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Advantages and Limitations of Iron Amino Acid Chelates as Iron Fortificants
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  July 2002: (II)S18–S21 Advantages and Limitations of Iron Amino Acid Chelatesas Iron Forticants Lindsay H. Allen, Ph.D. Introduction This review provides information concerning the valueof iron amino acid chelates as iron forticants. Approx-imately three years ago, the International Life SciencesInstitute held a technical consultationon iron amino acidchelates. At that time the available research data wasinadequateto form a conclusionconcerningthe bioavail-ability of iron from iron amino acid chelates; since then,however, several well designed experiments have inves-tigated the value of these compoundsfor the forticationof foods. These are described in the present review. Structure of Ferrous Bisglycinate and FerricTrisglycinate Ferrous bisglycinate(sold commercially as Ferrochel byAlbion Laboratories, Cleareld, UT) consists of a mol-ecule of ferrous iron attached to two molecules of gly-cine. The iron is bound to the carboxyl group of glycinein an anionic bond, and to the amino group in a coordi-nated, covalent bond, to form two heterocyclic rings.This structure may protect iron from interactions withdietary inhibitors of iron absorption, potentially makingit an ideal forticant for foods high in inhibitors such asphytate. Theoretically, it could also cause less peroxida-tion of polyunsaturated fatty acids and vitamins thansoluble iron. If Ferrochel is absorbed intact, however, itis important to know whether iron absorption from thismolecule is normally down-regulated as iron stores in-crease.Ferric trisglycinate is also sold commercially asFerrochel Taste-Free, which is composed of three gly-cine molecules combined with a ferric iron molecule(Albion Laboratories, Cleareld, UT). The absorption of the ferric iron from the trisglycinate is discussed herebriey, although the majority of this review will bedevoted to discussion of the qualities of the ferrousbisglycinate—Ferrochel—as an iron forticant. Recent Studies on the Absorption of Iron fromAmino Acid Chelates The four recent studiesreviewed here were conductedbyOlivares et al. in Chile, 1 Fox et al. in England, 2 Bovell-Benjamin et al. in the United States, 3 and Layrisse et al.in Venezuela. 4 In all of these studies iron absorption wasevaluated by labeling the iron amino acid chelate withradioactive or stable iron isotopes and measuring theamount incorporated into red blood cells approximatelytwo weeks later.In the research by Olivares et al. 1 the absorption of iron from ferrous bisglycinate in water given to 14 adultwomen was compared with its absorption from milk in adifferent group of 14 similar individuals. Only two sub- jects were iron decient. Because different subjectswereused in each study, and the amount of iron absorbed byeach individual is affected by their iron status, all sub- jects also consumed a reference dose of ferrous ascorbateto correct for interindividual differences in iron status.Ferrochel iron was less well absorbed from the milk (11%) than from the water (46%). Also, adding ascorbicacid increased the absorptionof Ferrochel iron from milk by 38%, to 15%. These results suggest that inhibitorsandenhancers can affect the absorption of the bisglycinateiron. The authors commented that there was a muchlarger (approximately 250%) increase in iron absorption,however, when ascorbic acid was added to ferrous sul-fate in a previous experiment. Another limitation of thisstudy was that there was no assessment of the absorptionof ferrous sulfate iron from milk; the authors reportedthat in a previous study they found this to be only 4%,which would mean approximately three times more fer-rous bisglycinate iron than ferrous sulfate iron is ab-sorbed from milk.In the study by Fox et al. in England, 2 infants wereadministered meals containing bisglycinate iron or fer-rous sulfate iron labeled with stable isotopes. There wasno signicant difference in the efciency of iron absorp-tion from the two iron sources either from a pureedvegetable weaning food or a high-phytate whole-graincereal weaning food; the phytate reduced the absorptionof iron to a similar extent from both forticants. Impor- Dr. Allen is with the Program in International Nu-trition, Department of Nutrition, University of Califor-nia, Davis, CA 95616, USA. S18 Nutrition Reviews , Vol. 60, No. 7   tantly, 0.83 mg ascorbic acid per mg iron was added tothe ferrous sulfate, however, which may have causedhigher iron absorption in the ferrous sulfate controlgroup than if the ferrous sulfate had been added alone.In the study by Bovell-Benjaminet al. 3 in the UnitedStates, the absorption of iron from ferrous bisglycinatewas compared with its absorption from ferrous sulfate.Both sources were fed to the same ten iron-decient menin a whole-maize porridgewith highphytatecontent.Thepurpose was to determine if the absorption of Ferrocheliron is protected from inhibition by phytate and whetherFerrochel iron exchanges with ferrous sulfate iron in theintestinal pool. In the rst experiment the two sources of iron were fed separately on two consecutive days, and inthe second the iron sources were fed togetherin the samemeal. Each iron source was labeled with a differentisotope. Had the Ferrochel degraded in the intestine andits iron exchanged with the ferrous sulfate iron, theobserved absorption of iron from the two sources wouldhave been identical owing to mixing of the free ironisotopes in the intestinal lumen. When the two ironsources were fed in two separate maize meals, however,iron absorption from the bisglycinate was ve to sixtimes higher than from the ferrous sulfate (on average,approximately 6–7% compared with 1–2%, respec-tively). This discrepancy persisted when the iron sourceswere mixed together in the same meal, indicating thatthere was no exchange of the isotopes from the two ironsources in the intestinal pool, and that the ferrous bis-glycinate molecule was probably absorbed in an intactform.In a second study, the same investigators 3 assessedwhether the absorption of the iron from Ferrochel isdown-regulated normally by higher iron stores. Ironabsorption from ferrous ascorbate in water and Ferrochelin water was compared in 21 healthy adult women witha range of iron status (serum ferritin from 2 to 63 g/L).When given in water, iron absorption from the bisglyci-nate was 31% compared with 72% from the ascorbate.Absorption of iron from both compounds was inverselyand similarly correlated with iron status ( r   0.61between ferrous ascorbate and serum ferritin, and  r  0.78 between ferrous bisglycinate and serum fer-ritin). Finally, the absorption of ferric trisglycinate ironin water (39%) was similar to that of the ferrous bisgly-cinate iron, but the trisglycinate iron was quite poorlyabsorbed (2.3%) from the maize porridge meal. In sum-mary, these two studies show the superior absorption of iron from the ferrous bisglycinatein the presence of highphytate and suggest that the bisglycinate iron is takeninto the intestinal cells in the chelated form. It is proba-ble, however, that the chelate is degraded within theintestinal cell because the absorption of its iron is regu-lated normally by iron status.Layrisse et al. studied iron bioavailability frombreakfasts enriched with ferrous bisglycinate to whichphytates and polyphenols (iron absorption inhibitors)were added. 4 Five different experiments were conductedin a total of 74 subjects. When ferrous bisglycinate andferrous sulfate were given together or in different meals(in breads made from corn our or white wheat our,with cheese and margarine) the iron absorption from thebisglycinate was twice that from the sulfate although itwas slightly less than iron absorption from iron EDTA.The efciency of iron absorption from the fortied cornour was 5.1% from ferrous sulfate and 10.1% (signi-cantly higher) from the ferrous bisglycinate; these datasupport the study by Bovell-Benjamin et al. 3 that foundhigher absorption of the bisglycinate iron from maize.However, the addition of phytase to the bisglycinate-fortied corn bread did increase iron absorption by ap-proximately 30%, indicating that there was some inhibi-tion of absorption of the bisglycinate iron by phytate.The polyphenolsin espresso coffee and tea reduced ironabsorption from the ferrous bisglycinate by 50% butthere was no ferrous sulfate control for comparison. Theinvestigators concluded that ferrous bisglycinate is asuitable compound for food fortication. Stability of Foods Fortied with Iron AminoAcid Chelates In addition to assessing iron bioavailabilityfrom the ironamino acid chelates, it is important to evaluate how theseiron sources affect the quality of foods to which they areadded. The promotion of oxidative rancidity in fats, andassociated off-avors and colors, is a universal problemwith most solubleiron forticants such as ferrous sulfate.Bovell-Benjamin et al. 5 evaluated the effect of the che-lates on the quality of whole-maize meal, in which 60%of the total fatty acids are polyunsaturated and thereforeparticularly susceptible to lipid oxidation. Several forti-cants were compared: ferrous sulfate, ferrous bisglyci-nate, ferric trisglycinate, sodium iron EDTA, and azero-iron control. Each forticant was added at 30 or 60mg iron per kg dry maize meal, and stored at 30, 40, or50 degrees Celsius for 20 days. The production of hex-anal, a breakdown product of lipid peroxidation, wasassessed. The ferrous bisglycinate caused more lipidperoxidation than any of the other iron compoundstested. This peroxidation was completely prevented bythe addition of the antioxidant butylated hydroxyanisole(BHA) at 25 ppm (lower concentrationswere not tested).By contrast, citric acid, tocopherol, and histidine had noprotective effect. Ferric trisglycinate did not producerancidity, presumably because of its lower solubility.Sensory evaluationby 15 trained evaluatorswas alsoconducted to evaluate 16 appearance, avor, and textureattributes in the same maize samples (treatment de- S19 Nutrition Reviews , Vol. 60, No. 7   scribed in previous paragraph). In general, the color of the maize was not different with either of the two ironamino acid chelates compared with the zero-iron control.The ferrous bisglycinate–fortied samples (but not ferrictrisglycinate), however, were signicantly more rancid,especiallyat the higherconcentrationsand higherstoragetemperature. Rancidityparalleled the hexanal productionvalues.Because these trials employed a sensory evaluationpanel trained to detect small differences in sensory prop-erties, an additional study was conducted to determinewhether untrained individuals, namely young childrenand their mothers, could detect these differences in thequality of the maize meal stored under the same condi-tions. 6 In this consumer-acceptance trial, parents wereasked to evaluate their own liking of the maize porridge,as well as the reaction of their child to the porridge, on a9-point hedonic scale. The porridges made from theferrous bisglycinate–fortied maize were generally asacceptable to young children and their parents as azero-iron control, and the addition of BHA to the ferrousbisglycinate did not affect the acceptability rating.Relatively little attention has been paid to the effectof iron on the stability of vitamin mixes to which it isadded. Marchetti et al. 7 assessed the effect of addingsulfates versus amino acid chelates of copper, zinc, iron,manganese, and cobalt to mixtures of vitamins stored ateither 20 or 37 degrees Celsius for 90 and 180 days. Theauthors did not describe the exact nature of the chelates(e.g., ferrous bisglycinate or ferric trisglycinate). At 37degrees Celsius the metal sulfates caused signicantlosses of vitamins B 2 and B 6 , and at 20 degrees Celsius,losses of ascorbic acid, retinol,and vitaminK. There wassignicantly less loss when the amino acid chelates wereadded. After 180 days at 37 degrees Celsius, for exam-ple, loss of retinol was approximately 65% with themetal sulfates compared with 46% with the amino acidchelates. Additional studies are needed to document theextent to which specic metal amino acid chelates con-serve vitamins in mixes used to fortify foods or to beconsumed as supplements. Both the efcacy of the sup-plements and the cost of the vitamin losses are importantconsiderations. Mineral-Mineral Interactions It is plausible that iron amino acid chelates, if theyindeed remain chelated in the intestinal lumen and aretaken into the intestinal cells intact, cause less inhibitionof the absorption of other minerals such as zinc (espe-cially if the latter is also provided as an amino acidchelate). This issue remains to be investigated. Commercial Products Fortied with Iron AminoAcid Chelates Many commercial products are already fortied withiron amino acid chelates. Amino acid chelates weresrcinally developed for the animal feed industry, whichhas purchased chelated minerals for many years becauseof the conviction that their greater efcacy is worth theinvestment. Ferrous bisglycinate appears to be an excel-lent forticant for increasing the iron content of milk; itis used to fortify milk and dairy products sold in Brazil,Chile, Argentina, South Africa, and Italy. Unlike ferroussulfate, bisglycinatedoes not change the color or taste of milk, and does not cause peroxidation of the milk lipidseven during long-term storage. Reportedly, the bisglyci-nate needs to be added after the milk is homogenized;theexplanationfor this may be that a protein layer surroundsthe micelles in homogenized milk preventing oxidationof the lipids in the core of the micelle. (Prior homoge-nization does not prevent the adverse sensory changescaused by ferrous sulfate, however.) Granola, biscuits,cereal products, cookies for children, and fruit drinks aresuccessfully fortied with ferrous bisglycinateprovidingsubstantial amounts of iron. Cost Considerations A frequently voiced objection to the use of amino acidchelates is their higher cost relative to ferrous sulfate orother cheaper iron sources. The current cost estimateprovided by the manufacturers is approximately $600/kgor, because it contains 20% iron, $120/kg iron. If asindicated by the experiments of Bovell-Benjamin et al. 3 and Layrisse et al. 4 described above, the bioavailabilityof ferrous bisglycinate iron is two to six times higherthan that of ferrous sulfate iron, however, it should bepossible to add substantially less of the ferrous bisglyci-nate and achieve the same level of iron absorption. Dr.Dary discusses the relative costs of iron forticantsfurther in this volume. Conclusions The advantage of using ferrous bisglycinate as an ironforticant is its much higher absorption from foods thatare high in iron absorption inhibitors, such as wholemaize. If given in water, or possibly in foods low ininhibitors, the bisglycinate may not provide such a largeadvantage. Although there is some evidence that ferrousbisglycinate is intact when taken up by the intestinalcells, the efciency of iron absorptionfrom this source isapparently normally down-regulated by iron status. Anadditional advantage of the bisglycinate is that it can beused as an iron forticant for dairy productsand is addedto a wide variety of commercial products. There may befewer adverse interactions between ferrous bisglycinate S20 Nutrition Reviews , Vol. 60, No. 7   iron and other vitamins in multivitamin preparationsalthough further studies of this important question areneeded. It is also possible, but not known, that aminoacid chelates of iron cause less inhibition of the absorp-tion of other minerals such as zinc. A disadvantageof thebisglycinate is its higher redox potential and subse-quentlygreater tendencyto cause lipid oxidationin somesituations, such as in whole-meal maize. Whereas atrained sensory evaluationpanel could detect the adverseeffect of ferrous bisglycinate on the sensory qualities of maize meal, however, mothers and young children couldnot. Moreover, the addition of a small of amount of anantioxidant, such as BHA, prevented these sensorychanges and the chelate is used to fortify many commer-cial cereal-based foods. The bisglycinate is a more ex-pensive source of iron than ferrous sulfate, but smalleramounts could be used as a result of its higher bioavail-ability. Acknowledgement The studies by the author described in references 3, 5,and 6 were funded in part by Albion Laboratories, themanufacturers of Ferrochel. 1. Olivares M, Pizarro F, Pineda O, et al. Milk inhibitsand ascorbic acid favors ferrous bis-glycine chelatebioavailability in humans. J Nutr 1997;127:1407–112. Fox TE, Eagles J, Fairweather-Tait SJ. Bioavailabilityof iron glycine as a forticant in infant foods. Am JClin Nutr 1998;67:664 –83. Bovell-Benjamin AC, Viteri FE, Allen LH. Iron absorp-tion from ferrous bisglycinate and ferric trisglycinatein whole maize is regulated by iron status. Am J ClinNutr 2000;71:1563–94. Layrisse M, Garcia-Casal MN, Solano L, et al. Ironbioavailability in humans from breakfasts enrichedwith iron bis-glycine chelate, phytates and polyphe-nols. J Nutr 2000;130:2195–95. Bovell-Benjamin AC, Allen LH, Guinard J-X. Sensoryquality and lipid oxidation of maize porridge as af-fected by iron amino acid chelates and EDTA. J FoodSci 1999;64:371–66. Bovell-Benjamin AC, Allen LH, Guinard J-X. Tod-dler’s acceptance of whole maize meal porridge for-tied with ferrous bisglycinate. Food Quality andPreference 1999;10:123–87. Marchetti M, Ashmead DM, Tossani N, et al. Com-parison of the rates of vitamin degradation whenmixed with metal sulphates or metal amino acidchelates. Journal of Food Composition and Analysis2000;13:875–84 S21Nutrition Reviews , Vol. 60, No. 7 
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