers by this author, Turner SUSTAIN, Washington, DC, USA Search for more papers by this author, and Wreesmann Akzo Nobel, Arnhem, Netherlands Search for more papers by this authorPublished Online:March 14, 2013https://doi.org/10.1024/0300-9831.74.6.463PDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinkedInReddit SectionsMoreFiguresReferencesRelatedDetailsCited byIron Fortification Practices and Implications for Iron Addition to Salt15 February 2021 | The Journal of Nutrition, Vol. 151, No. Supplement_1Refining Treatment Strategies for Iron Deficient Athletes15 October 2020 | Sports Medicine, Vol. 17Efficacy and Safety of Iron FortificationUse of ferrous fumarate to fortify foods for infants and young children26 August 2010 | Nutrition Reviews, Vol. 68, No. 9Prevención de la carencia de hierro en la lactancia, la infancia y la adolescenciaAnnales Nestlé (Ed. española), Vol. 68, No. 3Prévention de la carence en fer chez le nourrisson, l’enfant et l’adolescentAnnales Nestlé (Ed. française), Vol. 68, No. 3The efficacy of ferrous bisglycinate and electrolytic iron as fortificants in bread in iron-deficient school children8 March 2007 | British Journal of Nutrition, Vol. 95, No. 3 Volume 74Issue 6November 2004ISSN: 0300-9831eISSN: 1664-2821 InformationInternational Journal for Vitamin and Nutrition Research (2013), 74, pp. 463-466 https://doi.org/10.1024/0300-9831.74.6.463.© 2013Hogrefe AGKeywordsIron bioavailabilityfood fortificationabsorption enhancerscostPDF download

Fortification of cereal flours may be a useful public health strategy to combat iron deficiency. Cereal flours that are used shortly after production (e.g., baking flour) can be fortified with soluble iron compounds, such as ferrous sulfate, whereas the majority of flours stored for longer periods is usually fortified with elemental iron powders to avoid unacceptable sensory changes. Elemental iron powders are less well absorbed than soluble iron compounds and they vary widely in their absorption depending on manufacturing method and physicochemical characteristics. Costs vary with powder type, but elemental iron powders are generally less expensive than ferrous sulfate. This review evaluates the usefulness of the different elemental iron powders based on results from in vitro studies, rat assays, human bioavailability studies, and efficacy studies monitoring iron status in human subjects. It concludes that, at the present time, only electrolytic iron powder can be recommended as an iron fortificant. Because it is only approximately half as well absorbed as ferrous sulfate, it should be added to provide double the amount of iron.

Iron fortification has been used for decades in a number of industrialized countries to combat iron deficiency and seems to have played a significant role in reducing its prevalence, especially in infants and women. The overall strategy has been one in which staples such as wheat, flour, have been fortified with iron. While the effects appear to have been positive, there are still problems not yet completely resolved. In this context, the selection of the fortificant always represents a compromise between a choice of chemically reactive compounds of high bioavailability, such as ferrous sulfate, and inert compounds, which are poorly absorbed. Ferrous sulfate is very effective when added during the preparation of bread and bakery products and infant formulas, but cannot be used in stores flour because of organoleptic problems and inert compounds, such as elemental iron powders, have to be used. The search, therefore, continues for compounds of high bioavailability which do not cause organoleptic changes in the vehicles to which they are added. Problems associated with effective iron fortification programmes are compounded in a number of developing countries by a variety of factors. Most potential vehicles are not centrally processed, inhibitory ligands in staple cereal diets depress the absorption of both intrinsic and fortification iron, anemia is often of multifactorial in etiology, financial resources are scanty and governmental support sometimes lacking. Despite such difficulties there are encouraging signs of progress in a number of countries, using a variety of fortificants and vehicles. In the present review particular attention is paid to the potential role of NaFeEDTA as a fortificant in developing countries. It is much less affected by the inhibitors of iron absorption present in diets of low bioavailability, it can be added to a number of vehicles without causing organoleptic problems and its efficacy has been underlined in three intervention studies.

Hereditary haemochromatosis (HH) is an autosomal recessive disorder leading to excessive absorption of dietary iron. The gene affected in the common variety has recently been identified near the HLA-A locus on chromosome 6 and designated HFE. The HFE mutation, C282Y, responsible for most cases of HH is found in as many as 8-18% of people of European descent; 6-32 per 1000 are therefore homozygous, but only a variable proportion accumulate enough iron to develop organ damage with the associated clinical manifestations. Clinical expression depends on the amount of absorbable iron in the diet, the amount of iron being lost (greater in women through menstruation and pregnancies) and the severity of the genetic defect. The excess iron can be removed by serial phlebotomies. In symptomatic individuals this reverses some of the manifestations and prolongs survival significantly; if treatment is instituted before symptoms appear all manifestations are prevented. The objective must therefore be to identify and treat affected individuals in the presymptomatic stage. In this context, the role of population screening is currently being debated.

The human leukocyte antigen (HLA)-linked iron-loading gene (HFE) associated with the autosomal recessive disorder known as hereditary hemochromatosis occurs in about 10% of subjects of European descent, most of whom are unaffected heterozygotes. In contrast, the 3 to 5 per 1,000 who are homozygotes are at risk of developing severe and potentially lethal iron overload, with damage to a number of organs, including the liver, pancreas, heart, joints, and the endocrine glands. Although the removal of the excess iron by repeated venesections is simple, effective, and safe therapy, much of the organ damage, once it has occurred, is irreversible. Because symptoms are often nonspecific, it is important for physicians in the relevant specialties to develop a high index of suspicion and to apply widely the appropriate screening tests, including transferrin saturation and serum ferritin concentration. Equally important is the detection of affected family members, who are usually siblings, before they have developed significant iron overload. In addition, screening of populations in which the prevalence of hereditary hemochromatosis is high has become an attractive and cost-effective option, especially now that the molecular structure of the HFE gene has been defined. Using this approach it is now possible to detect individuals homozygous or heterozygous for the gene using a simple polymerase chain reaction-based test. The application of this exciting new tool promises to provide fresh insights into the range of phenotypic expression in hereditary hemochromatosis. A challenge for the future will be to define the genetic or environmental factors responsible for iron overload in up to 20% of patients with clinical hemochromatosis who do not have the HFE gene.

In celebrating this very special day, it is appropriate to look back on the achievements of the Brisbane Liver Group, in which June Halliday has played such a key and pivotal role. Over the years the group's interests have included a whole range of interwoven iron themes, but as hereditary (genetic) haemochromatosis (HH) is central to a number of these themes, it provides a good starting point.