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IRON. Iron is the second most abundant mineral on earth and is an essential nutrient for nearly all organisms. Iron is necessary for many varied functions in mammals, including the synthesis of DNA, the generation of energy from macronutrients by aerobic respiration, and the transport and metabolism of oxygen. Iron is highly reactive and is potentially toxic at high levels of intake; therefore, its utilization and storage present a major challenge for biological systems. Cellular iron exists primarily in its reduced ferrous (Fe⁺²) and oxidized ferric (Fe⁺³) states, and conversion of the mineral between these states serves to catalyze many reactions. One example is Fenton's reaction, whereby hydrogen peroxide is converted to highly reactive hydroxyl radicals (.OH).

Dietary Forms and Factors Affecting Iron Requirements

The Recommended Daily Allowance (RDA) for iron is 8 milligrams per day for men and postmenopausal women and 18 milligrams per day for premenopausal women. Adult males contain about 4 grams of total body iron (50 milligrams per kilogram of body weight), whereas menstruating women contain 40 milligrams per kilogram of body weight. Full-term infants are born with sufficient

iron stores to meet metabolic demands for the first 4 months of life. Breast milk contains 0.2 mg iron/liter; breast-feeding infants receive about 0.27 milligrams per day.

There are two natural dietary forms of iron: (1) inorganic salts of ferric iron, and (2) iron bound to a cyclic carbon ring called heme in the form of hemoglobin and myoglobin in meat products. Inorganic iron is readily liberated from food in the acidic lumen of the stomach but is not absorbed well in the small intestine because of its poor solubility at physiological pH and because it is sequestered by many dietary components that hinder absorption, including phytates, polyphenols, calcium, and fiber. Therefore, only a small percentage of injected iron salts are actually absorbed into the body, thereby indicating that iron salts have a low bioavailability, or ability to be effectively absorbed. However, other low-molecular-weight dietary components bind inorganic iron and facilitate its absorption. These compounds, which include vitamin C and lactic acids, are commonly found in citrus and deciduous fruits and are known as metal chelators. In addition, an unidentified "meat factor" present in animal tissue also enhances the absorption of iron salts. Finally, heme iron has a much greater bioavailability than iron salts because fewer factors interfere with its absorption and it displays greater solubility in water. Hence, heme iron can account for up to 35 percent of absorbed iron in diets when accounting for only 10 percent of total dietary iron intake. In the United States, artificially fortified foods in the form of fortified grain products are a major source of dietary iron and account for nearly 50 percent of all iron consumed.

Iron absorption and transport from the intestinal lumen to the circulatory system is tightly regulated and complex. Enterocyte cells, which are responsible for the uptake and transport of nutrients from the intestinal mucosa, mediate the uptake and transport of iron to the plasma. These cells, once mature, function for only 48 to 72 hours before they are shed and excreted. The capacity of the mature enterocyte to transport inorganic iron is determined very early in its development and is inversely proportional to plasma iron status. The enterocyte iron transport protein, DMT1 (divalent metal transporter), facilitates iron uptake from the intestinal lumen into the enterocyte. DMT1 concentrations at the cell surface are increased when whole-body iron stores are depleted, which increases the rate of cellular iron accumulation into the enterocyte once it is matured. The induction of DMT1 protein synthesis results from increased DMT1 messenger RNA levels. During iron deficiency, the iron regulatory protein (IRP) binds to the 3' untranslated region of the DMT1 messenger RNA and increases its stability. Heme iron is transported into the enterocyte from the intestinal lumen by an unidentified heme iron receptor, and cellular enzymes in the enterocyte release iron from the heme ring. Iron is exported from the basolateral surface of the enterocyte to plasma by the iron transport protein ferroportin1 (Fp1). Fp1 is believed to assist in the direct transfer of iron to a soluble plasma iron transport protein called transferrin. Transferrin facilitates the delivery of two molecules of iron among the sites of absorption and storage and to all tissues and organs. The transferrin-iron complex enters the cell by binding to a specific protein, the transferrin receptor, which is present on the plasma membrane of all cells. Once transferrin binds to its receptor, the receptor-transferrin complex is engulfed by the cell, forming an internal vesicle called an endosome. Once in the cell, iron is released from transferrin by the acidification of the endosome, and the transferrin receptor is recycled to the cell surface where it can bind additional transferrin molecules.

Iron Physiology

Intestinal absorption is the primary mechanism that regulates whole body iron concentrations. There are no specific mechanisms to remove excess iron from mammals. Inorganic iron excretion is limited because of its low solubility in aqueous environments and therefore daily iron loss is minimal in the absence of blood loss. Fecal (from shed enterocytes and biliary heme products), urogenital, and integumental losses account for 4 mg/day of iron loss. Menstruation, blood donation, and pregnancy also can cause significant iron loss. Variations in iron status and requirements are influenced by individual genetic makeup as well as by differences in menstrual losses. The latter averages 0.6 mg/day but can greatly exceed that value in the individual, resulting in a need to absorb an additional 3 to 4 mg/day to maintain adequate iron status. An additional 4 to 5 mg/day of iron must be absorbed during pregnancy. States of rapid growth during childhood through adolescence also increase iron requirements.

Most absorbed iron is used by the bone marrow to make hemoglobin, an abundant protein that binds and distributes oxygen throughout the body. The remaining iron is distributed to other tissues where it is incorporated into iron-requiring proteins or stored. Nearly 70 percent of total body iron is present in red blood cells bound to hemoglobin. Another 15 percent is bound to metabolic enzymes and numerous other proteins, including muscle myoglobin, which transports oxygen to the mitochondria, and cytochromes, which act as electron carriers during respiration. The remaining iron is stored in the liver, spleen, and macrophages and can be distributed to other cells during states of dietary iron deficiency. The primary iron storage protein is ferritin, which is a hollow sphere comprised of 24 protein subunits. One ferritin molecule can store about 3,000 ferric iron molecules that can be mobilized readily when required. There are two types of ferritin subunits, heavy-chain and light-chain ferritin. Heavy-chain ferritin sequesters Fe⁺² and oxidizes it to Fe⁺³; light-chain ferritin aids in the formation of the mineral iron core within the protein. Tissue, gender, hormones, and iron status can influence the ratio of heavy-chain and light-chain subunits that comprise a ferritin molecule, but the physiological significance of this ratio is not well understood.

Consequences of Altered Iron Status

Iron deficiency is the most common of all micronutrient deficiencies in the world, and the anemia that results affects an estimated 2 billion people. Dietary iron deficiency results in reduced iron stores in the liver, bone marrow, and spleen, followed by diminished erythropoiesis, which is the production of red blood cells, and anemia, and ultimately results in decreased activity of iron-dependent enzymes. Iron uptake in the intestine is responsive to total body stores such that iron-deficient individuals display increased iron absorption as described above. Clinical manifestations of iron deficiency include impaired endurance exercise due to an inability to deliver oxygen to tissues, microcytic anemia, glossitis, and blue scerra. Maternal iron deficiency during pregnancy is associated with several adverse outcomes for the newborn infant, including premature delivery, low birth weight, permanent cognitive deficits, developmental delay, and a wide range of behavioral disturbances. The onset of anemia and depletion of tissue iron concentrations occur concurrently, whereas the other negative consequences of iron deficiency occur after hemoglobin concentrations fall.

The tolerable upper level intake for iron for adults is 45 mg/day; intakes that exceed this level result in gastrointestinal distress. Dietary overload can occur, although it is uncommon, except in individuals with primary hereditary hemochromatosis, an iron-storage disease, which can result in up to fifty-fold increases in storage iron deposits. Hemochromatosis most commonly results from a common genetic mutation or genetic polymorphism in the HFE gene that is prevalent in populations of European descent but can also result from mutations in other iron-related proteins including a transferrin receptor. The HFE protein is involved in intestinal regulation of iron accumulation, but its precise biochemical function is unknown. This genetic disorder, if untreated by regular phlebotomy, results in liver cirrhosis, cadiomyopathy, arthritis, and cancer.

See also Gene Expression, Nutrient Regulation of; Nutrients; Nutrient Bioavailability.

Patrick J. Stover