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Iron


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Iron has the longest and best described history among all the micronutrients. It is a key element in the metabolism of almost all living organisms. In humans, iron is an essential component of hundreds of proteins and enzymes (1, 2).

Function

Oxygen transport and storage

Heme is an iron-containing compound found in a number of biologically important molecules. Hemoglobin and myoglobin are heme-containing proteins that are involved in the transport and storage of oxygen. Hemoglobin is the primary protein found in red blood cells and represents about two thirds of the body's iron. The vital role of hemoglobin in transporting oxygen from the lungs to the rest of the body is derived from its unique ability to acquire oxygen rapidly during the short time it spends in contact with the lungs and to release oxygen as needed during its circulation through the tissues. Myoglobin functions in the transport and short-term storage of oxygen in muscle cells, helping to match the supply of oxygen to the demand of working muscles (3, 4).

Electron transport and energy metabolism 

Cytochromes are heme-containing compounds that have important roles in mitochondrial electron transport; therefore, cytochromes are critical to cellular energy prduction and thus life. They serve as electron carriers during the synthesis of ATP, the primary energy storage compound in cells. Cytochrome P450 is a family of enzymes that functions in the metabolism of a number of important biological molecules, as well as the detoxification and metabolism of drugs and pollutants. Nonheme iron-containing enzymes, such as NADH dehydrogenase and succinate dehydrogenase, are also critical to energy metabolism (3)

Antioxidant and beneficial pro-oxidant functions 

Catalase and peroxidases are heme-containing enzymes that protect cells against the accumulation of hydrogen peroxide, a potentially damaging reactive oxygen species (ROS), by catalyzing a reaction that converts hydrogen peroxide to water and oxygen. As part of the immune response, some white blood cells engulf bacteria and expose them to ROS in order to kill them. The synthesis of one such ROS, hypochlorous acid, by neutrophils is catalyzed by the heme-containing enzyme myeloperoxidase (3, 4).

Oxygen sensing

Inadequate oxygen (hypoxia), such as that experienced by those who live at high altitudes or those with chronic lung disease, induces compensatory physiologic responses, including increased red blood cell formation, increased blood vessel growth (angiogenesis), and increased production of enzymes utilized in anaerobic metabolism. Under hypoxic conditions, transcription factors known as hypoxia inducible factors (HIF) bind to response elements in genes that encode various proteins involved in compensatory responses to hypoxia and increase their synthesis. Recent research indicates that an iron-dependent prolyl hydroxylase enzyme plays a critical role in regulating HIF and, consequently, physiologic responses to hypoxia. When cellular oxygen tension is adequate, newly synthesized HIFa subunits are modified by a prolyl hydroxylase enzyme in an iron-dependent process that targets HIFa for rapid degradation. When cellular oxygen tension drops below a critical threshold, prolyl hydroxylase can no longer target HIFa for degradation, allowing HIFa to bind to HIFb and form an active transcription factor that is able to enter the nucleus and bind to specific response elements on genes (5, 6)

DNA synthesis

Ribonucleotide reductase is an iron-dependent enzyme that is required for DNA synthesis (2, 7). Thus, iron is required for a number of vital functions, including growth, reproduction, healing, and immune function.

Regulation

Regulation of intracellular iron

Iron response elements are short sequences of nucleotides found in the messenger RNA (mRNA) that code for key proteins in the regulation of iron storage and metabolism. Iron regulatory proteins (IRPs) can bind to iron response elements and affect mRNA translation and stability, thereby regulating the synthesis of specific proteins, such as the iron storage protein, ferritin, and the transferrin receptor, which is important in maintaining iron homeostasis inside the cell. It has been proposed that when the iron supply is high, more iron binds to IRPs, thereby preventing them from binding to iron response elements on mRNA. For the ferritin mRNA, this allows for increased translation, thereby promoting iron storage. In the case of transferrin receptor mRNA, the message is destabilized and becomes degraded to lower the amount of iron uptake. When the iron supply is low, less iron binds to IRPs, allowing increased binding of IRPs to iron response elements. Thus, when less iron is available, translation of mRNA that codes for ferritin is reduced because iron is not available for storage. Translation of mRNA that codes for the key regulatory enzyme of heme synthesis in immature red blood cells is also reduced to conserve iron. In contrast, IRP binding to iron response elements in mRNA that codes for transferrin receptors inhibits mRNA degradation, resulting in increased synthesis of transferrin receptors and increased iron transport to cells (4, 8).

Systemic regulation of iron homeostasis

While iron is an essential mineral, it is potentially toxic because free iron inside the cell can lead to the generation of free radicals that cause oxidative stress and cellular damage. Thus, it is important for the body to systemically regulate iron homeostasis. The body tightly regulates the transport of iron throughout various body compartments, such as developing red blood cells, circulating macrophages, liver cells that store iron, and other tissues (9). As mentioned above, intracellular iron levels are regulated according to the body's iron needs, but systemic signals also regulate iron homeostasis in the body. Hepcidin, a peptide hormone synthesized by liver cells, is a key regulator of systemic iron homeostasis. Hepcidin functions to inhibit the release of iron from certain cells, such as enterocytes and macrophages, into plasma (10). Thus, hepcidin expression is increased when iron requirements are high and decreased when iron requirements are low (i.e., when there are sufficient iron stores). Studies in mice have shown that a lack of hepcidin expression is associated with conditions of iron overload (11), whereas an overexpression of hepcidin is associated with iron-deficiency anemia (12). Hepcidin expression is in turn regulated by a number of proteins, such as the negative regulator, TMPRSS6, and various positive regulators, including transferrin receptor 2, hemojuvelin, and bone morphogenetic proteins (13).

Nutrient interactions

Vitamin A

Vitamin A deficiency may exacerbate iron-deficiency anemia. Vitamin A supplementation has been shown to have beneficial effects on iron-deficiency anemia and improve iron status among children and pregnant women. The combination of vitamin A and iron seems to ameliorate anemia more effectively than either iron or vitamin A alone (14).

Copper

Adequate copper nutritional status appears to be necessary for normal iron metabolism and red blood cell formation. Anemia is a clinical sign of copper deficiency. Animal studies demonstrate a role for copper in iron absorption (15), and iron has been found to accumulate in the livers of copper deficient animals, indicating that copper is required for iron transport to the bone marrow for red blood cell formation (16).

Zinc

High doses of iron supplements taken together with zinc supplements on an empty stomach can inhibit the absorption of zinc. When taken with food, supplemental iron does not appear to inhibit zinc absorption. Iron-fortified foods have no effect on zinc absorption (17, 18).

Calcium

When consumed together in a single meal, calcium has been found to decrease the absorption of heme and nonheme iron (17). Thus, calcium and iron supplements should not be taken together. For more information about calcium-nutrient interactions, see the separate article on Calcium.

Deficiency

Iron deficiency is the most common nutrient deficiency in the U.S. and the world. Three levels of iron deficiency are generally identified and are listed below from least to most severe (3):

Storage iron depletion

Iron stores are depleted, but the functional iron supply is not limited.

Early functional iron deficiency

The supply of functional iron is low enough to impair red blood cell formation but not low enough to cause measurable anemia

Iron-deficiency anemia

Iron-deficiency anemia results when there is inadequate iron to support normal red blood cell formation. The anemia of iron deficiency is characterized as microcytic and hypochromic, meaning red blood cells are measurably smaller than normal and their hemoglobin content is decreased. At this stage of iron deficiency, symptoms may be a result of inadequate oxygen delivery due to anemia and/or sub-optimal function of iron-dependent enzymes. Low red cell count, low hematocrit, and low hemoglobin concentrations are all used in the clinical diagnosis of iron-deficiency anemia. It is important to remember that iron deficiency is not the only cause of anemia, and that the diagnosis or treatment of iron deficiency solely on the basis of anemia may lead to misdiagnosis or inappropriate treatment of the underlying cause (19). See Folic acid and Vitamin B12 for information on other nutritional causes of anemia.

Symptoms of iron deficiency

Most of the symptoms of iron deficiency are a result of the associated anemia and may include fatigue, rapid heart rate, palpitations, and rapid breathing on exertion. Iron deficiency impairs athletic performance and physical work capacity in several ways. In iron-deficiency anemia, the reduced hemoglobin content of red blood cells results in decreased oxygen delivery to active tissues. Decreased myoglobin levels in muscle cells limit the amount of oxygen that can be delivered to mitochondria for oxidative metabolism. Iron depletion also decreases the oxidative capacity of muscle by diminishing the mitochondrial content of cytochromes and other iron-dependent enzymes required for electron transport and ATP synthesis. Lactic acid production is also increased in iron deficiency (20). The ability to maintain a normal body temperature on exposure to cold is also impaired in iron-deficient individuals. Severe iron-deficiency anemia may result in brittle and spoon-shaped nails, sores at the corners of the mouth, taste bud atrophy, and a sore tongue. In some cases, advanced iron-deficiency anemia may cause difficulty in swallowing due to the formation of webs of tissue in the throat and esophagus. The development of esophageal webs, also known as Plummer-Vinson syndrome, may require a genetic predisposition in addition to iron deficiency. Further, pica, a behavioral disturbance characterized by the consumption of non-food items, may be a symptom and a cause of iron deficiency (19).

Individuals at increased risk of iron deficiency

Infants and children between the ages of 6 months and 4 years

A full-term infant's iron stores are usually sufficient to last for six months. High iron requirements are due to the rapid growth rates sustained during this period (4).

Adolescents

Early adolescence is another period of rapid growth. In females, the blood loss that occurs with menstruation adds to the increased iron requirement of adolescence (4).

Pregnant women

The iron requirement is significantly increased during pregnancy due to increased iron utilization by the developing fetus and placenta, as well as blood volume expansion (4).

Individuals with chronic blood loss

Chronic bleeding or acute blood loss may result in iron deficiency. One milliliter (ml) of blood with a hemoglobin concentration of 150 grams/liter contains 0.5 mg of iron. Thus, chronic loss of very small amounts of blood may result in iron deficiency. A common cause of chronic blood loss and iron deficiency in developing countries is intestinal parasitic infection. Individuals who donate blood frequently, especially menstruating women, may need to increase their iron intake to prevent deficiency because each 500 ml of blood donated contains between 200 and 250 mg of iron (7).

Individuals with celiac disease

Celiac disease (celiac sprue) is an autoimmune disorder estimated to occur in 1% of the population. When people with celiac disease consume foods or products that contain gluten, the immune system response damages the intestinal villi, which may result in nutrient malabsorption and iron-deficiency anemia (21).

Individuals with helicobacter pylori infection

H. pylori infection is associated with iron-deficiency anemia, especially in children, even in the absence of gastrointestinal bleeding (22).

Individuals who have had gastric bypass surgery

Some types of gastric bypass (bariatric) surgery increase the risk of iron deficiency by causing malabsorption of iron, among other nutrients (23).

Vegetarians

Because iron from plants is less efficiently absorbed than that from animal sources, the U.S. Food and Nutrition Board (FNB) has estimated that the bioavailability of iron from a vegetarian diet is only 10%, while it is 18% from a mixed diet. Therefore, the recommended dietary allowance (RDA) for iron from a completely vegetarian diet should be adjusted as follows: 14 mg/day for adult men and postmenopausal women, 33 mg/day for premenopausal women, and 26 mg/day for adolescent girls (17).

Individuals who engage in regular intense exercise

Daily iron losses have been found to be greater in athletes involved in intense endurance training. This may be due to increased microscopic bleeding from the gastrointestinal tract or increased fragility and hemolysis of red blood cells. The Food and Nutrition Board estimates that the average requirement for iron may be 30% higher for those who engage in regular intense exercise (17).

The Recommended Dietary Allowance (RDA)

The RDA for iron was revised in 2001 and is based on the prevention of iron deficiency and maintenance of adequate iron stores in individuals eating a mixed diet (17).

Recommended Dietary Allowance (RDA) for Iron
Life Stage Age  Males (mg/day) Females (mg/day)
Infants 0-6 months 0.27 (AI) 0.27 (AI)
Infants 7-12 months 11 11
Children 1-3 years 7 7
Children 4-8 years 10 10
Children 9-13 years 8 8
Adolescents 14-18 years 11 15
Adults 19-50 years 8 18
Adults 51 years and older 8 8
Pregnancy all ages - 27
Breast-feeding 18 years and younger - 10
Breast-feeding 19 years and older - 9

 

Disease Prevention

The following health problems and diseases may be prevented through the treatment or prevention of iron deficiency. 

Impaired intellectual development in children

Most observational studies have found relationships between iron-deficiency anemia in children and poor cognitive development, poor school achievement, and behavior problems. However, it is difficult to separate the effects of iron-deficiency anemia from other types of deprivation in such studies, and confounding factors may contribute to the association between iron deficiency and cognitive deficits (24). In anemic children under the age of two years, only one randomized, double-blind trial found a significant benefit of iron supplementation on indices of cognitive development. However, four randomized controlled trials found a significant benefit of iron supplementation on cognition and school achievement in children over two years of age, while two studies found no effect. Thus, studies to date indicate improvements in cognitive performance in children over two years of age, but children younger than two years appear more resistant to such improvements (25). A recent systematic review of 17 randomized controlled trials concluded that iron supplementation modestly improves scores of mental development in children over seven years of age but has no effect on mental development of children under the age of 27 months (26). Several possible mechanisms link iron-deficiency anemia to altered cognition. Anemic children tend to move around and explore their environment less than children without anemia, which may lead to developmental delays (27). Conduction of auditory and optic nerve impulses to the brain has been found to be slower in children with iron-deficiency anemia. This effect could be associated with changes in nerve myelination, which have been observed in iron-deficient animals (28). Neurotransmitter synthesis may also be sensitive to iron deficiency (20).

Lead toxicity

Iron deficiency may increase the risk of lead poisoning in children. A number of epidemiological studies have found iron deficiency to be associated with increased blood lead levels in young children. Iron deficiency and lead poisoning share a number of the same risk factors, but iron deficiency has been found to increase the intestinal absorption of lead in humans and animals. However, the use of iron supplementation in lead poisoning should be reserved for those individuals who are truly iron deficient or for those individuals with continuing lead exposure, such as continued residence in lead-exposed housing (3, 29).

Pregnancy complications

Epidemiological studies provide strong evidence of an association between severe anemia in pregnant women and adverse pregnancy outcomes, such as low birth weight, premature birth, and maternal mortality. Iron deficiency can be a major contributory factor to severe anemia, but evidence that iron-deficiency anemia is a causal factor in poor pregnancy outcomes is still lacking (30, 31). Nevertheless, most experts consider the control of maternal anemia to be an important part of prenatal health care. Elevated hemoglobin, especially in later pregnancy, is also associated with poor pregnancy outcomes, but there is no evidence that this association is related to high iron intakes or iron supplementation. Rather, elevated hemoglobin in pregnancy is more likely to be explained by underlying conditions like pregnancy-induced hypertension or preeclampsia, which are well known to contribute to poor pregnancy outcomes (31).

Impaired immune function 

Iron is required by most infectious agents, as well as by the infected host in order to mount an effective immune response. Sufficient iron is critical to several immune functions, including the differentiation and proliferation of T lymphocytes and the generation of reactive oxygen species (ROS) by iron-dependent enzymes, which are used for killing pathogens. During an acute inflammatory response, serum iron levels decrease while levels of ferritin (the iron storage protein) increase, suggesting that sequestering iron from pathogens is an important host response to infection (20, 32). Despite the critical functions of iron in the immune response, the nature of the relationship between iron deficiency and susceptibility to infection, especially with respect to malaria, remains controversial. High-dose iron supplementation of children residing in the tropics has been associated with increased risk of clinical malaria and other infections, such as pneumonia. Studies in cell culture and animals suggest that the survival of infectious agents that spend part of their life cycle within host cells, such as plasmodia (malaria) and mycobacteria (tuberculosis), may be enhanced by iron therapy. Controlled clinical studies are needed to determine the appropriate use of iron supplementation in regions where malaria is common, as well as in the presence of infectious diseases, such as HIV, tuberculosis, and typhoid (33).

Disease Treatment

Restless legs syndrome

Restless legs syndrome (RLS) is a neurologic movement disorder that is often associated with sleep problems. People with RLS experience unpleasant sensations resulting in an irresistible urge to move their legs. These sensations are more common at rest and often interfere with sleep (34). RLS occurs in some people with iron deficiency, and some RLS patients benefit from iron supplementation. One study found that ferritin levels were lower and transferrin levels were higher in the cerebrospinal fluid of individuals with RLS compared to control subjects, suggesting that low iron concentrations in the brain may play a role in RLS (35). Magnetic resonance imaging (MRI) measurements of brain iron concentrations also indicate that iron insufficiency in certain regions of the brain may occur in patients with RLS (36). The mechanism by which low iron concentration in the brain contributes to RLS is not known, but may be related to the fact that the activity of an iron-dependent enzyme (tyrosine hydroxylase) is a limiting factor in the synthesis of the neurotransmitter, dopamine.

Sources

Food Sources

The amount of iron in food (or supplements) that is absorbed and used by the body is influenced by the iron nutritional status of the individual and whether or not the iron is in the form of heme. Because it is absorbed by a different mechanism than nonheme iron, heme iron is more readily absorbed and its absorption is less affected by other dietary factors. Individuals who are anemic or iron deficient absorb a larger percentage of the iron they consume (especially nonheme iron) than individuals who are not anemic and have sufficient iron stores (3, 18).

Heme iron

Heme iron comes mainly from hemoglobin and myoglobin in meat, poultry, and fish. Although heme iron accounts for only 10-15% of the iron found in the diet, it may provide up to one third of total absorbed dietary iron. The absorption of heme iron is less influenced by other dietary factors than that of nonheme iron (2, 18).

Nonheme iron

Plants, dairy products, meat, and iron salts added to foods and supplements are all sources of nonheme iron. The absorption of nonheme iron is strongly influenced by enhancers and inhibitors present in the same meal (3, 18).

Enhancers of nonheme iron absorption

  • Vitamin C (ascorbic acid): Vitamin C strongly enhances the absorption of nonheme iron by reducing dietary ferric iron (Fe3+) to ferrous iron (Fe2+) and forming an absorbable, iron-ascorbic acid complex. 
  • Other organic acids: Citric, malic, tartaric, and lactic acids have some enhancing effects on nonheme iron absorption. 
  • Meat, fish, and poultry: Aside from providing highly absorbable heme iron, meat, fish, and poultry also enhance nonheme iron absorption. The mechanism for this enhancement of nonheme iron absorption is not clear (17, 18).

Inhibitors of nonheme iron absorption

  • Phytic acid (phytate): Phytic acid is present in legumes, grains, and rice and inhibits nonheme iron absorption, probably by binding to it. Small amounts of phytic acid (5 to 10 mg) can reduce nonheme iron absorption by 50%. The absorption of iron from legumes, such as soybeans, black beans, lentils, mung beans, and split peas, has been shown to be as low as 2% (7, 17).
  • Polyphenols: Polyphenols, found in some fruits, vegetables, coffee, tea, wines, and spices, can markedly inhibit the absorption of nonheme iron. This effect is reduced by the presence of vitamin C (7, 17).
  • Soy protein: Soy protein, such as that found in tofu, has an inhibitory effect on iron absorption that is independent of its phytic acid content (17).

National surveys in the U.S. indicate that the average dietary iron intake is 16-18 mg/day in men, 12 mg/day in pre- and postmenopausal women, and about 15 mg/day in pregnant women (17). Thus, the majority of premenopausal and pregnant women in the U.S. consume less than the RDA for iron and many men consume more than the RDA. In the U.S., most grain products are fortified with iron. The iron content of some relatively iron-rich foods is listed in milligrams (mg) in the table below. For more information on the nutrient content of specific foods, search the USDA food composition database.

Food Serving Iron content (mg)
Beef 3 ounces*, cooked 2.32
Chicken, dark meat 3 ounces, cooked 1.13
Oysters 6 medium 5.04
Shrimp 8 large, cooked 1.36
Tuna, light 3 ounces, canned 1.30
Black-strap molasses 1 tablespoon 3.50
Raisin bran cereal 1 cup, dry 5.79-18.00
Raisins, seedless 1 small box (1.5 ounces) 0.81
Prune juice 6 fluid ounces 2.28
Prunes (dried plums) ~ 5 prunes (1.7 ounces) 0.45
Potato, with skin 1 medium potato, baked 1.87
Kidney beans 1/2 cup, cooked 1.97
Lentils 1/2 cup, cooked 3.30
Tofu, firm 1/4 block (~1/3 cup) 2.15
Cashew nuts 1 ounce 1.89

*A three-ounce serving of meat is about the size of a deck of cards.

Supplements

Iron supplements are indicated for the prevention and treatment of iron deficiency. Individuals who are not at risk of iron deficiency (e.g., adult men and postmenopausal women) should not take iron supplements without an appropriate medical evaluation. A number of iron supplements are available, and different forms provide different proportions of elemental iron. Ferrous sulfate (heptahydrate) is 22% elemental iron; ferrous sulfate (monohydrate) is 33% elemental iron; ferrous gluconate is 12% elemental iron; and ferrous fumarate is 33% elemental iron (37). If not stated otherwise, all of the iron doses discussed in this presentation represent elemental iron.

Iron Overload

Several genetic disorders may lead to pathological accumulation of iron in the body. Hereditary hemochromatosis results in iron overload despite normal iron intake. Iron overload due to prolonged iron supplementation is very rare in healthy individuals without a genetic predisposition. This fact emphasizes the degree to which the body's tight control of intestinal iron absorption protects it from the adverse effects of iron overload (7). However, supplementation of individuals who are not iron deficient should be avoided due to the frequency of undetected hereditary hemochromatosis and recent concerns about the more subtle effects of chronic excess iron intake (see Safety).

Hereditary hemochromatosis

Hereditary hemochromatosis (HH) refers to genetic disorders of iron metabolism that result in tissue iron overload. If untreated, iron accumulation in the liver and other tissues may lead to cirrhosis of the liver, diabetes, heart muscle damage (cardiomyopathy), or joint problems (38). There are four main types of HH, which are classified according to the specific gene that is mutated. The most common type of HH, called type 1 or HFE-related HH, results from mutations in the HFE gene; this mutation was only identified in 1996 (39, 40). At present, the exact role of the protein encoded by the HFE gene is not well understood, but the protein is thought to play a role in regulating intestinal absorption of dietary iron and with sensing the body's iron stores (41). HH type 2, also referred to as juvenile hemochromatosis (disease onset typically occurs before age 30), results from mutations in genes that encode one of two proteins, hemojuvelin or hepcidin (42). HH type 3 results from mutations in the transferrin receptor 2 gene, and HH type 4 results from mutations in the gene encoding ferroportin, a protein important in the export of iron from cells (40).

Iron overload in HH is treated by phlebotomy, the removal of 500 ml of blood at a time, at intervals determined by the severity of the iron overload. Individuals with HH are advised to avoid supplemental iron, but are not generally advised to avoid iron-rich foods. Alcohol consumption is strongly discouraged due to the increased risk of cirrhosis of the liver (7). Genetic testing, which requires a blood sample, is available for those who may be at risk for HH, for example, individuals with a family history of hemochromatosis.

Hereditary anemias

Iron overload may occur in individuals with severe hereditary anemias that are not caused by iron deficiency. Excessive dietary absorption of iron may occur in response to the body's continued efforts to form red blood cells. Anemic patients at risk of iron overload include those with sideroblastic anemia, pyruvate kinase deficiency, and thalassemia major, especially when they are treated with numerous transfusions. Patients with hereditary spherocytosis and thalassemia minor do not usually develop iron overload unless they are misdiagnosed as having iron deficiency and treated with large doses of iron over many years (7). The thalassemias (major and minor) are common in individuals of Mediterranean descent. It has been hypothesized that a Mediterranean form of iron overload, distinct from HH, also exists (43).

Safety

Toxicity

Overdose

Accidental overdose of iron-containing products is the single largest cause of poisoning fatalities in children under six years of age. Although the oral lethal dose of elemental iron is approximately 200-250 mg/kg of body weight, considerably less has been fatal. Symptoms of acute toxicity may occur with iron doses of 20-60 mg/kg of body weight. Iron overdose is an emergency situation because the severity of iron toxicity is related to the amount of elemental iron absorbed. Acute iron poisoning produces symptoms in four stages: 1) Within 1-6 hours of ingestion, symptoms may include nausea, vomiting, abdominal pain, tarry stools, lethargy, weak and rapid pulse, low blood pressure, fever, difficulty breathing, and coma; 2) If not immediately fatal, symptoms may subside for about 24 hours; 3) Symptoms may return 12 to 48 hours after iron ingestion and may include serious signs of failure in the following organ systems: cardiovascular, kidney, liver, hematologic (blood), and central nervous systems; and 4) Long-term damage to the central nervous system, liver (cirrhosis), and stomach may develop two to six weeks after ingestion (17, 37).

Adverse effects

At therapeutic levels for iron deficiency, iron supplements may cause gastrointestinal irritation, nausea, vomiting, diarrhea, or constipation. Stools will often appear darker in color. Iron-containing liquids can temporarily stain teeth, but diluting the liquid helps to prevent this effect. Taking iron supplements with food instead of on an empty stomach may relieve gastrointestinal effects (37). The Food and Nutrition Board (FNB) of the Institute of Medicine based the tolerable upper intake level (UL) for iron on the prevention of gastrointestinal distress. The UL for adolescents and adults over the age of 14 years, including pregnant and breast-feeding women is 45 mg/day. It should be noted that the UL is not meant to apply to individuals being treated with iron under close medical supervision. Individuals with hereditary hemochromatosis or other conditions of iron overload, as well as individuals with alcoholic cirrhosis and other liver diseases, may experience adverse effects at iron intake levels below the UL (17).

Tolerable Upper Intake Level (UL) for Iron
Age Group   UL (mg/day)
Infants 0-12 months 40
Children 1-13 years 40
Adolescents 14-18 years 45
Adults 19 years and older 45

Diseases that have been associated with iron excess

Cardiovascular disease

Animal studies suggest a role for iron-induced oxidative stress in the pathology of atherosclerosis and myocardial infarction (heart attack) (44). However, epidemiological studies of iron nutritional status and cardiovascular diseases in humans have yielded conflicting results. A systematic review of 12 prospective cohort studies, including 7,800 cases of coronary heart disease (CHD), did not find good evidence to support the existence of strong associations between a number of different measures of iron status and CHD (45). Serum ferritin concentration is the measure of iron status thought to best reflect iron stores. However, the same review found no difference in the risk of CHD between individuals with serum ferritin concentrations of 200 mcg/liter or higher and those with ferritin concentrations of less than 200 mcg/liter in the five prospective studies that measured serum ferritin. Three large prospective studies found increased dietary heme iron, but not total dietary iron, to be associated with increased risk of myocardial infarction (46, 47) or with increased risk of CHD (48). When iron stores are high, nonheme iron absorption is inhibited more effectively than heme iron absorption, suggesting that iron from animal sources may play a more important role than total iron intake in CHD risk (44). Although the relationship between iron stores and CHD requires further clarification, it would be prudent for those who are not at risk of iron deficiency (e.g., adult men and postmenopausal women) to avoid excess iron intake.

Cancer

A dramatically increased risk of liver cancer (hepatocellular carcinoma) in individuals with cirrhosis due to iron overload in hereditary hemochromatosis has been well documented. However, the relationship between dietary iron and cancer risk in individuals without hemochromatosis is less clear (17). Several epidemiological studies have reported associations between measures of increased iron status and the incidence of colorectal cancer or the occurrence of precancerous polyps (adenomas), but the associations were not consistent. Dietary iron intake appears to be more consistently related to the risk of colorectal cancer than measures of iron status or iron stores (49, 50). Increased red meat consumption has been associated with an increased risk of colorectal cancer (51), but there are a number of potential mechanisms by which increased meat consumption could affect cancer risk other than increasing iron intake. For example, increased red meat consumption increases the secretion of bile acids, which can be toxic to colonic cells, and also increases exposure to carcinogenic compounds generated when meat is cooked (52). Increased iron in the contents of the colon, rather than increased body iron stores, could increase the risk of colon cancer by exposing colonic cells to potentially damaging reactive oxygen species derived from iron-catalyzed reactions, especially in the presence of a high-fat diet. Although this possibility is presently under investigation, the relationship between dietary iron intake, iron stores, and the risk of colorectal cancer remains unclear. For more information about colorectal cancer, see the Linus Pauling Institute Newsletter article, Colorectal Cancer: Early Detection and Prevention.

Type 2 Diabetes and Metabolic Syndrome

Iron has been implicated in the pathogenesis of type 2 diabetes mellitus. Some epidemiological studies have associated high serum or plasma levels of ferritin with an increased risk of type 2 diabetes (53-58) as well as metabolic syndrome (59, 60). Ferritin levels reflect the amount of iron stored in the body. A few studies have reported that diabetics have higher ferritin levels than nondiabetics (53, 61, 62). Other indices of iron excess, such as elevated transferrin saturation, may also be more prevalent in diabetics (55). Moreover, individuals with the iron overload disease, hereditary hemochromatosis, are known to be at a heightened risk of developing type 2 diabetes (58). Randomized controlled trials are needed to determine whether lowering body stores of iron will aid in the prevention of type 2 diabetes and metabolic syndrome.

Neurodegenerative disease

Iron is required for normal brain and nerve function through its involvement in cellular metabolism, as well as in the synthesis of neurotransmitters and myelin. However, accumulation of excess iron can result in increased oxidative stress, and the brain is particularly susceptible to oxidative damage. Iron accumulation and oxidative injury are presently under consideration as potential contributors to a number of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease (63, 64). The abnormal accumulation of iron in the brain does not appear to be a result of increased dietary iron, but rather, a disruption in the complex process of cellular iron regulation. Although the mechanisms for this disruption in iron regulation are not yet known, it is presently an active area of biomedical research (65, 66).

Drug Interactions

Medications that decrease stomach acidity, such as antacids, histamine (H2) receptor antagonists (e.g., cimetidine, ranitidine), and proton pump inhibitors (e.g., omeprazole, lansoprazole), may impair iron absorption. Taking iron supplements at the same time as the following medications may result in decreased absorption and efficacy of the medication: levodopa, levothyroxine, methyldopa, penicillamine, quinolones, tetracyclines, and bisphosphonates. Therefore, it is best to take these medications two hours apart from iron supplements. Cholestyramine resin, used to lower blood cholesterol levels, should also be taken two hours apart from iron supplements because it interferes with iron absorption. Allopurinol, a medication used to treat gout, may increase iron storage in the liver and should not be used in combination with iron supplements (37, 67).

Linus Pauling Institute Recommendation

Following the most recent RDA for iron should provide sufficient iron to prevent deficiency without causing adverse effects in most individuals. Although sufficient iron can be obtained through a varied diet, a considerable number of people do not consume adequate iron to prevent deficiency. A multivitamin/multimineral supplement containing 100% of the daily value (DV) for iron provides 18 mg of elemental iron. While this amount of iron may be beneficial for premenopausal women, it is well above the RDA for men and most postmenopausal women.

Adult men and postmenopausal women

Since hereditary hemochromatosis is relatively common and the effects of long-term dietary iron excess on chronic disease risk are not yet clear, men and postmenopausal women who are not at risk of iron deficiency should take a multivitamin-mineral supplement without iron. A number of multivitamins formulated specifically for men or those over 50 years of age do not contain iron.

Adults over the age of 65

A recent study in an elderly population found that high iron stores were much more common than iron deficiency (68). Thus, older adults should not generally take nutritional supplements containing iron unless they have been diagnosed with iron deficiency. Moreover, it is extremely important to determine the underlying cause of the iron deficiency, rather than simply treating it with iron supplements.

References


Written in January 2006 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in August 2009 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in August 2009 by:
Marianne Wessling-Resnick, Ph.D.
Professor of Nutritional Biochemistry
Harvard School of Public Health

Copyright 2001-2014  Linus Pauling Institute


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The Linus Pauling Institute Micronutrient Information Center provides scientific information on the health aspects of dietary factors and supplements, foods, and beverages for the general public. The information is made available with the understanding that the author and publisher are not providing medical, psychological, or nutritional counseling services on this site. The information should not be used in place of a consultation with a competent health care or nutrition professional.

The information on dietary factors and supplements, foods, and beverages contained on this Web site does not cover all possible uses, actions, precautions, side effects, and interactions. It is not intended as nutritional or medical advice for individual problems. Liability for individual actions or omissions based upon the contents of this site is expressly disclaimed.


 
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