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São Paulo, Brazil and Albion Laboratories, Inc., Clearfield, Utah
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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9.4 g hemoglobin/dL blood) and less severe iron deficiency anemia (9.5 to 11.0 g hemoglobin/dL blood) through fortification of liquid 3.3% butterfat milk with a bioavailable ferrous iron amino acid chelate (Ferrochel) at 3 mg iron/liter/day. Methods: A group of 185 children were selected from Tupã, Brazil who presented the above two stages of iron deficiency anemia plus normalcy. Initially, 54% had severe iron deficiency anemia, 33% were less severely anemic and 13% had normal hemoglobin concentrations. They received iron-fortified milk for a mean of 222±2 days. Hemoglobin concentrations were measured initially, at 133±13 days, and at 222±2 days.
Results: By mean 222 days, 57% of the childrens’ hemoglobins were normal. Highest rates of repletion were in the initially severe anemic group. Repeated measures ANOVAs demonstrated that hemoglobins at 0, 133 and 222 days for the total group, as well as for the severe and less severe iron deficiency anemic groups, represented statistically different populations at 
=0.0005. Children with initially normal hemoglobin concentrations showed no change at 0, 133 and 222 days (=0.10), suggesting the possibility of absorptive regulation of this form of iron.
Conclusions: Low hemoglobin concentrations in young children can be increased through daily consumption of fluid milk fortified with 3 mg ferrous amino acid chelate (Ferrochel).
Key words: iron deficiency anemia, hemoglobin, iron, iron amino acid chelate, milk, fortification
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Symptoms of iron deficiency in children include apathy, short attention span, irritability and reduced ability to learn [3]. Even mild deficiencies, as opposed to iron deficiency anemia, may impair school performance and intellectual ability [4]. The most observable marker of iron deficiency is the impaired capacity for work [5]. This marker may be evident prior to meeting the criteria for iron deficiency anemia [6]. In developing children, iron deficiency anemia can be particularly debilitating since neurological motor and mental capacities can remain compromised even when sufficient iron is supplemented [7]. This morbidity impairs both physical and mental abilities to work and represents a severe personal and societal burden to less industrialized nations where iron deficiency anemia has significant incidence.
It is imperative that nutritional intervention be applied to populations at-risk for iron deficiency as early in the development of the individual as possible. A proven method of intervention for iron deficiency anemia is through the fortification of foods targeted to particular susceptible groups. This spares the rigorous adherence to a daily intake of tablets or capsules which may receive poor compliance from younger age groups. Young children of 6 months to 4 years are the most susceptible to the long-range consequences of iron deficiency. While needing nutritional intervention, this is also the group with the least tolerance to some of the symptoms of dietary iron from inorganic metal salt sources, which may include disagreeable odors and tastes and gastrointestinal irritation and upset. The developmental impairments which young children with iron deficiency anemia may experience may be prevented by supplying the needed iron in food, provided that the form and amount of the iron is organoleptically pleasing or neutral, nonirritating, absorbable, bioavailable and tolerated by the deficient individuals.
In the State of São Paulo, Brazil, during 1990–91, a broad survey for the prevalence of iron deficiency anemia among children aged 6 to 24 months was conducted by the government Health Department. The government used WHO Guidelines of 9.5 to 11.0 g hemoglobin (Hb) per deciliter of whole blood (g Hb/dL) to identify iron deficiency anemia; less than 9.5 g Hb/dL indicated severe iron deficiency anemia. Fully 84% of the children tested in five regions of the State of São Paulo were assessed as having iron deficiency anemia, while 30% of these were severely anemic [8]. This prompted the state health authorities to initiate a program to fortify fluid milk with iron as a dietary intervention to reduce the high prevalence of iron deficiency anemia.
Iron amino acid chelate with the iron being in the ferrous state (Ferrochel, Albion Laboratories, Inc., Clearfield, UT), had previously been found to be well tolerated in non-pregnant women and adolescents [9,10]. As shown in Fig. 1, this ferrous form of iron amino acid chelate belongs to the class of bicyclic chelates where each respective amino acid bonds the same iron atom through its carboxyl oxygen and -amino groups. The amine to iron bond is a coordinate covalent bond formed as both of the electrons of the lone electron pair on the nitrogen atom are donated into a vacant orbital on the iron atom. The R-groups highlighted with asterisks in Fig. 1 constitute the molecular extensions which can change for each of the 20 protein-derived amino acids. In Ferrochel, the R-groups are typically hydrogen atoms. This iron amino acid chelate has been shown to have an increased bioavailability and reduced irritability over inorganic sources of iron. The CAS Reference Number for this molecule is 20150-34-9.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Ages and degree of iron deficiency anemia among the participants are summarized in Table 1. Severe iron deficiency anemia (9.4 g Hb/dL whole blood) was initially measured in 100 (54%) of the children, while an additional 61 (33%) were shown to have less severe iron deficiency anemia (9.5–11.0 g Hb/dL). The remaining 24 (13%) of the individuals had normal hemoglobin concentrations, according to WHO guidelines (
11.1 g Hb/dL). The initial finding of 87% anemia among the participants in this study was consistent with the aforementioned governmental survey in the State of São Paulo [8].
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Methods
In order to ensure fortification of the milk at the rate of 3 mg iron/L (as iron amino acid chelate), it was determined that an overage of 10% iron was required to compensate for processing losses. Since the iron amino acid chelate used in the study was a 20% iron product, this equated to 16.5 mg Ferrochel/L. The milk was fortified in 10,000 L batches by first mixing 165 g of the iron amino acid chelate into 50 L of centrifuged milk set to the Brazilian standard of 3.3% butterfat and then mixing this portion into sufficient centrifuged milk to make 10,000 L. Following blending, the milk was homogenized and pasteurized prior to being distributed to the test children.
Blood samples were obtained from each child at the inception of the study by finger pricking. Basal hemoglobin concentrations were measured by the HemoCue® photometric system (HemoCue, Box 1204, S-262 23 Ängelholm, Sweden). Hemoglobin concentrations were remeasured by the HemoCue® method around 4.4 months into the study and again at its conclusion.
The children received 1 L of the iron amino acid chelate fortified milk daily for 7.3 months. The mean daily ingestion of milk for the 185 test children at Tupã was estimated to be 750 mL, based on reports from mothers in a similar study conducted in the city of Angatuba, Brazil [9]. This yields a daily dose of approximately 2.1 mg iron per day. This reduction from the 1 L per day aliquot of milk was due to the tendency of the mothers of the test subjects to share some of the iron fortified milk with other young children in the family.
The analyses of variances (ANOVA’s) summarized in Table 4 were calculated using a univariate repeated measures analysis [12]. This technique subtracts the contribution of variability in the mean responses from subject to subject from the variability within each time of hemoglobin measurement resulting in a residual sum of squares. The F-ratio is ultimately calculated by dividing the residual sum of squares by the product of the number of individuals in the test or subsection minus one and the number of measurement sets minus one, according to the following formulas:
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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=0.0005).
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9.4 g Hb/dL), less severe iron deficiency anemia (9.5–11.0 g Hb/dL), and normalcy (11.1 g Hb/dL). Repeated measures ANOVA’s were again utilized to compare changes in hemoglobin concentrations. These ANOVA data are summarized in Table 3. As can be seen by the extremities of the F-Test as compared to the tabular test statistic, the hemoglobin measurements taken at initial, mean 133 days and mean 222 days for the groups which were initially measured as being both severely iron deficiency anemic and having less severe iron deficiency anemia represent statistically separate populations at =0.0005, indicating a 99.95% statistical confidence that the hemoglobin populations are different. It is also important to note that the repeated measures ANOVA for the children who were in the normal range at the commencement of the study demonstrated no statistical differences in the hemoglobin concentrations measured at initial, mean 133 days and mean 222 days—all these measurements represented the same hemoglobin population (p>0.10). Where nutrients are shown to be more bioavailable than other ionic or organic sources of the same sources of the nutrient, there may be concerns for overdosing or cumulative toxicities. The ANOVA on the hemoglobin concentrations from children who were initially normal appear to indicate that no iron overloading occurred from the iron amino acid chelate, however, this condition would need to be further assessed in future research by examining iron storage sites in the body. A toxicological assessment of swine from the third, fourth and fifth filial generations to receive feed grade Albion® Iron Amino Acid Chelate, as well as other Albion® Metal Amino Acid Chelates, found no pathological indication of excess iron absorption. This included an examination for (and lack of) the presence of hemosiderin in the swine tissues [13]. Fig. 2, 3 and 4 illustrate the progress of children who had hemoglobin concentrations in each of the three groups recognized by WHO as having either severe iron deficiency anemia, less severe iron deficiency anemia, or being normal at the beginning of the evaluation, at the mean 133 day hemoglobin measurement and at the mean 222 day termination of the study. These figures follow changes in hemoglobin in progressive increments of 1.0 g Hb/dL. The tops of the bar graphs are roughly Gaussian and depict the progress of improvement in hemoglobin concentrations. Since the incremental change in hemoglobin amounts shown in these figures occupies the same position for both the mean 133 day data and the mean 222 day data, the bar graphs do not appear to be as distant from each other as they are (because the changes represented in Figs. 2, 3 and 4 are superimposed on one another). Fig. 3 illustrates the rates of change in the segment of the children who were in the 9.5–11.0 g Hb/dL category at the inception of the study. The rates of change appear more centrally located around zero change than was depicted in Fig. 2 The greatest convergence of change appears in Fig. 4, which depicts the progress of hemoglobin change over the 0 to 133 day and 133 to 222 day segments. This convergence visually illustrates the statistical finding of no significant change (p>0.10) in the repeated measures ANOVA for the normal group, as summarized in Table 3.
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Additional regression analyses of hemoglobin repletion rates were calculated based on the initial age of the child for young children who received 3 mg iron/day as ferrous iron amino acid chelate (Ferrochel) over the course of 0 to mean 133 days and 0 to mean 222 days. The means were plotted against the midpoint for each age category because the children were growing older over the course of the study. Since the youngest children in this research group were 6-month old infants and, among the 47 individuals in this category, the mean age was around 9 months, 0.75 years is taken for the first midpoint along the abscissa, followed by 1.5 and 2.5 years, respectively. Slope, Y-intercept, and correlation coefficient for the mean differences of the 0 to mean 133 days regression line were 1.0811, -0.2784 and 0.9987, respectively, while those for the mean differences of the 0 to mean 222 days regression line were 0.9568, 0.5851 and 0.9832, respectively.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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This iron amino acid chelate given as a supplement was successful in alleviating iron deficiency anemia in adolescents [10]. A dose of 30 mg iron per day as ferrous iron amino acid chelate (Ferrochel) was found to be statistically as effective as 120 mg of iron as ferrous sulfate in raising hemoglobin levels. Analyses of variance showed that all doses of iron had the same effect in raising hemoglobin levels above those hemoglobin values measured at the inception of the study (p<0.001). Additionally, none of the 26 participants who received the 30 mg iron as this specific amino acid chelate cited any gastric or other adverse effects throughout the 4-week course of study, although they were questioned specifically for incidences of these effects.
The lead author of the above research (Pineda) has subsequently determined that 3 mg iron per day is highly effective in correcting chronic iron deficiency anemia in school children. This is due to the high calculated bioavailability of iron from the amino acid chelated source as opposed to iron sulfate which has an absorption rate of 1 to 5%, the latter value being achieved only after the inclusion of 80 to 100 mg ascorbic acid per dose [14]. Pineda determined that when milk is fortified with 3 mg iron per liter as the specific iron amino acid chelate, Ferrochel, it performs at least as well as 18 mg iron from an inorganic source.
Additional research by one of us (Name) has shown that this iron amino acid chelate maintains its integrity through both pasteurization and sterilization. Color, odor and taste response have been favorable when this iron source is mixed with milk. Additionally, the Ferrochel iron was found to be nonoxidizing and compatible with the butterfat content of the milk. In the amino acid chelated form, the sequestered atom of iron has no polarity (is neutral). Thus, research has verified that this form of iron amino acid chelate is stable when mixed with other food ingredients. It does not promote the degradation of vitamins, as so typically occurs with supplemental iron from inorganic sources. Additionally, Name has found it to retard lipid peroxidation sufficiently that it may be used in iron fortification of margarine [11].
The oral LD50 of Ferrochel in Sprague-Dawley rats has been independently determined as the equivalent of 2800 mg/kg for the whole product. Since Ferrochel is 20% iron by weight, the equivalent amount of the iron amino acid chelate needed for daily supplementation of 3 mg iron in milk would be 15 mg of the product. The margin of safety of this dosage in comparison to the 2800 mg/kg oral LD50 in rats is readily apparent.
The concept of food fortification utilizing any nutrient assures that the daily intake of the nutrient is sufficient to meet a known daily dietary requirement when the fortified food is added to other normal dietary sources of the nutrient. In Brazil, the lower economic segments of the populace use cow’s milk as a major component of their daily nutrition. Their diets are chiefly high in carbohydrates, usually in the form of sugar and nonfortified flour. The State of São Paulo, has a policy of distributing milk at the Basic Health Units to young children of low income families. In the past, powdered milk had been given, but the government converted to fluid milk in order to meet the preferences of the people in the interior of the State. The fluid milk is given at the rate of 1 L of milk per day for each child under the age of 4 years.
While the supplied cow’s milk contains many needed nutrients, it presents a poor source of iron. Human milk is a good source of bioavailable iron for infants initially, but as WHO has determined, this source of iron drops off relatively quickly and fails to meet the physiological demands of growing children [15]. The other main staples of nutrition in the interior of the State of São Paulo do not contain sufficient iron to meet these needs. Food fortification of the fluid milk which the government was already supplying was determined to be the best way to meet the needed iron requirements of young children.
Due to its high bioavailability and based on some preliminary fortification studies utilizing other staple dietary items, iron amino acid chelate (Ferrochel) was chosen as the iron source which had the best potential for correcting the incidence of iron deficiency anemia among young children for the least per capita expense, representing a few cents (in US currency) per child per year.
Owing to the relatively large sampling size of individuals in this investigation and the relatively low residual sums of squares, the mean squares residual was typically small compared to the mean squares between the hemoglobin sampling times, yielding a very high calculated F-ratio. Tabular F-Test statistics at =0.0005 [16] yielded numbers which were 8.7 and 8.8 times lower than their calculated F-ratios for lines 1 and 2, respectively, of Table 3. Table 3 discerned variance for hemoglobin sampling times for all 185 children and variance for the 100 children who had severe iron deficiency anemia at the commencement of the study. At this same value for alpha, the F-ratio for the 61 children initially presenting less severe iron deficiency anemia) was still 3.5 times higher than the tabular F-Test statistic, and therefore, hemoglobin measurements from mean 133 days to mean 222 days were considered statistically distinct. By contrast, the calculated F-ratio for initially normal children was 2.6 times less than the tabular F-Test statistic at =0.10, which clearly demonstrated that the children who commenced the study in normalcy stayed in normalcy for the subsequent two hemoglobin sampling times.
As demonstrated in Tables 3 and 4, the selected population of 185 young children which received 3 mg iron per day as this specific iron amino acid chelate (Ferrochel) in fortified milk progressively increased their hemoglobin concentrations during the course of study. The mean values at each point of hemoglobin measurement represent the two defined stages of iron deficiency anemia plus normalcy. The initial mean hemoglobin concentration of 9.3 g/dL relegates most of the starting population into severe iron deficiency anemia, while the 133 day hemoglobin mean of 10.5 g/dL clearly shows a migration of the population into a less severe iron deficiency anemic range. The final mean of 11.2 g Hb/dL for all children at mean 222 days receiving the iron amino acid chelate fortified milk demonstrated that most of the population achieved normalcy with approximately 3 mg iron per day in the ferrous amino acid chelated form. Specific progress by age group is summarized in Table 4. The most important delineation of this table is the similarity of means and medians across age groups in each category of iron deficiency severity and normalcy. These data highlight that all of the age groups tested were able to replete hemoglobin at basically the same rate. Thus the government of the State of São Paulo and others who are interested in this source of iron can expect the low dose regimen of Ferrochel to be equally effective with infants as well as toddlers.
The repeated measures ANOVA data summarized in Table 3 demonstrate that the uptake of iron as the specific ferrous amino acid chelate (Ferrochel) follows a similar pattern to that for inorganic salt sources of iron. Absorption of non-heme iron by the intestine is considered to be self-regulating with inorganic ferrous salts to the extent that greater need promotes greater absorption. However, pathologies at both ends of the spectrum may yet occur. If bioavailable iron is marginal in the diet, iron deficiency anemia is an outcome. Conversely, an overabundance of iron in the diet can eclipse intestinal regulation and excessive to toxic amounts of iron can accumulate in the body [16].
The benefits of increasing hemoglobin concentration with small daily doses of this highly bioavailable iron source allowed the repletion of hemoglobin in most of the anemic young children, or those who were in the process of doing so even among those who began the study as severely anemic, as shown in Table 4 and Figs. 2 and 3. Hemoglobin amounts in the children with normal hemoglobin readings at the inception of the study (Table 3 and Fig. 4) were not significantly different at subsequent measuring times (p>0.10). Thus, the Ferrochel iron amino acid chelate represents a successful food fortification regimen against both severe and less severe forms of iron deficiency anemia, while not inordinately raising the hemoglobin in children who have normal hemoglobin amounts.
Since very young children were selected for this iron repletion research, all were in a state of rapid growth and development with changing nutritional needs for iron. The regression line calculations show that older children require greater iron absorption and utilization. Increased absorption of iron shown by increased amounts of hemoglobin further illustrates that this amino acid chelated iron (Ferrochel) is suitable for hemoglobin repletion in severe or less severe iron deficiency anemia.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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ACKNOWLEDGMENTS |
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Ferrochel is a ferrous form of Iron Amino Acid Chelate manufactured by Albion Laboratories, Inc., 101 North Main St., Clearfield, Utah, USA. Ferrochel was provided as a gift from Newcorp Trading Importadora LTDA, Av. Guapira 722, São Paulo, Brazil.
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FOOTNOTES |
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Received October 1, 1996. Accepted July 1, 1997.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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