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TABLE 1 Dietary Reference Intakes for Iron by Life Stage Group DRI values (mg/day) EARa RDAb AIc ULd males females males females Life stage group 0 through 6 mo 0.27 40 7 through 12 mo 6.9 6.9 11 11 40 1 through 3 y 3.0 3.0 7 7 40 4 through 8 y 4.1 4.1 10 10 40 9 through 13 y 5.9 5.7 8 8 40 14 through 18 y 7.7 7.9 11 15 45 19 through 30 y 6.0 8.1 8 18 45 31 through 50 y 6.0 8.1 8 18 45 51 through 70 y 6.0 5.0 8 8 45 > 70 y 6.0 5.0 8 8 45 Pregnancy £ 18 y 23 27 45 19 through 50 y 22 27 45 Lactation £ 18 y 7 10 45 19 through 50 y 6.5 9 45 a EAR = Estimated Average Requirement. b RDA = Recommended Dietary Allowance. c AI = Adequate Intake. d UL = Tolerable Upper Intake Level. Unless otherwise specified, the UL represents total intake from food, water, and supplements.
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PART III: IRON 329 IRON I ron is a critical component of several proteins, including enzymes, cyto- chromes, myoglobin, and hemoglobin, the latter of which transports oxy- gen throughout the body. Almost two-thirds of the body’s iron is found in hemoglobin that is present in circulating erythrocytes and involved in the trans- port of oxygen from the environment to tissues throughout the body for me- tabolism. Iron can exist in various oxidation states, including the ferrous, ferric, and ferryl states. The requirements for iron are based on factorial modeling using the fol- lowing factors: basal iron losses; menstrual losses; fetal requirements in preg- nancy; increased requirement during growth for the expansion of blood vol- ume; and increased tissue and storage iron. The Tolerable Upper Intake Level (UL) is based on gastrointestinal distress as the critical adverse effect. DRI val- ues are listed by life stage group in Table 1. About half of the iron from meat, poultry, and fish is heme iron, which is highly bioavailable; the remainder is nonheme, which is less readily absorbed by the body. Iron in dairy foods, eggs, and all plant-based foods is entirely nonheme. Particularly rich sources of nonheme iron are fortified plant-based foods, such as breads, cereals, and breakfast bars. Iron deficiency anemia is the most common nutritional deficiency in the world. Adverse effects associated with excessive iron intake include gastrointes- tinal distress, secondary iron overload, and acute toxicity. IRON AND THE BODY Function Iron is a component of several proteins, including enzymes, cytochromes, myo- globin, and hemoglobin. Almost two-thirds of the body’s iron is found in he- moglobin that is present in circulating erythrocytes and involved in the trans- port of oxygen from the environment to tissues throughout the body for metabolism. A readily mobilizable iron store contains another 25 percent. Most of the remaining 15 percent is in the myoglobin of muscle tissue. Iron can exist in various oxidation states, including the ferrous, ferric, and ferryl states. Four major classes of iron-containing proteins exist in the mammalian sys- tem: iron-containing heme proteins (hemoglobin, myoglobin, cytochromes),
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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 330 iron-sulfur enzymes (flavoproteins, hemeflavoproteins), proteins for iron stor- age and transport (transferrin, lactoferrin, ferritin), and other iron-containing or activated enzymes (sulfur, nonheme enzymes). Absorption, Metabolism, Storage, and Excretion The iron content of the body is highly conserved and strongly influenced by the size of a person’s iron stores. The greater the stores, the less iron that is absorbed. Adult men need to absorb about 1 mg/day to maintain iron balance. Men- struating women need to absorb about 1.5 mg/day, with a small proportion of this group needing to absorb as much as 3.4 mg/day. Menstrual losses highly vary among women and explain why iron requirements in menstruating women are not symmetrically distributed. The median amount of iron lost through menstruation in adult women is approximately 0.51 mg/day; in adolescent girls it is approximately 0.45 mg/day. Women in the late stages of pregnancy must absorb 4–5 mg/day to maintain iron balance. Requirements are also higher in childhood, particularly during periods of rapid growth in early childhood (6 to 24 months of age) and adolescence. Iron absorption occurs in the upper small intestine via pathways that allow the absorption of heme and nonheme iron. Heme iron is more highly bioavailable than nonheme iron (see “Bioavailability” and “Dietary Sources”). Many factors can affect iron absorption (see “Dietary Interactions”). Therefore, exact figures for absorption of heme and nonheme iron are unknown. A conservative esti- mate for heme iron absorption is 25 percent; for nonheme iron the mean per- centage of absorption is estimated to be approximately 16.8 percent. Absorp- tion of bioavailable iron occurs by an energy-dependent carrier-mediated process; the iron is then intracellularly transported and transferred into the plasma. Iron that enters the cells may be incorporated into functional compounds, stored as ferritin, or used to regulate future cellular iron metabolism. The liver, spleen, and bone marrow are the primary sites of iron storage in the body. The majority of iron that is absorbed into enterocytes, but not taken up by transfer- rin, is excreted in the feces, since these intestinal cells are sloughed off every 3 to 5 days. Little iron is excreted into the urine. In the absence of bleeding (in- cluding menstruation) or pregnancy, only a small quantity of iron is lost each day. As stated above, iron is also lost through menstrual bleeding, and these losses can widely vary among premenopausal women.
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PART III: IRON 331 DETERMINING REQUIREMENTS Determining Requirements The requirements for iron are based on factorial modeling using the following factors: basal iron losses; menstrual losses; fetal requirements in pregnancy; increased requirements during growth for the expansion of blood volume; and increased tissue and storage iron. It is important to note that iron requirements are known to be skewed rather than normally distributed for menstruating women. Information on the distribution of iron requirements can be found in Appendix G. Special Considerations Individuals susceptible to iron deficiency: People with decreased stomach acidity, such as those who overconsume antacids, ingest alkaline clay, or have patho- logical conditions, such as achlorhydria or partial gastrectomy, may have im- paired iron absorption and be at greater risk for deficiency. Infants: Because cow milk is a poor source of bioavailable iron, it is not recom- mended for infants under the age of 1 year; in Canada, the recommendation is 9 months of age. Early inappropriate ingestion of cow milk is associated with a higher risk of iron deficiency anemia. U.S. and Canadian pediatric societies have concluded that infants who are not, or only partially, fed human milk should receive an iron-fortified formula. Supplementation is also recommended for preterm infants as their iron stores are low. Age of menarche: The RDA for iron for girls increases from 8 mg/day to 15 mg/ day at the age of 14 years to account for menstruation. For girls who have reached this age, but are not yet menstruating, the requirement is approxi- mately 10.5 mg/day, rather than 15 mg/day. Adolescent and preadolescent growth spurt: The rate of growth during the growth spurt can be more than double the average rate for boys and up to 50 percent higher for girls. The increased requirement for dietary iron for boys and girls in the growth spurt is 2.9 mg/day and 1.1 mg/day, respectively. Use of oral contraceptives and hormone replacement therapy (HRT): The use of oral contraceptives lowers menstrual blood loss. As a result, adolescent girls and women using oral contraceptives may have lower iron requirements. HRT may cause some uterine bleeding in some women. In this situation, women
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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 332 who are on HRT may have higher iron requirements than postmenopausal women who are not. Vegetarian diets: Because heme iron is more bioavailable than nonheme iron (milk products and eggs are of animal origin, but they contain only nonheme iron), it is estimated that the bioavailability of iron from a vegetarian diet is approximately 10 percent, rather than the 18 percent from a mixed Western diet. Hence, the requirement for iron is 1.8 times higher for vegetarians. It is important to emphasize that lower bioavailability diets (approaching 5 percent overall absorption) may be encountered with very strict vegetarian diets. Intestinal parasitic infection: A common problem in developing nations, intes- tinal parasites can cause significant blood loss, thereby increasing an individual’s iron requirement. Blood donation: A 500 mL donation just once a year translates to an additional iron loss of approximately 0.6 mg/day over the year. People who frequently donate blood have higher iron requirements. Regular, intense physical activity: Studies show that iron status is often mar- ginal or inadequate in many individuals, particularly females, who engage in regular, intense physical activity. The requirement of these individuals may be as much as 30–70 percent greater than those who do not participate in regular strenuous exercise. Criteria for Determining Iron Requirements, by Life Stage Group Life stage group Criterion 0 through 6 mo Average iron intake from human milk 7 through 12 mo Factorial modeling 1 through 70 y Factorial modeling > 70 y Extrapolation of factorial analysis from 51 through 70 y Pregnancy £ 18 y through 50 y Factorial modeling Lactation £ 18 y through 50 y Adolescent female EAR minus menstrual losses plus average amount of iron secreted in human milk
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PART III: IRON 333 The UL The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse effects for almost all healthy people. Members of the general population should not routinely exceed the UL. This value is based on gastrointestinal distress as the critical adverse effect and represents intake from food, water, and supplements. According to the National Health and Nutrition Examination Survey (NHANES III, 1988–1994), the highest intake from food and supplements at the 90th percentile reported for any life stage and gender groups, excluding pregnancy and lactation, was approximately 34 mg/day for men 51 years of age and older. This value is below the UL of 45 mg/day. Between 50 and 75 percent of pregnant and lactating women consumed iron from food and supplements at a greater level than 45 mg/day, but iron supplementation is usually supervised in prenatal and postnatal care programs. Based on a UL of 45 mg/day of iron for adults, the risk of adverse effects from dietary sources appears to be low. Special Considerations Individuals susceptible to adverse effects: People with the following condi- tions are susceptible to the adverse effects of excess iron intake: hereditary hemochromatosis; chronic alcoholism; alcoholic cirrhosis and other liver dis- eases; iron-loading abnormalities, particularly thalassemias; congenital atransferrinemia; and aceruloplasminemia. These individuals may not be pro- tected by the UL for iron. A UL for subpopulations such as persons with he- reditary hemochromatosis cannot be determined until information on the re- lationship between iron intake and the risk of adverse effects from excess iron stores becomes available. DIETARY SOURCES Foods About half of the iron from meat, fish, and poultry is a rich source of heme iron, which is highly bioavailable; the remainder is nonheme, which is less readily absorbed by the body. However, heme iron represents only 8–12 percent of dietary iron for boys and men and 7–10 percent of dietary iron for girls and women. Plant-based foods, such as vegetables, fruits, whole-grain breads, or whole-grain pasta contain 0.1–1.4 mg of nonheme iron per serving. Fortified products, including breads, cereals, and breakfast bars can contribute high amounts of nonheme iron to the diet. In the United States, some fortified cere- als contain as much as 24 mg of iron (nonheme) per 1-cup serving, while in Canada most cereals are formulated to contain 4 mg per serving.
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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 334 Dietary Supplements The 1986 National Health Interview Survey (NHIS) reported that approximately 21–25 percent of women and 16 percent of men consumed a supplement con- taining iron. According to NHANES III, the median intake of iron from supple- ments was approximately 1 mg/day for men and women. The median iron in- take from food plus supplements by pregnant women was approximately 21 mg/day. Bioavailability Heme iron, from meat, poultry, and fish, is generally very well absorbed by the body and only slightly influenced by other dietary factors. The absorption of nonheme iron, present in all foods, including meat, poultry, and fish, is strongly influenced by its solubility and interaction with other meal components that promote or inhibit its absorption (see “Dietary Interactions”). Because of the many factors that influence iron bioavailability, 18 percent bioavailability was used to estimate the average requirement of iron for non- pregnant adults, adolescents, and children over the age of 1 year consuming typical North American diets. The intake was assumed to contain some meat- based foods. Because the diets of children under the age of 1 year contain little meat and are rich in cereal and vegetables, a bioavailability of 10 percent was assumed in setting the requirements. During pregnancy, iron absorption was assumed to be 25 percent. Dietary Interactions There is evidence that iron may interact with other nutrients and dietary sub- stances (see Table 2). TABLE 2 Potential Interactions with Other Dietary Substances Substance Potential Interaction Notes SUBSTANCES THAT AFFECT IRON Ascorbic acid Ascorbic acid strongly There appears to be a linear relation between enhances the absorption of ascorbic acid intake and iron absorption up to at nonheme iron. least 100 mg of ascorbic acid per meal. Because ascorbic acid improves iron absorption through the release of nonheme iron bound to inhibitors, the enhanced iron absorption effect is most marked when ascorbic acid is consumed with foods containing high levels of inhibitors, including phytate and tannins.
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PART III: IRON 335 TABLE 2 Continued Substance Potential Interaction Notes Animal Meat, fish, and poultry The mechanism of this enhancing effect is poorly muscle improve nonheme iron studied, but is likely to involve low molecular weight tissue absorption. peptides that are released during digestion. Phytate Phytate inhibits nonheme The absorption of iron from foods high in phytate, iron absorption. such as soybeans, black beans, lentils, mung beans, and split peas, has been shown to be very low (0.84– 0.91 percent) and similar to each other. Unrefined rice and grains also contain phytate. Polyphenols Polyphenols inhibit nonheme Polyphenols, such as those in tea, inhibit iron iron absorption. absorption through the binding of iron to tannic acids in the intestine. The inhibitory effects of tannic acid are dose-dependent and reduced by the addition of ascorbic acid. Polyphenols are also found in many grain products, red wine, and herbs such as oregano. Vegetable Vegetable proteins inhibit This effect is independent of the phytate content of proteins nonheme iron absorption. the food. Calcium Calcium inhibits the This interaction is not well understood; however, it has absorption of both heme and been suggested that calcium inhibits heme and nonheme iron. nonheme iron absorption during transfer through the mucosal cell. Despite the significant reduction of iron absorption by calcium in single meals, little effect has been observed on serum ferritin concentrations in supplementation trials with calcium supplementation at levels of 1,000–1,500 mg/day. IRON AFFECTING OTHER SUBSTANCES Zinc High iron intakes may reduce In general, data indicate that supplemental iron may zinc absorption. inhibit zinc absorption if both are taken without food, but does not inhibit zinc absorption if it is consumed with food.
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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 336 INADEQUATE INTAKE AND DEFICIENCY Iron deficiency anemia is the most common nutritional deficiency in the world. The most important functional indicators of iron deficiency are reduced physi- cal work capacity, delayed psychomotor development in infants, impaired cog- nitive function, and adverse effects for both the mother and the fetus (such as maternal anemia, premature delivery, low birth weight, and increased perinatal infant mortality). A series of laboratory indicators can be used to precisely characterize iron status and to categorize the severity of iron deficiency. Three levels of iron defi- ciency are customarily identified: • Depleted iron stores, but where there appears to be no limitation in the supply of iron to the functional compartment • Early functional iron deficiency (iron-deficient erythropoiesis), where the supply of iron to the functional compartment is suboptimal but not sufficiently reduced to cause measurable anemia • Iron deficiency anemia, where there is a measurable deficit in the most accessible functional compartment, the erythrocyte Available laboratory tests can be used in combination with each other to iden- tify the evolution of iron deficiency through these three stages (see Table 3). TABLE 3 Laboratory Measurements Commonly Used in the Evaluation of Iron Status Stage of Iron Deficiency Indicator Diagnostic Range Depleted stores Stainable bone marrow iron Absent > 400 mg/dL Total iron binding capacity < 12 mg/L Serum ferritin concentration Early functional Transferrin saturation < 16% > 70 mg/dL erythrocyte iron deficiency Free erythrocyte protoporphyrin Serum transferrin receptor > 8.5 mg/L Iron deficiency Hemoglobin concentration < 130 g/L (male) anemia < 120 g/L (female) Mean cell volume < 80 fL
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PART III: IRON 337 EXCESS INTAKE The risk of adverse effects of excessive iron intake from dietary sources appears to be low in the general population. Adverse effects may include the following: • Acute toxicity with vomiting and diarrhea, followed by cardiovascular, central nervous system, kidney, liver, and hematological effects. • Gastrointestinal effects associated with high-dose supplements, such as constipation, nausea, vomiting, and diarrhea • Secondary iron overload, which occurs when body iron stores are in- creased as a consequence of parenteral iron administration, repeated blood transfusions, or hematological disorders that increase the rate of iron absorption Special Considerations Men and postmenopausal women: Currently the relationship between exces- sive iron intake and measure of iron status (e.g., serum ferritin concentrations) and both coronary heart disease and cancer is unclear. Nevertheless, the asso- ciation between a high iron intake and iron overload in sub-Saharan Africa makes it prudent to recommend that men and postmenopausal women avoid iron supplements and highly fortified foods.
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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 338 KEY POINTS FOR IRON Iron is a critical component of several proteins, including 3 cytochromes, myoglobin, and hemoglobin, the latter of which transports oxygen throughout the body. The requirements for iron are based on factorial modeling using 3 the following factors: basal iron losses; menstrual losses; fetal requirements in pregnancy; increased requirement during growth for the expansion of blood volume; and increased tissue and storage iron. The UL is based on gastrointestinal distress as the critical adverse effect. Special populations and situations in which iron requirements 3 may vary include infants who do not receive human milk (0–6 months), preterm infants, teens/preteens in the growth spurt, oral contraceptive users, postmenopausal women using cyclic HRT, vegetarians, athletes, and blood donors. People with the following conditions are susceptible to the 3 adverse effects of excess iron intake: hereditary hemochromatosis; chronic alcoholism; alcoholic cirrhosis, and other liver diseases; iron-loading abnormalities, particularly thalassemias; congenital atransferrinemia; and aceruloplasminemia. These individuals may not be protected by the UL for iron. About half of the iron from meat, poultry, and fish is heme iron, 3 which is highly bioavailable; the remainder is nonheme, which is less readily absorbed by the body. Particularly rich sources of nonheme iron are fortified plant- 3 based foods, such as breads, cereals, and breakfast bars. The absorption of nonheme iron is enhanced when it is consumed with foods that contain ascorbic acid (vitamin C) or meat, poultry, and fish. Iron deficiency anemia is the most common nutritional 3 deficiency in the world. The most important functional indicators of iron deficiency are 3 reduced physical work capacity, delayed psychomotor development in infants, impaired cognitive function, and adverse effects for both the mother and the fetus (such as maternal anemia, premature delivery, low birth weight, and increased perinatal infant mortality).
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PART III: IRON 339 Three levels of iron deficiency are customarily identified: 3 depleted iron stores, early functional iron deficiency, and iron deficiency anemia. Adverse effects associated with excessive iron intake include 3 acute toxicity, gastrointestinal distress, and secondary iron overload. Currently the relationship between excessive iron intake and 3 high serum ferritin concentrations and both coronary heart disease and cancer is unclear. Nevertheless, the association between a high iron intake and iron overload in sub-Saharan Africa makes it prudent to recommend that men and post- menopausal women avoid iron supplements and highly fortified foods.