When rice is polished it loses much of its natural iron during this process and so a method of fortifying rice by applying an edible coating that improves the available iron in the rice [ 46 ]. A third way to fortify rice is by using a product called Ultra Rice which is a high-iron simulated rice grain that can be mixed in with regular rice and is highly accepted with no reports of bad texture or taste [ 43 , 47 ].
During a randomized controlled trial in the Philippines iron fortified rice was proportionately mixed with regular rice to provide more available iron in a serving of rice. Hemoglobin concentrations of children in the study sites significantly increased from baseline to endline, and prevalence of anemia significantly decreased by 4. However, a study in Brazil found that the use of fortified rice only once weekly in child-care centres brought about similar results [ 47 ]. In addition to improved iron status, another study in Brazil found that study participants and their families exhibited a very high rate of acceptance of the fortified rice as part of their diet with no adverse effects or undesirable taste, colour or smell [ 49 ].
Iron fortified rice, with proven effectiveness in improving iron status as well as high acceptability of the product, may be an important part of national nutrition strategies. Wheat flour and maize flour can also be fortified to be more iron rich, and may be a useful tool in addressing iron deficiency in communities where large amounts of wheat flour and its products are consumed [ 50 ]. The WHO supports the fortification of wheat and maize flour but suspects that it will be the most effective in reducing iron deficiency when it is mandated at the national level [ 51 ].
In a trial that assessed the efficacy of fortified wheat flour it was found that there was a lower prevalence of iron deficiency in women who consumed the fortified flour more regularly [ 50 ].
Iron biofortified pearl millet has also been tested as an approach to address iron deficiency in communities of developing countries. A study in Benin found that consuming iron fortified pearl millet can double the absorption of iron in women and may be a highly effective approach to combatting iron deficiency in millet-eating communities [ 53 ].
Despite the improvement in hemoglobin concentration in trial communities, there were challenges and limitations to this approach for addressing iron deficiency and IDA. Primarily, the cost to households associated with switching to fortified products proved to be a challenge.
For example, in the Philippines when the market was flooded with unfortified rice by the government, the population began purchasing the cheaper, unfortified variety rather than the iron-fortified rice that was slightly more expensive, despite the added benefit [ 48 ].
The other studies reviewed did not test the possibility of selling fortified products in markets so it is uncertain how this would work in different countries. It is likely that higher costs of fortified rice could be a barrier to the sale of the fortified rice, and this strategy may be difficult to sustain within a competitive market environment.
It is possible to fortify condiments such as fish sauce and soy sauce, which are commonly consumed in Asian countries. A study conducted using iron fortified Thai fish sauce showed that iron absorption from ferric sulfate fortified fish sauce added to a meal of rice and vegetables showed positive results [ 54 ].
This suggests that fortified fish sauce may be an effective solution to combat iron deficiency in countries with high fish sauce use. A similar study conducted in Switzerland assessed NaFeEDTA fortified fish sauce and found that it is a potential fortification method to address iron deficiency and iron deficiency anemia [ 55 ]. In Cambodia fortified fish sauce and soy sauce are becoming more salient in the iron deficiency discussion and the government intends to legislate fortifying these condiments by [ 56 ].
In Vietnam, where fish sauce is consumed as part of the regular diet and produced locally, a study was conducted and found that women using iron fortified fish sauce for six months had an average higher hemoglobin concentrations by 8. However, there are still challenges associated with fortifying condiments which include a changing of the colour of the sauce due to the addition of fortificants as well as political challenges to monitoring and rolling out this type of initiative [ 54 , 56 ].
While the cost-effectiveness ratio of this type of fortification has been positive, these analyses do not include the costs of potential health implications of high sodium diets [ 58 ]. Sodium is known to cause many adverse health problems including hypertension, increased risk of cardiovascular disease and increased risk of stroke [ 59 ]. It is possible that this type of intervention may promote excessive salt intake and the negative health impacts may outweigh the benefit of increased iron intake [ 60 ].
Micronutrient powders include any fortified powders that have at least two micronutrients in their composition. These powders are added to food being prepared in the home and then consumed, providing the benefits of the micronutrients they contain.
This fortification method has received a great amount of attention in the nutrition world, as many micronutrient deficiencies are so prevalent around the world in both developed and developing countries and this strategy has the potential to address multiple deficiencies at once.
Various studies have shown that this is an effective method of increasing hemoglobin concentration and treating iron deficiency anemia in children [ 62 - 66 ]. In Cambodia two studies were conducted that demonstrated a significant decline in iron deficiency anemia among groups of children who were on a daily regiment of sprinkles versus a control group with no intervention [ 67 , 68 ].
A study in Kenya assessed Sprinkles in a more real world setting by selling the product in local markets and found that in this situation they remained efficacious in reducing iron deficiency [ 69 ].
These results were from studies that occurred in various countries including Ghana, India, Bangladesh, Kenya, Pakistan and Haiti, which represents a number of regions in the world [ 71 ]. While the randomized clinical trials that have been conducted to test various MNPs have been successful, these are all in highly controlled situations. Studies have consistently showed success in improving biomarkers such as hemoglobin concentration and a reduction in anemia prevalence, however the adherence to such programs in a less-controlled environment may differ.
Distribution, cultural cooking practices, and cultural perceptions of MNPs may impact the effectiveness of such programs, though in the case of MNPs there is potential for this intervention to remain efficacious.
Micronutrient powders were accepted in many communities by caregivers around the world because they can be incorporated into the regular feeding practices [ 64 , 68 ]. In a study conducted in Bangladesh on sprinkle adherence [ 63 ] it showed that adherence was higher and hematological improvements were greater in groups who received more flexible instructions for use of 60 Sprinkles packets, rather than being told to use them daily.
Further research into adherence and acceptability would be useful in order to develop a strong implementation strategy for different regions of the world.
Early studies demonstrated that cooking food in cast iron pots increases the iron content of certain foods and that this iron is bioavailable [ 72 ]. In the face of the global iron deficiency endemic, researchers believed that promoting the use of cast iron pots could be efficacious in reducing the incidence of iron deficiency and iron deficiency anemia. Studies have taken place that assess the effectiveness, cost effectiveness and acceptability of this approach. A laboratory study was conducted in order to assess the impact on the iron contents of green leafy vegetables when cooked in different pots.
There is still some debate whether or not the iron that leaches into the food is bioavailable, and the need for more extensive analysis into improving iron availability in more types of food such as maize and rice [ 74 ].
The main limitations of using cast iron pots to improve iron status are that there was low acceptability during randomized controlled trials [ 75 - 77 ].
Cast-iron pots were reported to be heavy, rust easily, and required more attention for cooking due being prone to higher cooking temperatures [ 75 ]. In one study it was found that participants were selling the cast iron pots in the market in order to supplement low family incomes [ 78 ]. On the other hand, cast iron pots required less wood for stoves since cooking times were faster, and the pots were considered to be very durable [ 75 ].
Despite increases in hemoglobin concentrations and a reduction in anemia in the trial communities, the use of cast iron pots is not an effective strategy for addressing iron deficiency and IDA in most cases. It is possible that in communities where the use of cast iron pots is already prevalent then promoting continued or increased use has potential to be a part of a larger strategy to eliminate iron deficiency and IDA because the communities already accept the use of these pots [ 79 ].
The Lucky Iron Fish, an intervention based on the same principles of cooking with a cast iron pot, has shown in a randomized controlled trial to be effective in increasing hemoglobin concentrations by This method involves boiling water or cooking soup with the Lucky Iron Fish an iron ingot shaped like a common Cambodian fish for 10 minutes and adding some form of ascorbic acid citrus juice, most commonly [ 80 , 81 ]. While this has potential to be effective in addressing iron deficiency it has only been tested on women of reproductive age, and thus it is not certain that the Lucky Iron Fish will provide the right amount of iron for children.
The clinical trial included only 6 pregnant women, and future research could seek out larger numbers of pregnant and lactating women to test the efficaciousness in these times of high iron demand.
Furthermore, gaining a better understanding of the type of iron that leaches into water and foods would be beneficial, as would further testing of fortifiable foods. Additional challenges associated with this approach are predominantly surrounding acceptability and education, as this intervention requires significant behavior change in home practices.
Research regarding the acceptability, adherence and cost-effectiveness of this strategy should take place in order to carefully compare it with alternate interventions to be included in a national nutrition strategy. Current projects addressing iron deficiency in Cambodia include: the government supported supplementation for pregnant and post-partum women; Sprinkles; weekly iron folic acid supplements for women of reproductive age; helminth control; fortified foods such as rice and fish sauce; and the Lucky Iron Fish [ 82 - 84 ].
However, the official government stance, as advised by the World Health Organization WHO is for a supplementation program, and thus no official fortification program is currently in place or widely accepted by the numerous government and non-government groups working to address nutrition issues in Cambodia [ 84 ].
Iron deficiency and its associated anemia remains a salient health issue in Cambodia and looking ahead a more multi-faceted approach may be necessary to successfully combat this challenge. Iron supplementation is known to be incredibly effective due to the high bioavailability of iron [ 85 - 87 ]. This is especially important to ensure during pregnancy when iron demands of women are greater, and the risks can be more severe [ 1 , 87 ].
Daily iron supplementation is the most effective strategy at protecting iron stores in women during pregnancy but large doses of iron are also associated with negative side effects [ 87 ]. The negative side effects may cause problems with compliance, thus damaging the effectiveness of these programs [ 86 ]. Collectively, the women reported that they were aware that at their community health centre they would have received free iron supplements for during pregnancy and after delivering their child.
Despite this, women chose by personal preference or circumstances dictated this to deliver in their homes with a local midwife from their village. The health centres can be expensive to travel to and are far away from their villages, in the case of the two villages that were visited. The roads used to travel are barely passable, which only becomes more difficult during the rainy season June — November [ 88 ].
This suggests that in some parts of Cambodia the government initiatives may not be reaching marginalized populations, the population that demonstrates the greatest need. There is a significant difference between fortification and supplementation with regards to economic feasibility, government involvement and effectiveness in improving health. Fortification has an opportunity to be a more cost-effective and efficacious treatment for iron deficiency and iron-deficiency anemia than supplementation in many developing countries.
Warm and hot extrusion partially or completely gelatinizes the starch so that it holds the kernel together and increases its transparency and sheen so as to more closely resemble nonfortified rice grains that are similarly transparent.
Cold extrusion requires a binder to hold the kernel together and, like warm extrusion, can be made with special pasta presses. Hot extrusion requires more expensive, single- or twin-screw extruders and more capital investment.
Extruded kernels are, however, extremely sensitive to color changes with added iron, and FPP is the only iron compound that causes no color change In rat studies, there was no evidence that the 2. A recent development in rice fortification is the discovery of a novel enhancer of iron absorption for FPP.
When trisodium citrate and citric acid were added with isotopically labeled FPP during rice extrusion, iron absorption from FPP in humans almost doubled to a level similar to that from ferrous sulfate, and it was suggested that the hot extrusion process transformed the insoluble FPP into more soluble FPP citrate complexes There were no reported color changes.
No special equipment is needed to fortify milk with micronutrients. The fat-soluble vitamins are first homogenized with an aliquot of milk in a premix, whereas the water-soluble minerals and vitamins are added directly, either manually or by metered addition. The fortified milk is subsequently agitated, pasteurized, homogenized, and heat treated before packaging. Dried milk can be fortified either prior to or after spray drying.
Reconstituted dried cow milk can be a useful fortification vehicle to provide iron to young children. It is, however, a modest inhibitor of iron absorption due to relatively high concentrations of calcium 63 and casein The addition of ascorbic acid to commercial powdered milk formulas 65 or to dried cow milk fortified with ferrous sulfate or ferrous gluconate is common practice and can overcome the inhibition of the milk constituents and improve iron absorption and efficacy in young children.
The combination of soluble iron compounds and ascorbic acid, however, causes unacceptable flavor changes to liquid milk; consequently, iron fortification of liquid milk has not been widely practiced.
FBG is sensorily acceptable in liquid milk and additionally partly overcomes milk's inhibition of iron absorption. However, the use of this patented compound has been limited because of its high cost Until recently, the primary use of salt as a vehicle for fortification has been with iodine and, over the last 20 y there has been a considerable expansion of salt iodization in combination with a modernization of salt refining The iodization process has been integrated into the existing production or refining lines using 2 different procedures.
Many countries have modern salt production facilities, but in many LMIC, there remain small and medium-sized producers using far less sophisticated iodization methods.
To manufacture DFS, the selected iron formulation is added to the dry iodized salt in a batch or continuous blender. Producing DFS requires several stages of blending and probably cannot be produced in small- or medium-scale facilities. They classified Type 1 as with ferrous fumarate, either nonencapsulated Type 1a , encapsulated fluidized bed agglomeration Type 1b , or encapsulated extrusion agglomeration Type 1c ; Type 2 as with ferrous sulfate plus SHMP; Type 3 as with ferrous sulfate plus SHMP, malic acid, and sodium dihydrogen phosphate; Type 4 as with ferrous sulfate encapsulated with partially hydrogenated vegetable oil; and Type 5 as with MGFP.
When possible, this nomenclature has been used in the articles that follow this introduction. Salt is more difficult to fortify with iron than cereals or milk because there is a wide variation in the quality of raw salt produced in terms of purity, moisture content, and particle size.
Some common salts, with high impurities and moisture, are extremely sensitive to the formation of unacceptable color changes on addition of iron, and additionally iron can lead to iodine losses during storage by catalyzing the oxidation of iodate or iodide to iodine gas Under unfavorable conditions, iodine losses can be almost complete Another concern, which has not been well investigated, is that iron in DFS could change the color of foods to which DFS is added, especially if meals or foods contain vegetables high in polyphenol compounds.
Ferrous sulfate and other soluble iron compounds, including NaFeEDTA, rapidly turned the salt brown and accelerated iodine losses. FPP and ferric orthophosphate FOP caused no adverse color reactions or iodine losses for several months under a variety of storage conditions but, at that time, were considered unsuitable for salt fortification because of their lower absorption. SHMP was an effective complexing agent and prevented adverse color formation with ferrous sulfate and other soluble iron compounds.
The SHMP prevented color formation and greatly decreased iodine losses with no decrease in iron absorption. Several large efficacy studies were undertaken but iron efficacy of this combination could not be convincingly confirmed, largely due to the use of Hb alone to monitor iron status. Repeating these feeding studies with biomarkers specific to iron status, and taking account of the inflammation status of the subjects, would be expected to show good efficacy of ferrous sulfate plus SHMP.
Nevertheless, the failure to demonstrate efficacy, and the need for high-quality dry salt, led to the development of a more sophisticated EFF by NI, and to further studies with FPP added at a higher fortification level and ground to a smaller particle size in an attempt to improve bioavailability.
Although good efficacy has been reported for both approaches, further improvements are still possible and, more importantly, further improvements are still needed with respect to the prevention of adverse color formation and iron-catalyzed iodine losses.
It was manufactured by a granulation process followed by a coating process. During the granulation process, a mixture of ferrous fumarate, water, HPMC, SHMP, and titanium dioxide were agglomerated on a fluidized bed dryer into granules of similar size to salt grains. During the subsequent coating procedure, microencapsulation technology was used to coat the agglomerated ferrous fumarate granules with a suspension of titanium dioxide in soy stearine However, because of sensory concerns, including the appearance of black specks in the salt and a tendency for some batches of EFF granules to float on water 72 , a new manufacturing process has recently been developed for EFF, which is now used in DFS Type 1c, using the extrusion process.
The new manufacturing process is still evolving and consists of the preparation of a ferrous fumarate dough with an edible flour, water, and vegetable oil. The dough is extruded through a fine pasta die, cutting the strands to size, coating with titanium dioxide, and microencapsulating by spraying with HPMC and soy stearine This evolving landscape for the manufacturing process and composition of extruded EFF poses limitations to the evaluation of this technology at the present time.
Studies evaluating adverse color formation and increased iron-catalyzed iodine losses in DFS, with both EFF and MGFP, have been inconsistent, but indicate that color formation and extensive iodine losses can occur when lower quality salt is used in DFS and stored in hot humid climates 44 , The need for further developments with DFS Type 1b and Type 5 to avoid color changes and iodine losses is thus clear and has led recently to a new manufacturing process used in DFSType 1c.
In relation to efficacy and iron absorption, there is a need to know whether the extrusion and encapsulation processes used to manufacture the EFF used in DFS Type 1c influence iron absorption from ferrous fumarate in humans. It would also be important to further investigate the potential for iron absorption enhancers in DFS.
Ascorbic acid was reported to cause an unacceptable pink coloration 70 and would not be stable during storage, but further studies on the influence of SHMP on iron absorption from ferrous sulfate, EFF, and FPP could provide useful information. There are also several enhancers of iron absorption that might increase absorption specifically from FPP. These include the addition of tetra sodium pyrophosphate 75 , trisodium citrate, and citric acid 61 and the addition of sodium hydrogen sulfate, which was reported to increase iron absorption from FOP in human subjects There are currently research efforts targeted at improving the iron compounds used in DFS by utilizing enhancers, and testing the bioavailability of new or existing DFS formulations in use Textbox 2.
Ferric pyrophosphate FPP is widely used to fortify commercial infant cereals that are sensitive to color changes and has demonstrated good efficacy in young children 9.
The main benefit of FPP is that it does not cause color reactions in foods that are sensitive to color changes with added iron. Its white color also makes it more easily blended into light-colored foods such as refined salt. Its disadvantages are that it is water-insoluble, and that it has a lower relative bioavailability than other major iron fortification compounds, so needs a higher fortification level. Given the importance of a formulation that avoids color changes in storage as well as in foods cooked with DFS, there are research efforts underway to reassess the potential of regular FPP as an iron compound for DFS and compare its bioavailability with the current Type 1c DFS using encapsulated ferrous fumarate M Zimmermann, ETH Zurich, personal communication, Additionally, enhancers to improve iron absorption from FPP will be tested in an attempt to improve its bioavailability.
These include citric acid and trisodium citrate which have increased iron bioavailability from FPP in fortified rice and sodium pyrophosphate which has increased iron bioavailability from FPP in bouillon.
The FPP and added enhancers will be encapsulated to minimize iodine losses. The enhanced FPP formulations will be tested for color stability and iodine retention in DFS storage studies, as well as bioavailability. This method, however, cannot be used for iron because iron intakes of menstruating women and children are not distributed normally. The additional iron intake needed is then adjusted if necessary based on the relative bioavailability of the iron fortification compound, and the iron fortification level is calculated based on the consumption pattern of the fortification vehicle.
The above approach is recommended when nationally representative dietary intake data have been collected. Such data are usually not available in LMIC, and a more pragmatic, evidence-based approach was used to define iron fortification levels for wheat and maize flour These population groups have the highest iron requirements and are the most at risk.
Because the effect of the encapsulation is unknown, the influence of the current extruded EFF capsule on iron absorption from ferrous fumarate in humans should be measured. There is little information to provide a recommendation for FBG in milk products but, assuming a 2-fold better iron absorption than from ferrous sulfate, the recommendation would be to provide 3.
Iron-fortified foods fed in large-scale programs or in well-controlled efficacy studies are judged to have demonstrated impact if the iron status of the study population is significantly increased over the feeding period.
As explained earlier, iron status cannot be monitored by Hb alone and must be monitored by specific iron status biomarkers. However, an additional concern is the presence of widespread infections and inflammation in the study population. Iron status must be evaluated differently depending on whether or not the study population is affected by inflammation.
In the presence of infection, SF and TfR can still be used but they must first be corrected for the effects of inflammation 77 , Infections and inflammation are common in tropical areas of Asia, Africa, Latin America, and the Caribbean. In these areas, inflammation has a major influence on iron metabolism, and on the biomarkers of iron status, complicating the measurement of iron status, and making the impact of iron fortification programs difficult to demonstrate.
Inflammation causes the liver to increase hepcidin production. Hepcidin then degrades the iron transporter ferroportin, and restricts the passage of iron into the plasma. The most important effect is a decrease in the recycling of red cell iron stored in the macrophages of the reticuloendothelial system.
The passage of iron into the plasma from the intestinal cells is also restricted by hepcidin and iron absorption is decreased However, it is the inflammation-induced decrease in the recycling of red cell iron that has the greatest impact on iron status, because iron recycling provides 10—20 times more daily iron than does dietary iron absorption Iron fortification interventions are understandably less effective in the presence of infections and inflammation.
The monitoring of iron status in areas of widespread infection and inflammation is further complicated because the biomarkers of iron status are also influenced by the inflammation. SF, a biomarker of liver iron stores, is perhaps the most widely used biomarker of iron status.
However, it is also an acute-phase protein that increases with inflammation. In order to be a useful iron status measure in these circumstances, the SF values must first be adjusted for inflammation A correction for inflammation also exists for TfR Recently, Ganz 80 proposed a hypothesis that could have a major influence on the measurement of iron status in the presence of infections and inflammation.
He suggested that when iron supply to the body is severely restricted, as with the prevention of iron recycling during infection and inflammation, red cell production is curtailed so that the extremely low iron supply can be preferentially utilized for the essential enzymes in the tissues e.
This means that using red cell parameters such as ZPP and TfR to monitor a subject's iron status in the presence of inflammation could underestimate iron status in the tissues If the Ganz hypothesis is confirmed, the only useful iron status biomarker to measure the impact of iron fortification programs in areas of infection and inflammation could be the adjusted SF.
The safety of iron interventions in malaria endemic areas is also an issue because iron supplements, especially when given without food, can increase the severity of the malarial infections The likely explanation is that the rate of iron influx into the plasma from high-dose oral supplements exceeds the rate of iron binding to transferrin and a quantity of non—transferrin-bound iron NTBI is formed It is proposed that NTBI increases the intensity of malarial infections by increasing the sequestration of malaria-infected RBCs in the capillaries of the brain and intestine, causing cerebral malaria and further increasing the permeability of the intestinal barrier to the passage of pathogens.
At the same time, high iron doses stimulate the growth of pathogenic bacteria in the stool, increasing the potential for bacteremia. The normal immune response to malaria, as well as other infections and inflammatory disorders, is to prevent further microbial growth by stimulating hepcidin synthesis and preventing the passage of iron into the plasma.
Unlike with iron supplements, little or no NTBI is formed on consumption of iron-fortified foods, even when the foods are fortified with ferrous sulfate 83 , and there is no evidence that iron-fortified foods increase the intensity of malaria or other infections.
Iron-fortified foods, however, can increase the number of pathogens in the lower gut to the detriment of the beneficial barrier bacteria Nevertheless, although Gera et al. They suggested that this was because the lower amount of iron added to fortified foods is closer to the physiological situation.
Salt, wheat flour, maize flour, rice, and milk are the 5 major staple foods or condiments that have been most utilized as vehicles for micronutrient fortification at the global level. All have been used as a national public health strategy to target ID or to target deficiencies in other micronutrients. By far the most successful intervention has been the iodine fortification of salt. As a result, goiter, cretinism, and severe iodine deficiency have been eradicated from many countries.
In comparison, and for reasons discussed earlier, the iron fortification of wheat and maize flours has made only a modest impact on anemia in LMIC, especially when compared with the marked decrease in neural tube defects when cereal flours and other cereal foods are fortified with folic acid. There are several reasons for the global success of salt iodization. The most important is that salt, unlike wheat, rice, or maize, is universally consumed in predictable amounts by all population groups in all countries worldwide.
Iodine absorption is also little influenced by other dietary components. Iron fortification of foods is frequently needed as a public health strategy to combat ID and IDA in many countries worldwide.
Iron-fortified foods will improve iron status provided the iron fortification compound is chosen wisely and fortification level estimated according to the amount of vehicle consumed, the estimated dietary iron bioavailability, and the relative absorption of the fortification compound.
The choice of iron fortification vehicle for national programs until now has largely been based on consumption patterns of wheat flour, maize flour, and rice, and to a lesser extent on the degree of industrialization of the respective cereal industries. Dried milk powder has been the preferred food vehicle to provide additional iron to infants and young children.
Based on consumption patterns, however, DFS has the potential to be the universal global carrier for both iodine and iron provided that the technical challenges for the iron fortification of salt can be overcome. The following articles in this series discuss to what extent we are ready to manufacture a DFS that has the potential to make a significant contribution to reduction in ID in many national contexts. Special thanks go to Becky Tsang for help in preparing the figure and text boxes. Publication costs for this supplement were defrayed in part by the payment of page charges.
The opinions expressed in this publication are those of the authors and are not attributable to the sponsors or the publisher, Editor, or Editorial Board of The Journal of Nutrition. National Center for Biotechnology Information , U.
J Nutr. Published online Feb Richard F Hurrell. Author information Article notes Copyright and License information Disclaimer. Address correspondence to RFH e-mail: hc. This article has been cited by other articles in PMC. ABSTRACT This introductory article provides an in-depth technical background for iron fortification, and thus introduces a series of articles in this supplement designed to present the current evidence on the fortification of salt with both iodine and iron, that is, double-fortified salt DFS.
Keywords: iron fortification, iron fortification vehicles, iron fortification technologies, iron fortification compounds, iron bioavailability, sensory changes. Introduction Food fortification has an impressive history of public health successes 1 , 2 , and national fortification programs have helped eliminate, or greatly decrease, many of the micronutrient deficiencies that were common in Europe and the United States at the beginning of the 20th century. Dietary Components that Influence Iron Absorption Iron-fortified foods such as cereal flours, rice, salt, or milk are all consumed as part of a mixed diet.
Factors Influencing the Choice of the Iron Fortification Compound A large number of iron compounds have been considered for the fortification of foods. Relative bioavailability The relative bioavailability of different iron fortification compounds has been discussed in detail by Hurrell 9. Open in a separate window.
Water-soluble iron compounds Based on bioavailability and cost, ferrous sulfate would usually be the first choice for iron fortification. Water-insoluble compounds, readily soluble in the gastric fluid Ferrous fumarate has the same bioavailability as ferrous sulfate but causes far less sensory changes. Compounds partly soluble in the gastric fluid FPP and elemental iron powders are the preferred iron compounds for foods that are highly sensitive to unacceptable color and flavor changes, because these compounds cause few if any sensory changes.
Encapsulated compounds Encapsulation technologies have been developed to maintain the higher bioavailability of an iron fortification compound without causing adverse sensory changes. Iron chelates When the food fortification vehicle, or the regular diet, is high in phytic acid or other iron absorption inhibitors, the best option to enhance iron absorption from the fortified staples and condiments is the addition of NaFeEDTA or FBG.
Cost Allen et al. Fortification Technologies, and Relevant Iron Fortification Compounds, for Major Food Fortification Vehicles Product development for fortifying new food vehicles or adding nutrients to existing food vehicles The purpose of fortifying staple foods is to improve micronutrient intake through foods already consumed within the diet.
Textbox 1 Steps needed for the development of a new iron-fortified food for introduction into a national fortification program. It is essential to determine the cause of the anemia.
Much research has been carried out in recent years to better understand these diseases. Hereditary hemochromatosis is the prototype of diseases linked to iron overload; it is an autosomal recessive disease resulting from an abnormality of the hemochromatosis gene HFE on chromosome 6, most commonly involving the CY mutation. There is a high prevalence in Northern Europe countries, but it has also been reported in several Brazilian publications 2 - 4.
This disease results from an inappropriate increase in iron absorption by the intestines with the surplus metal being accumulated in the tissues.
The Brazilian government, concerned about the high incidence of iron deficiency anemia in children and pregnant women in the country, instituted a policy of mass or universal food fortification. This measure was published on December 18, with 18 months for companies to comply; this period ended on June 18, In a recent work entitled "Considerations on the food fortification with iron and folic acid" published in the Revista Brasileira de Hematologia e Hemoterapia we demonstrated our concern about this measure 6.
Iron and folic acid are two medications used in medicine and, as such, have both beneficial and adverse effects and thus can be harmful to health. The beneficial effects have been widely analyzed in works on the theme, but little has been discussed about the toxicity of these drugs in the healthy population and in patients with iron overload.
As these flours are basic to our diet, it can be concluded that every citizen in the country, regardless of age, gender, ethnic background, occupation, socioeconomic condition, healthy or carrier of some illness, began to ingest iron and folic acid every day, whether needed or not. Some questions were asked related to: the use of these two important medicines in more than million people, without any medical control; the risk of administering iron to anemic patients without first discarding the hypothesis of anemia secondary to a gastrointestinal neoplasm for example and whether mandatory food fortification with iron does not worsen the health of ordinary people or patients suffering from iron overload illnesses.
The literature often includes prolonged medicinal iron ingestion as a cause of illness by iron overload 1 , 7 - A review of these cases would therefore be an excellent opportunity to clarify how this hematologic condition behaves.
Iron overload due to prolonged medicinal iron ingestion is an extremely rare occurrence. After an exhaustive search we found 12 published cases whose data are presented in Table 1. Ten were female with ages ranging from 10 to 77 years, the treatment time was 5 to 49 years and the total amount of ingested medicine determined in eight patients ranged from to 26, g. Discussing this subject, Beutler 7 , in the 8th edition of Williams Hematology, states: The homeostatic mechanisms of the body are such that the improper administration of oral iron is very unlikely to produce clinically significant iron overload.
Of the few cases described all except one a child without tissue damage were documented before the HFE gene clone appeared, leaving open the distinct possibility that patients were simply cases of hemochromatosis whose disease was accelerated by the excessive intake of iron.
It is very difficult to determine the amount of iron that is ingested every day by the Brazil population in the current system of universal food fortification. In addition to the amount in a normal diet which is about 14 mg per day , Brazilians ingest iron from fortified foods and, occasionally, from products enriched for commercial purposes.
The results show that there is a wide variation in the iron content of the wheat flour produced by these mills. The iron content of samples ranged from 4. Hence, the daily amount of iron that is ingested by a Brazilian citizen will also depend on the amount of metal in each batch of flour.
The mandatory fortification program in Brazil has been in force for days now. To get an idea of how much iron a Brazilian citizen ingested during this period we used a simple simulation: one kilogram of wheat flour produces 18 bread rolls with 3. If a person eats three rolls per day that is 10 mg of iron per day over days he has ingested a total of 30, mg of iron in addition to the amount in the normal diet.
In this way three situations arise:. Although this amount of iron to far different to that observed in the cases described above with 'medical iron intake', it is sure that some cases of hemochromatosis in the Brazilian population will be speeded up.
An aggravating circumstance is that it has not been defined when the obligatory fortification of food according to Resolution of ANVISA should be discontinued.
In truth, Resolution of ANVISA is a practical measure, but it is not cost effective for the patient, who pays all the costs of treatment. Of course, in this latter situation, the nutritional value of bread must be remembered. In Guidelines on food fortification with micronutrients 23 , the authors affirm: "Fortified foods often fail to reach the poorest segments of the general population, which have the greatest risk of micronutrient deficiencies. This is because these groups always have restricted access to fortified foods due to their low income and the underdeveloped distribution channel".
Hence, we question whether, with universal fortification, we are not favoring only the more privileged classes? When the cost of a treatment is calculated, expenses related to complications that arise with the therapy must also be considered. Universal fortification may result in an increase in patients with iron overload hemochromatosis, transfusional hemosiderosis, etc.
Food fortification has been considered by some authors to be the best strategy to increase iron intake of a population, especially for children and pregnant women 24 , The World Health Organization recognizes four types of fortification: universal or mass, open market commercial , targeted for high-risk groups , and household and community fortification. The guidelines of these fortifications are described in detail in the book Guidelines on food fortification with micronutrients This is a work of great scientific content published by the following editors:.
Six other distinguished personalities from the fields of economics, social sciences, nutrition, and food and nutritional sciences also collaborated in this magnificent work. It is strange that no hematologist was included in a work by the World Health Organization with so many renowned researchers; a hematologist, of course, would increase the understanding about the effects of offering iron to needy populations.
Guidelines on food fortification with micronutrients 23 ,defines fortification as "the practice of deliberately increasing the content of an essential micronutrient, for example, vitamins and minerals including trace elements in food, to improve the nutritional quality of the food supply to produce a benefit to public health with a minimal risk to health".
Universal iron fortification of foods certainly results in some beneficial effects in the needy population, in particular in children with nutritional deficiencies. However, should it be allowed to accelerate the evolution of cases of hemochromatosis and other illnesses involving iron overload? Numerous works have been published on this theme. The fortification of wheat flour with iron has been used in Canada, Great Britain and United States since with control of iron deficiency being provided in these countries.
In recent years there has been growing interest of fortification programs in developing nations However, the fortification of foods with iron was suspended in Sweden in This was considered one of the largest fortifications in the world with the addition of 4. At that time, Olsson et al. On applying these data to Brazil, a patient with hemochromatosis absorbed a total of Denmark also suspended the fortification of wheat flour with iron in Millman apud Lynch 26 reports that this fortification had no effect on the prevalence of iron deficiency in men and in over year-old women in the pre- and post-menopausal periods.
Lynch 26 , in a detailed work on the risk of iron fortification and nutritional anemia arrived at the following conclusion: "The only very well-documented risk of universal fortification is an increase in the rate of accumulation of iron in individuals with the HFE phenotypic of hemochromatosis who may require more frequent phlebotomies. An increased absorption of iron can also be expected in anemic patients with iron overload".
Adamson, in the 6th edition of the book Harrison 28 , says that there has been a decline in interest for the supplementation of iron in bread and cereals due to the prevalence of the hemochromatosis gene, which would result in a high risk of overload in these patients. Guidelines on food fortification with nutrients 23 recognizes that market-driven fortification can play a positive role in public health to needy populations by offering some products that they need.
The choice is voluntary and is characterized by being able to add a higher quantity of a particular nutrient that cannot be done in universal fortification because of technical and safety issues. This type of fortification is more widespread in industrialized countries. Thus, by giving the population, in particular children, a wide range of products enriched with iron, a remarkable contribution will be given to the Brazilian Government to solve the problem of iron deficiency.
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