Overview

Iron is an essential mineral that has many physiologic functions. It can be found in two forms in the body: heme and nonheme. Heme iron is part of the hemoglobin and myoglobin molecules. Hemoglobin is the oxygen-carrying pigment of erythrocytes. Myoglobin transports and stores oxygen within muscle and releases it to meet increased metabolic demands during muscle contraction. Several enzymes contain iron both in the heme and nonheme forms. These enzymes are involved in a variety of processes in the body including cellular respiration, detoxification, and protection against free radical damage.

Iron is absorbed from the diet by the mucosal cells of the small intestine. The amount of iron absorbed depends on the body’s store of iron: an individual with iron deficiency can absorb 50% of dietary iron while an individual with sufficient iron stores may absorb only 5% to 15%. Heme iron, which comes from hemoglobin and myoglobin in meat products, and nonheme iron, which comes from plant and dairy products, are absorbed by two different mechanisms. While heme iron usually accounts for only 15% of iron in the diet, it is absorbed two to three times more readily than nonheme iron. Nonheme iron accounts for approximately 85% of iron in the diet but its absorption from the small intestine is dependent on “solubility enhancers and inhibitors” that are consumed during the same meal. Ascorbic acid and factors present in meat enhance absorption by keeping it soluble and stimulating the secretion of gastric juices, respectively. Dietary inhibitors of nonheme iron absorption include calcium phosphate, tannins, phytic acids (present in unprocessed whole-grain products), and polyphenols (present in tea and some vegetables).

Transferrin, the iron-specific plasma transport protein, transports iron to tissues. The transferrin receptor regulates the entry of iron into tissues: when tissues are in an iron-rich environment, the cell surface transferrin receptor is downregulated; when tissues are in an iron-poor environment, the transferrin receptor is upregulated.

The storage forms of iron are called ferritin and hemosiderin. They are present in the liver, bone marrow, spleen, and muscle. Ferritin and hemosiderin are mobilized for hemoglobin production and other cellular iron needs.

Iron deficiency manifests itself as hypochromic microcytic anemia and is most common in infants and children (6 months to 4 years), adolescents (especially girls), and pregnant women. It is characterized by reduced work capacity in adults and a reduced ability to learn in children. The inability to maintain body temperature in a cold environment and decreased resistance to infection may also result from iron deficiency. Cardiovascular and respiratory changes that can lead to cardiac failure is the end result of progressive, untreated anemia.

Hemochromatosis梩he excess storage of iron in the body梒an lead to organ damage. It is most prevalent in individuals who have a genetic defect that causes the body to absorb more iron than normal, and may be the most common autosomal recessive disease in humans. Other causes of iron overload are excessive oral intake and repeated transfusions. Individuals with hemochromatosis are at a higher risk for hepatic carcinoma.

At least two of the following tests should be performed to diagnose iron deficiency (the most common cause of anemia) or overload.

Plasma ferritin梞easures iron stores
Transferrin saturation梞easures iron supplies to the tissues
Erythrocyte protoporphyrin梞easures the ratio of zinc protoporphyrin to heme. (Zinc is incorporated into protoporphyrin when iron stores are too low.)
Hemoglobin or hematocrit measurement�to 11 g/dL of hemoglobin is considered anemic
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Dietary Sources

The best source of iron in the diet is heme iron, which comes from the hemoglobin and myoglobin of animal protein. Heme iron is more readily absorbed and less affected by other dietary constituents than nonheme iron. Some good sources of heme iron are:

Liver
Lean red meat
Poultry
Fish
Oysters
Shellfish
Kidney
Heart
Nonheme iron absorption is affected by a number of factors. The best enhancer of nonheme iron absorption is vitamin C. Nonheme protein absorption is also enhanced by factors in meat. Inhibitors of nonheme protein absorption include calcium phosphate, bran, phytic acid, polyphenols, and tannins. The following are good nonheme sources of iron.

Dried beans
Fruits
Vegetables
Foods with added iron include the following.

Egg yolks
Dried fruits
Dark molasses
Whole-grain and enriched bread
Wines
Cereals
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Constituents/Composition

Iron occurs in foodstuffs as heme and nonheme iron. Heme iron, contained in food products from animals, is in the form of hemoglobin or myoglobin. Nonheme iron is iron salts and is contained in plant and dairy products. Nonheme iron makes up the majority of dietary iron, but heme iron is better absorbed.
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Commercial Preparations

Ferrous sulfate is used to fortify infant formula and canned foods, while foods stored in air-permeable packages are fortified with elemental iron powders (North America) or ferric pyrophosphate and ferric orthophosphate (Europe). Ferrous sulfate (FEOSOL and others) is the most widely used oral supplement, but other ferrous salts such as fumarate, succinate, and gluconate are absorbed equally as well. Iron dextran injection (INFED) is the parenteral preparation currently used in the United States.
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Therapeutic Uses

To replete iron stores in iron-deficiency anemia. Underlying causes of iron-deficiency anemia include the following:

Chronic blood loss (hemorrhoids, parasites, bleeding peptic ulcer, malignancy)
Inadequate iron intake or inefficient absorption (iron-poor diet, chronic gastrointestinal disturbances)
Increased iron requirement due to expanded blood volume (infancy, adolescence, pregnancy)
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Dosage Ranges and Duration of Administration

Recommended dietary allowances of iron are as follows.

Neonates to 6 months: 6 mg
Infants 6 months to 1 year: 10 mg
Children 1 to 10 year: 10 mg
Men 11 to 18 year: 12 mg
Men 19+ years: 10 mg
Women 11 to 50 years: 15 mg
Women 51+ years: 10 mg
Pregnant women: 30 mg
Lactating women: 15 mg
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Side Effects/Toxicology

Oral iron therapy:

Gastrointestinal disturbances (nausea, diarrhea, constipation, heartburn, upper gastric discomfort)
Hemochromatosis from long-term excessive intake
Iron toxicity causes severe organ damage and death. The most pronounced effects are hemorrhagic necrosis of the gastrointestinal tract, which manifests as vomiting and bloody diarrhea. (Lethal dose: 200 to 250 mg/kg; therapeutic dose: 2 to 5 mg/kg/day)
Parenteral iron therapy:

Headache, malaise, fever, generalized lymphadenopathy, arthralgias, urticaria, exacerbation of rheumatoid arthritis, phlebitis, and in rare instances anaphylactic reactions.
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Warnings/Contraindications/Precautions

Iron supplements should be kept in childproof bottles and out of the reach of children. Children between the ages of 12 and 24 months are at the highest risk of iron poisoning due to accidental ingestion.
Parenteral iron therapy should be used only when there are specific indications because of the chance of rare anaphylactic reactions, which can be fatal.
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Interactions

Angiotensin-Converting Enzyme (ACE) InhibitorsIron diminishes absorption of ACE inhibitors (Schaefer et al. 1998). In a double-blind, place-controlled, cross-over study, seven healthy adult volunteers took captopril (25 mg) concomitantly with either ferrous sulphate (300 mg) or placebo. Coadministration of iron salts with captopril resulted in a 37% decrease in area under the curve plasma levels for unconjugated captopril. This decrease may be due to an interaction in the gastrointestinal tract when these substances are ingested together.

Carbidopa; LevodopaIron salts may reduce the bioavailability of carbidopa and levodopa. However, the clinical relevance of this potential interaction is not known (PDR 2000).

CimetidineIron absorption is dependent upon gastric pH; therefore, medications that affect gastric pH may interfere with absorption of iron (PDR 2000). Iron can bind cimetidine in the gastrointestinal tract and reduce the absorption of this drug (Campbell et al. 1993). The bioavailability of the bound iron may also be decreased. Iron supplements should not be taken with cimetidine; doses of either substance should be staggered by 2 hours before or after administration of the other.

Cholestyramine Resin; ColestipolIn vitro investigations have demonstrated that cholestyramine and colestipol both bind iron citrate (Leonard et al. 1979). The amount of iron citrate bound by colestipol ranged from 95 to 98%. Cholestyramine bound 24 to 97% of the iron citrate in a pH-dependent manner.

LevothyroxineIron may decrease the effectiveness of levothyroxine. A case report describes a patient who became hypothyroid when ferrous sulfate was added to the medication regimen; increasing the dose of levothyroxine countered these effects (Shakir et al. 1997). However, when the ferrous sulfate was discontinued, the patient became hyperthyroid at the higher levothyroxine dose. Thyroid function should be monitored in patients taking iron salts and levothyroxine concomitantly.

Oral ContraceptivesOral contraceptives have been shown to increase the levels of iron in women (Tyrer 1984).

Quinolone AntibioticsQuinolone antibiotics form chelates with metal cations, such as aluminum, magnesium, calcium, iron, zinc, copper, and manganese (Kara et al. 1991; Li et al. 1999), which significantly reduces the absorption of these medications (Balfour and Wiseman 1999; Brouwers 1992; Campbell and Hasinoff 1991). In a clinical trial with 12 healthy volunteers, ferrous sulfate (325 mg po tid) produced a 65% reduction in the absorption of orally administered ciprofloxacin (Polk 1989). This reduction in bioavailability has also been observed when iron salts were coadministered with levofloxacin, norfloxacin, and ofloxacin (Akerele and Okhamafe 1991; Okhamafe et al. 1991). Dietary supplements and antacids containing aluminum and magnesium should be taken two to four hours before or after administration of these antibiotics (Hines Burnham et al. 2000; Li et al. 1999).

Tetracycline DerivativesTetracyclines form chelates with divalent and trivalent cations, including iron, aluminum, magnesium, and calcium (Neuvonen 1976). These chelates are poorly soluble and can significantly reduce the absorption and efficacy of tetracyclines (Hines Burnham et al. 2000; Neuvonen 1976). Iron salts should be taken at least 3 hours before or 2 hours after tetracyclines (Hines Burnham et al. 2000).
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References

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Balfour JA, Wiseman LR. Moxifloxacin. Drugs. 1999;57(3):363-374.

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Campbell NR, Hasinoff BB. Iron supplements: a common cause of drug interactions. Br J Clin Pharmacol. 1991;31(3):251-255.

Campbell NR, Hasinoff BB, Meddings JB, Anderson WD, Robertson S, Granberg K. Ferrous sulfate reduces cimetidine absorption. Dig Dis Sci. 1993;38(5):950-954.

Cook JD, Skikne BS. Intestinal regulation of body iron. Blood Rev.1987;1:267-272.

Duntas LH, Papanastasiou L, Mantzou E, Koutras DA. Incidence of sideropenia and effects of iron repletion treatment in women with subclinical hypothyroidism. Exp Clin Endocrinol Diabetes. 1999;107(6):356-360.

Ekhard ZE, Filer LJ, eds. Present Knowledge in Nutrition. 7th ed. Washington, DC: ILSI Press; 1996:191-201.

Fleming DJ, Jacques PF, Dallal GE, et al. Dietary determinants of iron stores in a free-living elderly population: the Framingham Heart Study.Am J Clin Nutr. 1998;67:722-733.

Hardman JG, Limbird LE, eds. Goodman and Gillman’s The Pharmacological Basis of Therapeutics. 9th ed. New York: McGraw-Hill; 1996:1326-1333.

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Kara M, Hasinoff BB, McKay DW, et al. Clinical and chemical interactions between iron preparations and ciprofloxacin. Br J Clin Pharmacol. 1991;31(3):257-261.

Leonard JP, Desager JP, Beckers C, Harvengt C. In vitro binding of various biological substances by two hypocholesterolaemic resins. Cholestyramine and colestipol. Arzneim Forsch/Drug Res.1979;29:979-981.

Li RC, Lo KN, Lam JS, et al. Effects of order of magnesium exposure on the postantibiotic effect and bactericidal activity of ciprofloxacin. J Chemother. 1999;11(4):243-247.

Mahan LK, Arlin MT, eds. Krause’s Food, Nutrition, and Diet Therapy.8th ed. Philadelphia, Pa: WB Saunders Co.; 1992:96-97.

National Research Council. Recommended Dietary Allowances. 10th ed. Washington, DC: National Academy Press; 1989:158-165.

Mason P. Nutrition and Dietary Advice in the Pharmacy. Oxford, UK: Blackwell Scientific; 1994:234-235.

Recommendations to Prevent and Control Iron Deficiency in the United States. Atlanta, Ga: Centers for Disease Control and Prevention. Morbid and Mortal Weekly Report; April 3, 1998;47(RR-3):1-29.

Neuvonen PJ. Interactions with the absorption of tetracyclines. Drugs. 1976;11(1):45-54.

Okhamafe AO, Akerele JO, Chukuka CS. Pharmacokinetic interactions of norfloxacin with some metallic agents. Int J Pharmaceutics.1991;68:11-16.

Physicians’ Desk Reference, 54th ed. Montvale, NJ: Medical Economics Company; 2000.

Polk RE. Drug-drug interactions with ciprofloxacin and other fluoroquinolones. Am J Med. 1989;87(Suppl5A):76-81.

Schaefer JP, Tam Y, Hasinoff BB, et al. Ferrous sulphate interacts with captopril. Br J Clin Pharmacol. 1998;46(4):377-381.

Shakir KM, Chute JP, Aprill BS, Lazarus AA. Ferrous sulfate-induced increase in requirement for thyroxine in a patient with primary hypothyroidism. South Med J. 1997;90(6):637-639.

The Food and Nutrition Information Center. National Agricultural Library (NAL), United States Department of Agriculture’s (USDA) Agricultural Research Service (ARS). Accessed atwww.nal.usda.gov/fnic/Dietary/rda.html on January 8, 1999.

Tyrer LB. Nutrition and the pill. J Reprod Med. 1984;29(7 Suppl):547-550.

Tzonou A, Lagiou P, Trichopoulou A, et al. Dietary iron and coronary heart disease: a study from Greece. Am J Epidemiol. 1998;147:161-166.

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